Glycine enol

A new chiral auxiliary based on a camphor-derived 8-lactol has been developed for the stereoselective alkylation of glycine enolate in order to give enantiomerically pure a-amino acid derivatives. As a key step for the synthesis of this useful auxiliary has served the rc-selective hydroformylation of a homoallylic alcohol employing the rhodium(I)/XANTPHOS catalyst (Scheme 11) [56]. 

An asymmetric synthesis of a-amino acids uses the alkylation of glycine enolates by mixed sulfates, e.g., methyl 1,2 5,6-di-O-isopropylidene-a-D-glucofuranose 3-sulfate, bearing a chiral leaving group1 13-15. 

Akiyama s group employed naturally occurring L-quebrachitol 6 to prepare the C2-symmetrical 18-membered chiral crown ether 7 [14]. Compound 7 was found to be an active catalyst for the enantioselective Michael additions of glycine enolates. Thus, deprotonation of ester 8 using potassium tert-butoxide in dichloromethane (DCM) in the presence of crown ether 7 (20 mol %), followed by addition of a Michael acceptor, gave amino-acid derivatives 9 with up to 96% ee, as shown in Scheme 8.4. 

Scheme 8.4 Crown ether-induced asymmetric Michael addition of a glycine enolate.

Recently, a conceptually different synthesis of MeBmt using an asymmetric glycine aldol reaction was reported by Evans and Weber [29]. The key step consists in the stereochemically controlled condensation of the chiral glycine enolate synthon (23) with the (R)-aldehyde (24) mediated by stannous triflate (tin salt of trifluoromethanesulphonic acid). The desired syn-aldol adduct (25) was isolated in form of the heterocyclic compound (26). The sense of asymmetric induction in the aldol reaction was established by conversion of (26) over three steps into uniform MeBmt (3). 

The asymmetric addition of glycine enolates to acrylates was also achieved by use of the tartaric acid-derived phase-transfer catalysts 27 and 28 (Scheme 4.9). Arai, Nishida and Tsuji [13] showed that the C2-symmetric ammonium cations 27a,b afford up to 77% ee when t-butyl acrylate is used as acceptor. The cations 28 are the most effective/selective PTC identified by broad variation of the substituents present on both the acetal moiety and nitrogen atoms [14], In this study by Shibasaki et al. enantiomeric excesses up to 82% were achieved by use of the catalyst 28a (Scheme 4.9) [14], Scheme 4.9 also shows the structure of the guanidine 29 prepared by Ma and Cheng in the absence of additional base this also catalyzes the Michael addition of the glycine derivative 22 to ethyl acrylate, albeit with modest ee of 30% [15],... 

The low reactivity of glycine enolate with unactivated alkyl halides to form a-amino acids could be overcome by stabilizing the nucleophile using m-aminoindanol-derived hippuric acid 53. This key substrate was readily prepared from commercially available azalactone 54 by a one-pot operation (85% yield, 2 steps). The lithium enolate of amide acetonide 53 with a wide range of alkyl halides proceeded in moderate yields (>60%) and excellent diastereoselectivities (>95% de). Assuming that lithium halide would facilitate the dissociation of the amide enolate from the aggregated state and thus enhance its reactivity, 4 equivalents of lithium chloride were used as additive and resulted in a 25% increase in yield (Scheme 24.11). Reactions with secondary halides... 

Chiral glycine enolate synthons have been employed in diastereoselective alkylation reactions [15]. A complementary approach to the synthesis of a-amino acids is the electrophilic amination of chiral enolates developed by Evans [16]. Lithium enolates derived from A-acyloxazolidinones 38, reacted readily with DTBAD to produce the hydrazide adducts 39 in excellent yields and diastereoselectivities (Scheme 18). Carboximides 38 were obtained by A-acylation of (S)-4-(phenylmethyl)-2-oxazoli-dinone and the lithium-Z-enolates of 38 were generated at -78 °C in THF under inert atmosphere using a freshly prepared solution of lithium diisopropylamide (LDA, 1.05 equiv.) [17]. 

SCHEME 118. Reaction of (5)-(+)-iV-(benzylidene)-p-toluenesulfinamide with glycine enolates at... 

For the complementary synthesis of a-substituted-a-amino acids via a chiral glycine enolate equivalent see 4-t-Butoxycarbonyl-5,6-diphenyl-2,5,5,6-tetrahydro-4H-oxazin-2-one. 

As illustrated in the aeeompanying proeedure, (N-t-Boe)allylglyeine, this morpholinone has proven to be one of the most versatile and useful ehiral glycine equivalents from which a large variety of amino acids can be prepared. Several other, recent asymmetric electrophilic glycine enolate and cation equivalents have been devised." ... 

SchOllkopfs bislactim ethers Other chiral glycine enolates Williams s method Seebach s relay chiral units Chiral Enolates from Hydroxy Acids Seebach s relay chiral units Chiral Enolates from Evans Oxazolidinones... 

Other chiral glycine enolates Williams s method... 

Continuing the theme of pyridine in amino acids we take (5 )-azatyrosine 56 as an example of Williams s chiral glycine enolate equivalent.5 The only difference between tyrosine 55 and aza-tyrosine 56 is the nitrogen atom in the benzene ring yet the one is an amino acid found in protein and the other an antibiotic. The most appealing approach to aza-tyrosine is the alkylation of some asymmetric equivalent of glycine enolate 57 and, probably, a protected version of 58. 

Two groups have developed methods for the asymmetric alkylation of glycine enolates using intraannular asymmetric induction. The first, developed by Schollkopf [70], involves condensation of two amino acid esters to a diketo-... 

Another method for asymmetric alkylation of a masked glycine was reported by Yamada, and is shown in Scheme 3.13 [72]. In this example of a chiral glycine enolate, the Schiff base of tert-hniy glycine and an a-pinene-derived ketone is dilithiated with two equivalents of LDA. Presumably, the lithium alkoxide is chelat-... 

Table 3.4. Stereoselective alkylations of Yamada s glycine enolate (Scheme 3.13) [721.

Schdllkopfs chiral glycine enolate equivalents, as in the elegant synthesis of the central diarylether unit of ristocetin [169]. It is remarkable that these limitations were partly lifted by using, instead of the manganese tricarbonyl complex the corresponding iron or ruthenium cyclopentadienyl complexes [170] (Scheme 62). 

Other chiral nucleophiles that have been employed include Schollkopf s (66) and Williams s (67) chiral glycine enolate equivalent [139,140]. 

SCHEME 5.22 Stereoselective synthesis of pyrrolidines 112 by Fischer alkenyl carbene complexes 106 with A -alkylidene glycine enolates 107. 

Among numerous studies employing this auxiliary [26], Davis enantiose-lective synthesis of (-)-agelastatin A (88), a cytotoxic tetracyclic marine alkaloid, is noteworthy (Scheme 11.13) [77]. In this synthetic endeavor, the major u,p-syn diamino ester 87 was obtained in 73% isolated yield through the dia-stereoselective addition of N-protected glycine enolate 85 to a,/S-unsaturated p-toluenesulfmyl imine 86. 

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