Synthesis of C3-C21 Segment of Aflastatin A Using Remote Asymmetric Induction Reactions

Article abstract of DOI:10.1021/acs.orglett.8b04008

The C3-C21 segment of aflastatin A has been synthesized by converging three segments including the C3-C8 segment, the C9-C15 segment, and the C16-C21 segment. Each segment has been synthesized from a vinylketene silyl N,O-acetal possessing a chiral auxili

Full text of DOI:10.1021/acs.orglett.8b04008

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of C3−C21 Segment of Aflastatin A Using Remote
Asymmetric Induction Reactions
Sawato Murakoshi and Seijiro Hosokawa*
Department of Applied Chemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo
169-8555, Japan
S
* Supporting Information
ABSTRACT: The C3−C21 segment of aflastatin A has been synthesized by converging three segments including the C3−C8
segment, the C9−C15 segment, and the C16−C21 segment. Each segment has been synthesized from a vinylketene silyl N,O-
acetal possessing a chiral auxiliary by a wide-range stereocontrol strategy. The C3−C8 segment was constructed in seven steps
including the stereoselective vinylogous Mukaiyama alkylation, while the C9−C15 segment and the C16−C21 segment were
synthesized using the vinylogous Mukaiyama aldol reaction in seven and eight steps, respectively.
flastatin A (1, Figure 1) is a giant acyclic polyketide
isolated as an inhibitor of aflatoxin production by Sakuda
stereocontrol strategy which is based on the initial construction
of the central part of the molecule and a subsequent
functionalization of the surroundings (Scheme 1).5 We have
already achieved short-step syntheses of several polyketides by
A
Scheme 1. Remote Asymmetric Induction Reaction and
Wide-Range Stereocontrol Strategy
Figure 1. Structure of aflastatin A (1).
and co-workers.1 The structure of aflastatin A (1) involves
many types of polyketide motifs including polypropionate,
deoxypropionate, polyacetate, and contiguous polyol struc-
tures. Therefore, the structure attracts chemists, and several
groups have been challenged to achieve its synthesis.2
However, only one total synthesis has been reported as a
doctoral thesis.3 Aflastatin A is still an attractive and
challenging target molecule because the complexity and large
size of this compound require efficient methodologies and
adequate strategies to achieve total synthesis.
During the course of our synthetic studies on polyketides,
we have developed the remote asymmetric induction reactions
with vinylketene silyl N,O-acetals4 and the wide range
Received: December 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthetic Plan of Aflastatin A (1)
combining the remote asymmetric induction reactions and
wide-range stereocontrol strategy.5 With these backgrounds,
we have been interested in the structure of aflastatin A
possessing a variety of polyketide motives. We have already
synthesized the C27−C48 moiety 5, the contiguous polyol
segment, by developing the Sn(II)-mediated aldol reaction.6
Herein, we present a synthesis of C3−C21 segment, the
polypropionate moiety, of aflastatin A.
Scheme 3. Synthesis of C3−C8 Segment (6)
Our synthetic plan for aflastatin A is disclosed in Scheme 2.
The tetramic acid moiety (C5′-C2 part) would be installed in
the final stage due to its lability. The remaining structure was
divided into two parts including C3−C21 segment 3 and
C22−C48 segment 4. The C3−C21 segment would be
synthesized by connection of three segments including C3−
C8 segment 6, C9−C15 segment 7, and C16−C21 segment 8.
These segments might be synthesized by employing the
remote asymmetric induction reactions with vinylketene silyl
N,O-acetals (9 and ent-9) and the wide range stereocontrol
strategy.
Synthesis of C3−C8 segment started from vinylketene silyl
N,O-acetal 9 (Scheme 3). Allylation of 9 proceeded at the γ
position in a stereoselective manner to afford adduct 10.4f α,β-
Unsaturated imide 10 was subjected to the Birch reduction,
which was quenched by 2-methylbenzimidazole,4f a bulky
proton source, to give the 4,6-syn (aflastatin A numbering)
product 11 with excellent stereoselectivity. When ammonium
chloride was employed as the protonation reagent in the Birch
reduction, moderate stereoselectivity (dr = 5:1) was observed.
Reduction of imide 11 with LiBH4 and benzylation of the
resulting hydroxy group afforded benzyl ether 12, which
underwent ozonolysis followed by reduction to yield primary
alcohol 13. Subsequent Mitsunobu reaction with 1-phenyl-1H-
tetrazole-5-thiol and oxidation in the presence of ammonium
heptamolybdate7 gave 1-phenyl-1H-tetrazole-5-yl sulfone 6,
the C3−C8 segment.
On the other hand, C9−C15 segment was synthesized from
vinylketene silyl N,O-acetal ent-9 (Scheme 4). The vinylogous
Mukaiyama aldol reaction with methacrylaldehyde proceeded-
stereoselectively to give anti adduct 15 in good yield.8
Reduction of imide 15 afforded diol 16, which underwent
the stereoselective epoxidation with m-CPBA9 followed by the
B
DOI: 10.1021/acs.orglett.8b04008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of C9−C15 Segment (7)
Scheme 5. Synthesis of C3−C15 Segment (25)
selective protection of the primary alcohol to furnish mono-
TBS ether 18. Hydroboration of the exo olefin of 18 proceeded
in good stereoselectivity to give diol 19.10,11 The hydroxy
groups of 19 were converted into silyl ethers, and the resulting
epoxide 20 underwent the semipinacol rearrangement12 to give
C9−C15 segment (7), which was subjected immediately to the
next reaction due to its lability.
Scheme 6. Synthesis of C16−C21 Segment
With both the C3−C8 segment (6) and C9−C15 segment
(7) in hand, connection of these segments and sequential
oxidation of the resulting adduct were deduced to synthesize
the C3−C15 segment (Scheme 5). The Kocienski reaction13
between sulfone 6 and aldehyde 7 and exposure of the adduct
under the acidic conditions promoted the selective O-
desilylation to furnish the diol 21.14 Sharpless asymmetric
dihydroxylation afforded tetraol 22, which was treated with an
excess amount of TESOTf and 2,6-lutidine to give silyl ether
23. The selective de-O-silylation of the primary triethylsilyl
ether afforded the primary alcohol 24, which underwent Dess−
Martin oxidation to yield C3−C15 segment (25). The
resulting aldehyde 25 was immediately subjected to the next
reaction to avoid undesired cyclization to afford δ-lactol.
The third segment, C16−C21 segment (8), was synthesized
from 9 (Scheme 6). The vinylogous Mukaiyama aldol reaction
with paraldehyde (26) proceeded to give anti adduct 27
predominantly.15 Reduction of the imide followed by
epoxidation, the same procedure as Scheme 4, gave epoxy
alcohol 29 in excellent stereoselectivity. The diol 29 was
converted into bisTBS ether 30 which was submitted to the
one-pot sequence including the semipinacol rearrangement,
reduction, and methanolysis to afford diol 32. Acetalization of
diol 32 with p-methoxybenzaldehyde dimethylacetal gave 1,3-
dioxane 33. De-O-silylation of 33 gave the secondary alcohol
34, which was oxidized to furnish the methyl ketone, C16−
C21 segment (8).
ketone 8 with LiHMDS to prepare the corresponding terminal
enolate and addition of a solution of aldehyde 25 promoted
the aldol reaction in a stereoselective manner. The resulting
adduct 35 was subjected to the Narasaka reduction16 to give
syn diol 36. Acetalization followed by the site-selective
The sequence from connection between C3−C15 (25)
segment and C16−C21 (8) segment to the synthesis of C3−
C21 segment is disclosed in Scheme 7. Treatment of methyl
C
DOI: 10.1021/acs.orglett.8b04008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 7. Synthesis of C3−C21 Segment
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Sumitomo
Foundation and the Tokyo Biochemical Research Foundation.
This work was also supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Frontier Research on Chemical
Communications” (Grant No. 18H04632) and JSPS KAKEN-
HI Grant No. JP17J10228.
REFERENCES
■
(1) (a) Sakuda, S.; Ono, M.; Furihata, K.; Nakayama, J.; Suzuki, A.;
Isogai, A. J. Am. Chem. Soc. 1996, 118, 7855−7856. (b) Ono, M.;
Sakuda, S.; Suzuki, A.; Isogai, A. J. Antibiot. 1997, 50, 111−118.
(c) Ikeda, H.; Matsumori, N.; Ono, M.; Suzuki, A.; Isogai, A.;
Nagasawa, H.; Sakuda, S. J. Org. Chem. 2000, 65, 438−444.
(d) Sakuda, S.; Matsumori, N.; Furihata, K.; Nagasawa, H.
Tetrahedron Lett. 2007, 48, 2527−2531.
(2) (a) Evans, D. A.; Glorius, F.; Burch, J. D. Org. Lett. 2005, 7,
3331−3333. (b) Evans, D. A.; Trenkle, W. C.; Zhang, J.; Burch, J. D.
Org. Lett. 2005, 7, 3335−3338. (c) Robles, O.; McDonald, F. E. Org.
Lett. 2008, 10, 1811−1814. (d) Narute, S. B.; Kiran, N. C.; Ramana,
C. V. Org. Biomol. Chem. 2011, 9, 5469−5475. (e) Narute, S. B.;
Ramana, C. V. Tetrahedron 2013, 69, 1830−1840.
(3) Beiger, J. J. Ph.D. Thesis, Harvard University, 2013.
(4) (a) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 13604−12605. (b) Hosokawa, S.; Tatsuta, K. Mini-Rev. Org.
Chem. 2008, 5, 1−18. (c) Mukaeda, Y.; Kato, T.; Hosokawa, S. Org.
Lett. 2012, 14, 5298−5301. (d) Tsukada, H.; Mukaeda, Y.;
Hosokawa, S. Org. Lett. 2013, 15, 678−681. (e) Takahashi, Y.;
Otsuka, M.; Harachi, M.; Mukaeda, Y.; Hosokawa, S. Org. Lett. 2014,
16, 4106−4109. (f) Nakamura, T.; Kubota, K.; Ieki, T.; Hosokawa, S.
Org. Lett. 2016, 18, 132−135.
(5) (a) Hosokawa, S. Acc. Chem. Res. 2018, 51, 1301−1314.
(b) Hosokawa, S. Yuki Gosei Kagaku Kyokaishi 2017, 75, 831−849.
(6) Murakoshi, S.; Hosokawa, S. Synlett 2015, 26, 2437−2441.
(7) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140−1142.
reduction of the p-methoxybenzylidene acetal17 afforded the
primary alcohol 37 in good yield. The resulting alcohol 37 was
subjected to Dess−Martin oxidation to give C3−C21 segment
(3).
In conclusion, a stereoselective and convergent synthesis of
the C3−C21 segment of aflastatin A has been achieved. All
segments were prepared in six to eight steps using the remote
asymmetric reactions including the allylation reaction (C3−C8
segment) and the vinylogous Mukaiyama aldol reactions (C9−
C15 and C16−C21 segments). Therefore, the C3−C21
segment of aflastatin A was synthesized in 17 steps of longest
linear sequence from vinylketene silyl N,O-acetal 9.
(8) Matsui, R.; Seto, K.; Sato, Y.; Suzuki, T.; Nakazaki, A.;
Kobayashi, S. Angew. Chem., Int. Ed. 2011, 50, 680−683.
(9) Hasan, I.; Kishi, Y. Tetrahedron Lett. 1980, 21, 4229−4232.
(10) (a) Peterson, I.; Channon, J. A. Tetrahedron Lett. 1992, 33,
797−800. (b) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.; Tamai,
T.; Tatsuta, K. Bull. Chem. Soc. Jpn. 1992, 65, 2974−2991. (c) Evans,
D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem. Soc. 1995,
117, 3448−3467.
(11) For determination of the stereochemistry of compounds in this
article, see the Supporting Information.
(12) Jung, M. E.; D’amico, D. C. J. Am. Chem. Soc. 1993, 115,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04008.
12208−12209.
■
(13) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 1998, 26−28.
S
(14) Removal of the trimethylsilyl group at the C11 position was
found to be critical to promote the Sharpless asymmetric epoxidation.
(15) Ohashi, T.; Hosokawa, S. Org. Lett. 2018, 20, 3021−3024.
(16) Narasaka, K.; Pai, F. C. Tetrahedron 1984, 40, 2233−2238.
(17) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 12, 1593−1596.
Experimental procedures, spectral data of compounds,
1H and 13C NMR spectra, and structural determination
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: seijiro@waseda.jp.
ORCID
Seijiro Hosokawa: 0000-0002-8036-532X
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b04008
Org. Lett. XXXX, XXX, XXX−XXX