Asymmetric synthesis of (αS)-polyfluoroalkylated N-Boc-prolinols by the diethyl zinc-induced asymmetric Meerwein–Ponndorf–Verley reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones

Abstract

The reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones with diethyl zinc was investigated. As a result, asymmetric Meerwein–Ponndorf–Verley reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones proceeded smoothly with the use of 5 equiv. of diethyl zinc as a reducing agent in hexane at room temperature to give (αS)-polyfluoroalkylated N-Boc-prolinols in good yields (31–73%) with high diastereomer ratios (up to αR/αS = 7/93). The absolute configuration at the α-position of the major diastereomer is opposite to that obtained by the reduction of N-Boc-pyrrolidyl ketone with NaBH₄ in ethanol. Furthermore, we also achieved the tandem perfluorobutylation-MPV reduction of N-Boc-proline ethyl ester to give (αS)-perfluorobutylated N-Boc-prolinol as a sole diastereomer in 45% yield.

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Introduction

Meerwein–Ponndorf–Verley (MPV) reduction is a classic reaction in organic synthesis. The MPV reduction of ketones normally requires metal alkoxides, e.g., alkali metal and aluminium alkoxides.¹ Although there are a few successful examples of MPV reduction using diethyl zinc (Et₂Zn),² there have been no reports on stereoselective MPV reduction with Et₂Zn.

On the other hand, considerable attention has been focused on prolinol derivative-catalyzed asymmetric synthesis, since prolinol derivatives are some of the most important and versatile asymmetric organocatalysts in catalytic asymmetric reactions.³ Although α-trifluoromethylated aminoalcohols have been used as chiral ligands,⁴ a chiral auxiliary⁵ and organocatalysts,⁶ there have been few reports on asymmetric synthesis or the use of α-fluoroalkylated optically pure prolinol derivatives.⁷

Recently, we developed (αR)-polyfluoroalkylated prolinols based on the perfluoroalkyl-induced highly stereoselective reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones with sodium borohydride (NaBH₄) (a, Scheme 1).^7a In this paper, we describe not only the complementary synthesis of (αS)-polyfluoroalkylated prolinols by the asymmetric MPV-type reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones with Et₂Zn, but also the one-pot asymmetric synthesis of (αS)-polyfluoroalkylated prolinols by the tandem perfluorobutylation-asymmetric MPV-type reduction⁸ of N-Boc proline ethyl ester (b, Scheme 1).

Scheme 1 Complementary synthesis of (αR)- and (αS)-polyfluoroalkylated prolinols.

Results and discussion

As shown in Table 1, treatment of perfluorobutyl N-Boc-pyrrolidyl ketone (1a) with 5 equiv. of Et₂Zn in hexane at 0 °C gave α-polyfluorobutylated prolinol 2a in 29% yield as a mixture of stereoisomers with an αR : αS ratio of 29 : 71, together with recovery of the starting ketone 1a (54%) (entry 2).

Table 1 Screening of the asymmetric MPV-type reduction conditions

Entry	Reducing agents (equiv.)	Solvent	Conditions	Yield (%)	αR : αS^a
a Determined by GC analysis. b Previous work. See ref. 7a. c Isolated yields of both diastereomers.
1^b	NaBH4(3)	EtOH	rt, 7 h	2a (78)^c	>99 : <1
2	Et2Zn (5)	Hexane	0 °C, 24 h	2a (29)^c, 1a (54)	29 : 71
3	Et2Zn (5)	Hexane	rt, 24 h	2a (73)^c	8 : 92
4	Et2Zn (2)	Hexane	rt, 24 h	2a (41)^c, 1a (46)	8 : 92
5	i-Pr2Zn (5)	Hexane	rt, 24 h	2a (74)^c	17 : 83
6	Et2Zn (5)	Hexane	Reflux	2a (57)^c, 3a (13)	14 : 86

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Interestingly, the absolute configuration at the α-position of the major diastereomer produced by MPV reduction is opposite to that obtained by the reduction of perfluorobutylated N-Boc-pyrrolidyl ketone 1a with NaBH₄ in ethanol, as reported previously (entry 1).^7a MPV reduction of the ketone 1a with Et₂Zn at room temperature resulted in a large increase in the yield (73%) of prolinol 2a with a much better diastereomer ratio (αR/αS = 92/8) (entry 3). The diastereomers of 2a are separable by normal column chromatography with silica gel. However, two conformational isomers of (αS)-2a that arise from an amide moiety were observed by NMR spectroscopy. Employment of 2 equiv. of Et₂Zn gave 2a in only 41% yield, together with the 46% recovery of the starting ketone 1a (entry 4). The use of diisopropyl zinc (i-Pr₂Zn) in place of Et₂Zn lowered the isomer ratio from 8/92 to 17/83 (entry 5). A higher reaction temperature gave both a lower diastereomer ratio (14/86) and a lower yield (57%), together with 1-perfluoroalkylated oxazolidinone 3a in 13% yield, which was produced via the cyclization of (αS)-2a (entry 6). Based on these results, the optimized reaction conditions are given in entry 2, which requires 5 equiv. of Et₂Zn at room temperature.

Based on the screening of the reaction conditions in Table 1, other perfluoroalkyl N-Boc-pyrrolidyl ketones 1b,c,d carrying perfluorohexyl, perfluorooctyl, and trifluoromethyl groups were examined (Table 2). Perfluorohexylated and perfluorooctylated N-Boc-pyrrolidyl ketones 1b,c participated nicely in the MPV reduction with 5 equiv. of Et₂Zn to give the corresponding α-polyfluorohexylated and perfluorooctylated prolinols 2b,c in 67–70% yields with αR/αS isomer ratios of 7–8/92–93. The reaction of trifluoromethylated N-Boc-pyrrolidyl ketone 1d containing ketone hydrate did not proceed smoothly to give the corresponding α-trifluoromethylated prolinol 2d in 31% yield as a mixture of stereoisomers with an αR : αS ratio of 8 : 92, together with recovery of the starting ketone 1a containing its hydrate (41%) (entry 4).

Table 2 Et₂Zn-induced MPV-type asymmetric reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones (1)

Entry	Rf	Product	Yield (%)	αR : αS^b
a The mixture of ketone 1d–ketone hydrate (59/41) was used. b Determined by GC analysis. c The mixture of ketone 1d–ketone hydrate (87/13) was recovered in 41% yield.
1	CF3(CF2)3	2a	73	8 : 92
2	CF3(CF2)5	2b	70	7 : 93
3	CF3(CF2)7	2c	67	8 : 92
4	CF3	2d	31^c	8 : 92

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The stereochemistries at the α-position of α-perfluorobutylated prolinol (2a) produced by MPV reduction with Et₂Zn could be confirmed to be S based on the vicinal coupling constant of the obtained 1-perfluorobutylated oxazolidinone 3a. The coupling constant between two protons at C-7-a and C1 of the obtained 1-perfluorobutylated oxazolidinone 3a was 7.9 Hz, which is similar to that previously reported for n-butylated oxazolidinone (1S)-4, as shown in Fig. 1.^7a The stereochemical assignments for the other α-polyfluorobutylated prolinols 2b,c were made by comparison of the chemical shifts in ¹⁹F NMR with those of αR- and αS-2a.

Fig. 1 Determination of relative stereochemistry.

Based on the absolute stereochemistry at the α-carbon of (αS)-perfluorobutylated prolinol ((αS)-2a), a proposed transition state (TS) is shown in Fig. 2. A hydride transfers from an ethyl group of Et₂Zn to perfluoroalkyl N-Boc-pyrrolidyl ketone 1 through a transition state (TS), where not only chelation between zinc metal and two oxygen atoms of two carbonyl groups of ketone and Boc groups 1 but also the steric repulsion between bulkier N-Boc-pyrrolidyl and ethyl groups are crucial.

Fig. 2 A proposed transition state.

Finally, the one-pot asymmetric synthesis of (αS)-perfluoroalkylated N-Boc-prolinol (αS)-2a through tandem perfluoroalkylation-MPV reduction of N-Boc proline ethyl ester was examined (Scheme 2). After N-Boc-proline ethyl ester was subjected to perfluorobutylation by the reaction of iodoperfluorobutane with a methyllithium–lithium bromide complex for 6 h at −78 °C, the resulting mixture was gradually warmed to room temperature overnight. Consequently, the one-pot tandem perfluorobutylation-MPV reduction successfully proceeded to give the (αS)-perfluorobutylated N-Boc-prolinol (αS)-2a as a sole diastereomer in 45% yield.

Scheme 2 One-pot tandem perfluoroalkylation-MPV reduction of N-Boc proline ethyl ester leading to (αS)-perfluoroalkylated N-Boc-prolinol 2a.

Conclusions

In conclusion, we have developed an asymmetric Meerwein–Ponndorf–Verley reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones with the use of 5 equiv. of Et₂Zn as a reducing agent to give (αS)-polyfluoroalkylated N-Boc-prolinols in good yields (31–73%) with high diastereomer ratios (up to αR/αS = 8/92). This method represents a complementary asymmetric synthesis of (αS)-polyfluoroalkylated N-Boc-prolinols, of which the absolute configuration of at the α-position of the major diastereomer is opposite to that obtained by the reduction of N-Boc-pyrrolidyl ketone with NaBH₄ in ethanol. Furthermore, we have also achieved the tandem perfluorobutylation-MPV reduction of N-Boc-proline ethyl ester to give (αS)-perfluorobutylated N-Boc-prolinol (αS)-2a as a sole diastereomer in 45% yield.

Acknowledgements

We thank Professor T. Konno of the Kyoto Institute of Technology for the HRMS measurements.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00008d

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