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D. B. Konrad et al.
Letter
Synlett
worth noting, that the free allylic C3 alcohol was essential
for a successful RCM reaction and a successful TBS depro-
tection with tris(dimethylamino)sulfonium difluoro-
trimethylsilicate (TASF). The resulting diol 17 was regio-
selectively benzoylated at the sterically more accessible C3
alcohol by using benzoyl chloride in pyridine at low tem-
peratures. These optimized conditions provided kwe-
ichowenol A (1) in good yield.23 To confirm the structure of
the natural product and gain insight into its preferred con-
formation, we subjected a sample of 1 to X-ray analysis
(Scheme 3). Remarkably, kweichowenol A (1) crystallized
as a racemate from the enantioenriched mixture that was
obtained through the synthesis.
Supporting Information
Supporting information for this article is available online at
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References and Notes
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Scheme 3 X-Ray structure of kweichowenol A (1)
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(22) Kiyooka Aldol Reaction Procedure for the Synthesis of 12
N-Ts-D-valine (SI-1, 7.82 g, 28.6 mmol, 1.1 equiv) was dissolved
in CH2Cl2 (130 mL), cooled to 0 °C, and BH3·THF (1 M in THF,
26.0 mL, 26.0 mmol, 1.0 equiv) was added dropwise over a
period of 10 min. The suspension was stirred at 0 °C for 30 min
before warming to rt and stirring for 1 h. Continuous bubbling
was observed, and the white solid slowly dissolved to give a
clear solution. After cooling the solution to –78 °C, cinnamalde-
hyde (11, 3.27 mL, 26.0 mmol, 1.0 equiv) in CH2Cl2 (70 mL) and
TBS ketene acetal (9, 8.56 mL, 31.2 mmol, 1.2 equiv) in CH2Cl2
(70 mL) were successively added via syringe pump (2.5
mL/min). Stirring was continued for 10 min at –78 °C and PB pH
In summary, we have devised a short asymmetric syn-
thesis of the polyoxygenated cyclohexene natural product
kweichowenol A (1), which proceeds in 11 steps starting
from commercially available starting materials. The instal-
lation of the oxygenation pattern on a linear precursor al-
lowed a rapid access to the cyclohexene core by exploiting
acyclic stereocontrol. Carbon–carbon bonds were formed
using a Kiyooka aldol reaction, Cram chelate-controlled Gri-
gnard reactions, and a RCM. Due to the common cyclohex-
ene oxygenation pattern, kweichowenol A (1) could serve
as a precursor to other members of the kweichowenol-type
natural product family, such as kweichowenol C (2), kwe-
ichowenol D (3), ferrudiol (4), and ellipeiopsol B (5). It is
also worth noting that the C1, C2, and C6 stereocenters of
the kweichowenol-type natural products correspond to the
C5, C6, and C7 stereocenters on the cyclohexane core of te-
trodotoxin. As such, we have laid the foundation towards an
asymmetric synthesis of this celebrated target.17,18,24
Acknowledgment
The authors thank Dr. Peter Mayer for X-Ray analyses. D.B.K is grateful
to the Friedrich-Ebert-Stiftung for a PhD scholarship.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D