Total synthesis of (-)-stemonine

Article abstract of DOI:10.1021/ol035368q

(Matrix Presented) An enantioselective total synthesis of (-)-stemonine (1) is reported via a convergent assembly of the acyclic precursor 2. Key transformations include a Staudinger-aza-Wittig reaction to form the central perhydroazepine ring system and

Full text of DOI:10.1021/ol035368q

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3361-3364
Total Synthesis of (−)-Stemonine
David R. Williams,* Khalida Shamim, Jayachandra P. Reddy,
George S. Amato, and Stephen M. Shaw
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405-7102
williamd@indiana.edu
Received July 22, 2003
ABSTRACT
An enantioselective total synthesis of (−)-stemonine (1) is reported via a convergent assembly of the acyclic precursor 2. Key transformations
include a Staudinger−aza-Wittig reaction to form the central perhydroazepine ring system and an iodine-induced tandem cyclization to construct
the pyrrolidino-butyrolactone framework.
Stemona alkaloids represent a class of approximately 50
structurally novel, polycyclic metabolites isolated from
monocotyledonous plants comprising the genera of Stemona,
Croomia, and Stichoneuron.1 Chinese and Japanese folk
medicine has recorded the extensive use of extracts and
herbal teas of Stemonaceae as remedies of respiratory
diseases, including tuberculosis, and as anthelmintics.2 Dried
plant materials are utilized as powerful insecticidal materials
for treatment of livestock throughout East Asia.3 Stemonine
(1), an important secondary metabolite of Stemona japonica,
was isolated and investigated as early as 1929.4,5 However,
the characterization of relative and absolute stereochemistry
remained unresolved until the report of the X-ray crystal-
lographic study of stemonine hydrobromide hemihydrate by
Koyama and Oda in 1970.6 Progress toward the synthesis
of Stemona alkaloids was elusive and uneventful until our
account of the total synthesis of (+)-croomine in 1989.7
Recent years have been marked by achievements of sev-
eral notable total syntheses of members of this family.8
Herein we disclose the first report of the total synthesis of
(-)-stemonine (1) nearly 75 years after its initial discovery.
We have applied a thematic strategy for the preparation
of Stemona alkaloids that has sought to assemble a fully
functionalized acyclic carbon chain as a prelude to sequential,
late-stage ring closure reactions. Since each alkaloid is
characterized by the presence of a unique 1-azabicyclo[5.3.0]-
decane as an integral part of the molecular architecture, the
facile and stereocontrolled formation of this moiety is a key
issue. In the case of (-)-stemonine (1), our retrosynthetic
plan suggested a convergent construction of the acyclic
precursor 2 from optically pure butyrolactone 3 and homoal-
lylic iodide 4 (Scheme 1).
The convenient preparation of iodide 4 is summarized in
Scheme 2, utilizing known aldehyde 6.9 The nonracemic
tosylate 5 is readily available via hydroxyl protection of (R)-
(-)-methyl-3-hydroxy-2-methyl propionate followed by hy-
(1) Dahlgren, R. M. T.; Clifford, H. T.; Yeo, P. F. The Families of the
Monocotyledons. Structure EVolution and Taxonomy; Springer-Verlag:
Berlin, 1985.
(2) (a) Sakata, K.; Aoki, K.; Chang, C.-F., Sakurai, A.; Tamura, S.;
Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457. (b) Shinozaki, H.; Ishida,
M. Brain. Res. 1985, 334, 33. (c) Ye, Y.; Qin, G.-W.; Xu, R.-S.
Phytochemistry 1994, 37, 1205.
(3) For recent reviews, see: (a) Pilli, R. A.; Ferriera de Oliviera, M.
Nat. Prod. Rep. 2000, 17, 117. (b) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat.
Prod. 1994, 57, 665.
(7) Williams, D. R.; Brown, D. L.; Benbow, J. M. J. Am. Chem. Soc.
1989, 111, 1923
(8) (a) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001,
3, 2721. (b) Padwa, A.; Gin, J. D. Org. Lett. 2002, 4, 1515. (c) Kende, A.
S.; Hernando, J. I. M.; Milbank, J. B. J. Tetrahedron 2002, 58, 61. (d)
Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848
(e) Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999, 121,
7431 and refs cited therein.
(4) Suzuki, K. J. Pharm. Soc. Jpn. 1929, 49, 457.
(5) Suzuki, K. J. Pharm. Soc. Jpn. 1931, 51, 419
(6) Koyama, H.; Oda, K. J. Chem. Soc. B. 1970, 1330.
(9) White, J. D.; Reddy, N. G.; Spessard, G. O. J. Am. Chem. Soc. 1988,
110, 1624.
10.1021/ol035368q CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003

Scheme 1. Retrosynthetic Analysis of (-)-Stemonine
Scheme 3 a
Scheme 2 a
aReaction conditions: (a) To a 0.25 M solution of 9 in Et2O at
-78 °C was added 3, 0.5 h; then collidine, TBSOTf, -78 °C to
room temperature, 86%. (b) LiEt3BH, THF, -78 °C to room
temperature, 94%, anti:syn ) 17:1. (c) MsCl, pyridine, rt, 95%.
(d) NaN3 (3 equiv), 15-crown-5 (3 equiv), HMPA, rt, 65%. (e)
TBSOTf, collidine, -78 °C, 97%. (f) Me2BBr, CH2Cl2, Et3N (0.3
equiv), -78 °C, 5 min, 76%. (g) Dess-Martin periodinane,
t
NaHCO3, CH2Cl2, rt. (h) NaClO2, NaH2PO4, BuOH, CH3CN,
2-methyl-2-butene, 0 °C. (i) CH2N2, Et2O, 83% (three steps).
a Reaction conditions: (a) NaCN, DMSO, 70 °C. (b) DIBAL,
Et2O, -78 °C to room temperature, then H3O+, 86% (four steps).
(c) To 7 was added KHMDS, Et2O, -78 °C, then 6. (d) TBAF,
THF, 0 °C to room temperature. (e) PPh3, I2, imidazole, CH2Cl2, 0
Introduction of enantiopure lactone 312 into a 0.25 M
solution of 9 at -78 °C (Scheme 3) efficiently provided a
single carbonyl addition reaction, which permitted in situ
t
°C, 80% (two steps). (f) BuLi, -78 °C.
t
protection of the resulting primary alkoxide as the butyl-
dimethylsilyl ether 10 in 86% overall yield from iodide 4.
Reduction of ketone 10 with lithium triethylborohydride
(Super Hydride) at -78 °C proceeded with high diastereo-
selectivity, yielding 11 as the major product (17:1 dr). The
(R)-configuration of the C9a alcohol 11 was rationalized as
the expected product of Felkin-Anh addition where the C8
carbon appendage bearing the â-TBS ether is designated as
the large substituent. Since the reduction yielded 1,3-anti and
1,3-syn diol derivatives, the assignment of stereochemistry
was confirmed by 13C NMR analysis of the corresponding
acetonides following deprotection of the secondary TBS
ether.13
dride reduction (LiAlH4) and conversion to 5. Cyanide
displacement followed by DIBAL reduction provided 6,
which was subjected to a Wittig reaction with ylide generated
from phosphonium salt 710 to afford (Z)-olefin 8 in 85% yield
and 95:5 Z:E selectivity. The (Z)-isomer was purified via
flash silica gel chromatography and transformed to iodide 4
uneventfully. This sequence of five steps from 5 provided
iodide 4 in high purity on a preparative scale with excellent
overall yield (59%).
The condensation of components 3 and 4, which required
formation of an effective homoallyl carbanion, was initially
problematic. Halogen-metal exchange of the corresponding
bromide of 4 to provide an active organolithium or Grignard
species led to several observed side products, including E2
elimination and protonation, as well as Wurtz coupling.
These difficulties were overcome by modification of the
procedures of Bailey11a and Negishi11b for essentially quan-
Stereocontrolled introduction of nitrogen was accom-
plished by azide displacement of the C9a mesylate of 12
(12) Lactone 3 has been previously described via the asymmetric aldol
condensation of imide i to give ii followed by silyl ether cleavage. Williams,
D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417.
t
titative metalation of 4 to 9 (Scheme 2) using butyllithium
(2.05 equiv added dropwise) in diethyl ether at -78 °C.
(10) (a) Pattenden, G.; Wiedenau, P. Tetrahedron Lett. 1997, 38, 3647.
(b) Boutellier, M.; Wallach, D.; Tamm, C. HelV. Chim. Acta 1993, 76, 2515.
(11) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404. (b)
Negishi, E.-I.; Swanson, D. R.; Rousser, C. J. J. Org. Chem. 1990, 55,
5406.
(13) (a) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron
Lett. 1990, 31, 7099.
3362
Org. Lett., Vol. 5, No. 18, 2003

Scheme 4 a
t
a Reaction conditions: (a) DDQ, CH2Cl2, BuOH, H2O, rt, 56%. (b) Dess-Martin periodinane, NaHCO3, CH2Cl2, rt, 86%. (c) EtPPh2,
benzene, rt, 18 h; the mixture was then concentrated in vacuo, and THF, NaBH4, and MeOH were added, 70%. (d) I2, CH2Cl2/Et2O (2.5:1),
rt, 48 h, 42%. (e) TBAF, THF, rt, 77%. (f) Dess-Martin periodinane, NaHCO3, CH2Cl2, rt, 69%. (g) CrO3, aq H2SO4, acetone, THF, rt,
68%.
(Scheme 3). In fact, a number of issues were overcome to
ensure the feasibility of this SN2 process. Initially, solvents
that provided for the dissolution of 12 and sodium or lithium
azide, including combinations of THF and 2-propanol,
ethanol, or NMP and DMPU, led to very poor yields of 13.
Reactions in anhydrous HMPA (NaN3; 6 equiv) at 40 °C
gave approximately 40 to 45% yields of 13 and significant
amounts (30-35%) of the corresponding C11 primary alcohol
14, as well as several minor products. Shorter reaction times
at elevated temperatures resulted in reduced yields of 13 and
products of intramolecular 1,3-dipolar cycloaddition. Ex-
perimentally, it was found that the addition of equimolar
quantities of 15-crown-5 facilitated reactions at 22 °C with
a 50% reduction of the starting sodium azide (3 equiv) to
yield desired 13 (65%).14 Varying amounts of mesylate 12
(10-15%) were recovered along with 15% of the C11 alcohol
14. On a preparative scale, protection of the latter, followed
by subjection of recovered mesylate to the reaction condi-
tions, provided azide 13 in an overall yield of 82%. Selective
cleavage of the C16 methoxymethyl ether in the presence of
the C11 primary TBS ether necessitated the inclusion of
triethylamine during brief exposure of 13 to Me2BBr at low
temperature.15 The resulting C16 alcohol was oxidized and
converted to the methyl ester, which provided for the fully
functionalized acyclic precursor 15.
treatment of 15 with DDQ16 (Scheme 4), and subsequent
Dess-Martin oxidation yielded aldehyde 2.17 Cyclization to
the perhydroazepine 16 via the Staudinger reaction of
aldehydic azide 2 with ethyldiphenylphosphine proceeded
with nitrogen evolution and generated the seven-membered
imine by an intramolecular aza-Wittig process.18 After imine
formation, reactions were concentrated in vacuo, and the
addition of THF was followed by an immediate reductive
quench with NaBH4 (1.5 equiv) and methanol (1.5 equiv)
giving the amine 16 (70% yield). Stereocontrolled formation
of the pyrrolidino-butyrolactone C-D ring system occurred
in a single step as a consequence of an iodine-induced
cyclization. Treatment of amine 16 with I2 in a solution of
CH2Cl2 and Et2O (2.5:1) for 48 h at 22 °C led to formation
of 19 in reproducible yields of 42% along with 20% recovery
of starting material. Excellent stereoselectivity is observed
by kinetic formation of 2,5-trans-disubstituted pyrrolidine 17
following the highly reversible π-complexation of iodine.19a
The tertiary amine can initiate a nucleophilic backside
(14) Optimal results were obtained with freshly opened bottles of 15-
crown-5 (Aldrich), which may provide traces of water. However, older
bottles of 15-crown-5 led to reduced yields of 15. Small amounts (4-8%)
of the tetrahydrofuran i were also obtained as a minor product.
The systematic ring closure of 15 to provide natural
product 1 relied upon our prior experience in the case of
(+)-croomine.7 Attempted removal of the C5 benzyl ether
of 15 by brief exposure to boron trichloride in CH2Cl2 at
-78 °C in the presence of Proton Sponge followed by the
addition of cold MeOH gave the desired alcohol, which was
contaminated by diol resulting from cleavage of the primary
TBS group. This task was cleanly accomplished upon
(15) (a) Guidon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983,
24, 3969. (b) Guidon, Y.; Morton, H. E.; Yoakim, C. J. Org. Chem. 1984,
49, 3912.
(16) Schreiber, S. L.; Ikemoto, N. J. Am. Chem. Soc. 1992, 114, 2535.
(17) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(18) Imine could be isolated following rapid purification via flash silica
gel chromatography but decomposed within 2 h at room temperature.
Spectral data for characterization of the imine are included in Supporting
Information.
Org. Lett., Vol. 5, No. 18, 2003
3363

displacement of the vicinal iodide in 17 leading to aziri-
dinium salt 18.19b This event ensures net retention of C13
stereochemistry, as the ester carbonyl participates in buty-
rolactone ring closure, yielding 19. Excess iodine, utilized
in attempts to consume all starting amino-alkene, led to
multiple side products from further oxidations. In the course
of these studies, the A ring trans-fused lactone related to 16
was readily obtained via the Staudinger reaction. However,
the analogous iodine-induced cyclization was not observed,
giving way to slow oxidative decomposition of the starting
azepine.
ring closure event. Nitrogen lone pair inversion leads to the
consideration of structures 23 and 24, but both of these
conformers have nonbonded eclipsing interactions of C1 and
R1. In addition, the (Z)-olefin places R2 under the azepine
ring in a reaction profile developed from 23.
Finally, the synthesis of 1 was completed by simultaneous
deprotection of TBS ethers at C8 and C11 followed by Dess-
Martin oxidation,20 which resulted in isolation of the stable
lactol 20. Brief exposure to Jones reagent gave synthetic (-)-
stemonine (1), which proved to be identical in all respects
to an authentic sample.21
We speculate that conformations of the azepine must
permit a favorable backside trajectory for intramolecular
opening of the iodonium complex, which provides for the
minimization of nonbonded interactions. Our models (Figure
1) indicate that the trans-2,5-pyrrolidine 17 is favored via
In summary, a highly stereocontrolled total synthesis of
(-)-stemonine (1) has been accomplished in 23 steps along
the longest linear sequence from known materials. We have
documented the preparative generation of a useful homoal-
lyllithium reagent via iodide-lithium exchange. Efforts have
demonstrated the use of the Staudinger reaction as a versatile
technique for the synthesis of complex alkaloids, and our
overall concept for the tandem, iodine-induced cyclization
of the pyrrolidino-butyrolactone system has proven to be
particularly noteworthy for its bond constructions and
stereoselectivity.
Acknowledgment. We thank Bryan Stroup for his
assistance in preparing 3 and 4 and gratefully acknowledge
the National Institutes of Health (GM-41560) for generous
support of this work.
Supporting Information Available: Experimental details
for compound 16, spectral data for coumponds 4, 6, 10, 11,
13, 15, 16, 19, and 1, and the proton NMR spectrum of
synthetic 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL035368Q
Figure 1.
(19) (a) Williams, D. R.; Osterhout, M. H.; McGill, J. M. Tetrahedron
Lett. 1989, 30, 1327. (b) Williams, D. R.; Osterhout, M. H.; McGill, J. M.
Tetrahedron Lett. 1989, 30, 1331.
(20) Selective oxidation of the C11 primary alcohol over the secondary
C8 alcohol was possible by portionwise (0.5 equiv at a time) addition of
Dess Martin periodinane under buffered conditions (10 equiv of NaHCO3)
with careful monitoring by TLC.
(21) We gratefully acknowledge Professor Yang Ye of Shanghai Institute
of Materia Medica for kindly providing an authentic sample of (-)-
stemonine, as well as 1H NMR, IR, and mass spectra of the natural product.
the iodonium species derived from conformer 21, in which
R1 and OTBS substituents on the azepine ring are pseu-
doequatorial and allylic A(1,3) strain is minimized. A reversal
of face selectivity, leading to cis-2,5-pyrrolidine, would stem
from conformer 22. However, the geometry of the (Z)-olefin
in 22 creates nonbonded interactions of C5 and R2 in the
3364
Org. Lett., Vol. 5, No. 18, 2003