Chiral auxiliaries asymmetric aldol reactions

Chiral Auxiliaries in Aldol Reaction Asymmetric aldol reactions ntilizing chiral auxiliaries have emerged as one of the most reliable methods in organic synthesis. Both syn-and anti-selective aldol reactions have been developed over the years. The field of asymmetric i yn-aldol reactions has been largely advanced by Evans since his development of dibntylboron enolate aldol chemistry based on amino acid-derived chiral oxazolidinones (Scheme 2.109) [9]. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

The use of tartrates as chiral auxiliaries in asymmetric reactions of allenyl bor-onic acid was first reported by Haruta et al.69 in 1982. However, it was not for several years that Roush et al.,70 after extensive study, achieved excellent results in the asymmetric aldol reactions induced by a new class of tartrate ester based allyl boronates. 

As discussed in Section 3.3.2, Corey demonstrated the utility of compound 55, prepared from 1,2-diphenyl-1,2-diamino ethane 54, as a chiral auxiliary for asymmetric aldol reaction. In a similar manner, his group utilized this compound 55 in both (R,R)- and (A,A)-forms for allylation reactions. Treatment of 55 with allyltributyltin in dry CH2CI2 at 0°C and then 23°C for 2 hours gives chiral allyl-borane 135. In this process, both the (R,R)- and (A,A)-forms can be obtained and applied in asymmetric allylation reactions. Thus, treatment of... 

In the above asymmetric aldol reaction, the introduction and the removal of the chiral auxiliary are carried out by simple procedures, and high asymmetric induction is achieved even at ice—bath temperature. However, at least a stoichiometric amount of a chiral auxiliary is required in such a stereo-differentiating reaction (chiral auxiliary is attached to the reactant.). 

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

Acyliron complexes with central chirality at the metal are obtained by substitution of a carbon monoxide with a phosphine ligand. Kinetic resolution of the racemic acyliron complex can be achieved by aldol reaction with (1 R)-( I (-camphor (Scheme 1.14) [41], Along with the enantiopure (R, c)-acyliron complex, the (Spe)-acyliron-camphor adduct is formed, which on treatment with base (NaH or NaOMe) is converted to the initial (SFe)-acyliron complex. Enantiopure acyliron complexes represent excellent chiral auxiliaries, which by reaction of the acyliron enolates with electrophiles provide high asymmetric inductions due to the proximity of the chiral metal center. Finally, demetallation releases the enantiopure organic products. 

Fukuyama et al. synthesized the alcohol 39 using Evans s chiral auxiliary in the total synthesis of leustroducsin B (37), a potent colony-stimulating factor inducer via NF-kB activation at the transcription level15 (Scheme 2.In). The asymmetric aldol reaction between 38 and the requisite aldehyde proceeded smoothly to afford 39. Protection of the secondary alcohol as the TES ether and removal of the chiral auxiliary with LiSEt furnished the thioester 40. 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is demonstrated in a recent enantioselective synthesis of solandelactones E and F <07OL3481>. Addition of aldehyde 132 to the enolate solution of /V-propionyl thiazolidinethione 131... 

Early investigations of asymmetric aldol reactions with chiral carbohydrate auxliliaries were carried out by Heathcock [152] and Bandraege [159], but often only low stereoselectivities were observed. In additional studies. Banks et al. [73] used oxazinone auxiliaries for aldol reactions, which had been employed for other asymmetric reactions. The lithium enolate of the A-acylated oxazinone 226 reacted with benzaldehyde, furnishing exclusively the iyn-aldols 227A and 227B in a ratio of 10 1 (Scheme 10.76). 

Stoever, M, Luetzen, A, KoeU, P, New glyco-oxazolidin-2-ones as chiral auxiliaries in boron-mediated asymmetric aldol reactions. Tetrahedron Asymmetry, 11, 371-374, 2000. 

Evans synthesis of bryostatin 2 (113) also relied upon asymmetric aldol reactions for the introduction of most of the 11 stereocenters [58], At different points, the synthesis used control from an auxiliary, a chiral Lewis acid, chiral ligands on the enolate metal and substrate control from a chiral aldehyde. Indeed, this represents the current state of the art in the aldol construction of complex polyketide natural products. 

In the previous synthesis, two asymmetric aldol reactions using dienyl silyl ethers were described, one using a chiral Lewis acid for stereoinduction while the other used substrate control from a chiral aldehyde. This can be compared with the use of chiral dienolate 131 in the synthesis of a Ci-Cie fragment of the bryo-statins (Scheme 9-41) [59J. Here, the menthyl-derived auxiliary is covalently attached to the enolate, and again an excellent level of asymmetric induction was achieved on addition to aldehyde 132 to give adduct 133. 

Since the middle of the 198O s remarkable progress has been achieved in the development of asymmetric aldol reactions of silyl enolates. In the beginning of this evolution, chiral auxiliary-controlled reactions were extensively studied for this challenging subject [106]. As new efficient catalysts and catalytic systems for the aldol reactions were developed, much attention focused on catalytic enantiocontrol using chiral Lewis acids and transition metal complexes. Thus, a number of chiral catalysts realizing high levels of enantioselectivity have been reported in the last decade. 

In the middle of the 198O s some silyl enolates derived from homochiral esters were reported to enable highly enantioselective synthesis of aldols [106]. Later, Oppolzer et al. disclosed the utility of camphor sultam as a chiral auxiliary for asymmetric aldol reactions [107]. Braun et al. have recently achieved high levels of asymmetric induction in the aldol reaction of ketones with homochiral silyl enolate 43 (Scheme 10.38) [108]. 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenio centers <05JA13810>. For example, addition of aldehyde 146 to the enolate solution of A -propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity (>98 2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps <05JOC9658>. 

Valinol 27 and phenylalaninol 29 are used to make the Evans chiral auxiliaries used in asymmetric aldol reactions (chapter 27) and Evans prefers reduction with borane itself as its complex with Me2S. The phenylalanine based auxiliary 30 is generally preferred as the compounds are more likely to be crystalline and can easily be made11 on a 150 g scale. 

There are bicyclic monoterpenes too - a-pinene 89 and p-pinene 91 share a common skeleton with four- and six-membered rings but have the alkene in different places. There is a discussion in chapter 24 on the variable ee of a-pinene and it is better to make the ( )-enantiomer from the more reliable P-pinene 91 (99% ee) that can be isomerised with strong base ( KAPA ) 92 in 93% yield to ( -)-90 without loss of ee. Many asymmetric reagents for reduction (chapter 24) and chiral auxiliaries for asymmetric aldol reactions (chapters 27 and 30) are based on a-pinene.25... 

A few secondary/tertiary diols have been used as chiral auxiliaries. The monoacetates of (R)- and (SJ-1.32 (R = Ph) [204] are interesting precursors for asymmetric aldol reactions [205-210], (S)-1 -Phenyl-3,3-bis(trifluoromethji)pro-... 

Acyl-1,3-thiazolidines-2-ones 1.123 (X = S, R = COOMe), obtained from cysteine methyl ether [261], have been introduced by Mukaiyama and coworkers for use in asymmetric aldol reactions [261, 433, 434, 435], In reactions of related //-acyl-1,3-oxazolidines-2-thiones 1.123 (X = O, R = COOMe), each enantiomer can be obtained either from L- or D-serine [434] and the auxiliaries can easily be recovered by methanolysis. Similarly, //-acyl derivatives of 1.121 (X = S) have been used in asymmetric aldol reactions [429, 436], and //-acyl- 1,3-thiazo-lidinethiones 1.123 (X = S, R = r -Pr) are useful in asymmetric acylation [437] and aldol and related reactions [437, 438], Cleavage of the chiral auxiliary is accomplished by aminolysis with O-benzylhydroxylamine or by reduction with LiAlH.,. ... 

The enolates of //-acylimidazolidinones derived from 1.131 generated from ephedrine 1.61 (R = H) are useful in asymmetric alkylations [447, 448] and aldol reactions [449, 450] and cuprate additions to the a,p-unsaturated acyl analogs have recently been described [451], These chiral auxiliaries are cleaved by MeONa/MeOH or LiEtBHj. Recently, Davies and coworkers have suggested the use of symmetrical AyV-diacyl-1,3-imidazolidin-2-ones 1.132, formed from diamines having a C2 axis of symmetry [452], for asymmetric aldol reactions [449]. Juaristi [453] has used peihydropyrimidin-4-ones for related purposes. 

Due to the importance of polypropionate antibiotics, mainy chiral auxiliaries have been introduced on propionic add derivatives in order to perform asymmetric aldol reactions. The use of esters of chiral alcohols usually gives disappointing results [147, 209]. In an important exception, Braun and Sacha [149] recommended the propionate of a trimethylsilyloxyalcohol 1.12. The reaction of the derived dicyclopentylchlorozirconium enolate with aliphatic aldehydes at -105°C leads to anti aldols with an excellent fedal stereoselectivity (Figure 6.78). The selectivity is lower with benzaldehyde. The use of titanium enolates of N-tosyl-aminoephedrine 1.61 (R = Ts) propionate has recently been advocated [1262],... 

Other oxazolidinones have been used as chiral auxiliaries in asymmetric aldol reactions. Bomane derivatives 1.121 (X = O or S) and 1.122 are readily transformed into V-acyl derivatives. The reactions of their boron or titanium enolates with aldehydes give the same selectivities as Evans s reagents [426, 428, 429, 431, 436], iV-Acylimidazolidinones 1.131 and 1.132 [449, 1270] lead to similar results, but the selectivities observed are somewhat lower. 

Iron chiral auxiliary for asymmetric aldol reaction, Michael addition, p-amino acid and p-lactam synthesis. 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

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