An Approach to the Synthesis of Stenine

Article abstract of DOI:10.1021/ol070397c

A type 2 N-acylnitroso intramolecular Diels-Alder reaction followed by reductive N - O bond cleavage formed the B and C rings of the Stemona alkaloid stenine. Further elaboration provided the functionalized tricyclic core.

Full text of DOI:10.1021/ol070397c

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2269-2271
An Approach to the Synthesis of
Stenine
Liang Zhu, Ryan Lauchli, Mandy Loo, and Kenneth J. Shea*
Department of Chemistry, Natural Sciences 1102, UniVersity of California IrVine,
IrVine, California 92697
kjshea@uci.edu
Received February 19, 2007
ABSTRACT
A type 2 N-acylnitroso intramolecular Diels−Alder reaction followed by reductive N−O bond cleavage formed the B and C rings of the Stemona
alkaloid stenine. Further elaboration provided the functionalized tricyclic core.
Extracts from the roots of stemonaceous plants (Stemona
and Croomia) have been used in China and Japan for
centuries as respiratory treatments for humans and as
anthelmintics for domestic animals.1 These extracts were
found to contain a wealth of complex alkaloids including
stenine (1), tuberostemonine (2), and stemoamide (3).2 These
larly challenging target to synthetic chemists.4 This challenge
has been answered in racemic form by Hart, Padwa, and
Aube´.5 To date, only Wipf and Morimoto have reported
enantioselective syntheses of this target.6 The difficulties of
this target lie in its fully substituted central cyclohexane ring,
(2) (a) Chung, H.-S.; Hon, P.-M.; Lin, G.; But, P. P.; Dong, H. Planta
Med. 2003, 69, 914. (b) Pilli, R. A.; da Conceic¸a˜o Ferreira De Olivera, M.
Nat. Prod. Rep. 2000, 17, 117.
(3) Some examples are: (a) Booker-Milburn, K. I.; Hirst, P.; Charmant,
J. P. H.; Taylor, L. H. J. Angew. Chem., Int. Ed. 2003, 42, 1642. (b)
Williams, D. R.; Shamim, K.; Reddy, J. P.; Amato, G. S.; Shaw, S. M.
Org. Lett. 2003, 5, 3361. (c) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am.
Chem. Soc. 2002, 124, 14848. (d) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc.
2000, 122, 4295. (e) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996,
118, 3299. (f) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem.
Soc. 1989, 111, 1923.
(4) Uyeo, S.; Irie, H.; Harada, H. Chem. Pharm. Bull. 1967, 15, 768.
(5) (a) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236. (b) Chen,
C.; Hart, D. J. J. Org. Chem. 1993, 58, 3840. (c) Ginn, J. D.; Padwa, A.
Org. Lett. 2002, 4, 1515. (d) Padwa, A.; Ginn, J. D. J. Org. Chem. 2005,
70, 5197. (e) Golden, J. E.; Aube´, J. Angew. Chem., Int. Ed. 2002, 41,
4316. (f) Zeng, Y.; Aube´, J. J. Am. Chem. Soc. 2002, 127, 15712.
(6) (a) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995,
117, 11106. (b) Morimoto, Y.; Nishida, K.; Hayashi, Y.; Shirahama, H.
Tetrahedron Lett. 1993, 34, 5773. (c) Morimoto, Y.; Iwahashi, M.; Nishida,
K.; Hayashi, Y.; Shirahama, H. Angew. Chem., Int. Ed. Engl. 1996, 35,
904. (d) Morimoto, Y.; Iwahashi, M.; Kinoshita, T.; Nishida, K. Chem.-
Eur. J. 2001, 7, 4107.
Stemona alkaloids provide attractive targets for total synthesis
due to their intriguing structures and the range of associated
biological activities.3 Stenine (1) has stood out as a particu-
(1) (a) Go¨tz, M.; Edwards, O. E. The Alkaloids; Academic Press: New
York, 1967; Vol. IX. (b) Go¨tz, M.; Strunz, G. M. Alkaloids: MTP
International ReView of Science, Series 1; Butterworths: London, England,
1973; Vol. IX. (c) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55,
571.
10.1021/ol070397c CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/10/2007

tricyclic core with an additional fused lactone ring, and seven
contiguous stereogenic centers.
Scheme 2
A common feature among many members of the Stemona
alkaloid class is the 7-membered azepane C ring. We have
recently found that azepanes can be accessed with control
of stereochemistry by a procedure utilizing a type 2 intra-
molecular Diels-Alder (T2IMDA) cyclization of a C-2
tethered diene joined to an acylnitroso dienophile. This
reaction gives rise to oxazinolactams.7 These cycloadducts
can be further elaborated by reductive cleavage of the N-O
bond to give azocin-2-ones. The T2IMDA method for
azepane construction could provide a general method for the
synthesis of Stemona alkaloids and their analogues. In this
Letter, we apply this strategy to the tricyclic BCD core of
stenine and lay the foundation for its total synthesis.
Our retrosynthetic analysis of stenine begins with the
removal of the lactone A ring and ethyl group on the B ring
to give the BCD core 4 (Scheme 1). On the basis of previous
methoxybenzoic acid (Scheme 2).8 The alcohol was protected
as the TBS ether. The ketone was treated with LDA and
then Tf2NPh to give triflate 10 in 58% yield. A Negishi
coupling was used to install the side chain at C-2 of the
cyclohexadiene ring.9 Diene 11 was converted to the corre-
sponding hydroxamic acid 8 by treatment with NH2OH‚HCl
and KOH. Oxidation of 8 by Bu4NIO4 at 0 °C generated an
acylnitroso species that underwent in situ cycloadditon. The
reaction is the first example of a cyclic diene as a participant
in the acylnitroso T2IMDA. The product, a 10:1 mixture of
diastereomers at C10, was isolated in 50% yield for the two
steps. Variation of temperature and solvent resulted in a
negligible effect on diastereoselectivity of the cycloaddition.
The two cycloadducts were found to be physically inseper-
able. The mixture of diastereomers was treated by Na/Hg in
the presence of Na2HPO4 to afford two separable products
in 51% yield. The structure of the desired major diastereomer
12 was confirmed by X-ray crystallography.
Scheme 1
work5,6 it was anticipated that both the A ring and the ethyl
group could be introduced at a late stage of the sequence.
Disconnection of the D ring of the tricyclic core 4 at the
C-N bond reveals the fused BC ring system 5. Further
disconnection to 6 by an adjustment at C11 and N-O bond
closure reveals the oxazinolactam. Compound 6 was expected
to be the product of a T2IMDA cyclization of acyclnitroso
7. Acyclnitroso 7 was anticipated to be accessible from
hydroxamic acid 8. The single stereocenter in 8 was expected
to control the π-facial selectivity of the cycloaddition and
ultimately all stereocenters in the molecule.
The synthesis of Diels-Alder cycloaddition precursor 8
began with 5-hydroxymethylcyclohex-2-enone 9, which was
obtained in three steps from commercially available tri-
(7) (a) Sparks, S. M.; Chow, C. P.; Zhu, L.; Shea, K. J. J. Org. Chem.
2004, 69, 3025. (b) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem.,
Int. Ed. 2001, 40, 820. (c) Sparks, S. M.; Vargas, J. D.; Shea, K. J. Org.
Lett. 2000, 2, 1473. (d) Chow, C. P.; Shea, K. J.; Sparks, S. M. Org. Lett.
2002, 4, 2637. For other applications of acylnitroso Diels-Alder reactions,
see: (e) Kibayashi, C.; Aoyagi, S. Synlett 1995, 873. (f) Streith, J.; Defoin,
A. Synthesis 1994, 1107. (g) Keck, G. E. Tetrahedron Lett. 1978, 19, 4767.
(h) Kirby, G. W. Chem. Soc. ReV. 1977, 6, 1.
Figure 1. ORTEP plot of compound 12.
Our next set of experiments focused on completion of the
tricyclic core. However, attempts to homologate the molecule
at C11 failed. It was concluded that it would be wise to
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Org. Lett., Vol. 9, No. 12, 2007

incorporate the two-carbon chain earlier in the synthesis. The
synthetic plan was revised to utilize known alcohol 13 as
the starting material.10 Alcohol 13 was protected as the TBS
ether to give intermediate 14 (Scheme 3). Ketone 14 was
Scheme 4
Scheme 3
ether was catalyzed by Ph3CBF4 to afford ether 21 in 60-
89% yield. Removal of TBS by HF and pyridine, followed
by tosylation and base-mediated cyclization, resulted in the
key tricyclic product 22.
In summary, the synthesis of the pivotal BCD ring system
of stenine has been achieved by an acylnitroso T2IMDA
cyclization. The key cycloadditions proceeded with good
selectivity in both instances to control stereochemistry of
the precursor to the azepane C ring in the natural product.
The tricyclic BCD core is set up for further elaboration
toward the total synthesis. In this approach, the stereocenter
in 13 sets subsequent asymmetric carbons. A large-scale
synthesis of enantioenriched 13 has been carried out by using
an enantioselective Michael addition.11 Enantioenriched 13
is currently being used for the enantioselective synthesis of
(-)-stenine. Future effort will be aimed at the completion
of the synthesis, as well as the exploration of applications
to other Stemona alkaloids.
kinetically deprotonated, and the resulting enolate was
trapped as TMS enol ether 15. Ether 15 was then oxidized
to enone 16 by using a Pd-mediated oxidation with diallyl
carbonate. Enone 16 was treated first with LDA and then
with Tf2NPh to give triflate 17 in 79% yield. Triflate 17
was treated with 4-ethoxy-4-oxobutylzinc bromide in the
presence of Pd2(dba)3, dppf, NMP, and Bu4NI to afford diene
18 in 76% yield. Diene 18 was converted to the correspond-
ing hydroxamic acid by treatment with NH2OH‚HCl and
KOH. Without further purification, oxidation and cyclo-
addition of the hydroxamic acid produced a 6:1 ratio of
diastereomers in 50% overall yield for the two steps.
The diastereomers were not separable, Treatment with Na/
Hg in the presence of Na2HPO4 afforded alcohol 20 and its
diastereomer in 61-76% combined yield (Scheme 4). The
desired major diastereomer could be purified by recrystal-
lization at this stage. Protection of alcohol 20 as the PMB
Acknowledgment. This research was supported by the
National Institutes of Health. We are grateful to Dr. Joseph
W. Ziller (UCI) for X-ray crystallographic work, Dr. Phil
Dennison (UCI) for NMR expertise, and Dr. John Greeves
(UCI) for mass spectral data. R.L. thanks the National
Institutes of Health for a predoctoral fellowship.
Supporting Information Available: Experimental details
and spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL070397C
(8) Smith, A. B., III; Richmond, R. E. J. Am. Chem. Soc. 1983, 105,
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