Chiral auxiliary, in asymmetric aldol reaction

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. 

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... 

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>. 

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. 

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... 

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 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]. 

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... 

With the current emphasis on enantioselective synthesis, it is not surprising that numerous, highly successful asymmetric versions of aldol reaction have been developed. Noncatalytic methods involve the use of stoichiometric amounts of a chiral auxiliary in diastereoselective aldol reactions. Small-molecule-catalyzed aldol reactions typically would involve the use of a chiral Lewis acid for aldehyde activation or a chiral Lewis base for donor... 

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. 

The nonracemic 2/7-1,3-benzoxazin-4(3//)-one 202 was successfully applied as a chiral auxiliary in asymmetric transformations the titanium enolate-mediated aldol reactions of its A-acyl derivatives provided the products in high yields and with excellent diastereoselectivity <1996SL455, 1996TL5565>. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

Pseudoephedrine proprionamide (39) has been employed as a chiral auxiliary in asymmetric acetate aldol reactions.135... 

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. 

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.,. ... 

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.). 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

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 asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

Thiazolidinethiones constitute a class of versatile chiral auxiliaries for asymmetric synthesis. Their easy preparation from readily available /3-amino alcohols and the high levels of asymmetric induction they provide make them excellent chiral auxiliaries for the preparation of chiral intermediates in the synthesis of natural products. These chiral auxiliaries have been utilized in a wide variety of synthetic transformations such as asymmetric aldol-type acyloin condensation, stereoselective alkylation of different electrophiles (Stetter reaction), and stereoselective differentiation of enantiotopic groups in molecules bearing prochiral centers <2002COR303>. 

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. 

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