Natural products Evans aldol reaction

Glucolipsin A, a glycolipid possessing glycokinase-activating properties, was discovered at Bristol-Myers Squibb, but the absolute stereochemistry of the natural product remained elusive. A. Furstner and co-workers elucidated the absolute stereochemistry via synthesis and spectroscopic analysis of the natural macrolide and its Cj-symmetric stereoisomers." In their approach, they utilized the Evans aldol reaction that provided the syn aldol product with good yield and excellent diastereoselectivity. 

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. 

Glucolipsin A (21) is a macrocyclic dilactone natural product that exhibits glucokinase-activating properties. Fiirstner et al. employed an Evans aldol strategy to synthesize the syn -aldol intermediate 2310 (Scheme 2.1j). The aldol reaction of the boron enolate of 14 with 14-methylpentadecanal (22) delivered the yyn-aldol product 23 in essentially diastereomerically pure form (99% de) after purification. Subsequent glycosidation of the alcohol 23 with trichloroacetimidate (24) was facilitated by catalytic amounts of TMSOTf (20 mol %) to afford the key intermediate (25) in moderate yield. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

D.L Boger et al. reported the total synthesis of bleomycin A2. They devised an efficient synthesis for the construction of the tripeptide S, tetrapeptide S, and pentapeptide S subunits of the natural product." " " In their strategy, they utilized an Evans aidoi reaction between the (Z)-enolate derived from (S)-4-isopropyl-3-propionyl-oxazolidin-2-one and A/-Boc-D-alaninal. In order to synthesize one of the diastereomers of the pentapeptide S subunit, they carried out an Evans aidoi reaction between the same aldehyde and the (Z)-enolate of (R)-4-isopropyl-3-propionyl-oxazolidin-2-one. The formation of the diastereomeric syn aldol product in this reaction clearly shows that the stereochemical outcome of the transformation is determined by the chiral auxiliary. 

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. 

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. 

Stereoselective anti-aldol reactions. As part of a synthesis of polypropionate natural products, Evans et al. have studied the stereoselectivity of the reaction of isobutyraldehyde with the chiral /3-kctoimide la, which has been shown to undergo syn-sclectivc aldol reactions.4 Surprisingly, the (E)-boron cnolatc, generated in ether from dicyclohexylchloroborane and ethyldimcthylaminc, reacts with isobutyraldehyde to give the anti, am/-aldol 2 and the syn, anri-aldol 2 in the ratio 84 16. Similar diastereoselectivity obtains with the reaction of the isomeric /3-kctoimide lb. 

Much tvork in the field of aldol reactions of ketones tvas performed by Evans to enable the synthesis of polypropionate natural products. They demonstrated that j5-ketoimides like 159 vere selectively and completely enolized at the C4 position rather than the potentially labile methyl-bearing C2 position, most probably because steric factors prohibited alignment of the carbonyl groups necessary to activate the C2 proton. As sho vn in Table 2.29, it vas demonstrated that these compounds vould react vith aldehydes to provide syn-syn product 161, via titanium enolates, vith good yield and excellent selectivity, and the corresponding syn-anti product 162 could be favored by use of a tin enolate reaction [58]. They invoked the chelated transition state assembly 160 to explain the product stereochemistry observed, in vhich the C2-methyl group directs diastereofacial selectivity. Interestingly, reduction vith Zn(BH4)2 provided the syn diol diastereoselec-tively. 

Several other natural products have been synthesized by using titanium enolate-based aldol methods. Many of these syntheses utilize ketone enolate aldol reactions to establish syn stereochemistry. Duthaler s anti aldol reaction was used in the synthesis of tautomycin. Use of Evan s ketone-aldol reaction was nicely exemplified in syntheses of denticulatin B and mem-brenone C. 

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. 

The so-generated ester serves at the same time as a protecting group and renders the Evans-Tishchenko reaction a transformation in natural product syntheses. Scheme 2.146 shows a typical combination of Paterson aldol reaction followed by anti-selective reduction. The DlPCl-mediated aldol reaction sets the configuration at the new secondary alcohol (102). This configuration is then used for the... 

Evans DA, Ng HP, Clark JS, Rieger DL. Diastereoselective anti aldol reactions of cbiral etbyl ketones. Enantioselective processes for the synthesis of polypropionate natural products. Tetrahedron 1992 48(11) 2127-2142. 

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