Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7077–7079
Total synthesis and absolute stereochemistry of
(9R,10S)-epoxyheptadecan-4,6-diyn-3-one, a diacylglycerol
acyltransferase inhibitor from Panax ginseng
Jung-Hoon Oh,a Hyun Sun Lee,a Mun-Chual Rho,a Young Kook Kim,a
Hyeong Kyu Lee,a Woo Song Lee,a Jae Nyoung Kim,b Sangku Leea,* and Sang-Hun Jungc
aKorea Research Institute of Bioscience and Biotechnology, 52 Oun, Yusong, Taejon 305-333, Republic of Korea
bDepartment of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
cCollege of Pharmacy, Chungnam National University, Taejon 305-764, Republic of Korea
Received 18 June 2004; revised 22 July 2004; accepted 26 July 2004
Abstract—Asymmetric synthesis of four possible stereoisomers of (9,10)-epoxyheptadecan-4,6-diyn-3-one was accomplished, and
the absolute configuration of the naturally occurring (9R,10S)-epoxyheptadecan-4,6-diyn-3-one (1) was elucidated.
Ó 2004 Elsevier Ltd. All rights reserved.
Acyl-CoA:diacylglycerol acyltransferase (DGAT, EG
2.3.1.20) is a microsomal enzyme that catalyzes the for-
mation of triacylglycerol from 1,2-diacylglycerol and
fatty acyl CoA.1 Triacylglycerol (TG) plays a crucial
role as energy-storage molecules in mammals. However,
a high level of TG is known to be a major risk factor for
coronary heart disease, obesity, and hypertriglyceride-
mia.2 Accordingly, DGAT inhibitors are expected to
be an attractive target for the prevention and treatment
of obesity and hypertriglyceridemia.
Herein we describe the synthesis of four possible stereo-
isomers of (9,10)-epoxyheptadecan-4,6-diyn-3-one and
the determination of the relative and absolute configura-
tion of naturally occurring (9R,10S)-epoxyheptadecan-
4,6-diyn-3-one (1) (Fig. 1).
The synthesis of (9R,10S)-epoxyheptadecan-4,6-diyn-3-
one (1) and its stereoisomers was achieved by a general
coupling of two components, polyacetylene 5 and epoxy
triflate 6, and subsequent oxidation of the resultant sec-
ondary alcohol to furnish 1 as shown in Scheme 1. We
envisioned that the relative stereochemistry at epoxy
moiety in 1 could be determined by the difference in ole-
fin geometry of allylic alcohol 7. And, the absolute ste-
reochemistry of epoxy triflate 6 could be determined
by Sharpless asymmetric epoxidaion4 of the correspond-
ing allylic alcohol 7 and followed by triflation, thereby
establishing the absolute chemistry of 1.
In the course of screening for inhibitors of diacylglycerol
acyltransferase (DGAT) from medicinal herbs, we iso-
lated a new polyacetylene compound bearing an epoxy
ring from the roots of Panax ginseng C. A. Meyer.
The polyacetylene compound, (9R,10S)-epoxyheptade-
can-4,6-diyn-3-one (1), exhibited DGAT inhibition with
D
IC50 of 9lg/mL and optical rotation of ½aꢀ ꢁ70.0 (c
25
1.0, CHCl3).3 The connectivity of 1 was established by
NMR analysis, however, the relative and absolute con-
figuration of an epoxy moiety in 1 was not elucidated.
As we have been interested in further biological studies
including in vivo activities, the stereochemistry of 1
should be determined, thereby enabling to provide a
synthetic way that would bring a large quantity of 1.
The acetylenic C1–C7 moiety 5 was prepared from acetyl-
ide-carbonyl condensation (Scheme 2). Addition of pro-
pionaldehyde to disodiobutadiynlide generated in situ
by the reaction of 1,4-dichloro-2-butyn (8) and sodium
amide in THF afforded hepta-4,6-diyn-3-ol (5).5 The
C8–C17 epoxy triflate moiety 6 was obtained starting
from 1-nonyne in four steps. Lithiation of 1-nonyne
(9) using n-BuLi and addition of paraformaldehyde pro-
vided dec-2-yn-1-ol (10).6 Acetylenic alcohol 10 was
selectively hydrogenated with Lindlar catalyst to yield
the corresponding cis-allylic alcohol 7. Sharpless
Keywords: Absolute configuration; Stereochemistry; Asymmetric syn-
thesis; Total synthesis; Epoxidation.
*
Corresponding author. Tel.: +82 42 860 4552; fax: +82 42 861
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.153