Synthetic studies on aculeximycin: Synthesis of C24-C40 segment by kobayashi aldolization and epoxide rearrangements

Article abstract of DOI:10.1021/acs.orglett.5b00965

Stereoselective synthesis of the C24-C40 segment of aculeximycin has been achieved by using the Kobayashi aldol reactions and epoxy-opening rearrangement reactions. The C33-C40 segment was synthesized by the Kobayashi aldol reaction followed by epoxidation and Jung rearrangement of epoxide 9, while the C25-C32 segment was constructed by the Kobayashi aldol reaction followed by epoxidation and the epoxy-opening rearrangement reaction of epoxide 13. These segments were connected by the aldol reaction and the sequential dehydration, reduction, and conversion of ethyl ester to ethyl ketone to give the C24-C40 segment 1. All stereogenic centers were constructed by substrate-controlled stereoselective reactions.

Full text of DOI:10.1021/acs.orglett.5b00965

Letter
pubs.acs.org/OrgLett
Synthetic Studies on Aculeximycin: Synthesis of C24−C40 Segment
by Kobayashi Aldolization and Epoxide Rearrangements
Takuya Kato, Tomohiko Sato, Yuki Kashiwagi, 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: Stereoselective synthesis of the C24−C40 segment of
aculeximycin has been achieved by using the Kobayashi aldol
reactions and epoxy-opening rearrangement reactions. The C33−
C40 segment was synthesized by the Kobayashi aldol reaction
followed by epoxidation and Jung rearrangement of epoxide 9, while
the C25−C32 segment was constructed by the Kobayashi aldol
reaction followed by epoxidation and the epoxy-opening rearrange-
ment reaction of epoxide 13. These segments were connected by the
aldol reaction and the sequential dehydration, reduction, and
conversion of ethyl ester to ethyl ketone to give the C24−C40
segment 1. All stereogenic centers were constructed by substrate-
controlled stereoselective reactions.
inspired us to synthesize this compound. Herein, we present a
concise synthesis of the C24−C40 segment of aculeximycin by
combination of the remote asymmetric induction reaction and
an epoxide-opening strategy.
In the course of our studies on polyketides, we have
developed the remote asymmetric induction reaction using the
vinylketene silyl N,O-acetal having a chiral auxiliary (Kobayashi
aldol reaction, Scheme 1).4 Since the reaction performs the
culeximycin was isolated as an antibiotic from the culture
Abroth of Streptosporangium albidum, by the Haneishi group
in 1983 (Figure 1).1 In 1995, the Harada group disclosed the
impressive structure of this compound by degradation and
derivatization studies as well as spectroscopic methods.2
Aculeximycin possesses a 30-membered ring attaching triose,
β-mannose, and vancosamine. This compound was found to be
a potent uncoupler of the oxidative phosphorylation of rat-liver
mitochondria.3 The structure of aculeximycin has attracted and
Scheme 1. Remote Asymmetric Induction Reactions Using
the Chiral Vinylketene Silyl N,O-Acetals
construction of stereogenic centers and introduction of a
carbon chain simultaneously, it has been applied to natural
product synthesis to accomplish syntheses in a few steps.5,6 We
decided to apply this reaction to the synthetic studies on
aculeximycin to establish an efficient route.
Our strategy to synthesize the C24−C40 segment 1 is
disclosed in Scheme 2. The C24−C40 segment would be
synthesized by an aldol condensation between C33−C40
segment 2 and C25−C32 segment 3 (Scheme 2). These
oligoketides might be constructed in a few steps by combining
the Kobayashi aldol reaction (Scheme 1) and two kinds of
Received: April 3, 2015
Figure 1. Structure of aculeximycin.
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b00965
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Letter
resulting diol was protected as TBS ether 9. Treatment of TBS-
protected epoxy alcohol 9 with TMSOTf in the presence of a
Scheme 2. Synthetic Plan of Aculeximycin C24−C40
Segment 1
Hunig base promoted semipinacol rearrangement to give
̈
aldehyde 2, the C33−C40 segment.10
Yet, the synthesis of C25−C32 segment 3 was performed as
shown in Scheme 5. The synthesis began with a Kobayashi
Scheme 5. Synthesis of C25−C32 Segment 3
epoxide-rearrangement reactions (Scheme 3). One of the
rearrangement reactions is the semipinacol rearrangement
Scheme 3. Epoxide-Opening Hydride Shift Reactions To
Give Aldols
aldol reaction using exo-olefin 10 and tiglic aldehyde 11 in the
presence of H2O11 to obtain allylic alcohol 12 with excellent
selectivity.12 After conversion of the imide moiety to an ester
function,13 vanadium-mediated epoxidation14 proceeded with
high selectivity. Epoxy alcohol 13 was treated with t-
Bu2Si(OTf)2 as a Lewis acid to promote the epoxide-carbonyl
rearrangement.15 The resulting anti β-hydroxy-α-methyl ketone
14 was protected as PMB ether 3.16 Although a stereoisomer
resulted from the epoxide-carbonyl rearrangement reaction
could not be separated from our desired compound, ketone 3
including a minor stereoisomer was submitted to the coupling
reaction between the C33−C40 and C25−C32 segments.
Coupling of the two segments and construction of the C24−
C40 segment 1 are shown in Scheme 6. The lithium enolate of
3 was reacted with aldehyde 2 to give an aldol adduct, which
was further converted to α,β-unsaturated ketone 15 in one pot
by sequential mesylation and elimination. The aldol reaction
proceeded stereoselectively (the resulting configuration of the
C33 position was not determined), and sequential dehydration
gave E isomers stereoselectively. Luche reduction of the
resulting ketone 15 proceeded stereoselectively to yield the
desired isomer 16.17 Removal of TMS under acidic conditions
gave diol 17, which was separated from other stereoisomers
including derivatives of the stereoisomer of 3 by column
chromatography. After protection of the diol as methoxymethyl
ethers, the ester group at the C25 position was converted to
ethyl ketone by the sequence of preparation of a Weinreb
amide18 and introduction of ethyl group with ethylmagnesium
bromide. The six-step sequence gave a very straightforward
route to C24−C40 segment 1.
(path a), and another is the epoxide-carbonyl isomerization
(path b). While path a known as Jung’s method7 has been
employed in natural product synthesis,8 the rearrangement of
path b has rarely been applied. Proper use of these reactions
would realize construction of a variety type of polyketides.
Synthesis of the C33−C40 segment 2 started from silyl
dienol ether 5 (Scheme 4). The remote asymmetric induction
reaction (Kobayashi aldol reaction) of dienol ether 5 with
butanal 6 proceeded efficiently to afford 7 in high yield and
excellent selectivity. The chiral auxiliary was removed by
hydride reduction to give allylic alcohol 8. Epoxidation9 of the
diol 8 made smooth progress in high selectivity, and the
Scheme 4. Synthesis of C33−C40 Segment 2
In conclusion, we achieved the synthesis of the C24−C40
segment of aculeximycin in a few steps. Both C25−C32 and
C33−C40 segments were synthesized by the Kobayashi aldol
reaction and epoxide-opening rearrangement reactions. In
B
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Scheme 6. Coupling of Segments and Synthesis of C24−C40
Segment 1
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from The
NOVARTIS Foundation (Japan) for the Promotion of Science,
The Kurata Memorial Hitachi Science and Technology
Foundation; The Naito Foundation; GCOE program “Center
for Practical Chemical Wisdom”; Scientific Research on
Innovative Areas #24102531 of The Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan; and
The Supporting Strategic Research Platform for Fusion
Biotechnology based on Biology, Chemistry, and Informatics
Project to Form the Strategic Research Platforms for Private
University and a matching fund subsidy from MEXT, Japan.
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: seijiro@waseda.jp.
Notes
The authors declare no competing financial interest.
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