Enantioselective synthesis of SB-203207

Article abstract of DOI:10.1021/ol5002973

Total synthesis of SB-203207 (1) was achieved, beginning with a desymmetrical C-H insertion reaction of a diazoester bearing our recently developed chiral auxiliary. Utilizing the optically active bicyclo[3.3.0]octane ring, four stereogenic centers were efficiently constructed in sequence. Finally, mild oxidation of 27 to carboxylic acid via a cyanohydrin intermediate and hydrolysis of cyanide to carboxyamide in the presence of the labile enamide group completed an efficient total synthesis of 1.

Full text of DOI:10.1021/ol5002973

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of SB-203207
Yasuo Hirooka,† Kazutada Ikeuchi,† Yuichiro Kawamoto,‡ Yusuke Akao,† Takumi Furuta,†,§
Tomohiro Asakawa,† Makoto Inai,† Toshiyuki Wakimoto,†,‡ Tohru Fukuyama,‡,∥ and Toshiyuki Kan*,†
†School of Pharmaceutical Sciences, University of Shizuoka and Global COE Program, 52-1 Yada, Suruga-ku, Shizuoka 422-8526,
Japan
‡Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
§Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
∥Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
S
* Supporting Information
ABSTRACT: Total synthesis of SB-203207 (1) was achieved,
beginning with a desymmetrical C−H insertion reaction of a
diazoester bearing our recently developed chiral auxiliary.
Utilizing the optically active bicyclo[3.3.0]octane ring, four
stereogenic centers were efficiently constructed in sequence.
Finally, mild oxidation of 27 to carboxylic acid via a
cyanohydrin intermediate and hydrolysis of cyanide to
carboxyamide in the presence of the labile enamide group completed an efficient total synthesis of 1.
Scheme 1. Structure and Synthetic Strategy of SB-203207
(1)
onproteinogenic α-disubstituted α-amino acid derivatives
Nhave recently attracted attention due to their potent
biological activities, and they represent challenging structural
targets for total synthesis.1 However, few efficient methods are
available for synthesizing complex α-amino acid derivatives
bearing functional groups. Recently, researchers in the
SmithKline Beecham group isolated SB-203207 (1) from a
Streptomyces species2 and showed that it inhibits isoleucyl tRNA
synthetase with an IC50 value below 2 nM. Such inhibitors are
promising candidates for the treatment of a variety of diseases,
so an efficient and flexible synthesis of 1 is highly desirable.3
Although a total synthesis of altemicidin (2), the core
compound of 1, was achieved by Kende and co-workers in
1995,4 and the conversion of naturally occurring 2 to 1 was
reported by the SmithKline Beecham group,3 a total synthesis
of 1 has not yet been reported.
During the course of our synthetic investigation of 2, we
reported a stereoselective synthesis of racemic intermediate 3
via a bicyclo[3.3.0]framework.5 In an effort to develop an
enantioselective synthesis of 1, we focused on the stereo-
selective preparation of 5. The heart of our synthetic plan is
illustrated in Scheme 1. We aimed to introduce the highly polar
leucenyl sulfonamide and vinylogous urea at a late stage in the
synthesis.
tion, and as reported herein we achieved an enantioselective
total synthesis of 1.
As shown in Scheme 2, the construction of an optically active
bicyclic[3.3.0]framework 12 was accomplished via an intra-
molecular C−H insertion reaction6 in 11. We have developed
an efficient C−H insertion methodology using a combination
7
of Rh2(S-DOSP)4 and a diazoester bearing our recently
developed chiral auxiliary.8 Although we had previously
prepared the cyclization precursor 11 by the transesterification
between the corresponding β-ketoester and the chiral alcohol
7,8c its reproducibility was poor on a large scale. Thus, in our
current approach, we started the synthesis with the
condensation of 7 with α-bromoacetyl bromide. Because the
preparation of diazoester 8 by the conventional diazotization
Although we had previously synthesized racemic 3 through
stereoselective introduction of a nitrogen atom and conversion
to the azabicyclo[4.3.0] skeleton,5 formation of the α-
disubstituted α-amino acid moiety of 2 from 3 proved
troublesome. However, we found an efficient oxidation method
that yielded the carboxylic acid through cyanohydrin and
acylcyanide intermediates. Some improvements of our previous
synthetic procedures5 were required for a large-scale prepara-
Received: January 28, 2014
Published: March 6, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. Preparation of Lactam 18
Scheme 3. Total Synthesis of SB-203207 (1)
from a glycine derivative was also found to be difficult, we
opted to use a novel diazotransfer method recently developed
by our group.9 Treatment of the α-bromoester with DBU in the
presence of bis tosyl hydrazine proceeded smoothly to give 8
without the decomposition of the labile ester moiety. After the
condensation of 8 and aldehyde 9 by means of a modified
Roskamp reaction,10 diazotransfer reaction of 10 provided the
C−H insertion precursor 11. Treatment of 11 with 0.1 mol %
of Rh2(R-DOSP)4 resulted in the desired C−H insertion
providing the optically active bicyclo[3.3.0]octane ring
compound 12. This transformation had the advantage of
providing a one-step generation of the two chiral centers of the
ring fusion. After the removal of the chiral auxiliary of 12 by
transesterification,11 stereoselective hydroxymethylation was
achieved under careful temperature control.12 On a large
scale, epimerization of the α-position of the β-ketoester readily
proceeded via retro-alkylation and alkylation. Subsequently,
stereoselective reduction was carried out by treatment with
NaBH(OAc)3 through chelation with the primary hydroxyl
group.13 This was followed by one-step protection of the
primary alcohol with TBDPS and the secondary alcohol with a
MOM ether.
Incorporation of an amino functionality and the construction
of the cyclic enamide from 15 were accomplished by using our
racemic synthesis.5 After the formation of amide 16 from allyl
ester 15, conversion to dimethyl acetal 17 was performed by
ozonolysis and sequential treatment with methanol and
HC(OMe)3 in the presence of CSA.14 After the selective
reduction of the hemiaminal of 17 with NaBH3CN, the
incorporation of the Ns group15 into lactam 18 was achieved by
treatment with LHMDS and NsCl, as shown in Scheme 3. The
TBDPS group was removed, and the lactam opening was
performed by utilizing activation by Ns imide with the
neighboring effect of the primary alcohol. Although a cyclic
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Organic Letters
Letter
enamide formation from 19 had been carried out by treatment
with CSA and quinolone in the previous synthesis,5 the
concomitant deprotection of the MOM ether occurred in a
large-scale reaction. However, we found that heating in benzene
in the presence of silica gel (anhydrous conditions) was suitable
for this transformation, giving 20 in high yield. Next, the
introduction of a nitrogen atom onto the quaternary carbon of
20 was performed by treatment with DPPA16 to give 21. After
the incorporation of a C1 unit into enamide 22 via modified
Vilsmeier reaction17 and the protection of 22 with a Boc group,
deprotection of the Ns group18 and N-methylation afforded 24.
Conversion of aldehyde 24 to nitrile 25 was performed by
treatment with hydroxylamine followed by the addition of
acetic anhydride and base. Although the conversion to aldehyde
26 proceeded smoothly by hydrolysis of the oxazolidinone ring
and DMP oxidation, further oxidation to the corresponding
acid derivative was difficult. Non-nucleophilic oxidation
reaction conditions were required because typical NaOCl2-
mediated Kraus oxidation,19 as well as TEMPO20- or
AZADO21-catalyzed oxidation, resulted in decomposition of
the reactive cyanoenamide group.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: +81-54-264-5745. Tel: +81-54-264-5746. E-mail: kant@
u-shizuoka-ken.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Grants-in-Aid for
Scientific Research on Priority Areas 12045232 and 24105530
from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT) of Japan.
REFERENCES
■
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desymmetric C−H insertion reaction for the construction of
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sequential stereocenters, a novel conversion of aldehyde to
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S
* Supporting Information
Experimental procedure and spectral data for all new
compounds. This material is available free of charge via the
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