General strategy for the syntheses of corynanthe, tacaman, and oxindole alkaloids

Article abstract of DOI:10.1021/jo061032t

We report herein the total synthesis of the corynanthe alkaloid dihydrocorynantheol and the formal syntheses of the indole alkaloids tacamonine, rhynchophylline, and hirsutine. The strategies for assembling the corynanthe and tacaman skeletal frameworks comprised of both the classical ABD → ABCD and ABC → ABCD approaches wherein the variously substituted piperidinone D-rings were formed via ring-closing metathesis (RCM) followed by a 1,4-addition to introduce the requisite side chain at C(15). Since 1,4-additions to α,β-unsaturated lactams represent an underdeveloped field, we conducted a series of studies with two unsaturated lactams employing organocuprates and metal enolates as the nucleophiles. These studies revealed that organocuprates derived from Grignard reagents and either stoichiometric amounts of CuCN or catalytic amounts of CuBr·DMS complex are excellent nucleophiles for such additions; TMSC1 was a crucial additive for optimizing these reactions. The anion derived from ethyl 1,3-dithiolane-2-carboxylate was also an excellent nucleophile in these 1,4-additions, although the stereochemistry of such 1,4-additions to carboline-derived, unsaturated lactams was sensitive to substitution on the indole nitrogen atom. The ABD → ABCD approach to these alkaloids featured a novel one-pot sequence of an RCM reaction and a zirconocene-catalyzed carbomagnesation followed by a second RCM to generate the D-ring.

Full text of DOI:10.1021/jo061032t

General Strategy for the Syntheses of Corynanthe, Tacaman, and
Oxindole Alkaloids
Alexander Deiters,† Martin Pettersson, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas, Austin, Texas 78712
sfmartin@mail.utexas.edu
ReceiVed May 22, 2006
We report herein the total synthesis of the corynanthe alkaloid dihydrocorynantheol and the formal
syntheses of the indole alkaloids tacamonine, rhynchophylline, and hirsutine. The strategies for assembling
the corynanthe and tacaman skeletal frameworks comprised of both the classical ABD f ABCD and
ABC f ABCD approaches wherein the variously substituted piperidinone D-rings were formed via ring-
closing metathesis (RCM) followed by a 1,4-addition to introduce the requisite side chain at C(15). Since
1,4-additions to R,â-unsaturated lactams represent an underdeveloped field, we conducted a series of
studies with two unsaturated lactams employing organocuprates and metal enolates as the nucleophiles.
These studies revealed that organocuprates derived from Grignard reagents and either stoichiometric
amounts of CuCN or catalytic amounts of CuBr‚DMS complex are excellent nucleophiles for such
additions; TMSCl was a crucial additive for optimizing these reactions. The anion derived from ethyl
1,3-dithiolane-2-carboxylate was also an excellent nucleophile in these 1,4-additions, although the
stereochemistry of such 1,4-additions to carboline-derived, unsaturated lactams was sensitive to substitution
on the indole nitrogen atom. The ABD f ABCD approach to these alkaloids featured a novel one-pot
sequence of an RCM reaction and a zirconocene-catalyzed carbomagnesation followed by a second RCM
to generate the D-ring.
Introduction
dienes containing nitrogen atoms in the tethering chain between
the two olefins could be cyclized via ring-closing metathesis
(RCM),3,4 we immediately recognized the tremendous potential
of such cyclizations as a general approach for alkaloid synthesis,
and we have completed the syntheses of a variety of alkaloids
employing an RCM reaction as a key step.5 Indeed, our use of
an RCM reaction to fabricate the ABCE ring system of
We have had a long-standing interest in developing unified
strategies for the synthesis of structurally diverse indole
alkaloids. A number of years ago we discovered that vinylogous
Mannich reactions1 could be exploited to quickly generate
intermediates that might be elaborated via subsequent hetero-
Diels-Alder reactions or Michael additions in designing general
approaches to a number of indole alkaloids including reserpine,
tetrahydroalstonine, geissoschizine, ajmalicine, rugulovasines A
and B, setoclavine, akuammicine, strychnine, and N-methyl-
vellosimine.2 When Fu and Grubbs showed in 1992 that R,ω-
(2) For examples, see: (a) Martin, S. F.; Ru¨eger, H.; Williamson, S. A.;
Grzejszczak, S. J. Am. Chem. Soc. 1987, 109, 6124. (b) Martin, S. F.;
Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc.
1991, 113, 6161. (c) Martin, S. F.; Clark, W. C.; Corbett, J. W. J. Org.
Chem. 1995, 60, 3236. (d) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J.
B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003. (e) Liras, S.; Lynch,
C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F. J. Am. Chem. Soc. 2001, 123,
5918. (f) Deiters, A.; Chen, K.; Eary, C. T.; Martin, S. F. J. Am. Chem.
Soc. 2003, 125, 4541.
† Current address: Department of Chemistry, North Carolina State University,
Raleigh, NC 27695-8204.
(1) For reviews, see: (a) Martin, S. F. Acc. Chem. Res. 2002, 35, 895.
(b) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
(3) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324.
10.1021/jo061032t CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/14/2006
J. Org. Chem. 2006, 71, 6547-6561
6547

Deiters et al.
SCHEME 1
manzamine A represents one of the first applications of RCM
to the synthesis of complex natural products.5d Herein, we report
a general approach to the synthesis of the corynanthe indole
alkaloids, which have the generic structure 1, by a novel strategy
in which RCM plays a pivotal role for elaborating the D-ring.
The obvious biogenetic relationship between the corynanthe
alkaloids and the oxindole and tacaman alkaloids, which are
characterized by the corresponding structures 2 and 3, inspired
us to adapt the strategy toward their synthesis.6
contains a branched homoallylic amino group, which represents
a modest synthetic challenge.9 Indeed, a preliminary series of
experiments made it apparent that preparing 6 by classical
amination protocols involving alkylations or reductive amina-
tions was problematic. Hence, we developed a novel route to 6
by an approach that featured a one-pot procedure for transform-
ing 8 into 7 via sequential RCM and zirconocene-catalyzed
carbomagnesation reactions. Although various carbometalations
have been widely used in organic synthesis,10 zirconocene-
catalyzed carbomagnesations of double bonds are less com-
mon,11 and to our knowledge such reactions have been used
only once in natural product synthesis.12
1. Synthesis of the Unsaturated Lactam 4. Compound 4
was a pivotal intermediate in the ABD f ABCD approach to
the indole alkaloids 1-3, and an efficient means for its synthesis
was developed that commenced with the EDCI-mediated amide
coupling between indole-3-acetic acid (9) and diallylamine to
furnish 8 in 88% yield (Scheme 2). The diallyl amide 8 was
then the substrate for a one-pot RCM-carbomagnesation
sequence to prepare 7. In the event, the RCM of 8 proceeded
smoothly with only 1 mol % Grubbs’ catalyst 11 in THF at
room temperature, and after the starting material had been
consumed, EtMgCl (4 equiv) and Cp2ZrCl2 (15 mol %) were
simply added, leading to the formation of 7 in 71% overall yield.
Hoveyda has shown that carbomagnesations of cyclic allyl
amides may occur enantioselectively using the chiral catalyst
Results and Discussion
A. ABD f ABCD Approach. Consideration of the general
structures 1-3 reveals that the common motif is an indole ring
that is joined via either a fused or a spiro C-ring to the piperidine
D-ring, which has an ethyl side chain at C(20).7 It thus occurred
to us that 4 might serve as a useful intermediate in an ABD f
ABCD entry to alkaloids of the corynanthe, oxindole, and
tacaman families (Scheme 1).8 The R,â-unsaturated lactam
moiety in 4 would allow for the introduction of substituents at
C(15) by a diastereoselective 1,4-addition, and the tetracyclic
corynanthe skeleton would then be formed via a Bischler-
Napieralski reaction and stereoselective reduction. An expedient
route to 4 would involve the RCM of the tryptamine derivative
5. Although 5 would superficially appear to be an easy synthetic
target, closer inspection reveals that the obvious precursor 6
(4) For selected reviews of olefin metathesis, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (b) Schrock, R. R. Tetrahedron
1999, 55, 8141. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (e) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (f) Connon,
S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (g) Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003;
Vol. 2. (h) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
(5) For some examples, see: (a) Martin, S. F.; Liao, Y.; Chen, H.-J.;
Pa¨tzel, M.; Ramser, M. N. Tetrahedron Lett. 1994, 35, 6005. (b) Martin,
S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.;
Wagman, A. S. Tetrahedron 1996, 52, 7251. (c) Fellows, I. M.; Kaelin, D.
E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781. (d) Humphrey,
J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A.
K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584. (e) Martin, S. F.;
Neipp, C. E. J. Org. Chem. 2003, 68, 8867. (f) Washburn, D. G.;
Heidebrecht, R. W., Jr.; Martin, S. F. Org. Lett. 2003, 5, 3523. (g)
Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004, 60, 7301.
(h) Andrade, R. A.; Martin, S. F. Org. Lett. 2005, 7, 5733.
(9) For approaches to homoallylic amines, see: (a) Neipp, C. E.;
Humphrey, J. M.; Martin, S. F. J. Org. Chem. 2001, 66, 531 and references
therein. (b) Ramachandran, P. V.; Burghardt, T. E. Chem.sEur. J. 2005,
11, 4387 and references therein.
(10) Reviews on carbometalations: (a) Marek, I.; Normant, J. F. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Ed.; Wiley-VCH:
Weinheim, Germany, 1998; p 271. (b) Fallis, A. G.; Forgione, P.
Tetrahedron 2001, 57, 5899. (c) Link, J. T. In The Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.;
Wiley: Sons: New York, 2002; Vol. 1, p. 1523.
(11) Reviews on Zr- and Ti-catalyzed carbomagnesations: (a) Negishi,
E.-I. Pure Appl. Chem. 2001, 73, 239. (b) Hoveyda, A. H. In Titanium and
Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; p 180.
(6) Sto¨ckigt, J. In Indole and Biogenetically Related Alkaloids; Phillipson,
J. D., Zenk, M. H., Eds.; Academic Press: London, 1980; Chapter 6, p
113.
(7) The atoms are numbered according to the “biogenetic numbering”
of Le Men and Taylor: Le Men, J.; Taylor, W. I. Experientia 1965, 21,
508.
(8) For a preliminary account of some of these results, see: Deiters, A.;
Martin, S. F. Org. Lett. 2002, 4, 3243.
(12) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1995, 117, 2943.
6548 J. Org. Chem., Vol. 71, No. 17, 2006

Corynanthe, Tacaman, and Oxindole Alkaloid Syntheses
SCHEME 2
SCHEME 3
(Apocynaceae), the root of which is used to treat snake bites in
Central Africa.14b Although tacamonine has been prepared
before,15 it occurred to us that 4 was nicely suited as an
intermediate, and we developed a facile one-pot procedure for
its transformation into 14, which had been previously converted
in two simple steps into 15.15b Thus, following reduction of 4
by catalytic hydrogenation [10% Pd/C, H2 (1 atm)], POCl3 was
added, and the reaction was heated at 100 °C for 3 h to give 14
in 92% yield (Scheme 3). The 1H NMR and 13C NMR spectra
of synthetic 14 were consistent with those reported in the
literature.16 This route to 14 comprises six distinct operations
and proceeded in 33% overall yield, making it comparable to
the best of the known syntheses of 14.
3. Total Synthesis of Dihydrocorynantheol (21). Members
of the corynanthe group of indole alkaloids have historically
received considerable interest because they exhibit a variety of
important biological properties, including antiparasitic, antiviral,
and analgesic activities.17 The archetypal alkaloid in this family
is 21, which was first isolated from the bark of Aspidosperma
marcgraVianum (Apocynaceae) in 1962.18 Dihydrocorynantheol
has been a popular target to showcase the development of novel
synthetic methodologies, and several partial and total syntheses
have been reported.19 However, the opportunity to design a more
concise approach to this important alkaloid and analogues
thereof was appealing, and 4 seemed a potentially useful
intermediate.
(EBTHI)Zr-binol,13 but we did not pursue this clear opportunity
to prepare enantiomerically pure 7.
Although it was not necessary to protect the acidic indole
NH in this sequence, the electron-withdrawing amide moiety
was critical to the success of both the RCM and the carbo-
magnesation steps in this sequence. For example, we found that
neither the free base 10 nor its hydrochloride salt cyclized in
the presence of Grubbs’ catalyst 11 in CH2Cl2 at room
temperature or by heating under reflux. Furthermore, the amine
13, which was independently prepared (62%) by reaction of
3-(2-bromoethyl)indole with 2,5-dihydropyrrole (2 equiv), did
not undergo carbomagnesation (EtMgCl and Cp2ZrCl2 in THF
at room temperature or 65 °C). Although this result suggests
that the amide might play a significant role in facilitating the
fragmentation of the intermediary organomagnesium species,
carbomagnesations of tertiary amines are in fact known.13 The
amide 7 was then reduced with LiAlH4 at room temperature to
provide the amine 6 (87%), which was treated with acryloyl
chloride in the presence of Et3N to deliver 5 in 73% yield,
thereby setting the stage for the second RCM reaction. Cycliza-
tion of 5 with 5 mol % 11 then furnished the R,â-unsaturated
lactam 4 in only five distinct chemical operations and 36%
overall yield from commercially available 9.
(15) (a) Massiot, G.; Oliveira, F. S.; Le´vy, J. Tetrahedron Lett. 1982,
23, 177. (b) Ihara, M.; Setsu, F.; Shohda, M.; Taniguchi, N.; Tokunaga,
Y.; Fukumoto, K. J. Org. Chem. 1994, 59, 5317. (c) Lounasmaa, M.;
Karinen, K.; Din Belle, D.; Tolvanen, A. Tetrahedron 1998, 54, 157. (d)
Lavilla, R.; Coll, O.; Bosch, J.; Orozco, M.; Luque, F. J. Eur. J. Org. Chem.
2001, 19, 3719. (e) Ho, T.-L.; Su, C.-Y. Tetrahedron 2001, 57, 507. (f)
Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti, A.; Silvani, A. Tetrahedron
Lett. 2001, 42, 7237. (g) Ho, T.-L.; Gorobets, E. Tetrahedron 2002, 58,
4969.
(16) (a) Wassermann, H. H.; Kuo, G.-H. Tetrahedron 1992, 48, 7071.
(b) Lounasmaa, M.; Karvinen, E. Heterocycles 1991, 32, 489.
(17) (a) Yamamoto, L. T.; Horie, S.; Takayama, H.; Aimi, N.; Sakai,
S.; Yano, S.; Shan, J.; Pang, P. K.; Ponglux, D.; Watanabe, K. Gen.
Pharmacol. 1999, 33, 73. (b) Staerk, D.; Lemmich, E.; Christensen, J.;
Kharazmi, A.; Olsen, C. E.; Jaroszewski, J. W. Planta Med. 2000, 66,
531.
(18) Lounasmaa, M.; Tolvanen, A. In Monoterpenoid Indole Alkaloids;
Saxton, J. E., Ed.; Wiley-Interscience: New York, 1994; Supplement to
Vol. 25, Part 4, Chapter 3.
2. Formal Synthesis of Tacamonine (15). 15 is a member
of the relatively small group of tacaman indole alkaloids14 and
was first isolated in 1984 from Tabernaemontana eglandulosa
(19) For example, see: (a) Ziegler, F. E.; Sweeny, J. G. Tetrahedron
Lett. 1969, 10, 1097. (b) Suzuki, T.; Sato, E.; Unno, K.; Kametani, T. Chem.
Pharm. Bull. 1986, 34, 1584. (c) Ihara, M.; Taniguchi, N.; Fukumoto, K.;
Kametani, T. J. Chem. Soc., Chem. Commun. 1987, 1438. (d) Beard, R.
L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091. (e) Ohba, M.; Ohashi, T.;
Fuji, T. Heterocycles 1991, 32, 319. (f) Lounasmaa, M.; Jokela, R.;
Tirkkonen, B.; Miettinen, J.; Halonen, M. Heterocycles 1992, 34, 321. (g)
Diez, A.; Vila, C.; Sinibaldi, M.-E.; Troin, Y.; Rubiralta, M. Tetrahedron
Lett. 1993, 34, 733.
(13) Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda,
A. H. J. Am. Chem. Soc. 1996, 118, 4291.
(14) (a) Beek, T. A. van; Lankhorst, P. P.; Verpoorte, R.; Baerheim
Svendsen, A. Planta Med. 1982, 44, 30. (b) Beek, T. A. van; Verpoorte,
R.; Baerheim Svendsen, A. Tetrahedron 1984, 40, 737.
J. Org. Chem, Vol. 71, No. 17, 2006 6549

Deiters et al.
SCHEME 4
SCHEME 5
1
ment for 19 derives from its mass and an analysis of its H
NMR spectrum. For example, the vicinal coupling constant of
9.0 Hz between the protons at C(14) and C(15) suggests a trans
diaxial relationship for these two protons. The cis stereochemical
relationship between protons at C(14) and C(20) is supported
by a strong NOE interaction as well as the appearance of the
proton at C(15) as an apparent quartet (J ) 9.0 Hz), consistent
with a trans diaxial relationship with the protons at C(20) and
C(14). The trans relationship between the protons at C(15′) and
C(20′) derives from the stereochemistry of other additions to 4
(vide infra) and the absence of an NOE between these protons.
The addition of TMSCl to this reaction completely suppressed
the formation of 19, and 16 was formed in 91% yield with high
diastereoselectivity (dr ) 92:8). Hence, TMSCl was used as an
additive in all other cuprate additions. When CuBr‚DMS or CuI
rather than CuCN was used to generate the Gilman reagent, 16
was obtained in no better than 35% yield.
We then explored other 1,4-additions to the R,â-unsaturated
lactam 4. For example, when 4 was allowed to react with
ethylmagnesium chloride in the presence of either stoichiometric
amounts of CuCN or catalytic amounts of CuBr‚DMS complex,
the expected adduct 17 was isolated in 99% yield, albeit with
a diastereomeric ratio of only about 77:23.24 The addition of
the sterically more demanding [1-(trimethylsilyl)vinyl]magne-
sium bromide required use of stoichiometric amounts of CuCN
to deliver 18 in good yield (75%) and excellent diastereoselec-
tivity (dr > 95:5).
The challenge at this stage of our synthetic effort was
inducing a stereoselective 1,4-addition onto 4, as simple R,â-
unsaturated lactams are notoriously poor Michael acceptors.20
Indeed, only a few examples of 1,4-additions of organometallic
reagents to unsaturated piperidinones have been reported.21 In
most of these cases an additional electron-withdrawing group
is present on either the nitrogen or the R-carbon center to
increase the electrophilicity of the unsaturated lactam. However,
employing such a strategy for activation would entail additional
steps involving introduction and removal of these redundant
functionalities. After surveying a number of organometallic
reagents and conditions,22 we discovered that optimal conditions
for effecting conjugate additions to 4 required organocuprates
derived from Grignard reagents and the use of TMSCl as an
additive.23 A brief discussion of some of these experiments is
informative. It should be noted in advance that protection of
the acidic indole NH was unnecessary in all of these reactions.
The reactions of vinyl organometallic reagents with 4 was
studied most extensively because the adduct 16 was an
intermediate in the eventual synthesis of dihydrocorynantheol.
When stoichiometric amounts of CuCN and vinylmagnesium
bromide were used, the resultant cyano Gilman cuprate added
to 4 to give 19 as the major product (57% yield); the desired
adduct 16 was formed in only 21% yield, albeit with >95:5
diastereoselectivity (Scheme 4). The formation of 19 presumably
ensues from the addition of the vinyl Gilman reagent to 4 to
generate a copper enolate that then added in a 1,4-sense to a
second molecule of 4; both of these additions appear to proceed
with complete stereoselectivity. The tentative structural assign-
Returning to the task at hand, we were ready to complete
the synthesis of 21. The requisite indoloquinolizidine skeleton
was then fabricated by a Bischler-Napieralski reaction of 16
(POCl3, toluene, 100 °C) followed by a stereoselective hydride
reduction (NaBH4, CH3OH, 0 °C) to furnish 20 in 87% yield
as the only diastereomer (Scheme 5). The relative configurations
at C(3), C(15), and C(20) were tentatively assigned on the basis
of NOE experiments. Regioselective hydroboration of the
pendant vinyl group in 20 (9-BBN, THF, room temperature)
followed by an oxidative workup (NaOH, H2O2, 0 °C) delivered
(20) (a) Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahedron
Lett. 1985, 26, 657. (b) Hagen, T. J. Synlett 1990, 63.
(21) (a) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989, 111,
300. (b) Herdeis, C.; Kaschinski, C.; Karla, R. Tetrahedron: Asymmetry
1996, 7, 867. (c) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins,
E. Org. Lett. 2001, 3, 611. (d) Hanessian, S.; van Otterlo, W. A. L.; Nilsson,
I. Bauer, U. Tetrahedron Lett. 2002, 43, 1995. (e) Lerchner, A.; Carreira,
E. M. J. Am. Chem. Soc. 2002, 124, 1486. (f) Cossy, J.; Mirguet, O.; Pardo,
D. G.; Desmurs, J.-R. New J. Chem. 2003, 27, 475. (g) Amat, M.; Pe´rez,
M.; Llor, N.; Escolano, C.; Luque, F. J.; Molins, E.; Bosch, J. J. Org. Chem.
2004, 69, 8681. (h) Pineshi, M.; Moro, D. D.; Gini, F.; Minnaard, A. J.;
Ferringa, B. Chem. Commun. 2004, 12, 1244. See also ref 20.
(22) Reagents that were evaluated included various combinations of RLi,
RMgCl, or RMgBr in the presence of catalytic and stoichiometric amounts
of CuBr‚DMS, CuI, or CuCN in THF or Et2O with or without TMSCl as
an additive.
1
21 in 66% yield. The analytical data (mp, H and 13C NMR
spectra) of synthetic 21 were consistent with those previously
reported.19d-f This stereoselective synthesis of 21 is exceedingly
efficient, consisting of only eight distinct chemical operations,
none of which involve protection or deprotection, to deliver 21
in 19% overall yield.
4. Formal Syntheses of Rhynchophylline (27) and Iso-
rhynchophylline (28). 27 and its C(7)-epimer 28 were isolated
(24) (a) van Tamelen, E. E.; Aldrich, P. A.; Katz, T. J. J. Am. Chem.
Soc. 1957, 79, 6426. (b) Battersby, A. R. J. Chem. Soc. C 1968, 2467. (c)
van Tamelen, E. E.; Hester, J. B. J. Am. Chem. Soc. 1969, 91, 7342.
(23) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019 (b)
Alexis, A.; Berlan. J.; Besace, Y. Tetrahedron Lett. 1986, 27, 1047.
6550 J. Org. Chem., Vol. 71, No. 17, 2006

Corynanthe, Tacaman, and Oxindole Alkaloid Syntheses
from Uncaria rhynchophylla (Rubiaceae),25 a species of plant
that has been used in traditional medicine in Malaysia for the
treatment of cardiovascular disorders such as hypertension. More
recently these alkaloids have been found to protect against
glutamate-induced neuronal death in cultured cerebellar granule
cells.26 The only total syntheses of rhynchophylline and iso-
rhynchophylline reported to date involve nine steps, but four
separations of diastereomers were required owing to the
nonselective introduction of the stereogenic center C(15) and
early formation of the configurationally labile oxindole skel-
eton.27 Because the stereocenter at C(15) was correctly set in
4, we envisioned that it might be an intermediate in an improved
synthesis of these alkaloids.
SCHEME 6
Our initial efforts toward elaborating 4 into 27 and 28
involved examining the feasibility of the 1,4-addition of anions
of dimethyl malonate to 4. Although the sodium and potassium
salts of dimethyl malonate added to 4 with high diastereo-
selectivity (dr > 95:5), the yields of the desired adduct were
only 30% at best.28 On the other hand, we discovered that the
addition of the lithium enolate of ethyl 1,3-dithiolane-2-
carboxylate proceeded with excellent diastereoselectivity (dr >
95:5) to afford the ethyl ester 22 in 71% yield (Scheme 6).29 It
is perhaps noteworthy that the addition of the closely related
anion of ethyl 1,3-dithiane-2-carboxylate to 4 proceeded in only
low yields (<25%). The natural product 27 possesses a methyl
ester, not an ethyl ester as in 22. However, all attempts to
produce the methyl ester corresponding to 22 by reaction of
the anion of methyl 1,3-dithiolane-2-carboxylate with 4 were
low yielding as a consequence of cross-Claisen reactions that
led to the preferential production of a â-keto ester derivative of
the desired adduct.
Compound 22 was then cyclized via a Bischler-Napieralski
reaction (POCl3, toluene, 70 °C, 2 h), and the iminium ion
intermediate was reduced in situ with NaBH4 (MeOH, 0 °C f
rt) to deliver 23 in 92% yield as a single diastereomer. The
preliminary assignment of the relative configurations at C(3),
C(15), and C(20) in 23 was consistent with the observed NOE
interactions between the axial protons at C(3) and C(15) and
between the protons at C(15) and C(19); no NOE contacts were
observed between the protons at C(15) and C(20). Having served
its role, the dithiolane moiety was removed by treating 23 with
1
Raney Ni to provide the ester 24 (95% yield). The H and 13C
that was incidental to the rearrangement step. The spectral data
of the synthetic 26 and epi-26 and the melting point of 26 were
consistent with those reported.27 The stereochemistry at C(7)
of the lower Rf spirocycle, which was assigned as 26 by Ban,27
was unambiguously confirmed by X-ray crystallographic analy-
sis of synthetic 26, thus correcting a structural misassignment
in a previous report claiming the synthesis of 26.32 Although
the C(7)-epimers are separable by chromatography, they are not
configurationally stable and interconvert readily under acidic
or basic conditions via a retro-Mannich/Mannich reaction in a
process commonly observed for alkaloids of the 2-oxindole
family.27,31 While both 26 and epi-26 could in principle be
advanced to their corresponding natural products, epi-26 has
been converted into both 27 and 28 in three and two steps,
respectively.27 Hence, the present route to epi-26 therefore
constitutes a formal synthesis of 27 and 28.
NMR data of 24 were consistent with those reported in the
literature.30 The oxindole framework was then installed in a
convenient three-step sequence,31 commencing with chlorination
of the indole ring in 24 to give 25. When the crude 25 was
treated with NaOMe, a 1,2-rearrangement ensued to give an
intermediate imino ether that was hydrolyzed under acidic
conditions to furnish a separable mixture of 26 (42% yield) and
epi-26 (33% yield), which are epimeric at C(7). The methyl
ester in 26 and epi-26 arose as planned from a transesterification
(25) (a) Kondo, H.; Fukuda, T.; Tomita, M. J. Pharm. Soc. Jpn. 1928,
48, 321. (b) Kondo, H.; Ikeda, T. J. Pharm. Soc. Jpn. 1937, 57, 881.
(26) Shimada, Y.; Goto, H.; Itoh, T.; Sakakibara, I.; Kubo, M.; Sasaki,
H.; Terasawa, K. J. Pharm. Pharmacol. 1999, 51, 715.
(27) Ban, Y.; Seto, M.; Oishi, T. Chem. Pharm. Bull. 1975, 23, 5.
(28) A 34% yield is reported for the same tranformation: Takano, S.;
Sato, M.; Ogasawara, K. Heterocycles 1981, 16, 799.
(29) For related 1,4-additions, see ref 21g and references therein.
(30) Andreae, S.; Blasko´, G.; Sza´ntay, C. J. Prakt. Chem. 1987, 329,
374.
B. ABC f ABCD Approach. Encouraged by the successful
1,4-additions of organocuprates and metal enolates to the
(31) (a) Awang, D. V. C.; Vincent, A.; Kindack, D. Can. J. Chem. 1984,
62, 2667. (b) Martin, S. F.; Mortimore, M. Tetrahedron Lett. 1990, 31,
4557. (c) Stahl, R.; Borschberg, H.-J.; Acklin, P. HelV. Chim. Acta 1996,
79, 1361.
(32) The preparation of 26 has been claimed, but the 1H NMR data
reported match our spectral data for epi-26. See: Rosenmund, P.; Hosseini-
Merescht, M.; Bub, C. Liebigs Ann. Chem. 1994, 151.
J. Org. Chem, Vol. 71, No. 17, 2006 6551

Deiters et al.
SCHEME 7
SCHEME 8
unsaturated lactam 4 that culminated in the syntheses of the
indole alkaloids 15, 21, 27, and 28, we decided to expand
on this strategy and to explore the potential utility of conju-
gate additions to tetracyclic compounds of the general structure
29. While conjugate additions to 4 followed by Bischler-
Napieralski cyclizations led to indole alkaloids in which the
protons at C(3) and C(15) were positioned in a cis relationship,
1,4-additions of nucleophiles to 29 should give compounds such
as 30 in which there is a trans relationship between these protons
owing to the stereoelectronic preference for axial attack (Scheme
7). Such a mode of addition would thus provide access to
members of the pseudo-corynanthe family such as hirsutine (31).
31 has long been a target for synthesis,33 in part due to the fact
that it is significantly more active against influenza A (subtype
H3N3) than ribavarin, which is in clinical use.34 Moreover, like
rhynchophylline and isorhynchophylline, hirsutine also protects
against glutamate-induced neuronal death in cultured cerebellar
granule cells.26 It also did not escape our attention that
intermediates in the synthesis of hirsutine could also be diverted
to prepare other alkaloids, including those of the oxindole
family.
1. Extending the Scope of 1,4-Additions to Unsaturated
Piperidinones. The requisite tetracyclic Michael acceptor 34
is a known compound, but previous reports of its synthesis
required six or seven steps, proceeding with a relatively low
overall yield.35 We thus developed a significantly improved route
to 34 that involved an RCM as a key step.36 In the event, the
dihydrocarboline 32, which may be prepared in two steps from
tryptamine,37 was treated with allyltributyltin and acryloyl
chloride to furnish 33 in 75% yield (Scheme 8). Cyclization of
33 in the presence of 4 mol % Grubbs’ catalyst 11 then delivered
34 in 87% yield.
The reactions of 34 with a number of nucleophiles were then
examined. Sodium and lithium enolates and silyl ketene acetals
derived from methyl acetate and copper enolates of N,N-
dimethyl acetamide and tert-butyl acetate failed to undergo the
desired addition. The 1,4-addition of the sodium enolate of
dimethyl malonate proceeded slowly (48 h) to give the expected
adduct in 74% yield, but the diastereoselectivity was poor (dr
) 60:40). On the other hand, as we observed in additions to 4,
1,4-addition of the lithium enolate derived from ethyl 1,3-
dithiolane-2-carboxylate to 34 proceeded in excellent dia-
stereoselectivity (dr ) 91:9) to give 36, which could be isolated
cleanly in 55-60% yield after facile separation of the diaster-
eomers by column chromatography. To obtain reproducible
results in this reaction, it was necessary to degas the solvent
thoroughly by three freeze-pump-thaw cycles. Even when this
was done, there was an erosion in the dr on scaleup. The relative
stereochemistry of the C(3)H and C(15)H protons of 36 was
tentatively assigned as being trans on the basis of the known
stereoelectronic preference for axial attack, coupled with the
prediction that the nucleophile should approach form the convex
face of the alkene. This structural assignment was unequivocally
confirmed at a later stage of the synthesis by single-crystal X-ray
analysis of 44 (vide infra).
(33) For example, see: (a) Aimi, N.; Yamanaka, E.; Endo, J.; Sakai, S.;
Haginawa, J. Tetrahedron 1973, 29, 2015. (b) Brown, R. T.; Chapple, C.
L.; Charalambides, A. A. J. Chem. Soc., Chem. Commun. 1974, 756. (c)
Wenkert, E.; Vankar, Y. D.; Yadav, J. S. J. Am. Chem. Soc. 1980, 102,
7972. (d) Brown, R. T.; Ford, M. J. Tetrahedron Lett. 1990, 31, 2033. (e)
Gomez-Pardo, D.; Desmae¨le, D; d’Angelo, J. Tetrahedron Lett. 1992, 33,
6633. (f) Lounasmaa, M.; Jokela, R.; Laine, C.; Hanhinen, P. Heterocycles
1998, 49, 445. (g) Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38,
2045.
(34) Takayama, H.; Iimura, Y.; Kitayama, M.; Aimi, N.; Konno, K.;
Inoue, H.; Fujiwara, M.; Mizuta, T.; Yokota, T.; Shigeta, S.; Tokuhisa, K.;
Hanasaki, Y.; Katsuura, K. Bioorg. Med. Chem. Lett. 1997, 7, 3145.
(35) For example, see: (a) Oehl, R.; Lenzer, G.; Rosenmund, P. Chem.
Ber. 1976, 109, 705. (b) Massiot, G.; Mulamba, T.; Levy, J. Bull. Soc.
Chim. Fr. 1982, II-241. (c) Massiot, G.; Mulamba, T J. Chem. Soc., Chem.
Commun. 1983, 1147.
(36) Since this work was completed, a related approach to the asymmetric
synthesis of 34 was reported. See: Itoh, T.; Miyazaki, M.; Nagata, K.;
Nakamura, S, Ohsawa, A. Heterocycles 2004, 63, 655.
(37) Martin, S. F.; Benage, B.; Hunter, J. E. J. Am. Chem. Soc. 1988,
110, 5925.
We also briefly explored the copper(I)-mediated conjugate
additions of organometallic reagents to 34 in the presence of
TMSCl. We had found that CuCN-derived cuprate reagents
were best for additions to 4, but use of catalytic amounts (10
6552 J. Org. Chem., Vol. 71, No. 17, 2006

Corynanthe, Tacaman, and Oxindole Alkaloid Syntheses
mol %) of CuBr‚DMS complex was better when 34 was the
substrate. This observation suggests that subtle effects are at
play in cuprate additions to unsaturated lactams. Although the
addition of the organocopper reagent derived from vinyl-
magnesium bromide to 34 proceeded in 80% yield to give 38,
the diastereoselectivity was poor (dr ) 60:40) (Scheme 8). On
the other hand, cuprates derived from ethylmagnesium bromide
and [1-(trimethylsilyl)vinyl]magnesium bromide added in excel-
lent (84-98%) yield to give the corresponding adducts 39 and
40 with >95:5 diastereoselectivity. Whereas addition of the
cuprate derived from [2-(trimethylsilyl)vinyl]magnesium bro-
mide and CuBr‚DMS to 34 was both inefficient (52%) and
nonselective (dr ) 65:35), the related reaction with [2-(tri-
methylsilyl)vinyl]lithium in the presence of CuI gave 41 in 84%
yield with >95:5 diastereoselectivity. It is noteworthy that the
vinylsilyl groups in 40 and 41 are masked equivalents of acetyl
and acetaldehyde substituents, respectively.38 The relative
stereochemical course in these additions was not rigorously
determined, but the structural assignment is consistent with NOE
studies conducted on compound 39.
Converting 36 into hirsutine requires introducing an ethyl
group onto 36 or a derived intermediate by alkylation at C(20).
It occurred to us that this extra step might be avoided if the
ethyl group were already incorporated in the unsaturated
lactam as found in 42. Although 42 is known,39 we developed
an improved and more concise route to this compound that
features the RCM of an R-ethylacrylamide derivative of 33 that
required only three steps and proceeded in 60% overall yield
from 32. Consistent with the report that 42 is a poor Michael
acceptor,39 we were unable to detect any 1,4-addition products
when 42 was allowed to react with either the lithium or sodium
enolates of ethyl 1,3-dithiolane-2-carboxylate or various cuprate
reagents. Either the addition was disfavored owing to steric or
electronic factors or the 1,4-adduct was kinetically unstable
under these conditions. We then considered the alternate
possibility that the enolate formed upon addition of lithiated
ethyl 1,3-dithiolane-2-carboxylate to 34 might be alkylated to
provide a derivative of 36 bearing an ethyl group at C(20).
However, this tactic was complicated by concomitant and
unavoidable ethylation of the indole nitrogen atom. We therefore
examined conjugate additions to the protected indole 35,
anticipating that alkylation of the intermediate enolate would
proceed without difficulty.
FIGURE 1. ORTEP plot of 35. The hydrogen atoms have been
removed for clarity. Displacement ellipsoids are scaled to the 50%
probability level.
A clue for this unexpected reversal in diastereoselectivity in
the addition to 35 may be found through analysis of its X-ray
structure (Figure 1). Examination of this structure of 35 reveals
that the R,â-unsaturated lactam is twisted away from the plane
of the indole and the bulky Boc group. Assuming that the
conformation of 35 in solution resembles that in the solid state,
the top face of the R,â-unsaturated lactam moiety is partially
shielded from nucleophilic attack by the Boc group, so it appears
that steric factors may override the usual stereoelectronic
preference for axial attack. Alternatively, axial attack might
occur on the other half-chair conformer of the unsaturated lactam
ring, although the approach of a nucleophile via that trajectory
would also incur a 1,3-diaxial interaction.
2. Formal Synthesis of 31. The observed stereoselectivities
in the conjugate additions to 34 and 35 provided crucial guidance
for planning the synthesis of 31. The next task involved
introducing an ethyl group, and prior experimentation (vide
supra) suggested that selective ethylation at C(20) of 36 might
be problematic, owing to competing alkylation of the indole
nitrogen atom. Indeed, a few preliminary experiments validated
this concern, and protecting the indole as its Boc derivative was
clearly indicated. Although it was possible to carry out the
protection in the same pot as the 1,4-addition to afford 43 in
60-65% yield, the two diastereomers thus obtained (dr ) 91:
9) were not easily separable by chromatography at this stage.
Instead, diastereomerically pure 36 was converted to 43 in 85%
yield upon reaction with Boc2O in the presence of catalytic
amounts of DMAP (Scheme 9).
Optimizing the tactics for introducing an ethyl group at C(20)
of 43 required rather extensive experimentation. The lithium
enolate derived from 43 was unreactive with ethyl iodide, even
in the presence of additives such as HMPA and DMPU, at -78
°C, and at higher temperatures the enolate underwent a retro-
Michael reaction to give 35. Use of KHMDS as the base in the
presence of HMPA led to extensive cleavage of the dithiolane
ring via elimination and S-alkylation of the thiolate thus formed.
Although the corresponding sodium enolate of 43 did undergo
alkylation at -78 °C, 44 was produced in only 40-45% yield.
Gratifyingly, we eventually discovered that reaction of the
sodium enolate of 43 with EtOTf in the presence of DMPU at
-100 °C furnished 44 in 67% yield and as a single diastereomer.
Starting material (25-30%) was invariably recovered from these
reactions, despite meticulous efforts to avoid adventitious water.
The structure of 44 was unequivocally established through
single-crystal X-ray analysis, thereby confirming not only the
stereochemistry of the alkylation but also the stereochemistry
of the conjugate addition to 34 to give 36 (vide supra). A severe
Toward this end, we found that 35 could be obtained in 99%
yield by protecting 34 under standard conditions (Scheme 8).
However, an even more efficient approach involved adding Boc-
anhydride and DMAP directly to the reaction mixture obtained
after completion of the RCM of 33, thus giving 35 in 93% yield
in one step from 33. Surprisingly, reaction of 35 with ethyl
2-lithio-1,3-dithiolane-2-carboxylate gave 37 in 71% yield and
high diastereoselectivity (dr > 95:5) (Scheme 8), not the
expected adduct in which the protons at C(3) and C(15) were
positioned trans as in 36.40 It should be noted that the stereo-
chemistry in 37 corresponds to that found in the corynanthe
alkaloids and thus may serve as a useful intermediate in their
synthesis.
(38) Boeckman, R. K., Jr.; Bruza, K. J. J. Org. Chem. 1979, 44, 4781.
(39) Yamanaka, E.; Narushima, M.; Inukai, K.; Sakai, S. Chem. Pharm.
Bull. 1986, 34, 77.
(40) Our observation of reversal of the diastereoselectivity by introducing
a tert-butyl carbamate was corroborated in the following paper, which was
published during the preparation of this manuscript: Allin, S. M.; Khera,
J. S.; Thomas, C. I.; Witherington, J.; Doyle, K.; Elsegood, M. R. J.; Edgar,
M. Tetrahedron Lett. 2006, 47, 1961.
J. Org. Chem, Vol. 71, No. 17, 2006 6553

Deiters et al.
SCHEME 9
SCHEME 10
only 10% and 14% yields, respectively. Hence, the same three-
step sequence we previously adopted was employed to convert
47 into a mixture (55:45) of 26 and epi-26 in 75% overall yield,
thereby completing a second formal synthesis of 27 and 28
(Scheme 10).27
Summary
We have developed a novel and general approach to a variety
of indole alkaloids possessing a corynanthe, an oxindole, or a
tacaman skeleton. By employing a sequence of two RCM
reactions and one zirconocene-catalyzed carbomagnesation, the
construction of the R,â-unsaturated piperidinone ring in the key
intermediate 4 was completed in just five chemical operations
and 36% overall yield. Although we did not explore this option,
it would be possible to use a known chiral zirconocene catalyst
in the carbomagnesation step to assemble 4 in enantiomerically
pure form. To install a variety of substituents at C(15) in 4, we
explored the feasibility of inducing conjugate additions of
various carbon nucleophiles onto R,â-unsaturated lactams, a still
underdeveloped area in organic synthesis. Our studies revealed
that organocuprates derived from organomagnesium compounds
and, depending upon the nature of the lactam, either stoichio-
metric amounts of CuCN or catalytic amounts of CuBr‚DMS
complex are superior nucleophiles for such 1,4-additions. It was
crucial to use TMSCl as an additive as its presence prevents
undesired side reactions. Having established the optimal pa-
rameters for effecting the requisite conjugate additions, we
completed an extremely concise total synthesis of the corynanthe
alkaloid 21 in just eight distinct chemical operations and 19%
overall yield. Inspired by the obvious biogenetic relationship
between the corynanthe alkaloids and those natural products
possessing the oxindole or pseudoeburnan skeleton, we adapted
our approach to 21 and developed novel formal syntheses of
15, 27, and 28 from 4. It is noteworthy that these syntheses
avoid the use of any protecting groups, thereby simplifying the
execution. In a related series of studies, we explored the 1,4-
addition of various organocuprates and enolates to the unsat-
urated lactam 34 as a key step in developing an alternate
approach to indole and oxindole alkaloids. During the course
of these studies, we discovered that the diastereoselectivity of
the 1,4-addition of the lithium enolate of ethyl 1,3-dithiolane-
2-carboxylate to 34 could be reversed by simply introducing a
Boc protecting group on the indole nitrogen atom prior to the
conjugate addition. This work led to a short formal synthesis
of 31 as well as second-generation syntheses of 27 and 28.
Taken together, the two strategies reported herein represent a
unified approach to indole alkaloids possessing either a H(3)/
steric interaction between the Boc group and the dithiolane
moiety is apparent in this structure, a factor that may account
for the observed propensity for the enolate of 43 to undergo
retro-Michael reaction.
Having thus served its dual role of enabling the 1,4-addition
to 35 and the selective alkylation at C(20) of 43, the dithiolane
moiety was reductively removed using Raney Ni to afford 45
in 93% yield. Subsequent removal of the Boc group by the
action of NaOMe proceeded as planned with concomitant
transesterification of the ethyl ester to furnish 46 in 86% yield.
Selective reduction of the lactam function in 46 was then
achieved according to the Borch protocol,41 delivering 47 in
1
81% yield. The H and 13C NMR spectral data for 47, which
had been previously converted into 31 in two steps,33g were
consistent with those reported in the literature,42 thereby
completing a formal synthesis of 31.
3. Second-Generation Formal Synthesis of 27 and 28. It
occurred to us that the indoloquinolizidine 47 might be an
intermediate in an alternative route to 27 and 28. This hypothesis
was founded upon our previous observations that the stereo-
chemistry at C(3) of oxindoles related to 26 and epi-26 could
also be equilibrated via retro-Mannich/Mannich reactions that
occur consequent to the oxidative rearrangement.2d A two-step
sequence for inducing the oxidative rearrangement of 47 was
first examined. However, when 47 was treated with tert-butyl
hypochlorite and the resultant crude chloroindolinine 48 heated
under reflux in MeOH/AcOH to effect rearrangement and
hydrolysis in the same pot,2d 26 and epi-26 were obtained in
(41) Borch, R. F. Tetrahedron Lett. 1968, 9, 61.
(42) (a) Lounasmaa, M.; Jokela, R.; Tirkkonen, B.; Miettinen, J.; Halonen,
M. Heterocycles 1992, 34, 321. (b) Seguin, E.; Koch, M. HelV. Chim. Acta
1980, 63, 1335.
6554 J. Org. Chem., Vol. 71, No. 17, 2006

Corynanthe, Tacaman, and Oxindole Alkaloid Syntheses
under reduced pressure, and the residue was purified by flash
column chromatography on silica gel, eluting with EtOAc/hexanes
(1:1), to give 250 mg (73%) of 5 as a colorless oil: 1H NMR (300
MHz, CDCl3, rotamers) δ 8.48 (br s, 0.5 H), 8.37 (br s, 0.5 H),
7.70 (d, J ) 7.8 Hz, 0.5 H), 7.56 (d, J ) 7.5 Hz, 0.5 H), 7.37-
7.33 (m, 1 H), 7.22-7.09 (comp, 2 H), 7.00 (d, J ) 2.1 Hz, 0.5
H), 6.35 (d, J ) 2.4 Hz, 0.5 H), 6.57 (dd, J ) 10.2, 16.5 Hz, 0.5
H), 6.45 (dd, J ) 10.2, 16.5 Hz, 0.5 H), 6.40 (dd, J ) 2.1, 16.5
Hz, 0.5 H), 6.26 (dd, J ) 2.4, 16.5 Hz, 0.5 H), 5.68 (dd, J ) 2.1,
10.2 Hz, 0.5 H), 5.63-5.41 (comp, 1.5 H), 5.06-4.95 (comp, 2
H), 3.71-3.58 (comp, 2 H), 3.50 (dd, J ) 6.0, 13.5 Hz, 0.5 H),
3.34-3.14 (comp, 1.5 H), 3.08-2.97 (comp, 2 H), 2.42-2.30 (m,
0.5 H), 2.24-2.14 (m, 0.5 H) 1.50-1.32 (m, 1 H), 1.30-1.10 (m,
1 H), 0.88-0.82 (comp, 3 H); 13C NMR (75 MHz, CDCl3, rotamers)
δ 166.6, 166.4, 140.2, 138.8, 136.3, 128.1, 127.6, 127.5, 127.3,
126.9, 122.2, 122.0, 121.8, 119.4, 119.2, 118.7, 118.1, 117.5, 116.3,
113.1, 111.9, 111.4, 111.2, 52.9, 50.7, 49.1, 48.5, 46.4, 45.0, 25.2,
25.1, 24.8, 23.2, 11.5; IR (neat) 3269, 2963, 2927, 1642, 1603,
1455, 1354, 1225, 916, 741 cm-1; mass spectrum (CI) m/z 297.1971
[C19H25N2O (M + 1) requires m/z 297.1967].
5-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-5,6-dihydro-1H-pyridin-2-
one (4). A solution of 5 (250 mg, 0.84 mmol) and ((C6H11)3P)2-
Cl2RuC2H3Ph (35 mg, 0.04 mmol, 5 mol %) in CH2Cl2 (30 mL)
was stirred for 20 h. (HOCH2)3P (50 mg) and Et3N (2 mL) were
added, and stirring was continued for 15 min. The solvents were
removed under reduced pressure, and the crude product was purified
by flash column chromatography on silica gel, eluting with EtOAc,
to give 206 mg (91%) of 4 as a colorless solid: mp 88-89 °C
(EtOAc); 1H NMR (300 MHz, CDCl3) 8.50 (br s, 1 H), 7.65 (d, J
) 7.8 Hz, 1 H), 7.35 (d, J ) 8.1 Hz, 1 H), 7.19-7.08 (comp, 2 H),
7.02 (d, J ) 2.1 Hz, 1 H), 6.41 (dd, 1 H, J ) 3.6, 9.8 Hz, 1 H),
5.90 (dd, J ) 1.8, 9.8 Hz, 1 H), 3.82-3.62 (comp, 2 H), 3.30 (dd,
J ) 6.0 Hz, 12.3, 1 H), 3.12 (dd, J ) 8.4, 12.3 Hz, 1 H), 3.04 (t,
J ) 7.4 Hz, 2 H), 2.21 (br s, 1 H), 1.46-1.26 (comp, 2 H), 0.84
(t, J ) 7.4 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 164.2, 144.0,
136.3, 127.4, 124.5, 122.2, 121.8, 119.1, 118.6, 112.8, 111.2, 50.7,
47.6, 35.9, 24.9, 23.6, 11.2; IR (neat) 3260, 1654, 1597, 1487, 817,
741 cm-1; MS (CI) m/z 269.1645 [C17H21N2O (M + 1) requires
m/z 269.1654].
H(15)-cis or a H(3)/H(15)-trans stereochemical relationship, and
further applications of these tactics to other problems in alkaloid
synthesis are in progress.
Experimental Section
N,N-Diallyl-2-(1H-indol-3-yl)acetamide (8). EDCI (5.47 g, 28.5
mmol) was added to a solution of indole-3-acetic acid (5.00 g, 28.5
mmol) in CH2Cl2 (100 mL) at 0 °C. After 3 min, diallylamine (5.30
mL, 43.0 mmol) was added, and the resultant solution was stirred
for 2 h at 0 °C and for 17 h at room temperature. Aqueous HCl (1
M, 40 mL) was added, and the phases were separated. The aqueous
layer was extracted with EtOAc (3 × 50 mL), and the combined
organic phases were washed with H2O (30 mL) and saturated
aqueous NaHCO3 (30 mL), dried (MgSO4), and filtered. The
solvents were removed under reduced pressure to give 6.37 g (88%)
of 8 as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.67 (br
s, 1 H), 7.59-7.06 (comp, 4 H), 6.95 (m, 1 H), 5.81-5.66 (comp,
2 H), 5.21-5.04 (comp, 4 H), 4.02 (d, J ) 6.0 Hz, 2 H), 3.89-
3.87 (m, 2 H), 3.80 (s, 2 H); 13C NMR (75 MHz, CDCl3) δ 171.8,
136.2, 133.07, 132.9, 127.1, 122.7, 121.8, 119.3, 118.5, 117.2,
116.6, 111.3, 108.8, 49.5, 47.9, 30.9; IR (neat) 3277, 1628, 1458,
1415, 1340, 1221, 924, 741 cm-1; MS (CI) m/z 255.1500
[C16H19N2O (M + 1) requires m/z 255.1497].
N-(2-Ethylbut-3-enyl)-2-(1H-indol-3-yl)acetamide (7). A mix-
ture of 8 (1.29 g, 5.08 mmol) and [(C6H11)3P]2Cl2RuC2H3Ph (42
mg, 0.05 mmol, 1 mol %) in THF (60 mL) was stirred for 29 h at
room temperature, whereupon a 2 M solution of EtMgCl in Et2O
(10.2 mL, 20.3 mmol) and Cp2ZrCl2 (222 mg, 0.76 mmol) were
added. The mixture was stirred for 1 h, and 2 M aqueous HCl (30
mL) was injected. The layers were separated, and the organic phase
was extracted with EtOAc (3 × 30 mL). The combined organic
phases were dried (MgSO4), and the volatiles were removed under
reduced pressure. The residue was purified by flash column
chromatography on silica gel, eluting with EtOAc/hexanes (1:1 f
7:3 f EtOAc), to give 926 mg (71%) of 7 as a yellow viscous oil:
1H NMR (300 MHz, CDCl3) δ 8.79 (br s, 1 H), 7.55-7.09 (comp,
5 H), 5.77 (br s, 1 H), 5.28 (ddd, J ) 9.0, 9.5, 16.8 Hz, 1 H), 4.76
(dd, J ) 1.6, 10.2 Hz, 1 H), 4.59 (ddd, J ) 0.6, 1.6, 16.8 Hz, 1 H),
3.73 (s, 2 H), 3.37 (ddd, J ) 4.9, 8.0, 13.0, 1 H), 2.86 (ddd, J )
4.9, 8.0, 13.0 Hz, 1 H), 1.90-1.80 (m, 1 H), 1.40-1.20 (m, 1 H),
1.20-1.03 (m, 1 H), 0.78 (t, J ) 7.4 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 171.5, 139.6, 136.4, 126.9, 123.8, 122.4, 119.8, 118.7,
116.6, 111.4, 108.7, 45.9, 42.6, 33.3, 24.9, 11.3; IR (neat) 3403,
3277, 2962, 2926, 1650, 1530, 1457, 1340, 918, 741 cm-1; MS
(CI) m/z 257.1657 [C16H21N2O (M + 1) requires m/z 257.1653].
(2-Ethylbut-3-enyl)[2-(1H-indol-3-yl)ethyl]amine (6). LiAlH4
(1.47 g, 38.6 mmol) was added to a solution of 7 (1.65 g, 6.44
mmol) in Et2O (130 mL), and the suspension was stirred at room
temperature overnight. After addition of more LiAlH4 (400 mg,
10.5 mmol), stirring was continued for 4 h, and then, sequentially,
H2O (1.9 mL), 15% aqueous NaOH (1.9 mL), and H2O (5.7 mL)
were added. The suspension was stirred for 30 min, the solids were
removed by vacuum filtration, and the filtrate was concentrated
under reduced pressure to give 1.36 g (87%) of 6 as a yellow oil.
The crude product was used without further purifications: 1H NMR
(300 MHz, CDCl3) δ 9.20 (s, 1 H, N(1)H), 7.63-7.00 (comp, 5
H), 5.49-5.36 (m, 1 H), 4.95 (m, 2 H), 3.00-2.87 (m, 4 H), 2.67
(dd, J ) 5.0, 11.4 Hz, 1 H), 2.47 (dd, J ) 8.7, 11.4 Hz, 1 H),
2.21-2.04 (m, 1 H), 1.44-1.32 (m, 1 H), 1.25-1.18 (m, 1 H),
0.84 (t, J ) 7.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 140.5,
136.3, 127.2, 122.1, 121.6, 118.9, 188.5, 116.6, 112.8, 111.1, 53.0,
49.5, 45.6, 25.5, 25.1, 11.4; IR (neat) 3058, 2920, 1454, 1354, 1231,
1108, 917, 740 cm-1; MS (CI) m/z 243.1853 [C16H23N2 (M + 1)
requires m/z 243.1861].
3-Ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizine (14).
Palladium (10% on carbon) was added to a solution of 4 (30 mg,
0.30 mmol) in toluene (4 mL). The suspension was pressurized by
a H2 balloon and stirred for 14 h. Freshly distilled POCl3 (63 µL,
0.67 mmol) was added, and the reaction mixture was heated to
100 °C for 3 h. A saturated aqueous solution of NH4OH (2 mL)
was added, and heating under reflux was continued for 30 min.
The reaction mixture was allowed to cool to room temperature,
the layers were separated, and the aqueous phase was extracted
with EtOAc (3 × 3 mL). The combined organic layers were dried
(MgSO4), and the volatiles were removed under reduced pressure.
The residue was purified by flash column chromatography on silica
gel, eluting with EtOAc/TEA (98:2), to furnish 26 mg (92%) of
1
14 as a brown viscous oil. The H and 13C NMR spectra were
consistent with those reported in the literature.16
trans-5-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-4-vinylpyridin-2-
one (16). A freshly prepared 0.9 M solution of vinylmagnesium
bromide in THF (8.3 mL, 7.45 mmol) was added to a suspension
of CuCN (333 mg, 3.73 mmol) in THF (15 mL) at -78 °C. The
reaction mixture was warmed to 0 °C for 3 min and then recooled
to -78 °C. A solution of 4 (200 mg, 0.75 mmol) in THF (4 mL)
was added, and after 5 min freshly distilled TMSCl (0.47 mL,
3.73 mmol) was added. The suspension was warmed to room
temperature over 3.5 h, and stirring was continued for 15 min. A
mixture of saturated aqueous NH4Cl/NH4OH (9:1, 5 mL) and H2O
(5 mL) were added, and the mixture was stirred for 20 min. A 1 M
solution of TBAF in THF (0.5 mL, 0.5 mmol) was added, and
stirring was continued for 15 min. The layers were separated, and
the aqueous phase was extracted with EtOAc (4 × 15 mL). The
combined organic phases were dried (MgSO4) and concentrated
N-(2-Ethylbut-3-enyl)-N-[2-(1H-indol-3-yl)ethyl]acrylamide
(5). Acryloyl chloride (94 µL, 1.15 mmol) was added to a stirred
solution of 5 (280 mg, 1.15 mmol) and Et3N (0.32 mL, 2.31 mmol)
in CH2Cl2 (15 mL) at 0 °C. After 13 h, the volatiles were evaporated
J. Org. Chem, Vol. 71, No. 17, 2006 6555

Deiters et al.
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel, eluting with EtOAc, to give
200 mg (91%, dr ) 98:2) of 16 as colorless needles: mp 159-
16.0 Hz, 1 H), 2.35-2.22 (comp, 2 H), 1.69-1.49 (comp, 2 H),
0.98-0.88 (m, 1 H), 0.72 (t, J ) 7.6 Hz, 3 H), 0.10 (s, 9 H); 13C
NMR (100 MHz, CDCl3) δ 169.7, 153.6, 136.5, 127.8, 125.7, 122.2,
122.1, 119.5, 119.0, 113.4, 111.5, 52.8, 48.7, 43.6, 39.8, 39.4, 24.5,
23.5, 11.8, -0.5; IR (neat) 3269, 2957, 1633, 1504, 1455, 1248,
837, 740 cm-1; MS (CI) m/z 369.2368 [C22H33N2OSi (M + 1)
requires m/z 369.2362].
1
161 °C (EtOAc); H NMR (300 MHz, CDCl3) δ 8.34 (br s, 1 H),
7.66 (d, J ) 7.8 Hz), 7.36 (d, J ) 8.1 Hz), 7.12-7.09 (m, 2 H),
7.04 (d, J ) 2.1 Hz), 5.62-5.50 (m, 1 H), 5.05-4.99 (comp, 2 H),
3.77-3.57 (comp, 2 H), 3.19 (dd, J ) 4.8, 12.1 Hz, 1 H), 3.05 (t,
J ) 7.5 Hz, 2 H), 2.87 (dd, J ) 9.9, 12.1 Hz, 1 H), 2.49 (dd, J )
4.5, 16.5 Hz, 1 H), 2.30-2.12 (comp, 2 H), 1.59-1.28 (comp, 2
H), 1.12-1.01 (m, 1 H), 0.74 (t, J ) 7.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 169.1, 139.7, 136.3, 127.5, 122.0, 121.9, 119.2,
118.7, 115.6, 113.1, 111.2, 52.1, 48.2, 42.5, 39.3, 37.4, 23.9, 23.0,
10.9; IR (CH2Cl2) 3255, 2962, 2927, 2868, 1625, 1503, 1456, 1357,
916, 741 cm-1; MS (CI) m/z 297.1969 [C19H25N2O (M + 1) requires
m/z 297.1967].
5,5′-Diethyl-1,1′-bis[2-(1H-indol-3-yl)ethyl]-4-vinyl[3,4′]-
bipiperidinyl-2,2′-dione (19). A freshly prepared 0.9 M solution
of vinylmagnesium bromide in THF (1.2 mL, 1.12 mmol) was
added to a suspension of CuCN (50 mg, 0.56 mmol) in THF (3
mL) at -78 °C. The reaction mixture was warmed to 0 °C for 3
min and then recooled to -78 °C. A solution of 4 (30 mg, 0.11
mmol) in THF (0.5 mL) was added. The suspension was warmed
to room temperature over 3 h, and stirring was continued for 15
min. A mixture of saturated aqueous NH4Cl/NH4OH (9:1, 1 mL)
was added, the layers were separated, and the aqueous phase was
extracted with EtOAc (3 × 1 mL). The combined organic phases
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel,
eluting with EtOAc f EtOAc/MeOH (9:1), to give 7 mg (21%, dr
> 95:5) of 16 and 18 mg (57%, dr > 95:5) of 19 as a colorless
foam: 1H NMR (400 MHz, CDCl3) δ 8.45 (br s, 1 H), 8.32 (br s,
1 H), 7.65 (d, J ) 7.6 Hz, 2 H), 7.35 (d, J ) 8.0 Hz, 1 H), 7.34 (d,
J ) 8.0 Hz, 1 H), 7.18 (t, J ) 6.8 Hz, 2 H), 7.12 (t, J ) 6.8 Hz,
2 H), 7.02 (d, J ) 2.0 Hz, 1 H), 6.99 (d, J ) 2.0 Hz, 1 H), 5.38
(ddd, J ) 9.6, 10.0, 17.2 Hz, 1 H), 5.07 (d, J ) 10.0 Hz, 1 H),
4.94 (d, J ) 16.8 Hz, 1 H), 3.83 (dt, J ) 8.0, 13.2 Hz, 1 H), 3.80-
3.71 (m, 1 H), 3.60-3.50 (comp, 2 H), 3.12 (dd, J ) 4.8, 11.8 Hz,
1 H), 3.09-2.94 (comp, 5 H), 2.89 (t, J ) 11.6 Hz, 1 H), 2.76 (dd,
J ) 9.6, 11.8 Hz, 1 H), 2.57 (dd, J ) 11.2, 16.4 Hz, 1 H), 2.38 (d,
J ) 8.8 Hz, 1 H), 2.36-2.30 (m, 1 H), 2.23 (dd, J ) 5.6, 16.4 Hz,
1 H), 1.99-1.91 (m, 1 H), 1.62-1.42 (comp, 2 H), 1.28-1.21 (m,
1 H), 1.05-0.85 (m, 1 H), 0.85-0.81 (m, 1 H), 0.70 (t, J ) 7.6
Hz, 3 H), 0.66 (t, J ) 7.6 Hz, 3 H); 13C NMR (125 MHz) δ 170.7,
170.1, 140.1, 136.5, 136.3, 127.5, 127.4, 122.2, 122.1, 122.0, 121.9,
119.3, 119.2, 118.7, 118.6, 117.7, 113.1, 112.7, 111.3, 111.2, 52.3,
51.5, 48.7, 48.1, 46.9, 46.5, 39.7, 39.2, 36.8, 35.4, 23.8, 23.4, 23.2,
23.1, 10.7, 10.6; IR (CH2Cl2) 3270, 2965, 2928, 1621, 1494, 1455,
1342, 1298, 1232, 909, 737 cm-1; MS (CI) m/z 565.3544
[C36H45N4O2 (M + 1) requires m/z 565.3543].
4,5-Diethyl-1-[2-(1H-indol-3-yl)ethyl]pyridin-2-one (17). A 2
M solution of ethylmagnesium chloride in THF (1.86 mL, 3.73
mmol) was added to a suspension of CuBr‚DMS (11 mg, 56 µmol)
in THF (15 mL) at -78 °C. The reaction mixture was warmed to
0 °C for 3 min and then recooled to -78 °C. Freshly distilled
TMSCl (0.14 mL, 1.11 mmol) and a solution of 4 (100 mg, 0.37
mmol) in THF (1.5 mL) were added. The suspension was warmed
to room temperature over 3.5 h, and stirring was continued for 15
min. A mixture of saturated aqueous NH4Cl/NH4OH (9:1, 6 mL)
was added. After the resulting mixture was stirred for 10 min, a 1
M solution of TBAF in THF (0.35 mL, 0.35 mmol) was added,
and stirring was continued for 15 min. The layers were separated,
and the aqueous phase was extracted with EtOAc (4 × 15 mL).
The combined organic phases were dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel, eluting with EtOAc, to give
110 mg (99%, dr ) 77:23) of 17 as a mixture of inseparable
diastereomers and as a colorless foam: 1H NMR (300 MHz, CDCl3,
mixture of diastereomers) δ 8.59 (br s, 1 H), 7.64 (d, J ) 7.7 Hz,
1 H), 7.34 (d, J ) 7.9 Hz, 1 H), 7.18-7.06 (comp, 2 H), 6.99 (d,
J ) 1.8 Hz, 1 H), 3.75-3.56 (comp, 2 H), 3.19-3.10 (comp, 1
H), 3.07-3.01 (comp, 2.2 H) 2.86 (dd, J ) 12.0, 8.2 Hz, 0.8 H),
2.50 (dd, J ) 17.3, 5.2 Hz, 0.8 H), 2.40 (dd, J ) 17.6, 5.6 Hz, 0.2
H), 2.27 (dd, J ) 17.6, 6.7 Hz, 0.2 H), 2.05 (dd, J ) 17.3, 8.6 Hz,
0.8 H), 1.78-1.59 (comp, 0.4 H), 1.51-1.02 (comp, 5.6 H), 091-
70.72 (comp, 6 H); 13C NMR (100 MHz, CDCl3, mixture of
diastereomers) δ 170.0, 136.3, 127.4, 122.1, 121.7, 119.1, 118.6,
112.8, 111.2, 51.5, 50.6. 48.1, 48.0, 38.9, 38.2, 37.6, 37.1, 36.1,
35.8, 25.5, 23.5, 23.1, 22.9, 21.8, 19.9, 12.0, 11.8, 10.9, 10.4; IR
spectrum identical to that previously reported;24 MS (CI) m/z
299.2133 [C19H27N2O (M + 1) requires m/z 299.2123].
trans-5-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-4-[1-(trimethylsilyl)-
vinyl]pyridin-2-one (18). Freshly prepared [1-(trimethylsilyl)vinyl]-
magnesium bromide (1.50 mmol) in THF (1.5 mL) was added to
a suspension of CuCN (67 mg, 0.75 mmol) in THF (5 mL) at -78
°C. The reaction mixture was warmed to 0 °C for 3 min and then
recooled to -78 °C. A solution of 4 (40 mg, 0.15 mmol) in THF
(1 mL) was added, and after 5 min freshly distilled TMSCl (95
µL, 0.75 mmol) was added. The suspension was warmed to room
temperature over 3.5 h, and stirring was continued for 15 min. A
mixture of saturated aqueous NH4Cl/NH4OH (9:1, 2 mL) and H2O
(2 mL) were added. After 30 min TBAF (0.3 mL) was injected
and stirring continued for 10 min. The layers were separated, and
the aqueous phase was extracted with EtOAc (4 × 15 mL). The
combined organic phases were dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel, eluting with EtOAc, to give
41 mg (75%, dr > 95:5) of 18 as colorless oil: 1H NMR (400
MHz, CDCl3) δ 8.42 (br s, 1 H), 7.68 (d, J ) 8.0 Hz, 1 H), 7.35
(d, J ) 8.0 Hz, 1 H), 7.18 (t, J ) 8.0 Hz, 1 H), 7.12 (t, J ) 8.0 Hz,
1 H), 7.04 (d, J ) 2.0 Hz, 1 H), 5.57 (d, J ) 1.8 Hz, 1 H), 5.49 (d,
J ) 1.8 Hz, 1 H), 3.75 (dt, J ) 7.4, 13.0 Hz, 1 H), 3.60 (dt, J )
7.4, 13.0 Hz, 1 H), 3.23 (dd, J ) 5.2, 12.4 Hz, 1 H), 3.06 (t, J )
7.6 Hz, 2 H), 2.84 (dd, J ) 9.2, 12.0 Hz, 1 H), 2.51 (dd, J ) 3.6,
3-Ethyl-2-vinyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinoli-
zine (20). Freshly distilled POCl3 (0.23 mL, 2.42 mmol) was added
to a suspension of 16 (90 mg, 0.30 mmol) in toluene (4 mL), and
the reaction mixture was heated to 100 °C for 1 h. The volatiles
were evaporated under reduced pressure, and MeOH (6 mL) was
added. The solution was cooled to 0 °C, and NaBH4 (92 mg, 2.42
mmol) was added. The reaction mixture was allowed to warm to
room temperature over 1 h. A saturated aqueous solution of
NaHCO3 (0.2 mL) was added, and the organic solvent was removed
under reduced pressure. The residue was dissolved in EtOAc (6
mL), and the solution was dried (MgSO4). The solvents were
removed under reduced pressure, and the residue was purified by
flash column chromatography on silica gel, eluting with EtOAc/
hexane (2:1), to furnish 74 mg (87%, dr > 95:5) of 20 as a yellow
1
solid: mp 162-163 °C (EtOAc/hexane); H NMR (300 MHz) δ
7.76 (br s, 1 H), 7.48 (d, J ) 7.2 Hz, 1 H), 7.28 (d, J ) 7.2 Hz, 1
H), 7.16-7.06 (comp, 2 H), 5.69-5.62 (m, 1 H), 5.12-5.03 (comp,
2 H), 3.26 (dd, J ) 2.1, 12.0 Hz, 1 H), 3.19-2.97 (m, 3 H), 2.74
(m, 1 H), 2.62 (dt, J ) 4.2, 10.8 Hz, 1 H), 2.12-2.01 (comp, 2 H),
1.93 (m, 1 H), 1.70-1.51 (comp, 3 H), 1.11-1.01 (m, 1 H), 0.91
(t, J ) 7.5 Hz, 3 H); 13C NMR (125 MHz) δ 141.9, 136.0, 134.7,
127.4, 121.3, 119.4, 118.1, 115.0, 110.7, 108.2, 60.1, 59.5, 53.3,
46.6, 41.6, 36.7, 24.3, 21.7, 11.2; IR (CH2Cl2) 3189, 2943, 2804,
2750, 1450, 1321, 911, 739 cm-1; MS (CI) m/z 281.2018 [C19H25N2
(M + 1) requires m/z 281.2017].
Dihydrocorynantheol (21). 9-BBN (0.5 M solution in THF, 0.54
mL, 0.27 mmol) was added to a solution of 20 (30 mg, 0.11 mmol)
in THF (3 mL), and the reaction mixture was stirred at room
6556 J. Org. Chem., Vol. 71, No. 17, 2006

Corynanthe, Tacaman, and Oxindole Alkaloid Syntheses
temperature for 12 h. The mixture was then cooled to 0 °C, and a
3 M solution of aqueous NaOH (134 µL) and a 30% aqueous
solution of H2O2 (134 µL) were added. Stirring was continued for
1 h, whereupon EtOAc (3 mL) and saturated aqueous NaHCO3 (3
mL) were added. The layers were separated, and the aqueous phase
was extracted with EtOAc (3 × 4 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel, eluting with EtOAc, to give 21 mg (66%) of 21 as a
pale yellow solid: mp 175-177 °C (lit.19a mp 178-180 °C). The
1H and 13C NMR spectra were consistent with those reported in
the literature.8,19c-f
1715, 1453, 1211, 1026, 741, 500 cm-1; MS (CI) m/z 431.1832
[C23H31N2O2S2 (M + 1) requires m/z 431.1827].
3-Ethyl-2-(carboethoxymethyl)-1,2,3,4,6,7,12,12b-octahydro-
indolo[2,3-a]quinolizine (24). A slurry of Raney nickel in water
(840 mg) was added to a solution of 23 (80 mg, 0.18 mmol) in
EtOH (6 mL), and the reaction mixture was stirred at room
temperature for 28 h. EtOAc (6 mL) was added, and the mixture
was dried (MgSO4). The solids were removed by filtration through
a plug of Celite, and the filtrate was concentrated under reduced
pressure to give 58 mg (95%) of 24 as a pale green foam. The
analytical data (1H and 13C NMR spectra) were consistent with those
reported.30
Spirooxindoles 26 and Epi-26. A solution of t-BuOCl in CCl4
(0.5 M, 0.22 mL, 0.11 mmol) was added to a suspension of 24 (25
mg, 0.07 mmol) in CH2Cl2 (5 mL) at -20 °C. The reaction mixture
was stirred for 0.5 h. After evaporation of the volatiles under
reduced pressure, the remaining yellow oil was dissolved in MeOH
(3 mL), and NaOCH3 (80 mg) was added. The resultant solution
was stirred for 6 h, whereupon saturated aqueous NaHCO3 (2.5
mL) and brine (2.5 mL) were added. The aqueous phase was
extracted with Et2O (3 × 5 mL), and the combined organic layers
were dried (MgSO4). The volatiles were evaporated under reduced
pressure, and the residue was dissolved in CH2Cl2 (6 mL). Water
(1 mL) was added, the mixture was cooled to 0 °C, and CF3SO3H
(62 µL, 0.70 mmol) was injected. The mixture was stirred for 1 h
at 0 °C and for an additional 5 h at room temperature. Saturated
aqueous NaHCO3 was then added until the aqueous phase had a
pH of 8. H2O (1 mL) and CH2Cl2 (3 mL) were added, and the
layers were separated. The aqueous phase was extracted with
CH2Cl2 (2 × 5 mL), and the combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. From
trans-2-{5-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-2-oxopiperidin-4-
yl}[1,3]dithiolane-2-carboxylic Acid Ethyl Ester (22). A solution
of n-BuLi in hexanes (1.95 M, 1.43 mL, 2.80 mmol) was added to
a solution of i-Pr2NH (0.47 mL, 3.35 mmol) in THF (10 mL) at
-78 °C. The solution was warmed to 0 °C and then stirred for 30
min. The mixture was then cooled to -78 °C, and ethyl 1,3-
dithiolane-2-carboxylate (0.40 mL, 2.80 mmol) was added. The
solution was stirred for 1 h, and a solution of 4 (150 mg, 0.56
mmol) in THF (2 mL) was injected. The brown solution was
allowed to warm to room temperature over 3 h and was stirred for
an additional 17 h. EtOH (2 mL) was added, and stirring was
continued for 1 h. Aqueous HCl (0.5 M, 5 mL) was added, and the
layers were separated. The aqueous phase was extracted with EtOAc
(3 × 10 mL), and the combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel, eluting with
EtOAc/hexanes (1:1 f EtOAc), to give 177 mg (71%, dr > 95:5)
of 22 as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.39 (br s, 1
H), 7.63 (d, J ) 7.5 Hz, 1 H), 7.35 (d, J ) 7.5 Hz, 1 H), 7.20-
7.08 (m, 2 H), 7.04 (d, J ) 2.1 Hz, 1 H), 4.20 (q, J ) 8.5 Hz, 2
H), 3.85 (dt, J ) 7.1, 7.1 Hz, 1 H), 3.78 (dt, J ) 7.1, 7.1 Hz, 1 H),
3.39-3.18 (comp, 5 H), 3.05-2.99 (comp, 2 H), 2.93 (dd, J )
5.7, 13.2 Hz, 1 H), 2.77 (dd, J ) 6, 15.4 Hz, 1 H), 2.71-2.64 (m,
1 H), 2.51 (dd, J ) 8.7, 15.4 Hz, 1 H), 1.66-1.54 (m, 1 H), 1.49-
1.36 (m, 1 H), 1.28 (t, J ) 8.5 Hz, 3 H), 1.24-1.12 (m, 1 H), 0.76
(t, J ) 7.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 171.6, 170.0,
136.3, 127.4, 122.0, 121.9, 119.2, 118.6, 112.9, 111.2, 75.0, 62.4,
50.1, 48.1, 43.0, 40.1, 39.8, 39.3, 34.7, 25.7, 23.4, 13.9, 11.7; IR
(neat) 2935, 2786, 1722, 1577, 1469, 1276, 1177, 996, 912, 747
cm-1; MS (CI) m/z 447.1771 [C23H31N2O3S2 (M + 1) requires m/z
447.1776].
2-(3-Ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-
2-yl)[1,3]dithiolane-2-carboxylic Acid Ethyl Ester (23). Freshly
distilled POCl3 (56 µL, 0.60 mmol) was added to a solution of 22
(38 mg, 0.09 mmol) in toluene (2 mL), and the reaction mixture
was heated to 70 °C for 2 h. The volatiles were evaporated over
1.5 h, whereupon MeOH (2 mL) was added, and the solution was
cooled to 0 °C. NaBH4 (26 mg, 0.68 mmol) was added, and the
reaction mixture was stirred for 1.5 h at 0 °C and was then allowed
to warm to room temperature over 30 min. Saturated aqueous
NaHCO3 (5 mL) and EtOAc (5 mL) were added, and the layers
were separated. The aqueous phase was extracted with EtOAc (3
× 4 mL), and the combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel, eluting with
EtOAc, to furnish 34 mg (92%, dr > 95:5) of 23 as a pale yellow
oil: 1H NMR (300 MHz, C6D6) δ 7.60-7.57 (m, 1 H), 7.25-7.21
(comp, 2 H), 7.05 (br s, 1 H), 7.00-6.97 (m, 1 H), 4.14-4.00
(comp, 2 H), 3.15 (d, J ) 12.0 Hz, 1 H), 3.10-2.97 (comp, 3 H),
2.90-2.77 (comp, 3 H), 2.76-2.63 (comp, 2 H), 2.62-2.49 (comp,
2 H), 2.42 (dt, J ) 4.2, 11.0 Hz, 1 H), 2.04-1.95 (comp, 2 H,
C(20)H), 1.94-1.77 (comp, 2 H, C(14)Ha), 1.30-1.19 (m, 1 H),
1.02 (t, J ) 6.9 Hz, 3 H), 0.86 (t, J ) 7.2 Hz, 3 H); 13C NMR (125
MHz, C6D6) δ 172.5, 136.7, 135.2, 128.3, 121.5, 119.7, 118.5,
111.3, 108.8, 75.9, 62.1, 60.1, 60.0, 52.8, 46.2, 44.0, 39.5, 39.4,
33.1, 23.7, 22.4, 13.8, 11.6; IR (neat) 3380, 2958, 2924, 2802, 2746,
1
the H NMR of the crude product a dr ) 60:40 (26/epi-26) was
determined. The crude mixture was then separated by flash column
chromatography on silica gel, eluting with EtOAc/hexane (1:1 f
100% EtOAc), to furnish 8 mg (33%) of epi-26 (less polar) as a
yellow oil and 10 mg (42%) of 26 (more polar) as a colorless
solid: mp 172-174 °C (Et2O/pentane) (lit.27 mp 167-168 °C).
Data for epi-26: 1NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1 H),
7.21 (d, J ) 7.4 Hz, 1 H), 7.14 (td, J ) 7.6, 1.2 Hz, 1 H), 6.94 (td,
J ) 7.4, 0.8 Hz, 1 H), 6.80 (d, J ) 7.6, Hz, 1 H), 3.46 (s, 3 H),
3.24-3.17 (comp, 2 H), 2.45 (dd, J ) 15.5, 3.8 Hz, 1 H), 2.30
(app q, J ) 8.7 Hz, 1 H) 2.22 (dd, J ) 11.3, 2.3 Hz, 1 H), 2.16
(ddd, J ) 12.8, 9.5, 2.4 Hz, 1 H), 1.90-1.79 (comp, 2 H), 1.69
(app t, J ) 10.9 Hz, 1 H), 1.52-1.44 (m, 1 H), 1.42-1.34 (m, 1
H), 1.20-1.12 (m, 1 H), 1.08-0.98 (comp, 2 H), 0.82 (t, J ) 7.4
Hz, 3 H), 0.60 (app q, J ) 11.9, 1 H); 13C NMR (125 MHz, DMSO-
d6) δ 179.9, 172.6, 141.4, 133.5, 127.4, 124.3, 121.4, 109.1, 70.9,
56.9, 55.9, 53.2, 51.1, 40.5, 37.3, 36.6, 34.6, 31.5, 22.7, 10.7; IR
(neat) 3208, 2932, 2804, 1726, 1708, 1619, 1470, 1342, 1223, 1167,
754 cm-1; MS (CI) m/z 343.2032 [C20H26N2O3 (M + 1) requires
1
m/z 343.2022], 197, 311, 343 (base). Data for 26: NMR (500 MHz,
DMSO-d6) δ 10.15 (s, 1 H, NH), 7.23 (d, J ) 9.2 Hz, 1 H), 7.14
(t, J ) 7.3, Hz, 1 H), 6.95 (t, J ) 7.4, Hz, 1 H), 6.77 (d, J ) 7.6,
Hz, 1 H), 3.48 (s, 3 H), 3.16-3.12 (comp, 2 H), 2.51-2.47
(multiplicity obscured by DMSO peak, 1 H), 2.40-2.34 (m, 1 H)
2.18-2.10 (comp, 2 H), 2.00 (dd, J ) 15.5, 8.6 Hz, 1 H), 1.85
(dd, J ) 12.4, 7.4 Hz, 1 H), 1.64 (app t, J ) 10.7 Hz, 1 H), 1.54-
1.45 (m, 1 H), 1.36-1.08 (comp, 4 H), 1.04-0.96 (m, 1 H), 0.81
(t, J ) 7.4 Hz); 13C NMR (125 MHz, DMSO-d6) δ 179.6, 172.7,
141.8, 133.8, 127.7, 123.1, 121.6, 108.8, 73.8, 56.4, 55.1, 54.0,
51.1, 37.4, 36.9, 34.3, 30.8, 22.8, 10.7; IR (neat) 3233, 2935, 2779,
1727, 1619, 1476, 1333, 1219, 1178, 758 cm-1
; MS (CI) m/z
343.2018 [C20H26N2O3 (M + 1) requires m/z 343.2022], 343 (base),
371.
1-(1-Allyl-1,3,4,9-tetrahydro-â-carbolin-2-yl)propenone (33).
Acryloyl chloride (485 mg, 435 µL, 5.36 mmol) was added to a
mixture of 4,9-dihydro-3H-â-carboline (1.00 g, 5.88 mmol) and
allyltributyltin (1.62 g, 1.51 mL, 4.88 mmol) in CH2Cl2 (60 mL)
at 0 °C. The reaction mixture was stirred for 2 h at 0 °C and 12 h
J. Org. Chem, Vol. 71, No. 17, 2006 6557

Deiters et al.
at room temperature. The volatiles were evaporated under reduced
pressure, and the residue was purified by flash column chroma-
tography on silica gel, eluting with EtOAc/hexanes (1:2 f 2:3), to
give 980 mg (75%) of 33 as a colorless oil: 1H NMR (300 MHz,
CDCl3, rotamers) δ 8.86 (br s, 0.7 H), 8.72 (br s, 0.3 H), 7.52 (d,
J ) 5.7 Hz, 0.3 H), 7.48 (d, J ) 5.7 Hz, 0.7 H), 7.50-7.32 (m, 1
H), 7.21-7.10 (comp, 2 H), 6.74 (dd, J ) 7.8, 12.4 Hz, 0.7 H),
6.66 (dd, J ) 7.5, 12.4 Hz, 0.3 H), 6.39 (dd, J ) 1.2, 12.4 Hz, 0.7
H), 6.37 (d, J ) 12.4 Hz, 0.3 H), 5.99-5.88 (comp, 2 H), 5.81
(dd, J ) 1.2, 8.1 Hz, 0.7 H), 5.72 (d, J ) 7.8 Hz, 0.3 H), 5.25-
5.01 (comp, 2 H), 4.21 (d, J ) 10.2 Hz, 0.7 H), 3.60-3.51 (m, 0.7
H), 3.12 (dt, J ) 3.6, 9.2 Hz, 0.3 H), 2.93-2.62 (comp, 4.3 H);
13C NMR (75 MHz, CDCl3, rotamers) δ 135.9, 134.0, 133.5, 133.2,
128.0, 127.9, 127.8, 126.2, 121.8, 121.5, 119.3, 119.1, 118.2, 118.0,
117.7, 111.1, 111.0, 109.2, 107.3; IR (neat) 3268, 3060, 2916, 1640,
1602, 1446, 1221, 974, 910, 741 cm-1; MS (CI) m/z 267.1506
[C17H19N2O (M + 1) requires m/z 267.1497].
6,7,12,12b-Tetrahydro-1H-indolo[2,3-a]quinolizin-4-one (34).
[(C6H11)3P]2Cl2RuC2HPh (462 mg, 0.561 mmol, 4 mol %) was
added to a solution of 33 (3.73 g, 14.0 mmol) in CH2Cl2 (610 mL)
at room temperature. The reaction mixture was stirred for 15 h,
whereupon dimethyl sulfoxide (2.00 mL, 2.20 g, 28.1 mmol) was
added, and the reaction was stirred at room temperature overnight.
The solvent was removed under reduced pressure, EtOAc (10 mL)
was added, and the mixture was cooled to 4 °C overnight. The
crude solid was triturated with EtOAc and recrystallized from
CH2Cl2/CHCl3, and the mother liquors were purified by flash
column chromatography on silica gel, eluting with EtOAc, to afford
a total of 2.91 g (87%) of 34 as a pale gray solid: mp 228-229
°C (CH2Cl2) (lit.36 mp 229-231 °C). The 1H and 13C NMR spectra
are consistent with those previously reported for 34.36
Reaction of the Sodium Enolate of Dimethyl Malonate with
34. 2-(4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-
2-yl)malonic Acid Dimethyl Ester. Dimethyl malonate (0.29 mL,
2.51 mmol) was added to a suspension of NaH (60% suspension
in mineral oil, 30 mg, 1.25 mmol) in THF (15 mL) and the resulting
mixture stirred for 5 min. Solid 34 (60 mg, 0.25 mmol) was added,
and the solution was heated under reflux for 48 h. The reaction
mixture was cooled to room temperature, and a saturated aqueous
solution of NaHCO3 (0.3 mL) and EtOAc (10 mL) was added.
Stirring was continued for 15 min, the mixture was dried (MgSO4),
and the volatiles were removed under reduced pressure. The crude
product was purified by flash column chromatography on silica
gel, eluting with EtOAc, to give 68 mg (74%, dr ) 60:40) of the
title compound as a colorless oil: 1H NMR (300 MHz, CDCl3,
mixture of diastereomers) δ 8.72 (br s, 0.6 H), 8.64 (br s, 0.4 H),
7.48 (d, J ) 7.5 Hz, 0.6 H), 7.46 (d, J ) 7.5 Hz, 0.4 H), 7.36 (d,
J ) 7.5 Hz, 0.4 H), 7.29 (d, J ) 7.8 Hz, 0.6 H), 7.19-7.06 (comp,
2 H), 5.18-5.10 (m, 0.6 H), 5.04-4.99 (m, 0.4 H), 4.97-4.90 (m,
0.4 H), 4.81 (dd, J ) 3.3, 10.8 Hz, 0.6 H), 3.77 (s, 1.2 H), 3.74 (s,
1.8 H), 3.73 (s, 1.8 H), 3.70 (s, 1.2 H), 3.40 (d, J ) 8.7 Hz, 0.4 H),
3.32 (d, J ) 7.8 Hz, 0.6 H), 3.02-2.94 (m, 0.6 H), 2.92-2.60
(comp, 4.4 H), 2.58-2.10 (comp, 2.4 H), 1.56 (q, J ) 11.4 Hz,
0.6 H); 13C NMR (100 MHz, CDCl3, mixture of diastereomers) δ
168.3, 168.2, 168.1, 168.0, 167.6, 136.3, 136.2, 132.9, 132.6, 127.2,
126.5, 122.0, 119.7, 119.6, 118.3, 118.1, 111.2, 110.9, 110.3, 109.0,
60.4, 55.5, 54.3, 53.6, 52.9, 52.7, 52.6, 42.0, 39.9, 36.5, 36.1, 32.8,
31.2, 29.9, 29.8, 21.0, 20.9, 20.8, 14.1; IR (neat) 3256, 2954, 1731,
1621, 1435, 1305, 1234, 1157, 1020, 910, 735 cm-1; MS (CI) m/z
371.1600 [C20H23N2O5 (M + 1) requires m/z 371.1607].
resulting solution was stirred at -78 °C for 30 min. A solution of
34 (80 mg, 0.34 mmol) in degassed THF (16 mL) at -78 °C was
added via cannula. The dry ice/acetone bath was removed, and the
reaction was stirred for 2 h at room temperature, whereupon NH4Cl
(2.0 mL) was added, and 50% of the volatiles were removed under
reduced pressure. The mixture was poured into a separatory funnel
containing 0.5 M HCl (20 mL) and extracted with EtOAc (3 × 30
mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The crude mixtures of
diastereomers (dr ) 91:9) were separated by flash column chro-
matography, eluting with hexanes/EtOAc (1:3 f 100% EtOAc),
to afford 84 mg (60%) of the major diasteromer 36 as a pale yellow
1
solid: mp 200-201 °C (CHCl3); H NMR (400 MHz, CDCl3) δ
8.23 (br s, 1 H), 7.48 (d, J ) 7.6 Hz, 1 H), 7.39 (d, J ) 7.6 Hz, 1
H), 7.20 (t, J ) 7.6 Hz, 1 H), 7.13 (t, J ) 7.6 Hz, 1 H), 5.03-4.94
(comp, 2 H), 4.32-4.20 (comp, 2 H), 3.49-3.28 (comp, 4 H),
3.12-2.98 (comp, 2 H), 2.79-2.69 (comp, 2 H), 2.68-2.50 (comp,
3 H), 2.18-2.03 (m, 1 H), 1.29 (t, J ) 7.0 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 171.8, 169.3, 136.0, 133.0, 127.4, 122.1,
119.8, 118.1, 111.2, 110.9, 72.9, 62.7, 53.8, 42.6, 40.8, 40.2, 36.6,
35.9, 30.3, 20.9, 14.1; IR (CH2Cl2) 3265, 2928, 1714, 1621, 1469,
1445, 1303, 1266, 1212, 1022, 908, 732 cm-1; MS (CI) m/z
417.1304 [C21H25N2O3S2 (M + 1) requires m/z 417.1307].
2-Vinyl-2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-
4-one (38). Freshly prepared vinylmagnesium bromide (0.84 mmol)
in THF (0.84 mL) was added to a suspension of CuBr‚DMS (1.7
mg, 8 µmol) in THF (3 mL) at -78 °C. The reaction mixture was
warmed to 0 °C for 3 min and then recooled to -78 °C. Freshly
distilled TMSCl (21 µL, 0.17 mmol) and a solution of 34 (20 mg,
0.08 mmol) in THF (2 mL) were added. The suspension was
warmed to room temperature over 2 h, whereupon a mixture of
saturated aqueous NH4Cl/NH4OH (9:1, 2 mL) was added, and
stirring was continued for 30 min. A 1 M solution of TBAF in
THF (0.2 mL, 0.20 mmol) was added, and the mixture was stirred
for 15 min, the layers were separated, and the aqueous phase was
extracted with EtOAc (2 × 3 mL). The combined organic phases
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel,
eluting with EtOAc, to give 18 mg (80%, dr ) 60:40) of 38 as a
mixture of nonseparable diastereomers: yellow solid; mp 258-
262 °C (CHCl3); 1H NMR (400 MHz, CDCl3, mixture of dia-
stereomers) δ 8.00 (br s, 1 H), 7.51-7.48 (m, 1 H), 7.33 (d, J )
8.0 Hz, 1 H), 7.19 (t, J ) 7.2 Hz, 1 H), 7.12 (t, J ) 8.0 Hz, 1 H),
5.92 (ddd, J ) 6.0, 10.4, 17.2 Hz, 0.4 H), 5.79 (ddd, J ) 6.4, 10.4,
16.8 Hz, 0.6 H), 5.22-5.05 (comp, 3 H), 4.88-4.80 (m, 1 H),
2.99-2.62 (comp, 3 H), 2.57-2.48 (comp, 2 H), 2.32-2.10 (comp,
2 H), 1.68-1.59 (m, 1 H); 13C NMR (100 MHz, CDCl3, mixture
of diastereomers) δ 168.4, 168.1, 139.8, 138.7, 136.1, 133.0, 132.8,
128.5, 126.6, 122.1, 119.8, 118.3, 118.2, 115.6, 114.6, 110.8, 110.2,
109.7, 109.5, 53.8, 56.7, 40.9, 39.9, 38.0, 36.7, 35.2, 35.1, 33.1,
21.1; IR (CH2Cl2) 3249, 2919, 2848, 1614, 1445, 1303, 1233, 911,
736 cm-1; MS (CI) m/z 267.1506 [C17H19N2O (M + 1) requires
m/z 267.1497].
2-Ethyl-2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-
4-one (39). EtMgCl (0.84 mmol) in THF (0.42 mL) was added to
a suspension of CuBr‚DMS (1.7 mg, 8 µmol) in THF (3 mL) at
-78 °C. The reaction mixture was warmed to 0 °C for 3 min and
then recooled to -78 °C. Freshly distilled TMSCl (21 µL, 0.17
mmol) and a solution of 34 (20 mg, 0.08 mmol) in THF (2 mL)
were added. The suspension was warmed to room temperature over
2 h. A mixture of saturated aqueous NH4Cl/NH4OH (9:1, 2 mL)
was added, and stirring was continued for 30 min. A 1 M solution
of TBAF in THF (0.2 mL, 0.20 mmol) was added, and the mixture
was stirred for 15 min, the layers were separated, and the aqueous
phase was extracted with EtOAc (2 × 3 mL). The combined organic
phases were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel, eluting with EtOAc, to give 22 mg (98%, dr > 95:5)
of 39 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.34 (br s,
2-(4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-
2-yl)[1,3]dithiolane-2-carboxylic Acid Ethyl Ester (36). A solu-
tion of n-BuLi (0.28 mL, 0.67 mmol) in hexanes (2.44 M) was
added to a solution of i-Pr2NH (81 mg, 112 µL, 0.80 mmol) in
degassed THF (16 mL) at -78 °C. After the resulting mixture was
stirred at -78 °C for 15 min, the flask was transferred to an ice/
water bath, and stirring was continued for 15 min. The mixture
was then recooled to -78 °C. Neat ethyl 1,3-dithiolane-2-
carboxylate (120 mg, 96 µL, 0.67 mmol) was added, and the
6558 J. Org. Chem., Vol. 71, No. 17, 2006

Corynanthe, Tacaman, and Oxindole Alkaloid Syntheses
1 H), 7.49 (d, J ) 7.2 Hz, 1 H), 7.34 (d, J ) 7.5 Hz, 1 H), 7.12 (t,
J ) 7.5 Hz, 1 H), 5.13-5.08 (m, 1 H), 4.91 (t, J ) 6.4 Hz, 1 H),
3.00-2.86 (comp, 2 H), 2.73 (d, J ) 11.6 Hz, 1 H), 2.55 (dd, J )
5.2, 17.2 Hz, 1 H), 2.26 (dd, J ) 7.2, 17.2 Hz, 1 H), 2.19-2.10
(comp, 2 H), 1.84-1.76 (m, 1 H), 1.52-1.40 (comp, 2 H), 0.98 (t,
J ) 7.5 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 169.2, 135.9,
133.3, 126.9, 121.9, 119.6, 118.1, 110.9, 109.9, 52.2, 41.4, 38.2,
32.4, 31.4, 26.9, 21.1, 11.6; IR (neat) 3256, 2959, 2922, 1614, 1449,
1302, 1266, 908, 734 cm-1; MS (CI) m/z 269.1657 [C17H21N2O
(M + 1) requires m/z 269.1654].
1-Allyl-2,3,4,9-tetrahydro-1H-â-carboline. BF3‚OEt2 (1.08 mL,
8.56 mmol) was added to a solution of 4,9-dihydro-3H-â-carboline
32 in THF (44 mL) cooled to -30 °C. The solution was stirred for
10 min, whereupon a 1.0 M solution of allylmagnesium bromide
in ether (1.0 M, 25.6 mL, 25.6 mmol) was added via addition funnel
over 45 min. After the addition was complete, the stirring was
continued at -30 °C for 2 h, whereupon saturated aqueous NaHCO3
(10 mL) was added. The resulting slurry was poured into a
separatory funnel containing saturated aqueaous NaHCO3 (50 mL)
and water (50 mL), and the mixture was extracted with EtOAc (3
× 50 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with Et3N/MeOH/CH2Cl2 (1:
3:97), to give 1.52 g (81%) of the title compound as a yellow solid.
The 1H NMR spectrum was identical to that previously reported in
the literature.43
1-(1-Allyl-1,3,4,9-tetrahydro-â-carbolin-2-yl)-2-ethylpro-
penone. A solution of 1-allyl-2,3,4,9-tetrahydro-1H-â-carboline
(100 mg, 0.42 mmol), 2-ethylacrylic acid (57 mg, 0.57 mmol), Et3N
(0.12 mL, 0.83 mmol), HOBT (113 mg, 0.83 mmol), and EDCI‚
HCl (88 mg, 0.46 mmol) in CH2Cl2 (4.2 mL) was stirred for 16 h
at room temperature. The reaction was poured into EtOAc (20 mL),
and the organic mixture was washed with 0.5 M aqueous HCl (2
× 10 mL), saturated aqueous NaHCO3 (2 × 10 mL), and brine (10
mL). The organic layer was dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by flash column
chromatography, eluting with hexanes/EtOAc (1:3), to afford 105
mg (85%) of the title compound as a white solid: mp 113-115
°C; 1H NMR (500 MHz) δ 8.33 (s, 1H), 7.45 (d, J ) 7.8 Hz, 1 H),
7.31 (d, J ) 8.0 Hz, 1 H), 7.18-7.12 (m, 1 H), 7.11-7.08 (m, 1
H), 6.01-5.91 (m, 1 H), 5.79 (t, J ) 6.6 Hz, 1 H), 5.19 (s, 1 H),
5.14-5.10 (comp, 2 H), 5.07 (s, 1 H), 4.25-4.18 (m, 1 H), 3.51-
3.41 (m, 1 H), 2.81-2.74 (comp, 2 H), 2.39 (q, J ) 7.3 Hz, 2 H),
1.11 (t, J ) 7.3 Hz, 3 H); 13C NMR (125 MHz) δ 171.8, 146.8,
136.1, 134.4, 133.6, 126.5, 121.9, 119.5, 118.4, 118.0, 112.6, 111.1,
107.7, 48.35, 41.86, 39.1, 27.3, 22.3, 11.7; IR (neat) 3258, 2962,
2906, 1601, 1470, 1442, 1300, 1180, 913, 741 cm-1; MS (CI) m/z
295.1807 [C19H22N2O (M + 1) requires m/z 295.1810], 253, 295
(base), 323, 335, 377.
2-[1-(Trimethylsilyl)vinyl]-2,3,6,7,12,12b-hexahydro-1H-indolo-
[2,3-a]quinolizin-4-one (40). Freshly prepared [1-(trimethylsilyl)-
vinyl]magnesium bromide (0.84 mmol) in THF (0.84 mL) was
added to a suspension of CuBr‚DMS (1.7 mg, 8 µmol) in THF (3
mL) at -78 °C. The reaction mixture was warmed to 0 °C for 3
min and then recooled to -78 °C. Freshly distilled TMSCl (21
µL, 0.17 mmol) and a solution of 34 (20 mg, 0.08 mmol) in THF
(2 mL) were added. The suspension was warmed to room
temperature over 2 h. A mixture of saturated aqueous NH4Cl/
NH4OH (9:1, 2 mL) was added, and stirring was continued for 30
min. A 1 M solution of TBAF in THF (0.2 mL, 0.20 mmol) was
added, and the mixture was stirred for 15 min, the layers were
separated, and the aqueous phase was extracted with EtOAc (2 ×
3 mL). The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel, eluting with EtOAc,
to give 24 mg (84%, dr > 95:5) of 40 as a white solid: mp 213-
1
215 °C (CHCl3); H NMR (400 MHz, CDCl3) δ 8.38 (br s, 1 H),
7.51 (d, J ) 7.6 Hz, 1 H), 7.34 (d, J ) 7.6 Hz, 1 H), 7.19 (t, J )
7.2 Hz, 1 H), 7.13 (t, J ) 7.2 Hz, 1 H), 5.66 (s, 1 H), 5.48 (d, J )
1.6 Hz), 5.26-5.14 (m, 1 H), 4.83 (dd, J ) 4.4, 11.6 Hz, 1 H),
2.94-2.73 (comp, 4 H), 2.72-2.65 (m, 1 H), 2.53-2.43 (m, 1 H),
2.88 (dd, J ) 12.4, 17.2 Hz, 1 H), 1.77 (q, J ) 12.4 Hz, 1 H), 0.17
(s, 9 H); 13C NMR (100 MHz, CDCl3) δ 168.7, 153.7, 136.1, 132.9,
126.6, 124.0, 122.0, 119.6, 118.3, 110.9, 109.2, 68.6, 54.3, 40.0,
39.7, 35.9, 35.4, 21.2; IR (CH2Cl2) 3259, 2954, 1614, 1445, 1305,
1249, 837, 737 cm-1; MS (CI) m/z 339.1893 [C20H27N2OSi (M +
1) requires m/z 339.1893].
2-[2-(Trimethylsilyl)vinyl]-2,3,6,7,12,12b-hexahydro-1H-indolo-
[2,3-a]quinolizin-4-one (41). A solution of t-BuLi (0.80 mmol) in
hexanes (0.5 mL) was added to a solution of (E)-2-(trimethylsilyl)-
vinyl bromide (62 µL, 0.40 mmol) in Et2O (0.8 mL) at -78 °C.
The reaction mixture was warmed to -20 °C for 0.5 h, recooled to
-78 °C, and then added to a suspension of CuI (38 mg, 0.20 mmol)
in Et2O (0.8 mL) at -78 °C. The reaction mixture was warmed to
-20 °C for 0.5 h and recooled to -78 °C, and TMSCl (22 µL,
0.20 mmol) was added. The mixture was stirred for 1 h and then
added to a solution of 34 (10 mg, 0.04 mmol) in Et2O (3 mL).
Then the mixture was allowed to warm to room temperature over
3 h, and stirring was continued for an additional 17 h. A mixture
of saturated aqueous NH4Cl/NH4OH (9:1, 0.5 mL) and a 1 M
solution of TBAF in THF (0.4 mL, 0.4 mmol) were added, and the
mixture was stirred for 15 min. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 1 mL). The
combined organic phases were dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel, eluting with EtOAc/hexanes
(1:1), to give 12 mg (84%, dr > 95:5) of 41 as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.85 (br s, 1 H), 7.49 (d, J ) 8.0 Hz,
1 H), 7.33 (d, J ) 8.0 Hz, 1 H), 7.18 (t, J ) 8.0 Hz, 1 H), 7.12 (t,
J ) 8.0 Hz, 1 H), 6.08 (dd, J ) 5.0, 18.5 Hz, 1 H), 5.78 (dd, J )
1.5, 18.5 Hz, 1 H), 5.14-5.10 (m, 1 H), 4.82-4.78 (m, 1 H), 2.96-
2.81 (comp, 2 H), 2.76-2.67 (comp, 2 H), 2.60-2.50 (comp, 2
H), 2.31-2.25 (m, 1 H), 2.11 (ddd, J ) 3.5, 8.5, 12.5 Hz, 1 H)
0.07 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ 168.8, 146.2, 136.1,
133.1, 131.3, 127.1, 122.2, 119.9, 118.4, 110.9, 110.4, 51.6, 40.8,
36.5, 34.9, 32.9, 21.0, 1.9; IR (CH2Cl2) 3260, 2950, 1620, 1451,
1304, 1247, 878, 838, 739 cm-1; MS (CI) m/z 339.1888
[C20H27N2OSi (M + 1) requires m/z 339.1892].
3-Ethyl-6,7,12,12b-tetrahydro-1H-indolo[2,3-a]quinolizin-4-
one (42). A solution of 1-(1-allyl-1,3,4,9-tetrahydro-â-carbolin-2-
yl)-2-ethylpropenone (21 mg, 0.07 mmol) and Grubbs’ second-
generation catalyst (9.1 mg, 0.01 mmol) in degassed CH2Cl2 (3.55
mL) was stirred at 45 °C under argon for 16 h. The mixture was
cooled to room temperature, DMSO (40 µL, 0.564 mmol) was
added, and the mixture was stirred for 16 h. The reaction was
concentrated under reduced pressure, and the residue was purified
by flash column chromatography, eluting with MeOH/CH2Cl2 (0.5:
99.5), to give 16 mg (87%) of 42 as a clear colorless glass. The 1H
NMR spectrum was identical to that previously reported in the
literature.39
4-Oxo-1,6,7,12b-tetrahydro-4H-indolo[2,3-a]quinolizine-12-
carboxylic Acid tert-Butyl Ester (35). A solution of 34 (1.10 g,
4.62 mmol), Boc2O (4.97 g, 23.1 mmol), and (dimethylamino)-
pyridine (DMAP) (113 mg, 0.92 mmol) in THF (100 mL) was
stirred at room temperature for 4 h, whereupon the reaction was
concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with hexanes/EtOAc (1:1
f 1:2) to give 1.54 g (99%) of 35 as a white solid: mp 181-183
°C; 1NMR (500 MHz) δ 8.06 (d, J ) 8.2 Hz, 1 H), 7.47-7.45 (m,
1 H), 7.32-7.28 (m, 1 H), 7.27-7.24 (m, 1 H), 6.67 (ddd, J )
9.6, 6.5, 2.1 Hz, 1 H), 6.07 (dd, J ) 9.6, 2.9 Hz, 1 H) 5.26-5.21
(m, 1 H), 5.00 (ddd, J ) 12.7, 4.6, 1.6 Hz, 1 H), 3.01 (ddd, J )
17.1, 6.5, 3.6 Hz, 1 H), 2.87-2.79 (comp, 3 H), 2.15 (dddd, J )
17.1, 13.1, 2.9, 2.1, Hz, 1 H), 1.67 (s, 9 H); 13C NMR (125 MHz)
δ 164.8, 150.0, 139.1, 136.6, 134.1, 128.5, 125.4, 124.7, 123.1,
(43) Nakamura, M.; Hirai, A,; Nakamura, E. J. Am. Chem. Soc. 1996,
118, 8489.
J. Org. Chem, Vol. 71, No. 17, 2006 6559

Deiters et al.
118.4, 118.0, 115.8, 84.5, 53.3, 37.6, 31.6, 28.2, 21.5; IR (CDCl3)
2982, 2919, 1727, 1659, 1607, 1423, 1366, 1308, 1146, 1052, 817,
718 cm-1; MS (CI) m/z 339.1721 [C20H23N2O3 (M + 1) requires
m/z 339.1709], 283, 311, 339 (base), 367, 422.
1413, 1311, 1214, 1141, 754 cm-1; MS (CI) m/z 517.1830
[C26H32N2O5S2 (M + 1) requires m/z 517.1831], 417, 461, 517
(base).
(3R*,15R*,24S*)-2-[2-(Ethoxycarbonyl)[1,3]dithiolan-2-yl)-3-
ethyl-4-oxo-1,3,4,6,7,12b-hexahydro-2H-indolo[2,3-a]quinolizine-
12-carboxylic Acid tert-Butyl Ester (44). A solution of sodium
hexamethyldisilazide in THF (0.39 mL, 2.0 M, 0.774 mmol) was
added dropwise over 12 min to a solution of 43 (200 mg, 0.387
mmol) in degassed THF (2.5 mL) at -78 °C. The mixture was
stirred at -78 °C for 1 h, whereupon it was cooled -100 °C. 1,3-
Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) (74 mg, 70
µL, 0.58 mmol) was added followed by ethyl triflate (276 mg, 0.20
mL, 1.55 mmol). The mixture was stirred at -100 °C for 2.5 h,
whereupon benzylamine (249 mg, 0.25 mL, 2.32 mmol) and ethanol
(0.2 mL) were added. The flask was transferred to a -78 °C bath,
and stirring was continued for 45 min. A saturated aqueous solution
of NH4Cl (2 mL) was added, and the cold bath was removed. After
the reaction was allowed to warm to room temperature, the mixture
was poured into a separatory funnel containing 0.5 M HCl (10 mL)
and EtOAc (10 mL). The layers were separated, and the aqueous
layer was extracted with EtOAc (2 × 10 mL). The combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with pentane/acetone (2:1) to give 39 mg (20%) of recovered
43 and 142 mg (67%, dr > 95:5) of 44 as a colorless foam that
could be recrystallized from CH2Cl2/heptane: mp 151-153 °C;
1NMR (500 MHz) δ 7.91-7.87 (m, 1 H), 7.43-7.40 (m, 1 H),
7.27-7.20 (comp, 2 H), 5.41-5.35 (m, 1 H), 5.18-5.12 (m, 1H),
4.32 (q, J ) 7.2 Hz, 2 H), 3.50-3.44 (comp, 2 H), 3.34-3.25
(comp, 3 H), 2.86-2.65 (comp, 6 H), 1.97-1.88 (m, 1 H), 1.76
(ddd, J ) 14.3, 11.8, 4.8 Hz, 1 H), 1.67 (s, 9 H), 1.60-1.50 (m,
1H), 1.34 (t, J ) 7.2 Hz, 3 H), 1.00 (t, J ) 7.4 Hz, 3 H); 13C NMR
(125 MHz) δ 172.7, 171.3, 150.3, 136.5, 135.9, 128.9, 124.4, 122.9,
118.5, 118.3, 115.5, 84.2, 74.1, 62.2, 53.0, 44.6, 41.7, 39.5, 39.2,
38.7, 28.5, 28.2, 27.2, 22.0, 13.9, 12.1; IR (neat) 2975, 2923, 1723,
1635, 1453, 1417, 1370, 1303, 1219, 1136, 1022, 731 cm-1; MS
(CI) m/z 545.2143 [C28H37N2O5S2 (M + 1) requires m/z 545.2144],
233, 339, 445, 545 (base).
(3R*,15S*,22S*)-2-[(Ethoxycarbonyl)methyl]-3-ethyl-4-oxo-
1,3,4,6,7,12b-hexahydro-2H-indolo[2,3-a]quinolizine-12-carbox-
ylic Acid tert-Butyl Ester (45). A slurry of Raney nickel in water
(2.9 g) was added to a solution of 44 (312 mg, 0.57 mmol) in EtOH
(20 mL), and the reaction was stirred at room temperature for 4 h.
EtOAc (20 mL) was added, and the mixture was dried (Na2SO4)
and filtered through Celite. The solids were washed with EtOAc
(20 mL), and the filtrate was concentrated under reduced pressure.
Purification of the residue by flash column chromatography, eluting
with hexane/EtOAc (1:1), gave 242 mg (93%) of 45 as a clear
colorless oil: 1NMR (125 MHz) δ 7.94-7.90 (m, 1 H), 7.44-
7.39 (m, 1 H), 7.30-7.20 (comp, 2 H), 5.21-5.18 (m, 1 H), 5.06-
5.03 (m, 1 H), 4.15 (q, J ) 7.0 Hz, 2 H), 2.83-2.76 (m, 1 H),
2.72-2.67 (comp, 2 H), 2.61 (dd, J ) 15.9, 7.4 Hz, 1 H), 2.52
(dd, J ) 15.9, 7.4 Hz, 1 H), 2.48-2.37 (comp, 3 H), 2.21-2.15
(m, 1 H), 1.87-1.79 (m, 1 H), 1.75-1.64 (comp, 10 H), 1.56-
1.52 (m, 1 H), 1.27 (t, J ) 7.0 Hz, 3 H), 0.98 (t, J ) 7.4 Hz, 3 H);
13C NMR (500 MHz) δ 172.2, 172.0, 150.3, 136.5, 135.7, 128.8,
124.4, 122.9, 118.4, 118.3, 115.5, 84.3, 60.5, 51.8, 47.6, 39.2, 38,1,
30.5, 29.7, 28.2, 25.5, 21.7, 14.2, 12.1; IR (neat) 2970, 2927, 1728,
1656, 1640, 1455, 1414, 1368, 1311, 1249, 1219, 1158, 1136, 1116,
745 cm-1; MS (CI) m/z 455.2559 [C26H35N2O5 (M + 1) requires
m/z 455.2546], 355, 399, 455 (base).
4-Oxo-1,6,7,12b-tetrahydro-4H-indolo[2,3-a]quinolizine-12-
carboxylic Acid tert-Butyl Ester (35). To a degassed solution of
[(C6H11)3P]2Cl2C2HPh (18 mg, 0.02 mmol, 4 mol %) in CH2Cl2
(25 mL) was added a solution of 35 (149 mg, 0.56 mmol) in
degassed CH2Cl2 (7 mL) via cannula. The reaction mixture was
stirred at room temperature for 24 h, whereupon Boc2O (603 mg,
2.80 mmol) and DMAP (14 mg, 0.11 mmol) were added. The
reaction mixture was stirred for 1.5 h, whereupon ethanol (0.2 mL)
and activated carbon (180 mg) were added. After being stirred for
20 h, the reaction was filtered through a plug of Celite, and the
filtrate was concentrated under reduced pressure. The residue was
purified by flash column chromatography, eluting with hexanes/
EtOAc (1:1 f 1:2) to give 175 mg (93%) of 35 as a white solid.
1
The H NMR spectrum was identical to that previously reported
(vide supra).
(3R*,15R*)-2-(4-Oxo-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-
a]quinolizin-2-yl)[1,3]dithiolane-2-carboxylic Acid Ethyl Ester
(37). A solution of n-BuLi (0.28 mL, 0.67 mmol) in hexanes (2.40
M) was added to a solution of i-Pr2NH (75 mg, 98 µL, 0.74 mmol)
in THF (16 mL) at -78 °C. After the resulting mixture was stirred
at -78 °C for 15 min, the flask was transferred to an ice/water
bath, and stirring was continued for 15 min. The mixture was then
recooled to -78 °C. Neat ethyl 1,3-dithiolane-2-carboxylate (180
mg, 0.14 mL, 1.01 mmol) was added, and the resulting solution
was stirred at -78 °C for 30 min. A solution of 35 (114 mg, 0.34
mmol) in THF (16 mL) at -78 °C was added via a cannula. The
dry ice/acetone bath was removed, and the reaction was stirred for
3 h at room temperature, whereupon NH4Cl (1.0 mL) was added,
and 50% of the volatiles were removed under reduced pressure.
The mixture was poured into a separatory funnel containing 0.5 M
HCl (30 mL) and extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with hexanes/EtOAc (1:2 f 1:3), to give 123 mg (71%, dr
> 95:5) of 37 as a white solid: mp 150-151 °C; 1NMR (500 MHz,
CDCl3) δ 8.01 (d, J ) 8.2 Hz, 1 H), 7.42-7.40 (m, 1 H), 7.30-
7.27 (m, 1 H), 7.24-7.21 (m, 1 H), 5.16-5.08 (comp, 2 H), 4.23
(app dq, J ) 7.2, 1.1 Hz, 2 H), 3.38-3.31 (comp, 2 H), 3.30-3.23
(comp, 2 H), 2.97 (tdd, J ) 11.9, 5.51, 2.6 Hz, 1 H), 2.87-2.81
(comp, 3 H), 2.81-2.65 (comp, 2 H), 2.50 (dd, J ) 17.5, 11.6 Hz,
1 H), 1.68 (s, 9 H), 1.44-1.37 (m, 1 H), 1.31 (t, J ) 7.2 Hz, 3 H);
13C NMR (125 MHz) δ 171.2, 168.7, 150.2, 136.8, 134.7, 128.6,
124.7, 123.0, 118.6, 118.3, 115.5, 84.5, 74.2, 62.5, 54.4, 40.2, 40.0,
39.0, 38.3, 35.8, 33.7, 28.1, 21.6, 13.9; IR (neat) 2974, 2923, 1727,
1640, 1457, 1431, 1411, 1365, 1314, 1222, 1141, 1023, 906, 728
cm-1; MS (CI) m/z 516.1747 [C26H32N2O5 S2 (M+) requires m/z
516.1753], 237, 289, 339, 362, 391, 517 (base).
(3R*,15S*)-2-[2-(Ethoxycarbonyl)[1,3]dithiolan-2-yl]-4-oxo-
1,3,4,6,7,12b-hexahydro-2H-indolo[2,3-a]quinolizine-12-carbox-
ylic Acid tert-Butyl Ester (43). A solution of 36 (550 mg, 1.32
mmol), Boc2O (1.14 g, 5.28 mmol), and DMAP (16 mg, 0.13 mmol)
in CH2Cl2 (40 mL) was stirred at room temperature for 4 h. The
reaction mixture was concentrated under reduced pressure, and the
residue was purified by flash column chromatography, eluting with
hexanes/EtOAc (1:2), to give 43 (578 mg, 85%) as a white solid:
1
mp 115-118 °C; NMR (500 MHz) δ 7.99 (d, J ) 8.1 Hz, 1 H),
7.42 (d, J ) 8.1 Hz, 1 H), 7.28 (m, 1 H), 7.23 (m, 1 H), 5.30-5.26
(m, 1 H), 4.96-4.94 (m, 1H) 4.23-4.10 (m, 1 H), 3.41-3.25
(comp, 4 H), 2.88 (app td, J ) 11.8, 3.6 Hz, 1 H), 2.84-2.79 (m,
1 H), 2.79-2.73 (m, 1 H), 2.71-2.65 (comp, 2 H), 2.42 (dd, J )
14.7, 11.6 Hz, 1 H), 2.99 (ddd, J ) 14.1, 8.8, 6.0 Hz, 1 H), 2.21-
2.15 (m, 1 H), 1.66 (s, 9 H), 1.17 (t, J ) 7.0 Hz, 3 H); 13C NMR
(125 MHz) δ 171.2, 171.1, 150.1, 136.7, 134.9, 128.7, 124.6, 123.0,
118.9, 118.3, 115.4, 84.4, 74.6, 62.5, 53.5, 40.5, 40.2, 39.9, 37.1,
35.8, 33.3, 28.2, 21.3, 13.9; IR (neat) 2980, 2924, 1723, 1649, 1453,
(3R*,15S*,20R*)-3-Ethyl-4-oxo-1,2,3,4,6,7,12b-octahydro-
indolo[2,3-a]quinolizin-2-yl]acetic Acid Methyl Ester (46). A
solution of 4.4 M NaOMe (1.20 mL, 5.28 mmol), which was freshly
prepared by the addition of sodium (404 mg, 17.6 mmol) to
degassed methanol (4 mL), was added to a solution of 45 (240
mg, 0.53 mmol) in degassed THF (5 mL) at 0 °C. The ice bath
was removed, and the reaction was stirred at room temperature for
1 h, whereupon the reaction was cooled to 0 °C, and a saturated
6560 J. Org. Chem., Vol. 71, No. 17, 2006

Corynanthe, Tacaman, and Oxindole Alkaloid Syntheses
aqueous solution of NH4Cl (3 mL) and water (15 mL) were added.
The mixture was poured into a separatory funnel containing EtOAc
(20 mL), and the layers were separated. The aqueous layer was
extracted with EtOAc (2 × 15 mL), and the combined organic
extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was recrystallized from CH2Cl2/ether, and
the mother liquor was purified by flash chromatography, eluting
with hexane/EtOAc (1:1), to afford a total of 155 mg (86%) of 46
as a white solid: mp 186-189 °C dec; 1NMR (500 MHz, CDCl3)
δ 7.92 (br s, 1H), 7.48 (d, J ) 7.6 Hz, 1 H), 7.33 (d, J ) 8.0 Hz,
1 H), 7.19-7.15 (m, 1 H), 7.12-7.09 (m, 1 H), 5.14-5.08 (m, 1
H), 4.83 (dd, J ) 9.4, 5.2 Hz, 1 H), 3.72 (s, 3 H), 2.89-2.81 (comp,
2 H), 2.77-2.70 (m, 1 H), 2.55-2.38 (comp, 3 H), 2.25-2.19
(comp, 2 H), 2.17-2.11 (m, 1 H), 1.82-1.74 (m, 1 H), 1.64-1.55
(m, 1 H), 0.92 (t, J ) 7.4 Hz, 3 H); 13C NMR (125 MHz) δ 172.5,
171.0, 136.2, 133.1, 127.0, 122.2, 119.9, 118.3, 111.0, 110.0, 51.8,
50.7, 48.2, 40.7, 37.3, 29.4, 28.6, 24.9, 21.1, 11.8; IR (neat) 3255,
2962, 2930, 1733, 1612, 1466, 1434, 1351, 1304, 1262, 1236, 1199,
1168, 739 cm-1; 340.1777 [C20H24N2O3 S2 (M+) requires m/z
340.1787], 241, 273, 305, 341 (base), 369.
(3R*,15S*,20S*)-3-Ethyl-1,2,3,4,6,7,12b-octahydroindolo[2,3-
a]quinolizin-2-yl]acetic Acid Methyl Ester (47). A slurry of 46
(72 mg, 0.21 mmol), trimethyloxonium tetrafluoroborate (83 mg,
0.56 mmol), and 2,6-di-tert-butylpyridine (118 mg, 0.14 mL, 0.619
mmol) in CH2Cl2 (7 mL) was stirred at room temperature for 21 h,
during which time a homogeneous yellow solution was produced.
The reaction mixture was cooled to 0 °C, and anhydrous MeOH
(2.5 mL) was added. After 15 min, NaBH4 (83 mg, 2.18 mmol)
was added, and the reaction mixture was stirred for an additional
20 min. Saturated NaHCO3 (5 mL) and CH2Cl2 (10 mL) were added
and the layers separated. The aqueous layer was extracted with
CH2Cl2 (2 × 8 mL). The combined organic fractions were dried
(Na2SO4), and the volatiles were removed under reduced pressure.
The residue was purified by flash chromatography, eluting with
2.5-10% MeOH in CH2Cl2, to afford 56 mg (81%) of 47 as a
foam: 1NMR (500 MHz, CDCl3) δ 8.00 (br s, 1H), 7.50 (d, J )
7.4 Hz, 1 H), 7.40-7.38 (m, 1 H), 7.18 (app td, J ) 7.4, 1.2 Hz,
1 H), 7.12 (app td, J ) 7.4, 1.2 Hz, 1 H), 4.13 (br s, 1 H), 3.75 (s,
3 H), 3.23 (dd, J ) 11.9, 5.2 Hz, 1 H), 3.10 (dd, J ) 11.9, 4.4 Hz,
1 H), 3.08-2.99 (m, 1 H), 2.76 (dd, J ) 11.4, 3.4 Hz, 1 H), 2.69-
2.64 (m, 1 H), 2.63 (dd, J ) 16.3, 4.4 Hz, 1 H), 2.56 (dd, J )
11.4, 8.0 Hz, 1 H), 2.31-2.24 (comp, 2 H), 1.82-1.74 (comp, 2
H), 1.58-1.49 (m, 1 H), 1.46-1.38 (m, 1 H), 1.27-1.19 (m, 1 H),
0.87 (t, J ) 7.4 Hz, 3 H); 13C NMR (125 MHz) δ 173.7, 136.0,
133.2, 127.6, 121.4, 119.4, 118.0, 111.1, 107.8, 54.3, 51.9, 51.6,
51.4, 41.2, 36.9, 32,8, 32.2, 24.1, 18.5, 11.5; IR (neat) 3397, 3245,
2941, 1731, 1452, 1168, 1004, 732 cm-1; MS (CI) m/z 327.2076
[C20H27N2O2 (M + 1) requires m/z 327.2073], 325, 327 (base), 326,
341.42
Acknowledgment. We thank the National Institutes of
Health, The Robert A. Welch Foundation, Merck Research
Laboratories, and Pfizer, Inc. for their generous support of this
research. A.D. gratefully acknowledges a Feodor-Lynen post-
doctoral fellowship from the Alexander von Humboldt Founda-
tion. M.P. gratefully acknowledges a graduate fellowship from
the Bristol-Myers Squibb Co. We also thank Dr. Vince Lynch
for X-ray crystallographic analyses.
Supporting Information Available: 1H NMR spectra for all
new compounds and crystallographic data for compounds 26, 35,
and 44. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061032T
J. Org. Chem, Vol. 71, No. 17, 2006 6561