A general synthetic entry to the pentacyclic Strychnos alkaloid family, using a [4 + 2]-cycloaddition/rearrangement cascade sequence

Article abstract of DOI:10.1021/jo8003716

(Chemical Equation Presented) The total synthesis of (±)- strychnopivotine, (±)-tubifolidine, (±)-strychnine, and (±)-valparicine is reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of a

Full text of DOI:10.1021/jo8003716

A General Synthetic Entry to the Pentacyclic Strychnos Alkaloid
Family, Using a [4 + 2]-Cycloaddition/Rearrangement Cascade
Sequence
Jutatip Boonsombat, Hongjun Zhang, Majid J. Chughtai, John Hartung, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed February 19, 2008
The total synthesis of (()-strychnopivotine, (()-tubifolidine, (()-strychnine, and (()-valparicine is
reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement
cascade of an indolyl-substituted amidofuran that delivers an aza-tetracyclic substructure containing the
ABCE-rings of the Strychnos alkaloid family. A large substituent group on the amide nitrogen atom
causes the reactive s-trans conformation of the amidofuran to be more highly populated, thereby facilitating
the Diels–Alder cycloaddition. The reaction also requires the presence of an electron-withdrawing
substituent on the indole nitrogen for the cycloaddition to proceed. The cycloaddition/rearrangement
cascade was remarkably efficient given that two heteroaromatic systems are compromised in the reaction.
Closure to the remaining D-ring of the Strychnos skeleton was carried out from the aza-tetracyclic
intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered
vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied
to (()-strychnopivotine (2), the only Strychnos alkaloid bearing a 2-acylindoline moiety in its pentacyclic
framework. A variation of this tactic was then utilized for a synthesis of the heptacyclic framework of
(()-strychnine. The total synthesis of (()-strychnine required only 13 steps from furanyl indole 18 and
proceeded in an overall yield of 4.4%.
Introduction
intensive study from the synthetic community. A great deal of
this continuing interest has focused on the synthesis of the
heptacyclic alkaloid strychnine (3).4,5 The related pentacyclic
curan family, however, has received far less attention.
Although there are many reports dealing with the preparation
of individual members of this genus, general approaches to the
core pentacyclic framework are limited.6–12 The several different
known strategies can be classified into those that form the crucial
Strychnos alkaloids belonging to the curan type constitute
an important group of architecturally complex and widely
distributed monoterpenoid indole alkaloids.1,2 The curan family
is characterized by the presence of a pentacyclic 3,5-ethanopyr-
rolo[2,3-d]carbazole framework (i.e., 1) bearing a two-carbon
appendage at C-20 and an oxidized one-carbon substituent (C-
17) at the C-16 position (Figure 1).3 During the past two
decades, the Strychnos alkaloid family has been the subject of
(3) The biogenetic numbering is used for pentacyclic structures such as 1,
see: Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508.
(4) (a) Robinson, R. Experientia 1946, 2, 28. (b) Holmes, H. L.; Openshaw,
H. T.; Robinson, R. J. Chem. Soc. 1946, 908.
(1) For leading reviews of Strychnos alkaloids, see: (a) Bosch, J.; Bonjoch,
J.; Amat, M. Alkaloids 1996, 48, 75 and references cited therein. (b) Bonjoch,
J.; Sole´, D. Chem. ReV. 2000, 100, 3455.
(5) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.;
Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749.
(2) Creasey, W. A. In The Monoterpene Indole Alkaloids; Saxton, J. E., Ed.;
Interscience: New York, 1983; p 800.
(6) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W.; Overman,
L. E. J. Am. Chem. Soc. 1993, 115, 3966.
10.1021/jo8003716 CCC: $40.75
Published on Web 04/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3539–3550 3539

Boonsombat et al.
SCHEME 1
FIGURE 1. Some representative Strychnos alkaloids.
quaternary center at C-7 in the last synthetic steps9–12 and those
in which the strategic bonds around C-7 are preformed at the
initial stages of the synthesis.6–8 The Overman group has
established a unique approach centered on an aza-Cope rear-
rangement/Mannich cyclization cascade that they successfully
used for the synthesis of akummicine, dehydrotubifoline, and
strychnine depending on the particular precursor employed in
the key cascade sequence.6 The Bonjoch group has made use
of cis-3a-(2-nitrophenyl)octahydroindol-4-ones as particularly
useful building blocks for assembling the pentacyclic ABCDE
ring system of the Strychnos alkaloids.7 Several Strychnos
alkaloids were prepared by Kuehne starting from a tryptophan
derivative that was employed in a condensation-sigmatropic
rearrangement-cyclization cascade to form the ABCE core
structure. The D-ring was then introduced Via an SN2
reaction.8Despite these earlier efforts, new and efficient
approaches toward the Strychnos pentacyclic framework are
still important as they would allow not only the synthesis of
other members of this family of natural products (i.e.,
strychnopivotine (2)) but also related non-natural analogues
possessing biological activity. Along these lines, we have
recently become involved in the development and optimiza-
tion of a new approach for the construction of the pentacyclic
framework present in the Strychnos system.13 In this paper, we
report a concise stereocontrolled approach toward the total
synthesis of several Strychnos alkaloids wherein an efficient [4
+ 2]-cycloaddition/rearrangement sequence previously devel-
oped in our laboratory plays a crucial role.14
Results and Discussion
Our synthetic approach toward the pentacyclic core found in
the Strychnos alkaloids was guided by a long-standing interest
in developing new applications of the intramolecular [4 +
2]-cycloaddition/rearrangement cascade of 2-amidofurans toward
the synthesis of complex natural products.14 Our recently
completed syntheses of (()-erysotramidine15 and (()-lycori-
cidine16 nicely demonstrate the utility of this process for the
construction of various alkaloids. On the basis of our earlier
work, we felt that we could also use this methodology for the
synthesis of strychnopivotine (2) and related alkaloids and this
is illustrated in Scheme 1. Strychnopivotine (2) was isolated
from the root bark of Strychnos Variabilis and its structural
elucidation was reported by Angenot and co-workers in
1980.17,18 As illustrated in Scheme 1, our retrosynthetic analysis
of strychnopivotine (2) involves closure of the D-ring in the
final step of the synthesis by a Bonjoch/Solé palladium-catalyzed
intramolecular coupling of the amido-tethered vinyl iodide 5
with a keto–enolate generated anion.19,20 A critical step of our
synthetic plan relies upon the efficient construction of the
tetracyclic substructure found in 5 by an intramolecular [4 +
2]-cycloaddition/rearrangement cascade of 2-amidofuran 6.
While the furan ring of 6 provides the 4π-constituent, the
dienophilic partner corresponds to an indole moiety. Previous
(7) (a) Solé, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994, 59, 7803. (b)
Solé, D.; Bonjoch, J.; García-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron Lett.
1996, 37, 5213. (c) Bonjoch, J.; Solé, D.; García-Rubio, S.; Bosch, J. J. Am.
Chem. Soc. 1997, 119, 7230.
(14) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998, 63,
5304. (b) Ginn, J. D.; Padwa, A. Org. Lett. 2002, 4, 1515. (c) Lynch, S. M.;
Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643. (d) Wang, Q.; Padwa, A. Org.
Lett. 2004, 6, 2189. (e) Padwa, A.; Ginn, J. D. J. Org. Chem. 2005, 70, 5197.
(f) Padwa, A.; Bur, S. K.; Zhang, H. J. Org. Chem. 2005, 70, 6833.
(15) Padwa, A.; Wang, Q. J. Org. Chem. 2006, 71, 7391.
(8) (a) Kuehne, M. E.; Xu, F.; Brook, C. S. J. Org. Chem. 1994, 59, 7803.
(b) Kuehne, M. E.; Xu, F. J. Org. Chem. 1997, 62, 7950. (c) Kuehne, M. E.;
Xu, F. J. Org. Chem. 1998, 63, 9434. (d) Kuehne, M. E.; Wang, T.; Seraphin,
D. J. Org. Chem. 1996, 61, 7873.
(16) Zhang, H.; Padwa, A. Org. Lett. 2006, 8, 247.
(17) Tits, M.; Tavernier, D.; Angenot, L. Phytochemistry 1980, 19, 1531.
(18) For some synthetic studies, see:(a) Teuber, H.-J.; Tsaklakidis, C.; Bats,
J. W. Liebigs Ann. Chem. 1992, 461. (b) Solé, D.; Urbaneja, X.; Cordero-Vargas,
A.; Bonjoch, J. Tetrahedron 2007, 63, 10177.
(9) (a) Dadson, B. A.; Harley-Mason, J.; Foster, G. H. J. Chem. Soc., Chem.
Commun. 1968, 1233. (b) Dadson, B. A.; Harley-Mason, J. J. Chem. Soc.,
Chem. Commun. 1970, 665. (c) Harley-Mason, J.; Taylor, C. G. J. Chem. Soc.,
Chem. Commun. 1970, 812. (d) Crawley, G. C.; Harley-Mason, J. J. Chem.
Soc., Chem. Commun. 1971, 685. (e) Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T.;
Takeda, E. Tetrahedron 1983, 39, 3657. (f) Amat, M.; Coll, M.-D.; Passarella,
D.; Bosch, J. Tetrahedron: Asymmetry 1996, 7, 2775.
(10) Amat, A.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55, 6299.
(11) (a) Kuehne, M. E.; Frasier, D. A.; Spitzer, T, D. J. Org. Chem. 1991,
56, 2696. (b) Kuehne, M. E.; Brook, C. S.; Frasier, D. A.; Xu, F. J. Org. Chem.
1994, 59, 5977.
(19) (a) Solé, D.; Peidró, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225. (b) Solé,
D.; Diaba, J.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746. (c) Bonjoch, J.; Diaba,
F.; Puigbó, G.; Peidró, E.; Solé, D. Tetrahedron Lett. 2003, 44, 8387. (d) Solé,
D.; Urbaneja, X.; Bonjoch, J. AdV. Synth. Catal. 2004, 346, 1646. (e) Solé, D.;
Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461.
(20) For some other examples of intramolecular Pd-catalyzed vinylations,
see:(a) Piers, E.; Oballa, R. M. Tetrahedron Lett. 1995, 36, 5857. (b) Yu, J.;
Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao, X.; Cook, J. M.
J. Org. Chem. 2003, 68, 7565. For an example of a Ni(0) promoted intramolecular
coupling of ketone enolates with aryl halides, see:(c) Semmelhack, M. F.; Chong,
B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem.
Soc. 1975, 97, 2507.
(12) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem. Soc.
1996, 118, 9804.
(13) For a preliminary report, see:(a) Zhang, H.; Boonsombat, J.; Padwa, A.
Org. Lett. 2007, 9, 279.
3540 J. Org. Chem. Vol. 73, No. 9, 2008

The Pentacyclic Strychnos Alkaloid Family
SCHEME 2
SCHEME 3
studies revealed that the 2,3-double bond of the indole ring could
serve as a dienophile in the IMDAF reaction only when the
indole nitrogen atom possessed an electron-withdrawing sub-
stituent.21 Further, to increase the efficiency of the cycloaddition
process, it was found that incorporation of a sp2 center within
the tether was beneficial and this was routinely accomplished
by using an amide linkage.21 However, when a secondary amide
was utilized, no cycloaddition occurred due to the propensity
of these amides to adopt the s-cis conformation 9.22 This
unfavorable conformation could be overcome by replacing the
amide hydrogen with a larger group, which caused the reactive
s-trans conformation 10 to be more highly populated, and
therefore the cycloaddition would be more prone to occur
(Scheme 2).
First Approach toward (()-Strychnopivotine (2). With this
background in mind, our synthetic endeavors toward strych-
nopivotine (2) began by the N-alkylation of indole 11 with Z-1-
bromo-2-iodobut-2-ene, which afforded furanyl amide 6 in
58%.23 The presence of the 2-iodo-2-butenyl side chain would
serve not only in the contemplated D-ring closing reaction, but
also to bias the amide into the desired s-trans conformation.
Indeed, heating a sample of 6 in toluene at 200 °C in a sealed
tube initiated the desired cycloaddition/rearrangement cascade
to give 5 in 80% yield and the stereospecificity of the cascade
process ensured that a cis-BC ring fusion was formed (Scheme
3). Reduction of the enamido π-bond present in 5 was achieved
via a three-step sequence.
SCHEME 4
This involved (a) protection of the keto group with ethylene
glycol to give ketal 12, (b) exposure of 12 to NaCNBH3 in the
presence of TFA to give 13, and (c) hydrolysis of the ketal to
the corresponding carbonyl group. Most surprisingly, our
attempts to induce D-ring closure by subjecting tetracycle 14
to the Bonjoch/Solé cyclization conditions19 (Pd(PPh3)4/PhOK)
provided the unexpected ꢀ-diketone 15 in 35% yield as the only
isolable product from the reaction mixture. A possible mech-
anism for this unusual reorganization is outlined in Scheme 4
and involves an initial migration of the acetyl group from the
indoline nitrogen onto the oxygen atom of the enolate anion.
The transient enol-ester 16 so formed then undergoes a
subsequent acyl group shift24 to furnish ꢀ-diketone 17. The
acetyl group present in the newly formed diketone 17 is close
enough in proximity to the vinyl center to undergo the enolate
cross-coupling reaction. It would appear as though coupling at
the more acidic position is seriously retarded as a consequence
of severe nonbonded interactions in its transition state for this
insertion.
Second Generation Approach toward (()-Strychnopivotine
(2). Considering the difficulty we encountered with the pal-
ladium-catalyzed intramolecular coupling reaction of the tetra-
cyclic keto-lactam 14, we decided to slightly modify our
approach toward (()-strychnopivotine (2). Comparison of the
geometry of 14 with the various systems studied by Bonjoch
and Solé19 led us to speculate that the presence of the amido
carbonyl group in the E-ring significantly increased the rigidity
of the skeleton thereby creating an element of strain in the
transition state for the critical coupling reaction. We reasoned
that by reducing the lactam carbonyl group to the corresponding
pyrrolidine, the source of strain in the transition state would be
(21) Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon, P.; Wang,
Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735.
(22) Stewart, W. E.; Siddall, T. H. Chem. ReV. 1970, 70, 517. See also: Eliel,
E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons:
New York, 1994; p 620.
(23) For the preparation of Z-1-bromo-2-iodobut-2-ene, see:Gamez, P.;
Ariente, C.; Gore, J.; Cazes, B. Tetrahedron 1998, 54, 14825.
(24) (a) Young, F. G.; Frostick, F. C.; Sanderson, J. J.; Hauser, C. R. J. Am.
Chem. Soc. 1950, 72, 3635. (b) Mao, C.-L.; Frostick, F. C.; Man, E. H.; Manyik,
R. M.; Wells, R. L.; Hauser, C. R. J. Org. Chem. 1969, 34, 1425.
J. Org. Chem. Vol. 73, No. 9, 2008 3541

Boonsombat et al.
SCHEME 5
of the indoline nitrogen present in 21 with 2,4-dimethoxyben-
zaldehyde in the presence of NaBH(OAc)3 afforded the
25
nitrogen-protected 2,4-dimethoxybenzylamine (DMB) derivative
in 94% yield. Oxidation of the resulting secondary alcohol to
the corresponding ketone 22 occurred smoothly in 79% yield
with tetrapropylammonium perruthenate (TPAP).26 The stage
was now set for the completion of the synthesis. The key
palladium-catalyzed cross-coupling was carried out on a sample
of 22 with Pd(PPh3)4 and PhOK. Gratifyingly, the reaction
proceeded smoothly to furnish aza-pentacycle 23 in 61% yield.
Finally, removal of the 2,4-dimethoxybenzyl group by reaction
with HCl followed by N-acetylation with acetic anhydride gave
(()-strychnopivotine (2) in 65% yield for the last two steps.
The synthetic sample obtained was identical with the reported
spectral properties of (()-strychnopivotine (2).17
(()-Tubifolidine (25). The synthesis of (()-tubifolidine (25),
a Strychnos alkaloid isolated by Schmid and co-workers in
1964,27 was chosen as the next synthetic target to further
highlight the methodology. Before its isolation, this alkaloid
was a known compound that had been obtained by a partial
synthesis in the context of a chemical correlation effected for
the structural elucidation of a more complex member of the
Strychnos family.28,29 Our synthesis of (()-tubifolidine (25) was
readily realized by the sequential reduction of intermediate 23
that had been prepared earlier. Thus, treatment of 23 under
Wolff–Kishner type conditions (Na, hydrazine in ethylene
glycol)30 served to remove the carbonyl group as well as the
dimethoxybenzyl protecting group in 62% yield to furnish alkene
24. Next, reduction of the C-20 appendage was attempted
(Scheme 6). The reaction solvent was found to be critical for
successful reduction, as was the necessity to buffer the
hydrogenation reaction with Na2CO3. By carrying out the
catalytic reduction of 24 with Pd/C as the catalyst in THF,
the sole product obtained in 50% yield corresponded to (()-
tubifolidine (25).9,29
(()-Valparicine (29). Kam and co-workers reported in 2006
on the isolation of the alkaloid valparicine (29) from the stem-
bark extracts of K. arborea, a member of the Kopsia family.31
Initial studies indicated that this alkaloid shows pronounced
cytotoxic activity against KB and Jurkat cells.32 It has been
proposed that valparicine (29) is biogenetically related to
pericine (26) by means of a Polonovski reaction wherein the
E-ring of the alkaloid is formed by cyclization of the indole
ring onto the resulting iminium ion as indicated in Scheme 7.31
Although strictly not a member of the Strychnos family, the
structural similarity with strychnopivotine (2) triggered our
interest in a synthesis of (()-valparicine (29). Having a sample
of 23 on hand, we treated this intermediate with trimethyl-
relieved and the desired coupling reaction would occur.
Unfortunately, all of our attempts to prepare the necessary
pyrrolidine by lactam reduction also resulted in the simultaneous
loss of the iodo group on the side chain. To circumvent this
over-reduction problem, we opted to reduce the lactam carbonyl
group prior to the installation of the vinyl iodide side chain.
For this purpose, furanyl indole 18 was prepared from indole
acetic acid (7) in a manner analogous to that used for the
synthesis of 6. The presence of the large o-methylbenzyl group
on the amido nitrogen atom causes the reactive s-trans
conformer to be more highly populated thereby promoting
the intramolecular cycloaddition. Indeed, the cycloaddition/
rearrangement cascade of 18 was quite facile given that two
aromatic systems are compromised in the reaction. Thus, heating
a sample of 18 at 150 °C in a microwave reactor in the presence
of a trace amount of MgI2 for 30 min afforded the desired aza-
tetracycle 19 in 95% yield (Scheme 5).
Our synthesis of the more advanced tetracycle 22 required
for eventual D-ring cyclization began by stereoselective reduc-
tion of the keto group in 19 with NaBH4 followed by
N-deacetylation using NaOMe. The lactam carbonyl group was
then reduced with LiAlH4 and the resulting enamine was further
reduced using NaBH(OAc)3 to give alcohol 20 as the major
diastereomer in 65% yield for the four-step sequence (Scheme
5). Removal of the o-methylbenzyl group by catalytic hydro-
genation followed by N-alkylation with Z-1-bromo-2-iodobut-
2-ene furnished alcohol 21 in 56% overall yield. Condensation
(25) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(26) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(27) Kump, W. G.; Patel, M. B.; Rowson, J. M.; Schmid, H. HelV. Chim.
Acta 1964, 47, 1497.
(28) Smith, G. F.; Wrobel, J. T. J. Chem. Soc. 1960, 972.
(29) For previous total syntheses see: (a) Harley-Mason, J. Pure Appl. Chem.
1975, 41, 167. (b) Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J.
Org. Chem. 1998, 63, 3657. (c) Alvarez, M.; Salas, M.; De Veciana, A.; Lavilla,
R.; Bosch, J. Tetrahedron Lett. 1990, 31, 5089.
(30) (a) Toyota, M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65, 4565. (b)
Marino, J. P.; Rubio, M. A.; Cao, G.; de Dios, A. J. Am. Chem. Soc. 2002, 124,
13398.
(31) Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Lett. 2006, 47, 5037.
(32) Lim, K.-H.; Hiraku, O.; Komiyama, K.; Koyano, T.; Hayashi, M.; Kam,
T.-S. J. Nat. Prod. 2007, 70, 1302.
3542 J. Org. Chem. Vol. 73, No. 9, 2008

The Pentacyclic Strychnos Alkaloid Family
SCHEME 6
bromide and sodium tert-butoxide38 for 40 min at 25 °C resulted
in the formation of (()-valparicine (29) together with recovered
starting material thereby completing the first total synthesis of
this alkaloid. The spectral data for the mixture obtained was
perfectly consistent with that reported by Kam and co-workers.31
(()-Strychnine (3). Strychnine, a well-known poison found
in large amounts in the Indian poison nut, has a long and rich
history as one of the more notorious members of the Strychnos
alkaloid family.1,2 Over the years, strychnine has attracted
considerable attention from the synthetic community mainly due
to its complex heptacyclic structure, containing 24 skeletal atoms
and six contiguous stereogenic centers. The alkaloid was first
isolated in 181839 and its highly toxic properties result from its
interaction with the glycine receptor site, thereby blocking the
flux of chloride ions, which results in disruption of nerve-cell
signaling.40 Extensive degradative and structural studies cul-
minated in the elucidation of strychnine’s structure by Robinson
in 1946.4,41 The relative and absolute configurations were later
confirmed by X-ray crystallographic analysis.42 Nearly 40 years
SCHEME 7
SCHEME 8
after Woodward’s pioneering achievement of strychnine,5
a
numberofotherresearchgroupshavereportedonitssynthesis.43,44
Strychnine still remains a popular target for demonstrating new
reactions and novel synthetic strategies.
Most of the reported syntheses of strychnine employ either
isostrychnine (32) or the Wieland-Gumlich aldehyde 33 as an
advanced intermediate. The Prelog-Taylor cyclization of iso-
(38) Kamal, A.; Howard, P. W.; Reddy, B. S. N.; Reddy, B. S. P.; Thurston,
D. E. Tetrahedron 1997, 53, 3223.
(39) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8, 323.
(40) (a) Aprison, M. H. In Glycine Neurotransmission; Wiley: New York,
1990; pp 1-23. (b) Grenningloh, G.; Rienitz, A.; Schmitt, B.; Methfessel, C.;
Zensen, M.; Beyreuther, K.; Gundelfinger, E. D.; Betz, H. Nature 1987, 328,
215. (c) Kleckner, N. W.; Dingledine, R. Science 1988, 241, 835.
(41) Openshaw, H. T.; Robinson, R. Nature 1946, 157, 438.
(42) (a) Robertson, J. H.; Beevers, C. A. Nature 1950, 165, 690. (b)
Robertson, J. H.; Beevers, C. A. Acta Crystallogr. 1951, 4, 270. (c) Bokhoven,
C.; Schoone, J. C.; Bijvoet, J. M. Acta Crystallogr. 1951, 4, 275. (d) Mostad,
A. Acta Chem. Scand. 1985, 39B, 705. (e) Peerdeman, A. F. Acta Crystallogr.
1956, 9, 824. (f) Nagarajan, K.; Weissmann, Ch.; Schmid, H.; Karrer, P. HelV.
Chim. Acta 1963, 46, 1212.
silylmethyl lithium and cerium(III) chloride33 and this was
followed by heating the resulting alcohol with potassium hydride
in THF, which delivered the C-16 methylene unit of 30 in 69%
yield. The DMB protecting group was then removed by warming
30 with 1.0 M HCl/MeOH to produce 31 in 49% yield (Scheme
8). To complete the synthesis, all that remained was an oxidation
of the C-N single bond between the C2 and N1 position. A
number of different oxidizing conditions were evaluated includ-
ing IBX,34 TPAP,35 Swern oxidation,36 and MnO2.37 However,
each of these reactions failed to deliver the expected product.
Eventually, it was found that stirring a sample of 31 with copper
(43) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker,
H. U.; Schenker, K. Tetrahedron 1963, 19, 247.
(44) (a) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.; Merritt,
A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403. (b) Magnus, P.; Giles, M.;
Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt, A.; Kim, C. S.;
Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116. (c) Stork, G. Presented at the
Ischia Advanced School of Organic Chemistry, Ischia Porto, Italy, September
21, 1992. (d) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.
1993, 115, 9293. (e) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem.
Soc. 1995, 117, 5776. (f) Kuehne, M. E.; Xu, F. J. Org. Chem. 1993, 58, 7490.
(g) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9427. (h) Rawal, V. H.;
Iwasa, S. J. Org. Chem. 1994, 59, 2685. (i) Sole´, D.; Bonjoch, J.; García-Rubio,
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Bonjoch, J.; García-Rubio, S.; Peidró, E.; Bosch, J. Chem. Eur. J. 2000, 6, 655.
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2000, 2, 2479. (l) Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.;
Schmidt, M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324. (m) Ito,
M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem. Soc.
2001, 123, 8003. (n) Nakanishi, M.; Mori, M. Angew. Chem., Int. Ed. 2002, 41,
1934. (o) Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. J. Am. Chem. Soc.
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3261. (q) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki,
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Shibasaki, M. Tetrahedron 2004, 60, 9569. (s) Kaburagi, Y.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246.
(33) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281.
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(35) Yamaguchi, J.; Takeda, T. Chem. Lett. 1992, 21, 1933.
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J. Org. Chem. Vol. 73, No. 9, 2008 3543

Boonsombat et al.
SCHEME 9
SCHEME 11
SCHEME 10
yield. This was followed by N-alkylation with Z-1-bromo-2-
iodo-4-(methoxymethoxy)but-2-ene to give alcohol 37 in 80%
yield. Condensation of the indoline nitrogen present in 37 with
25
2,4-dimethoxybenzaldehyde in the presence of NaBH(OAc)3
afforded the N-protected DMB derivative in 80% yield. Oxida-
tion of the resulting secondary alcohol to the corresponding
ketone 34 occurred smoothly in 69% yield with use of
tetrapropylammonium perruthenate (TPAP) (Scheme 11).26
We were pleased to find that the critical D-ring of strychnine
could be readily constructed by a palladium-catalyzed intramo-
lecular coupling of the amino-tethered vinyl iodide with the
keto–enolate derived from 34. The critical palladium-catalyzed
cyclization was carried out on a sample of 34 with Pd(PPh3)4
and PhOK. The reaction proceeded smoothly to furnish the aza-
pentacycle 38 in 56% yield (Scheme 12). Our initial attempts
to convert the keto group of 38 into the corresponding
enol ether 35 using methoxymethylene-triphenylphosphorane
(MeOCHdPPh3) were unsuccessful, probably as a consequence
of steric congestion about the ketone. Consequently, we turned
our attention to the phosphine oxide reagent MeOCH2P(O)Ph2,
whose anion is sterically less demanding and more nucleophilic
compared to the phosphorane MeOCdPPh3.47,48 Thus, treatment
of MeOCH2P(O)Ph2 with LDA in THF gave the lithio anion,
which reacted smoothly with ketone 38 at 0 °C to provide 35
as a single diastereomer in 72% isolated yield. The last major
hurdle involved an acid-promoted deprotection/hydrolysis of 35
into the Wieland-Gumlich aldehyde 33. The hydrolysis was
satisfactorily accomplished by the treatment of 35 with 3 N HCl
in THF at 55 °C for 10 h, which gave 33 in 54% isolated yield.
By using shorter reaction times and following the reaction by
NMR spectroscopy, we found that the initial reaction involved
sequential deprotection of the MOM group followed by hy-
drolysis of the DMB group to give 39 as a transient species.
The resulting enol ether portion of 39 was subsequently
converted into the Wieland-Gumlich aldehyde 33 (Scheme 12).
Although the conversion of 33 into strychnine had been reported
by Robinson in 1953,46 we decided to reproduce the described
protocol for the sake of a complete synthesis. Thus, the final
biomimetic condensation of 33 with malonic acid, sodium
acetate, and acetic acid provided (()-strychnine (3) in 80% yield
strychnine (32) to strychnine (3)45 (Scheme 9), however, suffers
from an unfavorable 3:1 equilibration ratio of these two
compounds. From this perspective, the alternative biomimetic
route to strychnine involving condensation of the Wieland-
Gumlich aldehyde 33 with an acetate equivalent for the
formation of the G ring seems to be the more attractive
approach,46 as it avoids the unfavorable equilibrium mixture.
With this in mind, we set out to prepare the Wieland-Gumlich
aldehyde 33 using the above IMDAF cascade/rearrangement
methodology.
As illustrated in Scheme 10, our retrosynthesis of strychnine
(3) relies upon the efficient construction of the pentacyclic
intermediate 35, which in turn would be derived from the
previously prepared tetracycle 19 used in the earlier strych-
nopivotine (2) synthesis. As before, we planned to generate the
D-ring of 35 by a palladium-catalyzed intramolecular coupling
of the amido-tethered vinyl iodide 34 with its keto–enolate.19,20
Intermediate 34 should be available from 19 by reduction of
the enamido group followed by amide deprotection and a
subsequent N-alkylation. The synthesis of tetracycle 34 began
from the previously prepared pyrrolidinyl substituted alcohol
20 as was outlined in Scheme 5. Removal of the o-methylbenzyl
group by catalytic hydrogenation furnished 36 in 70% isolated
(45) Prelog, V.; Battegay, J.; Taylor, W. I. HelV. Chim. Acta 1948, 31, 2244.
(46) Anet, F. A. L.; Robinson, R. Chem. Ind. 1953, 245.
3544 J. Org. Chem. Vol. 73, No. 9, 2008

The Pentacyclic Strychnos Alkaloid Family
SCHEME 12
(q, 1H, J ) 6.4 Hz), 6.18 (dd, 1H, J ) 3.6 and 1.2 Hz), 6.39 (dd,
1H, J ) 3.2 and 2.0 Hz), 7.20–7.42 (m, 5H), and 8.40 (d, 1H, J )
7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 21.6, 23.9, 30.7, 58.5,
102.7, 106.0, 111.2, 115.4, 116.5, 118.7, 123.4, 123.7, 125.2, 130.0,
134.1, 135.5, 140.2, 147.1, 168.4, and 170.9.
7-Acetyl-3-(2-iodobut-2-enyl)-3,5,6a,7-tetrahydropyrrolo[2,3-
d]carbazole-2,6-dione (5). A solution containing 0.40 g (0.87
mmol) of furanyl indole 6 in 1.3 mL of toluene was heated in a
sealed tube at 200 °C for 2 h. The reaction mixture was cooled to
rt and then concentrated under reduced pressure. The crude residue
was purified by flash silica gel column chromatography to provide
0.32 g (80%) of 5 as a pale yellow oil: IR (thin film) 3416, 3030,
2971, 2904, 1721, 1685, 1470, and 1388 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.84 (d, 3H, J ) 6.4 Hz), 2.37 (s, 3H), 2.72 (d, 1H, J )
16.8 Hz), 2.89 (dd, 1H, J ) 16.8 and 2.8 Hz), 3.00 (d, 1H, J )
16.8 Hz), 4.49 (d, 1H, J ) 15.2 Hz), 4.49 (s, 1H), 4.69 (d, 1H, J
) 15.2 Hz), 5.13 (dd, 1H, J ) 6.0 and 2.8 Hz), 6.03 (q, 1H, J )
6.4 Hz), 7.07 (t, 1H, J ) 7.6 Hz), 7.25–7.32 (m, 2H), and 8.16 (d,
1H, J ) 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 21.8, 23.9, 36.6,
45.7, 49.7, 51.8, 71.3, 94.6, 101.2, 117.9, 121.7, 125.2, 129.5, 134.0,
134.6, 140.6, 140.9, 169.6, 171.6, and 202.7; HRMS calcd for
[(C20H19IN2O3) + H]+ 463.0513, found 463.0516.
7-Acetyl-3-(2-iodobut-2-enyl)-6-(1,3-dioxolane)-3,5,6a,7-tet-
rahydropyrrolo[2,3-d]carbazole-2-one (12). To a solution contain-
ing 0.20 g (0.31 mmol) of ketone 5 in 6 mL of benzene was added
0.35 mL (6.2 mmol) of ethylene glycol followed by 0.06 g (0.3
mmol) of p-toluenesulfonic acid. The solution was heated at reflux
for 1 h, cooled to rt, and then poured into an aqueous NaHCO3
solution and extracted with EtOAc. The combined organic layer
was dried over Na2SO4 then filtered and the solvent was removed
under reduced pressure. The crude residue was purified by flash
silica gel column chromatography to give 0.18 g (85%) of 12 as
an orange solid: mp 192–193 °C; IR (thin film) 1726, 1680, 1655,
and with a 4.4% overall yield for the 13-step reaction sequence
starting from furanyl indole 18.
1
1476, and 1388 cm-1; H NMR (400 MHz, CDCl3) δ 1.70 (dd,
1H, J ) 15.6 and 3.2 Hz), 1.80 (dt, 3H, J ) 6.4 and 1.6 Hz), 2.25
(br s, 4H), 2.53 (d, 1H, J ) 17.2 Hz), 3.03 (d, 1H, J ) 17.2 Hz),
3.80–3.90 (m, 1H), 3.90–4.07 (m, 3H), 4.40 (d, 1H, J ) 15.6 Hz),
4.45 (br s, 1H), 4.64 (dt, 1H, J ) 15.6 and 1.6 Hz), 5.03 (dd, 1H,
J ) 7.6 and 3.2 Hz), 6.10 (qd, 1H, J ) 6.4 and 1.2 Hz), 7.10 (td,
1H, J ) 7.6 and 1.2 Hz), 7.55 (d, 1H, J ) 7.6 Hz), and 7.94 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 17.6, 22.6, 24.8, 32.1, 45.9,
47.0, 50.3, 52.8, 64.5, 65.8, 66.3, 73.9, 96.8, 97.5, 103.1, 109.6,
117.7, 123.1, 125.7, 129.7, 136.2, 142.0, and 173.2. Anal. Calcd
for C22H23IN2O4: C, 52.19; H, 4.58; N, 5.53, found C, 51.82; H,
4.70; N, 5.27.
In conclusion, a concise synthesis of several members of the
Strychnos family of alkaloids is reported. A central step in the
synthesis consists of an intramolecular [4 + 2]-cycloaddition/
rearrangement cascade of an indolyl-substituted amidofuran,
which delivers an aza-tetracyclic substructure containing the
ABCE-rings of the Strychnos alkaloid family. Closure of the
remaining D-ring was carried out from the aza-tetracyclic
intermediate by an intramolecular palladium-catalyzed enolate-
driven cross-coupling between the N-tethered vinyl iodide and
the keto group. We believe that the chemistry described herein
will be useful for the preparation of a variety of other alkaloids.
7-Acetyl-3-(2-iodobut-2-enyl)-6-(1,3-dioxolane)-3,5,6a,7-hexahy-
dropyrrolo[2,3-d]carbazole-2-one (13). To a solution containing
0.20 g (0.3 mmol) of enamide 12 in 2 mL of CH2Cl2 at 0 °C was
added 1 mL of TFA followed by 0.09 g (1.4 mmol) of NaCNBH3
in small portions over 30 min at 0 °C. The mixture was stirred for
1 h at 0 °C, diluted with CH2Cl2, and then quenched with an
aqueous NaHCO3 solution and extracted with CH2Cl2. The com-
bined organic layer was dried over Na2SO4 then filtered and the
solvent was removed under reduced pressure. The crude residue
was purified by flash silica gel column chromatography to give
0.11 g (53%) of 13 as a pale yellow oil: IR (thin film) 3416, 2960,
Experimental Section
2-(1-Acetyl-1H-indol-3-yl)-N-furan-2-yl-N-(2-iodobut-2-enyl)-
acetamide (6). To a 4.0 g (8.6 mmol) solution of indole 1121 in 35
mL of DMF at 0 °C was added 0.38 g (9.4 mmol) of NaH in small
portions and the resulting mixture was stirred at 0 °C for 2 h. A
solution of 2.7 g (10.3 mmol) of cis-1-bromo-2-iodobut-2-ene23 in
20 mL of DMF was added at 0 °C and this was followed by the
addition of 0.6 g (1.7 mmol) of tetrabutylammonium iodide. The
reaction mixture was stirred at 0 °C for 2 h and was then slowly
quenched with an aqueous NaHCO3 solution and extracted with
EtOAc. The organic layer was dried over Na2SO4 then filtered and
the solvent was removed under reduced pressure. The crude residue
was purified by flash silica gel column chromatography to give
3.7 g (67%) of 6 as a pale yellow oil: IR (thin film) 3124, 2914,
1
2914, 2873, 1701, 1655, and 1199 cm-1; H NMR (400 MHz,
CDCl3) δ 1.4–1.64 (m, 2H), 1.76–2.00 (m, 2H), 1.83 (d, 3H, J )
6.4 Hz), 2.35 (s, 3H), 2.42 (d, 1H, J ) 16.8 Hz), 2.66 (d, 1H, J )
16.8 Hz), 3.51–3.60 (m, 1H), 3.68–3.82 (m, 3H), 3.93–4.12 (m,
2H), 4.23 (s, 1H), 4.57 (d, 1H, J ) 14.8 Hz), 5.98 (q, 1H, J ) 6.4
Hz), 7.04–7.17 (m, 2H), 7.21–7.28 (m, 1H), and 8.02 (br d, 1H, J
) 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 20.5, 21.8, 23.4, 27.5,
46.6, 50.3, 50.8, 55.5, 64.5, 65.9, 70.8, 103.1, 108.5, 117.1, 120.4,
124.3, 128.5, 133.3, 134.8, 143.7, 169.8, and 173.0; HRMS calcd
for [(C22H23IN2O4) + H]+ 509.0932, found 509.0929.
1
1701, 1450, and 1388 cm-1; H NMR (400 MHz, CDCl3) δ 1.70
(d, 3H, J ) 6.0 Hz), 2.58 (s, 3H), 3.62 (s, 2H), 4.59 (s, 2H), 5.72
(47) Earnshaw, C.; Wallis, C. J.; Warren, S. J. Chem. Soc., Perkin Trans. 1
7-Acetyl-3-(2-iodobut-2-enyl)-3,3a,4,5,6a,7-hexahydropyr-
rolo[2,3-d]carbazol-2,6-dione (14). To a solution of 0.04 g (0.08
mmol) of acetal 13 in 2.0 mL of THF was added 3.0 mL of 6 N
1979, 3099.
(48) Patel, D. V.; Schmidt, R. J.; Gordon, E. M. J. Org. Chem. 1992, 57,
7143.
J. Org. Chem. Vol. 73, No. 9, 2008 3545

Boonsombat et al.
HCl and the resulting mixture was heated at 55 °C for 3 h. After
cooling to rt, the reaction mixture was quenched with solid NaHCO3
and then diluted with H2O and EtOAc. The organic phase was
separated and the aqueous layer was extracted with EtOAc. The
combined organic layer was washed with H2O and brine, dried over
MgSO4, and filtered. After concentration under reduced pressure,
the residue was taken up in 1.5 mL of CH2Cl2 and cooled to 0 °C.
To this solution was added 50 µL of triethylamine followed by 13
µL of acetyl chloride. The reaction mixture was stirred at rt for 2 h
and then quenched by the addition of a saturated NaHCO3 solution.
The organic layer was separated and the aqueous phase was
extracted with CH2Cl2. The combined organic layer was washed
with H2O then brine and dried over MgSO4. After removal of the
solvent under reduced pressure, the residue was purified by flash
silica gel chromatography to give 24 mg (64%) of ketone 14 as a
colorless oil: IR (neat) 1728, 1698, 1666, and 1398 cm-1; 1H NMR
(600 MHz, CD3CN) δ 1.79 (d, 3H, J ) 6.0 Hz), 1.97–2.01 (m,
1H), 2.03 (s, 3H), 2.21–2.26 (m, 1H), 2.29–2.34 (m, 1H), 2.42 (d,
1H, J ) 16.8 Hz), 2.66–2.72 (m, 1H), 3.04 (d, 1H, J ) 16.8 Hz),
4.09–4.12 (m, 1H), 4.11 (d, 1H, J ) 15.0 Hz), 4.76 (d, 1H, J )
15.0 Hz), 4.85 (s, 1H), 6.10 (q, 1H, J ) 6.0 Hz), 7.07 (t, 1H, J )
7.5 Hz), 7.26 (t, 1H, J ) 7.5 Hz), 7.36 (d, 1H, J ) 7.5 Hz), and
8.14 (d, 1H, J ) 7.5 Hz); 13C NMR (150 MHz, CDCl3) δ 22.1,
23.7, 24.3, 33.6, 46.9, 51.8, 53.6, 57.5, 74.1, 102.6, 118.2, 121.5,
124.8, 130.0, 131.1, 136.0, 142.6, 169.9, 172.8, and 204.1.
(0.16 mmol) of MgI2. The vessel was charged with nitrogen and
sealed with a microwave rubber cap. The sample was then placed
in microwave reactor and irradiated at 200 W at 150 °C for 30
min. After the mixture was cooled to rt, the solvent was removed
under reduced pressure. The resulting residue was purified by flash
silica gel column chromatography with a40% EtOAc/hexane
mixture as the eluent to provide 0.29 g (95%) of 19 as a pale yellow
solid: mp 184–186 °C; IR (thin film) 1716, 1657, 1594, 1467, 1384,
1
353, and 749 cm-1; H NMR (400 MHz, CDCl3) δ 2.34 (s, 3H),
2.42 (s, 3H), 2.71 (d, 1H, J ) 16.4 Hz), 2.81 (dd, 1H, J ) 20.4
and 2.4 Hz), 2.94 (dd, 1H, J ) 20.4 and 5.6 Hz), 3.10 (d, 1H, J )
16.4 Hz), 4.57 (s, 1H), 4.79 (d, 1H, J ) 16.0 Hz), 4.89 (d, 1H, J
) 16.0 Hz), 4.98 (dd, 1H, J ) 5.6 and 2.4 Hz), 6.92–7.05 (m, 2H),
7.12–7.28 (m, 5H), and 8.15 (d, 1H, J ) 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 19.3, 23.8, 36.6, 42.1, 45.7, 49.9, 71.2, 94.7, 117.9,
120.8, 125.1, 126.2, 126.7, 127.7, 129.5, 130.8, 132.7, 134.2, 135.5,
140.7, 140.9, 169.6, 171.9, and 202.9; HRMS calcd for [(C24H22-
N2O3) + H]+ 387.1703, found 387.1715.
3-(2-Methylbenzyl)-2,3,3a,4,5,6,6a,7-octahydro-1H-pyrrolo[2,3-
d]carbazol-6-ol (20). To a solution containing 1.0 g (2.6 mmol)
of enamide 19 in 24 mL of a 1:1 mixture of EtOH/THF at 0 °C
was added 0.098 g (2.6 mmol) of NaBH4 in one portion. The
mixture was stirred for 30 min at 0 °C, then quenched with an
aqueous NaHCO3 solution and extracted with EtOAc. The combined
organic phase was dried over Na2SO4 and the solvent was removed
under reduced pressure. The crude residue was taken up in 50 mL
of THF and 5.2 mL (2.6 mmol) of 0.1 N NaOMe in MeOH solution
was added. After being stirred for 15 min, the reaction was
quenched with an aqueous NH4Cl solution and extracted with
EtOAc. The combined organic phase was dried over Na2SO4 and
the solvent was removed under reduced pressure. The crude residue
was taken up in 50 mL of THF and 7.8 mL (7.8 mmol) of a 1 M
LiAlH4 in THF solution was added dropwise. The mixture was
heated at reflux for 3 h, cooled to 0 °C, and quenched by the
dropwise addition of 0.3 mL of H2O followed by 0.3 mL of a 15%
aqueous NaOH solution and 0.87 mL of H2O. The mixture was
filtered through Celite and then washed with EtOAc. The filtrate
was dried over Na2SO4 and the solvent was removed under reduced
pressure. The crude residue was taken up in 50 mL of 1,2-
dichloroethane, then cooled to -20 °C, and 2.2 g (10.4 mmol) of
NaBH(OAc)3 was gradually added over a 1 h interval. The reaction
mixture was stirred for an additional 2 h, diluted with CHCl3, and
quenched with an aqueous NaHCO3 solution and extracted with
CHCl3. The combined organic layer was dried over Na2SO4 and
the solvent was removed under reduced pressure. The crude residue
was purified by flash silica gel column chromatography to give
0.56 g (65%) of 20 as a pale yellow oil: IR (thin film) 3367, 3293,
Pentacyclic Diketone 15. To a solution containing 24 mg (0.052
mmol) of the above compound in 2.0 mL of THF at rt was
sequentially added 15 mg (0.16 mmol) of phenol, 0.13 mL of 1 M
t-BuOK in t-BuOH, and 6.0 mg (0.016 mmol) of Pd(PPh3)4. The
reaction mixture was heated at reflux under an argon atmosphere
for 4 h and then cooled to rt. The mixture was then diluted with 1
N NaOH and extracted with CH2Cl2. The combined organic layer
was washed with 1 N NaOH, H2O, and brine, then dried over
MgSO4. After concentration under reduced pressure, the residue
was purified by flash silica gel chromatography to give 7 mg (35%)
of the pentacyclic ketone 15 as a pale yellow solid: IR (neat) 3488,
1
1690, 1484, and 1413 cm-1; H NMR (400 MHz, CDCl3) δ 1.66
(dd, 3H, J ) 7.2 and 2.0 Hz), 1.77 (dd, 1H, J ) 15.6 and 3.6 Hz),
1.94 (ddd, J ) 15.6, 5.6, and 2.4 Hz), 2.45 (d, 1H, J ) 16.0 Hz),
2.65 (s, 1H), 2.68 (d, 1H, J ) 16.0 Hz), 3.21 (s, 1H), 3.23 (d, 1H,
J ) 16.0 Hz), 3.48 (d, 1H, J ) 16.0 Hz), 3.47–3.55 (m, 1H), 3.85
(d, 1H, J ) 5.6 Hz), 4.44 (s, 1H), 4.55 (d, 1H, J ) 16.0 Hz), 5.85
(q, 1H, J ) 7.2 Hz), 7.15 (td, 1H, J ) 7.6 and 0.8 Hz), 7.29 (d,
1H, J ) 7.6 Hz), 7.34 (td, 1H, J ) 7.6 and 0.8 Hz), and 7.65 (d,
1H, J ) 7.6 Hz); HRMS calcd for [(C20H21N2O3) + H]+ 337.1547,
found 337.1556.
2-(1-Acetyl-1H-indol-3-yl)-N-furan-2-yl-N-(2-methylbenzyl)-
acetamide (18). To a solution containing 5.7 g (20 mmol) of furanyl
indole 11 in 100 mL of DMF at 0 °C was added 0.8 g (20 mmol)
of NaH. The mixture was stirred for 2 h at 0 °C, and then a solution
of 5.6 g (24 mmol) of R-iodo-o-xylene in 30 mL of DMF was
added at 0 °C. The reaction mixture was stirred for 3 h and was
then quenched with H2O and extracted with EtOAc. The combined
organic layer was dried over NaHCO3 and the solvent was removed
under reduced pressure. The crude residue was purified by flash
silica gel column chromatography to give 4.7 g (61%) of 18 as a
yellow solid: mp 96–97 °C; IR (neat) 1695, 1674, 1601, 1442, 1368,
1258, and 739 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.11 (s, 3H),
2.58 (s, 3H), 3.65 (s, 2H), 4.90 (s, 2H), 5.63 (d, 1H, J ) 2.4 Hz),
6.32 (dd, 1H, J ) 3.6 and 2.4 Hz), 7.14–7.44 (m, 10H), and 8.43
(d, 1H, J ) 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 18.9, 23.9,
30.6, 49.4, 105.5, 111.2, 115.5, 116.5, 118.7, 123.4, 123.6, 125.3,
125.8, 127.6, 128.9, 130.0, 130.2, 134.3, 135.5, 136.5, 140.1, 147.6,
168.4, and 170.9. Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74;
N, 7.25, found C, 74.35; H, 5.81, N, 7.11.
1720, 1650, 1605, 1401, and 739 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 1.46–2.00 (m, 6H), 2.21 (ddd, 1H, J ) 13.6, 9.2 and 4.4
Hz), 2.42–2.50 (m, 1H), 2.81 (td, 1H, J ) 9.6 and 4.0 Hz), 3.42
(d, 1H, J ) 12.8 Hz), 3.78 (d, 1H, J ) 12.8 Hz), 3.82 (d, 1H, J )
4.0 Hz), 4.16–4.23 (m, 1H), 6.67 (d, 1H, J ) 8.0 Hz), 6.78 (t, 1H,
J ) 7.6 Hz), 7.07 (td, 1H, J ) 7.6 and 1.2 Hz), 7.12–7.18 (m, 4H),
and 7.26–7.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 19.1, 19.6,
25.9, 35.9, 50.9, 54.4, 54.7, 67.8, 68.6, 69.1, 109.5, 119.0, 123.3,
125.5, 126.8, 127.6, 129.2, 130.0, 137.1, 137.6,137.7, and 149.4;
HRMS calcd for [(C22H26N2O) + H]+ 335.2118, found 335.2114.
2,3,3a,4,5,6,6a,7-Octahydro-1H-pyrrolo[2,3-d]carbazol-6-ol (36).
To a 0.06 g (0.09 mmol) sample of Pd(OH)2/C (Pearlman’s catalyst)
in a sealed tube was added a solution of 0.1 g (0.3 mmol) of
pyrrolidine 20 in 1 mL of MeOH. The mixture was repeatedly
flushed with H2 and was then stirred at rt under 60 psi for 2 days.
At the end of this time, the mixture was filtered through Celite and
washed with 30 mL of MeOH, 30 mL of a 1:1 mixture of MeOH/
CH2Cl2, and 30 mL of triethylamine/MeOH/CH2Cl2 (5:25:70). The
combined organic solvent was removed under reduced pressure and
the crude residue was purified by flash silica gel column chroma-
tography to give 0.56 g (68%) of the titled compound as a pale
yellow oil: IR (thin film) 3321, 3045, 1602, 1487, 1467, 1057, and
7-Acetyl-3-(2-methylbenzyl)-3,5,6a,7-tetrahydropyrrolo[2,3-
d]carbazole-2,6-dione (19). To a solution of 0.3 g (0.8 mmol) of
indoyl furan 18 in 4 mL of toluene in a CEM Discover microwave
10 mL tube equipped with a magnetic stir bar was added 0.007 g
3546 J. Org. Chem. Vol. 73, No. 9, 2008

The Pentacyclic Strychnos Alkaloid Family
1
1
726 cm-1; H NMR (400 MHz, CD3OD) δ 1.38–1.51 (m, 1H),
pale yellow oil: IR (neat) 1711, 1606, 1484, and 1208 cm-1; H
1.65–1.74 (m, 1H), 1.79–1.90 (m, 2H), 2.14–2.32 (m, 2H),
3.04–3.12 (m, 1H), 3.36–3.46 (m, 1H), 3.55 (ddd, 1H, J ) 12.0,
9.2, and 8.0 Hz), 3.80 (d, 1H, J ) 4.4 Hz), 3.88 (dt, 1H, J ) 10.8
and 4.4 Hz), 6.64 (d, 1H, J ) 8.0 Hz), 6.66 (t, 1H, J ) 7.2 Hz),
6.99 (td, 1H, J ) 8.0 and 1.2 Hz), and 7.03 (d, 1H, J ) 7.2 Hz);
13C NMR (100 MHz, CDCl3) δ 26.2, 27.1, 32.5, 44.2, 56.4, 64.6,
68.5, 69.0, 111.3, 120.1, 122.6, 129.7, 136.7, and 151.1.
NMR (400 MHz, CDCl3) δ 1.77 (dd, 3H, J ) 6.4 and 1.2 Hz),
1.84–1.97 (m, 2H), 2.12–2.22 (m, 2H), 2.29–2.52 (m, 4H), 2.98
(d, 1H, J ) 14.0 Hz), 3.12–3.17 (m, 1H), 3.59 (s, 1H), 3.59 (dt,
1H, J ) 14.0 and 1.2 Hz), 3.59 (s, 1H), 3.78 (s, 3H), 3.79 (s, 3H),
4.12 (d, 1H, J ) 16.2 Hz), 4.25 (d, 1H, J ) 16.2 Hz), 5.83 (q, 1H,
J ) 6.4 Hz), 6.38–6.43 (m, 2H), 6.55 (d, 1H, J ) 7.6 Hz), 6.76
(td, 1H, J ) 7.6 and 0.8 Hz), and 7.03–7.12 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 20.4, 21.9, 32.5, 37.8, 47.8, 51.6, 55.4, 55.5,
59.1, 64.6, 67.9, 81.8, 98.6, 103.8, 107.5, 108.8, 118.4, 118.7, 122.8,
128.7, 129.5, 131.5, 132.8, 152.7, 158.4, 160.3, and 210.4; HRMS
calcd for [(C27H31N2O3I) + H]+ 559.1452, found 559.1445.
Pentacyclic Ketone 23. To a solution of 0.09 g (0.16 mmol) of
ketone 22 in 6.0 mL of THF at room temperature was added 46
mg (0.48 mmol) of phenol, 0.4 mL of 1 M t-BuOK in t-BuOH,
and 19 mg (0.016 mmol) of Pd(PPh3)4, respectively. The reaction
mixture was heated at reflux under an argon atmosphere for 3 h
and then cooled to room temperature. The mixture was diluted with
1 N NaOH and extracted with CH2Cl2. The combined organic
extracts were washed with 1 N NaOH, H2O, and brine, dried over
MgSO4, and filtered. After concentration under reduced pressure,
the residue was subjected to silica gel chromatography to give 42
mg (61%) of pentacyclic ketone 23 as a colorless oil: IR (neat)
3-(2-Iodobut-2-enyl)-2,3,3a,4,5,6,6a,7-octahydro-1H-pyrrolo[2,3-
d]carbazol-6-ol (21). To a solution of 25 mg (0.11 mmol) of the
above compound in 1.0 mL of DMF at rt was added 0.2 mL of
H2O and 75 mg (0.55 mmol) of K2CO3. The resulting solution was
cooled to 0 °C and was treated with a solution of 31 mg (0.12
mmol) of Z-1-bromo-2-iodobut-2-ene23 in 0.6 mL of DMF. The
reaction mixture was stirred at 0 °C for 12 h, quenched with H2O,
and extracted with Et2O. The combined organic layer was washed
with H2O and brine, then dried over MgSO4. After concentration
under reduced pressure, the residue was purified by flash silica gel
chromatography to give 35 mg (79%) of 21 as a colorless oil: IR
(neat) 3359, 2793,1607, 1483, 1464, and 1049 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.42–1.49 (m, 1H), 1.56–1.73 (m, 3H), 1.77 (d,
3H, J ) 6.4 Hz), 1.93–2.00 (m, 2H), 2.19–2.26 (m, 1H), 2.47 (dd,
1H, J ) 7.2 and 3.6 Hz), 2.66 (ddd, 1H, J ) 9.2, 9.2, and 6.8 Hz),
2.89 (ddd, 1H, J ) 9.2, 9.2, and 4.4 Hz), 3.14 (d, 1H, J ) 13.8
Hz), 3.44 (d, 1H, J ) 13.8 Hz), 3.81 (d, 1H, J ) 3.6 Hz), 4.03 (b
rs, 1H), 4.21–4.29 (m, 1H), 5.84 (q, 1H, J ) 6.4 Hz), 6.66 (d, 1H,
J ) 7.6 Hz), 6.76 (td, 1H, J ) 7.6 and 1.0 Hz), 7.06 (td, 1H, J )
7.6 and 1.0 Hz), and 7.21 (dd, 1H, J ) 7.6 and 1.0 Hz); 13C NMR
(150 MHz, CDCl3) δ 20.2, 21.9, 26.0, 36.2, 50.2, 54.7, 64.2, 66.7,
68.7, 69.2, 109.6, 110.4, 119.2, 123.8, 127.9, 130.9, 137.1, and
149.8; HRMS calcd for [(C18H23N2OI) + H]+ 411.0928, found
411.0925.
1
1713, 1606, 1485, 1462, and 1207 cm-1; H NMR (600 MHz,
CDCl3) δ 1.60 (d, 3H, J ) 6.6 Hz), 2.01 (dd, 1H, J ) 11.9 and 5.7
Hz), 2.08–2.15 (m, 2H), 2.30 (dt, 1H, J ) 14.4 and 3.6 Hz), 2.80
(ddd, 1H, J ) 10.8, 10.8, and 6.6 Hz), 2.97 (d, 1H, J ) 15.0 Hz),
3.31 (t, 1H, J ) 8.1 Hz), 3.37 (s, 1H), 3.73 (s, 1H), 3.77–3.81 (m,
8H), 4.36 (d, 1H, J ) 15.6 Hz), 4.49 (d, 1H, J ) 15.6 Hz), 5.51
(q, 1H, J ) 6.6 Hz), 6.39 (dd, 1H, J ) 8.4 and 1.8 Hz), 6.44 (d,
1H, J ) 1.8 Hz), 6.46 (d, 1H, J ) 8.4 Hz), 6.69 (t, 1H, J ) 7.5
Hz), 7.00 (d, 1H, J ) 7.5 Hz), 7.08 (t, 1H, J ) 7.5 Hz), and 7.10
(d, 1H, J ) 7.5 Hz); 13C NMR (150 MHz, CDCl3) δ 13.6, 24.5,
39.3, 44.6, 46.4, 52.3, 52.9, 55.4, 55.6, 58.6, 61.3, 75.0, 98.6, 103.8,
107.5, 118.0, 118.7, 122.0, 125.5, 129.0, 129.6, 130.2, 132.1, 151.3,
158.6, 160.3, and 210.8; HRMS calcd for [(C27H30N2O3) + H]+
431.2329, found 431.2325.
(()-Strychnopivotine (2). To a flask containing 20 mg (0.047
mmol) of pentacyclic ketone 23 was added 1.4 mL of HCl (1.2 N
HCl in MeOH) and the mixture was heated at 55 °C for 5 h. After
cooling to room temperature, the solution was diluted with a
saturated K2CO3 solution and extracted with CH2Cl2. The combined
organic layer was washed with H2O and brine, dried over MgSO4,
and filtered. The solvent was removed under reduced pressure and
the resulting residue, which contained the deprotected indoline, was
used in the next step without any purification: IR (neat) 3352, 2923,
1712, 1604, 1464, and 1109 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.57 (dt, 3H, J ) 6.8 and 1.6 Hz), 1.73 (d, 1H, J ) 14.8 Hz), 1.90
(ddd, 1H, J ) 12.4, 7.6, and 7.6 Hz), 2.18 (dd, 1H, J ) 12.4 and
6.4 Hz), 2.48 (dt, 1H, J ) 14.8 and 3.6 Hz), 2.91 (d, 1H, J ) 15.2
Hz), 2.95–3.00 (m, 1H), 3.38 (dd, 1H, J ) 10.0 and 8.0 Hz), 3.43
(br s, 1H), 3.77 (s, 1H), 3.90 (br t, 2H, J ) 7.6 Hz), 4.94 (br s,
1H), 5.57 (q, 1H, J ) 6.8 Hz), 6.75–6.85 (m, 2H), 6.97 (d, 1H, J
) 6.8 Hz), and 7.08 (td, 1H, J ) 7.6 and 1.2 Hz); 13C NMR (100
MHz, CDCl3) δ 13.2, 25.0, 39.8, 45.5, 51.9, 53.7, 59.2, 59.7, 68.7,
111.1, 120.0, 122.2, 127.1, 128.7, 129.5, 129.9, 151.3, and 210.8.
The crude residue was taken up in a mixture of 1.0 mL of
pyridine and 0.5 mL of CH2Cl2. To this solution was added 88 µL
(0.94 mmol) of Ac2O and the mixture was stirred at room
temperature for 48 h. The reaction mixture was quenched with a
saturated NaHCO3 solution and extracted with CH2Cl2. The organic
extracts were washed with a saturated NaHCO3 solution, H2O, and
brine, dried over MgSO4, and filtered. After concentration under
reduced pressure, the residue was purified by flash silica gel
chromatography to give 9 mg (65%) of (()-strychnopivotine (2)
as an amorphous solid: IR (neat) 2924, 1645, 1511, 1456, 1246,
and 1038 cm-1; 1H NMR (600 MHz, CD3CN) δ 1.54 (dt, 3H, J )
7.2 and 1.8 Hz), 1.60 (d, 1H, J ) 9.0 Hz), 1.76–1.82 (m, 1H), 2.05
(s, 3H), 2.13 (dd, 1H, J ) 13.2 and 6.0 Hz), 2.56 (dt, 1H, J ) 9.0
7-(2,4-Dimethoxybenzyl)-3-(2-iodobut-2-enyl)-2,3,3a,4,5,6,6a,7-
octahydro-1H-pyrrolo[2,3-d]carbazol-6-ol. To a solution of 0.1 g
(0.26 mmol) of 21 in 6.0 mL of 1,2-dichloroethane at 0 °C was
added 52 mg (0.3 mmol) of 2,4-dimethoxybenzaldehyde and 0.14 g
(65 mmol) of NaBH(OAc)3, followed by the dropwise addition of
44 µL (0.8 mmol) of acetic acid. The reaction mixture was stirred
at 0 °C for 10 min and then at rt for 12 h. The solution was
quenched with a saturated K2CO3 solution and extracted with
CH2Cl2. The combined organic layer was washed with H2O and
brine, then dried over MgSO4. After concentration under reduced
pressure, the residue was purified by flash chromatography to give
0.14 g (94%) of the titled compound as a pale yellow oil: IR (neat)
1
3500, 1606, 1485, 1259, and 1036 cm-1; H NMR (600 MHz,
CDCl3) δ 1.52–1.65 (m, 4H), 1.72–1.78 (m, 1H), 1.79 (d, 3H, J )
6.3 Hz), 1.92–1.97 (m, 1H), 1.99–2.08 (m, 2H), 2.32–2.37 (m, 1H),
2.74 (t, 1H, J ) 3.0 Hz), 3.01 (d, 1H, J ) 13.5 Hz), 3.05–3.10 (m,
1H), 3.47 (d, 1H, J ) 3.6 Hz), 3.61 (d, 1H, J ) 13.5 Hz), 3.80 (s,
3H), 3.82 (s, 3H), 4.26–4.30 (m, 1H), 4.32 (d, 1H, J ) 16.2 Hz),
4.50 (d, 1H, J ) 16.2 Hz), 5.86 (q, 1H, J ) 6.3 Hz), 6.43 (d, 1H,
J ) 8.4 Hz), 6.45 (d, 1H, J ) 8.4 Hz), 6.49 (s, 1H), 6.68 (t, 1H,
J ) 7.2 Hz), 7.03 (d, 1H, J ) 8.1 Hz), 7.05 (d, 1H, J ) 7.2 Hz),
and 7.25 (t, 1H, J ) 8.1 Hz); 13C NMR (150 MHz, CDCl3) δ 18.8,
21.9, 24.8, 39.8, 48.1, 51.2, 53.7, 55.5, 55.6, 65.5, 65.6, 68.2, 73.8,
98.7, 104.2, 107.1, 110.4, 118.0, 119.8, 121.8, 128.2, 129.2, 131.0,
135.3, 152.9, 158.3, and 160.2; HRMS calcd for [(C27H33N2OI) +
H]+ 561.1609, found 561.1623.
7-(2,4-Dimethoxybenzyl)-3-(2-iodobut-2-enyl)-1,2,3,3a,4,5,6,6a,7-
octahydropyrrolo[2,3-d]carbazol-6-one (22). To a solution con-
taining 0.12 g (0.21 mmol) of the above compound and 0.1 g of 4
Å molecular sieves in 9.0 mL of CH3CN at 0 °C was added 38 mg
(0.31 mmol) of N-methylmorpholine-N-oxide and 22 mg (0.06
mmol) of tetrapropylammonium perruthenate. After the solution
was stirred at 0 °C for 20 min, the cooling bath was removed and
the mixture was stirred at rt for an additional 3 h. The reaction
mixture was then filtered through Celite and the filtrate was
concentrated under reduced pressure. The residue was purified by
flash silica gel chromatography to afford 0.09 g (79%) of 22 as a
J. Org. Chem. Vol. 73, No. 9, 2008 3547

Boonsombat et al.
and 3.6 Hz), 2.88 (d, 1H, J ) 15.0 Hz), 3.00–3.06 (m, 1H), 3.30
(dd, 1H, J ) 9.9 and 8.1 Hz), 3.45 (s, 1H), 3.83 (d, 1H, J ) 15.0
Hz), 3.94 (s, 1H), 4.64 (s, 1H), 5.64 (q, 1H, J ) 7.2 Hz), 7.06 (td,
1H, J ) 7.2 and 1.2 Hz), 7.16 (d, 1H, J ) 7.2 Hz), 7.22 (td, 1H,
J ) 7.2 and 1.2 Hz), and 8.13 (d, 1H, J ) 7.2 Hz); 13C NMR (150
MHz, CD3CN) δ 13.7, 24.2, 26.6, 26.7, 41.5, 47.5, 52.4, 54.2, 59.8,
60.3, 71.2, 72.0, 117.4, 123.2, 123.4, 125.4, 127.2, 127.9, 128.3,
129.2, 129.7, 130.3, 131.8, 133.7, 144.4, 171.2, and 208.5; HRMS
calcd for [(C20H22N2O2) + H]+ 323.1754, found 323.1753.
(()-19,20-Dehydrotubifolidine (24). To a solution containing
0.07 g (0.16 mmol) of the pentacyclic ketone 23 in 10 mL of
ethylene glycol at rt was added 1.3 mL (41 mmol) of hydrazine
hydrate followed by 0.67 g (29 mmol) of sodium metal. After the
sodium metal had dissolved, the reaction mixture was heated to
160 °C for 1 h, then at 190 °C for 1 h, and finally at 210 °C for
3 h. After cooling to rt, the reaction mixture was partitioned between
H2O and CH2Cl2 and extracted with CH2Cl2. The combined organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was purified
by flash silica gel column chromatography to give 0.03 g (62%) of
24 as a white solid: mp 169–171 °C; IR (neat) 3360, 2925, 1607,
A sample of 40 mg (0.38 mmol) of potassium hydride (60% in
mineral oil) was washed with 5 mL of hexane and then suspended
in 0.5 mL of THF. To this suspension was added the above crude
residue in 0.5 mL of THF. The resulting mixture was stirred at rt
for 2 h, quenched by pouring the mixture into a saturated aqueous
NH4Cl solution, and then extracted with CH2Cl2. The combined
organic layer was washed with brine, dried over Na2SO4, then
filtered and the solvent was removed under reduced pressure. The
crude residue was purified by flash silica gel column chromatog-
raphy to give 0.04 g (69%) of 30 as a yellow solid: mp 138–142
1
°C; IR (neat) 2925, 1607, 1463, 1293, and 1207 cm-1; H NMR
(400 MHz, CDCl3) δ 1.69 (d, 3H, J ) 6.4 Hz), 1.94–2.10 (m, 2H),
2.30–2.41 (m, 2H), 3.03 (dt, 2H, J ) 11.6 and 7.4 Hz), 3.32 (d,
1H, J ) 14.4 Hz), 3.50–3.56 (m, 1H), 3.58 (s, 1H), 3.72–3.82 (m,
2H), 3.78 (s, 3H), 3.84 (s, 1H), 4.18 (d, 1H, J ) 16.4 Hz), 4.30 (d,
1H, J ) 16.4 Hz), 5.14 (d, 1H, J ) 8.8 Hz), 5.49 (q, 1H, J ) 6.4
Hz), 6.39 (d, 1H, J ) 7.6 Hz), 6.40 (d, 1H, J ) 8.8 Hz), 6.46 (d,
1H, J ) 2.4 Hz), 6.73 (t, 1H, J ) 7.6 Hz), and 7.01–7.12 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 13.5, 24.1, 33.3, 36.6, 45.0, 51.8,
52.6, 54.4, 55.2, 55.3, 63.3, 73.2, 98.4, 203.7, 108.3, 117.8, 118.3,
118.6, 122.2, 125.9, 128.8, 129.4, 131.4, 145.1, 150.6, 157.9, and
160.0; HRMS calcd for [(C28H32N2O2) + H]+ 429.2523, found
429.2537.
1583, 1465, and 740 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.22–1.33 (m, 2H), 1.55 (dt, 1H, J ) 14.0 and 2.0 Hz), 1.64 (d,
3H, J ) 7.2 Hz), 2.03–2.21 (m, 3H), 2.70–2.84 (m, 3H), 3.24 (t,
1H, J ) 8.8 Hz), 3.45 (dd, 1H, J ) 10.8 and 6.4 Hz), 3.52 (br s,
1H), 3.72 (d, 1H, J ) 14.0 Hz), 3.81 (br s, 1H), 5.37 (q, 1H, J )
7.2 Hz), 6.65 (d, 1H, J ) 7.6 Hz), 6.76 (td, 1H, J ) 7.6 and 0.4
Hz), and 7.04–7.08 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.2,
25.7, 27.8, 36.0, 38.8, 52.0, 53.0, 54.9, 59.2, 60.2, 110.0, 119.0,
121.2, 122.4, 127.8, 131.1, 136.9, and 150.4; HRMS calcd for
[(C18H22N2) + H]+ 267.1855, found 267.1856.
Pentacyclic Alkene 31. To a flask containing 50 mg (0.11 mmol)
of 30 was added 5 mL of HCl (1.0 N HCl in MeOH) and the
mixture was heated at 55 °C for 5 h. After cooling to rt, the reaction
was quenched with a saturated aqueous K2CO3 solution and then
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried over Na2SO4, and filtered. The solvent was
removed under reduced pressure, and the crude residue was purified
by flash silica gel chromatography to give 16 mg (49%) of 31 as
a yellow solid: mp 139–141 °C; IR (neat) 3367, 2925, 1607, 1484,
(()-Tubifolidine (25). To a solution containing 2.0 mg (0.008
mmol) of (()-dehydrotubifoline 24 in 1 mL of THF at rt under
nitrogen was added 2.0 mg (0.023 mmol) of Na2CO3, followed by
1.0 mg (0.023 mmol) of 10% Pd/C. The reaction flask was flushed
with hydrogen and was then stirred under a H2 atmosphere
overnight. The mixture was filtered through Celite and the solvent
was removed under reduced pressure. The crude residue was taken
up in CH2Cl2 and washed with a 1 N HCl solution. The aqueous
layer was neutralized with a 1 N NaOH solution and extracted with
CH2Cl2. The combined organic layer was dried over Na2SO4 then
filtered and concentrated under reduced pressure to give 1.0 mg
(50%) of (()-tubifolidine (25): IR (neat) 3359, 2924, 1653, 1606,
1
1464, and 741 cm-1; H NMR (400 MHz, CDCl3) δ 1.65 (d, 3H,
J ) 6.8 Hz), 1.88 (dt, 1H, J ) 13.6 and 2.4 Hz), 1.95–2.09 (m,
2H), 2.16–2.23 (m, 2H), 2.80–2.93 (m, 1H), 3.00 (d, 1H, J ) 14.8
Hz), 3.18–3.25 (m, 1H), 3.54–3.57 (m, 3H), 4.01 (s, 1H), 4.04 (br
s, 1H), 4.98 (s, 2H), 5.38 (q, 1H, J ) 6.8 Hz), 6.64 (d, 1H, J ) 7.2
Hz), 6.75 (td, 2H, J ) 7.2 and 1.2 Hz), and 7.04 (qd, 2H, J ) 7.2
and 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ 13.0, 26.4, 36.3, 38.9,
53.0, 53.7, 55.8, 62.5, 67.1, 109.2, 110.9, 119.0, 120.7, 122.3, 127.9,
132.7, 137.3, 149.9, and 150.0.
(()-Valparicine (29). To a solution containing 4.0 mg (0.016
mmol) of CuBr2 in 0.5 mL of THF was added a solution of 2.0 mg
(0.016 mmol) of t-BuONa in 0.5 mL of THF via cannula. The
resulting mixture was stirred for 15 min at rt, and then cooled to 0
°C. To this mixture was added a dropwise solution of 2.0 mg (0.007
mmol) of 31 in 0.5 mL of THF. After being stirred at 0 °C for 40
min, the mixture was quenched with an aqueous NH4OH solution
(3.5%) and then extracted with CH2Cl2. The combined organic layer
was washed with brine, dried over Na2SO4, and filtered. The solvent
was removed under reduced pressure and the crude residue was
subjected to flash silica gel column chromatography to give a 1:1
mixture of 31 and (()-valparicine (29). We were not able to separate
the mixture into its component parts by chromatography. The NMR
spectrum of (()-valparicine (29) was obtained by substraction of
peaks from the starting material 31 and is perfectly consistent with
the NMR data reported by Kam and co-workers:31 1H NMR (600
MHz, CDCl3) δ 1.15 -1.38 (2H, m), 1.77 (d, 3H, J ) 7.2 Hz),
1.97–2.04 (m, 2H), 2.07 (dt, 1H, J ) 13.8 and 3.0 Hz), 2.42 (ddd,
1H, J ) 13.2, 9.0, and 6.0 Hz), 3.18 -3.24 (1H, m), 3.26 (d, 1H,
J ) 15.0 Hz), 3.31 (ddd, 1H, J ) 11.4, 9.0, and 6.0 Hz), 3.73 (d,
1H, J ) 15.6 Hz), 3.84 (br s, 1H), 5.34 (s, 1H), 5.49 (q, 1H, J )
7.2 Hz), 7.22 (t, 1H, J ) 7.2 Hz), 7.33 (d, 1H, J ) 7.2 Hz), 7.36
(d, 1H, J ) 7.2 Hz), and 7.61 (d, 1H, J ) 7.2 Hz).
1
and 1464 cm-1; H NMR (600 MHz, CDCl3) δ 0.91 (t, 3H, J )
7.2 Hz), 1.26–1.40 (m, 4H), 1.74 (dt, 1H, J ) 13.2 and 3.0 Hz),
1.78–1.80 (m, 1H), 1.86 (ddd, 1H, J ) 13.2, 10.8, and 2.4 Hz),
1.90–1.94 (m, 1H), 1.98–2.03 (m, 1H), 2.08 (t, 1H, J ) 12.0
Hz), 2.42 (dt, 1H, J ) 13.2 and 8.4 Hz), 2.85 (t, 1H, J ) 10.8 Hz),
3.02–3.11 (m, 1H), 3.13–3.12 (m, 1H), 3.37 (br s, 1H), 3.62–3.66
(m, 1H), 6.63 (d, 1H, J ) 7.8 Hz), 6.77 (t, 1H, J ) 7.8 Hz), and
7.03–7.06 (m, 2H); HRMS calcd for [(C18H24N2) + H]+ 269.2012,
found 269.2009.
Pentacyclic Alkene 30. A sample of 0.8 g (2.2 mmol) of CeCl3
hydrate was heated at 60 °C under reduced pressure for 3 h to
remove the water of hydration. After cooling to rt, the solid was
dissolved in 0.5 mL of THF and the solution was stirred for 1 h at
rt. The mixture was cooled to -78 °C and 0.56 mL (0.56 mmol)
of 1 M trimethylsilylmethyl lithium in THF was added dropwise.
After being stirred at -78 °C for 30 min, a solution of the
pentacyclic ketone 23 in 0.5 mL of THF was added via cannula.
The solution was allowed to warm to rt, and was then heated at
reflux for 12 h. After cooling to rt, 98 µL (0.65 mmol) of N,N,N′,N′-
tetramethylethylenediamine was added in one portion. The mixture
was stirred for 30 min, poured into a saturated aqueous NaHCO3
solution, and extracted with CH2Cl2. The organic phase was washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude residue was used in the next step
without further purification.
Z-1-Bromo-2-iodo-4-methoxymethoxybut-2-ene. To a solution
containing 1.0 g (3.4 mmol) of Z-3-iodo-4-(tetrahydropyran-2-
yloxy)-2-butenol44f in 13 mL of CH2Cl2 at 0 °C was added 0.13
mL (0.81 mmol) of diisopropylethylamine followed by 0.06 mL
(0.81 mmol) of chloromethyl methyl ether. The reaction mixture
3548 J. Org. Chem. Vol. 73, No. 9, 2008

The Pentacyclic Strychnos Alkaloid Family
was stirred at 0 °C for 5 h, diluted with CH2Cl2, and washed with
an aqueous NaHCO3 solution. The combined organic extracts were
dried over Na2SO4, then filtered, and the solvent was removed under
reduced pressure. The crude residue was purified by flash silica
gel column chromatography to give 0.95 g (82%) of 2-(2-iodo-4-
methoxymethoxybut-2-enyloxy)tetrahydropyran as a colorless oil:
(d, 1H, J ) 13.8 Hz), 3.81 (s, 3H), 3.82 (s, 3H), 4.19 (d, 1H, J )
5.4 Hz), 4.24–4.28 (m, 1H), 4.32 (d, 1H, J ) 16.2 Hz), 4.50 (d,
1H, J ) 16.2 Hz), 4.66 (s, 1H), 6.14 (t, 1H, J ) 5.4 Hz), 6.43–6.46
(m, 2H), 6.49 (d, 1H, J ) 1.8 Hz), 6.68 (t, 1H, J ) 7.5 Hz),
7.02–7.05 (m, 2H), and 7.24(d, 1H, J ) 7.8 Hz); 13C NMR (100
MHz, CDCl3) δ 18.8, 24.7, 39.8, 48.0, 51.3, 53.5, 55.5, 55.6, 55.7,
65.4, 65.6, 68.1, 71.7, 73.6, 96.3, 98.7, 104.1, 107.1, 109.9, 118.0,
119.7, 121.7, 128.2, 129.1, 132.7, 135.2, 152.8, 158.2, and 160.2;
HRMS calcd for [(C29H37N2O5I) + H]+ 621.1820, found 621.1817.
1
IR (thin film) 1654, 1450, 1447, 1201, and 1021 cm-1; H NMR
(400 MHz, CDCl3) δ 1.45–1.90 (m, 5 H), 3.71 (s, 3H), 3.48–3.55
(m, 1H), 3.86 (ddd, 1H, J ) 12.4, 9.2, and 3.2 Hz), 4.16–4.21 (m,
3H), 4.64 (s, 2H), 4.68 (t, 1H, J ) 3.2 Hz), and 6.22 (tt, 1H, J )
5.6 and 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 18.7, 25.3, 30.3,
55.4, 62.0, 71.1, 74.2, 96.1, 97.1, 104.6, and 133.3.
7-(2,4-Dimethoxybenzyl)-3-(2-iodo-4-methoxymethoxybut-2-
enyl)-2,3,3a,4,5,6,6a,7-octahydropyrrolo[2,3-d]carbazol-6-one (34).
To a flask containing 0.9 g (1.5 mmol) of the above compound
and 0.73 g of 4 Å molecular sieves in 50 mL of CH3CN at 0 °C
was added 0.26 g (2.2 mmol) of N-methylmorpholine-N-oxide,
followed by the addition of 0.15 g (0.43 mmol) of tetra-n-
propylammonium perruthenate in several portions. After the solution
was stirred at 0 °C for 20 min, the cooling bath was removed and
the mixture was stirred at rt for an additional 2 h. The mixture was
then filtered through Celite and the filtrate was concentrated under
reduced pressure. The residue was purified by flash silica gel
chromatography to give 0.72 g (80%) of ketone 34 as a pale yellow
To a solution of 1.7 g (4.9 mmol) of the above compound in 49
mL of MeOH at 0 °C was added 0.09 g (0.49 mmol) of p-
toluenesulfonic acid. The reaction mixture was stirred at 0 °C for 1 h,
quenched with an aqueous NaHCO3 solution, and extracted with
EtOAc. The combined organic extracts were dried over Na2SO4, then
filtered, and the solvent was removed under reduced pressure. The
crude residue was purified by flash silica gel column chromatography
to give 0.76 g (60%) of 2-iodo-4-methoxymethoxybut-2-en-1-ol as a
colorless oil: IR (thin film) 3403, 2934, 1655, 1446, and 1037 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.91 (t, 1H, J ) 6.8 Hz), 3.38 (s, 3H),
4.17 (dt, 2H, J ) 5.6 and 1.2 Hz), 4.23 (dd, 2H, J ) 6.8 and 1.2 Hz),
4.62 (s, 2H), and 6.21 (tt, 1H, J ) 5.6 and 1.2 Hz); 13C NMR (100
MHz, CDCl3) δ 55.4, 70.9, 71.0, 96.0, 108.9, and 131.5.
1
oil: IR (neat) 1707, 1601, 1479, 1209, and 1037 cm-1; H NMR
(400 MHz, CDCl3) δ 1.83–1.98 (m, 2H), 2.13–2.23 (m, 2H),
2.30–2.53 (m, 3H), 2.54 (d, 1H, J ) 2.8 Hz), 2.99 (d, 1H, J )
14.0 Hz), 3.15–3.20 (m, 1H), 3.39 (s, 3H), 3.59 (dd, 1H, J ) 14.0
and 1.6 Hz), 3.60 (s, 1H), 3.78 (s, 3H), 3.79 (s, 3H), 4.12 (d, 1H,
J ) 16.4 Hz), 4.15–4.18 (m, 1H), 4.25 (d, 1H, J ) 16.4 Hz), 4.65
(s, 2H), 6.10 (t, 1H, J ) 4.2 Hz), 6.40 (dd, 1H, J ) 8.2 and 2.4
Hz), 6.43 (d, 1H, J ) 2.4 Hz), 6.55 (d, 1H, J ) 8.2 Hz), 6.77 (td,
1H, J ) 7.6 and 0.8 Hz), and 7.03–7.13 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 20.4, 32.5, 37.8, 47.8, 51.8, 55.4, 55.5, 55.7, 59.0,
64.5, 67.9, 71.6, 81.7, 96.4, 98.6, 103.9, 107.2, 108.8, 118.4, 118.7,
122.8, 128.8, 129.5, 132.7, 133.3, 152.7, 158.4, 160.3, and 210.3.
Pentacyclic Ketone 38. To a solution of 0.35 g (0.57 mmol) of
34 in 6.0 mL of THF at room temperature was added 0.13 g (0.11
mmol) of Pd(PPh3)4, 0.74 mL of 1 M t-BuOK in t-BuOH, and 80
mg (0.85 mmol) of phenol in 8 mL of THF. The reaction mixture
was heated at reflux under argon for 2 h, cooled to rt, diluted with
a 1 N NaOH solution, and extracted with CH2Cl2. The combined
organic extracts were washed with 1 N NaOH, H2O, and brine,
dried over MgSO4, and filtered. After concentration under reduced
pressure, the residue was purified by silica gel chromatography to
give 0.15 g (56%) of the pentacyclic ketone 38 as a pale yellow
To a solution of 0.48 g (1.9 mmol) of the above alcohol in 28
mL of CH2Cl2 at -30 °C was added 0.59 g (2.2 mmol) of
triphenylphosphine followed by 0.46 g (2.6 mmol) of N-bromo-
succinimide. The reaction mixture was maintained at -30 °C for
1 h, diluted with Et2O, and washed with an aqueous NaHCO3
solution. The combined organic extracts were dried over Na2SO4,
then filtered, and the solvent was removed under reduced pressure.
The crude residue was purified by flash silica gel column chro-
matography to give 0.47 g (79%) of Z-1-bromo-2-iodo-4-meth-
oxymethoxybut-2-ene as a colorless oil: IR (thin film) 2929, 1633,
1
1448, 1211, 1037 cm-1; H NMR (400 MHz, CDCl3) δ 3.38 (s,
3H), 4.14 (d, 2H, J ) 5.2 Hz), 4.33 (s, 1H), 4.64 (s, 1H), 6.28 (t,
1H, J ) 5.6 Hz); 13C NMR (100 MHz, CDCl3) δ 42.1, 55.5, 71.4,
96.2, 101.6, and 137.1.
7-(2,4-Dimethoxybenzyl)-3-(2-iodo-4-methoxymethoxybut-2-
enyl)-2,3,3a,4, 5,6,6a,7-octahydro-1H-pyrrolo[2,3-d]carbazol-6-
ol. To a solution of 0.12 g (0.54 mmol) of pyrrolidine 36 in 5.0
mL of DMF at rt was added 1.2 mL of H2O and 0.37 g (2.7 mmol)
of K2CO3. The resulting mixture was cooled to 0 °C, and this was
followed by the addition of a solution of 0.21 g (0.65 mmol) of
the above bromide in 1.0 mL of DMF. The solution was stirred at
0 °C for 12 h and then partitioned between Et2O and H2O. The
organic layer was separated and the aqueous layer was extracted
with Et2O. The combined organic extracts were washed with H2O
and brine, dried over MgSO4, and filtered. After concentration under
reduced pressure, the residue was purified by flash chromatography
to provide 0.2 g (80%) of vinyl iodide 37 as a pale yellow oil that
was immediately used in the next step.
1
oil: IR (neat) 1711, 1607, 1484, and 1038 cm-1; H NMR (400
MHz, CDCl3) δ 1.93 (dd, 1H, J ) 12.8, and 5.0 Hz), 2.14–2.34
(m, 3H), 2.66–2.74 (m, 1H), 3.05 (d, 1H, J ) 16.0 Hz), 3.20 (t,
1H, J ) 8.4 Hz), 3.33 (s, 1H), 3.35 (s, 3H), 3.65 (br s, 2H), 3.77
(s, 3H), 3.78 (s, 3H), 3.79 (d, 1H, J ) 16.0 Hz), 4.10 (dd, 1H, J )
13.2 and 4.4 Hz), 4.22–4.37 (m, 3H), 4.61 (s, 2H), 5.57 (dd, 1H,
J ) 8.4 and 4.4 Hz), 6.40 (dd, 1H, J ) 7.8 and 2.2 Hz), 6.44 (d,
1H, J ) 2.2 Hz), 6.49 (d, 1H, J ) 7.8 Hz), 6.74 (td, 1H, J ) 7.4
and 0.6 Hz), and 7.03–7.11 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 23.3, 38.7, 43.8, 46.9, 51.8, 52.6, 55.4, 55.5, 55.6, 58.3, 62.3,
63.6, 76.8, 96.1, 98.6, 103.8, 108.5, 118.6, 118.7, 122.3, 125.8,
128.9, 129.3, 130.9, 137.5, 151.9, 158.4, 160.2, and 209.5; HRMS
calcd for [(C29H34N2O5) + H]+ 491.2540, found 491.2534.
Pentacyclic Enol Ether 35. To a flask containing 0.45 mL (3.2
mol) of diisopropyl amine in 4.0 mL of THF at 0 °C was slowly
added 1.2 mL (2.9 mmol) of n-BuLi (2.5 M in hexane). The
resulting LDA solution was added dropwise to a suspension of
Ph2P(O)CH2OMe in 6.0 mL of THF at 0 °C. The reaction mixture
was stirred at this temperature for 20 min and to the resulting red
solution was added a solution containing 0.14 g (0.29 mmol) of
pentacyclic ketone 38 in 2.0 mL of THF. After the solution was
stirred for 20 min, the cooling bath was removed and the reaction
mixture was stirred at rt for 22 h. The solution was quenched with
a saturated NH4Cl solution and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
To a flask containing 54 mg (0.11 mmol) of 37 was added 3.0
mL of 1,2-dichloroethane. To the resulting solution at 0 °C was
added 23 mg (0.14 mmol) of 2,4-dimethoxybenzaldehyde and 61
mg (0.29 mmol) of NaBH(OAc)3, followed by the addition of 20
µL (0.34 mmol) of acetic acid. The reaction mixture was stirred at
0 °C for 10 min and then at rt for 12 h. The solution was quenched
with a saturated K2CO3 solution and extracted with CH2Cl2. The
combined organic extracts were washed with H2O and brine, dried
over MgSO4, and filtered. After concentration under reduced
pressure, the residue was purified by flash silica gel chromatography
to give 61 mg (86%) of the titled compound as a colorless oil: IR
1
(neat) 3456, 1673, 1606, and 1485 cm-1; H NMR (600 MHz,
CDCl3) δ 1.54–1.62 (m, 2H), 1.68 (d, 1H, J ) 6.0 Hz), 1.74–1.79
(m, 1H), 1.93–2.06 (m, 3H), 2.38 (td, 1H, J ) 9.0 and 6.6 Hz),
2.80 (t, 1H, J ) 0.6 Hz), 3.06 (d, 1H, J ) 13.8 Hz), 3.11 (td, 1H,
J ) 9.0 and 5.1 Hz), 3.40 (s, 3H), 3.46 (d, 1H, J ) 3.6 Hz), 3.62
J. Org. Chem. Vol. 73, No. 9, 2008 3549

Boonsombat et al.
residue was purified by flash silica gel chromatography to provide
90 mg (72%) of vinyl ether 35 as a pale yellow foam: IR (neat)
1607, 1485, 1121, and 1038 cm-1; 1H NMR (600 MHz, CDCl3) δ
1.79–1.84 (m, 1H), 2.20–2.25 (m, 1H), 2.45–2.53 (m, 2H),
3.00–3.08 (m, 1H), 3.17–3.28 (m, 2H), 3.35 (s, 3H), 3.35–3.42 (m,
1H), 3.47–3.53 (m, 6H), 3.80 (s, 3H), 3.83 (s, 3H), 4.08 (dd, 1H,
J ) 12.0 and 6.0 Hz), 4.11 (d, 1H, J ) 16.8 Hz), 4.18–4.21 (m,
2H), 4.58 (s, 1H), 4.63 (d, 1H, J ) 6.6 Hz), 4.65 (d, 1H, J ) 6.6
Hz), 5.38 (t, 1H, J ) 6.0 Hz), 6.14 (s, 1H), 6.23 (d, 1H, J ) 8.1
Hz), 6.41 (dd, 1H, J ) 8.1 and 2.4 Hz), 6.47 (d, 1H, J ) 2.4 Hz),
6.71 (t, 1H, J ) 7.5 Hz), 6.99 (t, 1H, J ) 7.5 Hz), 7.06 (d, 1H, J
) 7.5 Hz), and 7.07 (d, 1H, J ) 7.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 25.2, 29.9, 39.2, 45.6, 52.1, 54.0, 55.1, 55.4, 55.5, 55.6,
59.9, 62.7, 66.9, 67.5, 95.7, 98.4, 103.8, 108.0, 112.4, 118.3, 120.3,
122.1, 128.0, 128.4, 128.6, 132.0, 151.4, 151.9, 157.7, and 159.6;
HRMS calcd for [(C31H38N2O5) + H]+ 591.2853, found 591.2847.
(()-Strychnine (3). To a solution containing 8.0 mg (0.015
mmol) of the pentacyclic enol ether 35 in 1.5 mL of THF was
added 1.5 mL of 4 M HCl. The reaction mixture was heated at 55
°C for 10 h, cooled to 0 °C, neutralized with a saturated NH4OH
solution, and extracted with EtOAc. The organic extracts were
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was heated at 60 °C under
vacuum overnight to remove the 1,4-diol derived from acid hy-
drolysis of THF under the reaction conditions. The resulting crude
residue consisted of the Wieland-Gumlich aldehyde 33: 1H NMR
(600 Hz, CDCl3) δ 1.54 (d, 1H, J ) 14.4 Hz), 1.57–1.62 (m, 1H),
1.82 (d, 1H, J ) 10.8 Hz), 2.06 (dd, 1H, J ) 12.6 and 6.6 Hz),
2.26–2.30 (m, 1H), 2.66 (s, 1H), 2.67 (d, 1H, J ) 14.4 Hz),
2.80–2.84 (m, 1H), 3.26 (dd, 1H, J ) 8.0 and 8.0 Hz), 3.75 (d,
1H, J ) 14.4 Hz), 3.82 (d, 1H, J ) 10.8 Hz), 3.92–3.99 (m, 2H),
4.23 (dd, 1H, J ) 14.4 and 7.2 Hz), 5.00 (s, 1H), 5.81 (br s, 1H),
6.80 (d, 1H, J ) 7.5 Hz), 6.88 (t, 1H, J ) 7.5 Hz), 7.04 (d, 1H, J
) 7.5 Hz), 7.10 (d, 1H, J ) 7.5 Hz).
To the crude residue was added 0.5 mL of acetic acid, 48 mg of
malonic acid, 48 mg of sodium acetate, and 10 µL of acetic
anhydride, and the resulting mixture was heated at 120 °C for 2 h.
The reaction mixture was cooled to rt, diluted with H2O, basified
with a 50% NaOH solution, and extracted with EtOAc. The
combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by preparative TLC to afford 2.3 mg (43%
for the 2 steps) of (()-strychnine (3) as a white solid: mp 278–283
°C (lit.44 mp 275–285 °C) for the two-step sequence: H NMR
1
(400 MHz, CDCl3) δ 1.28 (dt, 1H, J ) 10.4 and 3.2 Hz), 1.48 (d,
1H, J ) 14.0 Hz), 1.89–1.93 (m, 2H), 2.37 (dt, 1H, J ) 14.0 and
4.4 Hz), 2.67 (dd, 1H, J ) 17.2 and 3.2 Hz), 2.76 (d, 1H, J ) 15.2
Hz), 2.89 (dd, 1H, J ) 18.4 and 10.0 Hz), 3.14 (dd, 1H, J ) 17.2
and 8.4 Hz), 3.15–3.17 (m, 1H), 3.22–3.28 (m, 1H), 3.99 (br s,
1H), 4.06 (dd, 1H, J ) 13.6 and 5.6 Hz), 4.16 (dd, 1H, J ) 13.6
and 7.4 Hz), 4.29 (dt, 1H, J ) 8.4 and 3.2 Hz), 5.94 (t, 1H, J )
5.6 Hz), 7.10 (td, 1H, J ) 7.6 and 1.2 Hz), 7.17 (dd, 1H, J ) 7.6
and 1.2 Hz), 7.26 (td, 1H, J ) 7.6 and 1.2 Hz), 8.09 (dd, 1H, J )
7.6 and 1.2 Hz).
Acknowledgement. The financial support provided by the
National Science Foundation (CHE-0450779) is greatly ap-
preciated. We thank Professor Larry Overman for providing a
1H NMR spectrum of the Wieland-Gumlich aldehyde and
Professor Toh-Seok Kam for providing a 1H NMR spectrum of
valparicine for comparative purposes.
Supporting Information Available: 1H and 13C NMR data
for various key compounds lacking CHN analyses. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO8003716
3550 J. Org. Chem. Vol. 73, No. 9, 2008