Aldol reaction vinylogous, asymmetric

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

Using chiral catalysts, not only various enantioselective Mukaiyama and vinylogous Mukaiyama aldol reactions have been developed but also asymmetric reactions of a,a-difluoro silyl enol ethers (1) with carbonyl compounds have been reported ... 

The asymmetric vinylogous Mukaiyama aldol reaction was applied in several natural product syntheses, such as macquarimicins <2003JA14722, 2004JA11254>, leucascandrolide A <2002AGE4098, 2003JOC9274>, and dactylo-lide <2005AGE3485>. 

Chiral sulfoximines liganded to copper(II) give highly enantioselective vinylogous Mukaiyama-type aldol reactions under mild conditions.137 A chiral sulfinyl group has been used to achieve 1,5- and 1,6-asymmetric induction in Mukaiyama aldols, using Yb(OTf)3 catalysis.138... 

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

Recently, Dong and Sun disclosed an unprecedented intermolecular asymmetric a-aldol reaction of vinylogous NHC-enolates, a type of versatile but less explored species relative to simple NHC-enolates. In contrast to the known C—C bond formation at the y-position of vinylogous NHC-enolates, this reaction exhibits complete a-selectivity. Unlike most cycloaddition reactions of NHC-enolates with external carbonyl electrophiles, this reaction does not involve a cycloaddition step. Notably, two challengingstereocenters, one quaternary and the other labile tertiary (both allylic and a-carbonyl), are also established in an acyclic product with excellent stereocontrol. A range of highly enantioenriched p,y-unsaturated P -fluoroalkylated esters have been synthesized with high efficiency under mild conditions. These products can be easily transformed into other useful molecules, such as densely functionalized tetrahydrofurans (Scheme 7.90). 

Also, asymmetric vinylogous aldol reactions could be effectively catalysed by diols 2 via hydrogen bonding, as shown by Rawal et al. in 2005 several... 

Scheme 24.5 Asymmetric vinylogous aldol reaction catalysed by TADDOLs.

Bifunctional organocatalysts - aminothioureas and aminosquaramides - have been tested in direct asymmetric direct vinylogous aldol reactions of y-crotonolactone (66) with aromatic aldehydes to give 5-substituted 2(5//)fiiranones (y-butenolides, 67) Best yield/r/e/ee performance was 98/90/99%, and the method is an alternative to the vinylogous aldol of silyloxy furans. 

A versatile y-vinylogous aldol reaction of a dioxinone-derived silyl enol ether, by enolate activation with an appropriate Lewis base, has been developed. Using chi- ral 2-(methylsulfinyl)benzaldehyde, adduct (69) has been obtained in high de and ee. 0 This 1,4-asymmetric induction features a dual role for the sulfinyl group chiral inductor and activator of a silyloxydiene. 

Scheme 2.27 Synthesis of dihydropyrones via asymmetric, vinylogous Mukaiyama aldol reactions (TBAT, tetra-n-butylammonium difluorotriphenylsiliconate).

Curti C, Ranieri B, Battistini L, Rassu G, Zambrano V, Pelosi G, Casiraghi G, Zanardi F (2010) Catalytic, asymmetric vinylogous mukaiyama aldol reactions of pyrrole- and furan-based dienoxy silanes how the diene heteroatom impacts stereocontrol. Adv Synth Catal 352 2011-2022... 

Fang L, Xue H, Yang J (2008) Synthesis of the C1-C12 fragment of iriomoteolide la by sequential catalytic asymmetric vinylogous aldol reactions. Org Lett 10 4645 648... 

Remote asymmetric induction can be obtained through the use of chiral auxiliaries, such as valine derived oxazolidinones, within the framework of the vinylogous Mukaiyama aldol reaction. During the synthesis of khafrefungin, an antifungal agent, Kobayashi and coworkers reacted the vinylketene silyl A. O-acetal 56 with the aldehyde 57 to yield the a r/-aldol adduct 58 in excellent yield (98%) and high diastereoselectivity (> 20 1). ... 

Moreover, the protocol could be used for a vinylogous Mukaiyama aldol addition and offered a solution to the problem of the asymmetric acetoacetate aldol reaction. Thus, 2 mol% of the catalyst 198 is enough to promote the addition of silyl dienolate 214 to various aldehydes to give, after desilylation, O-protected P-keto-5-hydroxy esters [113]. The protocol is illustrated for an addition to P-stannylpropenal 213. Depending on the enantiomer of the catalyst 198 or ent-198 chosen to mediate the aldol addition, enantiomeric products 215 and ent-215 were obtained in 92% ee. In an elegant convergent total synthesis, both enantiomers were incorporated into macrolactin A, as shown in Scheme 5.65 [114,115]. 

Floreancig and co-workers communicated the synthesis of (+)-dactylolide in 2005. The key step of Floreancig s synthesis involved an asymmetric vinylogous Mu-kaiyama-aldol reaction and an intramolecular Prins cyclization of the acetal bearing substrate. The macrocyclization of the synthesis was achieved by Honer-Wadsworth-Emmons olefination as demonstrated by the Smith group in the first total synthesis of (+)-zampanolide (Schemes 2.55, 2.56). 

Cinchona alkaloid-derived ammonium phenoxides as Lewis base catalysts have been appUed to asymmetric vinylogous Mukaiyama-type aldol reactions (Scheme 14.8) [30]. In the first step of this reaction, silyl compound 14 reacts with ammonium phenoxide to produce ammonium dienolate 15 with generation of trimethyl(phenoxy) silane. The latter part of this reachon mechanism is basically simQar to the reaction mechanism of ammonium fluoride-catalyzed reactions with silyl nucleophiles as shown in Scheme 14.7. This reaction system was also appUed to other asymmetric transformations [6a, 31]. 

Nakamura et al. established the stereoselective synthesis of 3-hydroxy-2-oxindols by using 1,7-asymmetric induction. Scheme 8.51 shows the enantioselective synthesis of convo-lutamydine B 310, an antitumor agent. The vinylogous aldol reaction with dienolate 303 and enf-303 was found to be effective to yield 3-hydroxy-2-oxindols stereoselectively. 

Because the products of 1,7- and 1,6,7-asymmetric induction reactions have structures frequently found in polyketide compounds and multifunctional groups to be manipulated, these reactions have been applied to synthesize polyketide in short steps. For example, the saii-Helicobacter pylori agent actinopyrone A 313 was synthesized in nine steps from ent -305 (Scheme 8.52). The total synthesis started from the vinylogous Mukaiyama aldol reaction to give the C11-C18 moiety 311 as a single isomer. Protection of the secondary alcohol was followed by DIBAL reduction to give aldehyde 312. As mentioned, the methodology makes it possible to synthesize polyketide compounds in short steps. 

SCHEME 8.55. The catal)4ic asymmetric vinylogous Mukaiyama aldol reaction by Simsek and Kalesse. 

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