Studies on the synthesis of (±)-stenine: A combined intramolecular [4 + 2]-cycloaddition/rearrangement cascade

Article abstract of DOI:10.1021/jo050515e

Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with β-alkoxy-γ-dithiane lactams. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. Conformational effects imposed by the placement of a carbonyl group within the tether, combined with a rotational bias about the C(2)-N bond, enhances the rate of the IMDAF reaction of the seven-ring system so that it occurs readily at 25 °C. The feasibility of using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (±)-stenine was explored. The eventual synthesis of (±)-stenine was carried out by an intramolecular Diels-Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion sites present in stenine. All six stereocenters at the azepinoindole core were derived in high stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10 was converted to stenine in 11 additional steps via a sequence that features a Crabtree's-catalyst directed hydrogenation, iodolactonization, and a Keck allylation.

Full text of DOI:10.1021/jo050515e

Studies on the Synthesis of (()-Stenine: A Combined
Intramolecular [4 + 2]-Cycloaddition/Rearrangement Cascade
Albert Padwa* and John D. Ginn
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received March 14, 2005
Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via
the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with â-alkoxy-γ-dithiane
lactams. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF).
The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic
lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or
below room temperature. Conformational effects imposed by the placement of a carbonyl group
within the tether, combined with a rotational bias about the C(2)-N bond, enhances the rate of
the IMDAF reaction of the seven-ring system so that it occurs readily at 25 °C. The feasibility of
using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (()-stenine
was explored. The eventual synthesis of (()-stenine was carried out by an intramolecular Diels-
Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid
methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by
a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion
sites present in stenine. All six stereocenters at the azepinoindole core were derived in high
stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10
was converted to stenine in 11 additional steps via a sequence that features a Crabtree’s-catalyst
directed hydrogenation, iodolactonization, and a Keck allylation.
In recent years, we have been investigating the in-
tramolecular [4 + 2]-cycloaddition/rearrangement cas-
cade of 2-amidofurans as a strategy for the synthesis of
a variety of hexahydroindolinone alkaloids.1 This ap-
proach, demonstrated by the thermolysis of thiofuran 1
to lactam 4, proceeds by an initial Diels-Alder cycload-
dition to first produce oxabicycle 2 as a transient species
which undergoes a nitrogen-assisted ring opening to
generate the zwitterionic intermediate 3 (Scheme 1). A
5
subsequent 1,2-methylthio shift provides the observed
tricyclic lactam as a single diastereomer (4b) which, if
allowed to stand over a period of time, undergoes epimer-
-4
6
ization to furnish a mixture of stereoisomers. The
stereochemistry of the resulting tricyclic lactam 4 is
7
derived from an IMDAF cycloaddition where the sidearm
of the tethered alkenyl group is oriented syn (exo) with
respect to the oxygen bridge. Products resulting from an
endo sidearm transition state were neither detected nor
(
1) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
3, 5304. (b) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org.
Chem. 1998, 63, 3986.
6
(
2) (a) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J.
Org. Chem. 1999, 64, 3595. (b) Padwa, A.; Dimitroff, M.; Liu, B. Org.
Lett. 2000, 2, 3233.
(5) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J.
Org. Chem. 2002, 67, 3412.
(
3) (a) Padwa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem. 2001,
6
6, 1716. (b) Wang, Q.; Padwa, A. Org. Lett. 2004, 6, 2189.
4) (a) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org.
(6) A somewhat related methylthio group migration was reported
by Wu and co-workers in their studies of the intramolecular Diels-
Alder reaction of a furan containing a tethered allenyl ether dienophile;
see: (a) Wu, J.-H.; Shao, W. D.; Ying, F. H. Tetrahedron Lett. 1994,
35, 729. (b) Wu, H.-J.; Ying, F. H.; Shao, W. D. J. Org. Chem. 1995,
60, 6168. (c) Wu, H.-J.; Yen, C. H.; Chuang, C. T. J. Org. Chem. 1998,
63, 5064.
(
Chem. 1997, 62, 4088. (b) Padwa, A.; Brodney, M. A.; Satake, K.;
Straub, C. S. J. Org. Chem. 1999, 64, 4617. (c) Lynch, S. M.; Bur, S.
K.; Padwa, A. Org. Lett. 2002, 4, 4643. (d) Padwa, A.; Brodney, M. A.;
Lynch, S. M.; Rashatasakhon, P.; Wang, Q.; Zhang, H. J. Org. Chem.
2
004, 69, 3735.
1
0.1021/jo050515e CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/18/2005
J. Org. Chem. 2005, 70, 5197-5206
5197

Padwa and Ginn
SCHEME 1
SCHEME 2
SCHEME 3
isolated. This result is not so surprising since, in these
mobile cycloaddition equilibria, the exo adducts are
expected to be thermodynamically more favored. This
stereochemical result is also consistent with that reported
by others for related furanyl systems possessing short
tethers. It should be noted that tricyclic lactam 4
possesses a configuration in which the methylthio group
and the angular hydrogen are on the same face. This
feature, combined with the exclusive formation of one
diastereomer in the thermolysis of 1, suggest a concerted
peratures as low as 10 °C. We were not able to isolate or
even detect 2-thiomethylamido-furan 9 under the condi-
tions used for its formation (vide infra) as it rapidly
furnished the tricyclic lactam 10 in 87% yield at or below
room temperature. A similar rate difference between the
six and seven ring annealed furans was also noticed when
the unsubstituted ꢀ-lactam 11 was treated with DMTSF
8
,9
which gave rise to tricyclic lactam 13 in 85% yield at 25
10
°
C (Scheme 3). In contrast, the cyclization/rearrange-
1
,2-shift of the methylthio group. While a stepwise
ment cascade for the six-membered ring-fused thiofuran
a (or 1b) required heating at 110 °C in order to form
elimination-stereoselective addition of the methylthio
substituent is possible, the lack of stereodirecting fea-
tures within these systems is inconsistent with the
observed degree of stereoselectivity.
1
the tricyclic lactam 4a (or 4b) (see Scheme 1). That none
of the intermediate oxabicycles could be observed in the
course of these reactions suggests that the cycloaddition
step is rate determining.
The formation of tricyclic lactam 4a (or 4b) required
heating the 2-thio-substituted furan 1a (or 1b) at reflux
in toluene. Amido(thiomethyl)furan 5, on the other hand,
was highly reactive providing oxabicycle 6 in 77% yield
at room temperature. Heating a benzene solution of this
cycloadduct at reflux afforded the tricyclic lactam 7 in
Because there was no clear precedent regarding whether
the origin of the observed rate differences between the
six- and seven-membered ring systems resided in either
ground-state conformational effects or relative strain
within the transition states, we opted to investigate the
ground-state conformations of furans 1a and 12 as well
as the transition states through which these reactants
8
0% yield (Scheme 2). The facility of this [4 + 2]-cycload-
dition is presumably related to HOMO-LUMO interac-
tions where the presence of the electron-deficient car-
bomethoxy group in 5 diminishes the energy gap between
the interacting MOs and facilitates the overall reaction.
During the course of our studies with these systems,
we noted that the unactivated seven-ring furan homo-
logue of 1 (i.e., 9) also underwent the cycloaddition/
rearrangement cascade but, most surprisingly, at tem-
must pass to obtain the corresponding oxabicycles. The
results of our calculations1
1-13
show that the six-
membered ring annealed to the furan in 1a adopts a half-
chair conformation in which the C(3)-C(2)-N-C(4)
dihedral angle is 156.0°. The seven-membered ring
annealed to the furan in 12 adopts a low-energy confor-
mation that imparts a 119.7° angle, but a simple ring
flip provides another conformation in which the angle
increases to 132.7°. The rapid interconversion between
these two conformers of furan 12 (a calculated 2.2 kcal/
mol energy difference) allows 12 to adopt a reactive
conformation more easily than furan 1a. The observed
difference in reactivity between the six and seven-
(
7) For examples of intramolecular Diels-Alder reaction of furans
(
IMDAF) that contain heteroatoms attached directly to the furan ring;
see: (a) Padwa, A.; Kappe, C. O.; Cochran, J. E.; Snyder, J. P. J. Org.
Chem. 1997, 62, 2786. (b) Gewald, K. Chem. Ber. 1966, 99, 1002. (c)
Boyd, G. V.; Heatherington, K. J. Chem. Soc., Perkin Trans. 1 1973,
2
523. (d) Nixon, W. J.; Garland, J. T.; DeWitt-Blanton, C., Jr. Synthesis
1
980, 56. (e) Aran, V. J.; Soto, J. L. Synthesis 1982, 513. (f) Semmel-
hack, M. F.; Park, J, Organometallics 1986, 5, 2550. (g) Chatani, N.;
Hanafusa, T. J. Org. Chem. 1987, 52, 4408. (h) Cutler, S. J.; El-
Kabbani, F. M.; Keane, C.; Fisher-Shore, S. L.; DeWitt-Blanton, C.,
Jr. Heterocycles 1990, 31, 651. (i) Vaidya, N. A.; Nixon, W. J.; Fatmi,
A. A.; DeWitt-Blanton, C. J. Org. Chem. 1982, 47, 2483. (j) Schlessing-
er, R. H.; Bergstrom, C. P. Tetrahedron Lett. 1996, 37, 2133. (k)
Schlessinger, R. H.; Wu, X.-H.; Pettus, T. R. R. Synlett 1995, 536. (l)
Schlessinger, R. H.; Pettus, T. R. R.; Springer, J. P.; Hoogsteen, K. J.
Org. Chem. 1994, 59, 3246. (m) Schlessinger, R. H.; Bergstrom, C. P.
J. Org. Chem. 1995, 60, 16.
(9) (a) De Clercq, P. J.; Van Royen, L. A. Synth. Commun. 1979, 9,
771. (b) Van Royen, L. A.; Mijngher, R.; De Clercq, P. J. Bull. Soc.
Chim. Belg. 1984, 93, 1019. (c) Fischer, K.; H u¨ nig, S. J. Org. Chem.
1987, 52, 564.
(10) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
(11) Ground-state conformations were explored by optimizing struc-
12,13
tures using the B3LYP/3-21G* model
as implemented by Gaussian
98. We thank Dr. Scott K. Bur for carrying out these calculations.
(12) For Becke’s three-parameter exchange functional, see: Becke,
A. D. J. Chem. Phys. 1993, 98, 5648.
(
8) (a) Woo, S.; Keay, B. A. Tetrahedron: Asymmetry 1994, 5, 1411.
(
b) Rogers, C.; Keay, B. A. Tetrahedron Lett. 1991, 32, 6477. (c) Rogers,
C.; Keay, B. A. Synlett, 1991, 353. (d) Rogers, C.; Keay, B. A. Can. J.
Chem. 1992, 70, 2929.
(13) For the LYP correlation functional, see: Lee, C.; Yang, W.; Parr,
R. Phys. Rev. B 1988, 37, 785.
5198 J. Org. Chem., Vol. 70, No. 13, 2005

Synthesis of (()-Stenine
SCHEME 4
Chen reported a total synthesis of racemic stenine in
990.18 Enantioselective syntheses of (-)-stenine were
1
19
20
later independently described by Wipf and Morimoto.
These three early syntheses of stenine feature the step-
wise construction of the hydroindole portion (BD rings),
with closure to the seven-membered azepine ring being
postponed until the end of the synthesis. More recently,
Aub e´ and Golden completed a formal synthesis of (()-
stenine by making use of a clever domino Diels-Alder/
Schmidt reaction strategy.21 We envisioned an alternative
approach to stenine, in which the azepine ring would be
incorporated at an early point in the synthetic sequence
and then used as a template for setting the required
stereochemistry.22 Our synthesis relies on an intramo-
lecular Diels-Alder reaction of a 2-amido-5-methylthio
substituted furan derived from lactam 8 (or 16) to create
the azepinoindole skeleton (see Scheme 4). This would
be followed by a series of reductions to set the syn-anti
stereochemical relationship at the incipient ring fusion
sites present in stenine.
membered ring systems correlates with a bias in the
rotation about the C(2)-N bond which allows the 7-ring
system to readily achieve the proper two-plane orienta-
tion approach needed for the Diels-Alder cycloaddition.
Significant ring strain in the transition state with the
six-membered ring system may also account for its higher
activation energy.
First-Generation Approach
We approached the synthesis of stenine in two different
ways using the dimethyl(methylthio)sulfonium tetrafluo-
roborate (DMTSF) induced cyclization-cycloaddition cas-
23
cade as the key reaction step for both undertakings. The
overall approach was devised on the assumption that it
should be possible to induce cyclization of the amide
carbonyl group onto the resulting thionium ion formed
from the DMTSF reaction of the dithioacetal. It is known
Considering the facility with which lactam 8 is con-
verted into tricyclic lactam 10 and to further demonstrate
the viability of our sequential cycloaddition process as a
practical strategy for the synthesis of complex hetero-
cycles, we have explored the feasibility of using this key
reaction in the context of a total synthesis of the Stemona
alkaloid (()-stenine (15). Scheme 4 depicts the basic
features of our strategy directed toward this compound.
Alkaloids from Stemona plants have been used in Chi-
nese and Japanese folk medicine as cough-relief agents
24
that treatment of thioketals with DMTSF causes the
carbon-sulfur bond to become labile upon methylthiola-
25
tion. The resulting (methylthio)sulfonium ion easily
dissociates to produce a thionium ion and methyl disul-
26
fide. Once the dihydrofuran ring has been forged,
elimination of water (or acetic acid) should proceed
readily to furnish the desired 2-(methylthio)amidofuran
necessary for the Diels-Alder cycloaddition.
In the first plan, the synthesis of ꢀ-lactam 16 (ethyl
group already in place) was achieved by a mixed aldol
reaction of N-trimethylsilyl ꢀ-caprolactam 18 with 1,1-
1
4
and insecticides. The alkaloids of this family, having
relatively complex polycyclic structures, have been clas-
sified into six groups according to their structural fea-
1
5
tures. The pyrrolo[1,2-a]azepine nucleus is a common
structural motif shared by several of the Stemona alka-
loids, including stenine (15), whose hydroindole core
27
bis(methylsulfanyl)butan-2-one followed by quenching
with acid to give lactam 19 in 65% yield as a 5:1-mixture
16
skeleton contains six contiguous stereocenters. Several
groups have completed the synthesis of simple as well
as more complex members of the Stemona group.17 The
(
18) (a) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236. (b)
Chen, C. Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840.
novel polycyclic architecture of stenine has attracted
(19) (a) Goldstein, D. M.; Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1995,
117, 11106. (b) Wipf, P.; Kim, Y. Tetrahedorn Lett. 1992, 33, 5477. (c)
Wipf, P.; Goldstein, D. M. Tetrahedron Lett. 1996, 37, 739.
synthetic efforts by several research groups.1
8-22
Hart and
(
20) (a) Morimoto, Y.; Iwahashi, M.; Nishida, K.; Hayashi, Y.;
(14) (a) Gotz, M.; Edwards, O. E. In The Alkaloids; Manske, R. H.
Shirahama, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 904. (b)
Morimoto, M.; Iwahashi, M. Synlett 1995, 1221. (c) Morimoto, Y.;
Iwahashi, M.; Kinoshita, T.; Nishida, K. Chem. Eur. J. 2001, 7, 4107.
(21) Golden, J. E.; Aub e´ , J. Angew. Chem., Int. Ed. 2002, 41, 4316.
(22) For a preliminary report of our work, see: Ginn, J. D.; Padwa,
A. Org. Lett. 2002, 4, 1515.
(23) Padwa, A.; Ginn, J. D.; McClure, M. S. Org. Lett. 1999, 1, 1559.
(24) (a) Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103,
6529. (b) Trost, B. M.; Sato, T. J. Am. Chem. Soc. 1985, 107, 719.
Commercially available from Aldrich Chemical Co.
(25) (a) Kice, J. L.; Favstritsky, N. A. J. Am. Chem. Soc. 1969, 91,
1751. (b) Smallcombe, S. H.; Caserio, M. C. J. Am. Chem. Soc. 1971,
93, 5826. (c) Kim, J. K.; Pau, J. K.; Caserio, M. C. J. Org. Chem. 1979,
44, 1544.
F., Ed.; Academic Press: New York, 1967; Vol. IX, pp 545-551. (b)
Gotz, M.; Edwards, O. E. In The Alkaloids; Weisner, K., Ed.; Academic
Press: London, 1973; Vol. IX, pp 143-160.
(
15) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. J. Tetrahedron
2
1
2
002, 58, 61.
16) (a) Pilli, R. A.; Ferreira de Olivera, M. C. Nat. Prod. Rep. 2000,
7, 117. (b) Lin, W.-H.; Ye, Y.; Xu, R.-S. J. Nat. Prod. 1992, 55, 571.
17) (a) Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc.
002, 124, 14848. (b) Williams, D. R.; Fromhold, M. G.; Earley, J. D.
(
(
Org. Lett. 2001, 3, 2721. (c) Martin, S. F.; Barr, K. J.; Smith, D. W.;
Bur, S. K. J. Am. Chem. Soc. 1999, 121, 6990. (d) Jacobi, P. A.; Lee,
K. J. Am. Chem. Soc. 2000, 122, 4295. (e) Sibi, M. P.; Subramanian,
T. Synlett 2004, 1211. (f) Lindsay, K. B.; Pyne, S. G. Synlett 2004, 779.
(
g) Br u¨ ggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.;
(26) (a) Braish, T. F.; Saddler, J. C.; Fuchs, P. L. J. Org. Chem. 1988,
53, 3647. (b) Gracia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org.
Chem. 1994, 59, 3939.
(27) Solladi e´ , G.; Boeffel, D.; Maignan, J. Tetrahedron 1996, 52,
2065.
Schwink, L,; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284. (h) Rigby,
J. H.; Laurent, S.; Cavezza, A. M. J.; Heeg, M. J. J. Org. Chem. 1998,
6
6
3, 5587. (i) Hinman, M. M.; Heathcock, C. H. J. Org. Chem. 2001,
6, 7751. (j) Xiang, L.; Kozikowski, A. P. Synlett 1990, 279.
J. Org. Chem, Vol. 70, No. 13, 2005 5199

Padwa and Ginn
SCHEME 5a
SCHEME 6
The relative stereochemistry of each diastereomer was
established by nOe difference experiments. Irradiation
of H11 in 24 showed an 8% enhancement for the signal
of H10 as might be expected of vicinal protons in a cis-
configuration.30
a
+
Reagents: (a) LDA, (MeS)2CHCOEt, H ; (b) MeO2CCH2CHd
CHCH2COCl; (c) DMTSF, NEt3; (d) p-toulenesulfonic acid, THF,
2
5 °C.
of diastereomers (Scheme 5). Acylation of 19 with trans-
-chlorocarbonyl-pent-3-enoic acid methyl ester28 in the
5
Second-Generation Approach
presence of 4 Å powdered molecular sieves as a neutral
scavenger furnished the key imide 16 necessary for the
critical cyclization step. We were pleased to find that
when 16 was treated with DMTSF, dihydrofuran 20 was
isolated in 67% yield as a mixture of diastereomers. This
mixture of alcohols was treated with p-toluenesulfonic
acid at 25 °C in THF to furnish azepinoindole 21 in 72%
isolated yield as a single diastereomer. Under the acidic
conditions used for the dehydration of 20, the thiofuran
intermediate was not detected as it underwent a rapid
IMDAF/methylthio rearrangement cascade to give 21 in
Since all of our efforts to improve the diastereoselec-
tivity associated with the Raney-nickel reduction of 21
failed, we were forced to examine a slightly longer, but
ultimately practical alternative strategy toward stenine.
As was mentioned earlier, the DMTSF-induced reaction
of imide 8 proceeded readily at 25 °C and furnished the
rearranged tricyclic lactam 10 in 87% yield. Removal of
the methylthio group was easily accomplished by treating
10 with Raney Ni in ethanol, which afforded azepinoin-
dole 26 as a single diastereomer in 95% isolated yield.
Subsequent reduction of the keto group under Luche
conditions29 provided alcohol 27 in 77% isolated yield as
a single diastereomer (Scheme 7). Interestingly, when 27
was treated with mild acid it underwent a clean double
bond isomerization to give the isomeric enamide 28 in
70% yield and whose structure is related to the fused
tricyclic azepinoindole core found in didehydrotubero-
stemonine.16
7
2% yield. The stereochemical assignment of 21 was
made on the basis of analogy with related systems where
X-ray data had been obtained.
With a feasible route to the tricyclic core of the
Stemona family in hand, we explored the possibility of
2 5
forming lactone 14 (R ) C H ; Scheme 4) by selective
reduction of the keto carbonyl group in 21 followed by a
subsequent lactonization reaction. Unfortunately, all of
our attempts to selectively reduce the keto carbonyl group
present in 21 were unsuccessful. In each case examined,
either the keto carbonyl group failed to be reduced or else
over-reduction of the enamido and ester groups occurred.
This may be a consequence of the steric environment
around the keto center which is adjacent to both tertiary
and quaternary sites. To create a more favorable steric
environment for reduction, we decided to first remove the
thiomethyl functionality by reduction with Raney-nickel.
This resulted in an inseparable 3:1 mixture of diastere-
omers of 22 in 37% yield together with 12% of phenol
The next step in the synthesis involved a controlled
hydrogenation of the enamido π-bond. Hindered, substi-
tuted double bonds are often difficult to hydrogenate,
requiring forcing conditions, and frequently lead to a
mixture of isomers.31 Indeed, the hydrogenation of 27
under heterogeneous conditions using several palladium
or rhodium catalysts resulted in a mixture of products.
Homo-allylic alcohols have been demonstrated to direct
the hydrogenation of olefins when cationic iridium or
rhodium catalysts are used.32 Excellent stereochemical
control could be obtained by hydrogenation of 27 with
23. While the diastereomers of 22 could not be totally
3 6 2 2
the catalyst system [Ir(cod)pyr(Pcy )]PF /CH Cl de-
separated, their relative stereochemistry was established
by a subsequent Luche reduction29 which furnished
alcohols 24 (39%) and 25 (13%), respectively (Scheme 6).
(30) Noggle, J. H.; Schirmer, R. E. The Nuclear Overhauser Effect;
Academic Press: New York, 1971.
(
(
31) Nell, P. G. Synlett 2001, 160.
32) For the preferred addition of hydrogen from one face of a
(
28) DiMaio, J.; Gibbs, B.; Lefebvre, J.; Konishi, Y.; Munn, D.; Yue,
S. J. Med. Chem. 1992, 35, 3331.
29) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
homoallylic alcohol, see: (a) Crabtree, R. H.; Davis, M. W. Organo-
metallics 1983, 2, 681. (b) Stork, G.; Kahne, D. E. J. Am. Chem. Soc.
1983, 105, 1072.
(
5200 J. Org. Chem., Vol. 70, No. 13, 2005

Synthesis of (()-Stenine
SCHEME 7a
SCHEME 8a
a
Reagents: (a) Raney-Ni, EtOH; (b) NaBH4, CeCl3, MeOH; (c)
2
N HCl; (d) Crabtree’s catalyst, H2, CH2Cl2; (e) MsCl, NEt3, DBU,
heat.
a
Reagents: (a) LiOH, H2O; (b) I, MeCN; (c) CH2dCHCH2SnBu3,
scribed by Crabtree and co-workers33 to give 29 in 80%
yield. The addition of hydrogen is directed by the pres-
ence of the C10 hydroxyl group delivering the desired syn-
AlBN, (d) OSO4, NaIO4; (e) HSCH2CH2SH, BF3‚Et2O; (f) Lawes-
son’s reagent, (g) Raney-Ni (h) LDA, HMPA, MeI.
32
nickel furnished 36 in 93% yield. Methylation of the
lactone enolate derived by treating 36 with LDA followed
by reaction with methyl iodide afforded racemic stenine
anti stereochemistry at the ring fusion sites. The
relevant coupling constants in the NMR spectrum of 29
(J12 ) 10.2 Hz; J13 ) 5.5 Hz) were fully consistent with
(
15) in 2.1% overall yield for the 16-step sequence
its assignment and comparable in value to those found
in related systems.17h Final confirmation of the stereo-
starting from ꢀ-caprolactam. Confirmation of the struc-
ture was obtained by comparison of the spectral data with
that of an authentic sample provided by Professor Wipf.
In conclusion, this cascade approach to the Stemona
alkaloid stenine demonstrates the utility of the intramo-
lecular [4 + 2]-cycloaddition of 2-alkylthio-5-amidofurans
for preparing stereochemically complex perhydroindole
ring systems. All six centers at the azepinoindole core
can be derived in high stereoselectivity from the func-
tionality present in the rearranged cycloadduct 10. We
are currently refining this strategy and further applying
the methodology toward other Stemona alkaloids.
chemistry comes from a single-crystal X-ray analysis of
2
9. This result demonstrates that rapid access to the
stereochemically correct azepinoindole moiety of stenine
and related Stemona alkaloids) can be achieved via a
(
Crabtree’s-catalyst directed hydrogenation reaction. Be-
fore the planned iodolactonization of the γ,δ-unsaturated
ester, alcohol 29 was converted to the corresponding
mesylate and this was followed by treatment with DBU
in refluxing toluene to effect elimination providing 30 in
6
4% yield. The requirement of forcing conditions for
elimination is undoubtedly related to the need of the
system to adopt an antiperiplanar relationship of the
Experimental Section
4
mesylate and H proton (see 29). This can only be
achieved by populating the more strained boat conforma-
tion, thereby diminishing the rate of elimination.
The conversion of tricyclic lactam 30 to (()-stenine 15
was accomplished using the sequence of reactions out-
lined in Scheme 8. Thus, hydrolysis of the methyl ester
in 30 with LiOH followed by treatment with iodine gave
iodolactone 31 in 60% yield.18,19 Subsequent Keck ally-
Acetic Acid 2,2-Bis(methylsulfanyl)-1-(2-oxopiperidin-
3-yl) Ethyl Ester. To 5.0 mL (36 mmol) diisopropylamine in
THF (100 mL) cooled to 0 °C was added n-butyllithium (24
mL of a 1.5 M solution in hexane). The mixture was stirred at
0
°C for 30 min, and then 6.1 g (36 mmol) of 1-trimethylsila-
37
nylpiperidin-2-one dissolved in THF (50 mL) was added. The
reaction mixture was stirred at 0 °C for 30 min and then cooled
to -78 °C. A solution of 5.0 g (37 mmol) of 2,2-bis(methylsul-
34
lation with allyltributylstannane using the Hart/Wipf
38
fanyl)acetaldehyde dissolved in THF (50 mL) was added over
1
8,19
protocol
furnished 32 in 62% yield and with excellent
a 3 h period. After the addition was complete, 5.0 mL (53
mmol) of acetic anhydride was added, and the mixture was
slowly warmed to room temperature and stirred for 12 h. The
35
diastereoselectivity. Johnson-Lemieux oxidation of the
allyl group afforded the expected aldehyde 33, which was
treated with 1,2-ethanedithiol and BF
3
solution was poured into a saturated aqueous NaHCO solu-
3
2
‚Et O to give 34
tion and the organic phase was separated. The aqueous phase
was washed with ethyl acetate, and the organic layer was dried
in 50% yield for both steps. Conversion of the amide to
the corresponding thioamide with Lawesson’s reagent36
provided 35 in 77% yield. Desulfurization with Raney
4
over anhydrous MgSO . The solvent was removed under
reduced pressure and the residue was purified by flash silica
gel chromatography (5% EtOAc/hexane) to provide 6.9 g (70%)
of the titled compound as a 1:1-mixture of diastereomers: IR
(
33) Crabtree, R. H.; Felkin, H.; Fillebeen-Khan, T.; Morris, G. E.
J. Organomet. Chem. 1979, 168, 183.
-1 1
(
3
neat), 1742, 1661, and 1231 cm ; H NMR (400 MHz, CDCl )
(
34) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.
35) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
(
Org. Chem. 1956, 21, 478.
(37) Hua, D. H.; Miao, S. W.; Bharathi, S. N. Katsuhira, T.; Bravo,
(36) Pedersen, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-O.
A. A. J. Org. Chem. 1990, 55, 3682.
Bull. Soc. Chim. Belg. 1978, 87, 223.
(38) Nakane, M.; Hutchinson, C. J. Org. Chem. 1978, 43, 3922.
J. Org. Chem, Vol. 70, No. 13, 2005 5201

Padwa and Ginn
(
diastereomer A δ 1.62 (m, 1H), 1.73 (m, 1H), 1.92 (m, 2H),
N-(2-Methylsulfanyl-5,6-dihydro-4H-furo[2,3-b]pyridin-
7-yl)-6-oxohex-3-enoic 1-Acid Methyl Ester (1b). To a 0.9
2
6
.08 (s, 3H), 2.10 (s, 3H), 2.18 (s, 3H), 3.09 (ddd, 1H, J ) 10.8,
.0, and 2.4 Hz), 3.25 (m, 2H), 4.58 (d, 1H, J ) 10 Hz), 5.19
3
g (2.2 mmol) sample of the above in CH CN (11 mL) at -40
(
dd, 1H, J ) 10 and 2.4 Hz), and 6.13 (s, 1H); (diastereomer B
°C was added 0.45 g (2.2 mmol) of DMTSF. The reaction
δ 1.71 (m, 2H), 1.96 (m, 2H), 2.08 (s, 3H), 2.16 (s, 3H), 2.18 (s,
mixture was stirred at -40 °C for 3 h, and then 1.5 mL (11
3
H), 3.05 (m, 1H), 3.29 (m, 2H), 4.06 (d, 1H, J ) 7.6 Hz), and
3
mmol) of NEt was added. The mixture was diluted with ether
5
.69 (dd, 1H, J ) 7.6 and 4.8 Hz), and 5.83 (s, 1H); 13C NMR
3
and then poured into a saturated aqueous NaHCO solution.
(
100 MHz, CDCl
3
) (diastereomer A δ 12.9, 13.6, 21.3, 22.3, 25.2,
The organic phase was separated, and the aqueous phase was
washed with ether. The combined organic layer was dried over
4
1
2.3, 42.8, 56.9, 74.3, 170.7, and 171.0; (diastereomer B δ 13.4,
4.2, 21.0, 21.7, 22.0, 31.2, 43.2, 57.2, 72.3, 169.9, and 171.7;
2 3
anhydrous K CO , and the solvent was removed under reduced
HRMS calcd for C11
H
19NO
S
3 2
277.0806, found 277.0804.
pressure. The residue was purified by flash silica gel chroma-
tography (5% EtOAc/hexane) to give 0.4 g (62%) of 1b as a
yellow oil: IR (neat) 1735, 1668, 1622, 1512, 1237, and 1165
Acetic Acid 1-(1-But-3-enoyl-2-oxopiperidin-3-yl)-2,2-
bis(methylsulfanyl) Ethyl Ester. To a 2.1 g (7.6 mmol)
-
1 1
sample of the above lactam dissolved in CH
2
Cl
2
(40 mL) was
3
cm ; H NMR (300 MHz, CDCl ) δ 1.85-1.93 (m, 2H), 2.38
added 7.6 g of oven-dried 4 Å powdered molecular sieves
(s, 3H), 2.45 (t, 2H, J ) 6.6 Hz), 3.01 (d, 2H, J ) 6.6 Hz), 3.68
(d, 2H, J ) 6.3 Hz), 3.68 (s, 3H), 3.80-3.84 (m, 2H), 5.66-
3
9
followed by 1.3 g (13 mmol) of but-3-enoyl chloride. The
reaction mixture was stirred at 25 °C for 15 h and then filtered
1
3
3
5.85 (m, 2H), and 6.38 (s, 1H); C NMR (75 MHz, CDCl ) δ
through a silica gel column and washed with Et
phase was washed with a saturated aqueous NaHCO
and dried over anhydrous MgSO . The solvent was removed
2
O. The organic
20.2, 20.6, 23.2, 38.1, 39.8, 43.2, 52.0, 105.4, 117.8, 125.6, 127.3,
solution
141.2, 146.2, 169.0, and 172.3; HRMS calcd for C15
4
H19NO S
3
309.1035, found 309.1037.
4
under reduced pressure, and the crude mixture was subjected
to flash silica gel chromatography (4% EtOAc/hexane) to give
(7-Methylsulfanyl-2,8-dioxo-1,2,5,6,7,8,9,9a-octahydro-
4H-pyrrolo[3,2,1-ij]quinolin-9-yl)acetic Acid Methyl Es-
ter (4b). A solution of 0.2 g (0. 68 mmol) of 1b in toluene (7
mL) was heated at reflux for 4 h. The reaction mixture was
cooled to rt, and the solvent was removed under reduced
pressure. The residue was purified by flash silica gel chroma-
tography (4% EtOAc/hexane) to give 0.18 g (86%) of 4b which
was first obtained as a single diastereomer (pale yellow oil)
but rapidly epimerized to a 3:1-mixture upon purification: IR
2
.5 g (94%) of the titled compound as a yellow oil which
contained a 1:1 mixture of diastereomers that were separated
by HPLC (reversed phase 1:1 MeOH/H O) for analytical
characterization: IR (neat) 3076, 3012, 2917, 2857, 1751, 1689,
2
640, 1425, and 1238 cm-1
diastereomer A) 1.68-1.85 (m, 2H), 1.92-1.98 (m, 1H), 2.03-
.10 (m, 1H), 2.08 (s, 3H), 2.15 (s, 3H), 2.20 (s, 3H), 3.23-3.30
m, 1H), 3.66 (dd, 2H, J ) 6.8 and 0.8 Hz), 3.72-3.77 (m, 2H),
1
1
3
; H NMR (400 MHz, CDCl ) δ
(
2
(
-
1 1
(neat) 1738, 1674, 1513, 1282, 1205, and 1162 cm ; H NMR
(400 MHz, CDCl ) δ 1.76-1.90 (m, 3H), 1.94-2.02 (m, 1H),
3
8
1
3
.90 (d, 1H, J ) 8.0 Hz), 5.10-5.16 (m, 2H), 5.70 (dd, 1H, J )
.0 and 4.2 Hz), and 5.94-6.04 (m, 1H)); (diastereomer B) δ
.60-1.80 (m, 2H), 1.94-2.07 (m, 2H), 2.11 (s, 3H), 2.21 (s,
H), 2.14 (s, 3H), 3.15 (m, 1H), 3.57-3.64 (m, 1H), 3.66-3.69
3
2.01 (s, 3H, minor), 2.04 (s, 3H, major), 2.24-2.34 (m, 2H),
2.36-2.43 (m, 1H), 2.54 (dd, 1H, J ) 16.4 and 8.8 Hz, major),
2.63 (dd, 1H, J ) 17.0 and 9.4 Hz, minor), 2.72-2.88 (m, 2H),
3.14-3.21 (m, 1H, minor), 3.28-3.38 (m, 1H, major), 3.53 (s,
(
m, 2H), 3.82-3.89 (m, 1H), 4.22 (d, 1H, J ) 9.6 Hz), 5.11-
5
6
1
1
2
.17 (m, 2H), 5.40 (dd, 1H, J ) 9.6 and 3.2 Hz), and 5.97-
1H), 3.56-3.65 (m, 1H), 3.64 (s, 3H, major), and 3.65 (s, 3H,
1
3
13
.07 (m, 1H); C NMR (100 MHz, CDCl
3
) (diastereomer A) δ
minor); C NMR (100 MHz, CDCl
3
) δ 15.2, 15.6, 20.8, 21.0,
3.2, 14.0, 21.0, 21.7, 43.6, 44.2, 46.0, 56.8, 72.1, 118.4, 131.4,
69.8, 173.7, and 174.8; (diastereomer B) δ 12.9, 13.6, 21.2,
1.9, 23.7, 43.9, 44.3, 46.3, 56.4, 73.6, 118.3, 131.6, 170.3, 172.4,
22.5, 23.4, 31.5, 34.5, 34.6, 35.8, 38.6, 38.9, 44.1, 49.5, 51.9,
52.0, 52.7, 52.8, 54.0, 54.0, 102.8, 103.7, 137.1, 139.4, 172.1,
172.2, 172.6, 172.7, 201.2, and 201.9; HRMS calcd for C15
NO S 309.1035, found 309.1032.
19
H -
and 175.1; HRMS calcd for C15
H
23NO
4
S
2
345.1068, found
4
345.1064.
2-(2-[3-(1-Acetoxy-2,2-bis(methylsulfanyl)ethyl)-2-ox-
opiperidin-1-yl]-2-oxoethyl)acrylic Acid Methyl Ester. To
a 0.5 g (1.8 mmol) sample of acetic acid 2,2-bis(methylsulfanyl)-
Acetic Acid 1-[1-(3-Methylbut-3-enoyl)-2-oxopiperidin-
-yl]-2,2-bis-6-[3-(1-acetoxy-2,2-bis(methylsulfanyl)ethyl)-
-oxopiperidin-1-yl]-6-oxohex-3-enoic Acid Methyl Ester.
3
2
1-(2-oxopiperidin-3-yl) ethyl ester in CH
2 2
Cl (10 mL) was added
To a 0.2 g (0.7 mmol) sample of acetic acid 2,2-bis(methylsul-
1.8 g of oven-dried powdered 4 Å molecular sieves and 0.44 g
4
0
fanyl)-1-(2-oxopiperidin-3-yl) ethyl ester in CH
2
Cl
2
(3.5 mL)
(2.7 mmol) of 3-methoxycarbonyl-but-3-enoyl chloride. The
mixture was stirred at room temperature for 15 h, followed
by filtration through a plug of silica with ether. The filtrate
were added 0.8 g of oven dried 4 Å powdered molecular sieves
and 0.2 g (1.1 mmol) of 5-chlorocarbonyl-pent-3-enoic acid
2
8
methyl ester. The mixture was stirred at room temperature
for 15 h, and this was followed by filtration through a plug of
was washed with a saturated aqueous NaHCO
3
solution and
dried over MgSO , and the solvent was removed under reduced
4
silica with Et
saturated aqueous NaHCO
MgSO , and the solvent was removed under reduced pressure.
The residue was purified by flash silica gel chromatography
3% EtOAc/hexane) to give 0.3 g (96%) of the titled compound
2
O. The organic layer was washed with a
pressure. The residue was purified by flash silica gel chroma-
tography (5% EtOAc/hexane) to give 0.6 g (90%) of the titled
compound as a pale oil which consisted of a 1:1 mixture of
3
solution and dried over anhydrous
4
-1 1
diastereomers: IR (neat) 1744, 1699, 1371, and 1149 cm ; H
NMR (400 MHz, CDCl ) δ 1.63-1.83 (m, 4H), 1.92-2.00 (m,
(
3
as a yellow that consisted of a 1:1 mixture of diastereomers:
IR (neat) 2950, 2918, 1738, 1688, 1434, 1392, 1370, 1290, 1224,
2H), 2.08 (s, 3H), 2.11 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 2.14
(s, 3H), 2.19 (s, 3H), 2.16-2.22 (m, 1H), 2.33-2.89 (m, 1H),
2.55-3.62 (m, 1H), 3.62-3.78 (m, 4H), 3.73 (s, 6H), 3.85-3.88
(m, 6H), 4.22 (d, 1H, J ) 9.6 Hz), 5.39 (dd, 1H, J ) 9.6 and
3.2 Hz), 5.69 (m, 2H), 5.70 (dd, 1H, J ) 8.4 and 4.0 Hz), and
-
1 1
and 1156 cm ; H NMR (400 MHz, CDCl
3
) δ 1.60-1.85 (m,
5
2
3
3
H), 1.91-2.02 (m, 3H), 2.07 (s, 3H), 2.11 (s, 3H), 2.11 (s, 3H),
.14 (s, 3H), 2.14 (s, 3H), 2.19 (s, 3H), 3.09-3.10 (m, 4H), 3.11-
.19 (m, 1H), 3.22-3.34 (m, 1H), 3.56-3.68 (m, 5H), 3.67 (s,
H), 3.67 (s, 3H), 3.71-3.77 (m, 2H), 3.82-3.88 (m, 1H), 3.89
1
3
3
5.26 (dd, 2H, J ) 3.2 and 1.2 Hz); C NMR (100 MHz, CDCl )
δ 12.9, 13.1, 13.5, 13.9, 20.9, 21.0, 21.1, 21.6, 21.8, 23.7, 43.4,
43.5, 43.7, 44.1, 46.0, 46.3, 52.2, 56.5, 56.7, 72.0, 73.6, 127.9,
128.0, 135.1, 135.2, 167.1, 169.8, 170.3, 172.5, 173.7, 174.0,
(
d, 1H, J ) 8.0 Hz), 4.21 (d, 1H, J ) 9.2 Hz), 5.40 (dd, 1H, J
9.2 and 3.2 Hz), 5.61-5.70 (m, 3H), and 5.73-5.83 (m, 2H);
C NMR (100 MHz, CDCl
)
1
3
3
) δ 12.9, 13.2, 13.6, 14.0, 21.0, 21.2,
and 174.2. Anal. Calcd for C17
6 2
H25NO S : C, 50.60; H, 6.24; N,
2
5
1
1.6, 21.9, 23.7, 38.0, 43.0, 43.1, 43.5, 44.0, 46.0, 46.3, 52.0,
6.5, 56.8, 72.1, 73.5, 125.5, 125.6, 127.1, 127.3, 169.8, 170.3,
3.47. Found: C, 50.33; H, 6.19; N, 3.56.
Acetic Acid 2,2-Bis(methylsulfanyl)-1-(2-oxoazepan-3-
yl) Ethyl Ester. To 5.3 mL (38 mmol) of diisopropylamine in
72.3, 172.3, 172.4, 174.8, and 175.0; HRMS calcd for C18
417.1280, found 417.1276.
H
27
-
6 2
NO S
(
40) Achiwa, K.; Chaloner, P.; Parker, D. J. Organomet. Chem. 1981,
(39) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006.
218, 249.
5202 J. Org. Chem., Vol. 70, No. 13, 2005

Synthesis of (()-Stenine
THF (100 mL) at 0 °C was added 30 mL of a 1.25 M solution
of n-butyllithium in hexane (38 mmol). The mixture was
stirred at 0 °C for 30 min. To this solution was added 8.0 g
3.47 (d, 1H, J ) 0.9 Hz), 3.65-3.68 (m, 1H), 3.69 (s, 3H), 3.71
(s, 3H), 3.78 (ddd, 1H, J ) 9.3, 6.3, and 3.3 Hz), 4.06-4.12 (m,
13
3
1H), and 4.15-4.21 (m, 1H); C NMR (75 MHz, CDCl ) δ 16.0,
(
38 mmol) of 1-trimethylsilanylazepan-2-one37 dissolved in
16.1, 26.8, 27.0, 27.2, 27.7, 30.6, 31.3, 33.0, 34.9, 35.4, 36.3,
36.5, 41.7, 43.0, 43.1, 44.8, 48.8, 52.1, 52.2, 55.8, 57.2, 107.4,
110.1, 139.2, 141.0, 172.2, 172.3, 174.0, 174.5, 201.1, and 202.2.
THF (50 mL). The reaction mixture was stirred at 0 °C for 30
min and then cooled to -78 °C. A solution of 5.2 g (38 mmol)
of 2,2-bis(methylsulfanyl)acetaldehyde dissolved in THF (50
mL) was added dropwise. After the addition of the aldehyde
was complete, 5.2 mL (55 mmol) of acetic anhydride was added,
and the mixture was slowly warmed to rt and stirred for 12 h.
The solution was poured into a saturated aqueous solution of
Anal. Calcd for C16
Found: C, 59.31; H, 6.42; N, 4.21.
-{3-[1-(Bis(methylsulfanyl)methyl)-1-hydroxypropyl]-
-oxoazepan-1-yl}-6-oxohex-3-enoic Acid Methyl Ester
16). To an 8.0 g (28 mmol) sample of lactam 19 in CH Cl
150 mL) were added 28 g of oven-dried 4 Å powdered
molecular sieves and 7.0 g (40 mmol) of 5-chlorocarbonylpent-
4
H21NO S: C, 59.42; H, 6.55; N, 4.33.
6
2
(
2
2
NaHCO
phase was washed with EtOAc and the combined organic
layers were dried over anhydrous MgSO . The solvent was
3
, and the organic phase was separated. The aqueous
(
28
4
3
-enoic acid methyl ester. The reaction mixture was stirred
removed under reduced pressure, and the residue was purified
by flash silica gel chromatography (3% EtOAc/hexane) to
provide 8.8 g (80%) of the titled compound as a yellow oil
consisting of a 4:1 mixture of diastereomers: IR (neat) 1743,
at rt for 15 h, followed by filtration through a plug of silica
with ether. The organic layer was washed with a saturated
3 4
aqueous NaHCO solution and dried over anhydrous MgSO ,
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography (5%
EtOAc/hexane) to give 8.2 g (71%) of 16 as a yellow oil which
contained a 15:1 mixture of diastereomers: IR (neat) 1730,
-
1 1
1
3
666, 1434, and 1236 cm ; H NMR (400 MHz, CDCl ) (major)
δ 1.42-1.83 (m, 5H), 1.96-2.08 (m, 1H), 2.21 (s, 6H), 2.15 (s,
3
1
H), 3.10-3.35 (m, 3H), 4.39 (d, 1H, J ) 10.4 Hz), 5.32 (dd,
H, J ) 10.0 and 7.2 Hz), and 5.84 (t, 1H, J ) 8.0 Hz); (minor)
1656, 1437, and 1387 cm-1
1
; H NMR (400 MHz, CDCl ) (major)
3
δ 1.36-1.48 (m, 2H), 1.53-1.64 (m, 1H), 1.67-1.71 (m, 1H),
δ 0.92 (t, 3H, J ) 7.6 Hz), 1.48-1.79 (m, 5H), 1.83-1.88 (m,
1H), 1.95-2.02 (m, 1H), 2.17 (q, 1H, J ) 7.6 Hz), 2.20 (s, 3H),
2.29 (s, 3H), 3.08-3.12 (m, 2H), 3.26-3.34 (m, 1H), 3.42 (dd,
1H, J ) 9.4 and 3.4 Hz), 3.54 (dd, 1H, J ) 17.8 and 0.8 Hz),
3.67 (s, 3H), 3.77 (ddd, 1H, J ) 17.8, 6.6, and 0.8 Hz), 4.07 (d,
1H, J ) 0.8 Hz), 4.29 (s, 1H), 4.68 (dt, 1H, J ) 15.2 and 4.4
1
.79-1.84 (m, 1H), 1.98-2.03 (m, 1H), 2.12 (s, 3H), 2.17 (s,
H), 2.18 (s, 3H), 3.15-3.21 (m, 2H), 3.32-3.40 (m, 1H), 4.20
3
(
d, 1H, J ) 3.2 Hz), 5.65 (dd, 1H, J ) 9.2 and 2.8 Hz), and
6
.04 (t, 1H, J ) 6.0 Hz); 13C NMR (100 MHz, CDCl
3
) (major)
δ 12.8, 14.5, 21.3, 27.0, 29.2, 29.3, 42.4, 45.5, 56.5, 73.7, 171.1,
and 176.4; (minor) δ 14.8, 15.4, 21.0, 25.9, 29.3, 29.4, 42.2, 45.5,
Hz), and 5.63-5.83 (m, 2H); 13C NMR (100 MHz, CDCl )
3
5
4
7.2, 73.6, 170.6, and 177.4. Anal. Calcd for C12
9.46; H, 7.26; N, 4.81. Found: C, 49.31; H, 7.22; N, 4.73.
-[3-(1-Acetoxy-2,2-bis(methylsulfanyl)ethyl)-2-oxo-
azepan-1-yl]-6-oxohex-3-enoic Acid Methyl Ester (8). To
a 5.4 g (18 mmol) sample of the above lactam in CH Cl (100
H
21NO
3
2
S : C,
(major) δ 8.9, 17.8, 18.0, 25.5, 26.6, 27.0, 28.2, 37.9, 42.2, 43.4,
48.8, 52.0, 65.8, 81.4, 125.7, 127.2, 172.3, 174.7, and 180.7;
6
HRMS calcd for C19
4 2 2
H29NO S [M - H O] 399.1538, found
399.1546.
2
2
N-(3-Ethyl-3-hydroxy-2-methylsulfanyl-2,3,4,5,6,7-hexahydro-
furo[2,3-b]azepin-8-yl)-6-oxohex-3-enoic Acid Methyl Es-
mL) was added 18 g of oven-dried 4 Å powdered molecular
sieves and 4.7 g (16 mmol) of 5-chlorocarbonylpent-3-enoic acid
ter (20). To an 8.2 g (20 mmol) sample of 16 in CH CN (100
3
2
8
methyl ester. The mixture was stirred at 25 °C for 15 h and
was then filtered through a plug of silica with ether. The
mL) at -40 °C was added 3.9 g (20 mmol) of DMTSF. The
reaction mixture was stirred at -40 °C for 3 h, and then 14
organic layer was washed with a saturated aqueous NaHCO
solution and dried over anhydrous MgSO , and the solvent was
3
mL (100 mmol) of NEt was added. The mixture was diluted
3
4
with ether and poured into a saturated aqueous NaHCO3
solution. The organic phase was separated, and the aqueous
phase was washed with ether. The combined organic layer was
dried over anhydrous K CO and the solvent was removed
removed under reduced pressure. The residue was purified by
flash silica gel chromatography (5% EtOAc/hexane) to give 6.7
g (85%) of 8 as a yellow oil consisting of a 4:1 mixture of
diastereomers. A sample of the major diastereomer was
separated by flash silica gel chromatography: IR (neat) 1741,
2
3
under reduced pressure. The residue was purified by flash
silica gel chromatography (5% EtOAc/hexane) to give 4.8 g
(67%) of 20 which was first obtained as a single diastereomer
(pale yellow oil) but rapidly epimerized to a 1:1 mixture upon
purification: IR (neat) 1735, 1670, 1438, 1386, 1329, and 1165
-
1 1
1
694, 1369, and 1142 cm ; H NMR (300 MHz, CDCl
3
) δ 1.38-
1
.69 (m, 2H), 1.76-1.94 (m, 3H), 2.11 (s, 3H), 2.12 (s, 3H), 2.14
(
s, 3H), 3.17-3.09 (m, 2H), 3.11-3.24 (m, 1H), 3.42-3.48 (m,
-
1 1
1
4
5
2
1
H), 3.53-3.61 (m, 1H), 3.66 (s, 3H), 4.17 (d, 1H, J ) 6.9 Hz),
.66-4.72 (m, 1H), 5.36 (dd, 1H, J ) 6.9 and 6.0 Hz), and
cm ; H NMR (400 MHz, CDCl ) δ 0.94 (t, 3H, J ) 7.2 Hz),
3
1.50-1.81 (m, 6H), 2.06 (t, 2H, J ) 6.0 Hz), 2.26 (s, 3H), 3.08-
3.14 (m, 4H), 3.35-3.45 (m, 2H), 3.67 (s, 3H), 3.68 (d, 1H, J )
1.6 Hz), 3.81-3.87 (m, 1H), 5.65-5.73 (m, 1H), and 5.76-5.83
.58-5.82 (m, 2H); 13C NMR (75 MHz, CDCl
) δ 12.8, 14.6,
1.2, 27.2, 27.6, 38.0, 42.5, 43.1, 48.3, 52.0, 56.5, 73.8, 125.5,
27.5, 170.8, 172.3, and 174.5. Anal. Calcd for C19
3
1
3
H
29NO
6 2
S :
(m, 1H); C NMR (75 MHz, CDCl
3
) δ 8.7, 14.2, 21.3, 25.5, 29.8,
C, 52.88; H, 6.77; N, 3.25. Found: C, 52.69; H, 6.63; N, 3.08.
8-Methylsulfanyl-2,9-dioxo-1,2,4,5,6,7,8,9,10,10a-decahy-
droazepino[3,2,1-hi]-indol-10-yl)acetic Acid Methyl Ester
10). To a 3.5 g (8.0 mmol) sample of imide 8 in CH CN (40
30.4, 37.2, 38.8, 46.2, 52.1, 85.0, 94.3, 107.9, 125.9, 127.4, 149.7,
70.7, and 172.7; HRMS calcd for C18
76.1770, found 376.1767.
1
3
5
H27NO SLi [M + Li]
(
(
3
(8-Ethyl-8-methylsulfanyl-2,9-dioxo-1,2,4,5,6,7,8,9,10,-
mL) at -40 °C was added 1.6 g (8.0 mmol) of DMTSF. The
reaction mixture was stirred at -40 °C for 3 h, and then 5.6
mL (40 mmol) of triethylamine was added. The mixture was
diluted with ether and poured into a saturated aqueous
10a-decahydroazepino-[3,2,1-hi]indol-10-yl)acetic Acid
Methyl Ester (21). To a 1.0 g (2.7 mmol) sample of 20 in THF
(27 mL) cooled to 0 °C was added 0.05 g (0.3 mmol) of
p-toluenesulfonic acid. The mixture was stirred at rt for 2 h
NaHCO
aqueous phase was washed with ether. The combined organic
layer was dried over anhydrous K CO , and the solvent was
3
solution. The organic phase was separated, and the
and then poured into a saturated aqueous solution of NaHCO
and extracted with ether. The organic layer was dried over
3
2
3
4
anhydrous MgSO , and the solvent was removed under
removed under reduced pressure. The residue was purified by
flash silica gel chromatography (4% EtOAc/hexane) to give 2.2
g (87%) of 10 which was first obtained as a single diastereomer
reduced pressure. The residue was purified by flash silica gel
chromatography (4% EtOAc/hexane) to give 0.7 g (72%) of 21
-
1
as a clear oil: IR (neat) 1720, 1668, 1360, 1254, and 1174 cm
;
1
(
pale yellow oil) but rapidly epimerized to a 1:1 mixture upon
3
H NMR (400 MHz, CDCl ) δ 0.84 (t, 3H, J ) 7.6 Hz), 1.79-
-
1 1
purification: IR (neat) 1725, 1674, 1357, and 1206 cm ; H
NMR (300 MHz, CDCl ) δ 1.62-1.72 (m, 4H), 1.87-1.98 (m,
H), 2.07 (s, 3H), 2.09 (s, 3H), 2.28-2.41 (m, 4H), 2.47-2.58
m, 4H), 2.63-2.87 (m, 4H), 3.08-3.36 (m, 4H), 3.40 (s, 1H),
1.89 (m, 4H), 1.89 (s, 3H), 1.95-1.99 (m, 1H), 2.04-2.13 (m,
1H), 2.32-2.48 (m, 4H), 2.61 (dd, 1H, J ) 16.2 and 9.0 Hz),
2.75-2.87 (m, 2H), 2.93-3.01 (m, 1H), 3.47-3.61 (m, 1H), 3.71
3
4
(
1
3
(s, 3H), and 3.98-4.04 (m, 1H); C NMR (100 MHz, CDCl
3
) δ
J. Org. Chem, Vol. 70, No. 13, 2005 5203

Padwa and Ginn
1
6
0.1, 13.2, 24.8, 26.4, 26.9, 28.8, 32.8, 36.1, 37.3, 42.0, 50.2,
1.8, 112.5, 142.5, 172.5, 174.1, and 204.9; HRMS calcd for
(2,9-Dioxo-1,2,4,5,6,7,8,9,10,10a-decahydroazepino[3,2,1-
hi]indol-10-yl)acetic Acid Methyl Ester (26). To a 6.8 g
(21 mmol) sample of tricyclic lactam 10 in ethanol (100 mL)
was added an excess of W-2 Raney nickel. The mixture was
stirred at 25 °C for 4 h and was then filtered through a plug
of Celite with ethanol. The solvent was removed under reduced
pressure, and the residue was purified by flash silica gel
chromatography (3% EtOAc/hexane) to give 5.6 g (95%) of 26
as a white solid: mp 67-68 °C; IR (KBr) 1721, 1682, 1397,
C
18
H
25NO
4
S 351.1504, found 351.1408.
(8-Ethyl-2,9-dioxo-1,2,4,5,6,7,8,9,10,10a-decahydroaze-
pino[3,2,1-hi]indol-10-yl)acetic Acid Methyl Ester (22).
To a 0.1 g (0.3 mmol) sample of 21 in ethanol (2.8 mL) was
added an excess of W-2 Raney nickel. The mixture was stirred
at room temperature for 2 h and then filtered through a plug
of silica with ethanol. The solvent was removed under reduced
pressur,e and the residue was purified by flash silica gel
chromatography (5% EtOAc/hexane) to give 0.03 g (37%) of
-
1 1
and 1208 cm ; H NMR (600 MHz, CDCl
3
) δ 1.59-1.63 (m,
2
H), 1.74-2.00 (m, 2H), 2.15-2.20 (m, 2H), 2.36 (dd, 1H, J )
1
6.3 and 9.0 Hz), 2.40 (dd, 1H, J ) 16.8 and 4.2 Hz), 2.60 (dd,
2
2 as a yellow oil consisting of a 3:1 mixture of inseparable
1
H, J ) 16.3 and 7.2 Hz), 2.72 (dd, 1H, J ) 16.8 and 7.2 Hz),
diastereomers: IR (neat) 1724, 1681, 1454, 1364, 1325, and
1
3
-
1
1
2.83-3.07 (m, 5H), 3.68 (s, 3H), and 4.21-4.25 (m, 1H);
C
1
174 cm ; H NMR (400 MHz, CDCl
Hz, minor), 0.89 (t, 3H, J ) 7.6 Hz, major), 1.56-1.79 (m, 3H),
.85-1.97 (m, 2H), 2.00-2.15 (m, 2H), 2.21-2.39 (m, 3H), 2.43
d, 1H, J ) 4.8 Hz, major), 2.51-2.62 (m, 1H), 2.67 (dd, 1H, J
16.8 and 6.8 Hz), 2.74-2.92 (m, 2H), 3.11-3.18 (m, 1H),
.67 (s, 3H, minor), 3.68 (s, 3H, major), 4.19-4.25 (m, 1H);
3
) δ 0.75 (t, 3H, J ) 7.2
3
NMR (100 MHz, CDCl ) δ 27.2, 31.6, 33.4, 36.0, 38.9, 44.3,
4
5.1, 49.3, 52.1, 108.8, 136.1, 172.4, 174.0, and 207.8. Anal.
Calcd for C15 : C, 64.95; H, 6.91; N, 5.05. Found: C,
4.86; H, 6.84; N, 4.93.
9-Hydroxy-2-oxo-1,2,4,5,6,7,8,9,10,10a-decahydroaze-
1
(
H
19NO
4
6
)
(
3
13
pino[3,2,1-hi]-indol-10-yl) Acetic Acid Methyl Ester (27).
To a 5.9 g (21 mmol) sample of 26 in methanol (100 mL) at 0
3
C NMR (100 MHz, CDCl ) δ (major) 10.4, 22.8, 26.9, 27.3,
3
1
3
2
3
1.1, 31.9, 36.2, 37.6, 43.0, 49.6, 52.1, 54.3, 112.9, 138.6, 172.5,
°
C was added 8.7 g (23 mmol) of CeCl
was added 0.9 g (24 mmol) of NaBH
reaction mixture was stirred at 0 °C for 3 h and then 50 mL
of H O was added. The mixture was concentrated under
reduced pressure, diluted with H O, and extracted with EtOAc.
The combined organic layer was dried over anhydrous MgSO
3
‚7H
2
O. To this mixture
74.0, and 210.0; δ (minor) 11.4, 16.1, 27.1, 27.4, 30.4, 31.4,
4
in three portions. The
6.8, 41.7, 43.1, 46.6, 55.8, 114.9, 138.6, 172.4, 174.0, and
+
09.8; HRMS calcd for C17
H23NO
4
Li [M + Li] 312.1787, found
2
12.1786.
2
(8-Ethyl-9-hydroxy-2-oxo-1,2,4,5,6,7-hexahydroazepino-
4
[
3,2,1-hi]indol-10-yl)acetic Acid Methyl Ester (23). In
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography (5%
EtOAc/hexane) to give 4.5 g (77%) of 27 as a pale yellow oil:
addition to the above compound, 0.01 g (12%) of phenol 23 was
isolated as white solid: mp 140-142 °C; IR (film) 1727, 1686,
614, 1449, 1341, 1213, and 1170 cm-1; H NMR (400 MHz,
1
1
-1 1
IR (neat) 1732, 1439, 1403, and 1365 cm ; H NMR (400 MHz,
CDCl
3
) δ 1.12 (t, 3H, J ) 7.6 Hz), 1.96-2.04 (m, 4H), 2.41 (q,
H, J ) 7.6 H), 2.93-2.96 (m, 2H), 3.42 (s, 2H), 3.58 (s, 2H),
.74 (s, 3H), 3.94-3.97 (m, 2H), and 6.98 (s, 1H); 13C NMR
) δ 14.9, 19.9, 24.3, 25.9, 26.2, 34.7, 35.6, 40.1,
3.1, 115.6, 122.1, 124.5, 130.8 138.1, 148.5, 174.1, and 175.1.
: C, 67.31; H, 6.98; N, 4.62. Found:
CDCl
3
) δ 1.49-1.54 (m, 2H), 1.84-1.88 (m, 2H), 1.92-2.00 (m,
2
2
1
H), 2.09-2.24 (m, 4H), 2.38-2.60 (m, 6H), 2.83-2.89 (m, 1H),
13
3
.62-3.68 (m, 1H), 3.68 (s, 3H), and 4.52-4.29 (m, 1H);
C
(
100 MHz, CDCl
3
3
NMR (100 MHz, CDCl ) δ 27.1, 27.8, 33.5, 35.2, 36.0, 41.1,
5
4
1.6, 43.6, 43.7, 52.1, 71.0, 111.6, 135.3, 174.0, and 174.4. Anal.
Calcd for C15 : C, 64.48; H, 7.58; N, 5.02. Found: C,
4.37; H, 7.61; N, 4.96.
9-Hydroxy-2-oxo-1,2,4,5,6,7,7a,8,9,10-decahydroazepino-
3,2,1-hi]indol-10-yl)acetic Acid Methyl Ester (28). To a
.5 g (9.4 mmol) sample of 27 in 50 mL of methanol at 0 °C
Anal. Calcd for C17
H
21NO
4
H
21NO
4
C, 67.67; H, 7.00; N, 4.57.
8-Ethyl-9-hydroxy-2-oxo-1,2,4,5,6,7,8,9,10,10a-decahy-
droazepino[3,2,1-hi]indol-10-yl)acetic Acid Methyl Ester
24). To a 0.1 g (0.4 mmol) sample of 22 in methanol (2 mL)
cooled to 0 °C was added 0.16 g (0.4 mmol) of CeCl ‚7H O. To
this mixture was added 0.02 g (0.5 mmol) of NaBH in three
portions. The reaction mixture was stirred at 0 °C for 3 h
followed by the addition of 1 mL of H O. The mixture was
concentrated under reduced pressure, diluted with H O, and
extracted with EtOAc. The combined organic layer was dried
over anhydrous MgSO and the solvent was removed under
reduced pressure to provide a 3:1 mixture of diastereomers
4 and 25. The residue was purified by flash silica gel
6
(
(
[
2
(
3
2
was added a 2 N HCl solution, and the mixture was stirred
for 3 h at rt and was then extracted with EtOAc. The combined
4
4
organic layer was dried over anhydrous MgSO , and the
2
solvent was removed under reduced pressure. The residue was
purified by flash silica gel chromatography (3% EtOAc/hexane)
to give 1.9 g (70%) of 28 as a white solid: mp 129-131 °C; IR
2
4
-1 1
(
film) 1734, 1682, 1658, 1438, 1241, and 1165 cm ; H NMR
400 MHz, CDCl ) δ 1.21-1.53 (m, 4H), 1.80-1.98 (m, 3H),
.16 (ddd, 1H, J ) 13.2, 6.2, and 3.4 Hz), 2.36-2.42 (m, 1H),
.42-2.54 (m, 1H), 2.74-2.80 (m, 1H), 2.83-3.00 (m, 2H),
(
3
2
2
2
3
chromato-graphy (5% EtOAc/hexane). The major fraction
isolated from the column contained 0.045 g (39%) of 24 as a
pale yellow oil: IR (neat) 1735, 1672, 1439, 1357, and 1209
13
.51-3.59 (m, 1H), 3.67 (s, 3H), and 4.28-4.32 (m, 1H);
) δ 29.9, 30.3, 35.2, 36.5, 36.5, 37.9,
0.1, 40.4, 41.8, 52.1, 71.5, 109.5, 142.9, 174.6, and 176.5. Anal.
: C, 64.50; H, 7.58; N, 5.01. Found: C,
4.22; H, 7.51; N, 4.93.
9-Hydroxy-2-oxo-dodecahydroazepino[3,2,1-hi]indol-
0-yl)acetic Acid Methyl Ester (29). To an oven-dried,
C
NMR (100 MHz, CDCl
3
-
1 1
cm ; H NMR (400 MHz, CDCl
.36-1.47 (m, 1H), 1.67-1.88 (m, 1H), 1.91 (d, 1H, J ) 6.0
Hz), 1.91-2.09 (m, 2H), 2.10-2.18 (m, 1H), 2.18 (dd, 1H, J )
5.6 and 10.8 Hz), 2.30-2.47 (m, 3H), 2.60 (dd, 1H, J ) 15.6
and 9.0 Hz), 2.75-2.83 (m, 1H), 3.15-3.22 (m, 1H), 3.68 (s,
3
) δ 1.00 (t, 3H, J ) 7.2 Hz),
4
1
Calcd for C15
H
21NO
4
6
1
(
1
13
3
H), 3.99-4.05 (m, 1H), and 4.06-4.10 (m, 1H); C NMR (100
MHz, CDCl ) δ 12.2, 20.9, 26.3, 26.9, 28.4, 35.4, 35.8, 36.2 41.4,
1.6, 47.8, 52.0, 68.1, 114.6, 138.3, 173.5, and 174.4; HRMS
calcd for C17 307.1784, found 307.1779.
heavy-walled, high-pressure flask was added a solution of 0.5
3
g (1.8 mmol) of 27 dissolved in CH
2 2
Cl (50 mL). To this mixture
4
32,33
was added 0.07 g (0.09 mmol) of Crabtree’s catalyst.
The
H
25NO
4
flask was evacuated, refilled with hydrogen three times, placed
under an atmosphere of hydrogen (40 psi), and shaken for 10
h. The flask was evacuated, and the solvent was removed
under reduced pressure. The residue was purified by recrys-
tallization from acetone-hexane to give 0.4 g (80%) of 29 as a
colorless solid: mp 142-144 °C; IR (film) 1730, 1674, 1363,
The minor faction isolated from the column contained 0.01
g (13%) of 25 as a pale yellow oil: IR (neat) 1736, 1673, 1405,
and 1157 cm ; H NMR (400 MHz, CDCl ) δ 1.03 (t, 3H, J )
3
-
1 1
7
4
1
1
.6 Hz), 1.48-1.72 (m, 4H), 1.83-1.89 (m, 2H), 2.10-2.28 (m,
H), 2.33 (d, 1H, J ) 7.2 Hz), 2.41-2.48 (m, 3H), 2.54 (dd,
H, J ) 16.0 and 7.2 Hz), 2.97-3.03 (m, 1H), 3.11-3.14 (m,
H), 3.65-3.76 (m, 1H), 3.70 (s, 3H), and 4.18-4.22 (m, 1H);
-
1 1
3
1261, and 1217 cm ; H NMR (400 MHz, CDCl ) δ 1.18-1.25
(m, 2H), 1.54-1.59 (m, 2H), 1.70-1.79 (m, 3H), 1.81-1.90 (m,
2H), 1.97 (ddd, 1H, J ) 13.6, 4.4, and 2.4 Hz), 2.11 (dd, 1H, J
) 15.0 and 12.2 Hz), 2.17-2.25 (m, 1H), 2.32 (td, 2H, J ) 15.6
and 6.0 Hz), 2.45 (bs, 1H), 2.52-2.60 (m, 1H), 2.57 (dd, 2H, J
13
C NMR (100 MHz, CDCl
6.3, 39.0, 42.2, 42.8, 48.1, 52.2, 74.5, 117.1, 135.6, 174.5, and
74.5; HRMS calcd for C17 307.1784, found 307.1773.
3
) δ 15.2, 22.3, 27.1, 27.6, 31.7, 35.3,
3
1
H
25NO
4
5204 J. Org. Chem., Vol. 70, No. 13, 2005

Synthesis of (()-Stenine
15.6 and 5.0 Hz), 3.38-3.45 (m, 1H), 3.40 (dd, 1H, J ) 10.0
)
The reaction mixture was cooled to 25 °C, and 0.4 mL (2.7
2
mmol) of DBU was added. The mixture was diluted with H O
1
3
and 5.6 Hz), 3.66 (s, 3H), and 4.05-4.10 (m, 1H); C NMR
100 MHz, CDCl ) δ 29.8, 30.2, 31.4, 35.6, 35.9, 38.7, 40.4, 40.8,
1.2, 43.8, 52.1, 64.9, 71.3, 173.9, and 174.0. Anal. Calcd for
: C, 64.03; H, 8.24; N, 4.98. Found: C, 63.80; H,
.14; N, 4.91.
2-Oxo-1,2,4,5,6,7,7a,10,10a,10b-decahydroazepino[3,2,1-
hi]indol-10-yl)acetic Acid Methyl Ester (30). To a 1.9 g
6.6 mmol) sample of 29 in CH Cl (30 mL) at 0 °C was added
.9 mL (13 mmol) of NEt and 1.0 mL (13 mmol) of methane-
sulfonyl chloride. The mixture was stirred at 0 °C for 3 h and
then poured into H O and extracted with CH Cl . The com-
SO , and
(
3
2 2
and extracted with CH Cl . The combined organic layer was
4
dried over anhydrous MgSO and the solvent was removed
4
C
8
15
H
23NO
4
under reduced pressure. The residue was purified by flash
silica gel chromatography (4% EtOAc/hexane) to give 0.2 g
(62%) of 32 as a white solid: mp 125-126 °C; IR (KBr) 1772,
(
-
1 1
3
1694, 1376, 1263, and 1175 cm ; H NMR (400 MHz, CDCl )
(
1
2
2
δ 1.22-1.45 (m, 3H), 1.59-1.69 (m, 3H), 1.76-1.80 (m, 1H),
1.91-2.12 (m, 3H), 2.31 (dd, 1H, J ) 17.8 and 9.0 Hz), 2.35-
2.37 (m, 2H), 2.47-2.66 (m, 3H), 2.47-2.66 (m, 3H), 2.73-
2.80 (m, 1H), 3.36 (dd, 1H, J ) 10.8 and 7.6 Hz), 4.12-4.16
(m, 1H), 4.58 (dd, 1H, J ) 10.8 and 8.6 Hz), 5.13-5.17 (m,
3
2
2
2
bined organic layer was dried over anhydrous Na
2
4
1
3
the solvent was removed under reduced pressure to give the
3
2H), and 5.79-5.89 (m, 1H); C NMR (100 MHz, CDCl ) δ
titled compound as a thick oil which was immediately used in
28.6, 29.7, 30.4, 33.6, 34.7, 36.9, 37.9, 37.9, 40.4, 42.0, 42.5,
61.4, 80.9, 118.8, 134.3, 173.7, and 176.1. Anal. Calcd for
C H NO : C, 70.56; H, 8.01; N, 4.84. Found: C, 70.45; H,
1
the next step: H NMR (300 MHz, CDCl
3
) δ 1.22-1.29 (m,
2
2
3
3
H), 1.35-1.40 (t, 1H, J ) 7.2 Hz), 1.80-1.93 (m, 3H), 1.99-
1
7
23
3
.09 (m, 1H), 2.12-2.42 (m, 6H), 2.53-2.60 (m, 2H), 3.04 (s,
H), 3.14-3.17 (m, 1H), 3.45 (dd, 1H, J ) 10.5 and 5.7 Hz),
8.11; N, 4.78.
Furo[2,3-e](8-[1,3]dithiolan-2-ylmethyl-2-oxo-1,2,4,5,6,7,-
a,8,9,10,10a,10b-dodecahydroazepino[3,2,1-hi]indol)-12-
.69 (s, 3H), 4.10-4.15 (m, 1H), and 4.55-4.63 (m, 1H); 13
C
7
NMR (75 MHz, CDCl
8.9, 40.3, 40.7, 41.6, 52.2, 64.0, 80.4, 172.3, and 173.4.
To a sample of the above mesylate in toluene (30 mL) was
added 4.9 mL (33 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene
DBU). The mixture was heated at reflux for 6 h and then
cooled to 25 °C. The solution was poured into H O and
extracted with CH Cl . The combined organic layer was dried
over anhydrous MgSO , and the solvent was removed under
3
) δ 29.7, 30.1, 31.4, 34.8, 35.8, 37.8, 38.3,
one (34). To a 0.2 g (0.8 mmol) sample of 32 in a 1:1 mixture
of THF:H O (8 mL) was added 0.04 g (0.2 mmol) of osmium
3
2
tetroxide followed by 0.8 g (2.4 mmol) of sodium periodate. The
reaction mixture was stirred for 30 min at room temperature
(
and was poured into H
2
O and extracted with CH
2
Cl
2
. The
and
2
combined organic layer was dried over anhydrous MgSO
4
2
2
then filtered through a plug of Celite. The solvent was removed
under reduced pressure to give 0.17 g of furo[2,3-e][2-oxo-8-
4
reduced pressure. The residue was purified by flash silica gel
chromatography (5% EtOAc/hexane) to give 1.1 g (64%) of 30
as a white solid: mp 97-99 °C; IR (film) 1736, 1690, 1358,
(
2-oxoethyl)-1,2,4,5,6,7,7a,-8,9,10,10a,10b-dodecahydroazepino-
[
3,2,1-hi]indol]-12-one (33) as a light yellow oil which was
immediately used in the next step.
-
1 1
1
193, and 1162 cm ; H NMR (400 MHz, CDCl
3
) δ 1.21-1.38
To a 0.15 g (0.6 mmol) sample of the above compound in
(
m, 3H), 1.61-1.95 (m, 4H), 2.10 (dd, 1H, J ) 15.2 and 12.4
2 2
CH Cl (6 mL) cooled to -15 °C was added 0.06 mL (0.6 mmol)
Hz), 2.23-2.44 (m, 4H), 2.50-2.58 (m, 2H), 3.54 (dd, 1H, J )
of 1,2-ethanedithiol followed by 0.08 mL (0.6 mmol) of boron
1
1
0.4 and 6.8 Hz), 3.66 (s, 3H), 4.10-4.15 (m, 1H), 5.53 (dt,
H, J ) 10.0 and 1.6 Hz), and 5.63 (ddd, 1H, J ) 10.0, 4.8,
trifluoride-etherate. The reaction mixture was stirred at -15
1
3
°C for 2 h and then poured into H
Cl
SO
2
O and extracted with CH
2
-
-
3
and 2.8 Hz); C NMR (100 MHz, CDCl ) δ 29.7, 30.1, 31.0,
2
. The combined organic layer was dried over anhydrous Na
2
3
5.9, 37.1, 38.6, 39.2, 41.1, 41.3, 51.9, 63.5 130.6, 130.9, 172.6,
and 173.9. Anal. Calcd for C15 : C, 68.42; H, 8.04; N,
.32. Found: C, 68.36; H, 8.09; N, 5.28.
Furo[2,3-e](8-iodo-2-oxo-1,2,4,5,6,7,7a,8,9,10,10a,10b-
4
and the solvent was removed under reduced pressure. The
residue was purified by flash silica gel chromatography (5%
H
21NO
3
5
EtOAc/hexane) to give 0.095 g (50%) of 34 as a clear oil: IR
-
1 1
(
film) 1774, 1684, 1269, 1216, and 1165 cm ; H NMR (400
dodecahydroazepino-[3,2,1-hi]indol)-12-one (31). To a 0.3
g (1.0 mmol) sample of 30 in a 5:3 mixture of THF/MeOH (8
mL) at 0 °C was added an aqueous solution of LiOH (4.0 mL
of a 1.0 M solution). The mixture was stirred at 0 °C for 3 h
and was then acidified to pH 4 and concentrated under reduced
MHz, CDCl
3
) δ 1.22-1.49 (m, 3H), 1.58-1.66 (m, 1H), 1.71-
.80 (m, 3H), 1.92-2.10 (m, 4H), 2.13-2.20 (m, 1H), 2.32 (dd,
H, J ) 17.4 and 9.2 Hz), 2.45-2.51 (m, 1H), 2.53 (dd, 1H, J
1
1
)
)
15.0 and 6.6 Hz), 2.61 (p, 1H, J ) 9.2 Hz), 2.74 (dd, 1H, J
17.4 and 9.6 Hz), 3.19-3.29 (m, 4H), 3.45 (dd, 1H, J ) 10.8
pressure. The residue was diluted with H
CH Cl , and the solvent was removed under reduced pressure.
CN (10 mL) and cooled to
2
O and extracted with
and 7.6 Hz), 4.11-4.15 (m, 1H), 4.57 (dd, 1H, J ) 11.2 and
2
2
13
8
.4 Hz), and 4.77 (dd, J ) 9.6 and 5.2 Hz); C NMR (100 MHz,
CDCl ) δ 28.5, 30.0, 30.4, 33.8, 36.8, 37.8, 38.3, 38.4, 38.7, 42.1,
3.0, 43.4, 44.3, 55.0, 61.5, 83.5, 173.7, and 175.6. Anal. Calcd
for C18 : C, 58.84; H, 6.86; N, 3.81. Found: C, 58.75;
H, 6.71; N, 3.65.
The residue was suspended in CH
3
3
0
°C. To this mixture were added a 5% aqueous solution of
4
NaHCO
3
(10 mL) and 0.8 g (3.0 mmol) of I
2
. The mixture was
H
3 2
25NO S
stirred in the dark at 0 °C for 4 h and was poured into a 10%
aqueous solution of Na
combined organic layer was dried over anhydrous MgSO
the solvent was removed under reduced pressure. The residue
was purified by washing with cold CHCl to give 0.2 g (60%)
of 31 as a white solid: mp 155-156 °C; IR (film) 1762, 1674,
2
S
O
2 3
and extracted with CH
2
Cl
2
. The
4
, and
Furo[2,3-e](8-[1,3]dithiolan-2-yl-methyl-2-thioxo-
1,2,4,5,6,7,7a,8,9,10,10a,10b-dodecahydroazepino[3,2,1-hi]-
indol)-12-one (35). To a 0.07 g (0.2 mmol) sample of 34 in
3
2 2
CH Cl was added 0.04 (0.1 mmol) of Lawesson’s reagent. The
1
1
1
2
1
1
3
1
4
418, 1173, and 1135 cm-1
;
1
H NMR (400 MHz, CD
2
Cl
2
) δ
mixture was stirred at 25 °C for 3 h and then filtered through
a plug of silica gel with EtOAc. The solvent was removed under
reduced pressure and the residue was purified by flash silica
gel chromatography (3% EtOAc/hexane) to give 0.06 g (77%)
of 35 as a clear oil: IR (film) 1773, 1479, 1310, 1215, and 1119
.26-1.35 (m, 2H), 1.49-1.59 (m, 2H), 1.76-1.78 (m, 1H),
.88-2.08 (m, 3H), 2.33-2.51 (m, 3H), 2.58-2.65 (m, 1H),
.71-2.78 (m, 2H), 3.74 (dd, 1H, 11.2 and 8.0 Hz), 3.99 (dd,
H, J ) 10.0 and 7.6 Hz), 4.07-4.10 (m, 1H), and 4.93 (dd,
H, J ) 9.6 and 7.6 Hz); 13C NMR (75 MHz, CD
Cl
0.0, 30.9, 32.7, 34.3, 36.5, 37.1, 38.4, 42.2, 49.6, 61.1, 83.3,
-1
1
2
2
) δ 29.4,
cm ; H NMR (400 MHz, CDCl ) δ 1.22-1.53 (m, 3H), 1.63-
3
1.99 (m, 6H), 2.03-2.17 (m, 2H), 2.31 (dd, 1H, J ) 17.2 and
8.0 Hz), 2.59-2.77 (m, 3H), 2.79 (t, 1H, J ) 12.6 Hz), 3.12-
3.28 (m, 5H), 3.75 (dd, 1H, J ) 11.6 and 7.6 Hz), 4.55 (dd, 1H,
J ) 10.0 and 8.0 Hz), 4.73 (dd, 1H, J ) 9.6 and 5.6 Hz), and
3
73.3, and 174.8. Anal. Calcd for C14H18INO : C, 44.82; H,
.84; N, 3.73. Found: C, 44.62; H, 4.81; N, 3.65.
Furo[2,3-e](8-allyl-2-oxo-1,2,4,5,6,7,7a,8,9,10,10a,10b-
1
3
dodecahydroazepino-[3,2,1-hi]indol)-12-one (32). To a 0.5
g (1.3 mmol) sample of 31 in benzene (15 mL) was added 0.8
mL (2.7 mmol) of allyltributyltin and 0.04 g (0.3 mmol) of 2,2′-
azobis-isobutyronitrile (AIBN). The mixture was heated at
reflux for 6 h during which time the solid slowly dissolved.
4.74-4.78 (m, 1H); C NMR (100 MHz, CDCl
29.7, 33.3, 37.8, 38.3, 38.7, 39.2, 42.6, 43.3, 44.1, 47.3, 48.5,
51.8, 68.0, 83.2, 175.3, and 200.9. Anal. Calcd for C18
NO : C, 56.38; H, 6.58; N, 3.66. Found: C, 56.29; H, 6.51;
N, 3.49.
3
) δ 28.3, 28.8,
25
H -
2 3
S
J. Org. Chem, Vol. 70, No. 13, 2005 5205

Padwa and Ginn
Furo[2,3-e](8-ethyl-1,2,4,5,6,7,7a,8,9,10,10a,10b-dodecahydro-
azepino[3,2,1-hi]indol)-12-one (36). To a 0.01 g (0.026
mmol) sample of thioamide 35 in EtOH (0.5 mL) was added
an excess of W-2 Raney nickel. The mixture was heated at
reflux for 4 h and then cooled to room temperature and filtered
through a plug of Celite with ethanol. The solvent was removed
under reduced pressure, and the residue was purified by flash
silica gel chromatography on hexamethyldisilizane treated
silica (20 wt %) (5% EtOAc/hexane) to give 0.007 g (93%) of
%) (5% EtOAc/hexane) to give 0.002 g (65%) of stenine (15) as
a light yellow oil: IR (neat) 1794, 1774, 1381, 1327, and 1172
-
1 1
3
cm ; H NMR (600 MHz, CDCl ) δ 0.93 (t, 3H, J ) 7.5 Hz),
1.29 (d, 3H, J ) 7.2 Hz), 1.24-1.70 (m, 8H), 1.87-1.99 (m,
4H), 2.07-2.14 (m, 2H), 2.19-2.22 (m, 1H), 2.29-2.37 (m, 2H),
2.47-2.52 (m, 1H), 2.86-2.88 (m, 1H), 3.16-3.19 (m, 1H), 4.48
1
3
(dd, 1H, J ) 11.7 and 9.3 Hz); C NMR (150 MHz, CDCl ) δ
3
10.0, 15.2, 22.5, 26.4, 27.8, 29.8, 30.0, 40.1, 40.7, 42.7, 43.4,
4
27
7.7, 53.3, 55.3, 68.2, 80.7, and 179.9. Anal. Calcd for C17H -
3
6 as a light yellow oil: IR (neat) 1775, 1458, 1379, 1329, and
NO
2
: C, 73.59; H, 9.82; N, 5.05. Found: C, 73.47; H, 9.66; N,
-
1 1
1
3
175 cm ; H NMR (600 MHz, CDCl ) δ 0.91 (t, 3H, J ) 7.2
4
.83.
Hz), 1.21-1.67 (m, 9H), 1.88-2.05 (m, 4H), 2.17 (dd, 1H, J )
1
(
1.4 and 9.0 Hz), 2.24-2.30 (m, 2H), 2.42-2.48 (m, 2H), 2.71
dd, 1H, J ) 18.3 and 9.9 Hz), 2.85 (dt, 1H, J ) 12.6 and 4.2
Hz), 3.13 (td, 1H, J ) 9.0 and 4.2 Hz), and 4.57 (dd, 1H, J )
Acknowledgment. We appreciate the financial sup-
port provided by the National Science Foundation
(Grant No. CHE-0450779) and the National Institutes
of Health (GM 059384) for generous support of this
work. We thank our colleague, Dr. Kenneth Hardcastle,
for his assistance with the X-ray crystallographic studies
together with grants NSF CHE-9974864 and NIH S10-
RR13673. We wish to thank Professors David Hart and
Peter Wipf for providing spectral data for stenine as well
as an authentic sample.
1
2
6
9
1.4 and 9.0 Hz); 13C NMR (150 MHz, CDCl
6.7, 27.6, 29.7, 30.1, 34.2, 39.4, 39.8, 43.1, 43.3, 53.6, 55.1,
8.3, 83.2, and 177.2. Anal. Calcd for C16 : C, 72.95; H,
.57; N, 5.32. Found: C, 72.83; H, 9.46; N, 5.22.
()-Stenine (15). To a solution containing 0.005 mL (0.04
3
) δ 10.1, 22.7,
H
25NO
2
(
mmol) of diisopropylamine in THF (0.1 mL) cooled to 0 °C was
added n-butyllithium (0.02 mL of a 1.5 M solution in hexane).
After being stirred for 1 h, the mixture was cooled to -78 °C,
and a solution of 0.003 g (0.011 mmol) of 36 in THF (0.1 mL)
was added dropwise. To this mixture was added 0.005 mL
(
0.003 mmol) of HMPA. The solution was stirred at -78 °C
Supporting Information Available: An ORTEP drawing
for structure 29 as well as NMR data of various key com-
pounds. The authors have deposited atomic coordinates for
these structures with the Cambridge Crystallographic Data
Centre. This material is available free of charge via the
Internet at http://pubs.acs.org.
for 1 h followed by the addition of 0.003 mL (0.05 mmol) of
methyl iodide. After being stirred for 1 h, the reaction mixture
was poured into a saturated aqueous solution of NH
extracted with CH Cl . The organic phase was dried over
anhydrous Na SO and the solvent was removed under re-
4
Cl and
2
2
2
4
duced pressure. The residue was purified by flash silica gel
chromatography on hexamethyldisilzane treated silica (20 wt
JO050515E
5206 J. Org. Chem., Vol. 70, No. 13, 2005