Stereoselective hydroxylation methylene group

Boyd, D.R., Sharma, N.D., Bowers, N.I. et al. (1996) Stereoselective dioxygenase-catalyzed benzylic hydroxyl-ation at prochiral methylene groups in the chemoenzymatic synthesis of enantiopure vicinal aminoindanols. Tetrahedron Asymmetry, , 1559-1562. 

Allylic alcohols are also cyclopropanated over 100 times faster than their unfunctionalized alkene equivalents. Coordination between the zinc atom and the hydroxyl group in the transition state explains both the stereoselectivity and the rate increase. Unfortunately, while the Simmons-Smith reaction works well when a methylene (CH2) group is being transferred, it is less good with substituted methylene groups (RCH or R2C ). 

Kirby, G. W., and M. J. Varley Synthesis of Tryptophan Stereoselectively Labelled with Tritium and Deuterium in the P-Methylene Group the Steric Course of Hydroxylation in Sporidesmin Biosynthesis. J. C. S. Chem. Comm. 833-834 (1974). 

Stereoselective microbial hydroxylations occurring at methylene groups of chiral substrates are frequently reported [4]. The present discussion will focus on the more unusual situation of stereoselective hydroxylations that occur at methylene groups of achiral, prochiral, or racemic substrates, resulting in the introduction of chirality to the product. 

In a further extension of this reaction Winstein and Dauben showed that the action of the methylene-transfer reagent (1) on A -cycloal-kenols, e.g., (2), proceeds by stereospecific cis addition to give the cw-cyclo-propyl carbinol (5). It was also observed that both the rate and yield of the hydroxyl-assisted reaction are increased substantially. It has been suggested that the high stereoselectivity observed in these instances is best explained by complex formation or reaction of the reagent (1) with the hydroxyl group of (2) followed by intromolecular transfer of methylene. 

The aldehyde function at C-85 in 25 is unmasked by oxidative hydrolysis of the thioacetal group (I2, NaHCOs) (98 % yield), and the resulting aldehyde 26 is coupled to Z-iodoolefin 10 by a NiCh/CrCH-mediated process to afford a ca. 3 2 mixture of diaste-reoisomeric allylic alcohols 27, epimeric at C-85 (90 % yield). The low stereoselectivity of this coupling reaction is, of course, inconsequential, since the next operation involves oxidation [pyridinium dichromate (PDC)] to the corresponding enone and. olefination with methylene triphenylphosphorane to furnish the desired diene system (70-75% overall yield from dithioacetal 9). Deprotection of the C-77 primary hydroxyl group by mild acid hydrolysis (PPTS, MeOH-ClHhCh), followed by Swem oxidation, then leads to the C77-C115 aldehyde 28 in excellent overall yield. 

Koizumi and co-workers used optically active allylic chloroselenuranes bearing a 2-exo-hydroxyl-lO-bornyl group to produce optically active allylic selenium ylides in situ [52]. The nucleophilic reaction of the corresponding chiral chloro-selenurane and selenoxide with an active methylene compound occurs in a highly stereoselective manner to give the corresponding chiral selenium ylides with retention of configuration [53] (Scheme 33). 

The same group used a ketal tether as an alternative connecting group in the synthesis of the 1,4-linked C-disaccharide 236 [85 b]. Tebbe methylenation of acetate 237 provided the corresponding enol ether 238, which upon treatment with alcohol 235 in the presence of CSA at -40°C in acetonitrile, furnished linked disaccharide 239 in 81% yield. Subsequent radical cyclization, acidic hydrolysis of the tether and peracetylation provided the D-mannose-containing C-disaccharide 236 as the major product in 35% yield from 239 (Scheme 10-75). Cyclization was not completely stereoselective and a small amount of the )8-C-manno isomer was also isolated (a/)3 10 1). This result is in contrast to similar studies on tether-directed /J-C-mannoside syntheses (vide infra) where a much shorter tether attached to the axial 2-hydroxyl group forces obtention of the desired P-configuration. 

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