Concise total synthesis of (-)-mersicarpine

Article abstract of DOI:10.1021/ol300735g

A concise total synthesis of (-)-mersicarpine from a known cyclohexanone was accomplished. The azepinoindole core was constructed by a DIBAL-H-mediated reductive ring-expansion reaction of oxime.

Full text of DOI:10.1021/ol300735g

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2320–2322
Concise Total Synthesis of
(À)-Mersicarpine
Yusuke Iwama, Kentaro Okano, Kenji Sugimoto,† and Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku,
Sendai 980-8578, Japan
tokuyama@mail.pharm.tohoku.ac.jp
Received March 22, 2012
ABSTRACT
A concise total synthesis of (À)-mersicarpine from a known cyclohexanone was accomplished. The azepinoindole core was constructed by a
DIBAL-H-mediated reductive ring-expansion reaction of oxime.
Mersicarpine (1), isolated from the Kopsia species of
plants by Kam and co-workers in 2004,1 has an unusual
tetracyclic structure, in which indoline, seven-membered
cyclic imine, and δ-lactam are fused with each other
around a tertiary hydroxyl group adjacent to the quatern-
ary carbon center. The bioactivity of 1 has not been
reported so far; however, these unique structural features
have attracted considerable attention in the synthetic
community. In 2008, Kerr and co-workers reported the
first total synthesis of (()-1 using Mn(OAc)3-mediated
radical cyclization of keto-ester.2 The synthesis was carried
out from indoline in 14 steps in 11% overall yield. In 2009,
Zard and a co-worker reported the formal synthesis of
(()-1 by an intermolecular radical additionÀcyclization cas-
cade using lauroyl peroxide, which describes an improved
synthesis of Kerr’s intermediate.3 In 2010, Fukuyama and
co-workers reported the first enantioselective synthesis of
(À)-1 including mechanistic studies on the autoxidation of
azepinoindole using oxygen isotope labeling.4 The synth-
esis features a gold-catalyzed indole formation and a
stepwise introduction of the nitrogen atom at the 3-posi-
tion of indole that required ten steps (14% overall yield)
from the known keto-ester 9. Herein, we describe a nine-
step, six-pot synthesis of (À)-mersicarpine (1) from keto-
ester 9 utilizing the DIBAL-H-mediated reductive ring-
expansion reaction established in our group.
Recently, we extensively investigated a reductive ring-
expansion reaction of oximes with DIBAL-H for its reac-
tion scope and mechanistic details.5 In contrast to a
Beckmann rearrangement,6 aromatic ring fused cyclic
ketoximes gave the corresponding reductive ring-expan-
sion products with an aromatic ring-nitrogen bond that
was independent of the geometry of the oxime. For
example, treatment of oxime 2 with excess DIBAL-H gave
azepinoindole 3 as an exclusive product, which was isolated
as benzamide 4 due to instability under air (Scheme 1).7,8
We considered that this methodology should be highly
useful for synthesis of 3-amino indoles from easily acces-
sible precursors, which cannot be executed in a straightfor-
ward manner.4 To demonstrate the utility of this reac-
tion, we selected (À)-mersicarpine (1) as a synthetic target
and planned a synthetic strategy as shown in Scheme 2.
Mersicarpine (1) would be derived from tetracyclic
azepinoindole 5 according to Fukuyama’s autoxidation
(5) (a) Cho, H.; Iwama, Y.; Sugimoto, K.; Kwon, E.; Tokuyama, H.
Heterocycles 2009, 78, 1183. (b) Cho, H.; Iwama, Y.; Sugimoto, K.;
Mori, S.; Tokuyama, H. J. Org. Chem. 2010, 75, 627. (c) Cho, H.;
Sugimoto, K.; Iwama, Y.; Mitsuhashi, N.; Okano, K.; Tokuyama, H.
Heterocycles 2011, 82, 1633.
† Current address: Graduate School of Medicine and Pharmaceutical
Sciences, University of Toyama.
(1) Kam, T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M. Tetra-
hedron Lett. 2004, 45, 5995.
(6) Donaruma, L. G.; Heldt, W. Z. Org. React. 1960, 11, 1.
(7) Hester, J. B., Jr. J. Org. Chem. 1967, 32, 3804.
(8) Formation of 3 was monitored by TLC. However, purification of
3 by silica gel column chromatography resulted in decomposition due to
instability.
(2) Magolan, J.; Carson, C. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437.
(3) Biechy, A.; Zard, S. Z. Org. Lett. 2009, 11, 2800.
(4) Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T. J. Am.
Chem. Soc. 2010, 132, 1236.
r
10.1021/ol300735g
Published on Web 04/18/2012
2012 American Chemical Society

Scheme 1. DIBAL-H-Mediated Construction of Azepinoindole
Scheme 3. Preparation of Tricyclic Oxime 6
Scheme 2. Retrosynthetic Analysis of (À)-Mersicarpine (1)
Scheme 4. Reductive Ring-Expansion Reaction Followed by
Protection of Azepine 11 with Cbz Group
protocol. The azepine ring would be constructed by our
reductive ring-expansion reaction of six-membered oxime
6, which should be accessible from carbazole derivative 7 via
oxidation at the C-4 position. Carbazole derivative 7 would
be easily synthesized by Fischer indole synthesis using
phenylhydrazine (8) and optically active cyclohexanone 9.
Synthesis of (À)-mersicarpine (1) was initiated by pre-
paration of tricyclic oxime 6 from optically active cyclo-
hexanone 9,9,10 which was readily prepared by asymmetric
Michael addition according to the d’Angelo protocol9
(Scheme 3). Next, we examined Fischer indole synthesis
of 9 and phenylhydrazine (8). Treatment of ketone 9 with 2.0
equiv of phenylhydrazine and 1.9 equiv of methanesulfonic
acid11 in refluxing methanol afforded the desired tricyclic
indole 7 in 84% yield.12 Regioselective oxidation of 7 with
DDQ gave the corresponding ketone 10 in high yield,13
which was converted to oxime 6 in 96% yield.
With oxime 6 in hand, we then examined the crucial
reductive ring-expansion reaction (Scheme 4). Upon treat-
ment of oxime 6 with 10 equiv of DIBAL-H at 0 °C, the
expected reductive ring-expansion reaction proceeded to
give the desired azepinoindole 11. Due to the instability,
the yield of the reaction was estimated after conversion of
the crude 11 to Cbz carbamate 13, in which partially
generated mixed carbonate 12 was converted to 13 by
treatment with 2 M NaOH. Disappointingly, the initial
€
(9) Desmaele, D.; d’Angelo, J. J. Org. Chem. 1994, 59, 2292.
(10) The enantiomeric excess of keto-ester 9 was determined to be
>99% by chiral HPLC after conversion of 9 to the corresponding
benzyl ester. For the detailed experimental procedure, see Supporting
Information.
(11) Under the conventional Fischer conditions, the resultant indole
7 was readily cyclized to give lactam. The use of an additional acid was
effective to suppress the lactam formation. Among a variety of acids
such as TfOH, conc. H2SO4, HCl, MsOH, TFA, ClH2CCO2H, AcOH,
and PPTS, MsOH was the most effective.
(12) Lactam was isolated in 7% yield.
(13) (a) Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu, O. Het-
erocycles 1979, 12, 1457. (b) Sissouma, D.; Collet, S. C.; Guingant, A. Y.
Synlett 2004, 2612.
Org. Lett., Vol. 14, No. 9, 2012
2321

Scheme 5. One-Pot Procedure of Reductive Ring-Expansion
Reaction and Protection with a Cbz Group
Scheme 6. Total Synthesis of (À)-Mersicarpine (1)
trial resulted in only a low yield of the desired azepinoin-
dole 13 (entry 1). We found that careful control of the
reaction temperature was important for the high-yielding
process. Thus, treatment of 6 with DIBAL-H at À78 °C,
followed by gradual warming of the reaction mixture to 0 °C
over 2 h and then to room temperature over 1 h, dramati-
cally improved the yield and reproducibility (entry 2), and
13 was obtained in 55% yield.
Furthermore, we established a one-pot protocol for the
reductive ring-expansion-protection sequence (Scheme 5).
After extensive optimization, the reductive ring-expansion
reaction was best effected with 8 equiv of DIBAL-H. The
reaction mixture was then directly subjected to Schot-
tenÀBaumann conditions14 to give the desired product
13 in 74% yield.
Finally, the total synthesis of (À)-mersicarpine (1) was
completed by two-pot operations including lactam forma-
tion and autoxidation (Scheme 6). A one-pot direct con-
version of primary alcohol 13 to lactam 14 proceeded quite
smoothly with a combination of TPAP and NMO. After
removal of the Cbz group under hydrogenolysis, air was
purged to the reaction mixture to initiate autoxidation of
tetracyclic azepinoindole 5. Finally, dimethyl sulfide was
added to the reaction mixture to promote reduction of
the resultant peroxide 15 to furnish (À)-1 in 91% yield
from 14.4
In summary, we have achieved a concise total synthesis
of (À)-mersicarpine (1) from known keto-ester 9 in a nine
step, six-pot process in 30% overall yield. Our synthesis
features a regiospecific and DIBAL-H-mediated reductive
ring-expansion reaction for the construction of the azepi-
noindole core of mersicarpine from the six-membered
cyclic ketoxime 6, which was readily available by Fischer
indole synthesis.
Acknowledgment. This work was financially supported
by the Cabinet Office, Government of Japan through its
“Funding Program for Next Generation World-Leading
Researchers (LS008), the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, the KAKENHI,
a Grant-in-Aid for Scientific Research (B) (20390003),
Tohoku University Global COE program ‘International
Center of Research and Education for Molecular Complex
Chemistry’, Nagase Science and Technology Foundation,
and a JSPS predoctoral fellowship for Y.I. Professor
Hidetsura Cho (Tohoku University) is also acknowledged
for the valuable discussions on the DIBAL-H-mediated
reductive ring expansion.
Note Added after ASAP Publication. The authors affilia-
tion was incorrect in the version published ASAP on April
18, 2012; this reposted on April 26, 2012.
Supporting Information Available. Experimental pro-
cedures and 1H and 13C NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) (a) Sonntag, N. O. V. Chem. Rev. 1953, 52, 237. (b) Challis, B. C.;
Butler, A. R. Chem. Amino Group 1968, 277.
The authors declare no competing financial interest.
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Org. Lett., Vol. 14, No. 9, 2012