Asymmetric total synthesis of caribenol A

Article abstract of DOI:10.1021/ja106585n

A unified strategy toward the asymmetric total synthesis of carbenol A is reported, featuring intramolecular Diels-Alder (IMDA) and biomimetic oxidation reactions as key steps.

Full text of DOI:10.1021/ja106585n

Published on Web 09/10/2010
Asymmetric Total Synthesis of Caribenol A
Lian-Zhu Liu,† Jin-Chun Han,† Guo-Zong Yue,† Chuang-Chuang Li,*,† and Zhen Yang*,†,‡
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of
Peking UniVersity, Shenzhen 518055, China, and Key Laboratory of Bioorganic Chemistry and Molecular
Engineering, Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry,
Peking UniVersity, Beijing 100871, China
Received July 29, 2010; E-mail: zyang@pku.edu.cn
Because the reactivity and selectivity of IMDA reactions are often
Abstract: A unified strategy toward the asymmetric total synthesis
of carbenol A is reported, featuring intramolecular Diels-Alder
(IMDA) and biomimetic oxidation reactions as key steps.
highly substrate-dependent,5 particularly when 1,3-butadienes serve
as the substrates,5b we began with examining the IMDA reaction
of 4, which could be readily prepared through the reaction sequence
shown in Scheme 1. Intermediate 8 was synthesized from dienyl
iodide 57 and chiral enone 6.8 In that event, dienyl iodide 5 was
Caribenol A (1, Figure 1), which was isolated in 2007 by
Rodr´ıguez and co-workers from the West Indian gorgonian octo-
coral Pseudopterogorgia elisabethae, represents a family of novel
norditerpenes. It possesses a unique structure and prominent
biological activities.1 Of particular interest is its strong inhibitory
activity against Mycobacterium tuberculosis (H37Rv), which causes
tuberculosis, a disease that causes over three million deaths
worldwide each year.2
first treated with t-BuLi in Et2O at -78 °C to generate alkyl lithium,
and the in situ generated alkyl lithium reacted with enone 6 to give
a coupling product, which then underwent a PCC-mediated oxida-
tive rearrangement to afford 8 in 75% overall yield.
Scheme 1. Synthesis of Intermediate 11a
Caribenol A has an unprecedented tricarbocyclic ring system. It
carries three all-cis methyl groups at the C1, C4, and C8 positions
and a 5-hydroxyfuran-2(5H)-one motif, posing a particularly
synthetic challenge. Indeed, efforts have been directed toward
exploring feasible strategies for the chemical syntheses of these
scarce yet pharmacologically significant natural substances.3 In our
laboratories, we have aimed at identifying a pathway that allows
for rapid access to such tricyclic skeletons, which provides a
foundation for the total synthesis of caribenol A and the modular
construction of a library of analogs for further medicinal chemistry
studies.
a Reagents and conditions: (a) t-BuLi, Et2O, -78 °C, then 6, 87%; (b)
PCC, CH2Cl2, rt, 89%; (c) LiBEt3H, THF, -78 °C, 92%; (d) TBSOTf,
Et3N, CH2Cl2, -78 °C, 96%; (e) DIBAL-H, CH2Cl2, -78 °C, 94%; (f)
DMP, NaHCO3, CH2Cl2, 85%; (g) 7, n-BuLi, THF, -78 °C, 97%; (h) DMP,
NaHCO3, CH2Cl2, rt, 90%; (i) BHT, toluene, 120 °C, 24 h, 92%; (j)
Rh(PPh3)3Cl, H2, PhH, 66 °C, 95%; (k) HF/Pry, THF, rt, 91%; (l) NaBH4,
CeCl3, 7H2O, EtOH, 0 °C, 92%; (m) 4-nitrobenzoyl chloride, Et3N, DMAP,
CH2Cl2, 90%.
Figure 1. General Synthetic Strategy Targeting Caribenol A.
Previous investigations from our laboratories have revealed that
an intramolecular Diels-Alder (IMDA) reaction4 is an efficient
method for the construction of various skeletons of natural
products.5 Herein we report our recently achieved asymmetric total
synthesis of caribenol A via IMDA reaction (4 f 3), promoted by
a preorganized favorable conformation6 of intermedaite 4, and a
biomimetic oxidation (2 f 1) as key steps.
The silyl ether 9 was synthesized from 8. In this transformation,
LiBEt3H demonstrated to be an efficient agent for stereoselective
reduction of enone 8 to its allylic alcohol,9 which was then protected
to yield the silyl ether 9. To achieve the key intermediate 10, the
ester group in 9 was subjected to a reduction-oxidation sequence
to afford an aldehyde, which then reacted with the lithium derivative
of acetylene 7 to give 10 in 78% overall yield.
Based on our experience from early model studies,5a,c we had
predicted that 4 with an activated alkyne moiety could perform as
† Shenzhen Graduate School of Peking University.
‡ College of Chemistry, Peking University.
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13608 J. AM. CHEM. SOC. 2010, 132, 13608–13609
10.1021/ja106585n  2010 American Chemical Society

C O M M U N I C A T I O N S
an ideal precursor for the construction of the tricyclic core of
caribenol A by IMDA reaction. In our attempt to validate this
prediction, 10 was oxidized to 4 with DMP in the presence of
NaHCO3. However, when 4 was subjected to IMDA reaction, the
expected IMDA reaction did not occur, even with elevated
temperature. Further attempts to carry out the IMDA reaction at
lower temperature in the presence of various Lewis acids (e.g.,
MgBr2, ZnCl2, TMSOTf, AlCl3, MeAlCl2, and BF3 ·Et2O) were also
unsuccessful.
With continuous effort, we subsequently found that the desired
IMDA product could be generated in the presence of a catalytic
amount of 2,6-di-tert-butyl-4-methylphenol (BHT), leading to the
formation of 3 in 92% yield. 3 was converted to 11 Via sequential
hydrogenation-reduction-esterification reactions. Compound 11
was then derivatized into its 4-nitrobenzoate 12 by the treatment
of 11 with nitrobenzoyl chloride in the presence of Et3N and DMAP.
The structure of 12 has been confirmed by X-ray crystal structure
determination.
The pathway of achieving the total synthesis of caribenol A is
outlined in Scheme 2. Intermediate 13 was generated from 11 as a
sole product by an oxidation-hydrogenation sequence. The ob-
served excellent diastereoselectivity of 13 in hydrogenation con-
ceivably is derived from substrate conformation that possibly directs
the catalyst to approach the double bond from the less hindered
ꢀ-face.10 The treatment of 13 with KHMDS generated an enolate,
which reacted with Comins reagent (N-(5-chloro-2-pyridyl) triflim-
ide)11 to give an enol triflate. The enol triflate then underwent the
Pd-catalyzed coupling reaction with ZnMe2 to give 2 in 77% yield
in two steps.
The synthesized compound 1 has been proven to be identical to
the natural product caribenol A on the aspects of 1H NMR and 13
C
NMR.1 The optical rotation is also consistent with that of the
reported natural product ([R]20D ) +47° (c 0.4, CHCl3); lit.: [R]20
D
) +40.0° (c 1.0, CHCl3)).1
In summary, we have successfully applied an IMDA reaction to
construct the 5-7-6 tricyclic core of caribenol A (1) and have
effectively incorporated a hydroxyl group into its unique butenolide
moiety through a biomimetic oxidation. This strategy allows us to
achieve the total synthesis of caribenol A for the first time. We are
currently applying the same synthetic strategy to the synthesis of a
diversified caribenol-like library.
Acknowledgment. This work is financially supported by
grants of National Basic Research Program of China (973
Program, Grant 2010CB833201), the National Science and
Technology Major Project “Development of key technology for the
combinatorial synthesis of privileged scaffolds” (2009ZX09501-012),
the National Science Foundation of China (20821062, 20832003,
and 20902007), and the Shenzhen Basic Research Program (No.
JC200903160352A).
Supporting Information Available: Experimental procedures and
characterization data for the synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 2. Total Synthesis of Caribenol A (1)a
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