A Novel Strategy Towards the Asymmetric Synthesis of Orthogonally Funtionalised 2-N-Benzyl-N-α-methylbenzylamino- 5-carboxymethyl-cyclopentane-1-carboxylic acid.

Abstract

The asymmetric synthesis of the orthogonally funtionalised compounds tert‑butyl 2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethylcyclopentane-1-carboxylate and methyl 2-N-benzyl-N-α-methylbenzylamino-5–carboxymethylcyclo-pentane-1-carboxylate by a domino reaction of tert-butyl methyl (E,E)-octa-2,6-diendioate with lithium N-α-methylbenzyl-N-benzylamide initiated by a Michael addition, subsequent 5-exo-trig intramolecular cyclisation and posterior selective hydrolysis with trifluoroacetic acid is reported.

Introduction

The asymmetric synthesis of polyfunctionalised cyclopentane derivatives has been widely pursued in organic synthesis, with much recent interest focusing around strategies for the asymmetric synthesis of cis-pentacin (1) and trans-pentacin (2), respectively. The cis-diastereoisomer shows potent antifungal activity while Fülop et al. have recently demonstrated that oligomers of cis-pentacin adopt a sheet type structure in DMSO [1]. Furthermore, Gellman et al. have demonstrated that short chain β-peptides derived from trans-pentacin adopt 12-membered helical structures [2,3,4,5] and when a pyrrolidine–base β-amino acid is incorporated into the hexa-β-peptide 3, it confers water solubility when the ring nitrogen is protonated [6,7]. In addition, oligomers composed of the 3-substituted trans-pentacin residues 4, 5 and 6 fold in water, which should facilitate the design of β-peptides for biological applications (Figure 1) [8].

Figure 1.

Figure 1.

We have recently demonstrated the asymmetric synthesis of the eight stereoisomers of 2‑amino-5-carboxymethyl-cyclopentane-1-carboxylate (I) using (E,E)-octa-2,6-diendioate as the only prochiral precursor [9], as shown in the retrosynthesis in Scheme 1. The set of trans-C(1)-C(2)-stereoisomeric β-amino diacids (II) are readily prepared via a diastereoselective tandem conjugate addition-cyclisation protocol with either R- or (S)-N-benzyl-N-α-methylbenzylamine [R- or (S)-7], hydrogenolysis and ester hydrolysis. The synthsis of the array of cis-C(1)-C(2)-stereoisomeric β-amino diacids utilises a protocol involving N‑oxidation and Cope elimination of the major diastereoisomeric product arising from conjugate addition and cyclisation (II), giving homochiral R- or (S)-5-carboxymethylcyclo-pentene-1-carboxylate derivatives (III). Conjugate addition of either lithium R- or (S)-7 and diastereoselective protonation with 2,6-di-tert-butyl phenol, hydrogenolysis and ester hydrolysis, gives the cis-C(1)-C(2)-stereoisomeric β-amino diacids (IV). With the β-aminodiacids in hand the synthesis of the orthogonally protected aminodiester was envisaged in order to give further options when trying to link the monomer to build the β-peptide.

Scheme 1.

Scheme 1.

Results and Discussion

We have obtained dimethyl and di-(1-ethylpropyl)(E,E)-octa-2,6-diendioate on a multigram scale using the method published by Scheffer et al. [10]. Treatment of sebacic acid with thionyl chloride followed by bromine, while irradiating the entire apparatus with a 300-W sunlamp and then the addition of alcohol (methanol or 1-ethylpropanol) produces the appropriate dibromodiester, which yields the required diendioate upon refluxing with DMF. It was not possible to obtain the convenient di‑tert-butyl diester using this procedure and we used the methodology developed by Mestres et al. [11,12,13,14] (Scheme 2) to obtain diunsaturated dicarboxylic acids by oxidative coupling of the dianions of unsaturated carboxylic acids.

The oxidative coupling of the dianion derived from crotonic acid (8), as shown in Scheme 3, afforded a 70% yield of a 2:1 mixture of (E,E)-octa-2,6-diendioic and (E)-5-vinyl-hex-2-endioic acids (9 and 10) that could be easily separated by crystallization of 9 [13]. Methylation of these diacids using diazomethane or methanol in acid media is quantitative. The di-tert-butyldiester 13 is obtained (67% after CC) by reaction of diacid 10 with trifluoroacetic anhydride and tert-butanol, but under the same conditions diacid 9 afforded an easily separable mixture of di-tert-butyl ester 14 (42%) and monoester 15 (57%) which upon further treatment with diazomethane produced the orthogonally protected tert-butyl methyl (E,E)-octa-2,6-diendioate 16. Compound 14 has been used to synthesize the aforementioned β-aminocyclopentanoic acid [9] and 16 provided two differentiated Michael acceptors to be tested with the homochiral lithium amide.

Scheme 2.

Scheme 2.

Addition of tert-butyl methyl (E,E)-octa-2,6-diendioate 16 to homochiral lithium (S)- N-benzyl-N-α-methylbenzylamine [(S)-7] gave a 90% yield of a 3:1 mixture of 17 and 18 (Scheme 3). The ratio was determined by integration of the respective methyl group signals of each compound observed at 3.44 and 3.62 ppm in the ¹H-NMR spectra (vide infra). The absolute configuration of this compound was established by obtaining 19 ([α]_D²⁶ +50.5; lit. [9] –51.3 for the enantiomer) by reaction of the 17/18 mixture with trifluoroacetic acid and then diazomethane. Therefore both compounds have the same configuration, consistent with the asymmetric addition of the lithium amine and anti alkylation of the enolate produced. The only difference being the chemoselectivity observed due to the different alkyl group in each Michael acceptor, giving a favorable addition to the less bulky methyl.

Scheme 3.

Scheme 3.

The X-ray structure of 19 [9] shows the carbonyl on C-1 almost perpendicular to the ring plane, consequently very shielded by the adjacent groups at C-2 and C-5. So the 18/19 mixture could be easily resolved upon treatment with trifluoroacetic acid in a short period of time, as only the lateral tert-butyl ester at C-5 is hydrolyzed, giving rise to the straightforwardly separable unreacted diester 18 (21%) and the acid compound 20 (61%) from which 19 is obtained as well by methylation with diazomethane.

All the spectroscopic assignments of 20 and 19 have been unambiguously established by ¹H-NMR techniques, including 2-dimensional homonuclear COSY, heteronuclear HMQC and HMBC (noteworthy signals are shown in Figure 2, each methyl group is clearly differentiated), nOe and ROESY experiments.

Figure 2.

Figure 2.

Conclusions

Crotonic acid is an excellent starting material to obtain the orthogonally substituted tert-butyl, methyl (E,E)-octa-2,6-diendioate, which upon treatment with lithium N-α-methylbenzyl-N-benzylamine stereoselectively yields both methyl 2-N-benzyl-N-α-methylbenzylamino-5-tert-butoxy-carbonylmethylcyclopentane-1-carboxylate and tert-butyl 2-N-benzyl-N-α-methylbenzylamino-5-methoxycarbonylmethylcyclopentane-1-carboxylate in a 3:1 ratio, resulting from a domino reaction started by a chemoselective asymmetric Michael addition and subsequent 5-exo-trig intramolecular cyclization. A chemo- and stereoselective tert-butyl hydrolysis of the mixture of reaction with trifluoroacetic acid provides the easily separable unreacted diester 20 (21%) and the acid compound methyl 2-N-benzyl-N-α-methylbenzylamino-5-carboxymethylcyclopentane-1-carboxylate (21) (61%).

Here we demonstrate an efficient strategy towards the synthesis of a cyclopentane β-aminodiester with three different orthogonal protecting groups on each functionality, which can then submitted to appropriate modifications for use in β-peptide synthesis. The extension of this strategy to the preparation of a range of different orthogonally substituted cyclopentane and cyclohexane derived β-amino acids is currently under investigation in our laboratory.