Homoaldol reaction asymmetric

Some alkenyl carbamates leading to configurationally labile lithium intermediates could be subjected to asymmetric homoaldol reaction with less efficiency (Scheme 6) these reactions have not been optimized yet Azs... 

Z)-awh-4-Hydroxy-l-aIkenyl carbamates 363, when subjected to substrate-directed, vanadyl-catalysed epoxidation , lead to diastereomerically pure epoxides of type 364 (equation 99)247,252,269 qqjggg epoxides are highly reactive in the presence of Lewis or Brpnsted acids to form -hydroxylactol ethers 366 in some cases the intermediate lactol carbamates 365 could be isolated . However, most epoxides 364 survive purification by silica gel chromatography . The asymmetric homoaldol reaction, coupled with directed epoxidation, and solvolysis rapidly leads to high stereochemical complexity. Some examples are collected in equation 99. The furanosides 368 and 370, readily available from (/f)-0-benzyl lactaldehyde via the corresponding enol carbamates 367 and 369, respectively, have been employed in a short synthesis of the key intermediates of the Kinoshita rifamycin S synthesis . 1,5-Dienyl carbamates such as 371, obtained from 2-substituted enals, provide a facile access to branched carbohydrate analogues . 

In 1996, McWilliams and coworkers described a very interesting tandem asymmetric transformation whereby an asymmetric 1,2-migration from a higher-order zincate 60 was coupled with a stereoselective homoaldol reaction (equation 26)29. 

Enantioselective homoaldol reaction induced by sparteine and Ti catalyzed, also asymmetric deprotonation of allyl carbamates. 

The Merck labs described a process for conpling an asymmetric homologation to an asymmetfic homoaldol reaction in a previous communication. In this tandem asymmetric transformation, chiral amide enolates derived from aminoindanol amides (I) were homologated to the zinc homoenolates... 

It is especially remarkable that optically active homoaldol adducts can be obtained when enantiomeri-cally pure 2-alkenyl carbamates (47 R = alkyl) are employed. Apparently the deprotonation occurs with retention of configuration and leads to configurationally stable lithium derivatives, which, after metal exchange with Ti(OPr )4, again with retention, add to aldehydes with efficient 1,3-chirality transfer coupled with enantiofacial differentiation at the carbonyl group, indicating a rigid six-membered transition state. Recently even an asymmetric homoaldol reaction by enantioselective lithiation of prochiral primary alkenyl carbamates in the presence of (-)-sparteine was reported. ... 

Several other chiral homoenolate anion equivalents have been successfully exploited for asymmetric homoaldol reactions, e.g. (48) and (49), ° but their preparation seems more laborious than that of the carbamates (47). 

Over the past 12 years or so, significant progresses of the "direct" aldol reaction have been achieved. In particular, the aldol-type reactions of pyruvic acid and its derivatives are useful for the synthesis of isotetronic acid derivatives. In 2000, Jorgensen et al. [23] reported the first example of asymmetric homoaldol reaction of ethyl pyruvate 26a in this work, chiral (R)-f-Bu-bis(l,3-oxazolin-2 -yl)methane (BOX)-Cu(OTf)2 catalyst was used (Scheme 11). Organocata-lytic version of similar reactions has been investigated. For instance, Dondoni et al. examined catalyst efficiency of several prolin-based organocatalysts for homoaldol reaction of 26a and foxmd that a combination of (S)-l-(2-pyrro-lidinylmethyl)pyrrolidine 29 and trifluoroacetic acid is effective [24]. 

Although initially developed as a rather exotic reaction, the intramolecular transace-talization reaction can also be a very useful tool in asymmetric synthesis of important chiral compounds and natural products. Both, starting materials and products of the intramolecular transacetalization reaction are protected y-hydroxycarbonyl compounds, orhomoaldols (Scheme 13). Homoaldols are versatile motifs in organic synthesis that can be easily transformed into a vast array of important chiral compounds. However, due to the problematic homoaldol disconnection, these compounds are not readily available in a catalytic asymmetric fashion. 

A highly enantioselective kinetic resolution of protected homoaldols via a catalytic asymmetric transacetalization reaction could be achieved with a novel phosphoric acid STRIP (6) (Table 1) [25]. A catalyst loading of 1 mol% could be routinely used at 20°C, and even 0.1 mol% of the catalyst can give very similar enantiomeric ratios. The method is applicable to the resolution of a wide range of secondary and, most remarkably, of tertiary homoaldols. In most cases, both acyclic homoaldols 7 and cyclic homoaldols 8 could be obtained in enantiomeric ratios exceeding 95 5. Although chemical kinetic resolutions of secondary alcohols by other methods are well developed [26], these are not readily applicable to kinetic resolutions of tertiary alcohols [27-34]. 

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