Propellanes as Rigid Scaffolds for the Stereodefined Attachment of σ-Pharmacophoric Structural Elements to Achieve σ Affinity

Abstract

Following the concept of conformationally restriction of ligands to achieve high receptor affinity, we exploited the propellane system as rigid scaffold allowing the stereodefined attachment of various substituents. Three types of ligands were designed, synthesized and pharmacologically evaluated as σ₁ receptor ligands. Propellanes with (1) a 2-methoxy-5-methylphenylcarbamate group at the “left” five-membered ring and various amino groups on the “right” side; (2) benzylamino or analogous amino moieties on the “right” side and various substituents at the left five-membered ring and (3) various urea derivatives at one five-membered ring were investigated. The benzylamino substituted carbamate syn,syn-4a showed the highest σ₁ affinity within the group of four stereoisomers emphasizing the importance of the stereochemistry. The cyclohexylmethylamine 18 without further substituents at the propellane scaffold revealed unexpectedly high σ₁ affinity (K_i = 34 nM) confirming the relevance of the bioisosteric replacement of the benzylamino moiety by the cyclohexylmethylamino moiety. Reduction of the distance between the basic amino moiety and the “left” hydrophobic region by incorporation of the amino moiety into the propellane scaffold resulted in azapropellanes with particular high σ₁ affinity. As shown for the propellanamine 18, removal of the carbamate moiety increased the σ₁ affinity of 9a (K_i = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes anti-5 and 9a as well as propellane 18 adopt binding poses at the σ₁ receptor, which result in energetic values correlating well with their different σ₁ affinities. The affinity of the ligands is enthalpy driven. The additional interactions of the carbamate moiety of anti-5 with the σ₁ receptor protein cannot compensate the suboptimal orientations of the rigid propellane and its N-benzyl moiety within the σ₁ receptor-binding pocket, which explains the higher σ₁ affinity of the unsubstituted azapropellane 9a.

1. Introduction

In 1976, Martin and coworkers [1] postulated σ receptors as the third type of opioid receptors. The name σ receptor was derived from the benzomorphan SKF-10,047, which caused a unique pharmacological profile in animal studies. Twenty years later, the σ₁ receptor was cloned from different tissues of different speces [2,3,4,5,6]. Subsequently, several models of the structure of the σ₁ receptor were reported, until it was crystallized in 2016, confirming its unique structure [7,8]. The identification of the σ₂ receptor took an even longer time. In 2017, the identity of the σ₂ receptor and the endoplasmic reticulum (ER)-resident transmembrane protein 97 (TMEM97) was shown [9,10]. Very recently, the first structure of the human σ₂ receptor was reported. [11]

The σ₁ receptor is involved in various neuropsychiatric disorders, such as schizophrenia and depression [12,13,14,15,16]. Several clinically used antidepressants show medium to high σ₁ receptor affinity in addition to their main mechanism of action [17,18,19,20]. σ₁ receptors also play a role in drug/alcohol dependence and neurodegenerative disorders (e.g., Alzheimer’s disease) [21,22,23]. The σ₁ receptor antagonist S1RA has been successfully tested in phase II clinical studies for the treatment of neuropathic pain [24,25]. Since the exact signal transduction path of σ₁ receptors is not fully understood so far, analgesic activity in neuropathic pain mouse models is the best method to discriminate σ₁ receptor antagonists from agonists [26,27]. Several human tumors, including prostate, breast and bladder tumors, express a high density of σ₁ receptors. Strong metastasis and poor prognosis were associated with high expression levels of σ₁ receptors. Antagonists at σ₁ receptors were able to reduce tumor cell proliferation [28,29]. Several human tumor cells derived from various tissues (e.g., prostate, breast, colon and lung) overexpress σ₂ receptors. Agonists at the σ₂ receptor are capable of killing tumor cells via apoptotic and non-apoptotic machanisms [30,31,32,33,34].

The structures of σ₁ and σ₂ receptor ligands are quite diverse. Some prototypical σ ligands containing highly flexible structural elements are displayed in Figure 1. Binding of flexible ligands to a biological target is associated with an entropic penalty, since the binding site of the target forces the flexible ligand into a particular conformation leading to loss of conformational freedom of the ligand.

We are interested in rather rigid ligands with a defined three-dimensional structure fitting exactly into the binding pocket of the target protein. In this respect, we reported on spiro- and bicyclic ligands with high affinity and selectivity for σ₁ receptors. As an example, the spirocyclic piperidine derivative (S)-fluspidine (1) is depicted in Figure 2 [35,36,37,38]. (S)-Fluspidine (1) interacts with low nanomolar affinity with σ₁ receptors and shows 300-fold selectivity against the σ₂ subtype. The 18-F-labeled analog [¹⁸F]1 is currently investigated as the PET tracer for imaging of σ₁ receptors in the brain of patients suffering from major depression [39]. The piperazine derivative 2 rigidified by a propano bridge exhibits even higher σ₁ affinity than 1 and more than 40-fold selectivity over the σ₂ receptor [40]. On the other hand, the rigid granatane derivative 3 reported by Mach and coworkers [41] represents a ligand with a 30-fold preference for the σ₂ receptor. (Figure 2)

Inspired by these conformationally restricted spiro- and bicyclic σ ligands 1–3 we introduced the propellane as novel rigid scaffold to achieve high σ₁ and/or σ₂ receptor affinity. With K_i values of 77 nM and 82 nM the [4.3.3]propellane syn,syn-4a [42] and the 3-aza[4.4.3]propellane anti-5 [43] represent promising σ₁ receptor ligands. (Figure 2)

Herein, we started further exploiting the propellane system as rigid scaffold to attach various functional groups and substituents, designed to address σ₁ and/or σ₂ receptors. (Figure 3) Due to the rigid structure of the propellane scaffold, all substituents adopt an exact orientation. The manuscript contains three parts. In the first part (compounds of type A), the carbamate at the “left” part of the propellane system was kept constant and the substituent at the second cyclopentane ring was modified (compare substituents of granatane 3). The second part deals predominantly with propellanes of type B containing an arylmethylamino moiety (and analogous amino groups) at the “right” side of the propellane system and variations of the “left” side. The third part investigated, whether the amino moiety on the “right” side could be replaced bioisosterically by a urea moiety as shown for compounds of type C. The urea is not basic, but represents a strong H-bond donor and acceptor.

2. Chemistry

The synthesis of the carbamates 4 started with the mixture of the diastereomeric hydroxyketones anti-6 and syn-6 [42], which was reacted with 2-methoxy-5-methylphenyl isocyanate in the presence of,Bu₂Sn(OAc)₂. The carbamates anti-7 and syn-7 were isolated in 36% and 31% yield, respectively. (Scheme 1) The X-ray crystal structure of syn-7 confirmed the successful formation of the carbamate and its syn-configuration at 8-position (Figure 4). Moreover, the very long conjoining C–C bond, which belongs to all three rings of the propellane, was confirmed by the crystal structure (C1–C6 = 1.562(2) Å). Final reductive amination of the ketones anti-7 and syn-7 with primary amines and NaBH(OAc)₃ [44] provided the amines 8-anti-4 and 8-syn-4. Both type of compounds were obtained as mixture of diastereomers. The ratio of diastereomers was approximately 1:1, respectively.

The affinity of this first set of propellanylcarbamates 4 and 5 towards σ₁ and σ₂ receptors was determined in receptor binding studies. In these experiments, the test compounds compete with a radioligand for a limited amount of receptors. The tritium-labeled radioligands [³H]-(+)-pentazocine and [³H]-di-o-tolylguanidine were used in the σ₁ and σ₂ assay, respectively [45,46,47]. The affinity data of the propellanylcarbamates are summarized in

Table 1. Affinities of propellanylcarbamates 4 and 5 towards σ₁ and σ₂ receptors.

Compd.	Config. 8/12-Position	Config. 11-Position	R	Ki (nM) #
				σ1	σ2
anti,anti-4a §	anti	anti	Bn	0%	4700
anti,syn-4a §	anti	syn	Bn	2500	2200
syn,anti-4a §	syn	anti	Bn	580	5800
syn,syn-4a §	syn	syn	Bn	77 ± 18	1600
8-anti-4b	anti	anti:syn 1:1	3,4-(MeO)2-Bn	6%	1%
8-anti-4c	anti	anti:syn 1:1	4-Cl-Bn	6%	12%
8-anti-4d	anti	anti:syn 1:1	3,4-Cl2-Bn	0%	4%
8-anti-4e	anti	anti:syn 1:1	2,4-(Me)2-Bn	0%	1100
8-anti-4f	anti	anti:syn 1:1	3,5-(CF3)2-Bn	0%	0%
8-anti-4g	anti	anti:syn 6:4	4-NO2-Bn	24%	1950
8-anti-4h	anti	anti:syn 1:1	4-(Me2N)-Bn	0%	0%
8-anti-4i	anti	anti:syn 6:4	(furan-2-yl)-CH2	924	>6000
8-syn-4i	syn	anti:syn 1:1	(furan-2-yl)-CH2-	276	0%
8-anti-4k	anti	anti:syn 6:4	(indol-3-yl)-(CH2)2-	1200	0%
8-syn-4k	syn	anti:syn 4:6	(indol-3-yl)-(CH2)2-	983	1400
8-anti-4l	anti	anti:syn 1:1	Ph	13%	0%
8-anti-4m	anti	anti:syn 1:1	4-(MeO)-Ph	11%	0%
8-anti-4n	anti	anti:syn 1:1	3-Cl-4-(MeO)-Ph	0%	0%
8-anti-4o	anti	anti:syn 1:1	4-NH2-Ph	16%	12,000
8-anti-4p	anti	anti:syn 1:1	-CH2CH2Ph	668	0%
8-anti-4q	anti	anti:syn 1:1	-(CH2)3Ph	22%	0%
8-anti-4r	anti	anti:syn 1:11	-(CH2)3-NH2	16%	0%
8-anti-4s	anti	anti:syn 1:1	-CH2CH2OH	12%	0%
8-anti-4t	anti	anti:syn 1:1	-(CH2)5-OH	454	2%
8-anti-4u	anti	anti:syn 1:1	-CH2CH(CH3)2	5%	854
anti-5§	anti	-	Bn	82 ± 54	8%
syn-5§	syn	-	Bn	12%	0%
(+)-pentazocine		-	-	5.7 ± 2.2	-
Haloperidol		-	-	6.3 ± 1.6	78 ± 2.3
di-o-tolylguanidine		-	-	89 ± 29	58 ± 18

# The given K_i values represent means of three independent experiments (n = 3). Values in% represent the inhibition of the radioligand binding at a test compound concentration of 1 µM. Values without SEM represent the mean of two experiments. ^§ The affinity data of stereoisomeric propellanamines 4a and azapropellanes 5 have already been reported [42,43].

.

The group of diastereomeric benzylamines 4a show nicely the relationship between the stereochemistry and the σ₁ and σ₂ receptor affinity. Whereas the 8-anti-derivatives anti,anti-4a and anti,syn-4a exhibit very low σ₁ affinity, the 8-syn-derivatives are much more potent and syn,syn-4a shows the highest σ₁ affinity within the four diastereomeres (K_i = 77 nM). Although the granatane derivative 3 reveals high σ₂ affinity the diastereomeric propellane derivatives 4a with the same substitution pattern did not interact with σ₂ receptors up to a concentration of 1 µM [42].

Introduction of various substituents (OCH₃, Cl, CH₃, CF₃, NO₂, and NMe₂) at various positions of the benzyl moiety (8-anti-1b-1h) did not lead to remarkable σ₁ or σ₂ affinity. The furan-2-yl and indol-3-yl derivatives 8-anti-4i and 8-anti-4k show σ₁ affinity in the range of K_i = 1 µM. The corresponding 8-syn-derivatives 8-syn-4i and 8-syn-4k reveal higher σ₁ affinity than their 8-anti-analogs. The highest σ₁ affinity of propellanes bearing a hetarylmethyl moiety was found for the furan-2-yl derivative 8-syn-4i (K_i = 276 nM).

Removal or extension of the benzyl-CH₂ moiety provided (substituted) aniline 8-anti-4l -4o or homologous phenylethylamine and phenylpropylamine derivatives 8-anti-4p and 8-anti-4q. However, neither removal nor extension of the benzyl-CH₂ moiety led to considerable σ₁ or σ₂ affinity. Only the phenylethylamine derivative 8-anti-4p shows σ₁ affinity in the high nanomolar range (K_i = 668 nM).

With exception of the 5-hydroxypentyl derivative 8-anti-4t (K_i(σ₁) = 454 nM), propellane derivatives with a substituted alkylamino moiety in 11-position (8-anti-4r-4u) show only negligible affinity towards both σ receptor subtypes.

Introduction of the basic amino moiety into the propellane scaffold led to a reduced distance between the basic amino moiety and the carbamate group of the aza-propellanes 5. The aza-propellane anti-5 displays σ₁ affinity, which is comparable with the σ₁ affinity of syn,syn-4a.⁴³ It has to be noted that the stereodescriptors change due to a change of the hierarchy of the three rings by expansion of one cyclopentane moiety into a piperidine ring. Thus, the three-dimensional structure of syn,syn-4a corresponds to that of anti-5, which explains the similar σ₁ affinity (K_i = 77 nM and 82 nM) [43].

In the second part of the manuscript, the focus lies on propellanes containing arylmethylamino moieties on the “right” side and various substituents on the “left” side. Although the synthesis of benzylamine 8 (Figure 5) has already been reported in literature [48], its affinity towards σ receptors is missing. The 3-azapropellanes 9 (Figure 5) show promising σ₁ affinity, which depends on the substitution pattern and the configuration.⁴³ Therefore, we decided to investigate the σ receptor affinity of the benzylamine 8 and modify the substituents in the 11-position.

At first, the ketones 10–12 were reductively aminated with benzylamine and NaBH(OAc)₃⁴⁴ to yield the benzylamines 8, 13 and 14. The pure diastereomeric alcohols anti-11 and syn-11 were converted separately into the benzylamines 11-anti-13 and 11-syn-13, respectively, which were not further separated. Whereas the syn- and anti-configured benzylamines 8 were also not separated, the diastereomeric 1,3-dioxolanes 14 were separated by flash chromatography to obtain diastereomerically pure 8-anti-14 and 8-syn-14. (Scheme 2).

Furthermore, the unsubstituted ketone 10 was reductively aminated with tryptamine to yield the indolylethylamine 15. The mixture of diastereomeric benzylamines anti-8 and syn-8 was treated with ammonium formate and Pd(OH)₂ removing reductively the benzyl moiety. Upon treatment with aldehydes and NaBH(OAc)₃ [44], the resulting primary amine 16 was further transformed into the dimethylamino substituted benzylamine 17 and the cyclohexylmethylamine 18. (Scheme 2).

The σ₁ affinity of the 3-azapropellane anti-9b with an OH moiety at 12-position is three-fold higher than the σ₁ affinity of its syn-diastereomer syn-9b. (

Table 2. Affinities of substituted propellanamines 8 and 13–18 and azapropellanes 9 towards σ₁ and σ₂ receptors.

Compd.	Config. 8-Position	Config. 11/12-Position	R	X	Y	Ki (nM) #
						σ1	σ2
8	anti:syn 1:1	-	Bn	H	H	594	39%
9a§	-	-	Bn	H	H	17 ± 12	190
anti-9b§	-	anti	Bn	H	OH	122 ± 55	2040
syn-9b§	-	syn	Bn	OH	H	336 ± 158	690
11-anti-13	anti:syn 7:3	anti	Bn	OH	H	29%	1070
11-syn-13	anti:syn 1:1	syn	Bn	H	OH	619	27%
syn-14	syn	-	Bn	-OCH2CH2O-		750	7%
anti-14	anti	-	Bn	-OCH2CH2O-		1400	0%
15	anti:syn 1:1	-	(Indol-3-yl)CH2)2-	H	H	598	974
16	anti:syn 1:1	-	H	H	H	5%	13%
17	anti:syn 1:1	-	4-(Me2N)Bn	H	H	1200	1%
18	anti:syn 1:1	-	C6H11CH2-	H	H	34 ± 11	101

# The given K_i values represent means of three independent experiments (n = 3). Values in% represent the inhibition of the radioligand binding at a test compound concentration of 1 µM. Values without SEM represent the mean of two experiments. ^§ The affinity data of azapropellanes 8 and 9 have already been reported [43].

) However, the low nanomolar σ₁ affinity of the unsubstituted 3-azapropellane 9a (K_i = 17 nM) was unexpected.^42,43,48 Compared to the naked azapropellane 9a, the σ₁ affinity of the naked propellanamine 8 is 35-fold reduced. The 3-azapropellanes 9a and anti-9b and the naked propellanamine 8 show at least 10-fold selectivity for the σ₁ receptor over the σ₂ receptor. The least potent σ₁ ligand syn-9b has only a slight preference for the σ₁ receptor over the σ₂ subtype (Table 2).

Modifications of the 11-substituent and the N-substituent led to propellanamines 13–17 with very low σ₁ and σ₂ affinity. However, the cyclohexylmethyl moiety increased the σ₁ and the σ₂ affinity remarkably. With K_i values of 24 nM (σ₁ affinity) and 101 nM (σ₂ affinity), 18 represents the most potent σ ligand of this series of compounds. The increase of both σ₁ and σ₂ affinities by introduction of the cyclohexylmethyl moiety instead of the benzyl moiety has already been observed for some other classes of σ ligands [49,50].

In the third part of this project, the amino moiety on the “right” side was replaced by a urea to investigate, whether this H-bond donor and H-bond acceptor group could mimic the basic amino moiety. For this purpose, the propellane-8,11-dione 19 was reductively aminated with benzylamine. The resulting secondary amines syn-20 and anti-20 were separated by flash column chromatography and subsequently reacted with 2-methoxy-5-methylphenyl isocyanate to obtain the urea derivatives syn-21 and anti-21, respectively. Final reduction of the ketones syn-21 and anti-21 with NaBH₄ provided the four diastereomeric N-benzylurea derivatives syn,anti-22, syn,syn-22, anti,anti-22 and anti,syn-22 bearing a secondary alcohol in 11-position (Scheme 3).

The N-benzylurea derivatives anti-21, syn,anti-22 and anti,syn-22 were crystallized from EtOAc, leading to crystals suitable for X-ray crystal structure analysis. (Figure 6, Figure 7 and Figure 8).

The crystal structure of anti-21 nicely confirms the anticonfiguration of the urea at the propellane system. The conjoining bond C1–C6 is rather long (1.550(3) Å). The cyclohexane ring adopts a chair conformation and the cyclopentane ring bearing the urea adopts an envelope conformation, which leads to an outward orientation of the large urea (Figure 6).

The X-ray crystal structures of the diastereomeric N-benzylurea derivatives syn,anti-22 and anti,syn-22 containing an additional OH moiety in 11-position are shown in Figure 7 and Figure 8. Both structures prove the syn,anti- and anti,syn-configuration, respectively. The six-membered ring of the propellane scaffold of syn,anti-22 adopts a chair conformation. However, in the diastereomer anti,syn-22 a boat-like conformation was found for the cyclohexane ring. This boat-like conformation leads to an extraordinarily long conjoining bond (C1–C6 = 1.590(2) Å). Both five-membered rings of urea derivative anti,syn-22 adopt unusual envelope conformations and all three rings of the propellane scaffold flap in the same direction (Figure 8). This pattern was only reported for heterocyclic 8,11-dioxa[4.3.3]propellanes [51].

To obtain urea derivatives without the N-benzyl substituent, the primary amine 16 was reacted with various isocyanates. Since the primary amine 16 was employed as 1.1-mixture of anti- and syn-diastereomers, the urea derivatives 23a–d were obtained as 1:1-mixture of anti- and syn-diastereomers as well (Scheme 4).

Finally, the dioxolane substituted benzylamine 14 (mixture of syn- and anti-diastereomers) was debenzylated by a transfer hydrogenolysis using NH₄HCO₂ in the presence of Pd(OH)₂. The mixture of diastereomeric primary amines 24 was isolated in 75% yield and converted into urea upon treatment with 3,4-difluorophenyl isocyanate. After hydrolysis of the dioxolane, the diastereomeric difluorophenylurea derivatives syn-25 and anti-25 were isolated in 42% and 35% yield, respectively. Reduction of the ketones syn-25 and anti-25 with NaBH₄ provided diastereomeric alcohols 26. Whereas the mixture of syn,anti-26 and syn,syn-26 was obtained as 1:1-mixture of diastereomers, anti,anti-26 and anti,syn-26 were separated by flash chromatography (Scheme 5).

The syn-configuration of syn-25 was confirmed unequivocally by X-ray crystal structure analysis. In addition to the syn-configuration the chair conformation of the cyclohexane ring and the long conjoining bond C1–C6 = 1.546(3) Å was demonstrated (Figure 9).

The σ₁ and σ₂ affinities of the urea derivatives were determined in receptor binding studies. Unfortunately, the synthesized urea were not able to compete with the radioligands proving that the urea could not replace bioisosterically the basic amino moiety (

Table 3. Affinities of propellane-based urea derivatives 21–23, 25 and 26 towards σ₁ and σ₂ receptors.

Compd.	Config. 8-Position	Config. 11-Position	R	X	Y	Ki (nM) #
						σ1	σ2
syn-21	syn	-	MMP $	=O		13%	14%
anti-21	anti	-	MMP $	=O		5%	12%
syn,anti-22	syn	anti	MMP $	OH	H	0%	8%
syn,syn-22	syn	syn	MMP §	H	OH	0%	0%
anti,anti-22	anti	anti	MMP $	OH	H	0%	0%
anti,syn-22	anti	syn	MMP $	H	OH	0%	17%
23a	anti:syn 1:1	-	Ph	H	H	0%	15%
23b	anti:syn 1:1	-	C6H11	H	H	0%	0%
23c	anti:syn 1:1	-	MMP	H	H	0%	0%
23d	anti:syn 1:1	-	3,4-F2-Ph	H	H	0%	0%
syn-25	syn	-	3,4-F2-Ph	=O		10%	0%
anti-25	anti	-	3,4-F2-Ph	=O		0%	0%
8-syn-26	syn	syn:anti 1:1	3,4-F2-Ph	OH	H	10%	0%
anti,anti-26	anti	anti	3,4-F2-Ph	OH	H	0%	0%
anti,syn-26	anti	syn	3,4-F2-Ph	H	OH	0%	0%

# The given K_i values represent means of three independent experiments (n = 3). Values in% represent the inhibition of the radioligand binding at a test compound concentration of 1 µM. Values without SEM represent the mean of two experiments. ^$ MMP = 2-Methoxy-5-methylphenyl.

).

3. Computational Studies

Within the class of propellanamines and azapropellanes some promising σ₁ receptor ligands were identified. Therefore, molecular dynamics (MD) simulations were performed to shed light on their mechanism of binding. The starting structure for the σ₁ receptor was obtained from the RCSB Protein Data Bank (PDB ID 5HK1) [7]. Following a consolidated computational protocol [49,52], the binding modes of compounds 9a (Figure 10A,C) and anti-5 (Figure 10B,D) were initially recognized. A MM/PBSA (molecular mechanics/Poisson–Boltzmann surface area) approach [53] provided the binding free energy (ΔG) of the complexes of both compounds with the σ₁ receptor. The obtained energetic values are in good agreement with their different σ₁ affinity. The following ΔG values were obtained: −10.02 kcal/mol for 9a (K_i(σ₁) = 17 nM) and −8.87 kcal/mol for anti-5 (K_i(σ₁) = 82 nM).

As expected, both σ₁ ligands share the same thermodynamics pattern; their binding is enthalpy driven characterized by favorable van der Waals and electrostatic interactions. Specifically, our analysis resulted in an enthalpy contribution (ΔH) of −18.47 kcal/mol and −17.58 kcal/mol for 9a and anti-5, respectively. Instead, the entropic components (−TΔS) penalize the binding with the σ₁ receptor with the corresponding values of 8.45 kcal/mol and 8.71 kcal/mol for 9a and anti-5, respectively.

Through the per-residue binding free energy deconvolution (PRBFED) of the enthalpic terms (ΔH_res), the main amino acid residues of the σ₁ receptor involved in ligand binding were identified. Basically, by elucidation of the specific ligand/protein interactions, the PRBFED analysis (Figure 10E) allowed to better understand the preference of the σ₁ receptor for the smaller azapropellane 9a. Specifically, azapropellane 9a is provided with the basic chemical features of a prototypical σ₁ receptor ligand: the rings of the propellane system can perform stabilizing hydrophobic and van der Waals interactions with the σ₁ residues W89, F107, Y120 and W164 (ΔH_res = −3.27 kcal/mol, Figure 10E) while the N-benzyl group is perfectly encased in an hydrophobic cavity underlying σ₁ residues I124,V152, and H154 (ΔH_res = −1.64 kcal/mol). However, the most peculiar interaction is definitively performed by its charged N-atom, involved in a permanent ionic interaction with the carboxylic group of E172 (ΔH_res = −4.93 kcal/mol) with a detected average dynamics length (ADL) of 1.75 ± 0.12 Å (Figure 10A,F). Moreover, the optimal orientation of this interaction is guaranteed by a stable, internal hydrogen bond between the other O-atom of E172 and the OH moiety of Y103 (ADL = 1.73 ± 0.12 Å, Figure 10A,G). In the same series, the propellanamine derivative 18 exhibited a good σ₁ affinity (K_i(σ₁) = 34 nM). Our MD study confirmed a very similar binding mode and interaction spectra as observed for the azapropellane 9a (Figure S1, Supplementary Materials). Indeed, the charged secondary amine maintained the ionic interaction with E172 (ΔH_res = −4.44 kcal/mol, Figure S1) and the cyclohexyl moiety of 18 is able to positively interact in the hydrophobic cavity with σ₁ residues I124, V152 and H154 (ΔH_res = −1.72 kcal/mol). Accordingly, the σ₁/18 complex is provided with a favorable ΔG value of −9.78 kcal/mol.

Compared to 9a, the enthalpic contribution of anti-5 was almost 1 kcal/mol lower, although its 2-methoxy-5-methylphenyl carbamate moiety could provide additional interactions in the σ₁ receptor cavity (Figure 10B,D). However, these additional interactions of anti-5 with residues L95, L182 and Y206 (ΔH_res = −1.68 kcal/mol, Figure 10E) were not specific and could not compensate the decrease of the other interactions due to a not optimal orientation in the binding site. Indeed, anti-5 cannot establish an optimal H-bond with the carboxylate side chain of E172 (ΔH_res = −3.65 kcal/mol) as demonstrated by the less stable ADL detected in our MD simulation (ADL = 2.12 ± 0.35 Å, Figure 10B,F). Furthermore, the assumed binding pose of anti-5 does not allow an optimal position of its N-benzyl moiety in the hydrophobic cavity underlying I124, V152 and H154 (ΔH_res = −0.53 kcal/mol, Figure 10E). Moreover, optimal stabilizing interactions of the propellane system of anti-5 with W89, F107, Y120 and W164 (ΔH_res = −2.58 kcal/mol) were not reached.

4. Conclusions

In this manuscript, the rigid propellane system was used to attach σ₁ and σ₂ pharmacophoric substituents in a defined three-dimensional orientation. It was shown, that propellanes with both substituents at the five-membered rings adopting syn-configuration (e.g., syn,syn-4a) exhibited high σ₁ affinity underlining the importance of the stereochemistry. Urea instead of the amino moiety led to the loss of σ₁ and σ₂ affinity. High σ₁ affinity was achieved by incorporation of the basic amino moiety into the propellane scaffold. The azapropellanes anti-5 and 9a demonstrated high σ₁ affinity, which is enthalpy driven. Although the carbamate moiety of anti-5 contributed to the binding free energy of anti-5 within the σ₁ receptor binding pocket, it forces the complete propellane scaffold and its benzyl moiety into a less favorable orientation in the binding pocket. As a result, the σ₁ affinity of anti-5 is lower than the σ₁ affinity of 9a.

5. Experimental

5.1. Chemistry, General Methods

Unless otherwise mentioned, THF was dried with sodium/benzophenone and was freshly distilled before use. Thin layer chromatography (tlc): Silica gel 60 F₂₅₄ plates (Merck). Preparative thin layer chromatography (ptlc): Silica gel 60 F₂₅₄, plates (Merck) 20 × 20 cm, layer thickness 2 mm flash chromatography (fc): Silica gel 60, 40–64 μm (Merck); parentheses include: diameter of the column, length of column, fraction size, eluent, R_f value. Melting point: Melting point apparatus SMP 3 (Stuart Scientific), uncorrected. IR: IR spectrophotometer IRAffinity with MIRacle 10 accessory FT-ATR-IR (Shimadzu). ¹H NMR (400 MHz), ¹³C NMR (100 MHz): Mercury plus 400 spectrometer (Varian); δ in ppm relative to tetramethylsilane; coupling constants are given with 0:5 Hz resolution. Where necessary, the assignment of the signals in the ¹H NMR and ¹³C NMR spectra was performed using ¹H-¹H COSY, ¹H-¹³C HSQC NMR spectra, the stereochemistry was assigned using NOESY NMR spectra. MS: EI = electron impact and ESI = electrospray ionization: MicroTof (Bruker Daltronics, Bremen, Germany), calibration with sodium formate clusters before measurement. HPLC method for determination of the product purity: Merck Hitachi Equipment(Darmstadt, Germany); UV detector: L-7400; autosampler: L-7200; pump: L-7100; degasser: L-7614; Method: column: LiChrospher^® 60 RP-select B (5 mm), 250–4 mm cartridge; flow rate: 1:00 mLmin1; injection volume: 5:0 mL; detection at l = 210 nm; solvents: A: water with 0:05% (v/v) trifluoroacetic acid; B: acetonitrile with 0:05% (v/v) trifluoroacetic acid: gradient elution: (A%): 0–4 min: 90%, 4–29 min: gradient from 90% to 0%, 29–31 min: 0%, 31–31:5 min: gradient from 0% to 90% and 31:5–40 min: 90%.

5.2. General Procedure A for the Synthesis of Carbamates and Ureas

Under N₂, propellanol of propellanamine (1 equi.), the respective isocyanate (1.2 eq.) and the catalyst Bu₂Sn(OAc)₂ (0.2 eq.) were dissolved in THF (5 mL per 100 mg of propellanamine) and the mixture was stirred at rt for 24–48 h. Water (5 mL) was added and the mixture was stirred vigorously for 20 min. The mixture was extracted with EtOAc (3×), the combined EtOAc layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc.

5.3. Synthetic Procedures

5.3.1. (anti-11-Oxo[4.3.3]propellan-8-yl) N-(2-methoxy-5-methylphenyl)carbamate (anti-7) and (syn-11-Oxo[4.3.3]propellan-8-yl) N-(2-methoxy-5-methylphenyl)carbamate (syn-7)

According to General Procedure A, stereoisomeric hydroxyketones anti-6 and syn-6 (1.3 g, 6.69 mmol), 2-methoxy-5-methylphenyl isocyanate (1.4 g, 8.71 mmol) and the catalyst Bu₂Sn(OAc)₂ (0.36 mL, 1.34 mmol) were reacted in THF (25 mL) and worked-up. The residue was purified by fc (5 cm, cyclohexane:ethyl acetate = 1:0–7:3, 50 mL).

anti-7 (R_f = 0.52): Pale yellow solid, mp 143–144 °C, yield 0.86 g (36%), C₂₁H₂₇NO₄ (357.2). MS (EI): m/z (%) = 357 [M⁺], 181 [M-C₁₂H₁₇O]⁺, 137 [M-C₁₃H₁₇O₃]⁺, 122 [M-C₁₃H₁₈NO₃]⁺. Exact mass (APCI): m/z = 358.1979 (calcd. 358.2013 for C₂₁H₂₈NO₄ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3292 (ν N-H), 2931 (ν C-H aliphatic), 1732 (ν C=O_ketone), 1697 (ν C=O_carbamate), 1597 (δ N-H). ¹H NMR (CDCl₃): δ (ppm) = 1.32–1.45 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.75 (dd, J = 14.9/4.1Hz, 2H, 7-H_anti, 9-H_anti), 2.22 (s, 3H, CH₃) 2.24 (d, J = 19 Hz, 2H, 10-H_syn, 12-H_syn,), 2.35 (d, J = 19 Hz, 2H, 10-H_anti, 12-H_anti), 2.36 (dd, J = 14.8/8.8 Hz, 2H, 7-H_syn, 9-H_syn), 3.77 (s, 3H, OCH₃), 5.32 (tt, J = 8.4/4.4 Hz, 1H, 8-H), 6.67 (d, J = 8.3 Hz, 1H, 3-H_N-Ar), 6.71 (dd, J = 1.6/8.3 Hz, 1H, 4-H_N-Ar), 7.06 (s, broad, 1H, NH _carbamate), 7.83 (s, broad, 1H, 6-H_N-Ar). ¹³C NMR (CDCl₃): δ (ppm) = 21.2 (1C, CH₃), 21.4 (2C, C-3, C-4), 32.1 (2C, C-2, C-5), 43.9 (2C, C-7, C-9), 47.7, (2C, C1, C-6), 49.9 (2C, C-10, C-12), 55.9 (1C, OCH₃), 75.6 (1C, C-8), 110.0 (1C, C-3_N-Ar), 118.9 (1C, C- _N-Ar), 123.2 (1C, C-4_N-Ar), 127.4 (1C, C-1_N-Ar), 130.7 (1C, C-5_N-Ar), 145.7 (1C, C-2_N-Ar), 153.3 (1C, NH(CO)O), 219.2 (1C, C=O_ketone). Purity (HPLC): 95.9% (t_R = 21.40 min).

syn-7 (R_f = 0.48): Pale yellow solid, mp 115–118 °C, yield 0.74 g (31%), C₂₁H₂₇NO₄ (357.2). MS (EI): m/z (%) = 357 [M⁺], 181 [M-C₁₂H₁₇O]⁺, 137 [M-C₁₃H₁₇O₃]⁺, 122 [M-C₁₃H₁₈NO₃]⁺. Exact mass (APCI): m/z = 358.1991 (calcd. 358.2013 for C₂₁H₂₈NO₄ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3425 (ν N-H), 2931 (ν C-H aliphatic), 1737 (ν C=O_ketone), 1720 (ν C=O_carbamate), 1597 (δ N-H). ¹H NMR (CDCl₃): δ (ppm) = 1.33–1.43 (m, 4H, 2-H_eq, 3-H_eq, 4-H_eq, 5-H_eq), 1.47–1.51 (m, 2H, 2-H_ax, 4-H_ax), 1.62–1.68 (m, 2H, 3-H_ax, 5-H_ax), 1.97 (dd, J = 15.2/3.6 Hz, 2H, 7-H_syn, 9-H_syn), 2.10 (d, J = 19.2 Hz, 2H, 10-H_anti, 12-H_anti,), 2.15 (dd, J = 15.2/8.4 Hz, 2H, 7-H_anti, 9-H_anti), 2.21 (d, J = 19.2 Hz, 2H, 10-H_syn, 12-H_syn,), 2.23 (s, 3H, CH₃), 3.79 (s, 3H, OCH₃), 5.27 (tt, J = 8.7/3.7 Hz, 1H, 8-H), 6.68 (d, J = 8.4 Hz, 1H, 3-H_N-Ar), 6.72 (dd, J = 2/8.4 Hz, 1H, 4-H_N-Ar), 7.11 (s, broad, 1H, NH), 7.85 (s, broad, 1H, 6-H_N-Ar). ¹³C NMR (CDCl₃): δ (ppm) = 21.2 (1C, CH₃), 21.7 (2C, C-3, C-4), 31.9 (2C, C-2, C-5), 43.9 (2C, C-7, C-9), 47.6 (2C, C-1, C-6), 49.7 (2C, C-10, C-12), 56.0 (1C, OCH₃), 75.6 (1C, C-8), 110.1 (1C, C-3_N-Ar), 119.0 (1C, C-6_N-Ar), 123.1 (1C, C-4_N-Ar), 127.4 (1C, C-1_N-Ar), 130.8 (1C, C-5_N-Ar), 145.7 (1C, C-2_N-Ar), 153.4 (1C, NH(CO)O), 218.7 (1C, C=O_ketone). Purity (HPLC): 95.5% (t_R = 21.79 min).

5.3.2. [(8-anti-11-anti and 8-anti-11-syn)-11-(3,4-Dimethoxbenzylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4b)

NaBH(OAc)₃ (0.47 g, 2.24 mmol) was added to a solution of ketone anti-7 (0.20 g, 0.56 mmol), 3,4-dimethoxybenzylamine (0.11 g, 0.67 mmol) and acetic acid (32 μL, 0.56 mmol) in 1,2-dichloroethane (10 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 48 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate = 7:3 to 5:5, 10 mL, R_f = 0.25, cyclohexane:ethyl acetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4b and anti,syn-4b as brown oil, yield 0.24 g (85%). C₃₀H₄₀N₂O₅ (508.6). Exact mass (APCI): m/z = 509.2982 (calcd.509.3010 for C₃₀H₄₁N₂O₅ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3329 (ν N-H), 2927 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.29–1.49 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.61 (dd, J = 13.4/6.6 Hz, 2 × 0.5H, 7-H, 9-H), 1.67–1.75 (m, 4 × 0.5H, 7-H, 9-H, 10-H, 12-H), 1.92 (dd, J = 14.4/4.8 Hz, 2 × 0.5H, 10-H, 12-H), 1.98–2.10 (m, 2H, 7-H, 9-H), 2.14–2.26 (m, 2H, 10-H, 12-H), 2.28 (s, 3H, CH₃), 3.37–3.51 (m, 2 × 0.5H, 11-H), 3.70 (s, 2H, NCH₂Ar), 3.82 (s, 3 × 0.5H, p-OCH₃), 3.84 (s, 3 × 0.5H, p-OCH₃), 3.86 (s, 3 × 0.5H, OCH_{3Arylcarbamate}), 3.88 (s, 3 × 0.5H, m-OCH₃), 3.89 (s, 3 × 0.5H, m-OCH₃), 5.19–5.31 (m, 2 × 0.5H, 8-H), 6.73 (dd, J = 8.3/3.5 Hz, 1H, 6-H_Bn), 6.77 (m, 1H, 5-H_Bn), 6.81 (dd, J = 8.1/2.1 Hz, 1H, 4-H_Ar), 6.85 (d, J = 8.4 Hz, 1H, 3-H_Ar), 6.90 (t, J = 2.1 Hz, 1H, 2-H_Bn), 7.13 (s, 0.5H, NH), 7.18 (s, 0.5H, NH), 7.93 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.8, 20.9 (2C, C-3, C-4), 21.2 (1C, CH₃), 32.4, 32.7 (2C, C-2, C-5), 44.5, 44.8 (2C, C-10, C-12), 45.0 (2C, C-7, C-9), 49.7 (2C, C-1, C-6), 55.2 (1C, NHCH₂Ph), 55.7 (1C, C-11), 55.9, 59.1 (3C, 3 × OCH₃), 76.2 (1C, C-8), 110.2 (1C, C-3_Ar), 111.2 (1C, C-2_Bn), 112.1 (1C, C-5_Bn), 119.0 (1C, C-6_Ar), 121.1 (1C, C-6_Bn), 122.9 (1C, C-4_Ar), 127.8 (1C, C-1_Ar), 129.5 (1C, C-1_Bn), 130.8 (1C, C-5_Ar), 145.7 (1C, C-2_Ar), 148.1, 148.8 (2C, C-3_Bn, C-4_Bn) 153.6 (1C, C=O). anti,anti-4b:anti,syn-4b = 1:1. Purity (HPLC): 96.0% (t_R = 20.31 min).

5.3.3. [(8-anti-11-anti and 8-anti-11-syn)-11-(4-Chlorobenzylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4c)

NaBH(OAc)₃ (0.47 g, 2.24 mmol) was added to a solution of ketone anti-7 (0.20 g, 0.56 mmol), 4-chlorobenzylamine (95 mg, 0.67 mmol) and acetic acid (32 μL, 0.56 mmol) in 1,2-dichloroethane (10 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 6 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate:methanol = 5:3.5:1.5, 10 mL, R_f = 0.40) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4c and anti,syn-4c as yellow oil, yield 0.12 g (45%). C₂₈H₃₅ClN₂O₃ (482.2). Exact mass (APCI): m/z = 483.2387 (calcd.483.2409 for C₂₈H₃₆ClN₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3329 (ν N-H), 2927 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.30–1.53 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.59–1.76 (m, 2H, 7-H, 9-H), 1.89–2.09 (m, 4H, 10-CH₂, 12-CH₂), 2.14–2.27 (m, 2H, 7-H, 9-H), 2.29 (s, 3H, CH₃), 3.35–3.48 (m, 2 × 0.5H, 11-H), 3.73 (s, 2H, NCH₂Ph), 3.85 (s, 3H, OCH₃), 5.18–5.31 (m, 2 × 0.5H, 8-H), 6.73 (dd, J = 8.3/2.1 Hz, 1H, 4-H_Ar), 6.77 (d, J = 8.3 Hz, 1H, 3-H_Ar), 7.13 (s, 0.5H, NH), 7.18 (s, 0.5H, NH), 7.25–7.36 (m, 4H, 4-chlorophenyl), 7.93 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.0, 21.1 (2C, C-3, C-4), 21.5 (1C, CH₃), 32.4, 32.8 (2C, C-2, C-5), 44.7, 44.8, 45.0, 45.2 (4C, C-7, C-9, C-10, C-12), 49.7 (2C, C-1, C-6), 50.5 (1C, NCH₂Ph), 55.7, 55.9 (2 × 0.5C, OCH₃), 57.0 (1C, C-11), 76.0, 76.5 (2 × 0.5C, C-8), 109.9 (1C, C-3_Ar), 118.9 (1C, C-6_Ar), 122.9 (1C, C-4_Ar), 127.6, 128.6 (2C, C-3_Bn, C-5_Bn), 129.6, 129.8 (2C, C-2_Bn, C-6_Bn), 130.7 (1C, C-5_Ar), 138.7 (1C, C-1_Bn) 145.6 (1C, C-2_Ar), 153.6 (1C, C=O). anti,anti-4c:anti,syn-4c = 1:1. Purity (HPLC): 92.6% (t_R = 20.85 min).

5.3.4. [(8-anti-11-anti and 8-anti-11-syn)-11-(3,4-Dichlorobenzylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4d)

NaBH(OAc)₃ (0.47 g, 2.24 mmol) was added to a solution of ketone anti-7 (0.20 g, 0.56 mmol), 3,4-dichlorobenzylamine (0.12 g, 0.67 mmol) and acetic acid (32 μL, 0.56 mmol) in 1,2-dichloroethane (10 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 6 d. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate:methanol = 5:3.5:1.5, 10 mL, R_f = 0.49) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4d and anti,syn-4d as yellow oil, yield 0.17 g (59%). C₂₈H₃₄Cl₂N₂O₃ (517.5). Exact mass (APCI): m/z = 517.2015 (calcd.517.2019 for C₂₈H₃₅Cl₂N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3329 (ν N-H), 2927 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.28–1.55 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.60–1.75 (m, 2 × 1.5H, 7-H, 9-H), 1.88–2.10 (m, 4H, 10-CH₂, 12-CH₂), 2.14–2.25 (m, 2 × 0.5H, 7-H, 9-H), 2.28 (s, 3H, CH₃), 3.34–3.48 (m, 2 × 0.5H, 11-H), 3.72 (s, 2H, NCH₂Ph), 3.83 (s, 3H, OCH₃), 5.17–32 (m, 2 × 0.5H, 8-H), 6.73 (dd, J = 8.2/1.8 Hz, 1H, 4-H_Ar), 6.77 (d, J = 8.7 Hz, 1H, 3-H_Ar), 7.13 (s, 1H, NH), 7.20 (dd, J = 7.4/3.2 Hz, 1H, 5-H_{3,4-dichlorophenyl}), 7.38 (dd, J = 8.2/5.3 Hz, 1H, 6-H_{3,4-dichlorophenyl}), 7.46 (dd, J = 5.0/2.1 Hz, 1H, 2-H_{3,4-dichlorophenyl}), 7.92 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.0 (1C, CH₃), 21.1, 21.5 (2C, C-3, C-4), 32.4, 32.8 (2C, C-2, C-5), 44.6, 44.8, 45.0, 45.1 (4C, C-7, C-9, C10, C-12), 49.8, 50.5 (2C, C1, C-6), 51.7 (1C, NCH₂Ph), 55.9 (1C, OCH₃), 57.1 (1C, C-11), 76.0, 76.4 (2 × 0.5C, C-8), 110.0(1C, C-3_Ar), 118.9 (1C, C-6_Ar), 122.9 (1C, C-4_Ar),125. 6, 127.8 (2C, C-2_{3,4-dichlorophenyl}, C-6_{3,4-dichlorophenyl}), 103.3, 130.4, 130.5, 130.7, 130.8 (5C, C-3_{3,4-dichlorophenyl}, C-4_{3,4-dichlorophenyl}, C-5_{3,4-dichlorophenyl}, C-1_Ar, C-5Ar), 132.5 (1C, C-1_{3,4dichlorophenyl}) 146.0 (1C, C-2_Ar), 153.6 (1C, C=O). anti,anti-4d:anti,syn-4d = 1:1. Purity (HPLC): 88.6% (t_R = 21.17 min).

5.3.5. [(8-anti-11-anti and 8-anti-11-syn)-11-(2,4-Dimethylbenzylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4e)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), 3,4-dimethylbenzylamine (45 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 72 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 20 mL, R_f = 0.21) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4e and anti,syn-4e as brown oil, yield 0.12 g (93%). C₃₀H₄₀N₂O₃ (476.7). Exact mass (APCI): m/z = 477.3159 (calcd. 477.3112 for C₃₀H₄₁N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3329 (ν N-H), 2927 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.24–1.70 (m, 9H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(0.5H), 9-CH₂(0.5H)), 1.97–2.12 (m, 3H, 7-CH₂(0.5H), 9-CH₂(0.5H)), 10-CH₂(1H), 12-CH₂(1H)), 2.14–2.37 (m, 13H, 7-CH₂(1H), 9-CH₂(1H), 10-CH₂(1H), 12-CH₂(1H), CH₃), 3.45–3.51 (m, 0.5H, 11-H), 3.51–3.58 (m, 0.5H, 11-H), 3.76 (s, 2H, NCH₂Ph), 3.82 (s, 3 × 0.5H, OCH₃), 3.85 (s, 3 × 0.5H, OCH₃), 5.20 (tt, J = 8.4/4.0 Hz 0.5H, 8-H), 5.28 (tt, J = 8.4/5.0 Hz, 0.5H, 8-H), 6.71–6.80 (m, 2H, 3-H_Ar, 4-H_Ar), 6.95–7.03 (m, 2H, 5-H_{2,4-diMePhenyl}, 6-H_{2,4-diMePhenyl}), 7.11 (d, J = 3.8 Hz, 1H, 3-H_{2,4-diMePhenyl}), 7.36 (s, 1H, NH), 7.92 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 19.0 (1C, CH₃), 20.8, 21.1, 21.4 (4C, C-3, C-4, 2 × CH₃), 32.5, 32.8 (2C, C-2, C-5), 41.8, 44.6, 45.0 (4C, C-7, C-9, C-10, C-12), 49.7, 50.3 (2C, C-1, C-6), 55.7 (0.5C, C-11), 55.9 (1C, OCH₃), 57.2 (0.5C, C-11), 75.8 (0.5C, C-8), 76.4 (0.5C, C-8), 110.0 (1C, C-3_Ar), 119.1 (1C, C-6_Ar), 122.8 (1C, C-4_Ar), 127.0 (1C, C-5_{2,4-diMePhenyl}), 127.5, 127.7 (2 × 0.5C, C-1_Ar), 129.0 (1C, C-3_{2,4-diMePhenyl}), 130.6, 130.7 (2 × 0.5C, C-5_Ar), 131.5 (2C, C-1_{2,4-diMePhenyl}, C-6_{2,4-diMePhenyl}), 136.5 (1C, C-2_{2,4-diMePhenyl}), 137.8 (1C, C-4_{2,4-diMePhenyl}), 145.6 (1C, C-2_Ar), 153.7 (1C, C=O). anti,anti-4e:anti,syn-4e = 1:1. Purity (HPLC): 91.3% (t_R = 21.61 min).

5.3.6. [(8-anti-11-anti and 8-anti-11-syn)-11-[(3,5-Bis(trifluoromethyl)benzylamino]-[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4f)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), 3,5-bis(trifluoromethyl)benzylamine (82 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 72 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate = 7:3–1:1, 20 mL, R_f = 0.14, cyclohexane:ethyl acetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4f and anti,syn-4f as brown oil, yield 95 mg (59%). C₃₀H₃₄F₆N₂O₃ (584.6). Exact mass (APCI): m/z = 585.2596 (calcd. 585.2546 for C₃₀H₃₄F₆N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3433 (ν N-H), 2931 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.31–1.52 (m, 10H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(1H), 9-CH₂(1H)), 1.70 (dd, J = 14.0/5.4 Hz, 2 × 0.5H, 7-H, 9-H), 1.93 (dd, J = 14.4/4.9 Hz, 2 × 0.5H, /-H, 9-H), 2.02–2.13 (m, 2H, 10-H, 12-H), 2.16–2.27 (m, 2H, 10-H, 12-H), 2.28 (m, 3H, CH₃), 3.38–3.52 (m, 2 × 0.5H, 11-H), 3.83 (s, 3H, OCH₃), 3.88 (s, 2H, NCH₂Ph), 5.19–5.33 (m, 2 × 0.5H, 8-H), 6.73 (d, J = 8.3 Hz, 1H, 3-H_Ar), 6.77 (dd, J = 8.8/3.8 Hz, 1H, 4-H_Ar), 7.13 (s, 1H, NH), 7.77 (s, 1H, 4-H_3,5-diCF3Ph), 7.85 (d, J = 4.9 Hz, 2H, 2-H_3,5-diCF3Ph, 6-H_3,5-diCF3Ph), 7.92 (s, 1H, 6-H_Ar). A signal for the NH protons is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.0 (1C, CH₃), 21.1, 21.4 (2C, C-3, C-4), 32.4, 32.8 (2C, C-2, C-5), 44.9 (4C, C-7, C-9, C-10, C-12), 49.8, 50.4 (2C, C-1, C-6), 57.5, 56.3 (2 × 0.5C, C-11), 75.9, 76.4 (2 × 0.5C, C-8), 110.0 (1C, C-3_Ar), 118.9 (1C, C-6_Ar), 121.3 (d, J = 7.53 Hz, 1C, C-4_3,5-diCF3Ph), 122.9 (1C, C-4_Ar), 126.2 (q, J = 262.3 Hz, 2C, CF₃), 128.6 (2C, C-2_3,5-diCF3Ph, C-6_3,5-diCF3Ph), 130.7 (2C, C-1_Ar, C-5_Ar), 130.9 (2C, C-3_3,5-diCF3Ph, C-5_3,5-diCF3Ph), 141.4 (1C, C-1_3,5-diCF3Ph), 145.6 (1C, C-2_Ar), 153.6 (1C, C=O). anti,anti-4f:anti,syn-4f = 1:1. Purity (HPLC): 92.0% (t_R = 22.40 min).

5.3.7. [(8-anti-11-anti and 8-anti-11-syn)-11-(4-Nitrobenzylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4g)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), 4-nitrobenzylamine hydrochloride (70 mg, 0.34 mmol) and NEt₃ (58 μL, 0.42 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 24 h. Then acetic acid (16 μL, 0.28 mmol) was added and the mixture was stirred for additional 24 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 10 mL, R_f = 0.29) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4g and anti,syn-4g as yellow oil, yield 90 mg (65%). C₂₈H₃₅N₃O₅ (493.6). MS (ESI): m/z = 494 [M+H]⁺. Exact mass (APCI): m/z = 494.2680 (494.2649 calcd. for C₂₈H₃₆N₃O₅ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3425 (ν N-H), 2931 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H), 1519 (ν N-O), 1342 (ν N-O). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.36–1.55 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.68 (m, 4H, 7-H, 9-H, 10-H, 12-H), 1.90–2.11 (m, 2H, 10-H, 12-H), 2.17–2.27 (m, 2H, 7-H, 9-H), 2.28 (s, 3H, CH₃), 3.38–3.43 (m, 0.4H, 11-H), 3.46 (tt, J = 7.4, 5.8 Hz, 0.6H), 3.82 (s, 3 × 0.4H, OCH₃), 3.83 (s, 3 × 0.6H, OCH₃), 3.87 (s, 2H, NCH₂Ph), 5.22 (tt, J = 8.2, 5.3 Hz, 0.6H, 8-H), 5.28 (tt, J = 8.9/4.8 Hz, 0.4H, 8-H), 6.74 (dd, J = 8.3/1.3 Hz, 1H, 3-H_Ar), 6.77 (dd, J = 8.4/2.1 Hz, 1H, 4-H_Ar), 7.10 (s, 1H, NH), 7.51–7.56 (m, 2H, 2-H_4-NO2Ph, 6-H_4-NO2Ph), 7.91 (s, 1H, 6-H_Ar), 8.15–8.19 (m, 2H, 3-H_4-NO2Ph, 5-H_4-NO2Ph). A signal for the NH proton is not seen in the spectrum. Signals for the OH and NH protons are not seen in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 21.0, 21.1, 21.5 (3C, C-3, C-4, CH₃), 32.4, 32.8 (2C, C-2, C-5), 44.9, 45.0 (4C, C-7, C-9, C-10, C-12), 49.8, 50.5 (2C, C-1, C-6), 52.1 (1C, NCH₂Ph), 55.9 (1C, OCH₃), 56.1 (0.6C, C-11), 57.3 (0.4C, C-11), 76.0 (0.6C, C-8), 76.5 (0.4C, C-8), 110.0 (1C, C-3Ar), 118.9 (1C, C-6Ar), 122.9 (1C, C-4Ar), 123.8 (2C, C-3_4-NO2Ph, C-5_4-NO2Ph), 127.5 (1C, C-1_Ar), 129.0 (2C, C-2_4-NO2Ph, C-6_4-NO2Ph), 130.7 (1C, C-5_Ar), 145.6 (1C, C-2_Ar), 147.2 (1C, C-1_4-NO2Ph), 148.3 (1C, C-4_4-NO2Ph), 153.5 (1C, C=O). anti,anti-4g:anti,syn-4g = 6:4. Purity (HPLC): 98.0% (t_R = 20.04 min).

5.3.8. [(8-anti-11-anti and 8-anti-11-syn)-11-[(4-Dimethylamino)benzylamino]-[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4h)

NaBH(OAc)₃ (0.12 g, 0.57 mmol) was added to a solution of 4v (0.10 g, 0.28 mmol) and 4-(dimethylamino)benzaldehyde (50 mg, 0.34 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 20 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 10 mL, R_f = 0.30) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4h and anti,syn-4h as yellow oil, yield 70 mg (50%). C₃₀H₄₁N₃O₃ (491.7). Exact mass (APCI): m/z = 492.3228 (calcd. 492.3221 for C₃₀H₄₂N₃O₃ [M+2H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3429 (ν N-H), 2927 (ν C-H aliphatic), 1724 (ν C=O), 1612 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.28–1.60 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.61–1.88 (m, 3H, 7-H, 9-H, 10-H(0.5H), 12-H(0.5H)), 1.91–2.25 (m, 5H, 7-H, 9-H, 10-H(1.5H), 12-H(1.5H)), 2.28 (s, 3H, CH₃), 2.89 (s, 3H, NCH₃), 2.91 (s, 3H, NCH₃), 3.39–3.54 (m, 1H, 2 × 0.5 H, 11-H), 3.71 (s, 2H, NCH₂Ph), 3.82 (s, 3 × 0.5H, OCH₃), 3.84 (s, 3 × 0.5H, OCH₃), 5.17–5.31 (m, 2 × 0.5H, 8-H), 6.66–6.71 (m, 2H, 3-H_4-diMePh, 5-H_4-diMePh), 6.73–6.79 (m, 2H, 3-H_Ar, 4-H_Ar), 7.12 (s, 0.5H, NH), 7.22–7.26 (m, 2H, 2-H_4-diMePh, 6-H_4-diMePh), 7.29 (s, 0.5H, NH), 7.92 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.9, 21.1, 21.4 (3C, C-3, C-4, CH₃), 32.5, 32.8 (2C, C-2, C-5), 40.7, 40.8 (2C, N(CH₃)₂), 44.8, 45.0 (4C, C-7, C-9, C-10, C-12), 49.6, 50.3 (2C, C-1, C-6), 55.9 (0.5C, C-11), 56.3 (1C, OCH₃), 60.5 (0.5C, C-11), 75.9 (0.5C, C-8), 76.4 (0.5, C-8), 110.0 (1C, C-3_Ar), 112.7 (2C, C-3_4-diMePh, C-5_4-diMePh), 119.1 (1C, C-6_Ar), 122.8 (1C, C-4_Ar), 127.7 (1C, C-1_Ar), 129.9 (2C, C-2_4-diMePh, C-6_4-diMePh), 130.1 (1C, C-1_4-diMePh), 130.7 (1C, C-5_Ar), 145.8 (1C, C-2_Ar), 150.2 (1C, C-4_4-diMePh), 153.7 (1C, C=O). anti,anti-4h:anti,syn-4h = 1:1. Purity (HPLC): 98.4% (t_R = 17.89 min).

5.3.9. [(8-anti-11-anti and 8-anti-11-syn)-11-[(Furan-2-yl-mehtyl)amino][4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4i)

NaBH(OAc)₃ (0.36 g, 1.67 mmol) was added to a solution of ketone anti-7 (0.15 g, 0.42 mmol), furfurylamine (0.15 g, 0.55 mmol) and acetic acid (24 μL, 0.42 mmol) in 1,2-dichloroethane (10 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 48 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 10 mL, R_f = 0.59) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4i and anti,syn-4i as dark yellow oil, yield 0.15 mg (79%). C₂₆H₃₄N₂O₄ (438.6). MS (ESI): m/z = 439 [M+H]⁺. Exact mass (APCI): m/z = 439.2605 (calcd. 439.2591 for C₂₆H₃₅N₂O₄ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3425 (ν N-H), 2931 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.29–1.54 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.61 (dd, J = 13.3/6.8 Hz, 2 × 0.5H, 10-H, 12-H), 1.67–1.73 (m, 2H, 7-H, 9-H), 1.90 (dd, J = 14.4/4.9 Hz, 2 × 0.5H, 10-H, 12-H), 1.96–2.07 (m, 2H, 7-H, 9-H), 2.13–2.26 (m, 2H, 7-H, 9-H), 2.28 (m, 3H, CH₃), 3.35–3.49 (m, 2 × 0.5H, 11-H), 3.78 (s, 2H, NCH₂Furyl), 3.84 (s, 3H, OCH₃), 5.16–5.32 (m, 2 × 0.5H, 8-H), 6.18–6.24 (m, 1H, 3-H_Furan), 6.29–6.33 (m, 1H, 4-H_Furan), 6.71–6.79 (m, 2H, 3-H_Ar, 4-H_Ar), 7.13 (s, 0.5H, NH), 7.20 (s, 0.5H, NH), 7.32–7.38 (m, 1H, 5-H_Furan), 7.92 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. Signals for the OH and NH protons are not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.9, 21.1 (2C, C-3, C-4), 21.5 (1C, CH₃), 32.4, 32.8 (2C, C-2, C-5), 44.5, 44.9, 45.1, 45.2 (5C, C-7, C-9, C-10, C-12, NCH₂Furan), 49.7, 50.4 (2C, C-1, C-6), 55.5 (0.5C, C-11), 55.9 (1C, OCH₃), 56.8 (0.5C, C-11), 76.0 (0.5C, C-8), 76.4 (0.5C, C-8), 107.2, 107.6 (1C, C-3_Furan), 109.9 (1C, C-3_Ar), 110.4, 110.6 (1C, C-4_Furan), 118.9 (1C, C-6_Ar), 122.9(1C, C-4_Ar), 127.5 (1C, C-1_Ar), 130.6 (1C, C-5_Ar), 142.0, 142.3 (1C, C-5_Furan), 145.6 (1C, C-2_Ar), 146.0 (1C, C-2_Furan), 153.6 (1C, C=O). anti,anti-4i:anti,syn-4i = 6:4. Purity (HPLC): 91.4% (t_R = 19.33 min).

5.3.10. [(8-syn-11-syn and 8-syn-11-anti)-11-[(Furan-2-yl-mehtyl)amino][4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-syn-4i)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone syn-7 (0.10 g, 0.28 mmol), furfurylamine (29 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 5 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1 to 1:1, 10 mL, R_f = 0.18) to obtain a mixture of diastereoisomeric aminocarbamates syn,syn-4i and anti,syn-4i as yellow oil, yield 84 mg (66%). C₂₆H₃₄N₂O₄ (438.6). MS (ESI): m/z = 439 [M+H]⁺. Exact mass (APCI): m/z = 439.2631 (calcd. 439.2591 for C₂₆H₃₅N₂O₄ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3425 (ν N-H), 2931 (ν C-H aliphatic), 1720 (ν C=O), 1597 (δ N-H). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.33–1.58 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.70 (dd, J = 13.5/7.3 Hz, 2 × 0.5H, 7-H, 9-H), 1.80–1.90 (m, 3H), 1.97–2.07 (m, 3H), 2.29 (s, 3H, CH₃), 2.29–2.35 (m, 2 × 0.5H, 7-H, 9-H), 3.29–3.35 (m, 0.5H, 11-H), 3.35–3.41 (m, 0.5H, 11-H), 3.80–3.85 (m, 5H, OCH₃, NCH₂Furyl), 5.20 (tt, J = 8.3/4.7 Hz, 0.5H, 8-H), 5.31 (tt, J = 8.4/4.2 Hz, 0.5H, 8-H), 6.30 (dd, J = 6.2/3.5 Hz, 1H, 3-H_Furan), 6.33 (d, J = 2.8/2.0 Hz, 1H, 4-H_Furan), 6.73 (dd, J = 8.2/3.2 Hz, 1H, 3-H_Ar), 6.77 (dd, J = 7.1/5.0 Hz, 1H, 4-H_Ar), 7.12 (s, 1H, NH), 7.38 (ddd, J = 4.0/1.8/0.9 Hz, 1H, 5-H_Furan), 7.92 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 21.1, 21.2, 21.3 (3C, C-3, C-4, CH₃), 32.1, 33.1 (2C, C-2, C-5), 44.3, 44.6, 45.0, 45.0 (5C, C-7, C-9, C-10, C-12, NCH₂Furyl), 49.5, 50.0 (2C, C-1, C-6), 55.7 (0.5C, C-11), 55.9 (1C, OCH₃), 56.4 (0.5C, C-11), 76.0 (0.5C, C-8), 76.1 (0.5C, C-8), 108.5 (1C, C-3_Furan), 110.0 (1C, C-3_Ar), 110.6 (1C, C-4_Furan), 119.0 (1C, C-2_Furan), 122.8 (C-4_Ar), 127.5 (C-1_Ar), 130.7 (1C, C-5_Ar), 142.4 (1C, C-5_Furan), 145.6 (1C, C-2_Ar), 153.5 (1C, C=O). syn,syn-4i:syn,anti-4i = 1:1. Purity (HPLC): 97.6% (t_R = 19.35 min).

5.3.11. [(8-anti-11-anti and 8-anti-11-syn)-11-[2-(Indol-3-yl)ethylamino][4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4k)

NaBH(OAc)₃ (62 mg, 0.29 mmol) was added to a solution of ketone anti-7 (35 mg, 0.10 mmol), tryptamine (20 mg, 0.12 mmol) and acetic acid (6 μL, 0.10 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 96 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 10 mL, R_f = 0.18,) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4k and anti,syn-4k as brown oil, yield 20 mg (41%). C₃₁H₃₉N₃O₃ (501.7). Exact mass (APCI): m/z = 502.3190 (calcd. 502.3064 for C₃₁H₄₀N₃O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3429 (ν N-H), 2927 (ν C-H aliphatic), 1716 (ν C=O), 1597 (δ N-H). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.25–1.49 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.56 (dd, J = 14.5/5.0 Hz, 2 × 0.5H, 7-H, 9-H), 1.98–2.18 (m, 7H, 7-CH₂(1H), 9-CH₂(1H), 10-CH₂, 12-CH₂), 2.27 (s, 3H, CH₃), 3.17–3.25 (m, 2H, NCH₂CH₂Indole), 3.39–3.46 (m, 2H, NCH₂CH₂Indole), 3.59–3.66 (m, 0.6H, 11-H), 3.70 (tt, J = 9.4/7.3 Hz, 0.4H, 11-H), 3.77 (s, 3 × 0.4H, OCH₃), 3.78 (s, 3 × 0.6H, OCH₃), 5.15 (tt, J = 7.9/5.0 Hz, 0.6H, 8-H), 5.23 (tt, J = 8.1/4.9 Hz, 0.4H, 8-H), 6.71 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.74–6.78 (m, 1H, 4-H_Ar), 7.04–7.07 (m, 2H, 5-H_Indole, 6-H_Indole), 7.12–7.17 (m, 1H, 2-H_Indole), 7.33 (ddd, J = 8.1/2.1/1.0 Hz, 1H, 7-H_Indole), 7.59 (s, 1H, NH_carbamate) 7.63 (ddd, J = 8.2/2.5/1.0 Hz, 1H, 4-H_Indole), 7.86–7.89 (s, 1H, 6-H_Ar), 8.41 (s, 1H, NH_Indole). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.4 (1C, CH₃), 20.7, 21.1 (2C, C-3, C-4), 22.6 (1C, NCH₂CH₂Indole), 32.3, 32.8 (2C, C-2, C-5), 40.9, 41.6 (2C, C-10, C-12), 44.4, 45.1 (2C, C-7, C-9), 47.8 (1C, NCH₂CH₂Indole), 49.4, 49.8 (2C, C-1, C-6), 55.9 (1C, OCH₃), 56.7 (0.4C, C-11), 58.0 (0.6C, C-11), 75.5 (0.4C, C-8), 76.2 (0.6C, C-8), 110.0 (1C, C-3_Ar), 110.5, 111.6 (2 × 0.5C, C-7_Indole), 118.7 (1C, C-4_Indole), 119.7 (1C, C-6_Ar), 119.8 (1C, C-5_Indole), 122.4 (1C, C-2_Indole), 123.1 (2C, C-4_Ar, C-6_Indole), 126.9 (1C, C-3a_Indole), 127.7 (1C, C-1_Ar), 130.6 (1C, C-5_Ar), 136.5 (1C, C-7a_Indole), 146.3 (1C, C-2_Ar), 153.8 (1C, C=O). anti,anti-4k:anti,syn-4k = 6:4. Purity (HPLC): 66.3%, light sensitive (t_R = 20.8 min).

5.3.12. [(8-syn-11-syn and 8-syn-11-anti)-11-[(2-(Indol-3-yl)ethylamino][4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-syn-4k)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone syn-7 (0.10 g, 0.28 mmol), tryptamine (52 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 5 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 10 mL, R_f = 0.15,) to obtain a mixture of diastereoisomeric aminocarbamates syn,syn-4k and syn,anti-4k as brown oil, yield 60 mg (41%). C₃₁H₃₉N₃O₃ (501.7). Exact mass (APCI): m/z = 502.3078 (calcd. 502.3064 for C₃₁H₄₀N₃O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3421 (ν N-H), 2931 (ν C-H aliphatic), 1716 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.26–1.58 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.70–1.97 (m, 6H, 7-CH₂(1H), 9-CH₂(1H), 10-CH₂, 12-CH₂), 2.28 (s, 3H, CH₃), 2.30–2.43 (m, 2H, 7-H, 9-H), 3.11–3.21 (m, 2H, NCH₂CH₂Indolyl), 3.31–3.39 (m, 2H, NCH₂CH₂Indole), 3.57–3.66 (m, 1H, 11-H), 3.83 (m, 3H, OCH₃), 5.02–5.10 (m, 0.4H, 8-H), 5.22 (tt, J = 8.1/4.0 Hz, 0.6H, 8-H), 6.73 (d, J = 8.3 Hz, 1H, 3-H_Ar), 6.78 (dd, J = 8.3/2.1 Hz, 1H, 4-H_Ar), 7.02–7.17 (m, 4H, 2-H_Indole,5-H_Indole, 6-H_Indole, NH_Carbamate), 7.35 (d, J =, 1H, 7-H_Indole), 7.61 (d, J = 7.9 Hz, 1H, 4-H_Indole), 7.89 (s, 1H, 6-H_Ar), 8.74 (s, 1H, NH_Indole). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.7, 21.1 (3C, C-3, C-4, CH₃), 22.9 (1C, NCH₂CH₂Indole), 31.9, 32.9 (2C, C-2, C-5), 41.5, 41.6 (2C, C-10, C-12), 44.8, 45.0 (2C, C-7, C-9), 47.8 (1C, NCH₂CH₂Indole), 49.1, 49.8 (2C, C-1, C-6), 55.9 (1C, OCH₃), 56.7 (0.4C, C-11), 57.6 (0.6C, C-11), 75.6 (0.4C, C-8), 76.1 (0.6C, C-8), 110.0 (1C, C-3_Ar), 110.8, 111.6 (2 × 0.5C, C-7_Indole), 118.7 (1C, C-4_Indole), 119.1 (1C, C-6_Ar), 119.6 (1C, C-5_Indole), 122.3 (1C, C-2_Indole), 123.1 1 (2C, C-4_Ar, C-6_Indole), 127.0 (1C, C-3a_Indole), 127.5 (1C, C-1_Ar), 130.7 (1C, C-5_Ar), 136.5 (1C, C-7a_Indole), 145.7 (1C, C-2_Ar), 153.4 (1C, C=O). syn,syn-4k:syn,anti-4k = 4:6. Purity (HPLC): 97.8% (t_R = 20.97 min).

5.3.13. [(8-anti-11-anti and 8-anti-11-syn)-11-(Phenylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4l)

NaBH(OAc)₃ (0.30 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), aniline (31.3 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 48 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate = 8:2, 5 mL, R_f = 0.82, cyclohexane:ethyl acetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4l and anti,syn-4l as pale yellow oil, yield 84 mg (69%). C₂₇H₃₄N₂O₃ (434.6). Exact mass (APCI): m/z = 435.2599 (calcd.435.2642 for C₂₇H₃₅N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3394 (ν N-H), 2931 (ν C-H aliphatic), 1720 (ν C=O), 1600 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.32–1.54 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.66 (dd, J = 13.6/6.0 Hz, 2 × 0.5H, 10-H, 12-H), 1.72–1.82 (m, 2H, 7-H, 9-H), 1.90 (dd, J = 14.4/4.9 Hz, 2 × 0.5H, 10-H, 12-H), 2.21–2.35 (m, 7H, CH₃, 7-H, 9-H, 10-H, 12-H), 3.85 (s, 3H, OCH₃), 3.99–4.07 (m, 0.5H, 11-H), 4.07–4.12 (m, 0.5H, 11-H), 5.29 (tt, J = 8.5/4.8 Hz, 1H, 8-H), 6.61 (dd, J = 8.3/3.2 Hz, 2H, 2-H_Ph, 6-H_Ph), 6.70 (td, J = 7.2/1.3 Hz, 1H, 4H_Ph), 6.75 (d, J = 8.3 Hz, 1H, 3-H_Ar), 6.78 (d, J = 8.2 Hz, 1H, 4-H_Ar), 7.13–7.22 (m, 3H, 3-H_Ph, 5-_Ph, NH), 7.94 (s, 1H, 6-H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.9 (2 × 0.5C, C-3, C-4), 21.1 (1C, CH₃), 21.4 (2 × 0.5C, C-3, C-4), 32.3, 32.7 (2C, C-2, C-5), 44.6, 44.9 (4C, C7, C-9, C-10, C-12), 49.8, 50.4 (2C, C-1, C-6), 55.9 (1C, OCH₃), 60.5 (1C, C-11), 75.9, 76.3 (2 × 0.5C, C-8), 110.0 (1C, C-3_Ar), 119.0 (1C, C-4_Ph), 119.1 (1C, C-6_Ar), 123.0 (1C, C-4_Ar), 129.5 (4C, C-2_Ph, C-3_Ph, C-5_Ph, C-6_Ph), 130.7 (2C, C-1_Ar, C-5_Ar), 145.6 (1C, C-2_Ar), 145.8 (1C, C-1_Ph), 153.6 (1C, C=O). anti,anti-4l:anti,syn-4l = 1:1. Purity (HPLC): 98.2% (t_R = 20.55 min).

5.3.14. [(8-anti-11-anti and 8-anti-11-syn)-11-(4-Methoxyphenylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4m)

NaBH(OAc)₃ (0.47 g, 2.24 mmol) was added to a solution of ketone anti-7 (0.20 g, 0.56 mmol), 4-methoxyphenylamine (87 mg, 0.67 mmol) and acetic acid (32 μL, 0.56 mmol) in 1,2-dichloroethane (10 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 72 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:Et₂O = 8:2 to 1:1, 10 mL, R_f = 0.56, cyclohexane:ethylacetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4m and anti,syn-4m as brown oil, yield 0.19 g (74%). C₂₈H₃₆N₂O₄ (464.6). Exact mass (APCI): m/z = 465.2721 (calcd.465.2748 for C₂₈H₃₅Cl₂N₂O₄ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3390 (ν N-H), 2931 (ν C-H aliphatic), 1724 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.30–1.53 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.64 (dd, J = 13.6/6.1 Hz, 2 × 0.5H, 7-H, 9-H), 1.70–1.80 (m, 2H, 10-H, 12-H), 1.90 (dd, J = 14.4/4.8 Hz, 2 × 0.5H, 7-H, 9-H), 2.17–2.32 (m, 7H, CH₃, 7-H, 9-H, 10-H, 12-H), 3.74 (s, 3H, OCH_{3 4-OMephenyl}), 3.85 (s, 3H, OCH_{3 Ar}), 3.94–4.08 (m, 2 × 0.5H, 11-H), 5.23–5.33 (m, 2 × 0.5H, 8-H), 6.56–6.62 (m, 2H, 3-H_Ar, 4-H_Ar), 6.73–6.80 (m, 4H, 2-H_4-OMephenyl, 3-H_4-OMephenyl,, 5-H_4-OMephenyl, 6-H_4-OMephenyl), 7.18 (s, 1H, NH), 7.93 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.2, 21.2, 21.6 (3C, C-3, C-4, CH₃), 32.3, 32.7 (2C, C-2, C-5), 44.7, 44.8, 45.5, 45.9 (4C, C-7, C-9, C-10, C-12), 50.0, 50.6 (2C, C-1, C-6), 52.9, 53.0 (2 × 0.5C, C-11), 55.9, 56.0 (2C, 2 × OCH₃), 76.0, 76.3 (2 × 0.5C, C-8), 110.0 (1C, C-3_Ar), 115.0 (4C, C-2_4-OMephenyl, C-3_4-OMephenyl, C-5_4-OMephenyl, C-6_4-OMephenyl), 118.9 (1C, C-6_Ar), 122.9 (1C, C-4_Ar), 130.7, 130.7 (2C, C-1_Ar, C-5_Ar), 145.6 (1C, C-2_Ar), 146.0 (1C, C-1_4-OMephenyl), 152.3 (1C, C-4_4-OMephenyl), 153.6 (1C, C=O). anti,anti-4m:anti,syn-4m = 1:1. Purity (HPLC): 96.4% (t_R = 20.53 min).

5.3.15. [(8-anti-11-anti and 8-anti-11-syn)-11-(3-Chloro-4-methoxyphenylamino)-[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4n)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), 3-chloro-4-methoxyaniline (53 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 72 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:Et₂O = 7:3 to 1:1, 10 mL, R_f = 0.51, cyclohexane:ethylacetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4n and anti,syn-4n as brown oil, yield 0.13 g (63%). C₂₈H₃₅ClN₂O₄ (499.0). Exact mass (APCI): m/z = 499.2403 (calcd.499.2358 for C₂₈H₃₆ClN₂O₄ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3390 (ν N-H), 2931 (ν C-H aliphatic), 1720 (ν C=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.33–1.50 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.62–1.92 (m, 4H, 7-H, 9-H, 10-H, 12-H), 2.19–2.32 (m, 7H, 7-H, 9-H, 10-H, 12-H, CH₃), 3.82 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 3.90–4.04 (m, 2 × 0.5H, 11-H), 5.23–5.33 (m,2 × 0.5H, 8-H), 6.49–6.58 (m, 1H, 2-H_{4-Cl-5-MeOPhen}), 6.67–6.83 (m, 4H, 5-H_{4-Cl-5-MeOPhen}, 6-H_{4-Cl-5-MeOPhen}, 3-H_Ar, 4-H_Ar), 7.18 (s, 1H, NH_carbamate), 7.93 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.8 (1C, CH₃), 21.1 (2C, C-3, C-4), 32.3, 32.7 (2C, C-2, C-5), 44.5, 44.9 (4C, C-7, C-9, C-10, C-12), 49.8, 50.3 (2C, C-1, C-6), 55.9 (2C, 2 × OCH₃), 56.9 (2 × 0.5C, C-11), 75.7, 76.3 (2 × 0.5C, C-8), 110.0 (1C, C-3_Ar), 113.8 (1C, C-6_{4-Cl-5-MeOPhen}), 114.9 (1C, C-2_{4-Cl-5-MeOPhen}), 118.9 (1C, C-6_Ar), 119.2 (1C, C-5_{4-Cl-5-MeOPhen}), 123.0 (1C, C-4_Ar), 123.6 (1C, C-3_{4-Cl-5-MeOPhen}), 127.5 (1C, C-1_Ar), 130.7 (1C, C-5_Ar), 138.2 (1C, C-1_{4-Cl-5-MeOPhen}), 145.7, 147.7, (2C, C-2_Ar, C-4_{4-Cl-5-MeOPhen}) 153.6 (1C, C=O). anti,anti-4n:anti,syn-4n = 1:1. Purity (HPLC): 95.2% (t_R = 21.27 min).

5.3.16. [(8-anti-11-anti and 8-anti-11-syn)-11-(4-Aminophenylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4o)

NaBH(OAc)₃ (0.47 g, 2.24 mmol) was added to a solution of ketone anti-7 (0.20 g, 0.56 mmol), p-phenylenediamine (97 mg, 0.90 mmol) and acetic acid (32 μL, 0.56 mmol) in 1,2-dichloroethane (10 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 72 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, ethyl acetate:methanol = 9.5:0.5–8:2, 10 mL, R_f = 0.11, cyclohexane:ethylacetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4o and anti,syn-4o as violet oil, yield 0.19 g (76%). C₂₇H₃₅N₂O₃ (449.6). Exact mass (APCI): m/z = 450.2720 (calcd. 450.2751 for C₂₇H₃₆N₃O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3417 (ν N-H₂), 3290 (ν N-H), 2931 (ν C-H aliphatic), 1716 (ν C=O), 1604 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.37–1.51 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.63–92 (m, 4H, 7-H, 9-H, 10-H, 12-H), 2.17–2.28 (m, 4H, 7-H, 9-H, 10-H, 12-H), 2.29 (s, 3H, CH₃), 3.85 (s, 3H, OCH₃), 3.92–4.05 (m, 2 × 0.5H, 11-H), 5.22–5.32 (m, 2 × 0.5H, 8-H), 6.53–6.66 (m, 4H, 2-H_{4-aminophenyl}, 3-H_{4-aminophenyl}, 5-H_{4-aminophenyl}, 6-H_{4-aminophenyl}), 6.74 (dd, J = 8.3/1.4 Hz, 1H, 4-H_Ar), 6.78 (d, J = 8.5 Hz, 1H, 3-H_Ar), 7.14 (s, 0.5H, NH), 7.21 (s, 0.5H, NH), 7.28 (s, 1H, NH_carbamate), 7.93 (s, 1H, 6-H_Ar). A signal for the NH protons is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.1, 21.4 (3C, C-3, C-4, CH₃), 32.0, 32.7 (2C, C-2, C-5), 45.0, 45.4 (4C, C-7, C-9, C-10, C-12), 50.0 (2C, C-1, C-6), 55.9 (2C, C-11, OCH₃), 77.4 (2 × 0.5C, C-8), 110.1(1C, C-3_Ar), 119.0 (1C, C-6_Ar), 123.1 (5C, C-2_{4-aminophenyl}, C-3_{4-aminophenyl}, C-5_{4-aminophenyl}, C-6_{4-aminophenyl}, C-4_Ar), 130.6, 131.3 (3C, C-1_{4-aminophenyl}, C-4_{4-aminophenyl},C-5_Ar), 145.7 (1C, C-2_Ar), 151.8 (1C, C=O). anti,anti-4o:anti,syn-4o = 1:1. Purity (HPLC): 97.8% (t_R = 19.33 min).

5.3.17. [(8-anti-11-anti and 8-anti-11-syn)-11-(Phenethylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4p)

NaBH(OAc)₃ (0.67 g, 3.20 mmol) was added to a solution of ketone anti-7 (0.23 g, 0.64 mmol), 2-phenylethanamine (0.1 g, 0.85 mmol) and acetic acid (38 μL, 0.64 mmol) in 1,2-dichloroethane (10 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 6 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, methanol:ethyl acetate = 9:1, 5 mL, R_f = 0.27, cyclohexane:ethyl acetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4p and anti,syn-4p as pale yellow oil, yield 0.23 g (76%). C₂₉H₃₈N₂O₃ (462.6). Exact mass (APCI): m/z = 463.2952 (calcd.463.2955 for C₂₉H₃₉N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3379 (νN-H), 2931 (ν C-H aliphatic), 1732 (νC=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.27–1.45 (m, 6H, 2-CH₂(1H), 3-CH₂, 4-CH₂, 5-CH₂(1H)), 1.51 (m, 2 × 0.5H, 2-H, 5-H), 1.60 (m, 2 × 0.5H, 2-H, 5-H), 1.67 (dd, J = 14.4/5.1 Hz, 2 × 0.5H, 7-H, 9-H), 1.98–2.08 (m, 4H, 10-CH₂, 12-CH₂), 2.13–2.24 (m, 3H, 7-CH₂(1.5H), 9-CH₂(1.5H)), 2.29 (s, 3H, CH₃), 3.00–3.21 (m, 4H, NCH₂CH₂Ph), 3.50–3.60 (m, 0.5H, 11-H), 3.64 (q, J = 9.6/9.0 Hz, 0.5H, 11-H), 3.81 (s, 3 × 0.5H, OCH₃), 3.83 (s, 3 × 0.5H, OCH₃), 5.20 (tt, J = 7.7/5.1 Hz, 0.5H, 8-H), 5.28 (tt, J = 8.4/4.1 Hz, 0.5H, 8-H), 6.73 (dd, J = 8.2/2.1 Hz, 1H, 3-H_Ar), 6.77 (dd, J = 8.2/2.1 Hz, 1H, 4-H_Ar), 7.13 (s, 1H, NH), 7.19–7.42 (m, 5H, Ph), 7.91 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.6 (1C, CH₃), 21.0, 21.1 (2C, C-3, C-4), 32.5, 32.9 (2C, C-2, C5), 34.4 (1C, NCH₂CH₂Ph), 44.6 (2C, C-10, C-12), 45.2 (2C, C-7, C-9), 49.5 (1C, NCH₂CH₂Ph), 50.0 (2C, C-1, C-6), 55.8, 55.9 (1C, OCH₃), 56.6, 57.9 (2 × 0.5 C, C-11), 76.2 (1C, C-8), 109.9 (1C, C-3_Ar), 119.3 (1C, C-6_Ar), 122.9 (1C, C-4_Ar), 126.8 (1C, C-4_Ph), 127.3 (2C, C-3_Ph, C-5_Ph), 127.6 (2C, C-2_Ph, C-6_Ph), 128.9 (1C, C-1_Ar), 130.6 (1C, C-5_Ar), 137.9 (1C, C-1_Ph), 145.6, 145.9 (1C, C-2_Ar), 153.4, 153.7 (1C, C=O). anti,anti-4p:anti,syn-4p = 1:1. Purity (HPLC): 96.8% (t_R = 21.20 min).

5.3.18. [(8-anti-11-anti and 8-anti-11-syn)-11-(3-Phenylpropylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4q)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.13 g, 0.36 mmol), 3-phenypropan-1-amine (64 mg, 0.47 mmol) and acetic acid (30 μL, 0.36 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 72 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:Et₂O = 8:2–1:1, 10 mL, R_f = 0.56, cyclohexane:ethylacetate = 7:3) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4q and anti,syn-4q as pale yellow oil, yield 0.12 g (63%). C₃₀H₄₀N₂O₃ (476.7). Exact mass (APCI): m/z = 477.3134 (calcd. 477.3112 for C₃₀H₄₁N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3267 (νN-H), 2931 (ν C-H aliphatic), 1720 (νC=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.13–1.65 (m, 9H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(0.5H), 9-CH₂(0.5H)), 1.92–2.28 (m, 12H, 7-CH₂(1.5H), 9-CH₂(1.5H), 10-CH₂, 12-CH₂, CH₃, NCH₂CH₂CH₂Ph), 2.58–2.66 (m, 2H, NCH₂CH₂CH₂Ph), 2.81–2.88 (m, 2H, NCH₂CH₂CH₂Ph), 3.52–3.68 (m, 2 × 0.5H, 11-H), 3.79 (s, 3 × 0.5H, OCH₃), 3.84 (s, 3 × 0.5 H, OCH₃), 5.20 (m, 2 × 0.5H, 8-H), 6.70–6.80 (m, 2H, 3-H_Ar, 4-H_Ar), 7.13–7.18 (m, 4H, 2-H_Ph, 3-H_Ph, 5-H_Ph, 6-H_Ph), 7.22–7.26 (m, 1H, 4-H_Ph), 7.35 (s, 1H, NH_carbamate), 7.62 (s, 1H. NH), 7.92 (d, J = 2.0 Hz, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.4 (1C, CH₃), 20.8, 21.1 (2C, C-3, C-4), 29.4 (NCH₂CH₂CH₂Ph), 32.4 (NCH₂CH₂CH₂Ph), 32.7, 33.1 (2C, C-2, C-5), 40.9, 41.6, 44.3, 45.1 (4C, C-7, C-9, C-10, C-12), 47.1 (NCH₂CH₂CH₂Ph), 49.3, 49.7 (2C, C-1, C-6), 55.9, 56.0 (2 × 0.5C, C-11), 56.7, 58.0 (2 × 0.5C, OCH₃), 76.0 (1C, C-8), 110.2 (1C, C-3_Ar), 119.5 (1C, C-6_Ar), 123.0 (1C, C-4_Ar), 126.5 (1C, C-4), 128.5 (4C, C-2_Ph, C-3_Ph, C-5_Ph, C-6_Ph), 128.7(1C, C-1_Ar), 130.7 (1C, C-5_Ar), 140.0 (1C, C-1_Ph), 146.1 (1C, C-2_Ar), 153.7 (1C; C=O). anti,anti-4q:anti,syn-4q = 1:1. Purity (HPLC): 97.9% (t_R = 21.61 min).

5.3.19. [(8-anti-11-anti and 8-anti-11-syn)-11-[(3-Aminopropyl)amino][4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4r)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), propane-1,3-diamine (62 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 96 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1–1:1, 10 mL, R_f = 0.18) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4r and anti,syn-4r as colorless solid, mp 74–76 °C, yield 80 mg (66%). C₂₄H₃₇N₃O₃ (415.6). Exact mass (APCI): m/z = 417.2856 (calcd. 417.2991 for C₂₄H₃₉N₃O₃ [M+2H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3429 (ν N-H), 2927 (ν C-H aliphatic), 1720 (ν C=O), 1597 (δ N-H). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.26–1.51 (m, 10H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, NCH₂CH₂CH₂NH₂), 1.63–2.25 (m, 10H, 7-CH2, 9-CH₂, 10-CH₂, 12-CH₂, NCH₂CH₂CH₂NH₂), 2.24 (s, 3 × 0.5H, CH₃), 2.28 (s, 3 × 0.5H, CH₃), 2.82–2.88 (m, 2H, NCH₂CH₂CH₂NH₂), 3.39–3.53 (m, 2 × 0.5H, 11-H), 3.79 (s, 3 × 0.5H, OCH₃), 3.86 (s, 3 × 0.5H, OCH₃), 5.17–5.30 (m, 2 × 0.5H, 8-H), 6.69–6.78 (m, 2H, 3-H_Ar, 4-H_Ar), 7.14 (s, 1H, NH), 7.89 (s, 1H, 6-H_Ar). Signals for the NH protons are not seen in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.7 (1C, CH₃), 21.1, 21.4 (2C, C-3, C-4), 32.0, 32.3, 32.3, 32.8 (3C, C-2, C-5, NCH₂CH₂CH₂NH₂), 44.5, 44.9 (4C, C-7, C-9, C-10, C-12), 47.6 (1C, NCH₂CH₂CH₂NH₂), 49.6 (1C, NCH₂CH₂CH₂NH₂), 50.2 (2C, C-1, C-6), 55.9 (1C, OCH₃), 58.3 (0.5C, C-11), 59.1 (0.5C, C-11), 75.6 (0.5C, C-8), 76.0 (0.5C, C-8), 110.1 (1C, C-3_Ar), 119.3 (1C, C-6_Ar), 123.0 (C-4_Ar), 127.6 (1C, C-1_Ar), 130.6 (1C, C-5_Ar), 145.9 (1C, C-2_Ar), 153.6 (1C, C=O). anti,anti-4r:anti,syn-4r = 1:1. Purity (HPLC): 92.3% (t_R = 20.97 min).

5.3.20. [(8-anti-11-anti and 8-anti-11-syn)-11-(2-Hydroxyethyl-1-amino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4s)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), 2-aminoethanol (20 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 7 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, ethyl acetate:methanol = 8:2–1:1, 10 mL, R_f = 0.11, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4s and anti,syn-4s as yellow oil, yield 35 mg (33%). C₂₃H₃₄N₂O₄ (402.5). Exact mass (APCI): m/z = 403.2626 (calcd. 403.2591 for C₂₃H₃₅N₂O₄ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3429 (ν N-H), 2927 (ν C-H aliphatic), 1724 (νC=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.28–1.53 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.59–1.77 (m, 2H, 7-H, 9-H), 1.87–2.27 (m, 6H, 7-CH₂(1H), 9-CH₂(1H), 10-CH₂, 12-CH₂), 2.28 (m, 3H, CH₃), 2.76–2.84 (m, 2H, NCH₂CH₂OH), 3.37–3.53 (m, 2 × 0.5H, 11-H), 3.66–3.71 (m, 2H, NCH₂CH₂OH), 3.84 (s, 3H, OCH₃), 5.18–5.31 (m, 2 × 0.5H, 8-H), 6.73 (dd, J = 8.3/2.1 Hz, 1H, 4-H_Ar), 6.77 (d, J = 8.3 Hz, 1H, 3-H_Ar), 7.14 (s, 1H, NH), 7.92 (s, 1H, 6-H_Ar). Signals for the OH and NH protons are not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.9 (1C, CH₃), 21.1, 21.4 (2C, C-3, C-4), 32.4, 32.9 (2C, C-2, C-5), 44.5, 44.8, 45.0 (4C, C-7, C-9, C-10, C-12), 49.6 (2C, C-1, C-6), 50.2, 50.4 (2 × 0.5C, NCH₂CH₂OH), 55.9 (1C, OCH₃), 56.5 (0.5C, C-11), 57.7 (0.5C, C-11), 60.8 (1C, NCH₂CH₂OH), 75.9 (0.5C, C-8), 76.4 (0.5C, C-8), 109.9(1C, C-3_Ar), 118.9 (1C, C-6_Ar), 122.9 (1C, C-4_Ar), 127.5 (1C, C-1_Ar), 130.6 (1C, C-5_Ar), 145.6 (1C, C-2_Ar), 153.4 (1C, C=O). anti,anti-4s:anti,syn-4s = 1:1. Purity (HPLC): 92.5% (t_R = 17.37 min).

5.3.21. [(8-anti-11-anti and 8-anti-11-syn)-11-(5-Hydroxypentylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4t)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), 5-aminopentan-1-ol (35 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 11 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, ethyl acetate:methanol = 8:2–1:1, 20 mL, R_f = 0.23, ethyl acetate:methanol = 1:1) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4t and anti,syn-4t as yellow oil, yield 25 mg (21%). C₂₆H₄₀N₂O₄ (444.6). Exact mass (APCI): m/z = 445.3066 (calcd. 445.3061 for C₂₆H₄₀N₂O₄ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3425 (ν N-H), 3330 (νO-H), 2931 (ν C-H aliphatic), 1724 (νC=O), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.25–1.48 (m, 10H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, NCH₂CH₂CH₂CH₂CH₂O), 1.51–1.71 (m, 6H, 7-H, 9-H, 10-H, 12-H, NCH₂CH₂CH₂CH₂CH₂O), 1.95–2.25 (m, 6H, 7-H, 9-H, 10-H, 12-H, NCH₂CH₂CH₂CH₂CH₂O), 2.27 (s, 3 × 0.5H, CH₃), 2.29 (s, 3 × 0.5H, CH₃), 2.93 (m, 2H, NCH₂CH₂CH₂CH₂CH₂O), 3.65–3.80 (m, 3H, 11-H, CH₂O), 3.81 (s, 3 × 0.5H, OCH₃), 3.84 (m, 3 × 0.5H, OCH₃), 5.17–5.31 (m, 2 × 0.5H, 8-H), 6.70–6.80 (m, 2H, 3-H_Ar, 4-H_Ar), 7.16 (s, 1H, NH), 7.88 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. Signals for the OH and NH protons are not seen in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ(ppm) = 20.6 (2C, C-3, C-4), 21.1 (1C, CH₃), 23.3 (1C, NCH₂CH₂CH₂CH₂CH₂O), 25.8 (1C, NCH₂CH₂CH₂CH₂CH₂O), 31.3 (1C, NCH₂CH₂CH₂CH₂CH₂O), 32.7 (2C, C-2, C-5), 41.0 (2C, C-10, C-12), 45.1 (2C, C-7, C-9), 47.2 (1C, NCH₂CH₂CH₂CH₂CH₂O), 49.6 (2C, C-1, C-6), 55.9 (1C, OCH₃), 56.8 (0.5C, C-11), 58.2 (0.5C, C-11), 61.9 (1C, NCH₂CH₂CH₂CH₂CH₂O), 75.5 (0.5C, C-8), 76.2 (0.5C, C-8), 110.2 (1C, C-3_Ar), 119.5 (1C, C-6_Ar), 123.1 (1C, C-4_Ar), 127.5 (1C, C-1_Ar), 130.6 (1C, C-5_Ar), 146.0 (1C, C-2_Ar), 153.5 (1C, C=O). anti,anti-4t:anti,syn-4t = 1:1. Purity (HPLC): 94.4% (t_R = 22.40 min).

5.3.22. [(8-anti-11-anti and 8-anti-11-syn)-11-(Isobutylamino)[4.3.3]propellan-8-yl] N-(2-methoxy-5-methylphenyl)carbamate (8-anti-4u)

NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of ketone anti-7 (0.10 g, 0.28 mmol), isobutylamine (25 mg, 0.34 mmol) and acetic acid (16 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 6 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 20 mL, R_f = 0.23, ethyl acetate:methanol = 1:1) to obtain a mixture of diastereoisomeric aminocarbamates anti,anti-4u and anti,syn-4u as yellow oil, yield 0.11 g (92%). C₂₅H₃₈N₂O₃ (414.6). Exact mass (APCI): m/z = 415.2969 (calcd. 415.2955 for C₂₅H₃₉N₂O₃ [M+H]⁺). FT-IR (ATR, film): (ν (cm⁻¹) = 3429 ν N-H), 2927 (νC-H aliphatic), 1724 (ν C=O), 1597 (δN-H). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.00 (d, J = 6.6 Hz, 3H, NCH₂CH(CH₃)₂), 1.01 (d, J = 6.6 Hz, 3H, NCH₂CH(CH₃)₂), 1.30–1.43 (m, 6H, 2-CH₂(1H), 3-CH₂, 4-CH₂, 5-CH₂(1H)), 1.49–1.62 (m, 2H, 2-H, 5-H), 1.70–1.76 (m, 1H, NCH₂CH(CH₃)₂), 1.95–2.23 (m, 8H 7-CH₂, 9-CH₂, 10-CH₂, 12-CH₂), 2.28 (s, 3 × 0.5H, CH₃), 2.29 (s, 3 × 0.5H, CH₃), 2.55 (d, J = 6.9 Hz, 1H, NCH₂CH(CH₃)₂), 2.58 (d, J = 6.9 Hz, 1H, NCH₂CH(CH₃)₂), 3.48–3.54 (m, 0.5H, 11-H), 3.55–3.62 (m, 0.5H, 11-H), 3.82 (s, 1.5H, OCH₃), 3.84 (s, 1.5H, OCH₃), 5.21 (tt, J = 8.0/5.5 Hz, 0.5H, 8-H), 5.26 (tt, J = 8.4/4.2 Hz, 0.5H, 8-H), 6.71–6.79 (m, 2H, 3-H_Ar, 4-H_Ar), 7.14 (s, 1H, NH), 7.91 (s, 1H, 6-H_Ar). A signal for the NH proton is not seen in the spectrum. Signals for the OH and NH protons are not seen in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 21.0, 21.1, 21.1, 21.2 (5C, C-3, C-4, CH₃, NCH₂CH(CH₃)₂), 32.6, 33.0 (2C, C-2, C-5), 44.7, 45.3 (5C, C-7, C-9, C-10, C-12, NCH₂CH(CH₃)₂), 49.3, 50.0 (2C, C-1, C-6), 55.9 (2C, OCH₃, NCH₂CH(CH₃)₂), 56.8 (0.5C, C-11), 58.2 (0.5C, C-11), 75.7 (0.5C, C-8), 76.3 (0.5C, C-8), 110.1, 119.1, 122.9, 127.6, 130.7, 145.8, 153.6. anti,anti-4u:anti,syn-4u = 1:1. Purity (HPLC): 95.8% (t_R = 20.07 min).

5.3.23. [(8-anti-11-anti and 8-anti-11-syn)-11-(Benzylamino)[4.3.3]propellan-8-ol (11-anti-13)

NaBH(OAc)₃ (0.33 g, 1.55 mmol) was added to a solution of hydroxyketone anti-11 (0.10 g, 0.52 mmol), benzylamine (72 mg, 0.68 mmol) and acetic acid (30 μL, 0.52 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 8 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 10 mL, R_f = 0.28) to obtain a mixture of diastereoisomeric aminoalcohols anti,anti-13 and anti,syn-13 as colorless solid, mp 121–123 °C, yield 86 mg (61%). C₁₉H₂₇NO (285.4). MS (ESI): m/z = 286 [M+H]⁺. Exact mass (APCI): m/z = 286.2145 (calcd.286.2165 for C₁₉H₂₈NO [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3313 (δ O-H), 2931 (ν C-H aliphatic). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.24–1.40 (m, 6H, 2-CH₂(1H), 3-CH₂, 4-CH₂, 5-CH₂(1H)), 1.40–1.45 (m, 2H, 7-H, 9-H, 10-H, 12-H), 1.50–1.62 (m, 2H, 2-CH₂(1H), 5-CH₂(1H)), 1.96 (dd, J = 13.8/7.1 Hz, 2 × 0.3H, 10-H, 12-H), 2.03–2.16 (m, 4H, 7-H, 9-H, 10-H, 12-H), 2.30–2.36 (m, 2 × 0.3H, 7-H, 9-H), 3.45–3.51 (m, 0.3H, 11-H), 3.60–3.66 (m, 0.7H, 11-H), 3.93 (s, 2 × 0.3H, NCH₂Ph), 3.95 (s, 2 × 0.7H, NCH₂Ph), 4.32 (tt, J = 7.1/5.3 Hz, 0.7H, 8-H), 4.40 (tt, J = 8.0/4.2 Hz, 0.3H, 8-H), 7.31–7.40 (m, 3H, 3-H_Ph, 4-H_Ph, 5-H_Ph), 7.59 (dd, J = 6.7/1.3 Hz, 2H, 2-H_Ph, 6-H_Ph). Signals for the NH and OH protons are not observed in the spectrum ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 19.5 (2C, C-3, C-4), 32.8 (2C, C-2, C-5), 41.1 (2C, C-10, C-12), 48.9 (2C, C-7, C-9), 49.9 (2C, C-1, C-6), 50.6 (1C, NCH₂Ph), 54.4 (0.7C, C-11), 56.0 (0.3C, C-11), 71.6 (0.7C, C-8), 72.6 (0.3C, C-8), 129.0 (1C, C-4_Ph), 129.3 (2C, C-3_Ph, C-5_Ph), 130.5(2C, C-2_Ph, C-6_Ph). anti,anti-13:anti,syn-13 = 7:3. Purity (HPLC): 93.3% (t_R = 13.61, 15.15 min).

5.3.24. [(8-syn-11-syn and 8-syn-11-anti)-11-(Benzylamino)[4.3.3]propellan-8-ol (11-syn-13)

NaBH(OAc)₃ (0.33 g, 1.55 mmol) was added to a solution of hydroxyketone syn-11 (0.10 g, 0.52 mmol), benzylamine (72 mg, 0.68 mmol) and acetic acid (30 μL, 0.52 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 8 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 5.5:3.5:1, 10 mL, R_f = 0.28) to obtain a mixture of diastereoisomeric aminoalcohols syn,syn-13 and syn,anti-13 as colorless oil, yield 90 mg (64%). C₁₉H₂₇NO (285.4). MS (ESI): m/z = 286 [M+H]⁺. Exact mass (APCI): m/z = 286.2215 (calcd.286.2165 for C₁₉H₂₈NO [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3290 (ν O-H), 2927 (ν C-H aliphatic). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.2–61.39 (m, 2H, 3-CH₂(1H), 4-CH₂(1H)), 1.44–1.61 (m, 6H, 2-CH₂, 3-CH₂(1H), 4-CH₂(1H), 5-CH₂), 1.62–1.88 (m, 6H, 7-CH₂(1H), 9-CH₂(1H), 10-CH₂, 12-CH₂), 1.93 (dd, J = 13.3/8.3 Hz, 2 × 0.5H, 7-H, 9-H), 2.15 (dd, J = 13.8/7.5 Hz, 2 × 0.5H, 7-H, 9-H), 3.28 (q, J = 8.2 Hz, 0.5H, 11-H), 3.35 (q, J = 8.4 Hz, 0.5H, 11-H), 3.82 (s, 2H, NCH₂Ph), 4.33 (tt, J = 7.5/5.5 Hz, 0.5H, 8-H), 4.54 (tt, J = 7.5/5.4 Hz, 0.5H, 8-H), 7.27–7.32 (m, 1H, 4-H_Ph), 7.32–7.36 (m, 2H, 3-H_Ph, 5-H_Ph), 7.39–7.43 (m, 2H, 2-H_Ph, 6-H_Ph). Signals for the NH and OH protons are not observed in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.2, 20.6 (2C, C-3, C-4), 32.1, 33.4 (2C, C-2, C-5), 43.6, 47.9 (4C, C-7, C9, C-10, C-12), 49.3 (2C, C-1, C-6), 51.0 (1C, NCH₂Ph), 55.3 (0.5C, C-11), 55.6 (0.5C, C-11), 71.3 (0.5C, C-8), 72.1 (0.5C, C-8), 128.3 (1C, C-4_Ph), 128.7, 128.8 (2C, C-3_Ph, C-5_Ph), 129.3, 129.5 (2C, C-2_Ph, C-6_Ph), 134.4 (1C, C-1_Ph). syn,syn-13:syn,anti-13 = 1:1. Purity (HPLC): 93.1% (t_R = 12.42, 13.90 min).

5.3.25. (11′-anti)-Spiro-([1,3]dioxolane-2,8′-(N-benzyl[4.3.3]propellan))-11′-amine (anti-14) and (11′-syn)-spiro-([1,3-dioxolane-2,8′-(N-benzyl[4.3.3]propellan))-11′-amine (syn-14)

Under N₂, NaBH(OAc)₃ (1.35 g, 6.37 mmol) was added to a solution of monoketal 12 (0.5 g, 2.12 mmol), benzylamine (0.45 g, 4.24 mmol) and acetic acid (0.12 mL, 2.12 mmol) in 1,2-dichloroethane (15 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 24 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, cyclohexane:Et₂O: NEt₃ = 5.5:3.5:1, 20 mL).

syn-14 (R_f = 0.43) Pale yellow oil, yield 0.19 g (28%). C₂₁H₂₉NO₂ (327.5). MS (ESI): m/z = 328 [M+H]⁺. Exact mass (APCI): m/z = 328.2295 (328.2271 calcd. for C₂₁H₃₀NO₂ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 2927 (ν C-H aliphatic). ¹H NMR (400 MHz, Toluene-d₈): δ (ppm) = 1.60–1.65 (m, 4H, 3′-CH₂, 4′-CH₂,), 1.67–1.83 (m, 6H, 2′-CH₂, 5′-CH₂, 10′-CH₂(1H), 12′-CH₂(1H)), 2.11 (d, J = 14.0 Hz, 2H, 7′-H, 9′-H), 2.16–2.24 (m, 4H; 7′-H, 9′-H, 10′-H, 12′-H), 3.49 (tt, J = 8.5/5.6 Hz, 1H, 8′-H), 3.67–3.69 (m, 4H, OCH₂CH₂O), 3.76 (s, 2H, NCH₂Ph), 7.23 (m, 1H, 4-H_Ph), 7.38 (dd, 2H, J = 8.7/6.4 Hz, 2H, 3-H_Ph, 5-H_Ph), 7.49 (m, 2H, 2-H_Ph, 6-H_Ph). A signal for the NH proton is not observed in the spectrum. ¹³C NMR (100 MHz, Toluene-d₈): δ (ppm) = 21.9 (2C, C-3′, C-4′), 32.4 (2C, C-2′, C-5′), 44.9 (2C, C-10′, C-12′), 49.2 (2C, C-7′, C-9′), 49.6 (2C, C-1′, C-6′), 53.4 (1C, NCH₂Ph), 56.7 (C-11′), 63.9 (1C, C-8′), 64.0 (2C, OCH₂CH₂O), 105,1 (1C, C-4_Ph), 126.9 (2C, C-3_Ph, C-5_Ph), 128.4 (2C, C-2_Ph, C-6_Ph), 141.1 (1C, C-1_Ph). Purity (HPLC): 83.8% (t_R = 15.67 min).

anti-14 (R_f = 0.38) Pale yellow oil, yield 0.21 g (30%). C₂₁H₂₉NO₂ (327.5). MS (ESI): m/z = 328 [M+H]⁺. Exact mass (APCI): m/z = 328.2270 (328.2271 calcd. for C₂₁H₃₀NO₂ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 2927 (ν C-H aliphatic). ¹H NMR (400 MHz, Toluene-d₈): ν (ppm) = 1.39–1.52 (m, 4H, 3′-CH₂, 4′-CH₂,), 1.55–1.61 (m, 2H, 2′-H, 5′-H), 1.67–1.73 (m, 2H, 2′-H, 5′-H), 1.87 (dd, J = 13.2/6.3 Hz. 2H, 10′-H_anti, 12′-H_anti), 2.05 (dd, J = 13.2/8.5 Hz, 2H, 10′-H_syn, 12′-H_syn), 2.26 (d, J = 14.1 Hz, 2H, 7′-H, 9′-H), 2.40 (d, J = 14.1 Hz, 2H, 7′-H, 9′-H), 3.44 (tt, J = 8.3/6.3 Hz, 1H, 11′-H), 3.70 (s, 4H, OCH₂CH₂O), 3.78 (s, 2H, NCH₂Ph), 7.26 (m, 1H, 4-H_Ph), 7–38 (m, 2H, 3-H_Ph, 5-H_Ph), 7.49 (d, 2H, J = 7.6 Hz, 2-H_Ph, 6-H_Ph). A signal for the NH proton is not observed in the spectrum. ¹³C NMR (100 MHz, Toluene-d₈): δ (ppm) = 21.9 (2C, C-3′, C-4′), 31.9 (2C, C-2′, C-5′), 45.1 (2C, C-10′, C-12′), 49.4 (2C, C-7′, C-9′), 49.8 (2C, C-1′, C-6′), 53.3 (1C, NCH₂Ph), 56.9 (1C, C-11′), 63.9 (1C, C-8′), 64.0 (2C, OCH₂CH₂O), 117.5 (1C, C-4_Ph), 126.9 (2C, C-3_Ph, C-5_Ph), 128.4 (2C, C-2_Ph, C-6_Ph), 141.6 (1C, C-1_Ph). Purity (HPLC): 98.2% (t_R = 16.24 min).

5.3.26. syn- and anti-N-[2-(Indol-3-yl)ethyl]-[4.3.3]propellan-8-amine (15)

Under N₂, NaBH(OAc)₃ (0.3 g, 1.42 mmol) was added to a solution of monoketone 10 (0.1 g, 0.56 mmol), tryptamine (0.14 g, 8.41 mmol) and acetic acid (0.32 μL, 0.56 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 5 days. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 8:1:1 5 mL, R_f = 0.35) to obtain a mixture of diastereoisomeric amines syn-15 and anti-15 as a brown solid, mp 109–111 °C, yield 60 mg (33%). C₂₂H₃₀N₂ (322.5). MS (ESI): m/z = 323 [M+H]⁺. Exact mass (APCI): m/z = 323.2506 (calcd. 323.2482 for C₂₂H₃₁N₂ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3429 (νN-H), 2927 (ν C-H aliphatic). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.40–1.90 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.54–1.64 (m, 5H, 10-CH₂, 11-CH₂(1H), 12-CH₂), 1.68–1.71 (m, 3H, 7-CH₂(1H), 9-CH₂(1H), 11-CH₂(1H)), 1.83–1.86 (m, 2 × 0.5H, 7-H, 9-H), 1.89–1.93 (2 × 0.5H, 7-H, 9-H), 2.77 (s, broad, 1H, NH), 3.06–3.10 (m, 2H, NCH₂CH₂), 3.16–3.19 (m, 2H, NCH₂CH₂), 3.45 (m, 2 × 0.5H, 8-H), 7.06–7.10 (m, 2H, 5-H_indole, 6-H_indole), 7.15 (s, 1H, 2-H_indole), 7.35 (d, J = 8.1 Hz, 1H, 7-H_indole), 7.56 (d, J = 7.2 Hz, 1H, 4-H_indole), 8.95 (s, broad, 1H, NH_indole). ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.5, 20.9 (2C, C-3, C-4), 21.4, 22.3 (2 × 0.5 C, C-11), 23.2 (1C, NCH₂CH₂), 31.9, 32.6 (2C, C-2, C-5), 37.6, 39.1 (2C, C-10, C-12), 41.9, 42.2 (2C, C-7, C-9), 47.5 (1C, NCH₂CH₂), 49.9, 50.5 (2C, C-1, C-6), 56.5, 57.5 (2 × 0.5C, C-8), 111.4 (1C, C-3_indole), 111.5 (1C, C-7_indole), 118.7 (1C, C-4_indole), 119.7 (1C, C-5_indole), 122.3 (1C, C-2_indole), 122.9 (1C, C-6_indole), 127.1 (1C, C-3a_indole), 136.56 (1C, C-7a_indole). syn-15:anti-15 = 1:1. Purity (HPLC): 96.8% (t_R = 19.28 min).

5.3.27. syn- and anti-N-(4-(Dimethylaminobenzyl)-[4.3.3]propellan-8-amine (17)

Under N₂, NaBH(OAc)₃ (89 mg, 0.42 mmol) was added to a solution of propellanamine syn-16/anti-16 (50 mg, 0.28 mmol) and 4-(dimethylamino)benzaldehyde (44 mg, 0.29 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 72 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 8:1:1 20 mL, R_f = 0.32) to obtain a mixture of diastereoisomeric amines syn-17 and anti-17 as a yellow solid, mp 89–91 °C, yield 86 mg (98%). C₂₁H₃₂N₂ (312.5). MS (ESI): m/z = 313 [M+H]⁺. Exact mass (APCI): m/z = 313.2673 (calcd. 313.2638 for C₂₁H₃₃N₂ [M+H]⁺). ¹H NMR (600 MHz, CDCl₃): δ(ppm) = 1.27–1.50 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.54–1.78 (m, 7H, 7-CH₂(1H), 9-CH₂(1H), 10-CH₂, 11-CH₂(1H), 12-CH₂), 1.79–1.81 (m, 1H, 11-CH₂(1H), 1.86 (dd, J = 13.1/8.0 Hz, 2 × 0.5H, 7-H, 9-H), 1.92 (dd, J = 13.1/8.2, 2 × 0.5H, 7-H, 9-H), 2.04 (s, 1H, NH), 2.91 (s, 6H, N(CH₃)₂), 3.31–3.38 (m, 2 × 0.5H, 8-H), 3.70 (s, 2H, NCH₂Ar), 6.69 (d, J = 8.6 Hz, 2H, 3-H_Ar, 5-H_Ar), 7.25 (d, J = 8.6 Hz, 2H, 2-H_Ar, 6-H_Ar). ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.7, 20.9 (2C, C-3, C-4), 21.2 (1C, C-11), 31.9, 32.6 (2C, C-2, C-5), 37.6, 38.9 (2C, C-10, C-12), 40.6 (2C, N(CH₃)₂), 43.6, 44.1 (2C, C-7, C-9), 49.9, 50.4 (2C, C-1, C-6), 51.1 (1C, NCH₂Ar), 55.0, 55.9 (2 × 0.5C, C-8), 112.5 (2C, C-3_Ar, C-5_Ar), 129.9 (3C, C-1_Ar, C-2_Ar, C-6_Ar), 150.1 (1C, C-4_Ar). syn-17:anti-17 = 1:1. Purity (HPLC): 96.1% (t_R = 15.12 min).

5.3.28. syn- and anti-N-Cyclohexylmethyl[4.3.3]propellan-8-amine (18)

Under N₂, NaBH(OAc)₃ (71 mg, 0.34 mmol) was added to a solution of propellanamine syn-16/anti-16 (30 mg, 0.17 mmol) and cyclohexanecarbaldehyde (15 μL, 0.19 mmol) in 1,2-dichloroethane (5 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 12 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate:methanol = 8:1:1 20 mL, R_f = 0.53) to obtain a mixture of diastereoisomeric amines syn-18 and anti-18 as a colorless solid, mp 108–111 °C, yield 42 mg (91%). C₁₉H₃₃N (275.5). MS (ESI): m/z = 276 [M+H]⁺. Exact mass (APCI): m/z = 276.2710 (calcd. 276.2686 for C₁₉H₃₄N [M+H]⁺). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 0.89–0.98 (m, 2H, 2-CH_2Cy(1H), 6-CH_2Cy(1H), 1.16 (ttd, J = 12.5/3.3/1.2 Hz, 1H, 4-CH_2Cy(1H)), 1.21–1.42 (m, 8H, 2-CH₂(1H), 3-CH₂, 4-CH₂, 5-CH₂(1H), 3-CH_2Cy(1H), 5-CH_2Cy(1H)), 1.45–1.87 (m, 16H, 2-CH₂(1H), 5-CH₂(1H), 7-CH₂(1H), 9-CH₂(1H), 10-CH₂, 11-CH₂, 12-CH₂, 1-H_Cy, 2-CH_2Cy(1H), 3-CH_2Cy(1H), 4-CH_2Cy(1H), 5-CH_2Cy(1H), 6-CH_2Cy(1H)), 1.89 (dd, J = 13.1/8.0 Hz, 2 × 0.5H, 7-H, 9-H), 1.96 (dd, J = 13.1/8.3 Hz, 2 × 0.5H, 7-H, 9-H), 2.57 (dd, J = 6.8/1.5 Hz, 2H, NCH₂Cy), 3.37–3.45 (m, 2 × 0.5 H, 8-H). A signal for the NH proton is not seen in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.5, 20.9 (2C, C-3, C-4), 21.5, 22.5 (2 × 0.5C, C-11), 25.8 (2C, C-3_Cy, C-5_Cy), 26.4 (1C, C-4_Cy), 31.5 (2C, C-2_Cy, C-6_Cy), 32.1, 32.8 (2C, C-2, C-5), 36.0, 36.1 (2 × 0.5C, C-1_Cy), 37.8, 39.5 (2C, C-10, C-12), 42.9, 43.4 (2C, C-7, C-9), 49.8, 50.4 (2C, C-1, C-6), 54.2 (1C, NCH₂Cy), 56.9, 57.8 (2 × 0.5C, C-8). ). syn-18:anti-18 = 1:1. Purity (LC-MS): 97.4% (t_R = 6.957 min).

5.3.29. 11-syn-11-Benzylamino[4.3.3]propellan-11-one (syn-20) and 11-anti-11-Benzylamino[4.3.3]propellan-8-one (anti-20)

Under N₂, NaBH(OAc)₃ (4.40 g, 20.8 mmol) was added to a solution of diketone 19 (2.0 g, 10.4 mmol), benzylamine (1.34 g, 12.5 mmol) and acetic acid (0.60 mL, 10.40 mmol) in 1,2-dichloroethane (30 mL, dried over molecular sieves 4 Å). The mixture was stirred at rt for 96 h. Then NaOH (1 M) was added (pH 8–10), the mixture was extracted with CH₂Cl₂ (3×) and the combined organic layers were washed with brine (1×), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (5 cm, cyclohexane:ethyl acetate: NEt₃ = 6.95:2.95:0.1 to 2.95:6.95:0.1, 20 mL).

syn-20 (R_f = 0.29, cyclohexane: ethyl acetate: NEt₃ = 69.5:29.5:1) Pale yellow solid, mp 77–79 °C, yield 0.46 g (16%). C₁₉H₂₅NO (283.4). Exact mass (APCI): m/z = 284.1973 (calcd. 284.2009 for C₁₉H₂₆NO [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 2927 (ν C-H aliphatic), 1724 (ν C=O). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.31–1.39 (m, 4H, 3-CH₂, 4-CH₂), 1.44–1.50 (m, 2H, 2-CH₂(1H), 5-CH₂(1H)), 1.61–1.66 (m, 2H, 2-CH₂(1H), 5-CH₂(1H)), 1.71 (dd, J = 13.7/5.6 Hz, 2H, 10-H_syn, 12-H_syn), 1.89 (dd, J = 13.7/8.6 Hz, 2H, 10-H_anti, 12-H_anti), 2.06 (d, J = 19.1 Hz, 2H, 7-H_anti, 9-H_anti), 2.18 (d, J = 19.1 Hz, 2H, 7-H_syn, 9-H_syn), 3.37 (tt, J = 8.6/5.6 Hz, 1H, 11-H), 3.67 (s, 2H, NCH₂Ph), 7.16–7.20 (m, 1H, 4-H_Ph), 7.23–7.28 (m, 4H, 2-H_Ph, 3-H_Ph, 5-H_Ph, 6-H_Ph). A signal for the NH proton is not observed in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) =21.9 (2C, C-3, C-4), 32.7 (2C, C-2, C-5), 44.5 (2C, C-10, C-12), 47.8 (2C, C-1, C-6), 50.0 (2C, C-7, C-9), 53.1 (1C, NCH₂Ph), 56.1 (1C, C-11), 127.2 (1C, C-4_Ph), 128.4 (2C, C-3_Ph, C-5_Ph), 128.7 (2C, C-2_Ph, C-6_Ph), 140.5 (1C, C-1_Ph), 219.7 (1C, C=O). Purity (HPLC): 74.7% (t_R = 13.83 min).

anti-20 (R_f = 0.19, cyclohexane:ethyl acetate: NEt₃ = 6.95:2.95:0.1) Pale yellow oil, yield 0.24 g (9%). C₁₉H₂₅NO (283.4). Exact mass (APCI): m/z = 284.2069 (calcd. 284.2009 for C₁₉H₂₆NO [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 2927 (ν C-H aliphatic), 1724 (δ C=O). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.31–1.50 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.54 (dd, J = 13.6/5.9 Hz, 2H, 10-H_anti, 12-H_anti), 2.16 (dd, J = 13.6/8.5 Hz, 2H, 10-H_syn, 12-H_syn), 2.27 (d, J = 19.5 Hz, 2H, 7-H_syn, 9-H_syn), 2.44 (d, J = 19.5 Hz, 2H, 7-H_anti, 9-H_anti), 3.51 (tt, J = 8.5/5.9 Hz, 1H, 11-H), 3.70 (s, 2H, NCH₂Ph), 7.22–7.33 (m 5H, Ph). A signal for the NH proton is not observed in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.6 (2C, C-3, C-4), 32.2 (2C, C-2, C-5), 44.7 (2C, C-10, C-12), 47.9 (2C, C-1, C-6), 50.6 (2C, C-7, C-9), 52.9 (1C, NCH₂Ph), 56.3 (1C, C-11), 127.1 (1C, C-4_Ph), 128.3 (2C, C-3_Ph, C-5_Ph), 128.5 (2C, C-2_Ph, C-6_Ph), 140.5 (1C, C-1_Ph), 219.9 (1C, C=O). Purity (HPLC): 73.8% (t_R = 14.05 min).

5.3.30. 1 -Benzyl-3-(2-methoxy-5-methylphenyl)-1-(syn-11-oxo-[4.3.3]propellan-8-yl)urea (syn-21)

According to the General Procedure A, amine syn-20 (0.20 g, 0.70 mmol), 2-methoxy-5-methylphenyl isocyanate (0.14 g, 0.84 mmol) and Bu₂Sn(OAc)₂ (26 mg, 0.07 mmol) were dissolved in THF (15 mL) and the mixture was stirred at rt for 18 h. The crude product was purified by fc (3 cm, cyclohexane:ethyl acetate = 7:3, 20 mL, R_f = 0.44). Colorless solid, mp 168–170 °C, yield 0.22 g (70%). C₂₈H₃₄N₂O₃ (446.3). Exact mass (APCI): m/z = 447.2666 (calcd. 447.2642 for C₂₈H₃₅N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3390 (ν N-H), 2927 (ν C-H aliphatic), 1732 (ν C=O ketone), 1658 (νC=O urea), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.38–1.51 (m, 6H, 2-CH₂(1H), 3-CH₂, 4-CH₂, 5-CH₂(1H)), 1.57–1.66 (m, 2H, 2-CH₂(1H), 5-CH₂(1H)), 1.92 (dd, J = 13.8/9.1 Hz, 2H, 7-H, 9-H), 2.03 (dd, J = 13.8/9.3 Hz, 2H, 7-H, 9-H), 2.25 (s, 3H, CH₃), 2.28 (d, J = 18.4 Hz, 2H, 10-H, 12-H), 2.33 (d, J = 18.4 Hz, 2H, 10-H, 12-H), 3.46 (s, 3H, OCH₃), 4.60 (s, 2H, NCH₂Ph), 5.33 (p, J = 9.2 Hz, 1H, 8-H), 6.59 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.68 (dd, J = 8.2/2.1 Hz, 1H, 4-H_Ar), 6.95 (s, 1H, NH), 7.31–7.44 (m, 5H, Ph), 7.97 (d, J = 2.1 Hz, 1H, 6-H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.1 (1C, CH₃), 21.8 (2C, C-3, C-4), 33.4 (2C, C-2, C-5), 40.8 (2C, C-7, C-9), 46.4 (2C, C-1, C-6), 47.5 (1C, NCH₂Ph), 50.0 (2C, C-10, C-12), 53.8 (1C, C-8), 55.8 (1C, OCH₃), 109.9 (1C, C-3_Ar), 119.7 (1C, C-6_Ar), 122.2 (1C, C-4_Ar), 126.5 (1C, C-4_Ph), 127.9 (4C, C-2_Ph, C-3_Ph, C-5_Ph, C-6_Ph), 128.8 (1C, C-1_Ar), 130.7 (1C, C-5_Ar), 137.7 (1C, C-1_Ph), 145.7 (1C, C-2_Ar), 156.1 (1C,C=O urea), 218.6 (1C,C=O ketone). Purity (HPLC): 95.0% (t_R = 22.67 min).

5.3.31. 1 -Benzyl-3-(2-methoxy-5-methylphenyl)-1-(anti-11-oxo-[4.3.3]propellan-8-yl)urea (anti-21)

According to the General Procedure A, amine anti-20 (0.22 g, 0.78 mmol), 2-methoxy-5-methylphenyl isocyanate (0.15 g, 0.94 mmol) and Bu₂Sn(OAc)₂ (27 mg, 0.08 mmol) were dissolved in THF (20 mL) and the mixture was stirred at rt for 18 h. The crude product was purified by fc (3 cm, cyclohexane:ethyl acetate = 7:3, 20 mL, R_f = 0.40). Pale yellow solid, mp 133–136 °C, yield 0.28 g (82%). C₂₈H₃₄N₂O₃ (446.3). Exact mass (APCI): m/z = 447.2639 (calcd. 447.2642 for C₂₈H₃₅N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3425 (ν N-H), 2935 (ν C-H aliphatic), 1735 (νC=O ketone), 1654 (ν C=O urea), 1597 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.35–1.52 (m, 6H, 2-CH₂(1H), 3-CH₂, 4-CH₂, 5-CH₂(1H)), 1.58–1.66 (m, 2H, 2-CH₂(1H), 5-CH₂(1H)), 1.81 (dd, J = 13.5/9.6 Hz, 2H, 7-H_anti, 9-H_anti), 2.15 (dd, J = 13.5/9.1 Hz, 2H, 7-H_syn, 9-H_syn), 2.26 (s, 3H, CH₃), 2.32 (s, 4H, 10-CH₂, 12-CH₂), 3.45 (s, 3H, OCH₃), 4.51 (s, 2H, NCH₂Ph), 5.33 (q, J = 9.4 Hz, 1H, 8-H), 6.59 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.68 (dd, J = 8.2/1.6 Hz, 1H, 4-H_Ar), 6.94 (s, 1H, NH), 7.29–7.43 (m, 5H, Ph), 7.97 (d, J = 2.1 Hz, 1H, 6-H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.2 (1C, CH₃), 21.5 (2C, C-3, C-4), 32.7 (2C, C-2, C-5), 41.1 (2C, C-7, C-9), 46.7 (2C, C-1, C-6), 48.2 (1C, NCH₂Ph), 51.1 (2C, C-10, C-12), 55.2 (1C, C-8), 55.9 (1C, OCH₃), 110.0 (1C, C-3_Ar), 119.7 (1C, C-6_Ar), 122.3 (1C, C-4_Ar), 126.5 (1C, C-4_Ph), 128.0 9 (4C, C-2_Ph, C-3_Ph, C-5_Ph, C-6_Ph), 128.9 (1C, C-1_Ar), 129.3, 130.8 (1C, C-5_Ar), 137.4 (1C, C-1_Ph), 145.8 (1C, C-2_Ar), 156.1 (1C,C=O urea), 219.1 (1C,C=O ketone). Purity (HPLC): 80.8% (t_R = 22.66 min).

5.3.32. 1 -Benzyl-1-{(8-syn,11-anti)-11-hydroxy[4.3.3]propellan-8-yl}-3-(2-methoxy-5-methylphenyl)urea (syn,anti-22) and 1-benzyl-1-{(8-syn,11-syn)-11-hydroxy[4.3.3]propellan-8-yl}-3-(2-methoxy-5-methylphenyl)urea (syn,syn-22)

NaBH₄ (30 mg, 0.79 mmol) was added to a solution of the ketone syn-21 (0.35 g, 0.78 mmol) in a mixture of THF and methanol (9:1, 15 mL). The mixture was stirred at rt for 30 min, then water (1 mL) was added and stirred for additional 10 min. After evaporation of the organic solvent under vacuum, ethyl acetate (10 mL) was added. The mixture was washed with NaOH (1 M, 5 mL) and brine (5 mL), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (4 cm, petroleum ether:ethyl acetate = 8:2 to 6.5:3.5, 20 mL).

syn,anti-22 (R_f = 0.38, cyclohexane:ethyl acetate = 7:3): Colorless solid, mp 177–179 °C, yield 0.15 g (43%). C₂₈H₃₆N₂O₃ (448.6). Exact mass (APCI): m/z = 449.2870 (calcd. 449.2799 for C₂₈H₃₇N₂O₃ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3383 (ν O-H), 2927 (ν C-H aliphatic), 1639 (ν C=O_urea), 1535 (δN-H). ¹H NMR (400 MHz, CDCl₃): 1.34–1.44 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.67–1.73 (m, 4H, 7-H_anti, 9-H_anti, 10-H_anti, 12-H_anti), 1.88 (dd, J = 12.9/7.4 Hz, 2H, 7-H_syn, 9-H_syn), 2.02 (dd, J = 13.6/7.0 Hz, 2H, 10-H_syn, 12-H_syn), 2.26 (s, 3H, CH₃), 3.52 (s, 3H, OCH₃), 4.34 (tt, J = 7.0/5,9 Hz, 1H, 11-H), 4.56 (s, 2H, NCH₂Ph), 5.17 (tt, J = 10.9/7.4 Hz, 1H, 8-H), 6.61 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.68 (ddd, J = 8.2/2.1/0.8 Hz, 1H, 4-H_Ar), 7.06 (s, broad, 1H, NH), 7.26–7.40 (m, 5H, Ph), 8.04 (d, J = 2.1 Hz, 1H, 6-H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 18.7 (1C, CH₃), 21.2 (2C, C-3, C-4), 32.9 (2C, C-2, C-5), 41.2 (2C, C-7, C-9), 46.8 (1C, NCH₂Ph), 47.3 (2C, C-1, C-6), 50.2 (2C, C-10, C-12), 52.7(1C, C-8), 55.8 (1C, OCH₃), 71.8 (1C, C-11), 109.9 (1C, C-3_Ar), 119.6 (1C, C-6_Ar), 122.0 (1C, C-4_Ar), 126.6 (1C, C-4_Ph), 127.5 (2C, C-3_Ph, C-5_Ph), 128.9 (2C, C-2_Ph, C-6_Ph), 129.0(1C, C-1_Ar), 130.7 (1C, C-5_Ar), 138.5 (1C, C-1_Ph), 145.7 (1C, C-2_Ar), 156.1 (1C, C=O). Purity (HPLC): 94.9% (t_R = 22.69 min).

syn,syn-22 (R_f = 0.36, cyclohexane:ethyl acetate = 7:3): Pale yellow solid, mp 148–151 °C, yield 0.10 g (28%). C₂₈H₃₆N₂O₃ (448.6). Exact mass (APCI): m/z = 449.2770 (calcd. 449.2799 for C₂₈H₃₇N₂O₃ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3437 (ν O-H), 2931 (ν C-H aliphatic), 1643 (ν C=O_urea), 1535 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.39–1.51 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.62–1.82 (m, 6H, 7-CH₂, 9-CH_2, 10-H_syn, 12-H_syn), 2.03 (dd, J = 13.9/7.0 Hz, 2H, 10-H_anti, 12-H_anti), 2.25 (s, 3H, CH₃), 3.48 (s, 3H, OCH₃), 4.51 (s, 2H, NCH₂Ph), 4.54 (tt, J = 7.1/6.2, Hz, 1H, 11-H), 5.01 (tt, J = 10.6/7.9 Hz, 1H, 8-H), 6.59 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.68 (dd, J = 8.2, 2.1 Hz, 1H, 4-H_Ar), 7.05 (s, broad, 1H, NH), 7.27–7.42 (m, 5H, Ph), 7.99 (d, J = 2.1 Hz, 1H, 6-H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.1 (1C, CH₃), 21.1 (2C; C-3, C-4), 34.0 (2C, C-2, C-5), 42.3 (2C, C-7, C-9), 48.0 (2C, C-1, C-6), 46.9 (1C, NCH₂Ph) 49.4 (2C, C-10, C-12), 53.6 (1C, C-8), 55.8 (1C, OCH₃), 72.6 (1C, C-11), 109.9 (1C, C-3_Ar), 119.7 (1C, C-6_Ar), 122.2 (1C, C-4_Ar), 126.7 (1C, C-4_Ph), 127.8 (2C, C-3_Ph, C-5_Ph), 128.8 (2C, C-2_Ph, C-6_Ph), 129.0 (1C, C-1_Ar), 130.7 (1C, C-5_Ar), 137.8 (1C, C-1_Ph), 145.8 (1C, C-2_Ar), 156.0 (1C, C=O). Purity (HPLC): 97.7% (t_R = 22.15 min).

5.3.33. 1 -Benzyl-1-{(8-anti,11-anti)-11-hydroxy[4.3.3]propellan-8-yl}-3-(2-methoxy-5-methylphenyl)urea (anti,anti-22) and 1-benzyl-1-{(8-anti,11-syn)-11-hydroxy[4.3.3]propellan-8-yl}-3-(2-methoxy-5-methylphenyl)urea (anti,syn-22)

NaBH₄ (9 mg, 0.24 mmol) was added to a solution of the ketone anti-21 (0.15 g, 0.23 mmol) in a mixture of THF and methanol (9:1, 15 mL). The mixture was stirred at rt for 30 min, then water (1 mL) was added and stirred for additional 10 min. After evaporation of the organic solvent under vacuum, ethyl acetate (10 mL) was added. The mixture was washed with NaOH (1 M, 5 mL) and brine (5 mL), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (4 cm, petroleum ether:ethyl acetate = 8:2 to 6.5:3.5, 20 mL).

anti,anti-22 (R_f = 0.23, cyclohexane:ethyl acetate = 7:3): Colorless solid, mp 126–128 °C, yield 50 mg (33%). C₂₈H₃₆N₂O₃ (448.6). Exact mass (APCI): m/z = 449.2793 (calcd. 449.2799 for C₂₈H₃₇N₂O₃ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3394 (νO-H), 2924 (νC-H aliphatic), 1635 (ν C=O_urea), 1535 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.24–1.54 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.67 (dd, J = 14.0/4.6 Hz, 2H, 10-H_anti, 12-H_anti), 1.95 (m, 4H, 7-CH₂, 9-CH₂), 2.07 (dd, J = 14.0/7.6 Hz, 2H, 10-H_syn, 12-H_syn), 2.25 (s, 3H, CH₃), 3.45 (s, 3H, OCH₃), 4.46 (tt, J = 7.6/4.6 Hz, 1H, 11-H), 4.57 (s, 2H, NCH₂Ph), 5.25 (p, J = 9.5 Hz, 1H, 8-H), 6.58 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.66 (dd, J = 7.9/1.3 Hz, 1H, 4-H_Ar), 6.96 (s, 1H, NH), 7.26–7.40 (m, 5H, Ph), 8.01 (d, J = 2.1 Hz, 1H, 6-H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 20.8 (1C, CH₃), 21.1 (2C, C-3, C-4), 33.1 (2C, C-2, C-5), 43.1 (2C, C-7, C-9), 46.9 (1C, NCH₂Ph), 48.4 (2C, C-10, C-12), 49.3 (2C, C-1, C-6), 55.0 (1C, C-8), 55.8 (1C, OCH₃), 73.3 (1C, C-11), 109.9 (1C, C-3_Ar), 119.6 (1C, C-6_Ar), 122.0 (1C, C-4_Ar), 126.6 (1C, C-4_Ph), 127.6 (2C, C-3_Ph, C-5_Ph), 129.0 (2C, C-2_Ph, C-6_Ph), 129.1 (1C, C-1_Ar), 130.7 (1C, C-5_Ar), 138.1 (1C, C-1_Ph), 145.7 (1C, C-2_Ar), 156.1 (1C, C=O). Purity (HPLC): 95.5% (t_R = 21.94 min).

anti,syn-22 (R_f = 0.26, cyclohexane:ethyl acetate = 7:3): Pale yellow solid, mp 149–151 °C, yield 58 mg (38%). C₂₈H₃₆N₂O₃ (448.6). Exact mass (APCI): m/z = 449.2782 (calcd. 449.2799 for C₂₈H₃₇N₂O₃ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3379 (ν O-H), 2927 (ν C-H aliphatic), 1643 (ν C=O_urea), 1531 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.46–1.56 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.59 (dd, J = 12.9/10.9 Hz, 2H, 7-H_anti, 9-H_anti), 1.69 (dd, J = 13.5/6.4 Hz, 2H, 10-H_syn, 12-H_syn), 1.89 (d, J = 13.0/8.0 Hz, 2H, 7-H_syn, 9-H_syn), 1.94 (dd, J = 13.5/7.2 Hz, 2H, 10-H_anti, 12-H_anti), 2.25 (m, 3H, CH₃), 3.47 (s, 3H, OCH₃), 4.39 (p, J = 6.9 Hz, 1H, 11-H), 4.50 (s, 2H, NCH₂Ph), 5.08 (tt, J = 10.7/7.9 Hz, 1H, 8-H), 6.59 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.67 (ddd, J = 8.2/2.1/0.8 Hz, 1H, 4-H_Ar), 6.97 (s, broad, 1H, NH), 7.27–7.41 (m, 5H, Ph), 8.00 (d, J = 2.0 Hz, 1H, 6-H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 19.6 (1C, CH₃), 21.1 (2C, C-3, C-4), 32.3 (2C, C-2, C-5), 43.7 (2C, C-7, C-9), 46.7 (1C, NCH₂Ph), 47.6 (2C, C-10, C-12), 47.9 (2C, C-1, C-6), 53.9 (1C, C-8), 55.8 (1C, OCH₃), 71.5 (1C, C-11), 109.9 (1C, C-3_Ar), 119.6 (1C, C-6_Ar), 122.0 (1C, C-4_Ar), 126.5 (1C, C-4_Ph), 127.7 (2C, C-3_Ph, C-5_Ph), 128.9 (2C, C-2_Ph, C-6_Ph), 129.0 (1C, C-1_Ar), 130.7(1C, C-5_Ar), 138.1(1C, C-1_Ph), 145.7 (1C, C-2_Ar), 156.1 (1C,C=O). Purity (HPLC): 93.5% (t_R = 21.57 min).

5.3.34. 1 -Phenyl-3-(syn- and anti-[4.3.3]propellan-8-yl)urea (23a)

According to General Procedure A, propellanamine 16 (90 mg, 0.50 mmol), phenyl isocyanate (72 mg, 0.6 mmol) and Bu₂Sn(OAc)₂ (35 mg, 0.1 mmol) were dissolved in THF (5 mL) and the mixture was stirred at rt for 30 h. The crude product was purified by fc (1 cm, cyclohexane:ethyl acetate = 8:2, 5 mL, R_f = 0.36) to obtain a mixture of diastereoisomeric urea syn-23a and anti-23a as a brown solid, mp 134–138 °C, yield 30 mg (22%). C₁₉H₂₆N₂O (298.4). MS (ESI): m/z = 299 [M+H]⁺. Exact mass (APCI): m/z = 299.2131 (calcd. 299.2118 for C₁₉H₂₇N₂O [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3429 (ν N-H), 2927 (ν C-H aliphatic), 1647 (ν C=O), 1597 (δN-H). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.30–1.35 (m, 4H, 2-CH₂, 5-CH₂), 1.37–1.44 (m, 5H, 3-CH₂, 4-CH₂, 7-CH₂(0.5H), 9-CH₂(0.5H)), 1.48 (dd, J = 13.3/7.3 Hz, 2 × 0.5H, 7-H, 9-H), 1.51–1.54 (m, 2H, 10-CH₂(1H), 12-CH₂(1H)), 1.57–1.66 (m, 3H, 10-CH₂(1H), 11-CH₂(1H), 12-CH₂(1H)), 1.68–1.75 (m, 1H, 11-CH₂(1H)), 2.03 (dd, J = 13.4/8.3 Hz, 2 × 0.5H, 7-H, 9-H), 2.11 (dd, J = 13.4/8.7 Hz, 2 × 0.5H, 7-H, 9-H), 4.25–4.31 (m, 2 × 0.5H, 8-H), 7.07–7.16 (m, 1H, 4-H_phenyl), 7.26–7.28 (m, 2H, 3H_phenyl, 5-H_phenyl), 7.29–7.33 (M, 2H, 2-H_phenyl, 6-H_phenyl). Signals for the NH protons are not observed in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.8, 21.0 (2C, C-3, C-4), 21.2, 21.9 (2 × 0.5C, C-11), 31.7, 32.5 (2C, C-2, C-5), 37.6, 38.5 (2C, C-10, C-12), 46.0, 45.5 (2C, C-7, C-9), 49.4 (2C, C-1, C-6), 50.1, 50.7 (2 × 0.5C, C-8), 120.8, 121,7 (2C, C-3_phenyl, C-5_phenyl), 129.2 (1C, C-4_phenyl), 129.6, 129.9 (2C, C-2_phenyl, C-6_phenyl), 137.3 (1C, C-1_phenyl), 156.3 (1C, C=O). syn-23a:anti-23a = 1:1. Purity (HPLC): 97.4% (t_R = 21.03 min).

5.3.35. 1 -Cyclohexyl-3-(syn- and anti-[4.3.3]propellan-8-yl)urea (23b)

According to General Procedure A, propellanamine 16 (90 mg, 0.50 mmol), cyclohexyl isocyanate (75 mg, 0.6 mmol) and Bu₂Sn(OAc)₂ (35 mg, 0.1 mmol) were dissolved in THF (5 mL) and the mixture was stirred at rt for 24 h. The crude product was purified by fc (1 cm, cyclohexane:ethyl acetate = 7:3, 5 mL, R_f = 0.40) to obtain a mixture of diastereoisomeric urea syn-23b and anti-23b as a colorless solid, mp 187–193 °C, yield 73 mg (47%). C₁₉H₃₂N₂O (304.5). MS (ESI): m/z = 305 [M+H]⁺. Exact mass (APCI): m/z = 305.2587 (calcd. 305.2587 for C₁₉H₂₇N₂O [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3302 (ν N-H), 2924 (ν C-H aliphatic), 1616 (ν C=O), 1558 (δ N-H). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.10–1.18 (m, 2H, 2-CH_2Cy(1H), 6-CH_2Cy(1H)), 1.31–1.44 (m, 11H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(0.5H), 9-CH₂(0.5H), 4-CH_2Cy), 1.48 (d, J = 13.5/7.0 Hz, 2 × 0.5 H, 7-H, 9-H), 1.51–1.65 (m, 7H, 10-CH₂, 11-CH₂(1H), 12-CH₂, 3-CH_2Cy(1H), 5-CH_2Cy(1H)), 1.68–176 (m, 3H, 11-CH₂(1H), 3-CH_2Cy(1H), 5-CH_2Cy(1H)), 1.92 (m, 2H, 2-CH_2Cy(1H), 6-CH_2Cy(1H)) 2.00 (dd, J = 13.3/8.4 Hz, 2 × 0.5H, 7-H, 9-H), 2.08 (dd, J = 13.3/8.6 Hz, 2 × 0.5H, 7-H, 9-H), 3.51 (tt, J = 9.3/4.8 Hz, 2 × 0.5H, 1-H_Cy), 4.09–4.15 (m, 2 × 0.5H, 8-H). Signals for the NH protons are not observed in the spectrum. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.8, 20.9 (2C, C-3, C-4), 21.6 (1C, C-11), 24.8, 25.5 (2C, C-3_Cy, C-5_Cy), 26.9 (1C, C-4_Cy), 31.9, 32.3 (2C, C-2, C-5), 33.8 (2C, C-2_Cy, C-6_Cy), 37.9, 38.2 (2C, C-10, C-12), 45.5, 46.0 (2C, C-7, C-9), 49.8 (1C, C-1_Cy), 50.0 (1C, C-8), 50.5 (2C, C-1, C-6), 157.3 (1C, C=O). syn-23b:anti-23b = 1:1. Purity (HPLC): 98.3% (t_R = 21.62 min).

5.3.36. 1 -(2-Methoxy-5-methylphenyl)-3-(syn- and anti-[4.3.3]propellan-8-yl)urea (23c)

According to General Procedure A, propellanamine 16 (90 mg, 0.50 mmol), 2-methoxy-5-methylphenyl isocyanate (98 mg, 0.6 mmol) and Bu₂Sn(OAc)₂ (35 mg, 0.1 mmol) were dissolved in THF (5 mL) and the mixture was stirred at rt for 30 h. The crude product was purified by fc (1 cm, cyclohexane:ethyl acetate = 7:3, 5 mL, R_f = 0.55) to obtain a mixture of diastereoisomeric urea syn-23c and anti-23c as a beige solid, mp 215–220 °C, yield 160 mg (91%). C₂₁H₃₀N₂O₂ (342.5). MS (ESI): m/z = 343 [M+H]⁺. Exact mass (APCI): m/z = 343.2387 (calcd. 343.2380 for C₂₁H₃₁N₂O₂ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3332 (ν N-H), 2927 (νC-H aliphatic), 1639 (ν C=O), 1546 (δ N-H). ¹H NMR (600 MHz, CDCl₃): δ(ppm) = 1.32–1.46 (m, 9H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(0.5H), 9-CH₂(0.5H)), 1.45 (dd, J = 13.3/7.3 Hz, 2 × 0.5H, 7-H, 9-H), 1.53–1.74 (m, 6H, 10-CH₂, 11-CH₂, 12-CH₂), 2.06 (dd, J = 13.3/8.4 Hz, 2 × 0.5H, 7-H, 9-H), 2.14 (dd, J = 13.3/8.6 Hz, 2 × 0.5H, 7-H, 9-H), 2.27 (s, 3H, CH₃), 3.81 (s, 3H, OCH₃), 4.28–4.31 (m, 2 × 0.5H, 8-H), 6.72 (d, J = 8.2 Hz, 1H, 3-H_Ar), 6.76 (d, J = 8.0 Hz, 1H, 4-H_Ar), 6.80 (s, broad, 1H, NH), 7.90 (s, 1H, 6-H_Ar). ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.9, 21.1 (2C, C-3, C-4), 21.1 (1C, CH₃), 21.2, 21.9 (2 × 0.5C, C-11), 31.8, 32.5 (2C, C-2, C-5), 37.6, 38.6 (2C, C-10, C-12), 45.6, 46.2 (2C, C-7, C-9), 49.2, 49.9 (2 × 0.5C, C-8), 50.1, 50.6 (2C, C-1, C-6), 55.9 (1C, OCH₃), 110.1 (1C, C-3_Ar), 120.2 (1C, C-6_Ar), 122.5 (1C, C-4_Ar), 128.6 (1C, C-1_Ar), 130.9 (1C, C-5_Ar), 146.0 (1C, C-2_Ar), 155.2 (1C,C=O). syn-23c:anti-23c = 1:1. Purity (HPLC): 93.8% (t_R = 22.21 min).

5.3.37. 1 -(3,4-Difluorophenyl)-3-(syn- and anti-[4.3.3]propellan-8-yl)urea (23d)

According to the General Procedure A, propellanamine 16 (90 mg, 0.50 mmol), 3,4-difluorophenyl isocyanate (93 mg, 0.6 mmol) and Bu₂Sn(OAc)₂ (35 mg, 0.1 mmol) were dissolved in THF (5 mL) and the mixture was stirred at rt for 48 h. The crude product was purified by fc (1 cm, cyclohexane:ethyl acetate = 7:3, 5 mL, R_f = 0.56) to obtain a mixture of diastereoisomeric urea syn-23d and anti-23d as a pale orange solid, mp 168–175 °C, yield 100 mg (63%). C₁₉H₂₄F₂N₂O (334.4). MS (ESI): m/z = 335 [M+H]⁺. Exact mass (APCI): m/z = 335.1932 (calcd. 335.1929 for C₁₉H₂₅F₂N₂O [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3325 (ν N-H), 2927 (ν C-H aliphatic), 1643 (ν C=O), 1558 (δ N-H). ¹H NMR (600 MHz, CDCl₃): δ(ppm) = 1.27–1.43 (m, 9H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(0.5H), 9-CH₂(0.5)), 1.45–1.64 (m, 6H, 7-CH₂(0.5H), 9-CH₂(0.5H), 10-CH₂, 11-CH₂(1H), 12-CH₂), 1.67.172 (m, 1H, 11-CH₂(1H)), 2.01 (dd, J = 13.4/8.4 Hz, 2 × 0.5H, 7-H, 9-H), 2.08 (dd, J = 13.8/8.7 Hz, 2 × 0.5H, 7-H, 9-H), 4.22–4.27 (m, 2 × 0.5H, 8-H), 6.89–6.91 (m, 1H, 6-H_Ar), 6.99–7.06 (m, 1H, 5-H_Ar), 7.27–7.33 (m, 1H, 2-H_Ar). Signals for the NH protons are not observed. ¹³C NMR (150 MHz, CDCl₃): δ (ppm) = 20.9, 21.0 (2C, C-3, C-4), 21.1, 21.8 (2 × 0.5C, C-11), 31.7, 32.5 (2C, C-2, C-5), 37.5, 38.3 (2C, C-10, C-12), 45.5, 46.0 (2C, C-7, C-9), 49.3, 49.97 (2 × 0.5C, C-8), 50.2, 50.7 (2C, C-1, C-6), 110.0 (d, J = 19.3 Hz, 1C, C-2_Ar), 116.0 (d, J = 3.9 Hz, 1C, C-6_Ar), 117.4 (d, J = 18.1 Hz, 1C, C-5_Ar), 135.1 (1C, C-1_Ar), 150.3 (d, J = 260.6 Hz, 2C, C-3_Ar, C-4_Ar), 155.9 (1C, C=O). syn-23d:anti-23d = 1:1. Purity (HPLC): 98.2% (t_R = 21.73 min).

5.3.38. (11′-syn and 11′-anti)-Spiro ([1,3]dioxolane-2,8′-[4.3.3]propellan)-11′-amine (24)

Pd(OH)₂/C (20%, 70 mg) was added to a solution of the benzylpropellanamines 14 (0.7 g, 2.14 mmol) and ammonium formate (0.54 g, 8.56 mmol) in methanol (20 mL). The mixture was heated to reflux for 3 h. After evaporation of the solvent under vacuum, ethyl acetate (30 mL) was added. The mixture was washed with NaOH (1 M, 10 mL) and brine (10 mL), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (3 cm, ethyl acetate:methanol = 1:1, 20 mL, R_f = 0.11(cyclohexane : ethyl acetate : methanol = 6 : 3 : 1)). Pale yellow oil, yield 0.38 g (75%). C₁₄H₂₂NO₂ (237.3). MS (ESI): m/z = 238 [M+H]⁺. Exact mass (APCI): m/z = 238.1834 (calcd. 238.1802 for C₁₄H₂₄NO₂ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 2927 (aliphatic ν C-H), 1558 (ν N-H₂). ¹H NMR (600 MHz, CDCl₃): δ (ppm) = 1.28–1.58 (m, 8H, 2′-CH₂, 3′-CH₂, 4′-CH₂, 5′-CH₂), 1,63 (dd, J = 13.6/6.9 Hz, 2 × 0.5H, 10′-H, 12′-H), 1.71 (dd, J = 13.6/7.5 Hz, 2 × 0.5 H, 10′-H, 12′-H), 1.82 (d, J = 14.3 Hz, 2H, 7′-H, 9′-H), 1.93 (d, J = 14.3 Hz, 2H, 7′-H, 9′-H), 2.05 (dd, J = 13.6/8.8 Hz, 2 × 0.5H, 10′-H, 12′-H), 2.10 (dd, J = 13.6/8.7 Hz, 2 × 0.5H, 10′-H, 12′-H), 3.61–3.67 (m, 0.5 H, 11′-H), 3.68–3.71 (m, 0.5 H, 11′-H), 3.80 (m, 4H, OCH₂CH₂O). A signal for the NH₂ protons is not observed in the spectrum.

5.3.39. 1 -(3,4-Difluorophenyl)-3-(syn- and anti-spiro[1,3]dioxolane-2,8’-[4.3.3]propellan-11’-yl)urea

According to General Procedure A, amine 24 (0.35 g, 1.47 mmol), 3,4-difluorophenyl isocyanate (0.27 g, 1.76 mmol) and Bu₂Sn(OAc)₂ (52 mg, 0.15 mmol) were dissolved in THF (15 mL) and the mixture was stirred at rt for 48 h. The crude product was purified by fc (3 cm, cyclohexane:ethyl acetate = 7:3, 20 mL, R_f = 0.42) to obtain 0.55 g of a mixture of diastereoisomeric urea and an impurity with the same R_f value. This mixture was used for the next reaction step without further purification.

5.3.40. 1-(3,4-. Difluorophenyl)-3-(8-syn-11-oxo[4.3.3]propellan-8-yl)urea (syn-25) and 1-(3,4-Difluorophenyl)-3-(8-anti-11-oxo[4.3.3]propellan-8-yl)urea (anti-25)

The mixture obtained above (0.50 g, 1.37 mmol) and p-toluenesulfonic acid monohydrate (26 mg, 0.01 mmol) were dissolved in acetone (20 mL) and the mixture was heated to 60 °C for 2 h. The solvent was removed in vacuo and the residue was purified by fc (3 cm, cyclohexane:ethyl acetate = 9:1 to 6:4, 20 mL).

syn-25 (R_f = 0.23, cyclohexane:ethyl acetate = 7:3): Pale yellow solid, mp 161–173 °C, yield 0.20 g (42%). C₁₉H₂₂F₂NO₂ (348.4). MS (ESI): m/z = 349 [M+H]⁺. Exact mass (APCI): m/z = 349.1741 (calcd. 349.1722 for C₁₉H₂₃F₂N₂O₂ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3340 (ν N-H), 2931 (ν C-H aliphatic), 1735 (ν C=O_ketone), 1654 (ν C=O_urea), 1550 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.40–1.58 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂,), (1.75 (dd, J = 14.1/5.5 Hz, 2H, 7-H_syn, 9-H_syn), 2.15 (d, J = 18.8 Hz, 2H, 10-H, 12-H), 2.21 (dd, J = 14.1/9.2 Hz, 2H, 7-H_anti, 9-H_anti), 2.26 (d, J = 18.8 Hz, 2H, 10-H, 12-H), 4.35–4.44 (m, 1H, 8-H), 6.84–6.94 (m, 1H, 6-H_Ar), 7.01–7.08 (m, 1H, 5-H_Ar), 7.29–7.35 (m, 1H, 2-H_Ar). Signals for the NH protons are not observed in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.7 (2C, C-3, C-4), 32.5 (2C, C-2, C-5), 44.8 (2C, C-7, C-9), 47.6 (2C, C-10, C-12), 49.1 (1C, C-8), 49.4 (2C, C-1, C-6), 109.8 (d, J = 21.1 Hz, 1C, C-2_Ar), 115.8 (d, J = 8.8 Hz, 1C, C-6_Ar), 117.5 (d, J = 18.1 Hz, 1C, C-5_Ar), 15.2 (1C, C-1_Ar), 146.8 (dd, J = 244.8/13.0 Hz, 1C, C-4_Ar), 150.4 (dd, J = 247.4/13.3 Hz, 1C, C-3_Ar), 155.3 (1C, N(C=O)N), 218.5 (1C, C=O). Purity (HPLC): 92–6% (t_R = 18.24 min).

anti-25 (R_f = 0.31, cyclohexane:ethyl acetate = 7:3) Pale yellow solid, mp 100–103 °C, yield 0.17 g (35%). C₁₉H₂₂F₂NO₂ (348.4). MS (ESI): m/z = 349 [M+H]⁺. Exact mass (APCI): m/z = 349.1683 (349.1722 calcd. for C₁₉H₂₃F₂N₂O₂ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3302 (ν N-H), 2927 (ν C-H aliphatic), 1728 (ν C=O_ketone), 1658 (ν C=O_urea), 1527 (δ N-H). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.29–1.54 (m, 10H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(1H), 9-CH₂(1H)), 2.19–2.39 (m, 6H, 7-CH₂(1H), 9-CH₂(1H), 10-CH₂, 12-CH₂), 4.43–4.52 (m, 1H, 8-H), 6.90–6.94 (m, 1H, 6-H_Ar), 7.04 (dd, J = 9.4/8.9 Hz, 1H, 5-H_Ar), 7.32–7.32–7.40 (m, 1H, 2-H_Ar). Signals for the NH protons are not observed in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ(ppm) = 21.3 (2C, C-3, C-4), 31.8 (2C, C-2, C-5), 44.9 (2C, C-7, C-9), 47.8 (2C, C-1, C-6), 49.1 (1C, C-8), 50.5 (2C, C-10, C-12), 109.4 (d, J = 21.1 Hz, 1C, C-2_Ar), 115.3 (1C, C-6_Ar), 117.4 (d, J = 18.1 Hz, C-5_Ar), 135.5 (1C, C-1_Ar) 146.5 (dd, J = 247.4/12.0 Hz, 1C, C-4_Ar), 150.8 (dd, J = 245.6/13.3 Hz, 1C, C-3_Ar), 155.4 (1C, N(C=O)N), 220.3 (1C, C=O). Purity (HPLC): 98.7% (t_R = 18.43 min).

5.3.41. 1 -(3,4-Difluorophenyl)-3-(8-syn-11-syn- and 8-syn-11-anti-11-hydroxy[4.3.3]-propellan-8-yl)urea (syn,syn-26 and syn,anti-26)

NaBH₄ (20 mg, 0.53 mmol) was added to a solution of the ketone syn-25 (0.12 g, 0.34 mmol) in a mixture of THF and methanol (9:1, 10 mL). The mixture was stirred at rt for 30 min, then water (1 mL) was added and the mixture was stirred for additional 10 min. After evaporation of the organic solvent under vacuum, ethyl acetate (10 mL) was added. The mixture was washed with NaOH (1M, 5 mL) and brine (5 mL), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate = 6:4, 5 mL, R_f = 0.49). The mixture could not be separated. Colorless solid, mp 171–178 °C, yield 0.10 g (83%). C₁₉H₂₄F₂NO₂ (350.4). MS (ESI): m/z = 351 [M+H]⁺. Exact mass (APCI): m/z = 351.1884 (calcd. 351.1879 for C₁₉H₂₅F₂N₂O₂ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3298 (ν O-H), 2931 (ν C-H aliphatic), 1678 (ν C=O_urea), 1558 (δ N-H). ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) = 1.30–1.48 (m, 10H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂, 7-CH₂(1H), 9-CH₂(1H)), 1.50–1.60 (m, 2H, 10-H, 12-H), 1.77–1.90 (m, 3H, 7-CH₂(0.5H), 9-CH₂(0.5H), 10-H, 12-H), 2.01 (dd, J = 13.2/8.3 Hz, 2 × 0.5H, 7-H, 9-H), 4.00–4.10 (m, 0.5H, 8-H), 4.14–4.27 (m, 1.5H, 8-H(0.5H), 11-H), 6.95–7.01 (m, 1H, 6-H_Ar), 7.25 (dd, J = 10.7/9.2 Hz, 1H, 5-H_Ar), 7.61 (dddd, J = 13.7/7.5/3.5/.26 Hz, 1H, 2-H_Ar), 8.40 (s, 1H, NH), 8.41 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) = 19.7, 20.4 (2C, C-3, C-4), 31.9, 32.6 (2C, C-2, C-5), 44.6, 45.5 (2C, C-7, C-9), 47.2, 47.7 (2 × 0.5C, C-8), 47.9, 48.2 (2C, C-10, C-12), 48.4, 48.6 (2C, C-1, C-6), 69.6, 69.9 (2 × 0.5C, C-11), 106.3 (d, J = 21.9 Hz, 1C, C-2_Ar), 113.41 (dd, J = 5.7/3.1 Hz, 1C, C-6_Ar), 117.4 (d, J = 17.6 Hz, 1C, C-5_Ar), 137.7 (dd, J = 9.5/2.8 Hz, 1C, C-1_Ar), 143.8 (dd, J = 238.4/12.8 Hz, 1C, C-4_Ar), 149.0 (dd, J = 241.7/12.9 Hz, 1C, C-3_Ar), 154.4 (1C, N(C=O)N). syn,syn-26:syn,anti-26 = 1:1. Purity (HPLC): 99.2% (t_R = 18.26 min).

5.3.42. 1 -(3,4-Difluorophenyl)-3-(8-anti-11-anti-11-hydroxy[4.3.3]propellan-8-yl)urea (anti,anti-26) and 1-(3,4-Difluorophenyl)-3-(8-anti-11-syn-11-hydroxy[4.3.3]propellan-8-yl)urea (anti,syn-26)

NaBH₄ (20 mg, 0.53 mmol) was added to a solution of the keto urea anti-25 (0.12 g, 0.34 mmol) in a mixture of THF and methanol (9:1, 10 mL). The mixture was stirred at rt for 30 min, then water (1 mL) was added and the mixture was stirred for additional 10 min. After evaporation of the organic solvent under vacuum, ethyl acetate (10 mL) was added. The mixture was washed with NaOH (1 M, 5 mL) and brine (5 mL), dried (Na₂SO₄), filtered, the filtrate was concentrated in vacuo and the residue was purified by fc (1 cm, cyclohexane:ethyl acetate = 7:3–5:5, 5 mL).

anti,anti-26 (R_f = 0.22, cyclohexane:ethyl acetate = 7:3): Colorless solid, mp 201–203 °C, yield 32 mg (27%). C₁₉H₂₄F₂NO₂ (350.4). MS (ESI): m/z = 351 [M+H]⁺. Exact mass (APCI): m/z = 351.1901 (calcd. 351.1879 for C₁₉H₂₅F₂N₂O₂ [M+H]⁺). FT-IR (ATR, film): ν (cm⁻¹) = 3232 (ν O-H), 2924 (ν C-H aliphatic), 1670 (ν C=O_urea), 1566 (δ N-H). ¹H NMR (400 MHz, CDCl₃): 1.11–1.25 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.57 (dd, J = 14.0/4.7 Hz, 2H, 10-H_anti, 12-H_anti), 1.62 (dd, J = 13.6/6.9 Hz, 2H, 7-H_anti, 9-H_anti), 1.98 (dd, J = 14.0/8.2 Hz, 2H, 10-H_syn,, 12-H_syn), 2.03 (dd, J = 13.6/9.1 Hz, 2H, 7-H_syn, 9-H_syn), 4.23 (tt, J = 9.0/6.9 Hz, 1H, 8-H), 4.34 (tt, J = 8.1/4.7 Hz, 1H, 11-H), 6.76–6.81 (m, 1H, 6-H_Ar), 6.85 (dd, J = 9.9/8.7 Hz, 1H, 5-H_Ar), 7.40 (ddd, J = 13.1/7.3/2.5 Hz, 1H, 2-H_Ar). Signals for the NH protons and the OH proton are not observed in the spectrum. ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 21.1 (2C, C-3, C-4), 32.1 (2C, C-2, C-5), 45.9 (2C, C-7, C-9), 47.7 (2C, C-10, C-12), 48.8 (1C, C-8), 50.4 (2C, C-1, C-6), 71.9 (1C, C-11), 107.2 (d, J = 21.9 Hz, 1C, C-2_Ar), 113.1 (dd, J = 5.6/3.3 Hz, 1C, C-6_Ar), 116.5 (d, J = 17.9 Hz, 1C, C-5_Ar), 137.0 (dd, J = 9.3/2.8 Hz, C-1_Ar), 144.9 (dd, J = 240.6/13.1 Hz, 1C, C-4_Ar), 149.8 (dd, J = 242.8/13.1 Hz, 1C, C-3_Ar), 155.2 (1C, N(C=O)N). Purity (HPLC): 96.9% (t_R = 18.49 min).

anti,syn-26 (R_f = 0.13, cyclohexane:ethyl acetate = 7:3): Colorless solid, mp 186–189 °C, yield 10 mg (8%). C₁₉H₂₄F₂NO₂ (350.4). MS (ESI): m/z = 351 [M+H]⁺. Exact mass (APCI): m/z = 351.1907 (calcd. 351.1879 for C₁₉H₂₅F₂N₂O₂ [M+H]⁺ ). FT-IR (ATR, film): ν (cm⁻¹) = 3383 (ν O-H), 2924 (ν C-H aliphatic), 1654 (δ C=O_urea), 1570 (δ N-H). ¹H NMR (400 MHz, DMSO-d₆): 1.35 (dd, J = 13.3/8.1 Hz, 2H, 7-H_anti, 9-H_anti), 1.39–1.50 (m, 8H, 2-CH₂, 3-CH₂, 4-CH₂, 5-CH₂), 1.56 (dd, J = 13.4/5.4 Hz, 2H, 10-H_syn, 12-H_syn), 1.87 (dd, J = 13.6/7.5 Hz, 2H, 10-H_anti, 12-H_anti), 1.95 (dd, J = 13.3/6.0 Hz, 2H, 7-H_syn, 9-H_syn), 4.10 (tt, J = 8.1/6.0 Hz, 1H, 8-H), 4.30 (tt, J = 7.3/5.4 Hz, 1H, 11-H), 6.34 (d, J = 7.5 Hz, 1H, NHCONHAr), 6.98 (dddd, J = 9.0/4.1/2.5/1.5 Hz, 1H, 6-H_Ar), 7.25 (dd, J = 10.6/9.1 Hz, 1H, 5-H_Ar), 7.60 (ddd, J =13.7/7.5/2.6 Hz, 1H 2-H_Ar). 8.45 (s, 1H, NHCONHAr). A signal for the OH proton is not observed in the spectrum. ¹³C NMR (100 MHz, DMSO-d₆): δ (ppm) = 19.7 (2C, C-3, C-4), 31.2 (2C, C-2, C-5), 46.2 (2C, C-7, C-9), 47.1 (2C, C-10, C-12), 48.6 (2C, C-1, C-6), 47.7 (1C, C-8), 691 (1C, C-11), 106.3 (d, J = 21.8 Hz, 1C, C-2_Ar), 113.38 (1C, C-6_Ar), 137.8 (d, J = 6.8 Hz, C-1_Ar), 141.8 (d, J = 152.2 Hz, 1C, C-4_Ar), 149.1 (d, J = 242.1 Hz, 1C, C-3_Ar), 154.5 (1C, N(C=O)N). Purity (HPLC): 93.8% (t_R = 17.82 min).

5.4. Computational Details

The starting structure for the σ₁ receptor was obtained from the RCSB Protein Data Bank (PDB ID 5HK1, https://www.rcsb.org/structure/5HK1 (accessed date: 3 March 2021) [7], of which only the protomer with the more complete sequence was retained for the simulations. The CHARMM-GUI server [54] was used to embed the σ₁ monomer in a palmitoyl-oleyl-phosphatidyl-choline (POPC, 218 lipid molecules were added) bilayer solvated with explicit TIP3P [55] and water molecules to succeed complete hydration of the membrane and reach a physiological concentration of sodium and chloride ions (0.15 M NaCl). Antechamber program from AMBER20 [56] was used to assign gaff2 [57] atom types to each ligand, while ligand’s partial charges were derived by employing the RESP method offered by the RED server [58]. Docking and classical molecular dynamics simulations on σ₁ receptor in complex with the new azapropellane derivatives were carried out following a well validated procedure [49,52,59]. Briefly, the system density and volume were relaxed in NPT ensemble maintaining the Berendsen barostat for 20 ns. After this step, 50 ns of unrestrained NVT production simulation was run for each system. Following the MM/PBSA approach [55], each binding free energy values (ΔG) were calculated as the sum of the enthalpic (ΔH) and entropic contributions (-TΔS). The PRBFED analysis was carried out using the molecular mechanics/generalized Boltzmann surface area (MM/GBSA) approach [60] and was based on the same snapshots used in the binding free energy calculation. All images were created by the UCSF Chimera software v1.15 [61], and graphs were produced by GraphPad Prism v8 (GraphPad Software, San Diego, California USA, www.graphpad.com).

5.5. X-ray Diffraction

5.5.1. General

Data sets for compounds syn-7, anti-21, syn,anti-22, anti,syn-22 and syn-25 were collected with a Bruker Kappa CCD diffractometer. Programs used: data collection, COLLECT [62], data reduction Denzo-SMN [63]; absorption correction [64]; structure solution SHELXT-2015 [65]; structure refinement SHELXL-2015 [66] and graphics, XP [67]. R-values are given for observed reflections, and wR² values are given for all reflections.

Exceptions and special features: For compound syn-25 three independent molecules were found in the asymmetric unit. All these three molecules present different groups disordered over two positions. Several restraints (SADI, SAME, ISOR and SIMU) were used in order to improve refinement stability.

5.5.2. X-ray Crystal Structure Analysis of syn-7

A colorless plate-like specimen of C₂₁H₂₇NO₄, approximate dimensions 0.100 mm × 0.200 mm × 0.350 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The integration of the data using a monoclinic unit cell yielded a total of 3302 reflections to a maximum θ angle of 67.19° (0.84 Å resolution), of which 3302 were independent (average redundancy 1.000, completeness = 97.6%, R_sig = 2.02%) and 3062 (92.73%) were greater than 2σ(F²). The final cell constants of a = 6.9404(2) Å, b = 12.2651(4) Å, c = 22.3938(10) Å, β = 98.330(2)° and volume = 1886.15(12) ų were based upon the refinement of the XYZ-centroids of reflections above 20 σ(I). Data were corrected for absorption effects using the multi-scan method (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.7920 and 0.9330. The structure was solved and refined using the Bruker SHELXTL-2014/7 version Software Package, using the space group P2₁/c, with Z = 4 for the formula unit, C₂₁H₂₇NO₄. The final anisotropic full-matrix least-squares refinement on F² with 241 variables converged at R1 = 3.98%, for the observed data and wR2 = 9.96% for all data. The goodness-of-fit was 1.054. The largest peak in the final difference electron density synthesis was 0.198 e⁻/ų and the largest hole was −0.192 e⁻/ų with an RMS deviation of 0.034 e⁻/ų. On the basis of the final model, the calculated density was 1.259 g/cm³ and F(000), 768 e⁻. The hydrogen at N1 atom was refined freely. CCDC number: 2073466.

5.5.3. X-ray Crystal Structure Analysis of anti-21

A colorless prism-like specimen of C₂₈H₃₄N₂O₃, approximate dimensions 0.060 mm × 0.240 mm × 0.260 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The integration of the data using a monoclinic unit cell yielded a total of 4159 reflections to a maximum θ angle of 67.08° (0.84 Å resolution), of which 4159 were independent (average redundancy 1.000, completeness = 96.3%, R_sig = 2.90%) and 3509 (84.37%) were greater than 2σ(F²). The final cell constants of a = 8.5091(4) Å, b = 15.9061(5) Å, c = 17.8829(6) Å, β = 94.139(3)° and volume = 2414.08(16) ų were based upon the refinement of the XYZ-centroids of reflections above 20 σ(I). Data were corrected for absorption effects using the multiscan method (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.8530 and 0.9630. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P2₁/n, with Z = 4 for the formula unit, C₂₈H₃₄N₂O₃. The final anisotropic full-matrix least-squares refinement on F² with 304 variables converged at R1 = 7.05%, for the observed data and wR2 = 20.59% for all data. The goodness-of-fit was 1.041. The largest peak in the final difference electron density synthesis was 0.482 e⁻/ų and the largest hole was −0.353 e⁻/ų with an RMS deviation of 0.056 e⁻/ų. On the basis of the final model, the calculated density was 1.229 g/cm³ and F(000), 960 e⁻. The hydrogen at N2 atom was refined freely. CCDC number: 2073467.

5.5.4. X-ray Crystal Structure Analysis of syn,anti-22

A colorless plate-like specimen of C₂₈H₃₆N₂O₃, approximate dimensions 0.150 mm × 0.170 mm × 0.270 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The integration of the data using a monoclinic unit cell yielded a total of 4152 reflections to a maximum θ angle of 67.18° (0.84 Å resolution), of which 4152 were independent (average redundancy 1.000, completeness = 96.1%, R_sig = 2.57%) and 3721 (89.62%) were greater than 2σ(F²). The final cell constants of a = 7.5886(3) Å, b = 16.0072(4) Å, c = 20.2378(5) Å, β = 100.377(2)° and volume = 2418.12(13) ų were based upon the refinement of the XYZ-centroids of reflections above 20 σ(I). Data were corrected for absorption effects using the multi-scan method (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) were 0.8490 and 0.9120. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P2₁/c, with Z = 4 for the formula unit, C₂₈H₃₆N₂O₃. The final anisotropic full-matrix least-squares refinement on F² with 307 variables converged at R1 = 4.36%, for the observed data and wR2 = 11.81% for all data. The goodness-of-fit was 1.031. The largest peak in the final difference electron density synthesis was 0.175 e⁻/ų and the largest hole was −0.164 e⁻/ų with an RMS deviation of 0.032 e⁻/ų. On the basis of the final model, the calculated density was 1.232 g/cm³ and F(000), 968 e⁻. The hydrogens at N2 and O1 atoms were refined freely. CCDC number: 2073468.

5.5.5. X-ray Crystal Structure Analysis of anti,syn-22

A colorless needle-like specimen of C₂₈H₃₆N₂O₃, approximate dimensions 0.020 mm × 0.070 mm × 0.270 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The integration of the data using a monoclinic unit cell yielded a total of 4164 reflections to a maximum θ angle of 66.92° (0.84 Å resolution), of which 4164 were independent (average redundancy 1.000, completeness = 95.5%, R_sig = 3.04%) and 3332 (80.02%) were greater than 2σ(F²). The final cell constants of a = 7.9714(2) Å, b = 27.7657(10) Å, c = 11.1029(5) Å, β = 95.285(3)° and volume = 2446.97(15) ų were based upon the refinement of the XYZ-centroids of reflections above 20 σ(I). Data were corrected for absorption effects using the multiscan method (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.8500 and 0.9880. The structure was solved and refined using the Bruker SHELXTL-2014/7 version Software Package, using the space group P2₁/c, with Z = 4 for the formula unit, C₂₈H₃₆N₂O₃. The final anisotropic full-matrix least-squares refinement on F² with 308 variables converged at R1 = 5.00%, for the observed data and wR2 = 13.22% for all data. The goodness-of-fit was 1.031. The largest peak in the final difference electron density synthesis was 0.131 e⁻/ų and the largest hole was −0.239 e⁻/ų with an RMS deviation of 0.044 e⁻/ų. On the basis of the final model, the calculated density was 1.218 g/cm³ and F(000), 968 e⁻. The hydrogens at N2 and O1 atoms were refined freely. CCDC number: 2073469.

5.5.6. X-ray Crystal Structure Analysis of syn-25

A colorless prism-like specimen of C₁₉H₂₂F₂N₂O₂, approximate dimensions 0.100 mm × 0.140 mm × 0.180 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The integration of the data using a triclinic unit cell yielded a total of 9040 reflections to a maximum θ angle of 67.31° (0.84 Å resolution), of which 9040 were independent (average redundancy 1.000, completeness = 96.6%, R_sig = 2.87%) and 7415 (82.02%) were greater than 2σ(F²). The final cell constants of a = 12.9305(5) Å, b = 13.0504(5) Å, c = 17.0932(4) Å, α = 112.037(2)°, β = 97.638(2)°, γ = 97.0010(10)° and volume = 2603.27(16) ų were based upon the refinement of the XYZ-centroids of reflections above 20 σ(I). Data were corrected for absorption effects using the multiscan method (SADABS). The calculated minimum and maximum transmission coefficients (based on crystal size) were 0.8630 and 0.9200. The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P-1, with Z = 6 for the formula unit, C₁₉H₂₂F₂N₂O₂. The final anisotropic full-matrix least-squares refinement on F² with 928 variables converged at R1 = 6.16%, for the observed data and wR2 = 18.77% for all data. The goodness-of-fit was 1.038. The largest peak in the final difference electron density synthesis was 1.261 e⁻/ų and the largest hole was −0.361 e⁻/ų with an RMS deviation of 0.044 e⁻/ų. On the basis of the final model, the calculated density was 1.333 g/cm³ and F(000), 1104 e⁻. The hydrogens at N1A, N2A, N1B, N2B, N1C and N2C atoms were refined freely. CCDC number: 2073470.

5.6. Receptor Binding Studies

The affinity towards σ₁ and σ₂ receptors was recorded according to the procedures given in the Supplementary Materials and ref [45,46,47].