Tetrahedron Letters
Catalytic asymmetric synthesis of key intermediate for scytophycin C
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Jin Cui, Takumi Watanabe , Masakatsu Shibasaki
Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We achieved a formal total synthesis of scytophycin C. The synthesis demonstrates the utility of the
catalytic asymmetric direct thioamide-aldol reaction for the preparation of polyketide structures, and
was accomplished via diastereoselective allylation, and allylative cyclization as other key transforma-
tions. The reported process accesses Miyashita’s key fragment corresponding to the C7–C18 framework
in fewer steps (14 steps) than in previously reported syntheses.
Received 14 November 2015
Revised 1 December 2015
Accepted 9 December 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Scytophycin C
Catalytic asymmetric thioamide-aldol
reaction
Natural product synthesis
Cytotoxic agent
Introduction
Results and discussion
Scytophycins are cytotoxic and antifungal 22-membered
macrolides of marine origin discovered from the terrestrial blue-
green alga Scytonema pseudohofmanni. Scytophycin C (1) reported
by Moore and coworkers in 1986 particularly exhibits outstanding
antiproliferative activity against solid tumor cell lines.1 Both Pater-
son and Miyashita2–5 independently reported the total syntheses of
scytophycin C, which has intriguing biologic activity and a complex
structural nature. In Miyashita’s synthesis, C7–C18 fragment 2 is a
key intermediate from which the carbon framework was con-
structed via Mukaiyama aldol reaction and Horner–Wadsworth–
Emmons reaction. The fragment 2 was also prepared in the
synthetic study of the same natural product reported by Yadav
et al.3a Both syntheses of 2 commence with the chiral starting
material and require relatively long reaction sequences (18 steps
for Miyashita’s synthesis and 17 steps for Yadav’s synthesis),
which prompted us to develop an alternative route using a
catalytic asymmetric aldol strategy studied extensively in our
group to shorten the scheme (Fig. 1, bottom). In this Letter, we
describe a new synthesis of key intermediate 2 for scytophycin C
using the catalytic asymmetric thioamide-aldol reaction to
furnish the requisite stereocontrol.
The catalytic asymmetric direct thioamide-aldol reaction
shown in Scheme 1 was previously reported by our group, and is
characterized by the selective deprotonation of thioamide over
more acidic aldehyde rationalized by the activation by the soft
Lewis acidic copper complex with a bidentate phosphine ligand
(Ph-BPE) and hard Brønsted base precursor (chromanol derivative,
7). This reaction is advantageous due to its atom-economical
proton transfer process without the need for preactivation of a
prenucleophile by a structural modification (i.e., formation of
silylenol ether), and the feasibility of the thioamide substructure
transformation into variety of functionalities. The reaction was
effective for the enantio- and diastereoselective synthesis of
natural products and clinical drugs such as thuggacin,6 (ꢀ)-mem-
brenones,7 caprazamycin B,8 and atorvastatin.9 The present formal
total synthesis of scytophycin C started with the catalytic asym-
metric thioamide-aldol reaction using 5 and 6 as the substrates
(Scheme 1). Although this combination of substrates was reported
in our synthesis of thuggacin,6 the enantioselectivity was improved
from 93% ee to 95% ee in the present case.
Next, the secondary hydroxyl group of thioamide-aldol adduct 8
was protected as TBS ether 9, followed by conversion of the thioa-
mide moiety into a primary alcohol to afford 10 in good yield
(Scheme 2). Then, the hydroxy group was converted to PMB
ether 11, from which the TBDPS group was removed to give the sub-
strate for the catalytic stereoselective allylation reaction (12) devel-
oped by Krische and coworkers.10 The catalyst generated in situ
with [Ir(cod)Cl]2, (S)-Cl-MeO-BIPHEP ((S)-(ꢀ)-5,50-dichloro-6,
60-dimethoxy-2,20-bis(diphenylphosphino)-1,10-biphenyl), Cs2CO3,
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Corresponding authors. Tel.: +81 3 3441 4173; fax: +81 3 3441 7589 (T.W.);
tel.: +81 3 3447 7779; fax: +81 3 3441 7589 (M.S.).
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.