Asymmetric total syntheses of tuberostemonine, didehydrotuberostemonine, and 13-epituberostemonine

Article abstract of DOI:10.1021/ja044280k

Detailed experimental approaches toward the pentacyclic Stemona alkaloids tuberostemonine and didehydrotuberostemonine and the close analogue 13-epituberostemonine are described. The syntheses originate with a hydroindolinone derivative that can be obtain

Full text of DOI:10.1021/ja044280k

Published on Web 12/03/2004
Asymmetric Total Syntheses of Tuberostemonine,
Didehydrotuberostemonine, and 13-Epituberostemonine
Peter Wipf* and Stacey R. Spencer
Contribution from the Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
Received September 20, 2004; E-mail: pwipf@pitt.edu
Abstract: Detailed experimental approaches toward the pentacyclic Stemona alkaloids tuberostemonine
and didehydrotuberostemonine and the close analogue 13-epituberostemonine are described. The syntheses
originate with a hydroindolinone derivative that can be obtained on a large scale in a single step from
carbobenzoxy-protected L-tyrosine. Highlights of the conversion of this hydroindolinone to the target
structures are the three-fold use of ruthenium catalysts, first in azepine ring-closing metathesis and then
in alkene isomerization and cross-metathesis propenyl-vinyl exchange, as well as the stereoselective
attachment of a γ-butyrolactone ring to a tetracycle core structure by use of a lithiated asymmetric bicyclo-
[3.2.1]octane (ABO) ortho ester. Structural analysis by density functional theory (DFT) methods revealed
that the ease of oxidation of the natural product is likely due to the conformational preferences of the
pyrrolidine and the fused cyclohexane rings.
Introduction
Natural products from Stemona and Croomia plants have
served as inspiration for chemical, biological, and synthetic
studies since at least the 1930s, when the first derivatives were
described in the western literature.1-7 Extracts from these plants
have been used for centuries in eastern cultures for the treatment
of various respiratory problems, such as pertussis, bronchitis,
and tuberculosis (Figure 1). However, there is little validated
evidence for any beneficial human health effects of the pure
compounds, with the exception of insecticidal activities.6-10 In
particular, tuberostemonine was found to have a level of activity
as a feeding deterrent that rivaled that of azadirachtin.11 Since
the pioneering total synthesis of croomine in 1989 by Williams
et al.,12 a large number of synthetic studies have showcased
contemporary strategies and methodologies in innovative ap-
proaches toward these alkaloids.13-20 Recent noteworthy ex-
Figure 1. Selected examples of Stemona and Croomia alkaloids.
amplesincludethetotalsynthesesofstenine,21-25 stemoamide,26-30
and stemofoline.31,32
In 1934 and in 1936, tuberostemonine was first isolated from
Stemona tuberosa and Stemona sessifolia roots by two separate
groups.33-35 Bond connectivities were determined by Go¨tz’s and
(1) Lee, H. M.; Chen, K. K. J. Am. Pharm. Assoc. 1940, 29, 391.
(2) Edwards, O. E.; Feniak, G.; Handa, K. L. Can. J. Chem. 1962, 40, 455.
(3) Uyeo, S.; Irie, H.; Harada, H. Chem. Pharm. Bull. 1967, 15, 768.
(4) Lin, W.; Ye, Y.; Xu, R. J. Nat. Prod. 1992, 55, 571.
(5) Ye, Y.; Qin, G. W.; Xu, R. S. Phytochemistry 1994, 37, 1201.
(6) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17, 117.
(7) Ye, Y.; Velten, R. F. Tetrahedron Lett. 2003, 44, 7171.
(8) Sakata, K.; Aoki, K.; Chang, C. F.; Sakurai, A.; Tamura, S.; Murakoshi,
S. Agric. Biol. Chem. 1978, 42, 457.
(18) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. J. Org. Lett. 2001, 3,
2505.
(19) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721.
(20) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. J. Tetrahedron 2002, 58,
61.
(21) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840.
(22) Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106.
(23) Morimoto, Y.; Iwahashi, M.; Kinoshita, T.; Nishida, K. Chem. Eur. J. 2001,
7, 4107.
(9) Maruyama, M.; Takeda, K. Comp. Biochem. Physiol., C: Pharmacol.,
Toxicol. Endocrinol. 1994, 107C, 105.
(10) Jiwajinda, S.; Hirai, N.; Watanabe, K.; Santisoprasi, V.; Chuengsamarnyart,
N.; Koshimizu, K.; Ohigashi, H. Phytochemistry 2001, 56, 693.
(11) Brem, B.; Seger, C.; Pacher, P.; Hofer, O.; Vajrodaya, S.; Greger, H. J.
Agric. Food Chem. 2002, 50, 6383.
(24) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515.
(25) Golden, J. E.; Aube´, J. Angew. Chem., Int. Ed. 2002, 41, 4316.
(26) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35,
6417.
(27) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356.
(28) Kohno, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1996, 69, 2063.
(29) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295.
(30) (a) Gurjar, M. K.; Reddy, D. S. Tetrahedron Lett. 2002, 43, 295. (b) Sibi,
M. P.; Subramanian, T. Synlett 2004, 1211.
(31) Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999, 121,
7431.
(32) Brueggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.;
Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284.
(12) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989,
111, 1923.
(13) Xiang, L.; Kozikowski, A. P. Synlett 1990, 279.
(14) Beddoes, R. L.; Davies, M. P. H.; Thomas, E. J. J. Chem. Soc., Chem.
Commun. 1992, 538.
(15) Goldstein, D. M.; Wipf, P. Tetrahedron Lett. 1996, 37, 739.
(16) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
(17) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org. Chem. 1998,
63, 5587.
9
10.1021/ja044280k CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 225-235
225

A R T I C L E S
Wipf and Spencer
Figure 3. Retrosynthetic approach toward (-)-tuberostemonine.
skeleton of the target molecule. Upon air or Hg(II) oxidation
of tuberostemonine, oxotuberostemonine can be isolated,2 and
hypothetical but straightforward further C-C bond cleavage
reactions provide access to tuberostemonone as well as the key
intermediate 2. Strategic oxygenations of 2 followed by in-
tramolecular condensation reactions are envisioned to result in
the polycyclic scaffolds of stemoninine and parvistemonine.
We have recently completed the first total synthesis of (-)-
tuberostemonine.44 In contrast to our earlier approach toward
(-)-stenine,22 we planned for improved C(9)-chain extension
and azepine ring formation steps by the use of allylic electro-
philes for C- and N-alkylation, followed by a ring-closing
metathesis (RCM) reaction. Since the C(3)-butyrolactone is not
present in stenine, we also needed to devise an efficient protocol
for the installment of this moiety, which we decided to
accomplish with our fully protected homoenolate reagent 5
(Figure 3). The plan for the introduction of the remaining fused
butyrolactone and the ethyl side chain was to follow the stenine
precedence, i.e., use an amide acetal Claisen rearrangement of
the allylic alcohol in 3, followed by iodolactonization and Keck
allylation. Since the tyrosine carboxylate provides an ideal
handle for the introduction of the C(3)-butyrolactone and the
RCM was well precedented for azepine formation,45 we
expected a successful realization of this retrosynthetic strategy
toward (-)-tuberostemonine in about the same number of steps
(26) that were necessary for (-)-stenine.
Figure 2. Unified retrosynthetic strategy toward Stemona alkaloids.
Feniak’s groups in the 1960s,2,36,37 and the final stereochemical
assignment was completed by Uyeo and co-workers in 1967,38
based on the X-ray structure of tuberostemonine’s methobromide
salt. In consideration of the years since this structural work has
been published, it is not surprising that reliable high-resolution
spectroscopic data for tuberostemonine are absent from the
literature. A few chemical shifts were reported from a 60 MHz
1H NMR taken in the 1960s.39 An optical rotation and mass
spectral data have been published more recently,4 but no 13C
NMR spectrum nor a complete listing of the 1H NMR chemical
shifts has been reported.2 This dearth of spectroscopic data added
to the challenge of the total synthesis of tuberostemonine in
that it necessitated a rigorous proof of the connectivity and
stereochemistry of the, at least in small quantities, unusually
labile final product.
In our studies toward the Stemona alkaloids, we envisioned
a unified approach toward the major structural classes repre-
sented by tuberostemonine, tuberostemonone, and parvistemo-
nine from the readily available amino acid L-tyrosine by a series
of oxidative cyclizations and bond cleavage reactions (Figure
2). Specifically, hypervalent iodine oxidation of L-tyrosine led
to the bicyclic cis-indolinone 1,40-43 which provided the core
Results and Discussion
Synthesis of the Hydroindole Core of Tuberostemonine.
One of the key transformations in our synthetic strategy toward
the Stemona alkaloids is the oxidative spirocyclization of
L-tyrosine.43b In the past, the scalability of this reaction has been
limited when methanol was used as both the solvent and the
nucleophile to open up the intermediate spirocycle generated
by the phenolic oxidation of 7 with iodobenzene diacetate.
Because the phenolic oxidation is an intramolecular cyclization,
it works best under dilute conditions. The highest yield (54%)
of 1 was obtained on a 500 mg scale with an optimum
concentration of 0.08 M (Scheme 1). A screen of polar solvents
(CF3CH2OH, CH2Cl2, MeNO2, etc.) revealed that nitromethane
was best suited for larger scale reactions (100 g) at higher
(33) Suzuki, K. J. Pharm. Soc. Jpn. 1934, 54, 573.
(34) Kondo, H.; Suzuki, K.; Satomi, M. J. Pharm. Soc. Jpn.1939, 59, 443.
(35) Schild, H. Ber. Dtsch. Chem. Ges. 1936, 69B, 74.
(36) Goetz, M.; Boegri, T.; Gray, A. H.; Strunz, G. M. Tetrahedron 1968, 24,
2631.
(37) Edwards, O. E.; Feniak, G. Can. J. Chem. 1962, 40, 2416.
(38) Harada, H.; Irie, H.; Masaki, N.; Osaki, K.; Uyeo, S. Chem. Commun. 1967,
460.
(39) Goetz, M.; Boegri, T.; Gray, A. H. Tetrahedron Lett. 1961, 707.
(40) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33, 5477.
(41) Wipf, P.; Kim, Y. J. Org. Chem. 1993, 58, 1649.
(42) Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195.
(43) (a) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677. (b) For a review
on oxidative spirocyclizations, see Rodriguez, S.; Wipf, P. Synthesis 2004,
2767.
(44) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848.
(45) (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (b)
Pernerstorfer, J.; Schuster, M.; Blechert, S. Synthesis 1999, 138.
9
226 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Asymmetric Total Syntheses of Plant Alkaloids
A R T I C L E S
Scheme 1. Optimization of the Oxidative Spirocyclization of
Scheme 3. Double Allylation of Bicycle 12
l-Tyrosine
Scheme 2. Optimization of the π-Allylpalladium Reduction
Sequence
cycle of the ruthenium carbene reagent and also protect the am-
ine from being deallylated under the reaction conditions. Grubbs
catalyst has been shown to remove allyl groups from tertiary
amines if the ring-closing metathesis reaction is comparatively
slow.49
The resulting alcohol 14 was oxidized under catalytic
tetrapropylammonium perruthenate/4-methylmorpholine N-oxide
(TPAP/NMO) conditions50 to give the enone in 88% yield
(Scheme 3). On large scale, the Parikh-Doering protocol51 with
sulfur trioxide-pyridine complex in the presence of triethy-
lamine and dimethyl sulfoxide (DMSO) was slightly superior
for the oxidation of this alcohol. The enone was allylated under
low-temperature potassium bis(trimethylsilyl)amide (KHMDS)
conditions (-90 °C) in the presence of excess allyl iodide to
give 15 as the only detectable diastereomer in 66% yield. The
enone carbonyl group was subsequently reduced under Luche
conditions (NaBH4, CeCl3‚7H2O) to generate allylic alcohol 16
in good yield.
In preparation for the introduction of the C(3)-butyrolactone,
alcohol 16 was converted into the rearranged dimethylamide
under standard Eschenmoser-Claisen conditions.52 The methyl
ester was converted into the Weinreb amide derivative 17 by
use of dimethylaluminum chloride and N,O-hydroxylamine
hydrochloride.53 In contrast to the usual reactivity pattern,54 the
dimethylamide proved to be more reactive to nucleophilic
addition than the Weinreb hydroxamate (Scheme 4). Bromide
18 was readily prepared in high overall yield from the
commercially available methyl-(S)-(+)-3-hydroxy-2-methyl-
propionate and converted to the alkyllithium derivative with
lithium naphthalenide.55,56 Upon in situ addition of the amide
17, the undesired ketone 19 was formed as the major product.
After a series of related nucleophilic additions, it became clear
that the dimethylamide in 17 was a generally more reactive
electrophile than the hydroxamate carbonyl function, and
therefore the synthetic plan was modified and the sequence of
concentrations (0.3 M). The O-benzoylated bicycle 9 was
obtained in 51% yield from the intermediate spirocycle 8.
Ketone 9 was reduced to the equatorial alcohol 10 under
Luche conditions.46 Due to the extraordinary air sensitivity of
the palladium-catalyzed allylic reduction47 of the benzoate,
freeze-pump-thawing of the solvent and highest quality
tributylphosphine were necessary to avoid quantitative formation
of the undesired elimination side product 11 (Scheme 2). A
surprisingly simple solution to this experimental problem was
identified by replacing tributylphosphine with the more stable,
crystalline tribenzylphosphine. The reaction no longer required
vigorous degassing and has successfully been performed on
batches as large as 47 g with no noticeable decrease in yield.
First-Generation Approach toward Tuberostemonine. The
optimized sequence shown in Schemes 1 and 2 provided access
to large quantities of bicycle 12. The allylic alcohol was pro-
tected as the silyl ether, and the benzyl carbamate was removed
under catalytic palladium(II) acetate/triethylsilane hydrogenoly-
sis conditions.48 This method allowed selective cleavage of the
carbobenzoxy (Cbz) group in the presence of the alkene and
provided amine 13 in 87% yield over two steps (Scheme 3).
The cinnamyl group was installed on the secondary nitrogen
by use of K2CO3 in toluene, and the silyl ether was removed
with tetrabutylammonium fluoride. A cinnamyl group was cho-
sen instead of an unsubstituted allyl group in order to direct
the initial ruthenium attack in the metathesis reaction toward
the C-allyl group. It was reasoned that this strategy would allow
a greater number and faster frequency of turnover in the catalytic
(49) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Org. Lett. 2001, 3,
3781.
(50) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
(51) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
(52) Wipf, P. In ComprehensiVe Organic Synthesis, Trost, B. M., Fleming, I.,
Paquette, L. A., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 5, pp 827-74.
(53) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(54) Sibi, M. Org. Prep. Proc. Int. 1993, 25, 15.
(46) Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848.
(47) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. J. Org. Chem. 1992,
57, 1326.
(55) Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron 1997, 53, 16575.
(56) Wipf, P.; Tsuchimoto, T.; Takahashi, H. Pure Appl. Chem. 1999, 71, 415.
(48) Birkofer, L.; Bierwirth, E.; Ritter, A. Chem. Ber. 1961, 94, 821.
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 227

A R T I C L E S
Wipf and Spencer
Scheme 4. Unexpected Reactivity of Dimethylamide 17
Figure 4. Second-generation retrosynthetic analysis of (-)-tuberostemo-
nine.
Scheme 6. Low-Yielding Selenolactonization of a Tetracyclic
Intermediate
Scheme 5. Modified Synthetic Approach to the C(3)-Butyrolactone
prior to the lactonization step to give tetracycle 24 in moderate
yield, but lactonizations failed on this substrate as well (Scheme
6). Only the less oxidizing conditions of a selenolactonization58
provided an identifiable product, but the yield could not be
improved above 20%.
Second-Generation Approach toward Tuberostemonine.
The remaining double bond in the azepine ring of 24 provided
a likely reason for the lack of success in the lactonization studies,
but since a regioselective hydrogenation of 24 failed, a modified
retrosynthetic approach was pursued next (Figure 4). The end
game still envisioned conversion of an allyl group to the ethyl
group and preparation of the allyl lactone from a halolactone.
However, the halolactonization would now be performed on a
dimethylamide intermediate resulting from 28, with only one
alkene remaining in the substrate. Ortho ester addition was
staged on an activated ester derived from tricycle 29, which
could originate from the earlier intermediate 15 by means of
an RCM reaction.
The ring-closing metathesis reaction of 15 initially utilized
Grubbs’ first-generation catalyst.59 While the reaction proceeded
in the presence of high loadings of this catalyst, it stopped at
about 50% completion. With the second-generation, dihydroimi-
dazole-containing catalyst 32,60 in contrast, the reaction pro-
ceeded very smoothly in 2-2.5 h with as little as 2 mol %
catalyst loading (Figure 5).
Claisen rearrangement and nucleophilic ortho ester addition was
reversed. After silylation of 16, the corresponding Weinreb
amide 20 indeed underwent anionic ortho ester addition in 76%
yield (Scheme 5). Reduction of ketone 21 with L-Selectride led
to a chelation-controlled 6-7:1 diastereomeric ratio of alcohols
that were subjected to ortho ester hydrolysis with TsOH in
MeOH. Under these conditions, the alcohol spontaneously
cyclized to form the lactone. TsOH also removed the silyl ether
protecting group from the allylic alcohol in preparation for the
Eschenmoser-Claisen rearrangement. Heating of substrate 22
in xylenes in the presence of N,N-dimethylacetamide dimethyl-
acetal provided the desired dimethylamide 23 in 79% yield.
With the tricyclic dimethylamide 23 in hand, the stage was
set for the formation of the remaining two rings in tuberoste-
monine. However, amide 23 was found to decompose upon
exposure to a diverse set of lactonization conditions, including
iodolactonization with buffered I2 or NIS, bromolactonization,
and selenolactonization. The decomposition products showed
the loss of some of the 1H NMR alkene signals, but the spectra
also showed that the dimethylamide moiety was still present
and presumably had not participated in the reaction. We
speculated that the failed lactonization might be due to the
presence of three reactive double bonds in the substrate.
Therefore, the ring-closing metathesis reaction57 was performed
Differentiation of the two alkene moieties in 30 was surpris-
ingly difficult. The usual selective hydrogenation conditions,
that is, Wilkinson’s catalyst, diimide reductions, hydroborations,
etc.,61 failed to achieve differentiation. Even though the enone
(58) Petragnani, N.; Stefani, H. A.; Valduega, C. J. Tetrahedron 2001, 57, 1411.
(59) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(60) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(57) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
9
228 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Asymmetric Total Syntheses of Plant Alkaloids
A R T I C L E S
Scheme 8. Conversion of Enone 34 into Tetracyclic Amide 37
Scheme 9. Model Epoxidation-Ethylation Sequence
Figure 5. Catalyst dependency of the metathesis of 15.
Scheme 7. Selective Alkene Reduction Strategy
a significant amount of product that appeared to result from
naphthalene addition to the substrate.
was much less electron-rich than the azepine alkene, the former
was sterically very accessible even to bulky hydrogen sources.
In general, mixtures of starting material, monohydrogenation
at each site, and dihydrogenation products were all observed in
the crude reaction mixtures. Finally, a method that proceeded
with excellent selectivity and 81% yield over three steps was
identified (Scheme 7). Protection of the enone as the thiophenol
adduct,62 hydrogenation of the azepine olefin by homogeneous
catalysis, and then elimination of thiophenol with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) to regenerate the enone63 provided
an overall yield comparable to or higher than what could have
been expected from a one-step procedure.
Most of the steps in the conversion of 34 to the tetracycle 37
proceeded analogously to the first-generation approach (Scheme
8). Luche reduction of the ketone and protection of the equatorial
alcohol as the TBS ether provided 35 as a single isomer. The
ester functionality was then converted into the Weinreb amide
in 94% yield, followed by the addition of the lithiated ortho
ester. With this substrate, it was beneficial to use lithium di-
tert-butylbiphenylide64 as the radical anion source for the
lithium-halogen exchange, resulting in a 95% yield of ketone
36. Under the standard lithium naphthalenide conditions, only
low yields (ca. 25%) of this ketone were obtained, along with
Ketone 36 was reduced with L-Selectride to give two
diastereomeric alcohols in a 7:1 ratio that were cyclized with
TsOH in methanol. The desired lactone 28 derived from the
major alcohol diastereomer was obtained in 57% yield over the
two steps. A small amount (10%) of the lactone derived from
the minor alcohol diastereomer was also isolated after metha-
nolysis. To avoid a late-stage regioselective R-methylation of
the fused butyrolactone, N,N-dimethylpropionamide dimethyl-
acetal was employed in the subsequent Eschenmoser-Claisen
rearrangement. This transformation succeeded but, as expected,
gave almost no diastereoselectivity (ca. 1.2:1) at the methylated
carbon. Moreover, separation of these epimers was not yet
possible at this stage in the synthesis.
Monoalkene 37 provided us with the opportunity to inves-
tigate an alternative strategy for the formation of the fused
butyrolactone ring and the introduction of the characteristic ethyl
side chain of Stemona alkaloids. The iodolactonization-
allylation approach pioneered by Hart and Chen21 in their
synthesis of (()-stenine was very effective in the stereoselective
formation of the desired C-C and C-O bonds but suffered
from the need to remove an extra methylene group at the end
of the synthesis. An alternative epoxidation-nucleophilic ring-
opening process could reduce the number of steps and streamline
the end game. This modification in the route was tested on
model system 38 (Scheme 9). Epoxidation with 3-chloroper-
oxybenzoic acid (m-CPBA) was directed to the R-face of the
cyclohexene ring by the dimethylamide. In the workup of this
reaction, a polymer-supported triphenylphosphine was used in
(61) (a) Tucker, C. E.; Rao, S. A.; Knochel, P. J. Org. Chem. 1990, 55, 5446.
(b) White, J. D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem. 1999,
64, 684. (c) Dirat, O.; Kouklovsky, C.; Langlois, Y. J. Org. Chem. 1998,
63, 6634.
(62) deGroot, A.; Peperzak, R. M.; Vader, J. Synth. Commun. 1987, 17, 1607.
(63) Asaoka, M.; Shima, K.; Fujii, N.; Takei, H. Tetrahedron 1988, 44, 4757.
(64) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 229

A R T I C L E S
Wipf and Spencer
Scheme 12. Keck Allylation of 42 and Metathesis Strategy for
Scheme 10. Attempted Epoxide-Based Butyrolactone Annulation
of 37
Allyl-Ethyl Side-Chain Conversion
Scheme 11. Selenolactonization of 37 and Selected Two-Carbon
Radical Trapping Agents
isolated products from these reactions were either recovered
starting material or the products resulting from elimination of
phenylselenide.
Since a two-carbon chain extension protocol remained elusive,
allylation presented the sole viable alternative. Allylstannanes
are much more reactive radical trapping agents than the vinyl
or acetylenic compounds 43-47,67 but the lack of reactivity of
selenide 42 and the apparent ease of the resulting radical to
undergo a 1,2-acyloxy rearrangement68 required the use of a
large excess of the stannane. AIBN and a 1:1 mixture of
allyltributyltin and trifluorotoluene (BTF) as the solvent provided
the desired alkene 48 in 70% yield as a mixture of C(13)-epimers
(Scheme 12). The cosolvent BTF was necessary because the
polar tertiary amine was not soluble in neat allyltributyltin, and
the more common solvents toluene and CCl4 gave even lower
conversions.
order to test the feasibility of avoiding the use of thiosulfate
with the tuberostemonine precursors. The 2:1 diastereomeric
mixture of epoxides was subsequently opened with 2 equiv of
triethylaluminum.65 The crude reaction mixture was heated
overnight at reflux in toluene, and a 69% yield of the
diasteromeric lactones 40a and 40b was recovered. The
improved diastereoselectivity (4:1) revealed that the R-methyl
isomer either closed more slowly or was epimerized to the
â-isomer under these reaction conditions.
Encouraged by the success of this model study, we attempted
an analogous conversion of alkene 37 (Scheme 10). However,
sequential exposure of 37 to m-CPBA, triphenylphosphine
workup, and then triethylaluminum led to the aromatized
compound 41 as the only identifiable product. The exact
regiochemistry of the ethyl substituent was not determined.
The sensitivity of 37 toward oxidation became fully apparent
when conditions for halolactonization were examined. A range
of conditions that had been successful on less substituted
intermediates led to decomposition similar to what had been
observed with 24. Fortunately, however, the milder PhSeCl in
a mixture of acetonitrile and water provided a good yield of
the selenolactone product 42 (Scheme 11). To avoid the
anticipated major decomposition in the oxidative conversion of
the allyl side chain to the ethyl group,21,22 we explored a number
of two-carbon radical trapping agents known in the literature.66
Attention was focused on reagents that would lead to vinyl
sulfones, which could be cleaved with Raney nickel, or vinyl
halides or triple bonds, which could be reduced to the desired
ethyl substituent. However, only trace amounts of desired
product were identified in the presence of 43-47. The major
Tetracyclic amide 37 was formed as an approximately 1.2:1
mixture of methyl isomers. As the synthesis progressed, the
minor isomer was slowly consumed. After the selenolactoniza-
tion, the ratio changed to approximately 2-3:1. The isomers
were separable after the Keck allylation, but the minor isomer
could never be isolated cleanly and proved to be quite unstable.
The major, more polar, isomer was isolated in 43% yield after
Keck allylation, and so this compound was carried on through
the rest of the sequence. The remaining task was to convert the
allyl side chain of 48 into the ethyl group of tuberostemonine.
Oxidative methods (osmium tetroxide/sodium periodate or
osmium tetroxide/NMO or ozonolysis) led to extensive decom-
position of 48. It became clear that a nonoxidative protocol for
the cleavage of the C-C bond and the conversion of the allyl
into the ethyl substituent had to be identified. We speculated
that this could be accomplished by selective isomerization of
the terminal to the internal alkene followed by a cross-metathesis
reaction with ethylene gas. This would generate a vinyl group
that could be hydrogenated to give the desired ethyl chain. Test
69
reactions on a simplified model system revealed that RhCl3
was the only catalyst that isomerized the olefin fairly well at
room temperature, but only Wilkinson’s catalyst70 and conditions
with Grubbs’ catalyst 32 that had been reported for the
(65) Calvani, F.; Crotti, P.; Gardelli, C.; Pineschi, M. Tetrahedron 1994, 50,
12999.
(66) (a) Keck, G. E.; Byers, J. H.; Tafesh, A. M. J. Org. Chem. 1988, 53, 1127.
(b) Cossu, S.; DeLucchi, O.; Durr, R.; Fabris, F. Synth. Commun. 1996,
26, 211. (c) Kraus, G. A.; Andersh, B.; Su, Q.; Shi, J. Tetrahedron Lett.
1993, 34, 1741. (d) Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem.,
Int. Ed. 1999, 38, 1943. (e) Xiang, J.; Fuchs, P. L. Tetrahedron Lett. 1998,
39, 8597.
(67) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.
(68) Crich, D.; Huang, X.; Beckwith, A. L. J. J. Org. Chem. 1999, 64, 1762.
(69) Nakamura, H.; Arata, K.; Wakamatsu, T.; Ban, Y.; Shibasaki, M. Chem.
Pharm. Bull. 1990, 38, 2435.
(70) Warmerdam, E.; Tranoy, I.; Renoux, B.; Gesson, J.-P. Tetrahedron Lett.
1998, 39, 8077.
9
230 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Asymmetric Total Syntheses of Plant Alkaloids
A R T I C L E S
Scheme 13. Stereo- and Regioselective Lactone Methylation
Figure 6. NOESY and coupling constant analysis support the assignment
of the (R)-stereochemistry at C(13) of 50.
isomerization of allyl ethers71 worked well in the presence of a
tertiary amine. Since 32 was found to be compatible with the
advanced intermediate 24, we selected this catalyst for both
isomerization of 48 and subsequent in situ cross metathesis/
hydrogenation.72 Internal alkene 49 was obtained in 81% yield
(Scheme 12).
The tertiary amine/metal incompatibility also became an issue
during the optimization of the cross-metathesis reaction on
compound 49. At first, use of a variety of different metathesis
catalysts, long reaction times, and continuous bubbling of
ethylene gas in methylene chloride and/or toluene at various
temperatures failed to give any of the desired vinyl compound.
Finally, upon protecting the basic amine as the tosylate salt and
using the second-generation Grubbs’ catalyst 32, a modest
amount of cross-metathesis product was obtained. The reaction
was quite sluggish (78 h), and it worked best if fresh catalyst
was added approximately every 12 h during the course of the
reaction. The ethylene gas was replaced by a hydrogen
atmosphere and the vinyl compound was hydrogenated to give
the final product 50 in a modest 21% overall yield. While this
sequence completed the assembly of the carbon and heteroatom
13). Allylic alcohol 28 was subjected to the standard Eschen-
moser-Claisen rearrangement with the acetamide acetal, and
selenolactonization of the resulting dimethylamide provided the
fused lactone 51. Keck allylation of this substrate proved once
again to be cumbersome. Under the conditions used earlier
(allyltributyltin, BTF, AIBN), a 1:1 mixture of the desired
product and some unidentified, less-polar compound was
obtained. We suspected that the latter compound contained a
six-membered bridged lactone that arose from a radical shift or
rearrangement,73 a side reaction that should be diminished by
maximizing the concentration of the radical-trapping agent. Poor
results resulted when the reaction was performed in neat
allyltributyltin, but reasonable yields (70%) were obtained with
neat allyltriphenyltin.
1
scaffold of tuberostemonine, H-1H correlation spectroscopy
1
(COSY), H-13C heteronuclear multiple quantum coherence
spectroscopy (HMQC), heteronuclear multiple bond correlation
(HMBC), nuclear Overhauser effect spectroscopy (NOESY), and
J-data revealed that the configuration at C(13) was (R), i.e.,
epimeric to the natural product (Figure 6).
At this stage, the introduction of the methyl substituent by
use of lithium diisopropylamide (LDA)/hexamethylphosphora-
mide (HMPA) conditions was envisioned to lead to the desired
stereoisomer by preferential exo-attack of methyl iodide. In the
presence of excess LDA/HMPA, a 76% yield of the dimethy-
lated compound 52 was isolated. The use of bulkier (LiTMP)
or less reactive bases (LiHMDS or LDA without HMPA) did
not provide good yields of the desired monomethylated product
27. Dimethylation was still a major side reaction if excess base
was used. In the presence of 1.1 equiv of the LDA/HMPA
complex, however, a 59% yield of 27 along with 11% of the
dimethylated product 52 and 22% of recovered starting material
53 were isolated.
When 27 was exposed to alkene isomerization conditions in
toluene at reflux, a moderate yield (40-50%) of the desired
isomerized compound 54 was obtained. This yield could be
significantly improved (85%) by lowering the reaction temper-
ature and using methylene chloride instead of toluene (Scheme
14). Due to the instability of this isomer observed in the C(13)-
epituberostemonine synthesis, it is likely that the higher reaction
temperature was causing decomposition at a much faster rate.
The conditions used previously in the cross-metathesis
reaction were also successful in this case, but it was found that
It should be noted that attempts were made to develop
conditions for a sequential one-pot isomerization, cross-me-
tathesis, and hydrogenation, but these were not successful.
Treating 48 with Grubbs’ catalyst 32 in the presence of ethylene
gas led to isolation of the isomerized compound 49 and some
dimerized compound resulting from cross-metathesis of the
starting material 48. Ethylene was never incorporated in the
product(s). The allyltritylamine additive, which was necessary
for high conversion to the isomerized compound, inhibited not
only the dimerization cross-metathesis pathway but also any
cross-metathesis with ethylene when used in one-pot reaction
trials.
Completion of the Total Synthesis of Tuberostemonine.
The formation of 13-epituberosteminine 50 raised serious
concerns about the feasibility of our route, since the diastereomer
of intermediate 37 with the natural configuration at C(13) was
gradually lost due to instability in the subsequent conversions.
Accordingly, we decided to introduce the C(13) stereocenter
after the Claisen rearrangement-lactonization sequence (Scheme
(71) Hu, Y.-J.; Dominique, R.; Das, K. S.; Roy, R. Can. J. Chem. 2000, 78,
838.
(73) (a) Crich, D.; Beckwith, A. L.; Filzen, G. F.; Longmore, R. W. J. Am.
Chem. Soc. 1996, 118, 7422. (b) Crich, D.; Huang, X.; Beckwith, A. L. J.
J. Org. Chem. 1999, 64, 1762.
(72) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123,
11312.
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 231

A R T I C L E S
Wipf and Spencer
Figure 7. NOESY and coupling constant analysis support the assignment
of the natural (S)-stereochemistry at C(13) of 26.
Scheme 14. Completion of the Total Synthesis of
(-)-Tuberostemonine
Figure 8. DFT [B3LYP6-31+g(d), MacGaussian] minimized low-energy
conformations.
material (Figure 7). Significantly, the C(13) methyl group
showed strong correlations to the C-11 and C-12 â-hydrogens.
It is interesting to consider possible reasons for the unusually
high rate of decomposition of tuberostemonine 26 vs the less
labile C(13)-epimer 50 and, in particular, the closely related
alkaloid stenine. Synthetic stenine that was obtained in 199522
and stored neat under air for 8 years did not show any signs of
decomposition, whereas tuberostemonine decayed within hours.
Epituberostemonine 50 decomposed more slowly than tubero-
stemonine, with a half-life of days vs hours, and was consider-
ably more resistant to chromatography on silica gel. We
hypothesize that these dramatically different chemical properties
derive from different spatial dispositions of the nitrogen lone
pair in these alkaloids. The chairlike six-membered ring of
tuberostemonine forces an anti orientation of the nitrogen lone
pair and the methine hydrogen at C(3) (Figure 8). The preference
for the chairlike conformation of 26 is confirmed by the solid-
state structure of this compound.38 For 13-epituberostemonine
50, the energy difference between the six-membered ring chair
and twist-boat conformations is small (<2 kcal/mol), based on
density functional theory (DFT) calculations. The twist-boat
conformation of the cyclohexane moiety results in a syn
orientation of lone pair and C(3) methine hydrogen. Stenine
has a less oxidation-prone methylene group at this position and
a very significant preference (>4 kcal/mol, DFT) for the twist-
boat cyclohexane conformation. The strong influence of con-
formational properties on the rate of oxidation R to a tertiary
nitrogen atom is nicely precedented in the chemistry of
Rauwolfia alkaloids (Scheme 15). Oxidation of the anti isomer
57 to iminium ion 58 proceeded in 85% yield, whereas exposure
of the syn isomer 59 yielded no reaction.75,76 It is possible that
the high reactivity of natural tuberostemonine toward oxidation
catalyst 55, reported by both Blechert and Hoveyda,74 gave a
slightly better yield. More importantly, the use of this catalyst
allowed isolation of the terminal alkene intermediate without
multiple chromatographic purifications. Use of the tricyclo-
hexylphosphine-containing catalyst 32 caused significant de-
composition during the extensive purifications needed to remove
all of the ruthenium and phosphine oxide side products either
at this stage or after the final hydrogenation. Catalyst 55 helped
to avoid this serious obstacle by facilitating workup. Because
of the consistently observed chromatography problems with
these late-stage intermediates, a separate hydrogenation step was
selected. Catalytic palladium on carbon in the presence of 1
atm of hydrogen allowed for the isolation and characterization
of tuberostemonine (26) without the need for any additional
chromatographic purifications. The methanol solution from the
hydrogenation step was simply filtered through Celite, and NMR
data were obtained immediately upon concentration. Attempts
to further purify this compound by silica gel chromatography
or recrystallization resulted in substantial contamination of the
sample with decomposed (mostly oxidized) impurities.
Extensive 2D NMR analyses, including NOESY and J-
determinations, confirmed the assignment of the synthetic
(74) (a) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41, 9973.
(b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(75) Weisenborn, F. L.; Diassi, P. A. J. Am. Chem. Soc. 1956, 78, 2022.
(76) For conformational effects in alkaloid oxidations, see also Suau, R.; Silva,
M. V.; Valpuesta, M. Tetrahedron 1991, 47, 5841.
9
232 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Asymmetric Total Syntheses of Plant Alkaloids
A R T I C L E S
Scheme 15. Conformation-Dependent Oxidation of Tertiary
Amines Observed in the Conversion of Isoreserpine to Reserpine
Further developments of these strategies toward the unified
synthesis of other polycyclic Stemona alkaloids are currently
in progress.
Experimental Section
General Methods. All moisture-sensitive reactions were performed
under an atmosphere of N2, and glassware was dried in an oven at 140
°C prior to use. Tetrahydrofuran (THF) and ether were dried by
distillation over sodium benzophenone, and dry CH2Cl2 and toluene
were obtained by distillation from CaH2. Unless otherwise stated,
solvents or reagents were used as received without further purification.
Abbreviations: ABO, asymmetric bicyclo[3.2.1]octane; AIBN, 2,2′-
azobis(isobutyronitrile); BTF, benzotrifluoride; DBU, 1,8-diazabicyclo-
[5.4.0]undec-7-ene; l-Selectride, tri-sec-butylborohydride.
8-Des-ethyl-8(S)-allyl-(-)-13-epituberostemonine (48). To a solu-
tion of 42 (27 mg, 0.054 mmol) and AIBN (2.7 mg, 0.016 mmol) in
R,R,R-trifluorotoluene (0.25 µL) was added allyltributyltin (0.25 µL).
The reaction mixture was heated at 95 °C and concentrated in vacuo,
and the residue was dissolved in MeCN (50 mL). The MeCN layer
was washed with hexanes (3 × 25 mL), concentrated in vacuo, and
purified by chromatography on SiO2 that had been pretreated with 9:1
hexanes/EtOAc containing 0.5% NEt3 (hexanes/EtOAc, 9:1 to 1:1 to
0:1) to give 5.6 mg (27%) of the minor diastereomer 27 and 9.1 mg
(43%) of the major diastereomer 48 as white foams. 48: [R]D -14.1
(c 0.79, CHCl3, 21 °C); IR (neat) 2922, 1771, 1172 cm-1; 1H NMR δ
5.78-5.69 (m, 1 H), 5.05-5.00 (m, 2 H), 4.22-4.14 (m, 1 H), 4.20
(d, 1 H, J ) 3.4 Hz), 3.32 (dd, 1 H, J ) 15.2, 6.0 Hz), 3.25-3.17 (m,
1 H), 3.16 (dd, 1 H, J ) 7.4, 4.0 Hz), 2.85-2.73 (m, 2 H), 2.66-2.54
(m, 1 H), 2.40-2.09 (m, 6 H), 2.00 (br d, 1 H, J ) 10.7 Hz), 1.82-
1.67 (m, 3 H), 1.61-1.23 (m, 4 H), 1.22 (d, 6 H, J ) 7.0 Hz), 1.11-
1.02 (m, 2 H); 13C NMR δ 179.3, 178.5, 136.2, 117.1, 83.3, 80.7, 65.0,
64.0, 50.3, 44.8, 44.1, 41.2, 40.3, 37.1, 35.0 (2C), 34.0, 33.4, 32.6,
29.5, 26.7, 14.8, 11.7; MS (EI) m/z (rel intensity) 387 (M+, 4), 344
(14), 288 (100), 246 (8), 134 (4), 91 (6), 81 (8); HRMS m/z calculated
for C23H33NO4 387.2410, found 387.2394.
(-)-13-Epituberostemonine (50). To a solution of 48 (21 mg, 0.054
mmol) in toluene (0.85 mL) were added allyltritylamine (34 mg, 0.11
mmol), ruthenium catalyst 32 (10 mg, 0.011 mmol), and N,N-
diisopropylethylamine (9.4 µL, 0.054 mmol). The reaction mixture was
heated at reflux for 15 h, concentrated in vacuo, and purified by
chromatography on SiO2 prewashed with a solution of 0.5% NEt3 in
hexanes/EtOAc (9:1) (hexanes/EtOAc gradient elution from 9:1 to 2:1
to 1:1 to 0:1) to give 17 mg (81%) of an (E,Z) mixture (ca. 2:1) of 49
as a yellow oil. A solution of this mixture of double-bond isomers (20
mg, 0.052 mmol) in CH2Cl2 (2.3 mL) was treated with p-toluenesulfonic
acid monohydrate (9.9 mg, 0.052 mmol) and stirred at room temperature
for 30 min. After addition of catalyst 32 (0.88 mg, 1.0 µmol), the
solution was heated at reflux while ethylene gas was bubbled through
it with additional portions of catalyst 32 (0.88 mg, 1.0 mmol) added
approximately every 12 h. After 78 h, the mixture was concentrated
slightly by bubbling ethylene through it without a condenser until ca.
1 mL of CH2Cl2 remained. Methanol (2 mL) was added, and the mixture
was hydrogenated for 17 h at room temperature, concentrated in vacuo,
and dissolved in EtOAc (25 mL). The organic layer was washed with
saturated NaHCO3 (2 × 25 mL), dried (MgSO4), concentrated in vacuo,
and purified by preparative TLC on SiO2 (EtOAc with 0.5% NEt3) to
give 4.0 mg (21%) of 50 as a white foam: [R]D -22.0 (c 0.061, acetone,
21 °C); IR (neat) 2923, 1764, 1178 cm-1; 1H NMR (500 MHz) δ 4.23-
4.18 (m, 2 H), 3.33 (dd, 1 H, J ) 15.2, 6.1 Hz), 3.22 (dt, 1 H, J ) 9.9,
7.0 Hz), 3.14 (dd, 1 H, J ) 11.4, 3.7 Hz), 2.85-2.78 (m, 2 H), 2.64
(dddd, 1 H, J ) 19.5, 10.3, 7.7, 7.1 Hz), 2.37 (ddd, 1 H, J ) 12.4, 8.5,
5.4 Hz), 2.27 (ddd, 1 H, J ) 10.9, 6.5, 4.4 Hz), 2.21 (dt, 1 H, J )
11.9, 6.0 Hz), 2.04-1.98 (m, 2 H), 1.82-1.73 (m, 3 H), 1.63-1.35
(m, 6 H), 1.28 (d, 6 H, J ) 6.8 Hz), 1.26 (br s, 1 H), 1.10 (q, 1 H, J
) 11.3 Hz), 1.01 (t, 3 H, J ) 7.4 Hz); 13C NMR (125 MHz) δ 179.5,
178.8, 83.4, 81.8, 65.4, 64.3, 50.8, 47.0, 45.3, 41.6, 40.2, 35.3, 34.3,
Scheme 16. Conversion of Tuberostemonine (26) to
Didehydrotuberostemonine (60)
at the pyrrolidine ring is important for the biological function
of this compound.
Conversion of Tuberostemonine (26) to Didehydrotubero-
stemonine (60). Natural tuberostemonine was converted to its
pyrrole derivative, didehydrotuberostemonine, through oxidation
of the natural product with silver(I) oxide.4 This compound has
also been isolated from Stemona tuberosa,77,78 and high-field
NMR data have recently been reported.77 Since very little
spectral data had been published on natural tuberostemonine, a
small amount of the synthetic material was converted to
didehydrotuberostemonine to allow spectral comparisons. Syn-
thetic 26, which unfortunately had already become strongly
contaminated with decomposition products, was subjected to
silver(I) oxide and provided ca. 30% of a pyrrole product with
NMR signals consistent with didehydrotuberostemonine (60).
This conversion established the first total synthesis of this
pyrrole and provided a chemical confirmation of the assignment
of the synthetic material as (-)-tuberostemonine (Scheme 16).
Conclusions
The first total synthesis of the Stemona alkaloid tuberoste-
monine has been achieved in 27 steps and ca. 1% overall yield
from Cbz-L-tyrosine. Highlights of the synthesis include the use
of a ruthenium carbene catalyst for three different key trans-
formations: a ring-closing metathesis reaction, a double-bond
isomerization, and a cross-metathesis reaction. The power of
the ABO ortho ester chemistry as a homoenolate equivalent to
install a chiral γ-butyrolactone moiety on a structurally complex
substrate has been showcased. The utility of the oxidative
cyclization reaction of Cbz-L-tyrosine has again been demon-
strated to provide a rapid entry into the complex bicyclic core
of the Stemona alkaloids. In the context of this synthetic study,
we have discovered a conformation-dependent lability of the
natural product toward oxidation of the pyrrolidine ring; a
process that is most likely of biological relevance and results
in the formation of the pyrrole didehydrotuberostemonine.
(77) Lin, W.; Fu, H. J. Chin. Pharm. Sci. 1999, 8, 1.
(78) Ye, Y.; Qin, G.-W.; Xu, R.-S. Phytochemistry 1994, 37, 1201.
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 233

A R T I C L E S
Wipf and Spencer
33.8, 32.9, 29.9, 29.8, 26.9, 25.9, 15.0, 13.2, 12.0; MS (EI) m/z (rel
intensity) 375 (M+, 0.6), 374 (1.4), 344 (1), 276 (100), 119 (5), 111
(8); HRMS m/z calculated for C22H32NO4 (M - H) 374.2331, found
374.2322.
to give 91.4 mg (59%) of 27 as a white foam along with 33.4 mg
(22%) of recovered 53 and 17.7 mg (11%) of 52. 27: [R]D -3.3 (c
0.17, CD2Cl2, 21 °C); IR (neat) 2920, 1771, 1455, 1171, 1013 cm-1
;
1H NMR (CD2Cl2) δ 5.91-5.72 (m, 1 H), 5.10-5.05 (m, 2 H), 4.40
(dd, 1 H, J ) 9.1, 7.8 Hz), 4.25 (ddd, 1 H, J ) 10.8, 7.8, 5.4 Hz),
3.45-3.35 (m, 2 H), 3.00 (dd, 1 H, J ) 11.1, 6.8 Hz), 2.68-2.47 (m,
2 H), 2.40-2.10 (m, 5 H), 2.00 (dt, 2 H, J ) 10.3, 7.8 Hz), 1.88-1.72
(m, 3 H), 1.69-1.38 (m, 6 H), 1.22 (d, 3 H, J ) 7.3 Hz), 1.19 (d, 3 H,
J ) 6.9 Hz), 1.13-1.01 (m, 1 H); 13C NMR (CD2Cl2) δ 179.7, 179.4,
135.9, 117.5, 81.8, 80.1, 65.2, 63.6, 48.0, 47.4, 43.9, 41.9, 41.3, 41.0,
35.9, 35.1, 34.8, 32.3, 30.1, 30.0, 28.9, 15.0, 14.9; MS (EI) m/z (rel
intensity) 388 ([M + 1]+, 3), 360 (5), 344 (16), 288 (100), 274 (22),
246 (14), 172 (8), 134 (8), 91 (19), 81 (15); HRMS m/z calculated for
C23H33NO4 387.2410, found 387.2395. 52: [R]D -27.6 (c 0.11, acetone,
N,N-Dimethyl-2R,S-[2S-(4S-methyl-5-oxotetrahydrofuran-2-yl)-
1,2S,4,5,6,7,7aS,10,10aR,10bS-decahydroazepino[3,2,1-hi]indol-10-yl)-
propionamide. To a solution of 28 (105 mg, 0.36 mmol) in xylenes
(10 mL) was added N,N-dimethylacetamide dimethylacetal (0.44 mL,
2.9 mmol). The reaction mixture was heated at 130-140 °C for 16 h,
concentrated in vacuo, and purified by chromatography on SiO2
(pretreated with 1:1 hexanes/EtOAc with 0.5% NEt3) (hexanes/EtOAc,
1:1 to 0:1 with 5% MeOH) to give 102 mg (78%) of the dimethylamide
as a yellow foam: [R]D -26.6 (c 0.42, CHCl3, 21 °C); IR (neat) 2916,
1
1772, 1642, 1153 cm-1; H NMR δ 5.55 (ddd, 1 H, J ) 9.5, 4.9, 2.2
1
21 °C); IR (neat) 2923, 1769, 1448, 1157 cm-1; H NMR (CD2Cl2) δ
Hz), 5.39 (br d, 1 H, J ) 9.8 Hz), 4.23 (ddd, 1 H, J ) 10.9, 7.5, 5.6
Hz), 3.45 (br d, 1 H, J ) 13.6 Hz), 3.34 (dd, 1 H, J ) 14.7, 8.0 Hz),
3.14 (dd, 1 H, J ) 10.6, 5.8 Hz), 2.96 (s, 3 H), 2.90 (s, 3 H), 2.70 (dd,
1 H, J ) 14.6, 11.5 Hz), 2.58-2.43 (m, 2 H), 2.37-2.28 (m, 3 H),
2.16 (dd, 1 H, J ) 15.2, 8.7 Hz), 2.00 (dt, 1 H, J ) 12.2, 6.5 Hz), 1.73
(br d, 2 H, J ) 12.0 Hz), 1.55-1.35 (m, 6 H), 1.19 (d, 3 H, J ) 6.9
Hz), 1.16-1.05 (m, 1 H); 13C NMR δ 179.6, 171.5, 131.9, 129.8, 82.5,
65.7, 63.7, 47.2, 42.0, 41.3, 39.0, 37.3, 35.3, 34.7, 34.3, 31.2, 30.8,
29.9, 28.2, 14.7; MS (EI) m/z (rel intensity) 360 (M+, 1.5), 274 (6),
261 (100), 172 (17), 149 (11), 130 (8), 105 (6), 91 (7), 72 (19); HRMS
m/z calculated for C21H32N2O3 360.2413, found 360.2405.
5.91-5.78 (m, 1 H), 5.09 (d, 1 H, J ) 5.8 Hz), 5.06 (s, 1 H), 4.41 (dd,
1 H, J ) 9.2, 7.8 Hz), 4.38-4.27 (m, 1 H), 3.46-3.35 (m, 2 H), 3.01
(dd, 1 H, J ) 11.0, 6.7 Hz), 2.67-2.59 (m, 1 H), 2.38 (pentet, 1 H, J
) 7.4 Hz), 2.26 (dd, 2 H, J ) 6.7, 5.8 Hz), 2.15 (dt, 1 H, J ) 13.8, 7.0
Hz), 2.05-1.96 (m, 2 H), 1.84-1.74 (m, 3 H), 1.67 (dd, 2 H, J )
12.6, 10.7 Hz), 1.54-1.42 (m, 5 H), 1.23 (d, 3 H, J ) 7.3 Hz), 1.21 (s,
3 H), 1.20 (s, 3 H), 1.08-0.98 (m, 1 H); 13C NMR (CD2Cl2) δ 182.1,
179.4, 136.0, 117.6, 80.4, 80.2, 65.5, 63.8, 48.1, 47.6, 44.1, 42.0, 41.4,
41.1 (2 C), 39.6, 36.1, 32.5, 30.2 (2 C), 29.0, 24.9, 24.5, 15.0; MS
(EI) m/z (rel intensity) 401 (M+, 1), 399 (2), 288 (100), 172 (7), 97
(8), 84 (37), 71 (22), 58 (46); HRMS m/z calculated for C24H35NO4
401.2566, found 401.2570.
8-Des-ethyl-8S-phenylseleno-(-)-tuberostemonine (51). To a 0 °C
solution of the above dimethylamide (99 mg, 0.27 mmol) in a 5:1
mixture of MeCN/water (3.8 mL) was added phenylselenyl chloride
(83 mg, 0.45 mmol). The reaction mixture was stirred at 0 °C for 20
h, quenched with a saturated NaHCO3 solution, and extracted into
EtOAc (3 × 30 mL) and CH2Cl2 (1 × 30 mL). The combined organic
layers were dried (MgSO4), concentrated in vacuo, and purified by
chromatography on SiO2 (hexanes/EtOAc, 9:1 to 1:1) to give 87 mg
(67%) of 51 as a white foam: [R]D -16.4 (c 0.61, CHCl3, 21 °C); IR
(neat) 2921, 1770, 1165, 916 cm-1; 1H NMR δ 7.53 (dd, 2 H, J ) 4.6,
2.0 Hz), 7.31-7.28 (m, 3 H), 4.54 (dd, 1 H, J ) 3.8, 2.5 Hz), 4.22
(ddd, 1 H, J ) 10.8, 7.6, 5.4 Hz), 3.72 (s, 1 H), 3.43-3.22 (m, 3 H),
2.78 (dd, 1 H, J ) 15.4, 10.1 Hz), 2.69-2.53 (m, 4 H), 2.39 (d, 1 H,
J ) 16.3 Hz), 2.39-2.31 (m, 1 H), 2.10 (dt, 1 H, J ) 11.8, 6.1 Hz),
1.81-1.70 (m, 4 H), 1.56-1.33 (m, 3 H), 1.25 (d, 3 H, J ) 7.0 Hz),
1.19-1.08 (m, 1 H); 13C NMR δ 179.3, 175.7, 133.6, 129.5, 129.4,
128.0, 83.4, 82.5, 64.6, 64.3, 49.5, 47.9, 43.6, 38.8, 38.4, 35.9, 34.9,
34.1, 32.7, 31.4, 29.7, 26.9, 14.8; MS (EI) m/z (rel intensity) 488 (M+,
1), 390 (100), 332 (8), 230 (34), 199 (8), 184 (42), 174 (21), 158 (17),
134 (6), 91 (12), 78 (44), 67 (9); HRMS m/z calculated for C25H30-
NO4Se 488.1340, found 488.1317.
(-)-Tuberostemonine (26). To a solution of 27 (53.1 mg, 0.137
mmol) in CH2Cl2 (2.5 mL) were added allyltritylamine (82.0 mg, 0.274
mmol), ruthenium catalyst 32 (25.0 mg, 0.0274 mmol), and N,N-
diisopropylethylamine (23.9 µL, 0.137 mmol). The reaction mixture
was heated at reflux for 16 h, concentrated in vacuo, and purified by
chromatography on SiO2 (pretreated with 9:1 hexanes/EtOAc with 0.5%
NEt3) (hexanes/EtOAc gradient elution from 9:1 to 2:1 to 1:1 to 0:1)
to give 45.3 mg (85%) of an (E,Z)-mixture (ca. 2:1) of 54 as a yellow
oil. A solution of this mixture of double-bond isomers (47.1 mg, 0.122
mmol) in CH2Cl2 (5.2 mL) was treated with p-toluenesulfonic acid
monohydrate (23.2 mg, 0.122 mmol) and heated at reflux for 30 min.
After addition of catalyst 55 (3.81 mg, 0.0061 mmol), the solution was
heated at reflux while ethylene gas was bubbled through it with
additional portions of catalyst 55 (3.81 mg, 0.0061 mmol) added
approximately every 12 h. After 60 h, the mixture was diluted with
EtOAc and washed with saturated NaHCO3 and brine, dried (MgSO4),
concentrated in vacuo, and purified by chromatography on SiO2
prewashed with a solution of 0.5% NEt3 in hexanes/EtOAc (9:1)
(hexanes/EtOAc gradient elution from 9:1 to 2:1 to 1:1 to 1:2) to give
37.1 mg (81%) of 56 as a white foam. A solution of 56 in methanol
(4.6 mL) was hydrogenated for 17 h at room temperature in the presence
of 10% Pd/C (37.1 mg), filtered through a plug of Celite, and
concentrated in vacuo to give 36.0 mg (97%) of 26 as a white foam:
[R]D -29.4 (c 0.10, acetone, 21 °C) [lit.9 [R]D -25.4 (c 0.06, acetone,
21 °C)]; IR (neat) 2925, 1772, 1451, 1163 cm-1; 1H NMR (CD2Cl2) δ
4.41 (t, 1 H, J ) 7.8 Hz), 4.25 (ddd, 1 H, J ) 10.7, 7.8, 5.4 Hz),
3.42-3.37 (m, 2 H), 3.02 (dd, 1 H, J ) 11.2, 6.5 Hz), 2.68-2.51 (m,
2 H), 2.39-2.29 (m, 2 H), 2.15 (dt, 1 H, J ) 12.1, 6.7 Hz), 2.00 (dt,
1 H, J ) 10.2, 7.6 Hz), 1.83-1.74 (m, 4 H), 1.59-1.39 (m, 8 H), 1.22
(d, 3 H, J ) 7.3 Hz), 1.19 (d, 3 H, J ) 6.9 Hz), 1.12-1.01 (m, 1 H),
0.94 (t, 3 H, J ) 7.3 Hz); 13C NMR (CD2Cl2) δ 179.7 (s), 179.5 (s),
82.0 (d), 80.6 (d), 65.2 (d), 63.8 (d), 48.1 (t), 47.5 (d), 45.2 (d), 42.2
(d), 41.2 (d), 41.1 (d), 35.1 (d), 34.8 (t), 32.4 (t), 30.5 (t), 30.3 (t), 28.8
(t), 24.7 (t), 15.0 (q), 14.9 (q), 11.2 (q),; MS (EI) m/z (rel intensity)
375 (M+, 1), 374 (4), 373 (5), 344 (14), 304 (15), 290 (26), 276 (100),
260 (11), 200 (6), 134 (6); HRMS m/z calculated for C22H32NO4 (M -
H) 374.2331, found 374.2317.
8-Des-ethyl-8S-allyl-(-)-tuberostemonine (27). To a mixture of
51 (0.20 g, 0.41 mmol) and AIBN (21 mg, 0.082 mmol) was added
allyltriphenyltin (2.4 g, 6.1 mmol). The reaction mixture was heated at
100 °C for 14 h (the solid mixture becomes a cloudy solution
immediately upon heating), cooled to room temperature, and purified
by chromatography on SiO2 that had been pretreated with 9:1 hexanes/
EtOAc containing 0.5% NEt3 (hexanes/EtOAc, 9:1 to 1:1 to 0:1) to
give 0.11 g (70%) of the allyl intermediate as a white foam. A solution
of this lactone (150 mg, 0.402 mmol) in THF (4 mL) and HMPA (0.4
mL) was cooled to -78 °C and an LDA/HMPA solution (0.982 mL,
0.442 mmol) [0.45 M LDA solution made from diisopropylamine (0.175
n
mL, 1.25 mmol) and BuLi (1.6 M, 0.781 mL, 1.25 mmol) in THF
(1.6 mL) at 0 °C and then treated with HMPA (0.224 mL, 1.29 mmol)
at -78 °C] was added. The reaction mixture was stirred at -78 °C for
30 min, and then MeI (75.3 µL, 1.21 mmol) was added. This solution
was stirred at -78 °C for 20 min and quenched with saturated NaHCO3.
The product was extracted into EtOAc (3 × 15 mL), washed with
saturated NaHCO3 and brine, dried (MgSO4), concentrated in vacuo,
and purified by chromatography on SiO2 that had been prewashed with
4:1 hexanes/EtOAc containing 0.5% NEt3 (hexanes/EtOAc, 2:1 to 1:1)
Didehydrotuberostemonine (60). To a solution of 26 (13 mg, 0.035
mmol) in acetone (2.6 mL) was added freshly prepared (from 10%
9
234 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

Asymmetric Total Syntheses of Plant Alkaloids
A R T I C L E S
aqueous AgNO3 and 10% aqueous NaOH) Ag2O (13 mg, 0.056 mmol).
The reaction mixture was heated at 40 °C for 15 h and filtered through
a plug of Florisil (EtOAc containing 0.5% NEt3). The filtrate was
concentrated in vacuo and purified by preparative TLC (hexanes/EtOAc,
1:1) to give 3.9 mg (30%) of a 7:3 mixture of 60 and unidentified
impurities. 60: 1H NMR δ 5.99 (s), 5.38 (dd, 1 H, J ) 11.1, 5.1 Hz),
4.62 (dd, 1 H, J ) 7.8, 6.6 Hz), 4.27-4.20 (m, 1 H), 3.75-3.63 (m,
1 H), 3.08 (dd, 1 H, J ) 7.0, 5.9 Hz), 2.90-2.62 (m, 2 H), 2.59 (t, 1
H, J ) 7.3 Hz), 2.27-2.15 (m, 2 H), 2.12-1.83 (m, 5 H), 1.64-1.52
(m, 4 H), 1.40 (d, 3 H, J ) 7.3 Hz), 1.37 (d, 3 H, J ) 6.8 Hz), 1.02
(t, 3 H, J ) 7.5 Hz); 1H NMR (CD2Cl2) δ 6.00 (s), 5.36 (dd, 1 H, J )
11.3, 5.2 Hz), 4.61 (dd, 1 H, J ) 7.3, 6.4 Hz), 4.24-4.16 (m, 1 H),
3.75-3.62 (m, 1 H), 3.07 (t, 1 H, J ) 6.5 Hz), 2.82-2.56 (m, 2 H),
2.55 (pentet, 1 H, J ) 7.1 Hz), 2.24-2.11 (m, 2 H), 2.08-1.90 (m, 5
H), 1.60-1.49 (m, 4 H), 1.36 (d, 3 H, J ) 7.3 Hz), 1.30 (d, 3 H, J )
6.8 Hz), 1.01 (t, 3 H, J ) 7.4 Hz); MS (EI) m/z (rel intensity) 371
(M+, 100), 327 (66), 298 (32), 272 (97), 228 (21); HRMS m/z calculated
for C22H29NO4 371.2097, found 371.2095.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (AI-33506). We thank Dr.
Hidenori Takahashi for developing protocols for the preparation
of compounds 7-19 and Professor Robert Williams (Colorado
State University) for bringing ref 75 to our attention.
Supporting Information Available: Experimental procedures
and spectral data for 1, 9-25, 28, 30, 34-37, 39, 40a,b, and
42. This information is available free of charge via the Internet
at http://pubs.acs.org.
JA044280K
9
J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 235