Development of Guanidine-Bisurea Bifunctional Organocatalysts with a Chiral Pyrrolidine Moiety and Application to α-Hydroxylation of Tetralone-Derived β-Keto Esters

Abstract

Novel guanidine-bisurea bifunctional organocatalysts 5 bearing a chiral pyrrolidine moiety on guanidine were designed with the guidance of DFT calculations. The resulting organocatalysts 5 were examined for α-hydroxylation of tetralone-derived β-keto esters, and good selectivity was obtained with 5j bearing a methoxymethyl ether-containing chiral pyrrolidine moiety.

1. Introduction

We have reported a series of structurally flexible guanidine-bis(thio)urea organocatalysts 1 and 2 for asymmetric reactions (Figure 1A) [1,2], including Henry reactions [3], Mannich-type reactions [4,5], Michael reactions [6,7], and Friedel-Crafts reactions [8,9]. In these reactions, guanidine and (thio)urea groups in the catalysts are proposed to interact with nucleophiles and electrophiles, respectively, and new bond-forming processes proceed efficiently due to synergistic proximity. Moreover, chiral spacers connecting the guanidine and (thio)urea groups in the catalysts serve to construct a chiral environment for the reaction transition state, enabling highly enantioselective reactions to occur.

We have recently developed an enantioselective α-hydroxylation of tetralone-derived β-keto esters 3 by utilizing guanidine-urea catalyst 2a in the presence of cumene hydroperoxide (CHP), affording the α-hydroxylation products 4 in high yield with high enantioselectivity (Figure 1B) [10]. We considered that guanidine interacts with β-keto ester, and the urea group activates CHP, and we performed DFT calculations to examine the feasibility of this idea [11]. The calculations indicated that enolate interacts with functional groups of guanidine and urea in the catalyst, and the remainder of the urea group activates the oxidant, CHP. Moreover, steric interactions between the R group of guanidine and the substituent of the Bn group in the chiral spacer were revealed to contribute to construction of the chiral reaction environment (Figure 2). Based on the calculated transition state model, we focused on shifting the chiral site in the catalyst from the spacer to the substituent on guanidine. By shifting the chiral site, an alternative control of the chiral environment was expected, and we designed compounds 5 as a novel type of guanidine-bisurea bifunctional catalysts (Figure 2) [12]. In the previous catalyst 2a, chiral spacers were synthesized from the corresponding amino acids, and their diversity was limited. On the other hand, various substituents can be installed in the R⁴ group at the optically active pyrrolidine moiety in compound 5, so it should be possible to construct a range of chiral environments. In this paper, we describe the synthesis of a new type of guanidine-bisurea bifunctional catalysts 5, as well as their application to α-hydroxylation of tetralone-derived β-keto esters 3a [13,14,15,16,17].

Figure 1. (A) Structures of guanidine-bis(thio)urea bifunctional organocatalysts 1 and 2; (B) α-Hydroxylation of tetralone-derived β-keto ester 3 using 2a.

Figure 1. (A) Structures of guanidine-bis(thio)urea bifunctional organocatalysts 1 and 2; (B) α-Hydroxylation of tetralone-derived β-keto ester 3 using 2a.

Figure 2. Design of our chiral pyrrolidine-derived guanidine-bisurea bifunctional organocatalysts 5.

Figure 2. Design of our chiral pyrrolidine-derived guanidine-bisurea bifunctional organocatalysts 5.

2. Results and Discussion

Using the synthetic route established for 1 and 2, we examined the introduction of a chiral pyrrolidine 7b [18] into thiourea 6 to generate chiral guanidine 8 (Scheme 1). However, the reaction did not proceed under various conditions. Thus, we concluded that the reactivity of chiral pyrrolidine 7b may be too low owing to steric hindrance of the 2,5-substituents.

Scheme 1. Failure to obtain guanidine 8 from 6 and 7b.

Scheme 1. Failure to obtain guanidine 8 from 6 and 7b.

Then, we changed the introduction order of pyrrolidine 7 (Scheme 2). Thus, reaction of pyrrolidine 7b with isothiocyanate 10, obtained from NHBoc azide 9, in the presence of mercury (II) chloride gave corresponding thiourea 11b in 74% from 9. After conversion of the thiourea 11b into methyl pseudo-thiourea 12b by treatment with methyl iodide, the resulting 12b was reacted with amine 13 in the presence of mercury (II) chloride and triethylamine to give guanidinium salt 14b, which was further reacted with benzyloxycarbonyl chloride in the presence of triethylamine to give Cbz-protected guanidine 15b in 16% yields. Then, reduction of azide and deprotection of Cbz group took place simultaneously by hydrogenolysis in the presence of Pd(OH)₂, and resulting diamine was reacted with 3,5-bis(trifuluoromethyl)-phenyl isocyanate 16 to give guanidine-bisurea 5b in 33% from 15b. Based upon the present route (Scheme 2), 5c–j (R = n-Pr, n-Decyl, Bn, CH₂(1-Naphthyl), CH₂(2-Naphthyl), TBS and TIPS) were obtained by changing the R⁴ group on the chiral pyrrolidine, respectively. Furthermore, guanidine-bisurea catalyst 5a, which has hydroxyl group on the chital pyrrolidine, was synthesized from catalyst 5h by deprotection of TBS ether with hydrochloric acid (Scheme 3).

Scheme 2. Synthesis of chiral pyrrolidine-derived guanidine-bisurea bifunctional organocatalysts 5b.

Scheme 2. Synthesis of chiral pyrrolidine-derived guanidine-bisurea bifunctional organocatalysts 5b.

Scheme 3. Synthesis of chiral pyrrolidine-derived guanidine-bisurea bifunctional organocatalyst 5a.

Scheme 3. Synthesis of chiral pyrrolidine-derived guanidine-bisurea bifunctional organocatalyst 5a.

With the novel guanidine-bisurea catalysts 5a–j in hand, α-hydroxylation of tetralone-derived keto ester 3a was examined (Table 1). The reaction was carried out by following conditions, i.e., CHP (1.2 equiv.), K₂CO₃ (1 equiv.) in toluene at 0 °C, which we previously reported as optimized conditions in the presence of catalyst 2a. In case of 5a, catalytic activity was low, and hydroxylation product 4a was only obtained in 5% with 30% ee (entry 1). Then, 5b–d with alkyl ether groups of methyl, n-propyl, and n-decyl ethers were examined. In these cases, reactivities were increased, and moderate yield of 4a was obtained in 49%, 49% and 47%, respectively. Moreover, moderate enantioselectivities (38%–50% ee) were obtained (entries 2–4). Then, benzyl, 1-naphtylmethyl, and 2-naphtylmethyl ethers of 5e–g were explored as catalyst with expecting more effective interactions between oxidant of CHP with catalyst through the π-π interactions (entries 5–7). Unfortunately, however, reactivities and selectivities were still moderate, and hydroxylated 4a was obtained with 36%, 58%, 55% yield in 30%, 40%, and 32% ee, respectively. In case of more bulky substituents of silyl ethers of TBS 5h and TIPS 5i, reactivity was slightly increased, however, selectivity was still moderate (entries 8 and 9). On the other hand, compound 5j which has methoxymethyl (MOM) ether group catalyzed the reaction efficiently, and hydroxylated 4a was obtained with 73% yield in 65% ee, which were the best results among the catalysts we examined. Since the MOM group has two oxygen atoms, we currently proposed that those two oxygen atoms might considerably contribute the construction of chiral reaction environment through the chelations of multidentate nature of potassium with β-keto ester (Figure 3) [19,20]. Actually, by changing the base from potassium carbonate to cesium carbonate, which has bigger size of cation radius than potassium, enantioselectivity was dropped to 48% ee without affecting the reactivity (73% yield, Table 1, entry 11). Further improvements of the selectivity for the reaction by utilizing new type of catalysts 5 are in progress based upon the present findings.

Figure 3. Plausible transition state model of α-hydroxylation of 3a in the presence of 5j.

Figure 3. Plausible transition state model of α-hydroxylation of 3a in the presence of 5j.

Table 1. Investigation of α-hydroxylation of 3a using 5^a.

Entry	5		4a
		R4	Yield [%] b	ee [%] c
1	5a	H	5	30
2	5b	Me	49	38
3	5c	n-Pr	49	50
4	5d	n-Decyl	47	47
5	5e	Bn	36	30
6	5f	CH2(1-Naphtyl)	58	40
7	5g	CH2(2-Naphtyl)	55	32
8	5h	TBS	55	49
9	5i	TIPS	63	34
10	5j	MOM	73	65
11 d	5j	MOM	73	48

^a Reaction conditions: 3a (0.1 mmol), CHP (0.12 mmol) and K₂CO₃ (0.1 mmol) in the presence of 5 (5 mol %) in toluene (2.0 mL) at 0 °C for 24 h. ^b Isolated yield. ^c Determined by HPLC analysis using a chiral stationary phase. ^d Cs₂CO₃ (0.1 mmol) was used instead of K₂CO₃ as a base.

Table 1. Investigation of α-hydroxylation of 3a using 5^a.

Entry	5		4a
		R4	Yield [%] b	ee [%] c
1	5a	H	5	30
2	5b	Me	49	38
3	5c	n-Pr	49	50
4	5d	n-Decyl	47	47
5	5e	Bn	36	30
6	5f	CH2(1-Naphtyl)	58	40
7	5g	CH2(2-Naphtyl)	55	32
8	5h	TBS	55	49
9	5i	TIPS	63	34
10	5j	MOM	73	65
11 d	5j	MOM	73	48

^a Reaction conditions: 3a (0.1 mmol), CHP (0.12 mmol) and K₂CO₃ (0.1 mmol) in the presence of 5 (5 mol %) in toluene (2.0 mL) at 0 °C for 24 h. ^b Isolated yield. ^c Determined by HPLC analysis using a chiral stationary phase. ^d Cs₂CO₃ (0.1 mmol) was used instead of K₂CO₃ as a base.

3. Experimental Section

3.1. General Remarks

Flash chromatography was performed using silica gel 60 (spherical, particle size 0.040–0.100 mm. Kanto Co., Tokyo, Japan). Optical rotations were measured on a JASCO P-2200 polarimeter (JASCO, Tokyo, Japan). ¹H- and ¹³C-NMR spectra were recorded on AL300 (JEOL), ECX400 (JEOL), or AVANCE400 (Bruker) instruments (JEOL, Tokyo, Japan). Chemical shifts in [d₄]MeOH was reported in the scale relative to [d₄]MeOH (δ = 3.30 ppm) for ¹H-NMR spectroscopy. For ¹³C-NMR spectra, chemical shift was reported in the scale relative to [d₄]MeOH (δ = 49.0 ppm) (internal reference). Mass spectra were recorded on a JMS-T100LC (JEOL) spectrometer (JEOL). HPLC analysis on a chiral stationary phase was performed on JASCO 800-series instruments (JASCO). A Daicel Chiralpak AD-H column (0.46 cm × 25 cm) was used with hexane/ethanol as the eluent.

3.2. Typical Procedure for α-Hydroxylation of β-Keto Ester 3a Using 5

A test tube equipped with a magnetic stirring bar was charged with catalyst 5 (0.005 mmol), tetralone-derived β-keto ester 3a (0.1 mmol), K₂CO₃ (0.1 mmol), and toluene (2.0 mL) at room temperature. The mixture was cooled to 0 °C and stirred for 10 min. Then, cumene hydroperoxide (0.12 mmol) was added, and stirring was continued at 0 °C for 24 h. The reaction mixture was directly purified by column chromatography on silica gel (n-hexane/ethyl acetate 50:1 to 20:1) to give the product 4a. Enantiomeric excess and absolute configuration were determined by HPLC analysis of the product on a chiral column (DAICEL Chiralpak AD-H) with n-hexane/2-propanol (95:5).

3.3. Characterizations of Novel Guanidine-Bisurea Bifunctional Organocatalysts 5a–j

5a: ${\left[\alpha \right]}_D^{25}$ = +41.6 (c 2.1, MeOH); ¹H-NMR (300 MHz, CD₃OD) δ 7.98 (s, 4H), 7.43 (s, 2H), 4.13 (brs, 2H), 3.61 (dd, J = 11.0 Hz, 2H), 3.52–3.37 (m, 10H) 3.33–3.24 (m, 2H), 2.22–2.02 (m, 2H), 1.95–1.77 (m, 2H); ¹³C-NMR (75 MHz, CD₃OD) δ 159.8, 158.8, 144.0, 133.9 (q, J_C-F = 32.6 Hz), 125.6 (q, J_C-F = 271.3 Hz), 119.9, 116.5, 64.4, 64.1, 46.7, 41.1, 28.3 ; HRMS (ESI, M-Cl) calcd for C₂₉H₃₂F₁₂N₇O₄ 770.2324, found 770.2364.

5b: ${\left[\alpha \right]}_D^{25}$ = +38.3 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CD₃OD) δ 7.99 (s, 4H), 7.43 (s, 2H), 4.21 (brs, 2H), 3.53–3.24 (m, 12H), 3.19 (s, 6H), 2.22–2.03 (m, 2H), 1.87–1.69 (m, 2H); ¹³C-NMR (75 MHz, CD₃OD) δ 160.2, 158.7, 144.1, 133.9 (q, J_C-F = 33.2 Hz), 125.6 (q, J_C-F = 272.4 Hz), 119.8, 116.5, 75.5, 62.1, 60.3, 46.7, 40.9, 28.6; HRMS (ESI, M-Cl) calcd for C₃₁H₃₆F₁₂N₇O₄ 798.2637, found 798.2594.

5c: ${\left[\alpha \right]}_D^{25}$ = +49.2 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CD₃OD) δ 8.01 (s, 4H), 7.46 (s, 2H), 4.24 (brs, 2H), 3.53–3.12 (m, 16H), 2.28–2.08 (m, 2H), 1.94–1.76 (m, 2H), 1.52–1.37 (m, 4H), 0.78 (t, J = 7.2 Hz, 6H); ¹³C-NMR (75 MHz, CD₃OD) δ 159.9, 158.8, 144.1, 134.0 (q, J_C-F = 32.6 Hz), 125.6 (q, J_C-F = 271.3 Hz), 119.8, 116.5, 75.1, 73.4, 62.3, 46.9, 41.0, 28.9, 24.7, 11.7; HRMS (ESI, M-Cl) calcd for C₃₅H₄₄F₁₂N₇O₄ 854.3263, found 854.3236.

5d: ${\left[\alpha \right]}_D^{25}$ = +30.4 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CD₃OD) δ 8.02 (s, 4H), 7.44 (s, 2H), 4.23 (brs, 2H), 3.51–3.23 (m, 16H), 2.25–2.06 (m, 2H), 1.89–1.74 (m, 2H), 1.48–1.31 (m, 4H), 1.30–1.05 (m, 28H), 0.82 (t, J = 6.5 Hz, 6H); ¹³C-NMR (75 MHz, CD₃OD) δ 159.9, 158.7, 144.1, 134.0 (q, J_C-F = 33.2 Hz) 125.6 (q, J_C-F = 272.4 Hz), 119.8, 116.5, 73.5, 62.3, 46.9, 41.0, 33.9, 31.6, 31.4, 31.3, 28.9, 28.0, 24.6, 15.3; HRMS (ESI, M-Cl) calcd for C₄₉H₇₂F₁₂N₇O₄ 1050.5454, found 1050.5491.

5e: ${\left[\alpha \right]}_D^{25}$ = +21.5 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CD₃OD) δ 7.97 (s, 4H), 7.44 (s, 2H), 7.28–7.11 (m, 10H), 4.39 (s, 4H), 4.29 (brs, 2H), 3.52 (dd, J = 9.6 Hz, 2H), 3.45–3.17 (m, 10H), 2.28–2.10 (m, 2H), 1.91–1.78 (m, 2H); ¹³C-NMR (75 MHz, CD₃OD) δ 159.8, 158.8, 144.0, 140.0, 133.9 (q, J_C-F = 33.2 Hz), 130.3, 129.8, 129.7, 125.6 (q, J_C-F = 272.4 Hz), 119.8, 116.5, 75.2, 72.7, 62.1, 46.9, 40.9, 28.8; HRMS (ESI, M-Cl) calcd for C₄₃H₄₄F₁₂N₇O₄ 950.3263, found 950.3240.

5f: ${\left[\alpha \right]}_D^{25}$ = −3.8 (c 1.4, CHCl₃); ¹H-NMR (400 MHz, CD₃OD) δ 7.92 (s, 4H), 7.77–7.62 (m, 8H), 7.41 (s, 2H), 7.38–7.27 (m, 6H), 4.54 (s, 4H), 4.33 (brs, 2H), 3.58 (dd, J = 10.1 Hz, 2H), 3.45 (dd, J = 9.6 Hz, 2H), 3.37–3.12 (m, 8H), 2.34–2.11 (m, 2H), 1.97–1.80 (m, 2H); ¹³C-NMR (100 MHz, CD₃OD) δ 159.8, 158.7, 143.9, 137.4, 135.4, 135.3, 133.9 (q, J_C-F = 33.6 Hz), 130.1, 129.7, 129.5, 128.7, 128.1, 127.9, 127.7, 125.6 (q, J_C-F = 272.2 Hz), 119.9, 116.6, 75.4, 72.8, 62.2, 46.8, 40.9, 28.6; HRMS (ESI, M-Cl) calcd for C₄₉H₄₄F₁₂N₇O₄ 1050.3576, found 1050.3596.

5g: ${\left[\alpha \right]}_D^{25}$ = −7.7 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CD₃OD) δ 7.93 (s, 4H), 7.75–7.63 (m, 8H), 7.42 (s, 2H), 7.38–7.30 (m, 6H), 4.57 (s, 4H), 4.34 (brs, 2H), 3.60 (dd, J = 10.0 Hz, 2H), 3.47 (dd, J = 10.0 Hz, 2H), 3.37–3.15 (m, 8H), 2.31–2.15 (m, 2H), 2.01–1.84 (m, 2H); ¹³C-NMR (100 MHz, CD₃OD) δ 159.7, 158.7, 143.9, 137.4, 135.4, 135.2, 133.9 (q, J_C-F = 32.6 Hz), 130.1, 129.7, 129.5, 128.6, 128.0, 127.9, 127.7, 125.6 (q, J_C-F = 272.2 Hz), 119.8, 116.5, 75.3, 72.8, 62.2, 46.8, 40.8, 28.8; HRMS (ESI, M-Cl) calcd for C₄₉H₄₄F₁₂N₇O₄ 1050.3576, found 1050.3529.

5h: ${\left[\alpha \right]}_D^{25}$ = −25.6 (c 1.0, CHCl₃); ¹H-NMR (400 MHz, CD₃OD) δ 8.04 (s, 4H), 7.46 (s, 2H), 4.19 (brs, 2H), 3.70 (dd, J = 10.5 Hz, 2H), 3.61–3.38 (m, 10H), 2.25–2.10 (m, 2H), 1.97–1.85 (m, 2H), 0.79 (s, 18H), −0.03 (s, 6H), −0.04 (s, 6H); ¹³C-NMR (100 MHz, CD₃OD) δ 159.2, 158.8, 144.1, 134.0 (q, J_C-F = 33.6 Hz), 125.6 (q, J_C-F = 272.2 Hz), 119.9, 116.6, 65.0, 64.0, 47.6, 41.0, 28.8, 27.1, 19.8, −4.57, −4.65; HRMS (ESI, M-Cl) calcd for C₄₁H₆₀F₁₂N₇O₄Si₂ 998.4054, found 998.4007.

5i: ${\left[\alpha \right]}_D^{25}$ = −30.7 (c 1.0, CHCl₃); ¹H-NMR (300 MHz, CD₃OD) δ 8.04 (s, 4H), 7.50 (s, 2H), 4.23 (brs, 2H), 3.83 (dd, J = 10.7 Hz, 2H), 3.63 (dd, J = 10.7 Hz, 2H), 3.56–3.36 (m, 8H), 2.33–2.15 (m, 2H), 2.11–1.92 (m, 2H), 1.11–0.93 (m, 42H); ¹³C-NMR (100 MHz, CD₃OD) δ 159.5, 158.4, 144.1, 134.1 (q, J_C-F = 32.6 Hz), 125.7 (q, J_C-F = 271.3 Hz), 119.8, 116.7, 65.1, 64.2, 48.3, 40.9, 28.8, 19.3, 13.9; HRMS (ESI, M-Cl) calcd for C₄₇H₇₂F₁₂N₇O₄Si₂ 1082.4993, found 1082.4969.

5j: ${\left[\alpha \right]}_D^{25}$ = +16.8 (c 1.0, CHCl₃); ¹H-NMR (400 MHz, CD₃OD) δ 8.02 (s, 4H), 7.46 (s, 2H), 4.51 (s, 4H), 4.31 (brs, 2H), 3.57 (m, J = 10.5 Hz, 2H), 3.53–3.43 (m, 10H), 3.24 (s, 6H), 2.30–2.17 (m, 2H), 1.98–1.84 (m, 2H); ¹³C-NMR (100 MHz, CD₃OD) δ 159.7, 158.8, 144.0, 133.9 (q, J_C-F = 32.6 Hz), 127.0 (q, J_C-F = 272.2 Hz), 119.9, 116.5, 98.6, 70.0, 62.1, 56.6, 46.9, 40.1, 28.7 ; HRMS (ESI, M-Cl) calcd for C₃₃H₄₀F₁₂N₇O₆ 858.2848, found 858.2828.

¹H- and ¹³C-NMR date for chiral pyrrolidine-derived guanidine-bisurea bifunctional organocatalysts 5a–j were in the supplementary material.

4. Conclusions

In summary, we have designed novel guanidine-bisurea bifunctional organocatalysts 5, which have chiral substituents on the pyrrolidine ring, based on the DFT calculation experiments. Synthesis of compound 5 was accomplished by changing the installation order of amines into isothiocyanate 11. Then, catalytic activity of the newly designed 5 was examined by enantioselective α-hydroxylation of β-keto ester 3a. In this reaction, 5j bearing MOM group on the chiral pyrrolidine moiety was effective, and hydroxylated product of 3a was obtained with 73% yield in 65% ee. We currently believe that two oxygen atoms in MOM group considerably contribute the regulation of transition state to construct chiral reaction environment through the chelations of potassium with β-keto esters. Further investigations about the transition state of this catalytic reaction are under way in our laboratory.