First total synthesis and stereochemical revision of okaramine M

Article abstract of DOI:10.1016/j.tetlet.2010.09.026

We describe the first total synthesis of the reported and revised structures of okaramine M (1 and 7) through the Ugi three-component reaction of pyrroloindole imine 10 with p-methoxyphenyl isonitrile and N-Boc-l-tryptophan, followed by cyclization and ep

Full text of DOI:10.1016/j.tetlet.2010.09.026

Tetrahedron Letters 51 (2010) 6003–6005
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First total synthesis and stereochemical revision of okaramine M
Toshimasa Iizuka, Satoshi Takiguchi, Yuh-suke Kumakura, Naoki Tsukioka, Kazuhiro Higuchi,
⇑
Tomomi Kawasaki
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2010
Revised 3 September 2010
Accepted 9 September 2010
Available online 17 September 2010
We describe the first total synthesis of the reported and revised structures of okaramine M (1 and 7)
through the Ugi three-component reaction of pyrroloindole imine 10 with p-methoxyphenyl isonitrile
and N-Boc-L-tryptophan, followed by cyclization and epimerization.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Diketopiperazine
Pyrrolo[2,3-b]indole
Asymmetric synthesis
Oxidation
The okaramines are a family of dimeric tryptophane alkaloids
isolated from the fermentation broth of Penicillium simplicissimum
ATCC 90288, AHU 8402, and Aspergillus aculeatus KF-428 by Hay-
ashi and co-workers.1 Most okaramines are constructed of a hexa-
hydropyrrolo[2,3-b]indole-diketopiperazine ring system with a
hydroxy group at the C10b quaternary center. Among the okaram-
ines, okaramine M (1) is distinguished by a reverse-prenyl group at
the C10b quaternary carbon center of the ring system,1c which rep-
resents the key structural subunit in a number of biologically
important natural products such as fructigenine A (2),2 verrucofor-
tine (3),3 roquefortine D (4),4 brevicompanine B (5),5 and amauro-
mine (6)6 (Fig. 1). However, the absolute configuration at C10b in
the proposed structure 1 is opposite to that in related natural prod-
ucts 2–6. Although okaramine M has not yet demonstrated any
remarkable bioactivity, its potential ability, like that of 2–6, is still
attractive. The absolute stereochemistry and the prospective bioac-
tivity of okaramine M prompted us to undertake the synthesis of 1
and its diastereomers. Some approaches to the related alkaloids
4–6 according to Takase’s7 and Danishefsky’s methodologies8 are
known, but to the best of our knowledge, there is no report on
the total synthesis of okaramine M. Recently, we developed a con-
cise and efficient synthetic methodology using domino reactions
and multi-component reactions for the related pyrroloindole alka-
loids.9 Herein, we describe the first total synthesis of okaramine M
and in turn clarify its absolute configuration on the basis of the
synthetic evidence that natural okaramine M does not correspond
to the proposed structure 1, but rather to its diastereomer 7.
For syntheses of 1 and three diastereomers including 7, we have
chosen to use a racemic imine 10 in a three-component reaction fol-
lowed by cyclization and epimerization. As described previously,9
hexahydropyroroindole ( )-9 was prepared through a reductive
cyclization of ( )-810 followed by Boc-protection, acetylation, and
Boc-deprotection (Scheme 1). Instead of the TPAP/NMO-oxidation
previously used,9c oxidation of ( )-9 with NCS and DBU11 improved
the yield of ( )-10 and the handling during workup. Next, the Ugi
three-component reaction12 of ( )-10, p-methoxyphenyl (PMP)
isonitrile, and N-Boc-L-tryptophan afforded two diastereomeric
O
H
O
H
10b
NH
NH
N
N
N
N
H
H
Ac
Ac
O
O
NH
NH
proposed structure
of okaramine M (1)
revised structure
of okaramine M (7)
O
H
O
H
H
H
N
N
N
NH
N
N
N
H
H
H
R1
R2
O
H
O
R1 R2
Ph Ac
amauromine (6)
fructigenine A (2)
verrucofortine (3)
roquefortine D (4)
iBu
Im
H
H
brevicompanine B (5) iBu Ac
⇑
Corresponding author. Tel./fax: +81 424 95 8763.
E-mail address: kawasaki@my-pharm.ac.jp (T. Kawasaki).
Figure 1. Okaramine M and related alkaloids; Im = 4-imydazoyl.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.026

6004
T. Iizuka et al. / Tetrahedron Letters 51 (2010) 6003–6005
O
1. LiAlH4
N-Boc-L-Try
CN-PMP
2. Boc2O, DMAP
CN
PMP
3a
N
*
H
*
N
NH
3. AcCl, NaOH,
cat. Bu4NHSO4
4. TFA
N
O
N
N
N
H
toluene, rt
78%
N
NHBoc
NH
H
H
H
Ac
Ac
( )-9
Ac
O
58% (4 steps)
( )-8
(+)-10
(+)-12
NCS
N-Boc-L-Try
1. TFA, CH 2Cl2, rt
2. toluene, 100 °C
then DBU
CN-PMP
*
*
+
(–)-7
(–)-ent-13
N
toluene, rt
98%
toluene, rt
78%
N
3. NaOH, MeOH, 5 °C
H
Ac
Scheme 2. Synthesis of okaramine M (7) from an optically pure imine (3aR)-(+)-10.
( )-10
O
O
the coupling constants (J11 ,11a = 10.2 Hz; J11b,11a = 5.4 Hz). Treat-
a
ment of another dipeptide (+)-12 with TFA followed by heating
at 100 °C produced a cyclic product (+)-14 in 72% yield, of which
the configuration was decided by NOE analysis as shown. The spec-
tral data of (+)-13 and (+)-14 are incongruous with those of the
natural product. The forth diastereomer (À)-7 was obtained in
44% yield with a by-product (À)-ent-13 (9%) by treatment of (+)-
14 with NaOH at 5–10 °C.14 As predicted, the 1H and 13C NMR data
of (À)-7 were identical to those of the reported natural compound,1
PMP
N
PMP
N
H
+
H
N
O
N
N
N
H
NHBoc
NH
NHBoc
NH
H
Ac
Ac
O
(–)-11 35%
(+)-12 34%
1. TFA, CH2Cl2, rt
2. toluene, 100 °C
67% (2 steps)
1. TFA, CH2Cl2, rt
2. toluene, 100 °C
72% (2 steps)
and both the coupling constants (J11 ,11a = 5.5 Hz; J11b,11a = 12.0 Hz)
a
and the NOE correlation confirmed the stereochemistry of (À)-7 as
shown in Scheme 1. Consequently, we propose compound 7, which
is a diastereomer of 1 with different absolute configurations at the
5a and C10b chiral centers bearing a reverse-prenyl group, to be
the structure of the isolated natural product, as well as the struc-
tures of the related natural products 2–6.
NOE
NOE
NH
O
O
H
H
11a
11a
NH
NH
N
N
H
N
N
H
H
Ac
Ac
O
O
NH
(–)-1
Finally, we performed an asymmetric synthesis of revised okar-
amine M (7) from optically pure pyroroindole imine (3aR)-(+)-10
(99% ee) (Scheme 2).9c As a result, the Ugi three-component reac-
(+)-14
NaOH
NaOH
MeOH, 5 °C - rt
MeOH, rt
73%
tion of (+)-10, PMP-isonitrile, and N-Boc-L-tryptophan took place
H
stereoselectively to give (+)-12 in 78% yield. In a similar way, okar-
amine M (À)-(7) was obtained through Boc-deprotection of (+)-12,
cyclization, and epimerization.
In summary, we have successfully completed the first total syn-
thesis of the proposed and revised structures 1 and 7 of okaramine
M in a concise and efficient manner. The biological evaluation of
okaramine M will be disclosed in due course.
NOE
Hα
Hβ
NOE
NH
O
O
H
H
11
NH
H
NH
N
N
H
N
N
H
H
Ac
Ac
O
O
NH
44%
(+)-13
(–)-7
+
Acknowledgments
O
H
N
NH
We wish to thank Professor Hideo Hayashi (Osaka Prefecture
University) for providing the 1H and 13C NMR spectra of okaramine
M, and for fruitful discussions. This work was supported by Grants-
in-Aid for Scientific Research (C) (No. 19590020) and for the High-
Tech Research Center Project (S0801043) from the Ministry of Edu-
cation, Culture, Sports, Science and Technology (MEXT), Japan. We
are also grateful to N. Eguchi, T. Koseki, and S. Kubota at the Ana-
lytical Center of MPU for performing microanalysis, mass spec-
trometry, and NOE experiments.
N
H
Ac
O
NH
9%
(–)-ent-13
Scheme 1. Synthesis of okaramine M and its diastereomers through a racemic
imine ( )-10.
dipeptides (À)-11 and (+)-12 in 35% and 34% yields, respectively.13
Subsequent Boc-deprotection of (À)-11 with TFA and cyclization
on heating at 100 °C provided the proposed okaramine M (À)-1 in
67% two-step yield as a single isomer, whose stereochemistry was
confirmed by NOE experiments as shown. Unfortunately, the 1H
and 13C NMR data of our synthetic compound 1 did not match with
those of the reported natural compound.1
In order to confirm the stereochemistry of the natural com-
pound, we synthesized its corresponding diastereomers 13, 14,
and 7, of which the spectral data were analyzed by comparison
with the natural compound. On treatment of (À)-1 with NaOH at
room temperature, epimerization at C11a proceeded selectively
to give the desired diastereomer (+)-13 in 73% yield. The stereo-
chemistry was assigned on the basis of the NOE correlation and
Supplementary data
Supplementary data (characterization data and 1H and 13C NMR
spectra of synthetic okaramine M and its diastereomers) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.09.026.
References and notes
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