[147-85-3]  · C5H9NO2  · (S)-Proline  · (MW 115.15)

(chiral auxiliary1 in asymmetric synthesis)

Physical Data: mp 228-233 °C (dec.); [a]20D = -84° (c = 4, H2O); ninhydrin yellow in color.

Solubility: sol H2O, alcohol; insol ether.

Form Supplied in: white solid; widely available; inexpensive.

Analysis of Reagent Purity: measurement of optical rotation; mp.

Handling, Storage, and Precautions: cold and dry storage.

General Considerations.

In addition to its use in peptide chemistry, (S)-proline is often applied as a chiral precursor in the total syntheses of natural products, e.g. odorin,2 pumiliotoxin,3 petasinecine,4 or threonine.5 Some highly effective pharmaceuticals, such as optically pure ACE inhibitors, are prepared from L-proline.6 In the last two decades, (S)-proline has attracted much attention as an optically active auxiliary in asymmetric synthesis.

Asymmetric Aldolization.

Proline mediates the asymmetric aldol cyclization of the prochiral triketone (1a) to the optically active bicyclic enedione (S)-(3a) (eq 1).7,8 Optical yields up to 94% are realized, depending on the solvent used. The enedione (3) is prepared directly in the presence of an acid such as HClO4. In the absence of acid, the aldol (2) is frequently isolated. Among the amino acids tested, (S)-proline gives the best results in almost every case. With (S)-proline the (S) configured products (3) are usually obtained. Enediones such as (3) are important building blocks for the synthesis of steroids or alkaloids9 because natural steroids have the same configuration at C-13. Analogously, the Wieland-Miescher ketone (S)-(3e) is prepared with 70% ee from the cyclic prochiral triketone (1e) in the presence of (S)-proline.10 Optically pure enedione (S)-(3e) is obtained by a single crystallization of the product mixture having an enantiomeric excess over 50%.

An asymmetric aldolization was successfully applied to the preparation of gibbane.11 The total synthesis of the macrolide antibiotic erythromycin was developed involving an asymmetric aldolization step catalyzed by proline.12 Since the mid-1970s, a flood of papers has appeared dealing with the asymmetric aldolization of various triketones. Some results are listed for comparison in Table 1.

The intramolecular asymmetric cyclization of open chain symmetrical triketone (4) leading to (R)-(5) proceeds with 16% ee (eq 2).18

Even acyclic 1,5-diketones (6) are cyclized enantioselectivitely in the presence of (S)-proline.19 Depending on the structure of the cyclic a,b-unsaturated ketone, (R)-(7) is obtained in up to 43% (R = Me) optical yield (eq 3).

The mechanism of the proline-catalyzed enantioselective aldol reaction has been studied.20 An extension of the asymmetric aldolization deals with the cyclization of diketones.21 Also investigated was the dehydration of racemic b-ketols in the presence of (S)-proline and a kinetic resolution was observed.22

Asymmetric Michael Addition.

An intramolecular Michael reaction catalyzed by (S)-proline leads to the chiral thiadecalin (9) and thiahydrindan (11) and (12).23 Enone (8) undergoes cyclization in the presence of (S)-proline to give exclusively the trans isomer (9) (eq 4). The thiahydrindandions (11) and (12) are obtained from (10) as a 1:1 mixture of the cis and trans isomers (eq 5).

The intramolecular asymmetric Michael reaction of acyclic compounds obtained from chiral alkaloid building blocks using amines and (S)-proline has been investigated.24 The Michael addition of dimethyl malonate to a,b-unsaturated aldehydes proceeds smoothly with a catalytic amount of (S)-proline lithium salt.25 However, no asymmetric induction was observed.

Asymmetric Halolactonization.

An asymmetric halolactonization reaction using proline as a chiral auxiliary has been reported.26 Optically active a-hydroxy acids (16) are prepared from a,b-unsaturated acids via the corresponding (S)-proline amide (13) involving an asymmetric bromolactonization step (eq 6).26a

The unsaturated carboxylic acid (13) undergoes an asymmetric bromolactonization when treated with N-Bromosuccinimide in DMF. The bromolactone (14) and its diastereomer are obtained in a 94.5:5.5 ratio. Reduction and hydrolysis yields the a-hydroxy acid (16) in an overall optical yield of 90%. The same procedure gives chiral a-hydroxy ketones.26c

A modification of the asymmetric bromolactonization leads to optically active a,b-epoxy aldehydes (18).26d,e Treatment of the bromolactone (14) with Sodium Methoxide results in the formation of the epimeric epoxy ester (17) in a ratio of 2:1 (eq 7).

The reductive cleavage of the proline derivative yields the chiral a,b-epoxy aldehyde (2R,3S)-(18) in 98% ee. Even natural product syntheses can be realized utilizing the bromolactonization procedure.26h,i

Reduction of C=O and C=N Bonds.

Asymmetric reductions of prochiral ketones (19) to the corresponding chiral alcohols (20) using (S)-proline-modified borohydride reagents as the reductant have been published. The borane reductions of ketones (19) employing (S)-proline as chiral mediator proceeds with enantiomeric excesses up to >95%. It is proposed that the in situ produced (S)-prolinol reacts with borane to form the oxazaborolidine (S)-(21) as the reducing catalyst (eq 8).27

The (S)-prolinate-borane complex (S)-(22) reduces ketones to the corresponding alcohols with optical yields up to 50%.28 The asymmetric reduction of cyclic imines (24) with chiral sodium triacyloxyborohydride (S)-(23) was utilized to prepare optically active alkaloids (25) with optical yields up to 86% (eq 9).29

The hydrogenation of various ketones with heterogeneous Palladium on Carbon or Raney Nickel catalysts in the presence of (S)-proline proceeds to produce the corresponding optically active alcohols with low optical yields (up to 23%).30

Reduction of C=C Bonds.

The reduction of the C=C double bond of isophorone (26) with Pd/C in the presence of (S)-proline yields the saturated ketone (27) with 60% optical purity (eq 10).30a,31 With (S)-proline ester/Pd (or Pt) systems the hydrogenation of ethyl pyruvate, an a-keto ester, was investigated, but only insignificant enantioselectivities were reached.32

An efficient synthesis of (S)-amino acids from a-keto acids via a diastereoselective hydrogenation step with (S)-proline as the chiral inducer was reported (eq 11).33 Optical yields up to 90% were reached.

Racemization of Amino Acids.

The synthesis of (R)-alanine was achieved starting from (S)-alanine via formation of the imidazoline with (S)-proline.34 This result can be explained in terms of epimerization and stereoselective protonation with asymmetric induction by the chiral center originating from (S)-proline.

Resolution of Amino Acids.

For the optical resolution of racemic threonine via replacing resolution, (S)-proline was utilized as an optically active cosolute although the structure of the imino acid is different from that of threonine.35 The same procedure was applied less sucessfully to the resolution of (R,S)-thiazolidine carboxylic acid.36

Synthesis of Unnatural (S)-Proline Derivatives.

The condensation of pivaladehyde with (S)-proline yields stereoselectively, after lithiation and reaction with an electrophile, the bicyclic compound (28), which is a versatile educt for the synthesis of many a-substituted proline analogs (29) (eq 12).37 The reactions proceed via the formation of a chiral lithium enolate without the use of a chiral auxiliary (self-reproduction of chirality). The reaction with a variety of electrophiles cis to the t-Bu group yields a plethora of a-substituted (S)-proline derivatives (29). A limitation of this strategy is the acetal cleavage of some substituted products (28).38

The b-amino acid homoproline can be synthesized via an Arndt-Eistert reaction from (S)-proline.39

Synthesis of Optically Active Phophorus Compounds.

A series of chiral organophosphorus compounds (33) have been prepared in which the phophorus atom is the stereogenic center (eq 13).40 The best stereoselectivity is reached with (S)-proline esters (30) as the chiral auxiliary. The reaction of phosphonic acid chloride (31) with (S)-proline ethyl ester affords a mixture of diastereomeric amides (32) in high stereoselectivity. The diastereomers can easily be purified by chromatography. The chiral organophosphorus compounds (33) are obtained from hydrolysis of (32).

Alkylations and Allylations.

The asymmetric alkylation of chiral enamines derived from (S)-proline esters has been disclosed.41 The a-alkylation of cyclohexanone proceeds with an optical purity of 59%. (S)-Proline catalyzes the alkylation of xanthopurpurin (34) by 2-hydroxytetrahydropyran42 yielding (35), which was later used in the synthesis of the racemate of the pigment averufanin (eq 14).43 With phenylacetaldehyde, two molecules react to build up an anomeric mixture of lactols with a new pyran ring.44 In each case, no enantioselectivity is detected.

The stereoselective allylation of aldehydes was reported to proceed with allyltrifluorosilanes in the presence of (S)-proline.45 The reaction involves pentacoordinate silicate intermediates. Optical yields up to 30% are achieved in the copper-catalyzed allylic acetoxylation of cyclohexene with (S)-proline as a chiral ligand.46

The intramolecular asymmetric palladium-catalyzed allylation of aldehydes, including allylating functionality in the molecules, via chiral enamines prepared from (S)-proline esters has been reported (eq 15).47 The most promising result was reached with the (S)-proline allyl ester derivative (36). Upon treatment with Tetrakis(triphenylphosphine)palladium(0) and PPh3 in THF, the chiral enamine (36) undergoes an intramolecular allylation to afford an a-allyl hemiacetal (37). After an oxidation step the optically active lactones (38) with up to 84% ee were isolated in high chemical yields. The same authors have also reported sucessful palladium-catalyzed asymmetric allylations of chiral allylic (S)-proline ester enamines48 and amides49 with enantiomeric excesses up to 100%.

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Sabine Wallbaum & Jürgen Martens

Universität Oldenburg, Germany

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