Total synthesis of (-)-stemospironine.

Article abstract of DOI:10.1021/ol016336a

[structure: see text]. A stereocontrolled total synthesis of the polycyclic Stemona alkaloid, (-)-stemospironine (1) has been achieved. Key transformations include the use of a Staudinger reaction leading to the aza-Wittig ring closure of the perhydroazepine system. Formation of the vicinal pyrrolidine butyrolactone is described via the stereoselective intramolecular capture of an intermediate aziridinium salt.

Full text of DOI:10.1021/ol016336a

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2721-2724
Total Synthesis of (−)-Stemospironine
David R. Williams,* Mark G. Fromhold, and Jill D. Earley
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received June 22, 2001
ABSTRACT
A stereocontrolled total synthesis of the polycyclic Stemona alkaloid, (−)-stemospironine (1) has been achieved. Key transformations include
the use of a Staudinger reaction leading to the aza-Wittig ring closure of the perhydroazepine system. Formation of the vicinal pyrrolidine
butyrolactone is described via the stereoselective intramolecular capture of an intermediate aziridinium salt.
The roots and rhizomes of the plant family Stemonacae have
provided a rich source of approximately 50 structurally novel,
polycyclic alkaloids.1 Interest in these substances, broadly
described as Stemona alkaloids, originally stemmed from the
use of plant materials in herbal teas used in Chinese folk
medicine and from the extraordinary insecticidal activity
detected among various alkaloids of the class.2 Since the first
complete structural elucidation of a Stemona alkaloid in
1967,3 each example has been characterized with the
identification of the 1-azabicyclo[5.3.0]decane nucleus em-
bedded within the overall molecular architecture. In 1989,
we achieved the first synthesis of a prototypical Stemona
alkaloid as described by the enantiocontrolled total synthesis
of (+)-croomine.4 Over the past decade, a number of
ingenious strategies have inspired successful syntheses of
racemic stenine,5 (-)-stenine,6 (-)-stemoamide,7 as well as
its racemate,8 (+)-croomine,9 and (()-isostemofoline.10 Ad-
ditionally, related synthesis studies have recently been
described,11 and a route for the preparation of the pair of
racemic diastereomers, (()-stemonamide and (()-isostemon-
amide, has been reported.12 Stemospironine 1 was isolated
from methanolic extracts of the leaves of Stemona japonica,
and issues of relative and absolute stereochemistry were
unambiguously resolved by X-ray crystallographic analysis.13
Herein, we report the first total synthesis of 1 via the
stereoselective construction of a fully functionalized acyclic
carbon chain followed by sequential ring closure reactions.
Furthermore, our direct comparisons of naturally occurring
stemonidine 214 and synthetic 1 affirm the remarkable
(6) (a) Morimoto, Y.; Iwahashi, M.; Nishida, K.; Hayashi, Y.; Shirahama,
H. Angew. Chem., Int. Ed. Engl. 1996, 35, 904. (b) Wipf, P.; Kim, Y.;
Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106.
(7) (a) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett.
1994, 35, 6417. (b) Mori, M.; Kinoshita, A. J. Org. Chem. 1996, 61, 8356.
(c) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295.
(8) (a) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063.
(b) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119, 3409.
(9) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
(10) Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999,
121, 7431.
(11) (a) Jung, S. H.; Lee, J. E.; Joo, H. J.; Kim, S. H.; Koh, H. Y. Bull.
Korean Chem. Soc. 2000, 21, 159. (b) Rigby, J. H.; Laurent, S.; Cavezza,
A.; Heeg, M. J. J. Org. Chem. 1998, 63, 5587. (c) Wipf, P.; Goldstein, D.
M. Tetrahedron Lett. 1996, 37, 739. (d) Morimoto, Y.; Iwahashi, M. Synlett
1995, 1221. (e) Beddoes, R. L.; Davies, M. P. H.; Thomas, E. J. J. Chem.
Soc., Chem. Commun. 1992, 538.
(1) For recent examples, see: (a) Changying, Z.; Hongzheng, F.; Haimin,
L.; Jun, L.; Wenhan, L. J. Chinese Pharm. Sci. 1999, 8, 185. (b) Wenhan,
L.; Hongzheng, F. J. Chinese Pharm. Sci. 1999, 8, 1. (c) Zou, C.; Li, J.;
Lei, H.; Fu, H.; Lin, W. J. Chinese Pharm. Sci. 2000, 9, 113. (d) For a
related alkaloid, see: Sekine, T.; Ikegami, F.; Fukasawa, N.; Kashiwagi,
Y.; Aizawa, T.; Fujii, Y.; Ruangrungsi, N.; Murakoshi, I. J. Chem. Soc.,
Perkin Trans. 1 1995, 391.
(2) For recent reviews, see: (a) Pilli, R. A.; Ferreira de Oliveira, M.
Nat. Prod. Rep. 2000, 17, 117. (b) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat.
Prod. 1994, 57, 665.
(3) Harada, H.; Irie, H.; Masaka, N.; Osaki, K.; Oyeo, S. J. Chem. Soc.,
Chem. Commun. 1967, 460.
(4) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc.
1989, 111, 1923.
(12) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Org. Lett.
2001, 3, 2505.
(13) Murakoshi, S.; Sakata, K.; Aoki, K.; Chang, C. F.; Sakuri, A.;
Tamura, S. Agric. Biol. Chem. 1978, 42, 457.
(5) (a) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840. (b) Chen,
C.-Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236.
(14) Xu, R.-S.; Lu, Y.-J.; Chu, J.-H.; Iwashita, T.; Naoki, H.; Naya, Y.;
Nakanishi, K. Tetrahedron 1982, 38, 2667.
10.1021/ol016336a CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/03/2001

Scheme 1
similarities of these samples and support a detailed reex-
to O-coordinated allenic enolate 6a via localized exotherms
amination of stereochemical assignments purported for 2.
in the quenching process. Recent NMR investigations provide
evidence that thermodynamic equilibria may shuttle the initial
Z-organocopper intermediate through the allenoate to E-
alkenylcuprate 6b for stereospecific protonation.21 In our
studies, exclusive trans-addition affording E-R,â-unsaturated
ester 6 was observed upon slow warming from -78 to 23
°C prior to a protic quench and by the selection of the
isopropyl ester and the sterically demanding O-silyl protec-
tion (C8).22
Following fluoride-induced removal of the silyl ether, the
C8 allylic alcohol was treated with methyl iodide and sodium
hydride to yield the required methyl ether. This transforma-
tion occurred with no evidence for olefin isomerization as
facilitated via internal alkoxide conjugate addition and
elimination. Hydride reduction subsequently gave the desired
trisubstituted allylic alcohol 7, which provided a 90% yield
of oxiranes using the modified Sharpless asymmetric epoxi-
dation system as described by Zhou and co-workers.23 The
major epoxide 10 was isolated as a pure diastereomer
following flash silica gel chromatography of a mixture (4:1
ratio) of epoxide isomers. Oxidation of 8 with the Dess-
Martin periodinane,24 and in situ chain elongation via addition
of (carbomethoxymethylene)triphenylphosphorane yielded
E-unsaturated methyl ester 9 (60% for two steps).
The carbon connectivity of stemospironine was efficiently
assembled as shown in Scheme 1. Since the methyl substit-
uents of 1 at C11 and C16 could be incorporated into the target
structure from (S)-(+)-methyl 3-hydroxy-2-methylpropionate
and (R)-(-)-methyl 3-hydroxy-2-methylpropionate, respec-
tively, we sought to establish the C8, C9, C9a stereotriad at
an early stage. Beginning with the readily available ketone
3,15 chirality at C8 was introduced via Midland reduction16
of the conjugated ynone with (R)-Alpine-Borane,17 leading
to 4 (88% ee).18 The Grignard reagent 5 was prepared from
the corresponding bromide19 to set the stage for conjugate
addition to the acetylenic ester 4. It is widely appreciated
that such reactions of copper-catalyzed nucleophilic attack
proceed via syn addition at low temperatures.20 However,
the intermediate vinylic cuprate species can rapidly isomerize
(15) Ketone 3 was prepared by the addition of ethynylmagnesium
bromide to 4-benzyloxybutenal (THF, 0 °C, 80%) and subsequent Jones
oxidation at 0 °C (85%).
(16) Midland, M. M.; Tramontano, A.; Kazubski, A.; Graham, R. S.;
Tsai, D. J. S.; Cardin, D. B. Tetrahedron 1984, 40, 1371.
(17) Alpine-Borane is a trademark of Aldrich Chemical Co. Our
reductions were conducted with neat reagent, freshly prepared from (+)-
R-pinene (97% ee).
(18) Enantiomeric excess was determined using the Mosher ester analysis
of (R)-R-methoxy-R-(trifluoromethyl)phenyl acetates by proton NMR
integration of the acetylenic hydrogens. The minor (S)-isomer gave a signal
at 2.50 ppm whereas the major (R)-isomer appeared at 2.55 ppm. (See:
Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165.)
(19) The optically pure bromide and its corresponding Grignard reagent
5 were prepared from (S)-(+)-methyl-3-hydroxy-2-methylpropionate in four
steps (84% overall yield) via protection, hydride reduction, tosylation, and
exchange with LiBr (D’Antuono, J. Ph.D. Thesis, Indiana University, 1988).
For use of the related Gilman reagent, see: Williams, D. R.; Turske, R. A.
Org. Lett. 2000, 2, 3217.
(20) Selected examples: (a) Corey, E. J.; Katzenellenbogen, J. A. J. Am.
Chem. Soc. 1969, 91, 1851. (b) Piers, E.; Gavai, A. J. Org. Chem. 1990,
55, 2374. (c) Crimmins, M. T.; Nantermet, P. G.; Trotter, B. W.; Vallin, I.
M.; Watson, P. S.; McKerlie, L. A.; Reinhold: T. L.; Cheung, A. W. H.;
Steton, K. A.; Dedoponlou, D.; Gray, J. L. J. Org. Chem. 1993, 58, 1038.
(d) Millar, J. G. Tetrahedron Lett. 1997, 38, 7971.
The elaboration of the carbon skeleton began with reduc-
tion of the unsaturated ester and protection of the resulting
(21) Nilsson, K.; Andersson, T.; Ullenius, C.; Gerold, A.; Krause, N.
Chem. Eur. J. 1998, 4, 2051.
(22) The use of the tert-butyldimethyl silyl ether (TBS) at C8 was also
effective for production of the E-enoate. However, combinations of bulky
silyl ethers at C8 and ethyl/methyl esters analogous to 4 or the incorporation
of the desired C8 methoxy group in tandem with the choice of an isopropyl
ester resulted in mixtures of E/Z-products.
(23) (a) Wang, Z.-M.; Zhou, W.-S.; Lin, G.-Q. Tetrahedron 1987, 2935.
(b) Wang, Z.-M.; Zhou, W.-S. Synth. Comm. 1989, 2627.
(24) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
2722
Org. Lett., Vol. 3, No. 17, 2001

Scheme 2
primary alcohol as its corresponding pivaloate 10 (Scheme
membered imine for in situ reduction yielding azepine 17.
Finally, synthetic stemospironine 1 was produced by the
iodine-induced double cyclization reaction of 17. Our previ-
ous studies have documented the expected high regio- and
stereoselectivity for formation of trans-2,5-disubstituted
pyrrolidino iodides from related bis-homoallylic (Z)-N-
alkoxylalkenylamines.28 Nucleophilic anchimeric assistance
by the tertiary amine leads to aziridinium species 18 for
capture by the neighboring methyl ester for net retention of
C14 stereochemistry. Modest, albeit reproducible, yields
(30%) of synthetic 1 were isolated owing to the ease of over-
oxidation of the pyrrolidine product.29 Comparisons of
spectral data of our synthetic 1 ([R]24D) -7.5° (c 0.85 mg/
mL, CHCl3)) with data reported for natural (-)-stemospiro-
nine ([R]27D) -8.2° (c 0.92 mg/mL, CHCl3)) showed these
substances to be identical in all respects.30 In fact, these
efforts were guided by our previous total synthesis of (+)-
croomine (8-desmethoxystemospironine), for which we had
also secured unambiguous confirmation of stereochemical
assignments at C3, C9, C9a, and C14 through our independent
X-ray analysis.4
2). Selection of the tert-butyl ester blocking unit is significant
as bulky silyl ethers underwent facile cleavage in the
subsequent azide displacement reaction, which led to sub-
stantial amounts of tetrahydrofuran ring formation owing to
the proximate oxirane. This side reaction was completely
suppressed in the case of pivaloate 10 as epoxide opening
occurred in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi-
dinone (DMPU, Aldrich) with 5 equiv of solid ammonium
chloride to provide the azido alcohol 11 (85%). Saponifica-
tion of the ester followed by the Swern oxidation25 of the
resulting primary alcohol led to the isolation of a mixture
(3:1 ratio) of diastereomeric lactols 12 and hydroxy-aldehyde
in high yield. Treatment of this equilibrating mixture with
the triphenylphosphorane derived from 1326 in THF at -10
°C provided sole formation of Z-alkene 14. Hydrolysis of
the â-methoxyethyl ether was accomplished by treatment of
14 in THF with aqueous HCl at room temperature. Our
attempts to utilize various Lewis acids under mild conditions
proved problematic, featuring formation of a 1,3-dioxepane
as the major product.27 Subsequent removal of the primary
benzoate gave desired triol 15 for ring closure studies.
Oxidation of triol 15 proceeded in THF solution at -10
°C in the presence of a suspension of Celite via the dropwise
addition of a slight excess of Jones reagent (Scheme 3).
Dilution with ethyl acetate and filtration through Celite led
to a concentrate for treatment with ethereal diazomethane
directly yielding the lactone methyl ester 16 (80%). Cleavage
of the benzyl ether at low temperature was followed by
Dess-Martin oxidation23 of the resulting primary alcohol
to give the crucial azido-aldehyde intermediate for the aza-
Wittig process. Thus, a Staudinger reduction was initiated
by the addition of triphenylphosphine, leading to an aza-
ylide for intramolecular condensation providing a seven-
Scheme 3
(25) Mancuso, A. J.; Huang, S. L.; Swern, D. J. J. Org. Chem. 1978,
43, 2480.
(26) The requisite phosphonium salt 13 was prepared from known (2S)-
2-methyl-4-penten-1-ol (see: Evans, D. A.; Bender, S. L.; Morris, J. J. Am.
Chem. Soc. 1988, 110, 2506). Formation of the benzoate, ozonolysis, and
sodium borohydride reduction gave the primary alcohol for conversion to
the corresponding iodide and triphenylphosphine displacement. Details will
be provided in the full account of this work.
(27) Formation of the seven-membered cyclic ether occurs with retention
of stereochemistry at C9.
Org. Lett., Vol. 3, No. 17, 2001
2723

With assistance of colleagues in Shanghai,31 spectra and
a sample of (-)-stemonidine (2) were obtained, permitting
direct comparisons of proton NMR data with our synthetic
material. In this regard, we were unable to confirm differ-
ences in chemical shifts or coupling patterns. The remarkable
similarities of these samples support a claim that they share
a common structure, 1. Likewise, the comparisons in Table
1 for the 13C NMR data published for stemospironine and
the corresponding 13C NMR data that we have obtained for
synthetic 1 and (-)-stemonidine exhibit a close correlation.
However, we cannot eliminate the coincident possibility that
these natural products may be spirocyclic diastereomers.32,33
In summary, we have reported the first total synthesis of
(-)-stemospironine via an enantiocontrolled pathway featur-
ing a trans-selective conjugate addition, an intramolecular
aza-Wittig process, and the iodine-initiated, single-step
formation of the pyrrolidino butyrolactone system.
Table 1. Comparisons of 13C NMR Data (δ Values in CDCl3)
stemospironine13
synthetic 1
stemonidine
179.5 (2)
90.5
85.2
80.0
67.7
63.1
58.0
48.9
35.7
35.0
35.0
34.6
27.0
26.5
25.7
22.4
17.5
14.8
179.4 (2)
90.5
85.3
80.0
67.7
63.0
58.0
48.8
35.7
35.1
35.0
34.6
27.0
26.5
25.7
22.3
17.6
14.8
179.3 (2)
90.3
85.2
80.0
67.7
63.0
58.0
48.9
35.7
35.1
35.0
34.6
27.0
26.5
25.6
22.3
17.6
14.8
(28) Williams, D. R.; Osterhout, M. H.; McGill, J. M. Tetrahedron Lett.
(a) 1989, 30, 1327; (b) 1989, 30, 1331.
(29) Previously we had shown (ref 4) that it was advantageous to
introduce limited amounts of iodine solution and quench cyclizations at
approximately 50% completion, yielding the desired product (30-35%) and
recovered starting material (50-55%) for resubmission. In the case of
stemospironine, limited quantities of 18 precluded this approach, and the
complete consumption of starting alkene led to numerous polar byproducts.
(30) Although we were unable to procure a sample of stemospironine
from the original laboratories (ref 12), our synthetic material provided spectra
and physical data which were completely consistent with data reported for
the natural product as assigned by X-ray diffraction.
Acknowledgment. The authors gratefully acknowledge
the National Institutes of Health (GM-41560) and, in part,
the National Science Foundation (CHE86-18955) for the
generous support of our work.
(31) We gratefully acknowledge the assistance of Professor Yang Ye,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, for
providing spectra and an authentic sample of (-)-stemonidine.
(32) Professor R.-S. Xu has indicated ongoing revisions of 2. See: He,
X.; Lin, W.-H.; Xu, R.-S. Acta Chim. Sin. 1990, 48, 694.
(33) We can visualize slight differences in the line art of the proton NMR
spectra of 1 and (-)-stemonidine (see Supporting Information). However,
small differences in chemical shifts and coupling constants are within the
tolerances and limits of error of our instrumentation. Small quantities of
these samples have precluded additional experiments.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 6-11, 14-17, and
synthetic 1 with comparison data and proton NMR spectra
for natural stemonidine. This material is available free of
charge via Internet at http://pubs.acs.org.
OL016336A
2724
Org. Lett., Vol. 3, No. 17, 2001