Lipids

, Volume 34, Issue 4, pp 395–405

Anomalous enantioselectivity in the sharpless asymmetric dihydroxylation reaction of 24-nor-5β-cholest-23-ene-3α,7α,12α-triol: Synthesis of substrates for studies of cholesterol side-chain oxidation

Authors

  • Norman H. Ertel
    • Robert Wood Johnson Medical School
    • Medical ServiceVA New Jersey Health Care System
    • Department of MedicineUniversity of Medicine
    • Dentistry of New JerseyNew Jersey Medical School
    • Medical ServiceVA New Jersey Health Care System
    • Department of MedicineUniversity of Medicine
    • Dentistry of New JerseyNew Jersey Medical School
  • Kashav Rao
    • Medical ServiceVA New Jersey Health Care System
    • Department of MedicineUniversity of Medicine
    • Dentistry of New JerseyNew Jersey Medical School
  • Gerald Salen
    • Medical ServiceVA New Jersey Health Care System
    • Department of MedicineUniversity of Medicine
    • Dentistry of New JerseyNew Jersey Medical School
Article

DOI: 10.1007/s11745-999-0378-4

Cite this article as:
Ertel, N.H., Dayal, B., Rao, K. et al. Lipids (1999) 34: 395. doi:10.1007/s11745-999-0378-4

Abstract

Recently we described a block in bile acid synthesis in cerebrotendinous xanthomatosis (CTX), a lipid storage disease related to an inborn error of bile acid metabolism. In this disease a defect in hepatic microsomal (24S) hydroxylation blocks the transformation of 5β-cholestane-3α,7α,12α,25-tetrol into (24S) 5β-cholestane-3α,7α,12α,24,25-pentol and cholic acid. Mitochondrial cholesterol 27-hydroxylation has also been reported to be abnormal in CTX subjects, but the relative importance of the enzymatic defect in this alternative microsomal pathway (namely, the 24S hydroxylation of 5β-cholestane-3α,7α,12α,25-tetrol relative to the abnormality in mitochondrial 27-hydroxylase) has not been established in CTX. To delineate the sequence of side-chain hydroxylations and the enzymatic block in bile acid synthesis, we synthesized the (23 R and 23 S) 24-nor-5β-cholestane-3α,7α,12α,23,25-pentols utilizing a modified Sharpless asymmetric dihydroxylation reaction on 24-nor-5β-cholest-23-ene-3α,7α,12α-triol, a C26 analog of the naturally occurring C27 bile alcohol, 5β-cholest-24-ene-3α,7α,12α-triol. Stereospecific conversion of the unsaturated 24-nor triol to the corresponding chiral compounds (23R and 23S), 24-nor-5β-cholestane-3α,7α,12α,23,25-pentols, was quantitative. However, conversion of the unsaturated 24-nor triol to the chiral nor-pentols had absolute stereochemistry opposite to the products predicted by the Sharpless steric model. The absolute configurations and enantiomeric excess of the C26 nor-pentols and the C27 pentols (synthesized from 5β-cholest-24-ene-3α,7α,12α-triol for comparison) were confirmed by nuclear magnetic resonance and lanthanide-induced circular dichroism Cotton effect measurements. These results may contribute to a better understanding of the role of the 24S-hydroxylation vs. 27-hydroxylation step in cholic acid biosynthesis.

Abbreviations

AD

asymmetric dihydroxylation

CD

circular dichroism

CTX

cerebrotendinous xanthomatosis

DEPT

distortionless enhancement polarization transfer

EI-MS

electron ionization mass spectra

Eu(fod)3

tris-1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-octane-4,6-dionato)europium(III)

FAB-MS

fast atom bombardment-mass spectrometry

GLC

gas-liquid chromatography

NMR

nuclear magnetic resonance

PHAL

phthalazine

TLC

thin-layer chromatography

Copyright information

© AOCS Press 1999