A general and efficient strategy for 7-aryloctahydroindole and cis-3a-aryloctahydroindole alkaloids: Total syntheses of (±)-γ- lycorane and (±)-crinane

Article abstract of DOI:10.1021/jo0507690

A general and efficient approach to both 7-aryloctahydroindole and cis-3a-aryloctahydroindole alkaloids has been developed. The key step involves Michael additions of the corresponding kinetics and thermodynamics lithium enolates of ketone 9 to the versat

Full text of DOI:10.1021/jo0507690

A General and Efficient Strategy for
7-Aryloctahydroindole and
cis-3a-Aryloctahydroindole Alkaloids:
Total Syntheses of (()-γ-Lycorane and
(()-Crinane
Shuanhu Gao, Yong Qiang Tu,* Zhenlei Song,
Aixia Wang, Xiaohui Fan, and Yijun Jiang
State Key Laboratory of Applied Organic Chemistry and
Department of Chemistry, Lanzhou University, Lanzhou
730000, P. R. China
tuyq@lzu.edu.cn
Received April 15, 2005
FIGURE 1. Representative lycorine-type and crinine-type
alkloids.
alkaloids have been attracting considerable attention
from organic chemists over the years. Because establish-
ment of the five-membered nitrogen-containing ring of
the above two aryl substituted octahydroindole nuclei is
critical, a number of synthetic efforts have emerged to
address appropriate “C-C-NH2” synthons. Up to now,
Mitsunobu reaction,2b,5b Wadsworth-Emmons reaction,2e
and nucleophilic displacement2d have been intermolecu-
larly utilized to create the “C-C-NH2” segment. Despite
the above strategies for the different “C-C-NH2” syn-
thons, there have been no reports on the application of
the nitroethylene6 as a key building block for the con-
struction of the above two types of alkaloids.
In connection with our previous investigations, we have
recently reported the total syntheses of (()-crinane and
its analogue.7 This achievement encouraged us to develop
other kinds of conceptually new strategies, especially the
more general and efficient, for these two types and other
more complex alkaloids. Herein, we wish to present a
highly concise tactic for both of the above two aryl
A general and efficient approach to both 7-aryloctahydroin-
dole and cis-3a-aryloctahydroindole alkaloids has been
developed. The key step involves Michael additions of the
corresponding kinetics and thermodynamics lithium enolates
of ketone 9 to the versatile building blocks: nitroethylene
10. Two representative members, (()-γ-lycorane and (()-
crinane, have been synthesized in 22 and 36% overall yields,
respectively.
The lycorine-type and crinine-type alkaloids, which
possess 7-aryloctahydroindole and cis-3a-aryloctahydroin-
dole nuclei, respectively (as shown in Figure 1), constitute
a large class of structurally diverse natural products
existing widely in the Amaryllidaceae alkaloids,1 such as
γ-lycorane (1),2 lycorine (2),3 and crinine (4),4 as well as
some nonnatural products, such as crinane (3).5 Due to
their intriguing structures, the wide range of biological
activities, and ability to be a proving ground for new
strategy and synthetic methods, these two groups of
(3) For some previous syntheses of lycorine, see: (a) Tsuda, Y.; Sano,
T.; Taga, J.; Isobe, K.; Toda, J.; Irie, H.; Tanaka, H.; Takagi, S.; Yamaki,
M.; Murata, M. J. Chem. Soc., Chem. Commun. 1975, 933. (b)
Umezawa, B.; Hoshino, O.; Sawaki, S.; Sashida, H.; Mori, K. Hetero-
cycles 1979, 12, 1475. (c) Sano, T.; Kashiwaba, N.; Tada, J.; Tsuda, Y.;
Irie, H. Heterocycles 1980, 32, 1097. (d) Martin, S. F.; Tu, C.; Kimura,
M.; Simonsen, S. H. J. Org. Chem. 1982, 47, 3634. (e) Boeckman, R.
K., Jr.; Goldstein, S. W.; Walters, M. A. J. Am. Chem. Soc. 1988, 110,
8250. (f) Umezawa, B.; Hoshino, O.; Sawaki, H.; Mori, K.; Hamada,
Y.; Kotera, K.; Iitaka, Y. Tetrahedron 1984, 40, 1783. (g) Schultz, A.
G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210.
(h) Hoshino, O.; Ishizaki, M.; Kamei, K.; Taguchi, M.; Nagao, T.;
Iwaoka, K.; Sawai, S.; Umezawa, B.; Iitaka, Y. J. Chem. Soc., Perkin
Trans. 1 1996, 571. (i) Martin, S. F.; Tu, C. J. Org. Chem. 1981, 46,
3763. (j) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem.
Soc. 1993, 115, 7904.
(4) For some previous syntheses of crinine, see: (a) Muxfeldt, H.;
Schneider, R. S.; Mooberry, J. B. J. Am. Chem. Soc. 1966, 88, 3670.
(b) Whitlock, H. W.; Smith, G. L. J. Am. Chem. Soc. 1967, 89, 3600.
(c). Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53, 3184. (d)
Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607.
(5) For some previous syntheses of crinane, see: (a) Padwa, A.;
Brodney, M. A.; Dimitroff, M.; Liu, B.; Wu, T. H. J. Org. Chem. 2001,
66, 3119. (b) Schkeryantz, J. M.; Pearson, W. H. Tetrahedron 1996,
52, 3107. (c) Keck, G. E.; Webb, R. R. J. Am. Chem. Soc. 1981, 103,
3173. (d) Song, Z.-L.; Wang, B.-M.; Tu, Y.-Q.; Fan, C.-A.; Zhang S.-Y.
Org. Lett. 2003, 5, 2319.
* Corresponding author. Phone number: +86-931-8912410. Fax:
+86-931-8912582.
(1) For recent reviews of Amaryllidacea alkaloids, see: (a) Martin,
S. F. In The Alkaloids: Chemistry and Physiology; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 30, p 251. (b) Hoshino, O. The
Alkaloids: Chemistry and Physiology; Brossi, A., Ed.; Academic
Press: New York, 1998; Vol. 51, p 323. (c) Lewis, J. R. Nat. Prod. Rep.
1998, 15, 107. (d) Jin, Z.; Li, Z. G.; Huang, R. Q. Nat. Prod. Rep. 2002,
19, 454.
(2) Recent synthesis of γ-lycorane: (a) Yoshizaki, H.; Satoh, H.; Sato,
Y.; Nukui, S.; Shibasaki, M.; Mori, M. J. Org. Chem. 1995, 60, 2016.
(b) Ba¨ckvall, J. E.; Andersson, P. G.; Stone, G. B.; Gogoll, A. J. Org.
Chem. 1991, 56, 2988. (c) Padwa, A.; Brodney, M. A.; Lynch, S. M. J.
Org. Chem. 2001, 66, 1716. (d) Pearson, W. H.; Schkeryantz, J. M. J.
Org. Chem. 1992, 57, 6783. (e) Banwell, M. G.; Wu, A. W. J. Chem.
Soc., Perkin Trans. 1 1994, 2671. (f) Yasuhara, T.; Nishimura, K.;
Yamashita, M.; Fukuyama, N.; Yamada, K.-i.; Muraoka, O.; Tomioka,
K. Org. Lett. 2003, 5, 1123.
10.1021/jo0507690 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/07/2005
J. Org. Chem. 2005, 70, 6523-6525
6523

SCHEME 1. Retrosynthetic Analysis of
(()-γ-Lycorane and (()-Crinane
SCHEME 2. Total Synthesis of (()-γ-Lycorane
substituted octahydroindole nuclei and its application to
the total synthesis of (()-γ-lycorane (1) and (()-crinane
(3) from the same starting compound. Meanwhile, it is
worthy to note that, as the powerful acceptor of the
strategy key Michael addition reaction, nitroethylene6 is
a particularly versatile building block and can serve as
the needed “C-C-NH2” synthon.8 Herein, we hope this
work will enrich and expand its present limited utility
in organic chemistry,9 especially the total synthesis of
natural products.
nitroethylene 10 using the corresponding kinetics and
thermodynamics lithium enolates of ketone 9 would
provide the desired precursors 7 and 8, respectively.
Thus, two different routes were connected and could be
started from the same starting materials.
Our retrosynthetic considerations (Scheme 1) on 1 and
3 were focused on establishment of 7-aryloctahydroindole
5 and cis-3a-aryloctahydroindole 6, which can be con-
verted to the target molecules by some facile steps. In
turn, 5 and 6 might be prepared from γ-nitro carbonyl
compounds 7 and 8 through several transformations
involving the reductive cyclization and further reduction.
As the key strategy level step, Michael additions to
Initially, we selected (()-γ-lycorane (1), possessing the
basic structural elements of lycorine-type alkaloids, as
an optimal target to test our strategy. As demonstrated
in Scheme 2, 2-arylcyclohexanone 910 could be readily
synthesized from the commercially available cyclohexene
oxide 11 in 88% overall yield via two steps involving the
nucleophilic addition promoted by BF3‚Et2O11 and oxida-
tion of the formed alcohol by PCC. With 9 in hand, the
key Michael reaction was then investigated. As expected,
subjection of the kinetics lithium enolates of ketone 9 to
the nitroethylene 1012 gave rise to the desired γ-nitro
carbonyl compounds as a 25:1 mixture of diastereoiso-
mers in 85% combined yield, and the major isomer 713
was easily isolated by silica gel column chromatography.
The following reductive cyclization of γ-nitro carbonyl
compound 7 with Ni-Raney/H2 led to the unstable
cycloimine 12, which was transformed to the amine 5
directly by further reduction with NaBH3CN.2b Unfortu-
nately, attempted direct conversion of 5 to γ-lycorane (1)
by Pictet-Spengler cyclization using either Eschen-
moser’s salt or paraformaldehyde and CF3COOH was
unsuccessful to result in recovery of starting material 5.
Then, treatment of 5 with benzyl chloroformate in the
presence of pyridine afforded carbamate 13, which is the
(6) Historically, the utility of nitroolefins in conjugate addition
reactions has been limited by their facile polymerization in the presence
of nucleophiles. For the successful addition of ketones to nitroolefins
via their lithium enolates, enol silanes, enol ethers, or enamines, see:
(a) Yoshikoshi, A.; Mayashita, M. Acc. Chem. Res. 1985, 18, 284. (b)
Brook, M. A.; Seebach, D. Can. J. Chem. 1987, 65, 836. (c) Seebach,
D.; Brook, M. A. Helv. Chim. Acta 1985, 68, 319. (d) Seebach, D.; Leitz,
H. F.; Ehrig, V. Chem. Ber. 1975, 108, 1924. (e) Seebach, D.; Golinski,
J. Helv. Chim. Acta 1981, 64, 1413. (f) Blarer, S. J.; Schweizer, W. B.;
Seebach, D. Helv. Chim. Acta 1982, 65, 1637. (g) Denmark, S. E.;
Marcin, L. R. J. Org. Chem. 1993, 58, 3857. (h) Denmark, S. E.;
Schnute, M. E.; Senanayake, C. B. W. J. Org. Chem. 1993, 58, 1859.
(i) Denmark, S. E.; Senanayake, C. B. W. J. Org. Chem. 1993, 58, 1853.
(j) Cory, R. M.; Anderson, P. C.; Bailey, M. D.; McLaren, F. R.;
Renneboog, R. M.; Yamamoto, B. R. Can. J. Chem. 1985, 63, 2618. (k)
Cory, R. M.; Anderson, P. C.; McLaren, F. R.; Yamamoto, B. R. J. Chem.
Soc., Chem. Commun. 1981, 73. (l) Bradamente, P.; Pitacco, G.; Risaliti,
A.; Valentin, E. Tetrahedron Lett. 1982, 23, 2683. (m) Flintoft, R. J.;
Buzby, J. C.; Tucher, J. A. Tetrahedron Lett. 1999, 40, 4485. For
synthetic utility of nitroethylene, see: (n) Glassco, W.; Suchocki, J.;
George, C.; Martin, B. R. May, E. L. J. Med. Chem. 1993, 36, 3381. (o)
Johnson, M. R.; Fazio, M. J.; Ward, D. L.; Sousa, L. R. J. Org. Chem.
1983, 48, 494.
(7) (a) Song, Z.-L.; Wang, B.-M.; Tu, Y.-Q.; Fan, C.-A.; Zhang, S.-Y.
Org. Lett. 2003, 5, 2319. (b) Fan, C.-A.; Tu, Y.-Q.; Song, Z.-L.; Zhang,
E.; Shi, L.; Wang, M.; Wang, B.; Zhang, S.-Y. Org. Lett. 2004, 6, 4691.
(8) (a) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751.
(b) Perlmutter, P. Conjugate Addition in Organic Synthesis; Tarrytown,
NY, 1992.
(9) The utility of nitroethylene as a key building block for the
construction of Aspidosperma alkaloids has been reported by the Dugat
group: Nora, B. M.; Dugat, D.; Gramain, J. C.; Husson, H. P. J. Org.
Chem. 1993, 58, 6457.
(10) (a) Bunsuke U.; Osamu H.; Shohei S.; Seiichi S.; Naganori N.
J. Org. Chem. 1977, 42, 4272. (b) Hoshino, O.; Sawaki, S.; Shimamura,
N.; Onadera, A.; Umezawa, B. Chem. Pharm. Bull. 1987, 35, 2734.
(11) Eis, M. J.; Wrobel, J. E.; Ganem B. J. Am. Chem. Soc. 1984,
106, 3693.
(12) For preparation of nitroethylene, see: Ranganathan, D.; Rao,
C. B.; Ranganathan, S.; Mehrotra, A. K.; Iyengar, R. J. Org. Chem.
1980, 45, 1185.
(13) The stereochemical assignment of 7 was confirmed by the
spectral properties of further reaction products 5 which were in
agreement with those previously reported.
6524 J. Org. Chem., Vol. 70, No. 16, 2005

of MeLi,16 the corresponding thermodynamics lithium
enolate was formed, and the subsequent Michael addition
to nitroethylene 10 furnished the key intermediate 8 in
68% yield. Following the crucial construction of the
quaternary carbon center, the cis-3a-aryloctahydroindole
core structure 6 was readily obtained via the similar
transformations of reductive cyclization and the further
reduction in 75% overall yield. Its spectral properties
were in agreement with those previously reported.5b
Finally, according to the reported Pictet-Spengler cy-
clization procedure, treatment of 6 with Eschenmoser’s
salt at 40 °C in THF for 24 h yielded (()-crinane (3).
SCHEME 3. Total Synthesis of (()-Crinane
In summary, we have developed a general and highly
concise strategy for syntheses of both 7-aryloctahydroin-
dole and cis-3a-aryloctahydroindole alkaloids. The key
step is the Michael additions to nitroethylene 10 with
the corresponding kinetics and thermodynamics lithium
enolates of ketone 9, and the total syntheses of (()-γ-
lycorane and (()-crinane have been achieved. Application
of this methodology to other kinds of more complex
alkaloids is currently under investigation in our group.
known intermediate for the synthesis of 1.2b Finally, the
total synthesis of 1 was accomplished according to the
reported sequence through Bischler-Napieralski cycliza-
tion and the final lithium aluminum hydride reduction.2b
The successful synthesis of (()-γ-lycorane 1 encouraged
us to focus on another more challenging molecule, (()-
crinane (3), which contains a sterically congested qua-
ternary carbon center located at the hydroindolone
bridgehead, and a number of synthetic efforts have
emerged to address this problem.14 As shown in Scheme
3, our synthesis is started from the identical ketone 9,
which could be converted to the thermodynamics silyl
enol ethers 15 smoothly according to the reported pro-
tocol.15 By Li-Si exchange reaction of 15 with 1.0 equiv
Acknowledgment. We are grateful for the financial
support of the NSFC (Nos. 30271488, 20021001,
203900501) and the Cheung-Kong Scholars Program.
Supporting Information Available: Experimental pro-
cedures, spectroscopic and analytical data, and copies of NMR
spectra of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0507690
(14) For recent reviews on stereoselective construction of a quater-
nary carbon center, see: (a) Christoffers, J.; Mann, A. Angew. Chem.,
Int. Ed. 2001, 40, 4591. (b) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388. (c) Seebach, D.; Sting, A. R.; Hoffmann,
M. Angew. Chem., Int. Ed. 1996, 35, 2708. (d) Fuji, K. Chem. Rev. 1993,
93, 2037.
(15) Nakamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto, H. J. Am.
Chem. Soc. 2000, 122, 8120.
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96, 6179. (b) Dudley, G. B.; Danishefsky, S. J. Org. Lett. 2001, 3, 2399.
J. Org. Chem, Vol. 70, No. 16, 2005 6525