Auxiliary-Based Alkylation of Enolates

Chronologically, the successful and efficient asymmetric alkylation of enolates was preceded by the development of chiral azaenolates indeed, the meanwhile classic reagents hke Meyers oxazolines [4], Enders hydrazones RAMP and SAMP [5], and Schollkopf s bislactim ethers [6] were the first auxiharies to enable carbon-carbon bond formation with high (overall) enantioselectivity. 

shortly later, the first enolates with covalently bound chiral auxiharies were developed, it was on obvious idea to use carboxylic esters, amides, or imides as their precursors because they were designed to attach and remove the auxiliary group as the ipso-substituent at the carboxyl group [7]. An early way of ester alkylation developed by Helmchen and coworkers is particularly instructive because it combines stereocontrol through both a chiral auxiliary and the configuration of the enolate [8]. The controlled formation 

Helmchen and coworkers also used carboxylic esters with a related auxihary based upon the e. ico-amino borneol skeleton [8c]. If the alkylation protocol was applied to a-benzyloxy esters, the configuration of the alkylation products was identical, irrespective of the deprotonation method (presence or absence of HMPA). This result is plausible explained by the formation of the c/s-enolate forced by chelation, even under different conditions of deprotonation [8d]. The alkylation of the propionic ester of 10-sulfonylamido-isoborneol was studied by Oppolzer and coworkers [9]. 

In an improved procedure, the deprotonation with potassium hydride and LDA was shown to lead to higher diastereoselectivity, in particular with chiral iodides. Based thereupon, the amide 16 was obtained by alkylation with the enantiomer-ically pure iodide 15 in a diastereomeric ratio of 97 3. It served, after cleavage from the auxiliary, under the form of carboxylic acid 17, as a building block in a total synthesis of the polyether antibiotic ionomycin [12b]. 

The alkylation of enolates 12 with alkyl halides under /A -topicity (meaning that (5)-12 is attacked from its Si-face) was plausibly explained by assuming that the Re-fAce is shielded by the (deprotonated) hydroxymethyl residue at the pyrrolidine skeleton. Remarkably, the opposite stereochemical outcome was observed in the reaction of enolate 12 with epoxides, as experienced by Askin and coworkers. In the combination of enolates derived from the enantiomeric amides (S)- and (1J)-11 with chiral epoxides, the configuration of stereogenic a-carbonyl center is widely determined by the chiral auxiliary [13]. 

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In any treatment of auxiliary-based alkylations (as well as aldol additions, enolate oxidations, Mannich and Michael reactions), clearly, the carboximide enolates pioneered by the group of Evans are the center of attention. Developed in the early 1980, JV-acyl derivatives of oxazolidinones 45-47 (Scheme 4.9) became the epitomes of chiral auxiliaries [7,28] with countless applications in natural products and drug syntheses. The enantiomeric oxazolidinones (S)- and (R)-47 derived from the corresponding enantiomer of phenylalanine have the advantage that, when used for various transformations, the corresponding products have a higher tendency to crystallization and were shortly later added [29] to this collection of classics. 

An impressive showpiece of Evans auxiliary-based asymmetric syntheses enolates was delivered in the total synthesis of the marine natural product calyculin A, shown in Scheme 4.56, where the Evans enolate chemistry was utilized to create 10 out of 15 stereogenic centers [126] In detail CIO and C36 by enolate alkylation, C12/C13, C22/23 as well as C34/35 by aldol reactions, C17 by enolate oxidation (cf. Section 4.6), and C30 by a Michael addition (cf Section 4.5). This achievement is not only an acid test of these methods, but it may be considered as a plea for the auxiliary approach in general. 

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]. 

Treatment with base (usually LDA) at low temperature produces an enolate, and you can clearly see that the auxiliary has been designed to favour attack by electrophiles on only one face of that enolate. Notice too that the bulky auxiliary means that only the Z-enolate forms alkylation of the E-eno-late on the top face would give the diaster eoisomeric product. Coordination of the lithium ion to the other carbonyl oxygen makes the whole structure rigid, fixing the isopropyl group where it can provide maximum hindrance to attack on the wrong5 face. 

It is worthwhile to apply the memory of chirality principle to asymmetric alkylation of a-amino acids because nonproteinogenic a,a-disubstituted-a-amino acids are important class of compounds in the fields of medicinal and biological chemistry.21 Typical methods for their asymmetric synthesis involve chiral auxiliary-based enolate chemistry 22-24 However, the most straightforward synthesis would be direct asymmetric a-alkylation of the parent a-amino acids in the absence of external chiral sources. Asymmetric... 

A variety of methods exists for the synthesis of optically active amino acids, including asymmetric synthesis [85-93] and classic and enzymatic resolutions [94-97], However, most of these methods are not applicable to the preparation of a,a-disubstituted amino acids due to poor stereoselectivity and lower activity at the a-carbon. Attempts to resolve the racemic 2-amino-2-ethylhexanoic acid and its ester through classic resolution failed. Several approaches for the asymmetric synthesis of the amino acid were evaluated, including alkylation of 2-aminobutyric acid using a camphor-based chiral auxiliary and chiral phase-transfer catalyst. A process based on Schollkopf s asymmetric synthesis was developed (Scheme 12) [98]. Formation of piperazinone 24 through dimerization of methyl (5 )-(+)-2-aminobutyrate (25) was followed by enolization and methylation to give (35.6S)-2,5-dimethoxy-3,6-diethyl-3.6-dihydropyrazine (26) (Scheme 12). This dihydropyrazine intermediate is unstable in air and can be oxidized by oxygen to pyrazine 27, which has been isolated as a major impurity. 

Oppolzer and coworkers [147, 454] have developed a class of reagents based on the enantiomeric bomane-2,10-sultam skeleton 1.133. These chiral auxiliaries are easily prepared from the enantiomeric 10-camphosulfonic adds [455]. Saturated or a,P-unsaturated TV-acylsultams 1.134, occasionally prepared from Af-silyl precursors [396], have been used very frequently. Asymmetric alkylations, animations and aldol reactions of enolates or enoxysilane derivatives of 1.134 (R = R CH2) [147, 404, 407, 456-460] are highly selective. The a,(3-unsaturated TV-acylsultams 1.134 (R = R R"C=CH) suffer highly stereoselective organocuprate 1,4-additions [147, 173], cyclopropanations [461], [4+2] and [3+2] cydoadditions [73,276,454,462], OSO4 promoted dihydroxylations [454,463] and radical addi-... 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Helmchen and co-workers achieved good asymmetric induction in the alkylation of ester enolates using the camphor based sulfonamide auxiliary in acetate 439.Alkylation of the enolate derived from 439 with iodotetradecane proceeded primarily from the less hindered face (away from the sulfonamide group, to give a 98 2 mixture of 440 and 441. The diastereomer ratio was 98 2 favoring 440 and the yield of 74%. 

Scheme 4.2 An early auxiliary-based enolate alkylation preparation of pheromone (S)-10 from A/-propionyl (1S,2fi)-ephedrine 8.

The arylation of enolates based on chiral auxiliaries has by far not reached the relevance of the alkylation procedures. For the arylation, enantioselective catalysis (cf. Section 5.2) became much more relevant than the auxiliary approach. As the arylation is based on palladium catalysts, it is as elegant as obvious to use a ligand at the noble metal as the chiral inductor. 

Oppolzer has proposed a model to account for the stereoselectivity of alkylation of A-acyl sultams based on his auxiliary (Scheme 7.34). In this model, kinetic formation of the Z-(0)-enolate is assumed. The electrophile then approaches the enolate at the face opposite that of electron lone pair on nitrogen. In the enolate, the nitrogen atom is pyramidal and its configuration is imparted by the auxiliary. ... 

One of the early auxiliary-based carboxamides to be developed for enolate alkylations was the prolinol-derived amide 103, disclosed independently by Evans [77] and Sonnet [78] (Scheme 3.17). The corresponding enolates are sufficiently nucleophilic to participate in a wide range of alkylation reactions with activated and non-activated electrophiles. It was proposed that the high diastereoselectivity observed in the alkylation reaction arose from the chelated enolate 104. As is generally the case for amide-derived enolates, the Z-enolate is exclusively produced in the course of deprotonation. Some of... 

The investigations of Enders, Evans, and others have demonstrated the versatility of chiral auxiliaries based on the proline skeleton [80]. Katsuki designed and utilized a C2-symmetric, 2,5-disubstituted pyrrolidine auxiliary for asymmetric enolate alkylations (Equation 10) [81]. Enolates prepared from 112 generally undergo alkylations with superb diastereoselectivity dr >95 5). However, in contrast to the prolinol amide-derived systems described above, accessibility of the chiral auxiliary hinged upon a multi-step synthetic preparation involving resolution, and the hydrolytic removal of the auxiliary necessitated considerably harsher reaction conditions. 

The applications of oxazolidinone auxiliaries 114-116 in stereoselective enolate bond constructions are countless. A classic example that showcases their general synthetic utility in enolate alkylations is documented in Evans total synthesis of the antibiotic ionomycin (111, Scheme 3.22) [79]. Throughout this synthetic endeavor, no fewer than nine of the 14 stereogenic centers were installed through auxiliary-based enolate chemistry. Eight of these were accomplished through the use of oxazolidinones, with the two examples that involve diastereoselective enolate alkylations depicted in Scheme 3.22. The... 

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