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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

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Lipids

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.

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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

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Authors and Affiliations

  1. Robert Wood Johnson Medical School, New Brunswick, New Jersey

    Norman H. Ertel

  2. Medical Service, VA New Jersey Health Care System, 07018, East Orange, New Jersey

    Norman H. Ertel, Bishambar Dayal, Kashav Rao & Gerald Salen

  3. Department of Medicine, University of Medicine, 07103, Newark, New Jersey

    Norman H. Ertel, Bishambar Dayal, Kashav Rao & Gerald Salen

  4. Dentistry of New Jersey, New Jersey Medical School, 07103, Newark, New Jersey

    Norman H. Ertel, Bishambar Dayal, Kashav Rao & Gerald Salen

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  1. Norman H. Ertel
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  2. Bishambar Dayal
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  3. Kashav Rao
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  4. Gerald Salen
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Correspondence to Bishambar Dayal.

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Ertel, N.H., Dayal, B., Rao, K. et al. 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. Lipids 34, 395–405 (1999). https://doi.org/10.1007/s11745-999-0378-4

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  • DOI: https://doi.org/10.1007/s11745-999-0378-4

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