Asymmetric reactions amino acid enolates

Stereoselective syntheses of several unnatural amino acids were required to initiate this work. Evans group used asymmetric reactions of chiral enolates to generate these starting materials, as illustrated in the diagram shown below. In this particular example, an isothiocyanate functionality traps the alcohol of an aldol product giving a thiooxazolidinone that provides O- and N-protection in subsequent steps. 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

Asymmetric syntheses of (3- amino acids result from the addition of chiral enolates (399) to nitrone (400) via A-acyloxyiminium ion formation (642, 643). Regioselective convergence is obtained in the reactions of chiral boron- and titanium- enolates (399a,b), (401), and (402). This methodology was used in preparing four stereoisomers of a-methyl- 3-phenylalanine (403) in enantiomeric pure form (Scheme 2.179) (644). 

The asymmetric hydrogenation of enol esters can also be catalyzed by chiral amidophosphine phosphinite catalysts derived from chiral amino acids, but the enantioselectivity of these reactions has thus far been only moderate.35... 

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

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. 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

M. C. Sharma, A. K. Garcia, J. M. Gonzalez, A. Landa, C. Linden, A. a-Oxymethyl ketone enolates for the asymmetric Mannich reaction. From acetylene and N-alkoxycarbonylimines to /J-amino acids. Angew. Chem. Int. Ed. 2000, 39, 1063-1065. 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

Hoveyda and coworkers reported that the silver complex generated from AgF2 and an amino acid-based ligand could be used for the asymmetric aldol reaction with silyl enol ethers and a-ketoesters (Table 9.11).23... 

The use of Lewis acid drastically changes the regioselectivity. The highly enantioselective and O-selective nitroso aldol reactions of tin enolates with nitrosobenzene have been developed with the use of (i )-BINAP-silver complexes as catalysts. AgOTf and AgCICL complexes are optimal in the O-selective nitroso aldol reaction in both asymmetric induction (up to 97% ee) and regioselection (0/N= > 99/1), affording amino-oxy ketone. The product can be transformed to a-hydroxy ketone without any loss of enantioselectivity (Equation (71)).224... 

An approach has recently been made in which asymmetric aldol reactions are performed without the need for preformed metal enolates.1 In 2000, List and co-workers reported that the cyclic amino acid L-proline is an effective catalyst for the asymmetric aldol reaction of acetone with a variety of aromatic and aliphatic aldehydes2 (Scheme 2.3a). When L-proline was mixed with acetone... 

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... 

FMOC-protected amino acid fluorides afford the expected Reissert adducts 160 with a good stereoselectivities, the a-sulfonylamino acid fluorides undergo cycliza-tion to adduct 161 [47, 140, 141], Itho s protocol is amenable to using silyl enol ethers 157 as nucleophiles [142], Gibson has used bulky asymmetric acid chlorides as substrates in a Reissert reaction with TMS-CN the corresponding Reissert compound was then treated with aldehydes and sodium hydride to obtain the enantiopure adducts 4 (Scheme 3) [143],... 

Asymmetric cycloadditions of the chiral non-racemic nitrones 101 and 103 afford the isoxazolidinones 102 and 104 respectively, with high diastereoselectivity. This process can lead to an efficient asymmetric synthesis of /3-amino acids (equations 42 and 43) . This is the first example of asymmetric reactions with ynolates. It is noteworthy that the ynolates show higher reactivity and stereoselectivity than the corresponding lithium ester enolates and demonstrate the high potential of lithium ynolates in asymmetric reactions. 

Related a,p-Unsaturated Esters. Similar a,p-unsaturated esters bearing a heterocyclic chiral auxiliary of a-amino acid origin at the p-position are known and have been utilized in asymmetric synthesis. Effective asymmetric conjugate additions of cuprates to (2), (3), and (5)J epoxidations of (3), and dipolar cycloadditions of (2) have been reported. Although oxazoli-dine (4) is only obtained as an 86 14 equilibrating mixture of stereoisomers, reactions with the lithium (Z)-enolate of methyl N-benzylideneglycinate (see Ethyl N-Benzylideneglycinate) are exclusively diastereoselective. 

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