ORGANIC
LETTERS
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Vol. XX, No. XX
Revised Stereochemistry of
000–000
Ceramide-Trafficking Inhibitor HPA-12
by X‑ray Crystallography Analysis
Masaharu Ueno, Yi-Yong Huang, Akihito Yamano, and Shu Kobayashi*
†
†
‡
,†
Department of Chemistry, School of Science, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Application Laboratories,
Rigaku Corporation, 3-9-12, Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan
Received April 24, 2013
ABSTRACT
In response to Berke ꢀs ’s report revising the stereochemistry of HPA-12, an important ceramide-trafficking inhibitor that was discovered and
synthesized and its stereochemistry determined in 2001, the synthesis and the stereochemistry were reinvestigated. A large-scale synthetic
method for HPA-12 based on a Zn-catalyzed asymmetric Mannich-type reaction in water was developed. Single crystals of HPA-12 for X-ray
crystallographic analysis were obtained from ethyl propionate/n-hexane, and the stereochemistry was definitely determined to be 1R,3S,
consistent with Berke ꢀs ’s revised structure.
Sphingolipids are one of the constituents of membrane
lipids in mammalian cells and play important roles in cell
ceramide transport. Later, HPA-12 was demonstrated to
be a direct antagonist of the ceramide transport protein
CERT, which mediates interorganelle trafficking of cer-
amide from the ER to the Golgi site for the synthesis of
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growth, differentiation, and apoptosis. Ceramide produced
in the endoplasmic reticulum (ER) is transported to the Golgi
apparatus for conversion to sphingomyelin (SM). N-(3-
Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide
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SM. Since the target was specified, the CERT inhibitor
HPA-12 has been used as a convenient tool for various
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(
HPA-12) is a novel inhibitor of ceramide trafficking from
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biological in vitro studies.
the ER to the site of SM synthesis. HPA-12 does not
inhibit the activity of SM synthase or the ER-to-Golgi
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trafficking of proteins, suggesting specific inhibition of
HPA-12 was discovered from our amino alcohol library
in2001. Weaccomplishedthe first total synthesis and deter-
mined the absolute stereochemistry of HPA-12 (1, 1R,3R)
a
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in the same year. Subsequently, in 2011, Berke ꢀs et al.
†
The University of Tokyo.
Rigaku Corporation.
‡
(
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0.1021/ol401101u r XXXX American Chemical Society