Total synthesis of penostatin B

Article abstract of DOI:10.1021/ol203021c

The first total synthesis of penostatin B has been accomplished by using a highly diastereoselective Pauson-Khand reaction and an efficient relay ring-closing metathesis for the construction of the basic carbon skeleton of the natural product as the key steps.

Full text of DOI:10.1021/ol203021c

ORGANIC
LETTERS
2
012
Vol. 14, No. 1
44–247
Total Synthesis of Penostatin B
2
Kosuke Fujioka, Hiromasa Yokoe, Masahiro Yoshida, and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
1
-78-1 Sho-machi, Tokushima 770-8505, Japan
shishido@ph.tokushima-u.ac.jp
Received November 9, 2011
ABSTRACT
The first total synthesis of penostatin B has been accomplished by using a highly diastereoselective PausonÀKhand reaction and an efficient
relay ring-closing metathesis for the construction of the basic carbon skeleton of the natural product as the key steps.
3
Penostatins A (1) and B (2) are representatives of nine
molecules in this family that have been isolated from a
strain of Penicillium sp. originally separated from the
marine alga Enteromorpha intestinalis by Numata and
co-workers in 1996. Except for penostatin D, these
polyketide-derived penostatins all exhibited significant
1
cytotoxicity against cultured P388 cells. Their structures
diastereoselective PausonÀKhand reaction for the con-
struction of the tetrahydroindenone segment, an efficient
assembly of the dihydropyranone moiety using a relay
4
ring-closing metathesis, and a diastereoselective introduc-
tion of the alkenyl appendage at C12 on the dihydropyran
ring.
1
a
and absolute stereochemistry have been established on the
basis of spectral analyses and chemical transformations.
The penostatins A and B possess a synthetically challen-
ging array of structural features: five tertiary stereogenic
centers, a densely functionalized hexahydrocyclopenta-
[
f]chromenone skeleton, and the fascinating sigma linkage
at C12 (a skipped diene) (Figure 1). To date, although the
2
synthesis of (()-5-deoxypenostatin A has been reported,
none of the natural penostatins have been synthesized.
Herein, we present the first total synthesis of (()-
penostatin B (2), employing as the key steps a highly
Figure 1. Penostatins A and B.
Our retrosyntheticstrategyisillustratedinScheme 1. We
reasoned that the alkenyl side chain at C12 could be
introduced at a late stage of the synthesis via a Lewis acid
mediated alkenylation of the acetate 3. The dihydropyran
moiety in 3 would be assembled via the ring-closing
metathesis (RCM) protocol of the corresponding diene
precursor, which can bereadilyderivedfrom4. The alkenyl
alcohol 4 with four contiguous stereogenic centers would
be constructed diastereoselectively by the PausonÀKhand
(
1) (a) Takahashi, C.; Numata, A.; Yamada, T.; Minoura, K.;
Enomoto, S.; Konishi, K.; Nakai, M.; Matsuda, C.; Nomoto, K.
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1
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2
(
6
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8
1
0.1021/ol203021c r 2011 American Chemical Society
Published on Web 12/06/2011

Scheme 1. Retrosynthetic Analysis
Table 1. PausonÀKhand Reaction
product yield
entry substrate
conditions
(ratio)
(%)
1
2
3
8
5
5
Co
then NMO, CH
Co (CO) , CH
then NMO, CH
Co (CO) , CH
2
(CO)
8
, CH
2
, rt, 8 h,
9/10 (4/1)
72
2
Cl
2
, rt, 8 h
2
8
2
, rt, 8 h,
4 (>20:1)
4 (>20:1)
86
97
2
2
Cl , rt, 8 h
2
8
2
, rt, 8 h,
then evaporation, add
MeCN, 60 °C, 8 h
5
reaction of the dienyl alcohol 5, which in turn would be
synthesized from the aldehyde 6 by metal-mediated dia-
NOE experiments, and it was determined that the major
diastereoisomer 9was indeed the desired product (Figure 2).
When compound 5 was subjected to the same reaction
conditions as those for 8, the bicycle 4 was produced in
6
stereoselective pentadienylation. The aldehyde 6 can be
7
prepared from the glycidyl ester 7, which is readily avail-
able in both racemic and optically active forms (Scheme 1).
The aldehyde 6, prepared from (()-oxiran-2-ylmethyl
butyrate 7 via a four-step sequence, was treated with (E)-
tributyl(penta-2,4-dienyl)stannane in the presence of
86% yield as a single product (entry 2). A higher yield
(97%) and complete diastereoselectivity of the product 4
were obtained under these conditions without an oxidizing
6
3cÀe
InCl3 to give the pentadienylated alcohol 5 as a single
product in 75% yield. The diastereoselectivity can be
attributed to the indium-chelated chairlike transition state
agent (NMO) (entry 3).
(
T ) as shown in Scheme 2.
1
Scheme 2. Diastereoselective Synthesis of 5
Figure 2. NOE experiments.
The diastereoselective formation of the requisite tetra-
hydroindenone 4 can be explained by considering the
conformation of the transition states T and T for the
2
3
We next examined the key PausonÀKhand cyclization
for the construction of the tetrahydroindenone segment
with four contiguous stereogenic centers. To evaluate the
diastereoselectivity of the cyclization, the desilylated com-
pound 8 was prepared and its cyclizations were explored.
The results are shown in Table 1. Sequential treatment of a
solution of the desilylated substrate 8 in CH Cl with
8
PausonÀKhand reaction. In the transition state T ,
3
leading to the formation of the undesired isomer 10,
the R group on the cobalt complex moiety interacts with
an axially oriented vinyl group so that the substrate 5
with a bulkier substituent (R = TMS) resulted in the
exclusive formation of the desired bicycle 4 via T2
2
2
(
Scheme 3).
After desilylation, the enone double bond in 4 was
selectively reduced with DIBAH/MeLi in the presence of
3
b
Co (CO) and N-methylmorpholine N-oxide (NMO),
2
8
gave a chromatographically separable 4:1 mixture of the
diastereoisomers 9 and 10, in 72% yield (entry 1). The
1
stereostructures of both were determined by H NMR
9
CuI in HMPA/THF to give 11, which was condensed with
methacrylic acid in the presence of 2-methyl-6-nitrobenzoic
(
(
5) Magnuson, S. R. Tetrahedron 1995, 51, 2167–2213.
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3
3–34.
(
7) Trost, B. M.; Papillon, P. N.; Nussbaumer, T. J. J. Am. Chem.
Soc. 2005, 127, 17921–17937.
Org. Lett., Vol. 14, No. 1, 2012
245

Scheme 3. Plausible Mechanism of PausonÀKhand Reaction
Table 2. Attempted Ring-Closing Metathesis of 13
catalyst
(mol %)
time
(h)
yield
a
entry
additive
(%)
1
2
3
4
15 (15)
15 (25)
16 (10)
15 (5)
À
32
8
11 (61)
47 (77)
0 (75)
À
À
32
6
i
b
Ti(O Pr)
4
À
a
1
0
The yield in parentheses is the yield based on the recovered starting
material. The compound 17 was obtained in 46% yield.
anhydride (MNBA) to provide 13 in excellent yield
Scheme 4).
b
(
Scheme 4. Synthesis of the Substrate 13 for RCM
21, prepared from 19. Thus, compound 21 was treated
with 25 mol % of 15 in refluxing CH Cl to give 14 in 83%
2
2
yield. Thus, it was demonstrated that RRCM is a versatile
method to obtain the functionalized dihydropyranones
1
4
(Scheme 5).
With the diene 13 in hand, we next examined the RCM
1
1,12
for assembling the dihydropyranone ring in 14.
ment of 13 with the Grubbs’ second-generation catalyst 15
15 mol %) in refluxing CH Cl for 32 h provided only 14
Treat-
(
2
2
Scheme 5. Relay Ring-Closing Metathesis
in 11% yield (61% based on the recovered starting 13)
entry 1, Table 2). When the reaction was conducted using
5 mol % of 15, compound 14 was obtained in moderate
yield (47%; 77% brsm) (entry 2). Using the GrubbsÀ
(
2
i
11
Hoveyda catalyst 16 or 15 and Ti(O Pr) resulted in no
4
1
reaction (entry 3) or the formation of 17 in 46% yield
3
(
entry 4).
In an effort to improve the lower yield of 14, we
4
decided to use a relay ring-closing metathesis (RRCM).
Treatment of 11 with the carboxylic acid 18, prepared
from allyl alcohol via four steps, in the presence
of MNBA 12, triethylamine, and DMAP provided the
ester 20 in 93% yield. When 20 was exposed to 50 mol %
of 15 in refluxing CH Cl , 14 was produced in 78%
Having made the construction of the basic carbon
framework, we next examined the introduction of the
alkenyl appendage at C . Reduction of 14 with DIBAH
2
2
yield. Much better results were obtained when the
RRCM was conducted with the methyl homologue
1
2
(87%) followed by acetylation provided the diacetate 22,
as a mixture of diastereoisomers, which was treated
1
5
(
(
10) Shiina, I.; Ibuka, R.; Kubota, M. Chem. Lett. 2002, 286–287.
11) For a review, see: (a) Monfette, S.; Fogg, D. F. Chem. Rev. 2009,
with the vinyl stannane 23 in the presence of BF •OEt
3
2
to provide 24, as an inseparable 9:1 mixture of dia-
stereoisomers at C , in 74% (two steps from the diol).
1
09, 3783–3816. (b) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asym-
metry 2007, 18, 2479–2483. (c) Pospı
ꢀs il, J.; Mark oꢁ , I. E. Tetrahedron
Lett. 2008, 49, 1523–1526.
12) (a) F u€ rstner, A.; Langeman, K. J. Am. Chem. Soc. 1997, 119,
´
5
(
9
130–9136. (b) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett.
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4761–4764.
(
2
46
Org. Lett., Vol. 14, No. 1, 2012

The stereochemistry at C12 was established by NOE
experiments as shown in Scheme 6.
in the literature. The unique features of this work include
the use of a highly diastereoselective indium-mediated
pentadienylation and intramolecular PausonÀKhand cy-
clization, the successful application of an efficient RRCM
for assembling the dihydropyranone moiety, and the dia-
Scheme 6. Diastereoselective Alkenylation
stereoselective introduction of the C alkenyl side chain at
9
C . The synthetic route developed here is general and
1
2
efficient and could also be applied to the syntheses of other
penostatins.
Scheme 7. Total Synthesis of Penostatin B (2)
Alkaline hydrolysis of 24 followed by silylation pro-
vided the TBS ether 25 in 89% in two steps, and at this
stage the minor diastereoisomer with the 5R* config-
uration could be separated. Debenzylation using
1
6
LiDBB/MgBr •OEt
proceeded smoothly to give
the alcohol, which was oxidized with TPAP/NMO in
2
2
the presence of 4A MS to provide the ketone 26 in
1
Acknowledgment. We thank Emeritus Professor Atsushi
Numata (Osaka University of Pharmaceutical Sciences)
7
excellent yield. Finally, the ItoÀSaegusa oxidation,
1
13
followed by desilylation of the TBS ether with HF•pyr-
idine, provided (()-penostatin B (2) in 53% yield. The
H and C NMR properties of the synthetic material
for kindly providing us copies of H and C NMR of
penostatin B. A Grant-in-Aid Fellowship was given to
H.Y. from the JSPS for JSPS Fellows (20-11673). This
work was supported financially by a Grant-in-Aid for
the Program for Promotion of Basic and Applied Re-
search for Innovations in the Bio-oriented Industry
(BRAIN).
1
13
1
were identical with those of the natural penostatin B
(
Scheme 7).
In summary, we have completed the first total synthesis
of penostatin B in a longest linear sequence of 16 steps with
an overall yield of 12% from compound 6, which is known
Supporting Information Available. Experimental pro
ceduresand characterization data for the new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
16) Fukuda, K.; Miyashita, M.; Tanino, K. Tetrahedron Lett. 2010,
1, 4523–4525.
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011–1013.
5
(
1
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