Stereocontrolled additions

Stereocontrolled Additions to Dihydropyridines and Tetrahydropyridines Access to N-Heterocyclic Compounds Related to Natural Products... 

The final chapter in this volume by R. Kumar and R. Chandra (University of Delhi, India) deals with stereocontrolled additions to di- and tetrahydropyridines and particularly their application to natural product synthesis. 

Ketone 13 possesses the requisite structural features for an a-chelation-controlled carbonyl addition reaction.9-11 Treatment of 13 with 3-methyl-3-butenylmagnesium bromide leads, through the intermediacy of a five-membered chelate, to the formation of intermediate 12 together with a small amount of the C-12 epimer. The degree of stereoselectivity (ca. 50 1 in favor of the desired compound 12) exhibited in this substrate-stereocontrolled addition reaction is exceptional. It is instructive to note that sequential treatment of lactone 14 with 3-methyl-3-butenylmagnesium bromide and tert-butyldimethylsilyl chloride, followed by exposure of the resultant ketone to methylmagnesium bromide, produces the C-12 epimer of intermediate 12 with the same 50 1 stereoselectivity. 

Stereoselective synthesis of pseudo C2-symmetrical 1,3-dibenzyldiamino alcohol (S,S) (323) a core unit of HIV protease inhibitors, and the two meso-stereoisomers (323a) and (323b) was achieved by stereocontrolled addition of benzylmagnesium chloride to nitrones (63a) and (63b) (Scheme 2.137). The yield of (S,S)-(323), based on N-Boc-L-phenylalaninal, accounts for 23% (Scheme 2.137) (211). 

Transformation of chiral nitrones into enantiomer enriched a-chiral N -hydroxylamines and their derivatives, has been successfully employed in the enantioselective synthesis of (+ )-(R)- and (—)-(S)-zileuton (216). An expeditious synthesis of thymine polyoxin C (347), based on the stereocontrolled addition of 2-lithiofuran (a masked carboxylate group) to the A-benzyl nitrone derived from methyl 2,3-O-isopropylidene-dialdo-D-ribofuranoside, is described (Scheme 2.151) (194). 

The stereocontrolled addition of TMSCN to chiral 3.4-dihydro-277 - pyrroline N - oxides (394) is being used to prepare enantiopure 2-aminomethylpyrrolidines (395) and (396) (Scheme 2.172) (631). 

Fu and Dosa139 report the enantioselective addition of diphenylzinc to a range of aryl-alkyl and dialkyl ketones with good to excellent stereocontrol. Addition of 1.5 eq. of MeOH in the presence of a catalytic amount of (+)-DAIB 135 results in enhanced enantioselectivity and improved yield (Scheme 2-53). Table 2-16 gives the results of this reaction. 

Stereocontrolled addition of 2-furyl anion to 2,3-0-isopropylidene-D-glyceraldehyde can be achieved by the addition of some metal salts. 

Coordination of organometallic species has been used in studies of stereocontrol of the addition. These stereocontrolled addition reactions possess considerable preparative potential as outlined in the following examples. Addition of Grignard reagents to chiral aldoxime ethers such as 100 (equation 69) was found to proceed with a substantial stereoselectivity. ... 

Steroid side chain.1 The key step in a method for stereocontrolled addition of the side chain to 17-kelo steroids is hydroboration of a 17(20)-(Z)-ethylidene steroid (I), which proceeds selectively to give 2, with the desired natural configuration at C,- and C2ft. The product reacts with most alkylating reagents in rather low yield, possibly because of stcric factors however alkylation with the anion of chloroacetonitrile (potassium 2,6-di-r-butyl-4-methylphenoxide) in T1IF gives the nitrile 3 in 60 70% yield. One added attraction of this route is that 9-BBN reacts preferentially with a 17(20)-double bond in the presence of a 5(6 )-double bond. 

Stereocontrolled addition of 2-LTT (25b) to the nitrone 64 (Scheme 19), derived from... 

A. Dondoni, S. Franco, F. L. Merchan, P. Merino, and T. Tejero, Stereocontrolled addition of 2-thiazolyl organometallic reagents to C-galactopyranosylnitrone. A formal synthesis of de-stomic acid and lincosamine, Synlett p. 78 (1993). 

As mentioned earlier, direct hydride abstraction from 5-exo-substituted cyclohexadiene complexes is in general difficult, except for the 2-trimethylsilyl-substituted derivatives such as (48) and (50). Oxidative cyclization techniques have been developed to overcome this problem, exemplified by the conversion of (52) to (53) and thence to (54 Scheme 7). Stereocontrolled addition of a second nucleophile has already been illustrated by the conversion of (54) to (126) or (127), and the limitations imposed by a sterically demanding 6-exo substituent have been mentioned. 

Many efforts have been directed to the regioselective substitution of either HO-2 or -3 and to stereocontrolled addition reactions to the double bond. The acylation and alkylation of such hydroxyl groups is fairly sensitive to the reaction conditions. It is reported that alkylation of ascorbic acid in solvents of high dielectric constant favors 2-C-alkylation when powerful alkylation agents were employed.346... 

---