Evans asymmetric aldol reactions chiral auxiliaries

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

A stereocontrolled synthesis of the biologically active neolignan (+)-dehydrodiconiferyl alcohol, which was isolated from several Taxus species, was achieved via Evans asymmetric aldol condensation [58] using ferulic acid amide derived from D-phenylalanine. The reaction steps are shown in Fig. 9. This stereocontrolled reaction is also useful for preparing the enantiomer of (+)-dehydroconiferyl alcohol using chiral auxiliary oxazolidinone prepared from L-phenylalanine. This reaction also enables the syntheses of other natural products that possess the same phenylcoumaran framework. 

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. 

Having noticed certain limitations of chlorotitanium aldol reactions on Evans et al. s chiral auxiliary,21 in 1997 Crimmins and others developed a brilliant protocol to achieve a highly diastereoselective aldol reaction.22 Asymmetric aldol... 

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. 

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. 

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. 

An aldol reaction is the addition of an enolate to an electrophile, where the electrophile is an aldehyde or a ketone. You have already seen earlier in this chapter how enolates can be used to make new C-C bonds enantioselectively when we explained how to control enolate alkylation with Evans chiral auxiliaries. Evans auxiliaries also provide one of the most straightforward ways of carrying out asymmetric aldol reactions, and we will start with an example before explaining how asymmetric aldol reactions can be done using catalytic methods. 

Asymmetric aldol reactions utilizing chiral auxiliaries or templates 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 syn aldol reactions has been largely advanced by Evans since his development of dibutylboron enolate aldol chemistry based on amino acid-derived chiral oxazolidinones. This method requires expensive dibutylboron trifiate, hosvever, and the amino acid-derived chiral auxiliary is only readily available in one enantiomer and thus only provides one enantiomer of the syn aldol. Several methods developed on the basis of titanium enolates provide convenient access to both Evans and non-Evans syn aldol products. 

Evans has pioneered the use of carboximide-derived enolates in diastereo-selective enolate alkylation reactions [15, 82]. As discussed in subsequent chapters, N-acyl oxazolidinones (such as 114, 115, and 116) enjoy a unique position in asymmetric synthesis as chiral auxiliaries with wide applications in numerous mechanistically unrelated asymmetric transformations, among them aldol (Chapter 4), Diels-Alder (Chapter 17), enolate amination (Chapter 10), and conjugate addition (Chapter 12) reactions. Oxazolidinones 114 and 115 generally lead to Ca-substituted carboximide products in one dia-stereomeric series (cf 119, dr>99 1), while the complementary diastereo-meric adducts such as 122 dr =98 2) can be accessed through the use of oxazolidinone 116 (Scheme 3.18) [82]. 

Double asymmetric induction (See section 1.5.3) can also be employed in aldol reactions. When chiral aldehyde 15 is treated with achiral boron-mediated enolate 14, a mixture of diastereomers is obtained in a ratio of 1.75 1. However, when the same aldehyde 15 is allowed to react with enolates derived from Evans auxiliary 8, a syn-aldol product 16 is obtained with very high stereo-... 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Alkylation of Enolates Asymmetric syntheses involving enolate reactions such as alkylations, aldol additions and acylations in which the chiral auxiliary A -H is both readily obtained and easily recoverable after the desired bond construction had been achieved by Evans et al.175). 

Asymmetric. syn-aldol condensation reactions employing chiral auxiliaries were reported in 1981 by both Masamune et al.2 and Evans et al.3 Masamune et al. introduced boron enolates obtained from (.S )-mandclic acid, which underwent... 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

The asymmetric total synthesis of cytotoxic natural product (-)-FRI 82877 was accomplished by D.A. Evans and co-workers." " To establish the absolute stereochemistry, a boron mediated aldol reaction was utilized applying (R)-4-benzyl-A/-propionyl-2-oxazolidinone" as a chiral auxiliary to yield the syn aldol product. 

Finally we ll have a quick look at how combinations of these methods have been applied. In the aldol reactions we have looked at so far there has been no chirality at the start. Both the aldehyde and the enolate have been achiral species that have reacted in a stereoselective way to give a particular diastereomer. With the aldol reaction there is a lot of opportunity to introduce aspects of chirality. The enolate could be chiral as could the aldehyde. In addition to this, the whole reaction could be mediated by a chiral catalyst. Although chiral enolates are most commonly associated with asymmetric methods (most famously the method of Evans in Chapter 27) it is important to remember that the components could just as easily be chiral and racemic. The diastereoselectivity that allows the Evans s chemistry to work with optically pure materials will operate whether the auxiliary is optically pure or not. 

Excellent levels of asymmetric induction in various carbon-carbon bond-forming reactions, such as alkylation, conjugate addition and aldol reactions, are possible using a suitable chiral enolate and an achiral electrophile under appropriate reaction conditions. A variety of chiral enolates have been investigated, the most common and useful synthetically being those with a chiral auxiliary attached to the carbonyl group. The 2-oxazolidinone group, introduced by Evans, has proved to be an efficient and popular chiral auxiUary. Both enantiomers of the product are... 

Li and co-workers developed a novel asymmetric halo aldol reaction using Evans oxazolidinones as chiral auxiliaries for tandem I-C/C-C bond formations. This reaction provides a practical approach to a variety of halo aldols of a non-Evans type that cannot be easily prepared by other methods. Excellent diastereoselectivity (> 95% de) and yields (80-93%) have been obtained. This reaction can be considered as a Lewis acid (Et2Al-I)-promoted Morita-Baylis-Hillman (MBH) process. 

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