Masamune process

An attractive feature of the Masamune process is the subsequent ease of removal of the sulfonamide auxiliary to afford the corresponding acid (LiOH, THF/H2O) without loss of stereochemical integrity of the products. 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

Masamune has documented the addition of optically active ester enolates that afford lanfi-aldol adducts in superb yields and impressive stereoselectivity (Eq. (8.3)) [4]. The generation of a boryl enolate from 8 follows from groundbreaking studies of ester enolization by Masamune employing dialkyl boryl tri-flates and amines [5]. Careful selection of di-n-alkyl boron triflate (di-n-butyl versus dicyclopentyl or dicyclohexyl) and base (triethyl amine versus Hiinigs base) leads to the formation of enolates that participate in the <2u//-selective propionate aldol additions. Under optimal conditions, 8 is treated with 1-2 equiv of di-c-hex-yl boron triflate and triethyl amine at -78 °C followed by addition of aldehyde the products 9 and 10 are isolated in up to 99 1 antv.syn diastereomeric ratio. The asymmetric aldol process can be successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. 

If a prochiral silyl enol ether reacts with a prochiral C=X compound, a pair of racemic dia-stereoisomers results (equation 1). A reaction that gives an excess of one of these diastereoisomers is said to exhibit simple stereoselection. In this section we discuss the factors that govern the stereochemistry of this process. Diastereoisomers such as (1) and (2) will be called syn (1) and anti (2) in accord with the convention first proposed by Masamune et al Although only one enantiomer is depicted in each case, all structures in this section represent racemates. 

This reagent is unreactive towards terminal alkenes, so it was surprising that reduction of the isostruchiral carbonyl function is a facile process. Masamune has shown that the mesylate derivative (139) (generated from (138) and methanesulphonic acid) plays a key role. 

The oxazole ring was then introduced by a process using Masamune s protocol" for calyculin C. Thus reaction of 1302b with ethyl 3-bromo-2-oxo-butyrate followed by dehydration of the intermediate 4-hydroxyoxazoline (not shown) with TFAA in pyridine produced 1290 (Rj = C2H5), which was easily converted to 1187. 

In addition to the advances in auxiliary-controlled acetate aldol addition reactions, a number of innovative solutions for the preparation of propionate-derived 1,2-anti products have also appeared using auxiliaries other than Evans oxazolidinone. The various successful approaches to anti aldol adducts stem from the design of novel auxiliaries coupled with the study of metal and base effects on the reaction stereochemistry. Masamune documented that the addition of optically active ester enolate 112 to aldehydes afforded anti aldol adduct 113 in superb yield and diastereoselectivity (Equation 10) [70]. After careful selection of the reaction conditions for the enolization of the ester [71], the aldol addition was successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. An attractive feature of this process is the subsequent facile removal of the auxiliary (LiOH, THF/H2O) to afford the corresponding acid without concomitant deterioration of the configurational integrity of the products [70]. 

---