Chiral hexahydropyrrolo[2,1-b ][1,3]thiazoles

Chiral hexahydropyrrolo[2,1-b ][1,3]thiazoles 11 − 16 were obtained in 56 − 82% yields via the nucleophilic substitutions of ethyl (3 R ,5 S ,7a S )-5-(1 H -1,2,3-benzotriazol-1-yl)hexahydropyrrolo [2,1-b ][1,3]thiazole-3-carboxylate 10 with benzenethiol, NaCN, triethyl phosphite, allyl silanes, silyl enol ethers, or PhZnCl. The D.e. values at the 5-position range from 50% to >99% depending on the nucleophiles.


Results and Discussion
Synthesis of chiral benzotriazolyl intermediates 10.Reaction of L-cysteine ethyl ester hydrochloride 8 with succindialdehyde (9, obtained in situ by treatment of 2,5dimethoxytetrahydrofuran with 0.1 M HCl) and benzotriazole in CH 2 Cl 2 at room temperature for 24 h readily afforded benzotriazol-1-yl intermediate 10 in 88% yield as a single enantiomer (Scheme 1).The stereochemistry of 10 was determined by NOE NMR experiments.The 1 H NMR spectrum of 10 shows that H(3), H(7a) and H(5) appear at 4.31 ppm (doublet-doublet), 5.36 ppm (doublet) and 5.94 ppm (doublet-doublet), respectively.A significant positive NOE effect was observed between H(3) and H(5), and no NOE effect was observed between H(7a) with either H(3) or H(5).Thus, NOE analysis demonstrates that in 10 H(3) and H(5) are in cisorientation; while H(3) and H(7a) are in trans-orientation.The relative configurations in 10 are consistent with the previous oxygen analogue 1. 1     evidences for its absolute configuration determination, since the oily product is not fit for X-ray analysis and the α-H of cyclohexanone is overlapped with other protons.However, the absolute configuration at the 5-position in 15b indicates that the silyl enol ether attacks the iminium cation intermediate below the imine plane.We believe that route A is more favorable than route B, due to the larger repulsion between the cyclohexene and the iminium cation ring systems for route B. Thus attack A leads to enantiopure 15b; none of 15b′ was observed.Furthermore, the conformation in 15b is more stable than the conformation in 15b′ due to the larger gauche butane interaction in 15b′.Therefore, the new chiral center is believed to have R-configuration (c.f.Scheme 2).

Scheme 2
Our result (anti configuration between the 5-position and the new chiral center in 15b) is also consistent with the reported anti configuration of β-amino ketones via reactions of iminium cations with enamines. 8cleophilic substitutions of 10 with PhZnCl.(c.f.entry i in Table 1) In order to keep the ester group in 10, we used a weaker nucleophile, i.e., PhZnCl, obtained in situ by the treatment of phenylmagnesium bromide with ZnCl2.The nucleophilic substitutions of 10 with PhZnCl afforded the desired compound 16 in 65% yield with the major diastereoisomer having Rconfiguration at the 5-position.The D.e. value can be improved from 50% (using 1.5 equivalents of ZnCl2 based on PhMgBr) to 60% (using 4 equivalents of ZnCl2 based on PhMgBr).The reason is probably that the Lewis acid, ZnCl2, facilitates loss of the benzotriazolyl anion to form an iminium cation, which undergoes SN1 nucleophilic substitutions.Thus the addition of more ZnCl2 avoids SN2 nucleophilic substitutions leading to an inversion of the absolute configuration at the 5-position.
Compared to the configuration of Bt intermediate 10, the absolute configurations at the 5position remains unchanged in the major diastereoisomers of 11−16.This result is consistent with our previous report on the nucleophilic substitution of oxygen analogue 1 with PhZnCl. 1 Thus we believe that the nucleophilic substitutions of 10 should predominantly undergo S N 1 route instead of S N 2 route and that thermodynamic stability may play an important role on the determination of stereochemistry of final products.
In summary, we have developed a straightforward and efficient route to chiral hexahydropyrrolo [

Experimental Section
General Procedures.Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1H NMR (300 MHz), 13 C NMR (75 MHz) and NOE spectra were recorded on a Gemini 300 NMR spectrometer in CDCl 3 (with TMS for 1 H and chloroform-d for 13 C as the internal reference).HRMS were measured on an AEI-30 mass spectrometer.Elemental analyses were performed on a Carlo Erba-1106 instrument.Optical rotation values were measured by a Perkin-Elmer 341 polarimeter with the use of the sodium D line.Column chromatography was performed on silica gel (200−425 mesh), unless otherwise stated.All of the reactions were carried out under N 2 .

General procedure for the preparation of Bt intermediates
A mixture of 2,5-dimethoxytetrahydrofuran (0.66 g, 5.1 mmol) and HCl aqueous solution (0.1 M, 20 mL) was heated to 100 °C for 45 mins, then cooled to room temperature.CH 2 Cl 2 (40 mL), benzotriazole (0.61 g, 5.1 mmol) and L-cysteine ethyl ester hydrochloride (8, 0.93 g, 5 mmol) were successively added and stirred at room temperature for 24 h.The reaction mixture was washed with saturated Na 2 CO 3 solution and the aqueous phase was extracted with CH 2 Cl 2 .The combined organic phase was washed with brine and dried over anhydrous Na 2 SO 4 .After removal of the solvent in vacuo, the residue was purified by neutral alumina (80−200 mesh) column chromatography with hexanes/EtOAc

Procedure for the reaction of 10 with benzenethiol
To a solution of benzenethiol (0.33 g, 3.0 mmol) in dry THF (20 mL), NaH (60% in mineral oil, 0.10 g, 4 mmol) was added, and the mixture was stirred at 25 °C for 30 mins.One drop of methanol was added to quench excess NaH and then Bt intermediate 10 (0.64 g, 2 mmol) was added.The mixture was stirred at 25 °C for 24 h.After removal of THF in vacuo, 10% aqueous Na 2 CO 3 was added to the residue and the aqueous layer was extracted with CH 2 Cl 2 .The combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4 .After removal of the solvent in vacuo, the residue was purified by neutral alumina (80−200 mesh) column chromatography with hexanes/EtOAc (2:1) as an eluent to give 11.

Procedure for the reaction of 10 with NaCN
A mixture of NaCN (0.1 g, 2.0 mmol) and 10 (0.48 g, 1.5 mmol) in DMSO (7 mL) was stirred at 25 °C for 20 h.The solution was diluted with EtOAc and washed with 5% Na 2 CO 3 , brine and dried over anhydrous Na 2 SO 4 .After removal of the solvent in vacuo, the residue was purified by silica gel column chromatography with hexanes/EtOAc (5:  Procedure for the reaction of 10 with triethyl phosphite.To a solution of 10 (0.64 g, 2.0 mmol) in dry CH 2 Cl 2 (20 mL) at 0 °C, ZnBr 2 (0.89 g, 4.0 mmol) and triethyl phosphite (0.68 mL, 4.0 mmol) were sequentially added.The reaction mixture was stirred at 0 °C for 1 h and at room temperature overnight, and then quenched with 10% Na 2 CO 3 .After extraction with CH 2 Cl 2 , the combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 .After removal of the solvent in vacuo, the desired product 13 was purified by column chromatography (silica gel) with hexanes/EtOAc (2:1) as an eluent.

General procedure for the reaction of 10 with allyl silanes and silyl enol ethers
To a solution of 10 (0.64 g, 2.0 mmol) and allyl silanes (3 mmol) or silyl enol ethers (3 mmol) in dry CH 2 Cl 2 (10 mL), was added BF 3 • Et 2 O (0.36 mL, 3 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h and at 25 °C overnight.The mixture was quenched with 10% Na 2 CO 3 and extracted with CH 2 Cl 2 .The combined organic layers were dried over anhydrous Na 2 SO 4 .After removal of the solvent in vacuo, the residue was purified by column chromatography (silica gel) with hexane/EtOAc (5 : 1) as eluent to afford 14a,b or 15a−c.
Therefore, four new bonds are simultaneously formed in one step to generate the hexahydropyrrolo[2,1-b][1,3]thiazole ring system.

Table 1 .
Isolated yields and D. e. values for

Nucleophilic substitutions of 10 with allyl silanes or silyl enol ethers. Nucleophilic
H,13C NMR spectra and microanalyses results.bTheD.e. values were determined by the 1 H NMR spectra.