Double asymmetric synthesis aldol reactions

In Masamune s initial synthesis of the C -Cn polyacetate region of the bryo-statins (Scheme 9-37), the chiral reagents (S)- and (R)-53 were used to control the stereocenters at C3, C7 and Cn [36], The first of these reactions used R)-53 to set the C3 center in 115 and then two subsequent double asymmetric induction aldol reactions, to give 116 and 117, set the remaining stereocenters. 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

Methods that involve C—C bond formation with the establishment of two new stereogenic centers are of considerable interest in this context. The aldol reaction has proven very useful in this regard, particularly in view of die development of powerful chiral enolates capable of controlling the stereochemical course of reactions with chiral aldehydes via the principle of double asymmetric synthesis. ... 

The facial selectivity of (43) was found to be 1.75 1 from the ratio of aldol products (48) and (49) obtained by the reaction with the achiral boron enolate (50). The latter is structurally similar to reagents (37) and (38). These experiments confirm again the validity of the rule of double asymmetric synthesis. The product (44) can be further converted through a sequence of reactions to provide (+)-Prelog-Djerassi lactonic acid (51 Scheme 27) (i) trimethylsilylation (ii) hydroboration with thexylborane (single asym-... 

An asymmetric C-C coupling, one of the most important and challenging problems in synthetic organic chemistry, seems to be most appropriate for the creation of a complete set of diastereomers because of the applicability of a convergent, combinatorial strategy [38-40]. In Nature, such reactions are facilitated by lyases which catalyze the (usually reversible) addition of carbo-nucleophiles to C=0 double bonds, in a manner mechanistically most often categorized as aldol and Claisen additions or acyloin reactions [41], The most frequent reaction type is the aldol reaction, and some 30 lyases of the aldol type ( aldolases ) have been identified so far [42], of which the majority are involved in carbohydrate, amino acid, or hydroxy acid metabolism. This review will focus on the current state of development of this type of enzyme and will outline the scope and limitations for their preparative application in asymmetric synthesis. 

Masamune et al. have reviewed in detail the effects of double asymmetric induction not only for epoxidation, but also for the aldol, Diels-Alder, and catalytic hydrogenation reactions. The merits of this strategy are illustrated by an analysis of Woodward s synthesis" of erythromycin A (1), which has 10 chiral centers. 

Masamune s synthesis of bryostatin 7 (114) [36] contains early examples of double asymmetric induction, where the aldol reaction of chiral ketones could be... 

We referred above to a synthesis of bryostatin that contained a reduction controlled by a 1,3-relationship. Evans synthesis34 contains a 1,3-selective aldol as well as a 1,3-controlled reduction The aldehyde 202, made by an asymmetric aldol reaction, was combined with the double silyl enol ether of methyl acetoacetate to give, as expected, the anti-aldol 203. However, the only Lewis acid that gave this good result was (<-PrO)2TiCl2 and not BF3 thus emphasising the rather empirical aspect of this type of control. Evans s own 1,3-controlled reduction gave the anti,anti-triol 204 that was incorporated into bryostatin. 

The synthesis of the fragment C3-C13 was achieved in five steps from 169. Treatment of the tosylated stereotetrad 169 with 5 equivalents of lithium acetylide in DMSO led an acetylenic compound which was treated with ra-Buli and methyl iodide, and then reduced by Na/NH3 to produce the E-geometry of the C12-C13 double bond with concomitant removal of the PMB group at C5, giving the primary alcohol 170 (49% yield for the three-step sequence). Swern oxidation of 170 gave the corresponding aldehyde which was involved in an Evans-type asymmetric aldol reaction with the boron enolate A to produce the adduct 171 (dr > 95/5, 90% yield). (Scheme 33). 

Paterson reported a total synthesis of (+)-leucascandrolide A (199) in which essentially complete control over all of the stereochemistry is achieved. As outlined in Scheme 61, two Mitsunobu reactions were employed for macro-cyclization and installation of the side chain. The two ds-alkenes in the side chain were introduced by double Lindlar hydrogenation in the final stage. The oxygenated stereogenic centers on seco-acid 286 were constructed by reduction at C17 and C9, C-glycosidation at C15, and l,5-a ti-aldol reaction at Cll, all of which were by using substrate control. The 2,6-cis-tetrahydropyran in 287 was synthesized by the asymmetric hetero Diels-Alder reaction. 

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