Esters stereoselective formation

The coupling reaction between lithium dimethylcuprate and acyclic enol phosphates must be carried out between -47 and -98 C for stereoselective formation of g-methyl-a,g-unsaturated esters. 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

An example of a surprisingly facile and stereoselective formation of an eight-membered lactone from an acyclic precursor diene ester was observed during the total synthesis of the antitumor agent octalactin A (148) (Scheme 27) [81]. The dense substitution pattern in cyclization substrate 146 presumably imposes... 

Miyamoto, J., H. Kaneko, and Y. Takamatsu. 1986. Stereoselective formation of a cholesterol ester conjugate from fenvalerate by mouse microsomal carboxyesterase(s). Jour. Biochem. Toxicol. 1 79-94. 

Scheme 3.40. Stereoselective reaction between a-aminoalkyl-cuprates and allenic esters, with formation of 4-all

In order to obtain stereoselective formation of the chiral centers C-3, C-7, and C-14, we explored the use of chiral derivatives of our indoloaze-pine 153. Earlier, we had already found that the A(-benzylindoloazepine ester 215 rearranged on heating to an a-methylene lactam 216, indicating the possibility of thermal generation of an intermediate secondary amine indoloacrylate 217. It was also found that this intermediate could be trapped with a variety of aldehydes. Thus, D-seco D-E-trans vincadiffor-mine congeners (218) could be obtained by condensation of the indoloaze-pine 215 with aldehydes at 100°C (Scheme 54) (132). Consequently, introduction of a chiral substituent onto N of the indoloazepine 153 prior to condensation with our 4-ethyl-4,5-dihydroxypentanal acetonides 186 and 187 appeared to be an option for chiral induction in the formation of cen-... 

Whereas the Markovnikov addition of carboxylic acids to propargylic alcohols produces P-ketoesters, resulting from intramolecular transesterification [30, 31], the addition to propargylic alcohols in the presence of Ru(methallyl)2(dppe) 1 at 65 °C leads to hydroxylated alk-l-en-l-yl esters via formation of a hydroxy vinylidene intermediate [32, 33]. The stereoselectivities are lo ver than those obtained from non-hydroxylated substrates. These esters, which are protected forms of aldehydes, can easily be cleaved under thermal or acidic conditions to give conjugated enals, corresponding to the formal isomerization products of the starting alcohols (Scheme 10.6). 

Sometimes, alcohols can direct the oxidation of alkenes, resulting in highly stereoselective formation of tetrahydrofurans by the action of Collins reagent. Thus, 1,2-diols can form cyclic chromate esters that can intramole-cularly oxidize alkenes, positioned so as to allow the operation of five-membered cyclic transition states.119... 

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

Kinetic enolates. The kinetic enolate of a ketone or ester is generated with enhanced selectivity by a lithium dialkylamide in the presence of chlorotrimethylsilane. In addition, LOBA is superior to LDA for regioseicctivc generation of enolates and for stereoselective formation of (E)-enolatfes. 

Chiral Auxiliary. (/ ,/ )-( ) has been used as a chiral auxiliary to direct the stereochemistry of addition of a nucleophile to an acrylate moiety. Almost complete stereoselectivity is achieved in the addition of cyclopentanecarboxylic acid lithium dianion to the a-substituted acrylate substrate (eq 14). This methodology allows stereochemical control at the a-position of a p-amino ester and thus complements the methodology described above for the stereoselective formation of p-substituted p-amino esters. 

Aldol Reactions of Ester Derivatives. The Titanium(IV) C/tlor/dc-catalyzed addition of aldehydes to 0-silyl ketene acetals derived from acetate and propionate esters proceeds with high stereoselectivity. Formation of the silyl ketene acetal was found to be essential for high diastereoselectivity. Treatment of the silyl ketene acetal, derived from deprotonation of the acetate ester with LICA in THF and silyl trapping, with a corresponding aldehyde in the presence of TiCU (1.1 equiv) afforded the addition products in 93 7 diastereoselectivity and moderate yield (51-67%). Similarly, the propionate ester provides the anti-aldol product in high antilsyn selectivity (14 1) and facial selectivity (eq 4). 

For a highly stereoselective formation of silylketene acetals from esters and trialkylsilyl perchlorates see C. 

Treatment of bistrimethylsilyl enol ethers of glutaric esters with TiC leads to the stereoselective formation of rruns-1,2-cyclopropanedicarboxylic esters (equation 35). ... 

The effect of a free OH group is usually much more pronounced than that of the protected one. For example, oxiranes 58 and 59 were obtained with high stereoselectivity (directed by the free OH), although both oxy-substituents act in the opposite directions [ 1,44] (O Fig. 12). When the epoxidation is performed not on allylic alcohols but allylic esters the selectivity of this process is low both possible oxiranes are obtained in comparable amounts. The stereoselective formation of the 2-3-epoxides can be achieved also by the Sn2 process. Recently, Lowary proposed an efficient synthesis of 2,3-epoxy-arafci o-furanoside 61 from the parent glycoside 60 in a sequence of reactions presented in Scheme 20 [45]. Such anhydrosugars are convenient precursors for further functionalization at either the C-2 or C-3 position. 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

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