Amino acid ester enolates

An aromatic Claisen rearrangement has been used as a key step in a total synthesis of racemic heliannuols C and E.18 A formal synthesis of (-)-perhydrohistrionicotoxin has used Claisen rearrangement of an amino acid ester enolate as the key step, in which almost total chirality transfer was observed from (S, )-oct-3-en-2-ol in the sense predicted by a chair-shaped transition state with chelation control of enolate geometry.19 Treatment of 1-(cyclohex-l-enyl)-6-methoxy-2-propargylindanol derivatives with base... 

Kazmaier, U. Reactions of chelated amino acid ester enolates and their application to natural product synthesis. Bioorg. Chem. 1999, 201-206. 

Transition Metal-Catalyzed Allylie Alkylation. Chelated amino acid ester enolates were found to be suitable nucleophiles for palladium-catalyzed allylie alkylations (eq 25). They were conveniently prepared by deprotonation of a glycine derivative with LHMDS followed by transmetallation with zinc chloride. The palladium-catalyzed allylie alkylation then takes place in the presence of allyl carbonates to produce the desired anti amino acid derivative. ... 

Fe(OTf)2-catalyzed aziridination of enol silyl ethers with PhlNTs followed by ring opening led to a-N-tosylamido ketones in good yields (Scheme 27) [81]. With silyl ketene ketal (R = OMe) as substrate, the N-tosyl-protected amino acid ester was obtained in 50% yield. In contrast, the copper (I) salt CuClOq was found not effective for this substrate [82]. 

The addition of lithium or magnesium ester enolates to nitrones in THF at 78°C or in Et20 at — 20°C, constitutes a direct synthesis of /V-hydroxy- 3-amino acid esters (Scheme 2.180) (645). 

During attachment of a chiral amino acid ester to the resin, the base required in the reaction, particularly when used in excess, leads to facile racemizationJ369,4011 This occurs by C -proton abstraction and enolization of the amino acid ester (see Vol. E 22a, Section 1.2.1.2 and Section 7.4), which may also occur during chain assembly in the repetitive base treatments, especially with Fmoc/tBu chemistry and in case of razemization-prone amino acid residues. Thus careful control of the base is required or the use of dipeptide building blocks such as Fmoc-Asp-Gly-OFm,t369 as Ca-proton abstraction is not stabilized by enolization. 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

Numerous examples of the preparation of tetramic acids from N-acylated amino acid esters by a Dieckmann-type cyclocondensation have been reported (Entries 7-9, Table 15.4). Deprotonated 1,3-dicarbonyl compounds and unactivated amide enolates can be used as carbon nucleophiles. In most of these examples, the ester that acts as electrophile also links the substrate to the support, so that cyclization and cleavage from the support occur simultaneously. The preparation of five-membered cyclic imi-des is discussed in Section 13.8. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Let us analyze once more with a different emphasis what has just been said An N-protected amino acid chloride can be deprotonated by an amino acid ester with a free NH2 group because the enolate produced is stabilized, among other things, by the electron-withdrawing inductive effect of the Cl atom. This immediately suggests a solution to circumvent the described dilemma Activating the N-protected amino acid requires a derivative in which the... 

The amino acid ester with the free NH2 group can also react as a base. Hence, the amino acid chloride is deprotonated—reversibly—to the enolate.This is so readily pos-... 

In this chapter we show that the chirality of a ketone and some a-amino acid esters can, however, be preserved in their enolate forms, and asymmetric synthesis via the strategy shown in Scheme 3.2 becomes possible. In these reactions the chirality of the starting material appears to be memorized in the enolate intermediates, so we call this type of asymmetric transformation memory of chirality. The design, development, and rationale of the memory of chirality are described.1... 

Memory of chirality signifies asymmetric transformation in which the chirality of the starting materials is preserved in the configurationally labile intermediates (typically enolates) during the transformation. A typical example of memory of chirality is the alkylation of ketone 23 and a-amino acid ester 40. Before and after our first report on the memory of chirality in 1991, several related phenomena have been reported. 

Chiral auxiliaries may be applied to a-amino acid esters by forming imine derivatives. Enolates from 2-hydroxy-3-pinanone glycinate esters have been alkylated to produce mono- and di-substituted o-amino acids in good optical yields after hydrolysis. Recently, McIntosh et al reported the results of alkylations of the enolate (139) derived from the (+)-camphor imine of r-butyl glycinate with a variety of... 

Polyak, F., and Lubell, W.D. (1998)Rigid dipeptide mimics - Synthesis of enanti-opure 5- and 7-benzyl and 5,7-dibenzyl indolizidinone amino acids via enolization and alkylation of delta-oxo alpha,omega-di-[N-(9-(9-phenylfluorenyl))amino] azelate esters. J. Org. Chem. 63, 5937-5949. 

Mannich reaction. When mixed with Sc(OTf)3 an ArNH2, ethyl glyoxylate, and an enol ester assemble to give a 7-keto-Waryl-a-amino acid ester. ... 

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-... 

Stereoselective syn-aldol reaction syn-3-hydroxy-2-amino esters Reaction of the lithium enolate of ethyl N, N-dimethylglycine (1) with aldehydes in the presence of B(C2Hs)3 (1 equiv.) results in. ry -3-hydroxy-2-amino acid esters in >95% de (equation 1). The high diastereoseiectivity is explained by the exclusive or predominant... 

Retention of geometry, perfect chirality transfer, and high reactivity have been observed by the reaction of the chelated Zn enolate of amino acid ester 53 even when PPhs was used [23]. In addition, the non-stabilized enolate 53 was found to be very reactive. Reaction of the allylic carbonates 54 and 56 with the enolate 53 gave 55 and 57 with perfect chirality transfer and high diastereoselectivity. The carbonates and the enolates are highly reactive and the reaction starts even at —78 °C. Lower selectivity was observed by the reaction of the corresponding allylic acetate. 

Allylation at carbon of zinc-chelated enolates of amino acid esters of type EWG-NH-CHR-COOR to afford disubstituted glycine derivatives. " ... 

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