Enantioselective total synthesis of aspidophytine

Article abstract of DOI:10.1021/ol034445e

(Matrix presented) An enantioselective total synthesis of aspidophytine is described. The indole fragment bearing a cis-alkene substituent was efficiently prepared through radical cyclization of a 2-alkenylphenylisocyanide followed by Sonogashira coupling of the generated 2-iodoindole derivative with a functionalized acetylene unit. After formation of the 11-membered cyclic amine, the aspidosperma skeleton and lactone ring were constructed to complete the total synthesis.

Full text of DOI:10.1021/ol034445e

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1891-1893
Enantioselective Total Synthesis of
Aspidophytine
,†
Shinjiro Sumi,† Koji Matsumoto,† Hidetoshi Tokuyama,†,‡ and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, and PRESTO,
JST, 7-3-1 Hongo, Bunkyo-ku, Tokyo113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received March 13, 2003
ABSTRACT
An enantioselective total synthesis of aspidophytine is described. The indole fragment bearing a cis-alkene substituent was efficiently prepared
through radical cyclization of a 2-alkenylphenylisocyanide followed by Sonogashira coupling of the generated 2-iodoindole derivative with a
functionalized acetylene unit. After formation of the 11-membered cyclic amine, the aspidosperma skeleton and lactone ring were constructed
to complete the total synthesis.
In 1973, the groups of M. P. Cava and P. Yates reported the
structural determination of haplophytine (1),1 a dimeric indole
alkaloid isolated from the dried leaves of the plant Haplo-
phyton cimicidum.2,3 In addition to the X-ray crystallographic
study of haplophytine dihydrobromide,4a the structure was
also supported by extensive chemical investigations, in which
the right-half constituent aspidophytine (2), a lactonic
aspidospermine type of alkaloid, was obtained as the product
of acid cleavage of 1.1,5 Aspidophytine (2) should be not
only a precursor of biosynthesis but also a possible synthetic
intermediate to 1. Recently, Corey and co-workers reported
a concise and elegant protocol for the construction of 2.6 In
the course of our project on the development and applications
of the indole synthesis, the intriguing structure of this
compound prompted us to begin synthetic studies toward
the total synthesis of haplophytine (1).7-9 We describe herein
our stereoselective protocol for an efficient construction of
2.
† The University of Tokyo.
‡ PRESTO, JST.
(1) Yates, P.; MacLachlan, F. N.; Rae, I. D.; Rosenberger, M.; Szabo,
A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M.
V.; Zeigler, W. J. Am. Chem. Soc. 1973, 95, 7842.
(2) (a) Rogers, E. F.; Snyder, H. R.; Fischer, R. F. J. Am. Chem. Soc.
1952, 74, 1987. (b) Snyder, H. R.; Fischer, R. F.; Walker, J. F.; Els, H. E.;
Nussberger, G. A. J. Am. Chem. Soc. 1954, 76, 2819, 4601. (c) Synder, H.
R.; Strohmayer, H. F.; Mooney, R. A. J. Am. Chem. Soc. 1958, 80, 3708.
(3) For a review of the earlier work on haplophytine, see: Saxton, J. E.
Alkaloids 1965, 8, 673.
(4) (a) Zacharias, D. E. Acta Crystallogr., Sect. B 1970, 26, 1455. (b)
For a X-ray structure of haplophytine, see: Cheng, P.-T.; Nyburg, S. C.;
MacLachlan, F. N.; Yates, P. Can. J. Chem. 1975, 54, 726.
(5) (a) Cava, M. P.; Talapatra, S. K.; Nomura, K.; Weisbach, J. A.;
Douglas, B.; Shoop, E. C. Chem. Ind. (London) 1963, 1242. (b) Cava, M.
P.; Talapatra, S. K.; Yates, P.; Rosenberger, M.; Szabo, A. G.; Douglas,
B.; Raffauf, R. F.; Shoop, E. C.; Weisbach, J. A. Chem. Ind. (London)
1963, 1875. (c) Rae, I. D.; Rosenberger, M.; Szabo, A. G.; Willis, C. R.;
Yates, P.; Zacharias, D. E.; Jeffrey, G. A.; Douglas, B.; Kirkpatrick, J. L.;
Weisbach, J. A. J. Am. Chem. Soc. 1967, 89, 3061.
Figure 1.
The requisite terminal acetylene unit 8, which was to be
installed at the indole 2-position, was prepared using
(6) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 6771.
10.1021/ol034445e CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/26/2003

resolution of the allylic alcohol followed by Claisen-Johnson
rearrangement (Scheme 1). 1,2-Addition of lithium TIPS-
Scheme 2a
Scheme 1a
a (a) (EtO)2POCH2CO2Et, n-Bu4NI, CH2Cl2-aq NaOH, 5 °C,
25 min, 81%; (b) Zn, AcOH, CH2Cl2, 5 °C to rt, 1.5 h; (c) HCO2H,
Ac2O, 5 °C, 20 min; (d) POCl3, Py, CH2Cl2, 5 °C, 70 min, 63% (3
steps); (e) n-Bu3SnH, AIBN, MeCN, reflux, 1.5 h; I2, rt, 85%; (f)
DIBAL, toluene, 10 °C, 50 min; (g) Ac2O, Py, rt, 30 min, 85% (2
steps).
a (a) triisopropylsilylacetylene, n-BuLi, CeCl3, THF, -78 °C;
(b) 3% H2SO4, THF, rt, 6.5 h, 94% (2 steps); (c) vinyl acetate,
Lipase PS, t-BuOMe, 45-50 °C, 48% (99% ee); (d) CH3C(OEt)3,
t-BuCO2H, xylene, reflux, 10 h; (e) TBAF, THF, 50 °C, 45 min;
(f) OsO4, NMO, acetone-H2O, 0 °C to rt, 80 min; (g) NaIO4,
THF-H2O, 0 °C, 25 min; (h) NaBH4, EtOH, -20 °C, 15 min,
38% (5 steps); (i) TBDPSCl, DMAP, Et3N, CH2Cl2, -20 to -10
°C, 45 min, 95%; (j) (COCl)2, DMSO, CH2Cl2, -78 °C; Et3N; (k)
CSA, HC(OMe)3, MeOH, rt, 30 min, 74% (2 steps).
sequence including reduction, formylation of aniline, and
dehydration. Tin-mediated indole formation and treatment
of the 2-stannyl indole intermediate with iodine gave the
2-iodoindole derivative 12.7b Finally, the ester function was
reduced to the primary alcohol, which was protected as its
acetate to give the desired indole unit 13.
We then joined the two synthesized fragments 8 and 13
to form the 11-membered secondary amine, a precursor for
the construction of the aspidosperma skeleton (Scheme 3).
Sonogashira coupling13 of 8 and 13 gave the 2-alkynyl indole
derivative 14.7b It was found that Boc protection of the indole
nitrogen was key for the selective partial reduction of the
alkyne, and the cis-olefin was obtained as the exclusive
product. Formation of 11-membered ring was therefore
effectively accomplished using o-nitrobenzenesulfonyl (Ns)
group chemistry.14,15 Thus, after hydrolysis of the acetate,
the nitrogen function was introduced by the Mitsunobu
reaction16 of Ns-amide, followed by desilylation to give the
cyclization precursor 16. The crucial intramolecular Mit-
sunobu reaction took place smoothly to furnish the 11-
membered ring compound 17 in 92% yield.
The synthesis was completed by construction of the
aspidosperma skeleton and lactone ring. First, the protective
groups of the aldehyde and secondary amine were sequen-
tially removed with TMSBr and a combination of thiophenol
and Cs2CO3, respectively. Upon treatment with TFA and
buffer, initial loss of the Boc group was followed by an
intramolecular Mannich-type reaction17 to furnish the pen-
acetylide to cyclopentenone (3) in the presence of CeCl3 and
subsequent acid treatment gave the conjugated allylic alcohol
4.10 Resolution of 4 using Amano lipase PS gave the
corresponding S-enantiomer 5 (48%, 99% ee).11 The qua-
ternary carbon center was constructed by Claisen-Johnson
rearrangement, followed by desilylation, to give the desired
chiral ester 6. The cyclopentene ring was then cleaved by
osmylation and oxidation with NaIO4, and the resulting
dialdehyde was reduced to give diol 7. After regioselective
silylation, the remaining primary alcohol was converted to
the dimethyl acetal by Swern oxidation and subsequent acetal
formation to furnish the desired acetylene unit 8.
Preparation of the indole unit 13 commenced with Wittig
olefination of the known benzaldehyde 912 leading to the
ethyl cinnamate derivative 10 (Scheme 2). Conversion of
the nitro group to isonitrile was executed by a three-step
(7) (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116,
3127. (b) Tokuyama, H.; Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis
2000, 429. (c) Tokuyama, T.; Watanabe, M.; Hayashi, Y.; Kurokawa, T.;
Peng, G.; Fukuyama, T. Synlett 2001, 1403.
(8) Tokuyama, H.; Fukuyama, T. Chem. Rec. 2002, 2, 37.
(9) (a) Kobayashi, S.; Peng, G.; Fukuyama, T. Tetrahedron Lett. 1999,
40, 1519. (b) Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 883.
(10) (a) Bertrand, M.; Santelli-Rouvier, C. Bull. Chem. Soc. Fr. 1972,
2775. (b) Magnus, P.; Charter, R.; Davies, M.; Elliott, J.; Pitterna, T.
Tetrahedron 1990, 52, 6283.
(11) The corresponding acetate could be converted to the desired allylic
alcohol 5 possessing the S-configuration by Mitsunobu inversion as
follows: K2CO3, MeOH; PhCO2H, DEAD, PPh3, THF/toluene; K2CO3,
MeOH, quant, 89% ee (3 steps). For the determination of absolute
configuration, see Supporting Information.
(13) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(14) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831. (c) For a review on nitrobenzenesulfon-
amide chemistry, see: Kan, T.; Fukuyama, T. J. Synth. Org. Chem. Jpn.
2001, 59, 779.
(15) For the cyclization of medium-size cyclic amines, see: (a) Kan,
T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697. (b) Kan, T.; Fujiwara,
A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58, 6267.
(16) Mitsunobu, O. Synthesis 1981, 1.
(17) Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem. Soc. 1981,
103, 6990.
(12) (a) Ross, S. T.; Frantz, R. G.; Wilson, J. W.; Hahn, R. A.; Sarau,
H. M. J. Heterocycl. Chem. 1986, 23, 1805. (b) Magnus, P.; Westlund, N.
Tetrahedron Lett. 2000, 41, 9369.
1892
Org. Lett., Vol. 5, No. 11, 2003

Scheme 3a
a (a) acetylene 8, Pd(PPh3)4, CuI, Et3N, 70 °C, 2 h, 78%; (b) Boc2O, DMAP, MeCN, rt, 15 min, 94%; (c) Pd/C, H2, EtOH, rt, 3.5 h, 97%;
(d) K2CO3, MeOH, rt, 1 h, 96%; (e) NsNH2, PPh3, DEAD, PhH, rt, 5 min, 93%; (f) TBAF, THF, rt, 1 h, 93%; (g) PPh3, DEAD, PhH, rt,
5 min, 92%; (h) TMSBr, CH2Cl2, -78 °C, 15 min, 92%; (i) PhSH, Cs2CO3, MeCN, 55 °C, 20 min; (j) TFA, Me2S, CH2Cl2, rt, 5 min; pH
7.8 buffer, 56% (2 steps); (k) HCHO, NaBH3CN, pH 7.0 buffer, -70 °C to rt, 2.5 h, 67%; (l) NaOH, EtOH, 70 °C; K3Fe(CN)6, NaHCO3,
5 °C to rt, 40 min, 39%.
Acknowledgment. The authors thank Ms. S. Miki and
Mr. T. Matsuno (Meiji Seika Kaisya, Ltd.) for determination
of high-resolution mass spectra and NMR spectra, respec-
tively, and Dr. Y. Hirose (Amano Enzyme, Inc.) for
providing lipase PS. This work was partially supported by
the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
tacyclic compound 18 as a single isomer. Stereoselective 1,2-
reduction of the conjugated imine and reductive methylation
were effected in one pot to give 19. Finally, saponification
of the ester 19 and subsequent subjection of the resulting
carboxylic acid to oxidative lactone formation conditions6
provided aspidophytine 2. All spectral data of the synthetic
material were identical with those published.1,6
In summary, we have accomplished an enantioselective
total synthesis of aspidophytine (2) featuring a facile
preparation of the fully functionalized indole derivative and
11-membered ring formation utilizing Ns technology. Syn-
thetic studies on haplophytine (1) based on this efficient
synthetic method are currently under investigation in our
laboratories.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL034445E
Org. Lett., Vol. 5, No. 11, 2003
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