Total synthesis of (+)-vibsanin A

Article abstract of DOI:10.1021/acs.orglett.5b00086

The first total synthesis of (+)-vibsanin A, an 11-membered vibsane diterpenoid, was achieved, unambiguously establishing its relative and absolute stereochemistry. Highlights of the synthesis include the stereoselective formation of an all-carbon quaternary stereocenter by a zinc-mediated Barbier-type allylation in an aqueous medium, and the efficient construction of an 11-membered ring skeleton by a combination of an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction and a Mitsunobu reaction.

Full text of DOI:10.1021/acs.orglett.5b00086

Letter
pubs.acs.org/OrgLett
Total Synthesis of (+)-Vibsanin A
Ken-ichi Takao,* Kohei Tsunoda, Takuya Kurisu, Akihiro Sakama, Yoshiyasu Nishimura, Keisuke Yoshida,
and Kin-ichi Tadano
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
S
* Supporting Information
ABSTRACT: The first total synthesis of (+)-vibsanin A, an
11-membered vibsane diterpenoid, was achieved, unambigu-
ously establishing its relative and absolute stereochemistry.
Highlights of the synthesis include the stereoselective
formation of an all-carbon quaternary stereocenter by a zinc-
mediated Barbier-type allylation in an aqueous medium, and
the efficient construction of an 11-membered ring skeleton by a combination of an intramolecular Nozaki−Hiyama−Kishi
(NHK) reaction and a Mitsunobu reaction.
ibsane diterpenoids occur in only Viburnum species, and
V
more than 80 compounds have been found so far.1
Vibsanins A−F, 1−6, were first isolated by Kawazu in 1980
from the leaves of Viburnum awabuki, which was previously
used in Japan as a fish poison for fishing.2 Only vibsanin A 1
showed piscicidal activity against Oryzias latipes (killifish).
These diterpenoids can be divided into 11-membered ring
compounds 1, 2, and 6 and 7-membered ring compounds 3, 4,
and 5. Representative vibsane diterpenoid 1 possesses a unique
11-membered ring skeleton that contains an epoxy ring, two
unsaturated double bonds, and four stereogenic centers
including an all-carbon quaternary center. In the original
characterization, the stereochemistry of 5 was determined by
single-crystal X-ray diffraction analysis.3 Later, the absolute
structures of 2, 3, and 6 were established by Fukuyama and co-
workers through X-ray analysis of a derivative of 2, chemical
conversion of 2 into 3, and synthesis of the unnatural
diastereomer (6-epi-isomer) of 6.4 On the basis of these
structural studies, the assumed stereochemistry of 1 is shown in
Figure 1. Fukuyama and co-workers isolated rearranged vibsane
diterpenoids (neovibsanins) from the same plant and observed
their neurite outgrowth-promoting activity.5 Recently, vibsane
diterpenoids have attracted the attention of synthetic chemists,
and the total syntheses of 7-membered ring and rearranged
visbane diterpenoids have been reported.6 However, the total
synthesis of 11-membered ring vibsane diterpenoids has not yet
been reported. Vibsanin A 1 is a synthetically challenging target
due to its highly functionalized 11-membered ring skeleton, and
it is an attractive target due to the broad bioactivity of vibsane
diterpenoids.1 Here we describe the first total synthesis of 1 and
thereby unambiguously establish the relative and absolute
stereochemistry of natural (+)-vibsanin A.
Figure 1. Structures of vibsanins A−F, 1−6.
mediated ring closure.7a Yamamoto and co-workers used a
Tsuji−Trost reaction for achieving the highly stereoselective
synthesis of humulene.7b Also in Fukuyama’s synthesis of the
diastereomer (6-epi-isomer) of vibsanin F 6, a Tsuji−Trost
reaction was employed to form the 11-membered ring.4b
However, the newly formed trisubstituted olefin (C2−C3
double bond) had the Z-configuration, which had to be
converted to the E-configuration. Accordingly, the development
of new synthetic methods for 11-membered vibsane
diterpenoids is needed. Our retrosynthetic analysis of
(+)-vibsanin A 1 is shown in Scheme 1. The design of our
synthetic plan relied on the combination of an intramolecular
The development of novel and efficient methods for the
synthesis of 11-membered carbocycles is an important
challenge in synthetic organic chemistry. A number of methods
have been reported for synthesizing natural products based on
11-membered skeletons.7 For example, Corey and co-workers
succeeded in the total synthesis of humulene by using a Ni-
Received: January 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00086
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Letter
Scheme 1. Retrosynthetic Analysis of (+)-Vibsanin A 1
Scheme 2. Synthesis of Lower Fragment 9
Nozaki−Hiyama−Kishi (NHK) reaction and an allylic
rearrangement to assemble the 11-membered ring. The
intramolecular NHK reaction is a powerful cyclization method
that has given good results in some difficult cases.8,9 We
expected that the NHK reaction would enable the efficient
formation of the 11-membered ring skeleton of 1. Substrate 7
for the key NHK reaction would be obtained by coupling
fragments 8 and 9, both containing an alkenyl iodide moiety.
This convergent strategy could potentially streamline the
synthetic route. We envisaged that upper fragment 8 would
arise from commercially available 4-pentynyl acetate 10 through
an asymmetric epoxidation, whereas lower fragment 9 would be
derived from geranyl chloride 11 using our previously
established procedure involving a Barbier-type allylation.10
The synthesis of lower fragment 9 began with the
construction of the all-carbon quaternary stereocenter (Scheme
2). Quaternary stereocenters are a particular challenge for
stereoselective synthesis.11 This stereocenter was formed by a
zinc-mediated Barbier-type allylation in an aqueous medium10
of L-glyceraldehyde acetonide 1212 with geranyl chloride 11 to
generate a 6:1 mixture of diastereomers favoring desired (4S)-
isomer 14a.13 In this reaction, readily available L-ascorbic acid-
derived 12 was employed as a chiral source. The stereochemical
outcome obtained from the reaction can be explained using the
β-chelation/6-membered model 13.14 Benzylation of 14ab
followed by hydroboration with thexylborane and an oxidative
workup provided diol 15 with high regioselectivity.15 Before
hydroboration, protection of the C3-OH of 14ab was required
to ensure the desired regioselectivity. The minor diastereomer
derived from 14b was removed at this stage. The primary
alcohol was selectively protected as a tert-butyldiphenylsilyl
(TBDPS) ether, and treatment of the resulting secondary
alcohol with Martin sulfurane (Ph2S[OC(CF3)2Ph]2)16 regen-
erated the trisubstituted olefin to furnish 16 as a single
isomer.17 Selective hydrolysis of the isopropylidene acetal18 in
16 and deprotection of the benzyl group under Birch
conditions afforded triol 17. Oxidative cleavage of 17 provided
aldehyde 18, which was subjected to Takai olefination19 to
provide enantiomerically pure fragment 9.
Scheme 3. Synthesis of Upper Fragment 8
Upper fragment 8 was prepared from known iodo olefin−
alcohol 19, which can be obtained from 4-pentynyl acetate 10
in two steps (Scheme 3).20 Alcohol 19 was oxidized with
Dess−Martin reagent21 to an aldehyde, which was treated with
Ando reagent 2322 to give unsaturated ester 20 with good Z
selectivity. Reduction of 20 with DIBALH provided allylic
alcohol 21, and then asymmetric epoxidation of 21 was
examined. Although moderate enantioselectivity (70% ee) was
observed for the Sharpless asymmetric epoxidation under
catalytic conditions, stoichiometric conditions improved the
B
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Letter
enantioselectivity to provide epoxide 22 in 80% ee.23,24 Finally,
oxidation of 22 to an aldehyde afforded desired upper fragment
8 in an enantioenriched form.
The upper and lower fragments were coupled by converting
alkenyl iodide 9 into the alkenyl lithium intermediate using t-
BuLi and the subsequent addition of 2 equiv of aldehyde 8
(Scheme 4).25 The coupled products 24a and 24b were
base.30 Removal of the TBDPS group from 25, followed by
oxidation of the resulting primary alcohol, furnished aldehyde
7.
With iodo olefin−aldehyde 7 in hand, we then turned our
attention to the intramolecular NHK reaction. To our delight,
treatment of dilute solution of 7 (0.005 M) in DMSO with
CrCl2 and catalytic NiCl2 effected formation of the 11-
membered ring and provided the cyclized product 26 as a
single isomer.31 At this stage, the diastereomer derived from the
minor enantiomer of 8 was separated by column chromatog-
raphy, allowing the isolation of diastereomerically pure 26. As
expected, the allylic rearrangement of 26 to 27 was achieved by
the Mitsunobu reaction using p-nitrobenzoic acid.32 The newly
formed trisubstituted olefin in 27 was determined to have the
E-configuration by an NOE experiment, as shown in Scheme 4.
Consequently, the intramolecular NHK reaction followed by
the Mitsunobu reaction allowed us to construct the challenging
11-membered ring skeleton of vibsanin A with the correct
stereochemistry. Chemoselective methanolysis of diester 27
finally afforded (+)-vibsanin A 1. The spectroscopic data (1H
and 13C NMR) of natural 1 and synthetic 1 matched well.33
The optical rotation of synthetic 1 was consistent with that
reported for the natural product.2
Scheme 4. Completion of the Total Synthesis of
(+)-Vibsanin A 1
In summary, we have achieved the total synthesis of
(+)-vibsanin A 1. To our knowledge, this is the first successful
synthesis of a natural 11-membered vibsane diterpenoid. The
key features of the synthesis are a zinc-mediated Barbier-type
allylation of chiral aldehyde 12 with geranyl chloride 11 to form
the all-carbon quaternary stereocenter, and the combination of
an intramolecular NHK reaction and a Mitsunobu reaction to
construct the functionalized 11-membered ring skeleton. This
work has unambiguously established the absolute structure of
natural (+)-vibsanin A. Further application of the methodology
to the synthesis of other 11-membered vibsane diterpenoids is
currently in progress and will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: takao@applc.keio.ac.jp.
Notes
The authors declare no competing financial interest.
obtained in 52% and 10% yields, respectively, and unreacted 8
was recovered with good mass balance. In this case, the
lithium−halogen exchange of 8 was not observed. Because the
newly formed stereogenic center in major isomer 24a possessed
the opposite configuration to the synthetic target,26 ester-
ification of 24a under Mitsunobu conditions was explored.27
Although 3,3-dimethylacrylic acid was not a strong acid, the
Mitsunobu reaction with 24a proceeded smoothly in toluene at
−15 °C,28 giving desired ester 25 with configurational
inversion. Unexpectedly, acylation of the minor isomer 24b
proved to be problematic. Direct acylation using 3,3-
dimethylacrylic acid or 3,3-dimethylacryloyl chloride under
standard conditions caused the double-bond isomerization of
the 3,3-dimethylacryloyl moiety to give an inseparable mixture
of 25 and the β,γ-unsaturated isomer.29 However, the β,γ-
unsaturated isomer was converted to 25 by treatment with a
ACKNOWLEDGMENTS
■
We thank Professor Yoshiyasu Fukuyama (Tokushima Bunri
University) for providing spectra of natural 1. This work was
supported in part by the MEXT-Supported Program for the
Strategic Research Foundation at Private Universities, 2012-
2016.
REFERENCES
■
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C
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