1- ethyl-protected 3-hydroxy ketones

In a related process, triethylsilane plus SnCLr can expediently convert appropriately protected aldol products to fully protected 1,3-diols. Moreover, the synthesis of iyn-l,3-ethylidene acetals from l-(2-methoxyethoxy)ethyl-protected -hydroxy ketones with SnCLr and EtsSiH can occur with very high levels of diastereocontrol (eq 33). ... 

Trost and coworkers recently reported that these dinuclear zinc complexes catalyze Mannich reactions with unmodified aromatic hydroxy ketones as donors with excellent enantioselectivity [18]. Mannich-type reactions between an N-para-meth-oxyphenyl (PMP)-protected a-ethyl glyoxalate and hydroxyacetophenone in the presence of a catalytic amount of catalyst 5a afford the desired N-PMP protected amino acid derivative in 76 % yield with a dr of 7 1 and 95 % ee (Eq.5). 

Spiroketalization. The synthesis of talaron ycin B (3) with four chiral centers by cyclization of an acyclic precursor presents stcrcot hcmical problems. A solution involves cyclization of a protected (3-hydroxy ketone witii only one chiral center. Because of thermodynamic considerations (i.e.. all substituents being equatorial and the anomcric effect), cyclization of 1 with HgCl, in CH,CN lollowcd by acetonation results in the desired product (2, 65% yield) with a stereoselectivity of —10 1. Final steps involve conversion of the hydroxymethyl group to ethyl by tosylation and displacement with lithium dimethylcupratc (80% yield) and hydrolysis of the acetonidc group. 

Methyl ketones are often directly prepared from carboxylic acids by reaction with methyllithium. Other simple alkyl ketones may also be prepared in the same fashion, making this a method that should be considered whenever these substrates are required. An important demonstration of this protocol was reported by Masamune and coworkers in their synthesis of chiral propionate surrogates (Scheme 13). The ethyl and cyclopropyl ketones are important starting materials for macrolide total synthesis and have been prepared on a large scale. The overall yield for the ethyl ketone is 65% using 3.5 equiv. of ethyllithium without protection of the hydroxy group. 

Other classes of molecules which have been benzylated using this reagent include hydroxy ketones, hydroxy halides and esters such as tartrates, hydroxy propionates or butanoaies, long alkyl chain hydroxy esters, and hydroxy lactones. Under basic conditions problems such as enolization, aldol reactions, elimination and epoxide formation can cause problems and when 2-substituted esters, such as ethyl (5)-lactate, are required as homochiral starting materials, then protection using this method circumvents the considerable risk of racemization that accompanies the use of bases (eq 6). 

Methyl ketones from esters (12, 126).1 The reaction of a carboxylic acid or ester with CH3Li and ClSi(CH3)3 to provide a methyl ketone has been used to obtain a silyl protected (S)-3-hydroxy-2-butanone (2) from ethyl lactate (1). The addition of... 

Cyclohexylpropionic acid was deprotonated with 2.2 equivalent of lithium diisopropylamide and the resulting dianion was condensed with trifluoroacetaldehyde which was generated in situ from its ethyl hemiacetal. The P-hydroxy acid 1 was isolated as a racemic mixture of two diastereomers. Silylation with tert-butyldimethylsilyl triflate was followed by ester hydrolysis to give the acid 2. A Curtius rearrangement with diphenylphosphoryl azide in the presence of benzyl alcohol afforded the protected P-amino alcohol 3 which was used in the preparation of the trifluoromethyl alcohol I. Oxidation using the Dess-Martin periodinane reagent (9) yielded the trifluoromethyl ketone II as a mixture of diastereomers. The signal for the carbonyl carbon in the 13C-NMR spectrum of this ketone appeared at 94.5 ppm and this is consistent with the hydrated form of the trifluoromethyl ketone. 

An alternative route by the Danishefsky group was developed [142e-g] (Scheme 84). The aldol reaction of ethyl ketone 580, prepared from P-keto ester 579, with aldehyde 581 stereoselectively afforded 582 (dr = 5.4 1). After Troc protection followed by hydrolysis of the enol ether, Suzuki coupling with 583 followed by TBS deprotection gave the desired (12Z)-olefin 584. The Noyori reduction of the P-keto ester 584 gave 3a-alcohol with high stereoselectivity, which was converted into hydroxy carboxylic acid 585. Macrolactonization of 585 was accomplished by the Yamaguchi method, and subsequent deprotection and DMDO oxidation efficiently afforded epothilone B (5b). 

C2-homologizati on of sugars with, 264-265 Acetamide, JV-bromo- (AcNHBr, NBA) bromohydrination with, 275-276, 287 Acetaminophen (= paracetamol), 301 Acetate, piperidinium cat. for aldol add., 82 —, sodium a-epimerization of ketones, 277 opening of oxiranes, 282 Acetic acid, anhydride (AcfO) protection with. See Protection Pummerer rearr. with, 51, 265 —, esters (See also Protection of hydroxy groups) C-H acidity, 10 1-methylethenyi ester pr., 174 transenolization, 58 —, bromo-, esters pr., 179 a2-synthon, 19, 65, 309 d2-synthon, 19, 301 —, chloro-, esters pr., 179 hydantoins from, 308 —, cyano-, esters pr., 177 pyrrolines from, 298 —, (dialkoxyphosphinyl)-, esters pr 188 Wittig-Horner olefinations, 267, 282 —, diazo-, ethyl ester pr, 176, 178 cyclopropanes from, 74—75 —, dichloro- deblocking of pixyl ethers, 342 —, hydroxy-, esters pr., 176 —, hydroxyphenyl-, (S)- (l-mandelic acid) ... 

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