Synthesis of the pentacyclic skeleton of the aspidosperma alkaloids using rhodium carbenoids as reactive intermediates

Article abstract of DOI:10.1021/jo971424n

A series of diazo amido keto esters prepared from N-alkenyl-substituted 3-carbalkoxy-2-piperidone derivatives was treated with rhodium(II) acetate. Attack of the amido carbonyl oxygen at the resultant rhodium carbenoid center produced a transient push-pull carbonyl ylide dipole which underwent an intramolecular dipolar cycloaddition reaction. A related annulation sequence was used to prepare the pentacyclic skeleton of the aspidosperma family of alkaloids. Synthesis of the required diazo imide was carried out from 3- carboxy-3-ethyl-2-piperidone and N-methyl-3-indoleacetic acid. Treatment of the diazo imide with rhodium(II) acetate afforded a transient 1,3-dipole which subsequently underwent cycloaddition across the indole π-bond. The resulting clycloadduct is the consequence of endo cycloaddition with respect to the dipole which is fully in accord with the lowest energy transition state. The clycloadduct was converted in three steps into desacetoxy-4-oxo- 6,7-dihydrovindorosine. The stereochemistry of the final product was established by a X-ray crystallographic study.

Full text of DOI:10.1021/jo971424n

556
J . Org. Chem. 1998, 63, 556-565
Syn th esis of th e P en ta cyclic Sk eleton of th e Asp id osp er m a
Alk a loid s Usin g Rh od iu m Ca r ben oid s a s Rea ctive In ter m ed ia tes
Albert Padwa* and Alan T. Price
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received August 1, 1997X
A series of diazo amido keto esters prepared from N-alkenyl-substituted 3-carbalkoxy-2-piperidone
derivatives was treated with rhodium(II) acetate. Attack of the amido carbonyl oxygen at the
resultant rhodium carbenoid center produced a transient push-pull carbonyl ylide dipole which
underwent an intramolecular dipolar cycloaddition reaction. A related annulation sequence was
used to prepare the pentacyclic skeleton of the aspidosperma family of alkaloids. Synthesis of the
required diazo imide was carried out from 3-carboxy-3-ethyl-2-piperidone and N-methyl-3-
indoleacetic acid. Treatment of the diazo imide with rhodium(II) acetate afforded a transient 1,3-
dipole which subsequently underwent cycloaddition across the indole π-bond. The resulting
cycloadduct is the consequence of endo cycloaddition with respect to the dipole which is fully in
accord with the lowest energy transition state. The cycloadduct was converted in three steps into
desacetoxy-4-oxo-6,7-dihydrovindorosine. The stereochemistry of the final product was established
by a X-ray crystallographic study.
The aspidosperma alkaloids constitute a large family
the introduction of the B/E spirocyclic junction, shown
in aspidospermidine (2).6 The construction of the char-
acteristic 2,3,3-trisubstituted indoline unit by formation
of the quaternary stereocenter at C-7 is usually the
crucial step of the synthesis.7 Our synthetic approach
toward this class of alkaloids is part of a general approach
to the total synthesis of azaspirocyclic natural products
based on the tandem cyclization-cycloaddition reaction
of rhodium carbenoids as the key strategic element.8
Prompted by our recent work dealing with the internal
dipolar cycloaddition reaction of mesoionic oxazolium
ylides (4),9 we became interested in the rhodium(II)-
catalyzed reactions of diazo ketoamides such as 6. Attack
of the amido oxygen at the rhodium carbenoid produces
a carbonyl ylide dipole (i.e., 7) that is isomeric with the
isomu¨nchnone class of mesoionic betaines (4).
of natural products which have attracted considerable
attention over the years due to their diverse and inter-
esting structures.1 The continuing interest in their
synthesis stems in part from the presence of the highly
functionalized vindoline nucleus in the clinically useful
antineoplastic agents vincristine and vinblastine.2 Vin-
doline (1)3 is one of the more heavily oxygenated and
complex members of the aspidosperma family and has
attracted a great deal of attention owing to its unusual
structure and high pharmacological activity.4 It is the
main alkaloidal constituent of Catharanthus roseus
(vinca rosea) and corresponds to the dihydroindole com-
ponent present in the potent bis-indole oncolytic agent,
vinblastine.5
(6) For a few of the many references, see: Woodward, R. B.; Cava,
M.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J . Am.
Chem. Soc. 1954, 76, 4749. Wenkert, E. J . Am. Chem. Soc. 1962, 84,
98. Thomas, R. Tetrahedron Lett. 1961, 544. Qureshi, A. A.; Scott, A.
I. J . Chem. Soc., Chem. Commun. 1968, 945. Battersby, A. R.; Byrne,
J . C.; Kapil, R. S.; Martin, J . A.; Payne, T. G.; Arigoni, D.; Loew, P. J .
Chem. Soc., Chem. Commun. 1968, 951. Magnus, P.; Gallagher, T.;
Brown, P.; Pappalardo, P. Acc. Chem. Res 1984, 17, 35. Magnus, P.;
Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.; Merritt, A.; Vicker, N.
J . Am. Chem. Soc. 1992, 114, 4403. Rawal, V. H.; Michoud, C.;
Monestel, R. F. J . Am. Chem. Soc. 1993, 115, 3030. Angle, S. R.; Fevig,
J . M.; Knight, S. D.; Marquis, R. W., J r.; Overman, L. E. J . Am. Chem.
Soc. 1993, 115, 3966. Knight, S. D.; Overman, L. E.; Pairaudeau, G.
J . Am. Chem. Soc. 1993, 115, 9293.
The aspidosperma alkaloids share as part of their
structure, the [6.5.6.5] ABCE ring system, and a major
focus of interest has been in finding efficient routes for
(7) Intramolecular cyclizations of secodine-type intermediates (C3-
C7 bond): Kuehne, M. E.; Frasier, D. A.; Spitzer, T. D. J . Org. Chem.
1991, 56, 2696. Fischer indolization (C7-C8 bond): Stork, G.; Dolfini,
J . E. J . Am. Chem. Soc. 1963, 85, 2872. Pummerer reaction and related
processes (C6-C7 bond): Gallagher, T.; Magnus, P. J . Am. Chem. Soc.
1983, 105, 5, 4750. Amat, M.; Linares, A.; Bosch, J . J . Org. Chem.
1990, 55, 6299. Transannular cyclization (C3-C7 bond): Harley-Mason,
J . Pure Appl. Chem. 1975, 41, 167.
(8) For some leading references, see: Padwa, A.; Brodney, M. A.;
Marino, J . P., J r.; Sheehan, S. M. J . Org. Chem. 1997, 62, 78.
(9) Padwa, A.; Marino, J . P., J r.; Osterhout, M. H. J . Org. Chem.
1995, 60, 2704. Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.;
Semones, M. A.; Padwa, A. J . Org. Chem. 1994, 59, 5518. Padwa, A.;
Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T. J . Org.
Chem. 1994, 59, 1418. Hertzog, D. L.; Austin, D. J .; Nadler, W. R.;
Padwa, A. Tetrahedron Lett. 1992, 33, 4731. Osterhout, M. H.; Nadler,
W. R.; Padwa, A. Synthesis 1994, 123.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) Cordell, G. A. In The Alkaloids; Manske, R. H. F., Rodrigo, R.
G. A., Eds.; Academic Press: New York, 1979; Vol. 17, pp 199-384.
Saxton, J . E. Nat. Prod. Rep. 1993, 10, 349; 1994, 11, 493.
(2) Neuss, N. In Indole and Biogenetically Related Alkaloids; Phil-
lipson, J . D., Zenk, M. H., Eds.; Academic Press: New York, 1980;
Chapter 17.
(3) Gorman, M.; Neuss, N.; Biemann, K. J . Am. Chem. Soc. 1962,
84, 1058. Bu¨chi, G.; Ando, M.; Ohnnuma, T. J . Am. Chem. Soc. 1975,
97, 6880.
(4) Antitumor Bisindole Alkaloids from Catharanthus roseus. In The
Alkaloids; Brossi, A., Suffness, M., Eds.; Academic Press: San Diego,
1990; Vol. 37.
(5) Noble, R. L.; Beer, C. T.; Cutts, J . H. Ann. N.Y. Acad. Sci. 1958,
76, 882. Svoboda, G. H.; Neuss, N.; Gorman, M. J . J . Am. Pharm. Assoc.
Sci. Ed. 1959, 48, 659.
S0022-3263(97)01424-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/13/1998

Pentacyclic Skeleton of Aspidosperma Alkaloids
J . Org. Chem., Vol. 63, No. 3, 1998 557
Sch em e 1
π-system14 would be expected to result in simultaneous
generation of the CD-rings of the aspidosperma skeleton.
The stereospecific nature of the internal cycloaddition
reaction should also lead to the correct relative stereo-
chemistry of the four chiral centers about the C-ring. In
this paper we describe a synthetic entry to 2,3,3-trisub-
stituted indole alkaloids embodying the pyrrolo[2,3-d]-
carbazole skeleton (ABCE rings) based on an intramo-
lecular cycloaddition of a push-pull-stabilized carbonyl
ylide. The usefulness of this strategy is exemplified by
the synthesis of the dihydrovindorosine derivative 10.
In an earlier paper, we demonstrated that transient
push-pull carbonyl ylide dipoles such as 7b underwent
an intramolecular cycloaddition.10 As an extension of our
studies, we decided to apply the cycloaddition reaction
of this class of dipoles to the synthesis of the pentacyclic
skeleton of the aspidosperma ring system.11 Our syn-
thetic plan is shown in antithetic format in Scheme 1 and
is centered on the construction of the key oxabicyclic
intermediate 11. We reasoned that desacetoxy-4-oxo-6,7-
dihydrovindorosine (10) should be accessible by reduction
of 11, which, by analogy with our previous work,9 should
be available by the tandem rhodium(II)-catalyzed cy-
clization-cycloaddition12 of diazo imide 12. This target
was selected since the closely related C16-methoxy de-
rivative (9) had previously been converted by Kutney and
co-workers into vindoline in six steps.13 Cycloaddition
of the initially formed dipole across the pendent indole
Resu lts a n d Discu ssion
Intramolecular dipolar cycloadditions have been par-
ticularly useful in natural product synthesis, as this
reaction results in the formation of an additional ring
and exhibits increased reactivity due to entropic
factors.15-17 The regiochemistry of the process is com-
plicated by a complex interplay of factors such as the
nature of the 1,3-dipole, alkene polarity, ring strain, and
nonbonded interactions in the transition state.15 We
have found that the rhodium(II)-catalyzed formation of
carbonyl ylide intermediates derived from cyclic diazo
amides furnishes tetracycles such as 8b in good yield,
provided that the tether engaged in ring formation
carries a carbonyl group (i.e., 6b, X ) O).10 Without the
CdO functionality (i.e., 6a , X ) H), only decomposition
products were observed. By performing ab initio transi-
tion state geometry optimizations, we learned that a
severe cross-ring 1,3-diaxial interaction caused by the
bridgehead methyl group promoted a boat or twist-boat
conformation in the piperidine ring fused to the newly
forming one.10 The presence of a carbonyl group on the
tether helped to relieve the steric congestion by favoring
(10) Weingarten, M. D.; Prein, M.; Price, A. T.; Snyder, J . P.; Padwa,
A. J . Org. Chem. 1997, 62, 2001.
(11) For some earlier syntheses, see: Stork, G.; Dolfini, J . E. J . Am.
Chem. Soc. 1963, 85, 2872. Ban, Y.; Sato, Y.; Inoue, I.; Nagai, M.; Oishi,
T.; Terashima, M.; Yonemitsu, O.; Kanaoka, Y. Tetrahedron Lett. 1965,
2261. Overman, L. E.; Sworin, M.; Burk, R. M. J . Org. Chem. 1983,
48, 2685. Wenkert, E. Pure Appl. Chem. 1981, 53, 1271. Feldman, P.
L.; Rapoport, H. J . Am. Chem. Soc. 1987, 109, 1603. Kuehne, M. E.;
Earley, W. G. Tetrahedron 1983, 39, 3707. Desmae¨le, D.; d′Angelo, J .
J . Org. Chem. 1994, 59, 2292.
(12) Padwa, A.; Weingarten, M. D. Chem. Rev. (Washington, D.C.)
1996, 96, 223.
(13) Kutney, J .; Bunzli-Trepp, U.; Chan, K. K.; de Souza, J . P.;
Fujise, Y.; Honda, T.; Katsube, J .; Klein, F. K.; Leutwiler, A.; Morehead,
S.; Rohr, M.; Worth, B. R. J . Am. Chem. Soc. 1978, 100, 4220.
(14) Padwa, A.; Hertzog, D. L.; Nadler, W. R. J . Org. Chem. 1994,
59, 7072.
(15) Padwa, A. Angew. Chem., Int. Ed. Engl. 1976, 15, 123. Padwa,
A.; Schoffstall, A. Advances in Cycloaddition; Curran, D. P., Ed.; J AI
Press: Greenwich, CT, 1990; Vol. 2, pp 2-128.
(16) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10.
(17) Wade, A. Intramolecular 1,3-Dipolar Cycloadditions; Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, U.K., 1991; Chapter 4.10, p 111.

558 J . Org. Chem., Vol. 63, No. 3, 1998
Padwa and Price
ambiguously established by X-ray crystallography.19
Sch em e 2a
A
similar tandem cyclization-cycloaddition sequence also
occurred with the pyrrolidinyl-substituted diazo amido
ester 21 (n ) 1). The only product formed with this
system (85% yield) corresponded to cycloadduct 22. The
assignment of the stereochemistry of 22 was based on
comparison of NMR signals with those of the related
cycloadduct 18.
In the examples cited above, both the six- and five-
ring precursors 17 and 21 deliver cyclized products in
high yield even though they do not contain a carbonyl
group on the side chain tether. This stands in sharp
contrast to the situation encountered with diazo amido
ester 6 where the push-pull carbonyl ylide lacking a
CdO on the tether (i.e., 6a , X ) H2) failed to cyclize. The
difference in cycloaddition behavior of these systems
underscores the complexity of intramolecular cyclization
processes that create several fused rings in a single step
and simultaneously induce steric effects in the transition
state remote from the reaction centers. To further
explore the facility of the intramolecular tandem cycliza-
tion-cycloaddition reaction, we have investigated the Rh-
(II)-catalyzed reaction of diazo amido ester 23. In this
case, the tethered π-bond is attached to a phenyl ring,
which in turn is connected to the amide nitrogen atom.
We found that treatment of 23 with a catalytic quantity
of Rh2(OAc)4 in benzene at 80 °C provided cycloadduct
24 in 87% isolated yield. Thus, an alkenyl π-bond
anchored to a phenyl ring emerges as a remote-site
promoter of intramolecular cycloaddition yielding a cy-
cloadduct with multiple fused rings.
a
Reagents: (a) n-BuLi, THF, I(CH2)3CHdCH2; (b) NaH,
PhCH2Br; (c) KOH (MeOH); (d) (COCl)2; (e) hydrogen methyl
malonate, i-PrMgCl; (f) mesyl azide, NEt3.
a second boat conformation in the latter ring. When the
side chain is devoid of a carbonyl group, the reaction
barrier is much larger, thereby permitting competing
processes to intervene. Thus, the reactivity discrepancy
between diazo amido esters 6a vs 6b was attributed to
steric effects in the transition states.10
To further probe the forces responsible for intramo-
lecular ring formation with these push-pull carbonyl
ylides, we examined the Rh(II)-catalyzed behavior of
several other cyclic diazo amides containing tethered
π-bonds. Our studies began with an investigation of the
transition metal catalyzed reaction of diazo amido ester
17 (n ) 2). The requisite amide necessary for dipole
generation was obtained by alkenylation of 2-oxopiperi-
dine-3-carboxylic acid ethyl ester (15) with 5-iodo-1-
pentene followed by N-benzylation and saponification
which furnished carboxylic acid 16 (Scheme 2). Conver-
sion of 16 to the corresponding acid chloride was followed
by reaction with the magnesium dianion of hydrogen
methyl malonate. The resulting amido ester was treated
with mesyl azide in the presence of triethylamine18 to
provide R-diazo amide 17 in 80% as a labile yellow oil.
Formation of the push-pull carbonyl ylide dipole pro-
ceeded smoothly upon heating a sample of 17 in benzene
in the presence of Rh2(OAc)4. The resultant dipole
underwent ready intramolecular dipolar-cycloaddition
across the tethered π-bond to produce the tricyclic adduct
18 in 87% yield. Cycloadduct 18 is produced with
complete diastereoselectivity and is the result of exo-
cycloaddition with respect to the dipole. This is in full
accord with molecular mechanics calculations which show
a large ground state energy difference between the two
diastereomers. The stereochemical assignment was un-
Given the success in forming complex polyheterocyclic
systems from the intramolecular cycloaddition reaction
of push-pull carbonyl ylides, it seemed to us that
selective modification of the starting diazo amido ester
would allow application of the method toward the Aspi-
dosperma alkaloid family. In particular, the intramo-
lecular cycloaddition of a push-pull carbonyl ylide
derived from the model diazo amido ester 25 across the
tethered indolyl π-bond would bode well for the planned
Aspidosperma synthesis (vide infra). The key question
that needed to be addressed was whether the push-pull
carbonyl ylide derived from 25 would undergo cycload-
dition across the aromatic π-bond of indole. Heteroaro-
matic rings such as indole have, despite their aromaticity,
frontier orbital energies and shapes similar to those of
cyclopentadiene.20 Although a vast amount of informa-
tion is available concerning the reactivity of heteroaro-
matics in cycloadditions where the heteroaromatics enter
(19) The authors have deposited coordinates for structures 10, 11,
and 18 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.
(18) Taber, D. F.; Ruckle, R. E., J r.; Hennessy, M. J . J . Org. Chem.
1986, 51, 4077.
(20) Del Bene, J .; J affe, H. H. J . Chem. Phys. 1968, 48, 4050.

Pentacyclic Skeleton of Aspidosperma Alkaloids
J . Org. Chem., Vol. 63, No. 3, 1998 559
as 4πs components,21 a study of their dipolarophilic
activities has not been extensively examined to date.22-25
The dipolarophilic reactivity of the indole π-bond would
be expected to be somewhat diminished because of loss
of aromaticity in the cycloaddition transition state.
Gratifyingly, we found that the Rh(II)-catalyzed reaction
of 25 afforded the polyheterocyclic adduct 26 in 90% yield
and with complete diastereospecificity. Thus, the conver-
sion of 25 f 26 represents a rare example of dipolar
cycloaddition across an indolyl π-bond and opens up this
approach as a potentially general strategy for the syn-
thesis of a variety of indolyl alkaloids.
Sch em e 3a
After the successful transformation of diazo amido
ester 25 to the desired cycloadduct 26, we turned our
attention to the construction of the pyrrolo[2,3-d]carba-
zole skeleton found in the dihydrovindorosine derivative
10. Our synthesis of the required diazo imide 12 com-
mences with the easily available 3-carboxy-3-ethyl-2-
piperidone (27).26 Treatment of 27 with 1,1-carbonyldi-
imidazole followed by reaction with the dianion of
hydrogen methyl malonate27 afforded â-keto ester 14 in
60% yield (Scheme 3). N-Acylation of 14 with N-meth-
ylindole-3-acetyl chloride (13) using 4 Å molecular sieves
as a neutral acid scavenger28 gave the desired imide
(65%) which was readily converted to the requisite diazo
imide 12 using standard diazo transfer methodology.29
When diazo imide 12 was treated with a catalytic
quantity of Rh2(OAc)4 in benzene at 50 °C, cycloadduct
11 was isolated in 95% yield as a single diastereomer.
The structure of 11 was firmly established by NMR
analysis and by a X-ray crystallographic analysis19 which
revealed that the cycloadduct contains the same relative
stereochemical centers (C2, C3, C5, and C12) found in
a
Reagents: (a) (Im)2CO; (b) hydrogen methyl malonate, i-
PrMgCl; (c) indole acid chloride 13, molecular sieves; (d) MsN3/
NEt3; (e) Rh(II).
vindoline.30 The formation of 11 arises by cyclization of
the initially formed rhodium carbenoid derived from 12
onto the neighboring piperidone carbonyl oxygen to give
dipole 28 which subsequently cycloadds across the indole
π-bond. The isolation of 11 is the consequence of endo
cycloaddition with regard to the dipole, and this is in full
accord with the lowest energy transition state. The
cycloaddition can also be considered doubly diastereose-
lective in that the indole moiety approaches the dipole
exclusively from the side of the ethyl group and away
from the more sterically encumbered piperidone ring.
Having established a viable route to cycloadduct 11,
efforts were next focused on the reduction of the C10
lactam carbonyl group and reductive opening of the C3-
C19 oxido bridge. Treatment of 11 with Lawesson’s
reagent31 furnished the expected thiolactam (85%) which
was cleanly reduced (96%) to amine 29 when exposed to
Raney nickel in refluxing THF.32 Reduction of the oxido
bridge was achieved by catalytic hydrogenation over PtO2
using acidic methanol as the solvent to give 10 in 94%
yield as a single diastereomer.33 The C19-stereochemistry
was unequivocally established by a single-crystal X-ray
analysis.19 The overall reduction presumably proceeds
by an acid-catalyzed ring opening of the N,O-acetal group
to generate a transient iminium ion (i.e., 30) which reacts
further with hydrogen from the least congested face.
After the successful transformation of cycloadduct 11
to the dihydrovindorosine derivative 10, we decided to
(21) Sauer, J . Angew. Chem., Int. Ed. Engl. 1967, 6, 16. Carruthers,
W. Cycloaddition Reactions in Organic Synthesis; Pergamon Press:
Oxford, 1990.
(22) For an example where a 1,3-dipole undergoes intramolecular
1,3-dipolar cycloaddition across a benzene ring, see: Henke, B. R.;
Kouklis, A. J .; Heathcock, C. H. J . Org. Chem. 1992, 57, 7056.
(23) Corsico Coda, A.; Gru¨nanger, P.; Vernesi, G. Tetrahedron Lett.
1966, 2911. Caramella, P.; Cellerino, G.; Corsico Coda, A.; Invernizzi,
A. G.; Gru¨nanger, P.; Houk, K. N.; Albini, F. M. J . Org. Chem. 1976,
41, 3349. Caramella, P. Tetrahedron Lett. 1968, 743. Caramella, P.;
Cellerino, G.; Gru¨nanger, P.; Albini, F. M.; Cellerino, M. R. Tetrahedron
1978, 34, 3545. Caramella, P.; Cellerino, G.; Houk, K. N.; Albini, F.
M.; Santiago, C. J . Org. Chem. 1978, 43, 3006. Caramella, P.; Corsico
Coda, A.; Corsaro, A.; Monte, D. D.; Albini, F. M. Tetrahedron 1982,
38, 173.
(24) Hassner, A.; Murthy, K. S. K.; Padwa, A.; Chiacchio, U.; Dean,
D. C.; Schoffstall, A. M. J . Org. Chem. 1989, 54, 5277. Dehaen, W.;
Hassner, A. J . Org. Chem. 1991, 56, 896.
(25) Yin, H.; Franck, R. W.; Chen, S. L.; Quigley, G. J .; Todaro, L.
J . Org. Chem. 1992, 57, 644.
(26) Liebman, A. A.; Malarek, D. H.; Dorsky, A. M.; Kaegi, H. H. J .
Heterocycl. Chem. 1974, 11, 1105.
(27) Rapoport, H.; Feldman, P. L.; Mayer, M. P. J . Org. Chem. 1985,
50, 5223.
(30) Moza, B. K.; Troja´nek, J . Collect. Czech. Chem. Commun. 1963,
28, 1427. Bu¨chi, G.; Matsumoto, K. E.; Nishimura, H. J . Am. Chem.
Soc. 1971, 93, 3299.
(28) Weinstock, L. M.; Karady, S.; Roberts, F. E.; Hoinowski, A. M.;
Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M. Tetrahedron
Lett. 1975, 11, 3979.
(31) Lawesson, S. O.; Pederson, B. S. Tetrahedron 1979, 2433.
(32) Yde, B.; Yousif, N. M.; Pedersen, U.; Lawesson, S. O. Tetrahe-
dron 1984, 40, 2047. Laronze, J . Y.; Laronze-Fontaine, J .; Le´vy, J .; Le
Men, J . Tetrahedron Lett. 1974, 491.
(29) Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733.

560 J . Org. Chem., Vol. 63, No. 3, 1998
Padwa and Price
Sch em e 4a
study the reduction chemistry of 11 in further detail. One
of the problems with Kutney’s synthesis of vindoline was
that reduction of the C4-keto group proceeded in low yield
and with poor diastereoselectivity.13 Our hope was that
the oxido bridge present in cycloadduct 11 would offer
considerable steric bias and allow reduction of the C4-
carbonyl group to take place with much higher ste-
reospecificity than that encountered by Kutney.13 To test
this possibility, cycloadduct 11 was reduced with NaBH4
in THF/MeOH containing CeCl3‚7H2O which furnished
the C4-alcohol as a single diastereomer in 64% yield. The
alcohol was not isolated but instead was immediately
converted into the corresponding acetate 31 in quantita-
tive yield (Scheme 4). A small amount of diol 32 (18%)
derived from the secondary reduction of the C3-car-
bomethoxy group was also obtained. Treatment of 31
with Lawesson’s reagent furnished the expected thiolac-
tam which was subsequently reduced to amine 33 in 79%
overall yield for both steps. Catalytic reduction of 33
with PtO2 in methanol afforded the ring-opened com-
pound 34 in 92% yield. The NMR characteristics of 34
clearly indicate that hydride reduction of the C4-carbonyl
group (i.e., 11 f 31) had occurred from the same side as
the oxido bridge. Examination of molecular models
shows that the presence of the oxido bridge actually
accentuates the cuplike nature of the pyrrolo[2,3-d]-
carbazole skeleton. To date, our efforts to epimerize the
C4-alcohol at both the oxido bridge (31) or ring-opened
stage (34) have proven unsuccessful. Further work along
these lines is currently under investigation.
a
Reagents: (a) CeCl3‚7H2O, NaBH4, THF; (b) CH3COCl, Ac2O;
(c) Lawesson’s regent; (d) Raney Ni; (e) H3 (MeOH), PtO2.
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
residue was chromatographed on a silica gel column using an
ethyl acetate-hexane mixture as the eluent unless specified
otherwise.
Gen er a l P r oced u r e for th e Syn th esis of Dia zo Am id es.
A variation of the procedure described by Taber and co-
workers18 was used to prepare the diazo amide system. To a
solution containing 2 mmol of the appropriate amido ester and
2.2 mmol of mesyl azide in 5 mL of acetonitrile or CH2Cl2 was
added 4.0 mmol of NEt3 under N2 at rt. After the mixture
was stirred for 3 h, the solvent was removed under reduced
pressure and the residue was subjected to flash silica gel
chromatography.
2-Oxo-3-p en t-4-en ylp ip er id in e-3-ca r boxylic Acid Eth yl
Ester . To a stirred solution of 2.0 g (11.7 mmol) of 2-oxopi-
peridine-3-carboxylic acid ethyl ester (15)34 in 20 mL of THF
at -78 °C was added 7.3 mL (11.7 mmol) of a 1.6 M
n-butyllithium solution in hexane. The resulting solution was
allowed to warm to 0 °C and recooled to -78 °C, and 2.3 g
(11.7 mmol) of 5-iodo-1-pentene was added. The solution was
heated at 65 °C for 2 h, cooled to rt, and quenched with H2O.
The organic phase was separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic extracts were
washed with a saturated NaCl solution, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The resi-
due was subjected to flash silica gel chromatography to give
2.1 g (75%) of 2-oxo-3-pent-4-enylpiperidine-3-carboxylic acid
ethyl ester as a pale yellow oil: IR (neat) 3218, 1723, 1659,
1489, 1446, and 1247 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.23
(t, 3H, J ) 7.1 Hz), 1.20-1.50 (m, 2H), 1.70-1.95 (m, 6H),
2.00-2.30 (m, 2H), 3.20-3.40 (m, 2H), 4.17 (qd, 2H, J ) 7.1
and 2.4 Hz), 4.89-5.00 (m, 2H), 5.65-5.80 (m, 1H), and 6.32
(brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.1, 19.7, 23.9, 29.6,
34.0, 35.0, 42.3, 53.8, 61.3, 114.7, 138.3, 171.0, and 172.9. Anal.
Calcd. for C13H21NO3: C, 65.23; H, 8.85; N, 5.86. Found: C,
65.09; H, 8.71; N, 5.75.
In conclusion, the successful preparation of desacetoxy-
4-oxo-6,7-dihydrovindorosine 10 in seven steps was ac-
complished in 27% overall yield and establishes the merit
of our method as outlined in Scheme 1. The tandem
cyclization-cycloaddition sequence is particularly attrac-
tive as four of the stereocenters are formed in one step
with a high degree of stereocontrol. Work to extend these
discoveries to the total synthesis of vindoline are in
progress, and the results of these investigations will be
reported in due course.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
(33) Benchekroun-Mounir, N.; Dugat, D.; Gramain, J . C. Tetrahe-
dron Lett. 1992, 33, 4001.
(34) Danishefsky, S.; Singh, R. K. Org. Synth. 1981, 60, 66.

Pentacyclic Skeleton of Aspidosperma Alkaloids
J . Org. Chem., Vol. 63, No. 3, 1998 561
1-Ben zyl-2-oxo-3-p en t -4-en ylp ip er id in e-3-ca r b oxylic
Acid (16). To a stirred solution of 1.0 g (4.2 mmol) of the above
amido ester in 20 mL of THF at rt was slowly added 0.20 g
(5.0 mmol) of NaH (60% in mineral oil). The solution was
heated at 65 °C for 1 h and cooled to rt, and 0.89 g (5.2 mmol)
of benzyl bromide and 0.78 g (5.2 mmol) of NaI were added.
The mixture was heated at 65 °C for 1 h, cooled to rt, and
quenched with H2O. The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were concentrated under reduced pressure,
the residue was dissolved in 10 mL of methanol, and 5 mL
(15 mmol) of a 3 N KOH solution was added. The solution
was allowed to stir at rt for 10 h, washed with ether, acidified
to pH 2, and extracted with CH2Cl2. The CH2Cl2 extracts were
dried over anhydrous MgSO4 and concentrated under reduced
pressure to give 0.80 g (64%) of 16 as a yellow oil: IR (neat)
1728, 1598, 1445, and 1184 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.38 (dt, 2H, J ) 16.0 and 7.9 Hz), 1.66-2.03 (m, 7H), 2.25
(ddd, 1H, J ) 13.9, 9.7, and 3.9 Hz), 3.24 (t, 2H, J ) 6.1 Hz),
4.51 (d, 1H, J ) 14.6 Hz), 4.64 (d, 1H, J ) 14.6 Hz), 4.90-
5.00 (m, 2H), 5.64-5.80 (m, 1H), 7.17-7.35 (m, 5H), and 12.01
(brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.1, 23.7, 27.5, 33.4,
38.3, 47.9, 51.2, 52.2, 115.3, 127.9, 128.0, 128.9, 135.8, 137.6,
172.8, and 173.5. Anal. Calcd. for C18H23NO3: C, 71.72; H,
7.70; N, 5.86. Found: C, 71.59; H, 7.63; N, 5.91.
3-(1-Ben zyl-2-oxo-3-p en t -4-en ylp ip er id in -3-yl)-3-oxo-
p r op ion ic Acid Meth yl Ester . To a stirred solution of 0.25
g (0.8 mmol) of the above carboxylic acid in 5 mL of ether were
added 0.23 mL (2.5 mmol) of oxalyl chloride and one drop of
DMF. The solution was allowed to stir at rt for 30 min and
was concentrated under reduced pressure to remove the excess
oxalyl chloride. The residue was taken up in 1 mL of CH2Cl2,
and this mixture was slowly added to 4 mL of a 0.5 M THF
solution of the magnesium dianion of hydrogen methyl mal-
onate at 0 °C. The solution was allowed to stir for 1 h and
was quenched with a 1 N HCl solution. The organic layer was
separated, and the aqueous layer was extracted with ether.
The organic extracts were washed with a saturated NaCl
solution, dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was subjected to flash silica
gel chromatography to give 0.19 g (63%) of 3-(1-benzyl-2-oxo-
3-pent-4-enylpiperidin-3-yl)-3-oxopropionic acid methyl ester
as a colorless oil: IR (neat) 1741, 1707, 1643, 1435, and 1256
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.19-1.32 (m, 2H), 1.50-
1.75 (m, 3H), 1.86 (ddd, 2H, J ) 15.6, 9.6, and 3.6 Hz), 1.95-
2.05 (m, 2H), 2.37 (dt, 1H, J ) 13.6 and 4.1 Hz), 3.16 (t, 2H,
J ) 6.3 Hz), 3.62 (s, 3H), 3.67 (d, 1H, J ) 16.4 Hz), 3.84 (d,
1H, J ) 16.4 Hz), 4.49 (d, 1H, J ) 14.5 Hz), 4.58 (d, 1H, J )
14.5 Hz), 4.90-5.00 (m, 2H), 5.60-5.80 (m, 1H), and 7.10-
7.30 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 20.0, 23.6, 27.5,
33.8, 36.3, 45.2, 47.6, 51.0, 52.1, 60.5, 115.1, 127.5, 128.0, 128.6,
methyl ester (18) as a white solid: mp 133-134 °C; IR (KBr)
1771, 1765, 1739, and 1443 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.20-1.90 (m, 11H), 2.28 (t, 1H), 2.75-2.95 (m, 3H), 3.57
(d, 1H, J ) 15.9 Hz), 3.84 (s, 3H), 4.51 (d, 1H, J ) 15.9 Hz),
and 7.20-7.40 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 17.0, 20.2,
24.9, 28.0, 28.4, 32.7, 35.6, 48.8, 49.5, 52.7, 53.0, 85.4, 100.2,
126.8, 127.4, 128.4, 139.9, 167.3, and 209.5. Anal. Calcd for
C
21H25NO4: C, 70.96; H, 7.09; N, 3.94. Found: C, 70.77; H,
7.15; N, 3.92.
1-P h en yl-2-oxo-3-p en t -4-en ylp yr r olid in e-3-ca r b oxy-
lic Acid (20). To a solution containing 0.80 g (3.7 mmol) of
1-phenyl-2-oxopyrrolidine-3-carboxylic acid methyl ester (19)34
in 10 mL of THF at -78 °C was added 2.5 mL (4.0 mmol) of a
1.6 M solution of n-butyllithium in hexane. The solution was
allowed to warm to rt and recooled to -78 °C, and 1.43 g (7.3
mmol) of 5-iodo-1-pentene was added. The solution was heated
at reflux for 2 h and quenched with H2O, the organic phase
was separated, and the aqueous phase was extracted with CH2-
Cl2. The combined organic extracts were washed with a
saturated NaCl solution, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was dis-
solved in 10 mL of methanol, 4 mL of a 3 M KOH solution
was added, and the solution was allowed to stir at rt for 12 h.
The mixture was washed with ether, acidified to pH 2, and
extracted with CH2Cl2. The combined CH2Cl2 extracts were
dried over anhydrous MgSO4 and concentrated under reduced
pressure to give 0.65 g (65%) of 20 as a yellow oil: IR (neat)
1
3400 (br), 1693, 1498, and 1393 cm-1; H NMR (CDCl3, 300
MHz) δ 1.35-1.55 (m, 2H), 1.75-2.15 (m, 5H), 2.61 (ddd, 1H,
J ) 13.4, 8.2, and 5.3 Hz), 3.69-3.81 (m, 1H), 3.87 (dt, 1H, J
) 8.9 and 6.0 Hz), 4.90-5.01 (m, 2H), 5.60-5.80 (m, 1H), 7.10-
7.58 (m, 5H), and 10.01 (brs, 1H); 13C NMR (CDCl3, 75 MHz)
δ 23.9, 26.9, 33.6, 34.8, 46.2, 56.5, 115.3, 120.4, 125.5, 129.0,
137.7, 138.6, 172.8, and 174.1. Anal. Calcd for C16H19NO3:
C, 70.29; H, 7.01; N, 5.13. Found: C, 70.14; H, 6.89; N, 5.04.
3-(1-P h en yl-2-oxo-3-p en t-4-en ylp yr r olid in -3-yl)-3-oxo-
p r op ion ic Acid Meth yl Ester . To a stirred solution of 0.25
g (1.5 mmol) of carboxylic acid 20 in 10 mL of ether were added
0.40 mL (4.4 mmol) of oxalyl chloride and one drop of DMF.
The solution was allowed to stir at rt for 30 min and
concentrated under reduced pressure to remove the excess
oxalyl chloride. The residue was taken up in 1 mL of CH2Cl2,
and this mixture was slowly added to 6 mL of a 0.5 M THF
solution of the magnesium dianion of hydrogen methyl mal-
onate at 0 °C. The reaction mixture was allowed to stir for 1
h and was then quenched with a 1 N HCl solution. The
mixture was extracted with ether, and the ether extracts were
dried over anhydrous MgSO4 and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.25 g (52%) of 3-(1-phenyl-2-oxo-3-pent-
4-enylpyrrolidin-3-yl)-3-oxopropionic acid methyl ester as a
136.9, 137.9, 168.1, 169.2, and 202.0. Anal. Calcd for C21H27
-
colorless oil: IR (neat) 1743, 1683, 1491, 1392, and 1300 cm-1
;
NO4: C, 70.55; H, 7.62; N, 3.92. Found: C, 70.48; H, 7.44; N,
3.80.
1H NMR (CDCl3, 300 MHz) δ 1.20-1.41 (m, 2H), 1.75-2.20
(m, 5H), 2.87 (ddd, 1H, J ) 12.9, 7.6, and 3.1 Hz), 3.60 (s, 3H),
3.64 (d, 1H, J ) 16.6 Hz), 3.64-3.81 (m, 2H), 3.96 (d, 1H, J )
16.6 Hz), 4.95-5.04 (m, 2H), 5.70-5.82 (m, 1H), and 7.12-
7.60 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 23.7, 25.2, 33.6,
34.6, 44.4, 45.8, 52.3, 64.2, 115.6, 120.1, 125.1, 128.9, 137.5,
139.0, 167.7, 171.1, and 200.0. Anal. Calcd for C19H23NO4:
C, 69.27; H, 7.04; N, 4.25. Found: C, 69.03; H, 6.95; N, 4.17.
Rh od iu m (II)-Ca ta lyzed Rea ction of (1-P h en yl-2-oxo-
3-pen t-4-en ylpyr r olidin -3-yl)-2-diazo-3-oxopr opion ic Acid
Meth yl Ester (21). Diazo transfer of the above amido ester
according to the general procedure gave 21 (80%) as a pale
yellow oil: IR (neat) 2924, 2134, 1739, 1693, 1629, 1434, and
Rh od iu m (II)-Ca ta lyzed Rea ction of 3-(1-Ben zyl-2-oxo-
3-p en t-4-en ylp ip er id in -3-yl)-2-d ia zo-3-oxop r op ion ic Acid
Eth yl Ester (17). Diazo transfer of the above amido ester
according to the general procedure gave 17 (86%) as a yellow
oil: IR (neat) 2135, 1714, 1634, 1445, and 1315 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.20-2.10 (m, 8H), 2.26 (td, 1H, J ) 12.8
and 4.4 Hz), 3.15-3.19 (m, 2H), 3.47 (td, 1H, J ) 12.2 and 4.4
Hz), 3.69 (s, 3H), 3.91 (d, 1H, J ) 14.9 Hz), 4.90-5.01 (m, 2H),
5.05 (d, 1H, J ) 14.9 Hz), 5.65-5.90 (m, 1H), and 7.15-7.35
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ 19.3, 24.4, 28.7, 34.2,
35.1, 47.0, 49.9, 51.9, 57.6, 114.6, 127.2, 128.4, 128.7, 137.5,
138.6, 161.3, 170.6, and 191.4.
1
1318 cm-1; H NMR (CDCl3, 300 MHz) δ 1.40-1.60 (m, 2H),
Since diazo amide 17 decomposed on standing, it was
immediately subjected to the rhodium(II)-catalyzed reaction.
To a mixture of 2 mg of rhodium(II) acetate in 2 mL of benzene
at 80 °C was added 40 mg (0.10 mmol) of diazo amide 17 in
0.5 mL of benzene over a period of 5 min. The solution was
heated at 80 °C for an additional 1 h and then concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography to give 31 mg (87%) of 5-benzyl-10-
oxo-5-aza-6,9-epoxytricyclo[5.3.3.01,6]tridecane-9-carboxylic acid
1.85-2.20 (m, 5H), 2.68 (ddd, 1H, J ) 12.8, 9.2, and 7.2 Hz),
3.69 (s, 3H), 3.80-4.00 (m, 2H), 4.85-5.10 (m, 2H), 5.68-5.85
(m, 1H), 7.11 (t, 1H, J ) 7.3 Hz), 7.33 (t, 2H, J ) 8.0 Hz), and
7.59 (d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 23.7,
27.5, 34.0, 34.3, 46.6, 52.3, 61.3, 115.0, 120.3, 124.7, 128.8,
138.1, 139.2, 161.2, 172.2, and 189.0.
Since diazo amide 21 decomposed on standing, it was
immediately subjected to the rhodium(II)-catalyzed reaction.
To a mixture containing 2 mg of rhodium(II) acetate in 1 mL

562 J . Org. Chem., Vol. 63, No. 3, 1998
Padwa and Price
of benzene at 80 °C was added 0.10 g (0.3 mmol) of 21 in 0.5
mL of benzene over a period of 10 min. The solution was
heated at 80 °C for an additional 1 h and concentrated under
reduced pressure. The residue was subjected to flash silica
gel chromatography to give 80 mg (85%) of 5,8-epoxy-9-oxo-
4-phenyl-4-azatricyclo[4.3.3.01,5]dodecane-8-carboxylic acid meth-
yl ester (22) as a white solid: mp 139-140 °C; IR (KBr) 2930,
1764, 1744, 1389, and 1123 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.20-1.60 (m, 5H), 1.70 (dd, 1H, J ) 12.2 and 6.6 Hz), 1.98
(dd, 1H, J ) 13.7 and 3.7 Hz), 2.00-2.10 (m, 1H), 2.39-2.50
(m, 2H), 3.15-3.25 (m, 1H), 3.63 (t, 1H, J ) 9.3 Hz), 3.84 (s,
3H), 4.05-4.20 (m, 1H), and 6.90-7.40 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 16.3, 24.3, 28.3, 29.7, 30.6, 33.5, 52.7, 53.1,
58.8, 85.8, 104.8, 118.6, 120.9, 128.8, 144.0, 166.9, and 206.6.
Anal. Calcd for C19H21NO4: C, 69.71; H, 6.46; N, 4.28.
Found: C, 69.64; H, 6.52; N, 4.19.
to stir for 2 h and recooled to -78 °C, and 0.4 mL (6 mmol) of
iodomethane was added. The solution was stirred at rt for 12
h and quenched with H2O, the aqueous layer was extracted
with ether, and the ether extracts were dried over MgSO4. The
solution was concentrated under reduced pressure, and the
residue was taken up in 5 mL of methanol. To this solution
was added 2 mL (6 mmol) of a 3 N KOH solution, and the
mixture was allowed to stir at rt for 12 h. The solution was
washed with ether, acidified to pH 2, and extracted with CH2-
Cl2, and the CH2Cl2 extracts were dried over anhydrous
MgSO4. Concentration under reduced pressure gave 0.55 g
(92%) of 1-(2-allylphenyl)-3-methyl-2-oxopiperidine-3-carboxy-
lic acid as a yellow oil: IR (neat) 3427 (br), 1729, 1637, and
1
1454 cm-1; H NMR (CDCl3, 300 MHz) δ 1.66 (s, 3H), 1.80-
2.50 (m, 4H), 3.24 (d, 2H, J ) 6.6 Hz), 3.40-3.60 (m, 3H),
5.05-5.20 (m, 2H), 5.80-6.00 (m, 1H), and 7.05-7.40 (m, 4H);
13C NMR (CDCl3, 75 MHz) δ 19.1, 26.4, 30.4, 35.3, 47.7, 52.5,
116.6, 126.5, 128.0, 128.7, 130.8, 135.9, 136.6, 140.2, 173.9,
174.3. Anal. Calcd for C16H19NO3: C, 70.29; H, 7.01; N, 5.13.
Found: C, 70.08; H, 7.11; N, 5.12.
1-(2-Allylp h en yl)-2-oxop ip er id in e. To a stirred solution
of 2.0 g (15 mmol) of o-allylaniline35 in 20 mL of benzene was
added 3.0 g (21 mmol) of 5-bromovaleryl chloride, and the
solution was heated at 80 °C for 4 h. The mixture was cooled
to rt, and the solution was washed sequentially with H2O, a
saturated NaHCO3 solution, a 0.5 N HCl solution, and H2O.
The organic layer was dried over anhydrous MgSO4 and
concentrated under reduced pressure. The resulting oil was
dissolved in 10 mL of DMSO, and this solution was added
dropwise to a solution of 0.48 g (12 mmol) of NaH (60% in
mineral oil) in 10 mL of DMSO. The mixture was allowed to
stand at rt for 2 h and was quenched with H2O. The aqueous
layer was extracted with CH2Cl2, and the extracts were washed
sequentially with H2O, a 0.5 N HCl solution, and a saturated
NaCl solution. The organic layer was dried over anhydrous
MgSO4 and concentrated under reduced pressure, and the
residue was subjected to flash silica gel chromatography to
give 1.4 g (64%) of 1-(2-allylphenyl)-2-oxopiperidine as a
3-[1-(2-Allylp h en yl)-3-m et h yl-2-oxop ip er id in -3-yl]-3-
oxop r op ion ic Acid Eth yl Ester . To a stirred solution of 0.55
g (2 mmol) of the above carboxylic acid in 10 mL of ether were
added 0.72 mL (6 mmol) of oxalyl chloride and one drop of
DMF. The solution was allowed to stir at rt for 30 min and
was concentrated under reduced pressure to remove the excess
oxalyl chloride. The residue was taken up in 1 mL of CH2Cl2,
and this mixture was added slowly to 8.8 mL of a 0.5 M THF
solution of the magnesium dianion of hydrogen ethyl malonate
at 0 °C. The solution was allowed to stir for 1 h and was
quenched with a 1 N HCl solution. The reaction was extracted
with ether, and the ether extracts were dried over anhydrous
MgSO4 and concentrated under reduced pressure. The residue
was subjected to flash silica gel chromatography to give 0.40
g (60%) of 3-[1-(2-allylphenyl)-3-methyl-2-oxopiperidin-3-yl]-
3-oxopropionic acid ethyl ester as a colorless oil: IR (neat)
1743, 1710, 1635, and 1314 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.24 (t, 3H, J ) 7.1 Hz), 1.52 (s, 3H), 1.60-2.10 (m, 3H),
2.50-2.65 (m, 1H), 3.20-3.65 (m, 4H), 3.59 (d, 1H, J ) 16.1
Hz), 3.93 (d, 1H, J ) 16.1 Hz), 4.09-4.22 (m, 2H), 5.0-5.17
(m, 2H), 5.80-6.00 (m, 1H), and 7.02-7.18 (m, 4H); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 20.2, 23.4, 30.9, 35.2, 45.1, 51.9, 56.5,
61.2, 116.4, 127.2, 127.3, 127.6, 127.8, 130.4, 136.5, 137.0,
167.6, 170.2, and 202.5. Anal. Calcd for C20H25NO4: C, 69.93;
H, 7.34; N, 4.08. Found: C, 69.75; H, 7.24; N, 4.06.
Rh od iu m (II)-Ca ta lyzed Rea ction of 3-[1-(2-Allylp h en -
yl)-3-m eth yl-2-oxop ip er id in -3-yl]-2-d ia zo-3-oxop r op ion -
ic Acid Eth yl Ester (23). Diazo transfer of the above amido
ester according to the general procedure gave 3-[1-(2-allylphen-
yl)-3-methyl-2-oxopiperidin-3-yl]-2-diazo-3-oxopropionic acid
ethyl ester (23) (61%) as a yellow oil: 1H NMR (CDCl3, 300
MHz) δ 1.29 (t, 3H, J ) 7.1 Hz), 1.65 (s, 3H), 1.65-2.00 (m,
2H), 2.16 (ddt, 1H, J ) 13.3, 13.1, and 4.4 Hz), 2.48 (td, 1H, J
) 13.1 and 3.9 Hz), 4.07 (td, 1H, J ) 12.2 and 3.9 Hz) 4.26 (q,
2H, J ) 7.1 Hz), 3.20-3.38 (m, 3H), 4.95-5.10 (m, 2H), 5.80-
5.98 (m, 1H), and 7.19-7.39 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ 14.3, 19.9, 23.1, 31.3, 35.4, 51.4, 54.8, 61.2, 115.8,
126.9, 127.3, 127.5, 130.0, 136.9, 137.0, 142.0, 160.0, 161.3,
and 191.9.
Since diazo amide 23 decomposed on standing, it was
immediately subjected to the rhodium(II)-catalyzed reaction.
To a mixture of 2 mg of rhodium(II) acetate in 1 mL of benzene
at 80 °C was added 50 mg (0.14 mmol) of 23 in 0.5 mL of
benzene over a period of 10 min. The reaction mixture was
heated at reflux for an additional 1 h, cooled to rt, filtered
through a pad of silica, and concentrated under reduced
pressure to give 41 mg (87%) of 5,12a-epoxy-3a-methyl-4-oxo-
1,2,3,3a,4,5,6,6a,7,12a-decahydropyrido[3,2,1-de]acridine-5-
carboxylic acid ethyl ester (24) as a yellow oil: IR (neat) 1732,
1717, 1320, and 1058 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.05
(s, 3H), 1.32 (t, 3H, J ) 7.1 Hz), 1.52-2.00 (m, 4H), 2.10-2.35
(m, 3H), 2.54-2.74 (m, 2H), 3.48-3.60 (m, 1H), 3.90 (dt, 1H,
J ) 8.5 and 4.2 Hz), 4.32 (qd, 2H, J ) 7.1 and 1.8 Hz), 6.72 (t,
1H, J ) 7.2 Hz), 6.85 (d, 1H, J ) 8.2 Hz), 6.99 (d, 1H, J ) 7.2
Hz), and 7.13 (t, 1H, J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz)
1
colorless oil: IR (neat) 3068, 1645, 1489, and 1304 cm-1; H
NMR (CDCl3, 300 MHz) δ 1.80-2.05 (m, 4H), 2.51-2.58 (m,
2H), 3.28 (d, 2H, J ) 6.7 Hz), 3.36-3.62 (m, 2H), 5.00-5.18
(m, 2H), 5.80-6.00 (m, 1H), and 7.02-7.30 (m, 4H); 13C NMR
(CDCl3, 75 MHz) δ 21.5, 23.5, 32.7, 35.8, 51.8, 116.2, 127.7,
127.9, 130.1, 130.4, 136.6, 137.1, 141.9, and 169.7. Anal.
Calcd for C14H17NO: C, 78.09; H, 7.96; N, 6.51. Found: C,
77.96; H, 7.82; N, 6.41.
1-(2-Allylp h en yl)-2-oxop ip er id in e-3-ca r b oxylic Acid
Meth yl Ester . To a stirred solution of 1.5 g (7 mmol) of the
above lactam in 20 mL of THF at -78 °C was added a solution
of LDA (8.4 mmol) in 10 mL of THF over a period of 10 min.
The solution was allowed to stir for 1 h and was allowed to
warm to 0 °C. The mixture was recooled to -78 °C, and 0.71
mL (7 mmol) of HMPA was added. After the solution was
stirred for 5 min, 0.90 g (10.5 mmol) of methyl cyanoformate
was added.36 The mixture was allowed to stir for an additional
2 h at rt and was quenched with a 0.1 N HCl solution. The
organic layer was separated, and the aqueous layer was
extracted with ether. The combined organic extracts were
washed with a saturated NaCl solution, dried over MgSO4,
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 1.10 g
(57%) of 1-(2-allylphenyl)-2-oxopiperidine-3-carboxylic acid
methyl ester as a colorless oil: IR (neat) 1743, 1645, 1425,
1
and 1312 cm-1; H NMR (CDCl3, 300 MHz) δ 1.80-2.40 (m,
4H), 3.20-3.60 (m, 3H), 3.26 (d, 1H, J ) 6.5 Hz), 3.73 (s, 3H),
3.77 (d, 1H, J ) 6.5 Hz), 5.02-5.10 (m, 2H), 5.80-6.00 (m,
1H), and 7.00-7.40 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 20.9,
25.4, 35.2, 49.2, 51.7, 52.4, 116.0, 127.0, 127.6, 127.7, 128.1,
130.5, 136.9, 141.2, 165.6, and 171.5. Anal. Calcd for C16H19
-
NO3: C, 70.29; H, 7.01; N, 5.13. Found: C, 70.09; H, 6.96; N,
5.17.
1-(2-Allylp h en yl)-3-m eth yl-2-oxop ip er id in e-3-ca r boxy-
lic Acid . To a stirred solution of 0.6 g (2 mmol) of the above
lactam in 10 mL of THF at -78 °C was added 1.5 mL of a 1.6
M n-butyllithium solution in hexane. The mixture was allowed
(35) Smith, P. A. S.; Chou, S. S. P. J . Org. Chem. 1981, 46, 3970.
(36) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.

Pentacyclic Skeleton of Aspidosperma Alkaloids
J . Org. Chem., Vol. 63, No. 3, 1998 563
δ 14.2, 17.9, 19.4, 30.8, 33.1, 35.1, 36.2, 43.4, 62.0, 84.8, 97.8,
111.9, 118.4, 124.3, 127.5, 127.8, 128.3, 143.3, 166.2, and 209.4;
HRMS calcd for C20H23NO4 341.1628, found 341.1631.
mixture was allowed to stir at rt for 30 min, and 25 g (38 mmol)
of acrylonitrile was added. The solution was heated at 65 °C
under Ar for 8 h. The mixture was cooled to rt, filtered, and
washed with H2O. The organic layer was separated, washed
1-[2-(1-Meth yl-1H-in d ol-3-yl)a cetyl]-2-oxop ip er id in e-3-
ca r boxylic Acid Eth yl Ester . To a solution of 0.50 g (2.9
mmol) of 2-oxopiperidine-3-carboxylic acid ethyl ester in 10
mL of THF at -78 °C was added 4.0 mL (6.4 mmol) of a 1.6 M
n-butyllithium solution in hexane, and the mixture was
allowed to stir while being warmed to rt. The solution was
cooled to -78 °C, and 0.90 g (4.4 mmol) of N-methyl-3-
indoleacetyl chloride in 2 mL of CH2Cl2 was added over 5 min.
The solution was allowed to stir for 2 h and was quenched
with H2O. The organic layer was separated, and the aqueous
layer was extracted with ether. The combined organic extracts
were washed with a saturated NaCl solution, dried over
anhydrous MgSO4, and concentrated under reduced pressure.
The residue was subjected to flash silica gel chromatography
to give 0.45 g (45%) of 1-[2-(1-methyl-1H-indol-3-yl)acetyl]-2-
oxopiperidine-3-carboxylic acid ethyl ester as a yellow oil: IR
(neat) 2947, 1745, 1695, 1645, and 1496 cm-1; 1H NMR (CDCl3,
300 MHz) δ 1.30 (t, 3H, J ) 7.1 Hz), 1.65-2.20 (m, 4H), 3.53
(t, 1H, J ) 7.6 Hz), 3.60-3.80 (m, 2H), 3.73 (s, 3H), 4.25 (dq,
2H, J ) 7.1 and 2.0 Hz), 4.35 (d, 1H, J ) 16.9 Hz), 4.43 (d,
1H, J ) 16.9 Hz), and 7.00-7.65 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 14.1, 20.7, 24.2, 32.7, 35.5, 43.9, 51.5, 61.7, 107.2,
109.2, 119.1, 119.2, 121.6, 128.1, 128.4, 136.8, 169.8, 170.0,
and 175.1. Anal. Calcd for C19H22N2O4: C, 66.64; H, 6.48; N,
8.19. Found: C, 66.47; H, 6.41; N, 8.03.
with
a saturated NaCl solution, and dried over MgSO4.
Concentration under reduced pressure gave 80 g (92%) of
diethyl (2-(2-cyanoethyl)-2-ethyl)malonate as a colorless oil.
To a 75 g (310 mmol) sample of the above nitrile in 1 L of
EtOH was added 150 g (620 mmol) of CoCl2‚6H2O, and the
solution was allowed to stir for 30 min. To this mixture was
added 59 g (1.6 mol) of NaBH4 in small portions over 1 h such
that the temperature did not rise above 25 °C. The solution
was allowed to stir for 1 h, and then 500 mL of 3 N HCl was
added to dissolve the black precipitate resulting from the
NaBH4 addition. The solution was made basic (pH 10) by the
addition of concentrated NH4OH, and the mixture was ex-
tracted with ether. The organic extracts were washed with a
saturated NaCl solution, dried over MgSO4, and concentrated
under reduced pressure. The residue was taken up in 200 mL
of toluene and heated at reflux under Ar for 24 h. The solution
was cooled and concentrated under reduced pressure to give
56 g (90%) of 3-carbethoxy-3-ethyl-2-piperidone as a colorless
oil: IR (neat) 1738, 1666, 1239, and 1040 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.87 (t, 3H, J ) 7.4 Hz), 1.20 (t, 3H, J )
7.1 Hz), 1.68-2.15 (m, 6H), 3.18-3.40 (m, 2H), 4.00-4.23 (m,
2H), and 6.79 (brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 8.9, 14.1,
19.6, 28.4, 28.9, 42.4, 54.1, 61.2, 171.2, and 173.0. Anal. Calcd
for C10H17NO3: C, 60.26; H, 8.60; N, 7.03. Found: C, 60.13;
H, 8.45; N, 7.12.
Rh od iu m (II)-Ca ta lyzed Rea ction of 2-Dia zo-3-[1-[(1-
m eth yl-1H-in d ol-3-yl)a cetyl]-3-ca r beth oxy-2-oxop ip er i-
d in -3-yl]-3-oxop r op ion ic Acid Eth yl Ester (25). To a
stirred solution of 0.10 g (0.29 mmol) of the above imide in 5
mL of THF at 0 °C was added 0.18 mL (0.36 mmol) of a 2.0 M
solution of n-butylmagnesium chloride in THF. The solution
was allowed to stir at 0 °C for 1 h, and then 0.10 g (0.55 mmol)
of ethyl 2-diazomalonyl chloride was added. The solution was
allowed to stir at 0 °C for 2 h and was quenched with H2O.
The organic layer was separated, and the aqueous layer was
extracted with ether. The combined organic extracts were
washed with a saturated NaCl solution, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The resi-
due was subjected to flash silica gel chromatography to give
25 (59%) as a yellow oil: IR (neat) 2143, 1733, 1695, 1646,
To 56 g (280 mmol) of the above lactam was added 38 g (570
mmol) of 85% KOH pellets in 200 mL of H2O. The solution
was allowed to stir at rt for 12 h. The aqueous solution was
washed with ether, acidified to pH 2, and extracted with CH2-
Cl2. The organic extracts were washed with a saturated NaCl
solution and dried over MgSO4. Concentration under reduced
pressure gave 42 g (87%) of 27 as a white solid: mp 127-128
°C; IR (KBr) 3324, 2940, 1729, 1623, and 905 cm-1; H NMR
1
(CDCl3, 300 MHz) δ 0.94 (t, 3H, J ) 7.4 Hz), 1.75-2.00 (m,
6H), 3.20-3.45 (m, 2H), 7.12 (brs, 1H), and 10.72 (brs, 1H);
13C NMR (CDCl3, 75 MHz) δ 8.9, 19.0, 26.8, 31.3, 42.6, 52.2,
172.9, and 175.5. Anal. Calcd for C8H13NO3: C, 56.11; H, 7.66;
N, 8.18. Found: C, 56.07; H, 7.59; N, 8.13.
3-(3-E t h yl-2-oxop ip er id in -3-yl)-3-oxop r op ion ic Acid
Meth yl Ester (14). To 4.5 g (26 mmol) of the above carboxylic
acid in 50 mL of CH2Cl2 was added 5.0 g (31 mmol) of 1,1′-
carbonyldiimidazole, and the solution was allowed to stir at
rt under Ar for 12 h. The crude acylimidizolide was added
dropwise to a solution of 4.5 g (39 mmol) of hydrogen methyl
malonate and 60 mL (120 mmol) of 2 M isopropyl magnesium
chloride in 200 mL THF at rt. The solution was allowed to
stir at rt for 12 h, and 50 mL of 1 N HCl was added. The
organic layer was separated, and the aqueous layer was
extracted with ether. The combined organic extracts were
washed with a saturated NaCl solution, dried over MgSO4,
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 3.4 g (58%)
of 14 as a white solid: mp 80-81 °C; IR (neat) 1745, 1709,
1472, and 1320 cm-1 1H NMR (CDCl3, 300 MHz) δ 1.28 (t,
;
3H, J ) 7.0 Hz), 1.29 (t, 3H, J ) 7.0 Hz), 1.65-2.26 (m, 4H),
2.41 (ddd, 1H, J ) 13.7, 9.5, and 4.3 Hz), 2.66 (dt, 1H, J ) 9.5
and 4.3 Hz), 3.73 (s, 3H), 3.76-3.85 (m, 1H), 4.20-4.40 (m,
5H), and 7.00-7.60 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.0,
20.7, 24.2, 28.2, 32.6, 35.5, 43.9, 51.5, 61.7, 70.0, 107.2, 107.6,
109.1, 119.0, 121.5, 128.0, 128.4, 136.8, 160.8, 166.6, 169.8,
175.4, and 187.0.
Since diazo imide 25 decomposed on standing, it was
immediately subjected to the rhodium(II)-catalyzed reaction.
To 50 mg (0.1 mmol) of 25 in 0.5 mL of benzene was added 2
mg of rhodium(II) acetate. The mixture was heated to 50 °C
in an oil bath for 3 h and concentrated under reduced pressure,
and the residue was subjected to flash silica gel chromatog-
raphy to give 0.40 g (90%) of 3,18-dicarbethoxy-3,19-epoxy-
4,10-dioxo-1-methylaspidospermidine (26) as a white solid: mp
188-189 °C; IR (neat) 2933, 1727, 1697, 1642, 1482, and 1320
1652, and 1318 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.83 (t,
;
3H, J ) 7.4 Hz), 1.43-1.80 (m, 3H), 1.91 (dq, 2H, J ) 7.4 and
2.0 Hz), 2.35-2.45 (m, 1H), 3.22-3.33 (m, 2H), 3.67 (s, 3H),
3.69 (d, 1H, J ) 16.4 Hz), 3.86 (d, 1H, J ) 16.4 Hz), and 6.28
(brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 8.6, 19.8, 26.5, 29.4,
42.6, 45.2, 52.2, 60.4, 168.1, 171.5, and 201.6. Anal. Calcd
for C11H17NO4: C, 58.12; H, 7.54; N, 6.17. Found: C, 58.04;
H, 7.52; N, 6.09.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.99 (t, 3H, J ) 7.1 Hz),
1.36 (t, 3H, J ) 7.1 Hz), 1.70-1.82 (m, 1H), 1.95 (dt, 1H, J )
13.6 and 3.3 Hz), 2.08 (td, 1H, J ) 13.6 and 3.3 Hz), 2.18-
2.36 (m, 1H), 2.81 (d, 1H, J ) 17.3 Hz) 2.97 (s, 3H), 3.00 (d,
1H, J ) 17.3 Hz), 3.15-3.30 (m, 3H), 3.96 (dd, 1H, J ) 12.8
and 4.4 Hz), 4.30-4.42 (m, 2H), 4.43 (s, 1H), 6.40 (d, 1H, J )
7.8 Hz), 6.65 (t, 1H, J ) 7.3 Hz), 6.91 (d, 1H, J ) 7.3 Hz), and
7.12 (t, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 13.5,
14.1, 18.4, 28.4, 35.2, 38.0, 45.0, 53.9, 59.8, 61.4, 62.7, 80.4,
92.5, 104.9, 107.6, 118.0, 125.1, 125.7, 130.2, 154.2, 165.1,
165.5, 175.6, 195.7. Anal. Calcd for C24H26N2O7: C, 63.41;
H, 5.77; N, 6.17. Found: C, 63.28; H, 5.69; N, 6.04.
3-[3-Eth yl-1-[2-(1-m eth yl-1H-in d ol-3-yl)a cetyl]-2-oxop i-
p er id in -3-yl]-3-oxop r op ion ic Acid Meth yl Ester . To 600
mg (3.2 mmol) of N-methyl-3-indoleacetic acid (13) in 20 mL
of CH2Cl2 were added 0.87 mL (10 mmol) of oxalyl chloride
and one drop of DMF. The solution was allowed to stir at rt
for 4 h and was concentrated under reduced pressure. The
residue was taken up in 5 mL of CH2Cl2, and this mixture
was added to a solution of 0.61 g (2.7 mmol) of lactam 14 and
10 g of 4 Å mesh molecular sieves in 50 mL of CH2Cl2. The
mixture was allowed to stir at rt for 12 h, filtered, and
3-Ca r boxy-3-eth yl-2-p ip er id on e (27). To a 68 g (36
mmol) sample of diethyl ethylmalonate in 300 mL of a 1:1
THF:DME solution was added 100 g (72 mmol) of K2CO3. The

564 J . Org. Chem., Vol. 63, No. 3, 1998
Padwa and Price
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 690 mg (65%)
of 3-[3-ethyl-1-[2-(1-methyl-1H-indol-3-yl)acetyl]-2-oxopiperi-
din-3-yl]-3-oxopropionic acid methyl ester as a yellow oil: IR
(neat) 1746, 1691, 1330, and 1153 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.80 (t, 3H, J ) 7.4 Hz), 1.50 (ddd, 1H, J ) 13.9, 8.7,
and 5.6 Hz), 1.65-1.97 (m, 4H), 2.38 (dt, 1H, J ) 9.3 and 4.3
Hz), 3.45 (d, 2H, J ) 1.6 Hz), 3.56 (s, 3H), 3.62-3.70 (m, 2H),
3.71 (s, 3H), 4.36 (d, 2H, J ) 4.4 Hz), 7.02 (s, 1H), 7.09 (t, 1H,
J ) 7.2 Hz), 7.18 (d, 1H, J ) 7.7 Hz), 7.22 (t, 1H, J ) 8.0), and
7.57 (d, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 8.6,
19.8, 26.6, 29.4, 32.6, 36.0, 44.5, 44.6, 52.3, 63.5, 107.1, 109.2,
119.0, 119.2, 121.7, 128.0, 128.3, 136.8, 167.5, 173.4, 175.7,
and 200.2. Anal. Calcd for C22H26N2O5: C, 66.30; H, 6.58; N,
7.03. Found: C, 66.23; H, 6.44; N, 7.15.
152.9, 166.1, 204.6, and 208.2. Anal. Calcd for C22H24N2O4S:
C, 64.06; H, 5.86; N, 6.79. Found: C, 63.79; H, 5.93; N, 6.64.
3-Car bom eth oxy-4-oxo-3,19-epoxy-1-m eth ylaspidosper -
m a d in e (29). To a 300 mg (0.73 mmol) sample of the above
thiolactam in 15 mL of THF was added an excess of Raney
Ni. The solution was heated at 65 °C for 2 h, cooled, filtered
through a pad of Celite, and concentrated under reduced
pressure. The residue was dissolved in ethyl acetate and
filtered through a pad of silica gel to give 270 mg (96%) of
3-carbomethoxy-4-oxo-3,19-epoxy-1-methylaspidosperma-
dine (29) as a yellow oil: IR (neat) 1760, 1721, 1603, and 908
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.40-0.54 (m, 1H), 0.71
(t, 3H, J ) 7.2 Hz), 0.79-0.88 (m, 1H), 1.55-1.85 (m, 4H),
2.14-2.32 (m, 1H), 2.39 (ddd, 1H, J ) 14.6, 9.4, and 3.6 Hz),
2.80-3.05 (m, 2H), 2.94 (s, 3H), 3.17 (ddd, 1H, J ) 12.3, 7.2,
and 3.6 Hz), 3.48-3.56 (m, 1H), 3.84 (s, 3H), 4.25 (s, 1H), 6.36
(d, 1H, J ) 7.8 Hz), 6.60 (dt, 1H, J ) 7.3 and 0.5 Hz), 6.96
(dd, 1H, J ) 7.3 and 0.9 Hz), and 7.10 (dt, 1H, J ) 7.8 and 0.9
Hz); 13C NMR (CDCl3, 75 MHz) δ 9.2, 20.0, 25.2, 34.7, 38.0,
46.3, 50.4, 51.6, 52.8, 52.9, 63.3, 82.2, 91.9, 107.1, 117.6, 124.0,
129.1, 130.4, 130.6, 153.0, 167.9, and 208.5; HRMS calcd for
Rh od iu m (II)-Ca ta lyzed Rea ction of 2-Dia zo-3-[3-eth yl-
1-[2-(1-m eth yl-1H-in d ol-3-yl)a cetyl]-2-oxop ip er id in -3-yl]-
3-oxop r op ion ic Acid Meth yl Ester (12). To 500 mg (1.3
mmol) of the above keto ester in 15 mL of CH3CN was added
0.32 mL (2.3 mmol) of NEt3. The solution was allowed to stir
for 15 min at which time 0.25 mL (2.5 mmol) of mesyl azide
was added, and the reaction mixture was allowed to stir for 5
h. The reaction was quenched with H2O, the organic layer
was separated, and the aqueous layer was extracted with
ether. The combined organic extracts were washed with a
saturated NaCl solution, dried over MgSO4, and concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography to give 490 mg (90%) of 12 as a
yellow oil: IR (neat) 2135, 1717, 1685, 1651, 1616, and 1324
C
22H26N2O4 382.1892, found 382.1890.
4-Desa cetoxy-4-oxo-6,7-d ih yd r ovin d or osin e (10). To a
250 mg (0.65 mmol) sample of 29 in 10 mL of MeOH were
added 5 mg of PtO2 and one drop of concentrated HCl. The
solution was hydrogenated at rt under 40 psi of hydrogen for
2 h. The mixture was filtered through a pad of Celite, diluted
with ethyl acetate, washed with a saturated NaHCO3 solution,
and dried over MgSO4. Concentration under reduced pressure
followed by flash silica gel chromatography gave 230 mg (94%)
of 4-desacetoxy-4-oxo-6,7-dihydrovindorosine (10) as a white
solid: mp 167-168 °C; IR (neat) 1745, 1710, 1604, 1486, and
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.77 (t, 3H, J ) 7.4 Hz),
1.50-1.84 (m, 5H), 2.21 (td, 1H, J ) 12.5 and 4.7 Hz), 3.50-
3.70 (m, 1H), 3.62 (s, 3H), 3.65 (s, 3H), 4.11-4.18 (m, 1H), 4.11
(d, 1H, J ) 16.7), 4.24 (d, 1H, J ) 16.7), 6.90 (s, 1H), 6.97 (t,
1H, J ) 7.4 Hz), 7.09 (t, 1H, J ) 7.0 Hz), 7.27 (d, 1H, J ) 8.3
Hz), and 7.45 (d, 1H, J ) 7.7 Hz); 13C NMR (CDCl3, 75 MHz)
δ 9.7, 19.3, 27.9, 29.5, 32.6, 35.7, 44.4, 52.3, 59.9, 107.7, 109.1,
118.9, 119.0, 121.5, 128.0, 128.4, 136.8, 161.6, 173.7, 176.3,
and 190.5.
1
1244 cm-1; H NMR (CDCl3, 300 MHz) δ 0.43 (t, 3H, J ) 7.4
Hz), 0.98 (dt, 1H, J ) 12.7 and 5.5 Hz), 1.13-1.42 (m, 2H),
1.50-1.60 (m, 2H), 2.00 (dt, 1H, J ) 11.2 and 4.2 Hz), 2.28-
2.50 (m, 5H), 2.64 (s, 3H), 3.05-3.25 (m, 2H), 3.75 (s, 1H), 3.84
(s, 3H), 6.52 (d, 1H, J ) 7.9 Hz), 6.75-7.20 (m, 3H), and 8.74
(brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 7.2, 21.8, 26.4, 29.8,
40.2, 45.0, 50.8, 52.0, 52.4, 52.5, 53.6, 76.6, 78.9, 85.0, 111.3,
119.9, 122.6, 128.9, 134.8, 153.4, 170.2, and 204.2. Anal.
Calcd for C22H28N2O4: C, 68.71; H, 7.34; N, 7.29. Found: C,
68.52; H, 7.25; N, 7.18.
Since diazo imide 12 decomposed on standing, it was
immediately subjected to the rhodium(II)-catalyzed reaction.
To a solution of 450 mg (1.1 mmol) of 12 in 5 mL of benzene
under nitrogen was added 2 mg of rhodium(II) acetate. The
mixture was heated in an oil bath at 50 °C for 4 h and
concentrated under reduced pressure, and the residue was
subjected to flash silica gel chromatography to give 410 mg
(95%) of 3-carbomethoxy-4,10-dioxo-3,19-epoxy-1-methylaspi-
dospermadine (11) as a white solid: mp 207-208 °C; IR (KBr)
1768, 1722, 1605, 1487, and 1350 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.55-0.62 (m, 1H), 0.78 (t, 3H, J ) 7.1 Hz), 0.79-
0.91 (m, 1H), 1.50-1.98 (m, 4H), 2.68 (d, 1H, J ) 17.3 Hz),
2.91 (s, 3H), 2.97 (d, 1H, J ) 17.3 Hz), 3.09 (td, 1H, J ) 12.7
and 4.3 Hz), 3.60-3.79 (m, 1H), 3.81 (s, 3H), 4.30 (s, 1H), 6.45
(d, 1H, J ) 7.7 Hz), 6.67 (t, 1H, J ) 7.4 Hz), 6.92 (d, 1H, J )
7.4 Hz), and 7.18 (t, 1H, J ) 7.7 Hz); 13C NMR (CDCl3, 75
MHz) δ 9.0, 17.8, 19.8, 24.7, 34.8, 39.0, 45.5, 51.3, 53.1, 59.5,
80.7, 92.4, 104.5, 107.8, 118.2, 123.5, 127.3, 130.1, 153.0, 166.4,
176.7, and 205.3. Anal. Calcd for C22H24N2O5: C, 66.65; H,
6.10; N, 7.07. Found: C, 66.40; H, 6.18; N, 6.94.
3-Ca r b om et h oxy-4-a cet yl-10-oxo-3,19-ep oxy-1-m et h -
yla sp id osp er m a d in e (31). To a 250 mg (0.63 mmol) sample
of 3-carbomethoxy-4,10-dioxo-3,19-epoxy-1-methylaspidosper-
madine (11) in 4 mL of THF and 2 mL of MeOH was added
0.47 g of CeCl3‚7H2O. To this mixture was added 70 mg (1.88
mmol) of NaBH4, and the solution was allowed to stir at rt for
4 h. The reaction was diluted with ether, washed with H2O
and a saturated NaCl solution, dried over anhydrous MgSO4,
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 45 mg
(18%) of 3-(hydroxymethyl)-4-hydroxy-10-oxo-3,19-epoxy-1-
methylaspidospermadine (32) as the minor component of the
crude reaction mixture: mp 124-125 °C; IR (neat) 3324, 2950,
1604, and 1441 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.51-0.82
(m, 5H), 1.40-1.55 (m, 3H), 1.87 (d, 1H, J ) 11.7 Hz), 2.56 (d,
1H, J ) 13.8 Hz), 2.83 (s, 3H), 2.85-3.00 (m, 1H), 3.40-4.00
(m, 5H), 4.18 (s, 1H), 6.02 (d, 1H, J ) 10.2 Hz), 6.61 (d, 1H, J
) 8.0 Hz), 6.80 (t, 1H, J ) 7.4 Hz), 6.92 (d, 1H, J ) 7.4 Hz),
and 7.15 (t, 1H, J ) 8.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 9.8,
18.7, 18.8, 30.1, 38.5, 39.4, 45.0, 47.6, 60.0, 63.2, 81.1, 82.7,
106.1, 111.3, 121.4, 124.1, 129.4, 131.6, 152.5, and 176.6. Anal.
Calcd for C21H26N2O4: C, 68.09; H, 7.07; N, 7.56. Found: C,
68.18; H, 6.91; N, 7.52.
The major fraction isolated from the silica gel column
contained 160 mg (64%) of 3-carbomethoxy-4-hydroxy-10-oxo-
3,19-epoxy-1-methylaspidospermadine as a clear oil: IR (neat)
3324, 1703, 1604, 1441, and 1367 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.60-0.98 (m, 5H), 1.45-2.00 (m, 3H), 2.62 (d, 1H, J
) 16.9 Hz), 2.93 (d, 1H, J ) 16.9 Hz), 3.03 (s, 3H), 3.09 (dd,
1H, J ) 12.4 and 4.4 Hz), 3.83 (dd, 1H, J ) 12.4 and 4.4 Hz),
3.83 (dd, 1H, J ) 12.4 and 5.0 Hz), 3.89 (s, 3H), 4.10 (d, 1H,
J ) 10.4 Hz), 4.28 (s, 1H), 6.20 (d, 1H, J ) 10.4 Hz), 6.70 (d,
1H, J ) 7.8 Hz), 6.88 (t, 1H, J ) 7.3 Hz), 6.97 (d 1H, J ) 7.3
3-Ca r b om et h oxy-4-oxo-3,19-ep oxy-10-t h ioxo-1-m et h -
yla sp id osp er m a d in e. To a 250 mg (0.63 mmol) sample of
11 in 10 mL of toluene was added 260 mg (0.64 mmol) of
Lawesson’s reagent.31 The solution was heated at 110 °C
under Ar for 5 h and concentrated under reduced pressure,
and the residue was subjected to flash silica gel chromatog-
raphy to give 220 mg (85%) of 3-carbomethoxy-4-oxo-3,19-
epoxy-10-thio-1-methylaspidospermadine as a yellow solid: mp
170-171 °C; IR (neat) 1773, 1744, 1602, 1368, and 1311 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.56-0.67 (m, 1H), 0.75 (t, 3H,
J ) 6.8 Hz), 0.80-0.91 (m, 1H), 1.60-2.00 (m, 4H), 2.98 (s,
3H), 3.27 (dt, 1H, J ) 13.1 and 4.5 Hz), 3.32-3.47 (m, 2H),
3.88 (s, 3H), 4.30-4.40 (m, 1H), 4.43 (s, 1H), 6.42 (d, 1H, J )
8.0 Hz), 6.60-6.90 (m, 2H), and 7.15-7.20 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 8.9, 18.0, 19.7, 24.1, 35.9, 43.5, 51.7, 53.2,
55.6, 57.4, 62.2, 79.9, 93.3, 107.8, 118.4, 123.6, 126.8, 130.2,

Pentacyclic Skeleton of Aspidosperma Alkaloids
J . Org. Chem., Vol. 63, No. 3, 1998 565
Hz), and 7.23 (t, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 75 MHz)
δ 9.7, 18.7, 18.8, 30.2, 38.3, 39.3, 45.1, 47.3, 52.9, 60.0, 81.4,
83.5, 84.8, 107.4, 111.7, 121.6, 123.0, 129.7, 130.9, 152.5, 170.5,
and 175.9.
mixture was filtered through a pad of Celite and concentrated
under reduced pressure. The residue was dissolved in ethyl
acetate and filtered through silica gel to give 41 mg (88%) of
3-carbomethoxy-4-acetyl-3,19-epoxy-1-methylaspidosperma-
dine (33) as a yellow oil: IR (neat) 1740, 1602, and 1490, and
To a 100 mg (0.25 mmol) sample of the above alcohol was
added 2 mL of acetic anhydride, and the solution was allowed
to stir at rt for 10 min and then 0.10 g (1.3 mmol) of acetyl
chloride was added. The mixture was stirred at rt for 8 h,
extracted with ether, and washed with a saturated NaHCO3
solution. The combined ether extracts were washed with a
saturated NaCl solution, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 110 mg (98%)
of 31 as a yellow oil: IR (neat) 1745, 1730, 1604, and 1371
1
1248 cm-1; H NMR (CDCl3, 300 MHz) δ 0.46 (t, 3H, J ) 7.4
Hz), 0.65-1.11 (m, 2H), 1.50-1.90 (m, 5H), 1.90 (s, 3H), 2.18-
2.24 (m, 2H), 2.89 (s, 3H), 2.93-3.02 (m, 2H), 3.35 (dt, 1H, J
) 8.3 and 5.1 Hz), 3.84 (s, 3H), 4.20 (s, 1H), 4.88 (s, 1H), 6.30
(d, 1H, J ) 7.9 Hz), 6.57 (t, 1H, J ) 7.4 Hz), 6.96 (d, 1H, J )
7.4 Hz), and 7.10 (dt, 1H, J ) 7.9 and 1.0 Hz); 13C NMR (CDCl3,
75 MHz) δ 9.5, 19.5, 20.5, 20.7, 30.4, 34.3, 41.3, 44.5, 46.6,
50.9, 52.7, 63.0, 68.0, 81.1, 82.1, 83.4, 105.7, 116.4, 125.1, 128.5,
131.6, 152.8, 170.6, and 171.4; HRMS calcd for C24H30N2O5
426.2156, found 426.2159.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.45 (t, 3H, J ) 7.3 Hz),
0.77 (td, 1H, J ) 14.6 and 7.0 Hz), 0.93 (td, 1H, J ) 14.6 and
7.5 Hz), 1.48-1.70 (m, 3H), 1.77 (dt, 1H, J ) 13.4 and 3.0 Hz),
1.93 (s, 3H), 2.65 (d, 1H, J ) 17.3 Hz), 2.86 (d, 1H, J ) 17.3
Hz), 2.89 (s, 3H), 3.05 (dt, 1H, J ) 12.7 and 4.9 Hz), 3.80-
3.96 (m, 1H), 3.84 (s, 3H), 4.36 (s, 1H), 4.99 (s, 1H), 6.35 (d,
1H, J ) 8.0 Hz), 6.58 (t, 1H, J ) 7.3 Hz), 6.86 (d, 1H, J ) 7.3
Hz), and 7.10-7.16 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 9.3,
18.3, 19.1, 20.6, 29.6, 34.2, 39.2, 45.0, 48.0, 52.9, 59.1, 80.1,
81.4, 83.4, 106.3, 107.6, 117.1, 124.3, 128.2, 129.6, 152.6, 170.0,
170.3, and 176.2; HRMS calcd for C24H28N2O6 440.1948, found
440.1949.
6,7-Dih yd r o-4-epi-vin d or osin e (34). To a 45 mg (0.10
mmol) sample of 33 in 10 mL of MeOH was added 5 mg of
PtO2. The solution was hydrogenated at rt under 40 psi of
hydrogen for 2 h. The mixture was filtered through a pad of
Celite, diluted with ethyl acetate, washed with a saturated
NaHCO3 solution, and dried over MgSO4. Concentration
under reduced pressure followed by flash silica gel chroma-
tography gave 42 mg (92%) of 6,7-dihydro-4-epi-vindorosine
(34) as a white solid: mp 89-90 °C; IR (neat) 1737, 1602, 1487,
and 1240 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.27 (t, 3H, J )
7.4 Hz), 0.80-1.00 (m, 2H), 1.25-2.01 (m, 6H), 2.10 (s, 3H),
2.38-2.40 (m, 3H), 2.75 (s, 3H), 3.05-3.16 (m, 2H), 3.78 (s,
3H), 4.07 (s, 1H), 5.49 (s, 1H), 6.42 (d, 1H, J ) 8.0 Hz), 6.69 (t,
1H, J ) 8.0 Hz), 7.00-7.19 (m, 2H), and 10.6 (brs, 1H); 13C
NMR (CDCl3, 75 MHz) δ 8.6, 21.4, 21.5, 27.7, 33.1, 34.3, 39.9,
41.9, 51.3, 52.3, 52.9, 53.4, 72.6, 76.3, 76.5, 78.5, 106.9, 118.0,
122.9, 128.8, 134.4, 152.8, 170.6, and 171.4. Anal. Calcd for
3-C a r b o m e t h o x y -4-a c e t y l-10-t h io x o -3,19-e p o x y -1-
m eth yla sp id osp er m a d in e. To a 70 mg (0.16 mmol) sample
of 31 in 5 mL of toluene was added 75 mg (0.18 mmol) of
Lawesson’s reagent, and the reaction mixture was heated at
110 °C for 2 h. The solution was cooled and concentrated
under reduced pressure, and the residue was subjected to flash
silica gel chromatography to give 65 mg (89%) of 3-car-
bomethoxy-4-acetyl-10-thio-3,19-epoxy-1-methylaspidosperma-
dine as a white solid: mp 164-165 °C; IR (neat) 1738, 1604,
C
24H32N2O5: C, 67.25; H, 7.53; N, 6.54. Found: C, 67.13; H,
7.49; N, 6.62.
1309, and 1231 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.47 (t,
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26751) for generous
support of this work. Use of high-field NMR spectrom-
eters used in these studies was made possible through
equipment grants from the NIH and NSF.
3H, J ) 7.3 Hz), 0.76-1.86 (m, 6H), 1.94 (s, 3H), 2.90 (s, 3H),
3.17 (dt, 1H, J ) 13.3 and 5.1 Hz), 3.28 (s, 2H), 3.85 (s, 3H),
4.39 (s, 1H), 4.40 (dd, 1H, J ) 14.0 and 5.1 Hz), 5.01 (d, 1H,
J ) 1.1 Hz), 6.36 (d, 1H, J ) 8.0 Hz), 6.58 (t, 1H, J ) 7.4 Hz),
6.85 (d, 1H, J ) 7.4 Hz), and 7.11-7.16 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 9.3, 18.4, 19.1, 20.6, 28.8, 34.4, 43.8, 45.7,
53.0, 59.9, 61.7, 79.8, 81.2, 84.3, 106.4, 110.6, 117.3, 124.5,
127.7, 129.7, 152.6, 169.6, 170.2, and 207.2. Anal. Calcd for
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for new compounds lacking analyses together
with an ORTEP drawing for structures 10, 11, and 18 (7
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
C
24H28N2O5S: C, 63.14; H, 6.18; N, 6.14. Found: C, 63.05; H,
6.22; N, 6.04.
3-Ca r b om e t h oxy-4-a ce t yl-3,19-e p oxy-1-m e t h yla sp i-
d osp er m a d in e (33). To a 50 mg (0.11 mmol) sample of the
above compound in 5 mL of THF was added an excess of Raney
Ni, and the mixture was allowed to stir at rt for 2 h. The
J O971424N