Carboxylic acid silyl esters 4-hydroxy

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... 

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

In the first step amine 11 is coupled with carboxylic acid 15 to form an amide The method employed here for coupling an a-chiral carboxylic acid with an amine was developed in the context of peptide synthesis. Its success is based on DCC-mediated formation (see Chapter 5) of the reactive 1-hydroxy benzotriazole ester 55, which reacts with an amine to give the corresponding amide. In most cases reaction takes place without raccmi/ation, and often in the absence of side reactions that cause other procedures to The alcohol is converted into a silyl ether in the second step. 

These derivatives of carboxylic acids behave analogously to ester silyl ketene acetals (Section 2.3.2.4.3.i). Thus treatment with peracid in hexane followed by acidic work-up allows isolation of good yields of the a-hydroxy acids. 

Asymmetric syrc-selective aldol reaction of four carbons enolates (with attached chiral auxiliary) 290 and acrolein equivalent 291 was the key step in the Pettus synthesis of KDO [153]. Condensation adduct 292 was converted into the hydroxy lactone 293, which in turn after silyl deprotection and diol side chain installation gave lactone 204. Final addition of a carboxylic acid to the lactone carbonyl group of 204 was done with a-ethoxy vinyllithium. Reductive ozonolysis of the surrogate provided the ethyl ester 138 (Scheme 62). 

The diols (97) from asymmetric dil droxylation are easily converted to cyclic sii e esters (98) and thence to cyclic sulfate esters (99).This two-step process, reaction of the diol (97) with thionyl chloride followed by ruthenium tetroxide catalyzed oxidation, can be done in one pot if desired and transforms the relatively unreactive diol into an epoxide mimic, ue. the 1,2-cyclic sulfate (99), which is an excellent electrophile. A survey of reactions shows that cyclic sulfates can be opened by hydride, azide, fluoride, thiocyanide, carboxylate and nitrate ions. Benzylmagnesium chloride and thie anion of dimethyl malonate can also be used to open the cyclic sulfates. Opening by a nucleophile leads to formation of an intermediate 3-sidfate aiuon (100) which is easily hydrolyzed to a -hydroxy compound (101). Conditions for cat ytic acid hydrolysis have been developed that allow for selective removal of the sulfate ester in the presence of other acid sensitive groups such as acetals, ketals and silyl ethers. 

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