Diastereoselective synthesis ester enolates

Kim, D. and Kim, I.H. (1997) A stereoselective total synthesis of ( )-oppositol by a doubly diastereoselective intramolecular ester enolate alkylation. Tetrahedron Lett., 38, 415 16. 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

An efficient synthesis of optically active pentanedioates is possible using ester enolates based on chiral alcohols. This is illustrated by the addition of the lithium (fl-cnolate of (1 R,2S,5R)-5-methyl-2-(1-methyl-l-phenylethyl)cyclohexyl propanedioate to methyl ( )-2-butenoate at — 100 °C which shows simple and induced diastereoselectivity. 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Scheme 16 Diastereoselective synthesis of 2,3-diamino esters and alcohols by the addition of achiral glycine iminoester enolates to chiral M-sulfinylimines...

As previously described, in basic conditions the proUne-derived a-sulfonyl amide 141 generates the imine function, which afterwards undergoes addition by a nucleophile, e.g., a nitronate ion see the diastereoselective synthesis of the diamino nitroalkane derivative 172, which is the precursor of the piperazine-2-carboxyUc acid 173, through a Nef reaction [45]. Similarly, the addition of the Uthium enolate of ethyl acetateto the a-sulfonyl amide 174 gave the diamino ester derivative 175, wich was then converted to (-)-l-aminopyrrolizidine 176 (Scheme 27). 

Entry 2 shows an E-enolate of a hindered ester reacting with an aldehyde having both an a-methyl and (3-methoxy group. The reaction shows a 13 1 preference for the Felkin approach product (3,4-syn) and is controlled by the steric effect of the a-methyl substituent. Another example of steric control with an ester enolate is found in a step in the synthesis of (-t-)-discodermolide.99 The E-enolate of a hindered aryl ester was generated using LiTMP and LiBr. Reaction through a Felkin TS resulted in syn diastereoselectivity for the hydroxy and ester groups at the new bond. 

Scheme 3.7. Diastereoselective formation of /S-silyl ( )- or (Z)-ester enolates by silylcuprate conjugate addition followed by alkylation with aldehydes [49]. Stereoselective synthesis of ( )-and (Z)-allyl silanes [50].

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

The addition of ester enolates to oi.P-unsaturated esters occurs with identical diastereoselectivity as shown for a,(3-enones this is exemplified by the diastereoselective synthesis of erythro- and threo-2,3-disubstituted glutarate esters (178 and 179). 146 -c Similarly, Yamaguchi reports a general synthesis of /ra/tJ-2-alkoxycarbonyl-l-cycloalkanepropionates (181-184) from w-halo-a,(3-unsaturated esters (180),... 

Schunk and Enders [134] disclosed the first solid-phase synthesis of (5-1 actants via ester enolate-imine condensation employing an immobilized ester enolate in a simple three-step procedure (Scheme 31). The protocol showed high purity, excellent diastereoselectivity, and good yields of the product. The substrates were attached to the polymer with a Tl-triazene linker, which was cleaved traceless. The... 

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. 

Nucleophilic addition of ester enolates to enantiopure nitrones, followed by cyclization of the resulting hydro-xylamine, is a general approach to isoxazolidin-5-ones and can be applied to the stereoselective synthesis of these heterocycles <2005CRC775>. In some cases, the cyclization occurs spontaneously under the reaction conditions. For example, the addition of the sodium enolate of methyl acetate to chiral nitrone 551 gave directly the isoxazolidin-5-ones 552 in quantitative yield and high ty -diastereoselectivity (Equation 91) <1998CC493>. 

Ester enolates add to 464 producing adducts with varying diastereoselectivities depending on the nature of the ester. In the synthesis of (+ )-blastmycinone (546), aldol reaction of lithiated 542 with 464 gives adduct 543 with high a /-selectivity (>35 1) [166]. Desulfurization, debenzylation, and acid-catalyzed lactonization gives optically pure lactone 545 in 62% overall yield from 543. Stereospecific alkylation of the lactone with butyl iodide followed by acylation affords the desired product (Scheme 77). 

The HDA reaction features in a diastereoselective synthesis of c/j-2,6-disubstituted 5,6-dihydro-2//-pyrans, but this is based on the initial formation of a dihydropyran-4-one. Regio- and stereo- chemistry are controlled during the reduction to the pyranol and an ester enolate Claisen rearrangement completes the sequence <97AJC43>. 

Diastereoselective synthesis of a /3-lactam side chain precursor using a chiral imine has also been accomplished by Fujisawa and his collaborators who condensed a chiral imine with an ester enolate in a stereocontrolled way. Thus, reaction of 7.1.17 with enolate afforded the desired cislactam in 84% diastereomeric excess and 90% yield. The other enantiomer of the cis /3-lactam (diastereomeric when R is attached) was not detected (244). 

As illustrated, it is possible to carry out the ester enolate Claisen rearrangement in a highly diastereoselective fashion via control of the enolate geometry. However, from a synthetic point of view, the generation of racemic products is not fully satisfying. For an application to amino acid synthesis, it is important not only to control the relative, but also the absolute configuration of the stereogenic centers [li]. 

The initial synthetic applications of the ester enolate Claisen rearrangement were reported from the Ireland group. Silyl ketene acetal generated from 143 readily rearranged to the carboxylic acid 144 in moderate yield and diastereoselectivity. The product 144 was subsequently elaborated for the completion of the total synthesis of lasalocid... 

Sato, T., K. Tajima, and T. Fujisawa Diastereoselective synthesis of erythro- and threo-2-hydroxy-3-methyl-4-pentenoic acids by the ester enolate Claisen rearrangement of 2-butenyl 2-hydroxy acetate. Tetrahedron Letters 24, 729 (1983). 

Zinc enolates like 41 served as nucleophiles in a study aimed at a rhodium-catalyzed reaction with enantiomerically enriched allylic phosphates. Nonracemic products were obtained under efficient chirality transfer from the substrate and with remarkable diastereoselectivity [23]. Kazmaier enolates were used to manipulate the backbone of small peptides [27] by palladium-catalyzed allylations of a terminal glycine ester [28]. In the course of these studies, central glycine was also allylated in a diastereoselective manner through assumed chelated zinc enolates of glycine in a peptidic bond to proline or JV-alkyl amino acids [29]. Although this is, of course, not an asymmetric synthesis, the protocol is remarkable inasmuch as, in contrast to the palladium-mediated conversion, the noncatalyzed reaction of the enolate with the corresponding allylic bromide occurs in a more or less stereorandom manner. 

The diastereoselective synthesis of p-hydroxy-a-amino esters 200 and 201 has been achieved. Use of a chiral auxiliary on the enolate component leads to good a ri-selectivity, but in the absence of this additional vehicle for stereocontrol, both syn and anti isomers 202 were produced (Scheme 42). ... 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

Amination. Three laboratories2-4 have reported use of esters of azodicarbox-ylic acid for amination of chiral substrates to provide a synthesis of optically active a-hydrazino and a-amino acids. The di-r-butyl ester is particularly useful because the diastereoselectivity improves with increasing size of the ester group, and in addition these esters are hydrolyzed by TFA at 25°. Two laboratories21 used the lithium enolates of chiral N-acyloxazolidones (2) as the chiral precursors. A typical procedure is outlined in equation (I). Thus reaction of the lithium enolate of 2... 

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