A general synthetic entry to Strychnos alkaloids of the curan type via a common 3a-(2-nitrophenyl)hexahydroindol-4-one intermediate. Total syntheses of (±)- and (-)-tubifolidine, (±)-akuammicine, (±)-19,20-dihydroakuammicine, (±)-norfluorocurarine, (±)-ec

Article abstract of DOI:10.1021/ja970347a

A general strategy for the synthesis of pentacyclic Strychnos alkaloids with the curan skeleton has been developed. It utilizes 3a-(2-nitrophenyl)hexahydroindol-4-one (23), which was prepared from 2-allyl-2-(2-nitrophenyl)-1,3-cyclohexanedione (15), as th

Full text of DOI:10.1021/ja970347a

7230
J. Am. Chem. Soc. 1997, 119, 7230-7240
A General Synthetic Entry to Strychnos Alkaloids of the Curan
Type via a Common 3a-(2-Nitrophenyl)hexahydroindol-4-one
Intermediate. Total Syntheses of (()- and (-)-Tubifolidine,
(()-Akuammicine, (()-19,20-Dihydroakuammicine,
(()-Norfluorocurarine, (()-Echitamidine, and
(()-20-Epilochneridine1
Josep Bonjoch,* Daniel Sole´, Silvina Garc´ıa-Rubio, and Joan Bosch*
Contribution from the Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of
Barcelona, 08028 Barcelona, Spain
ReceiVed February 3, 1997X
Abstract: A general strategy for the synthesis of pentacyclic Strychnos alkaloids with the curan skeleton has been
developed. It utilizes 3a-(2-nitrophenyl)hexahydroindol-4-one (23), which was prepared from 2-allyl-2-(2-nitrophenyl)-
1,3-cyclohexanedione (15), as the common, pivotal intermediate. Three different procedures have been employed
for the closure of the bridged piperidine D ring from 23: (i) an intramolecular Michael-type conjugate addition; (ii)
a Ni(COD)2-promoted biscyclization that assembles B and D rings in a single synthetic step, and (iii) an intramolecular
cyclization of an enone-propargylic silane system. When necessary, depending on the procedure used, introduction
of the oxidized one-carbon substituent at C-16, closure of the indole ring, and/or adjustment of the functionality of
the C-20 two-carbon chain constitute the last stages of the synthetic route to the title alkaloids. The procedure
involving the cyclization of a propargylic silane has been successfully extended to the enantiospecific synthesis of
(-)-tubifolidine starting from the enantiopure 3a-(2-nitrophenyl)hexahydroindolone (-)-51, which was prepared taking
advantage of the prochiral character of cyclohexanedione 15.
Introduction
oxidized one-carbon substituent (C-17) at C-16 (hydroxymethyl,
formyl, or methoxycarbonyl).
The Strychnos alkaloids constitute an important group of
architecturally complex and widely distributed monoterpenoid
indole alkaloids.2 According to their biogenesis,3 they can be
arranged in two classes, Strychnan and Aspidospermatan, with
a topographical relationship. The majority of Strychnan alka-
loids belong to the curan type,5 which are structurally character-
ized by the presence of a pentacyclic 3,5-ethanopyrrolo[2,3-
d]carbazole framework (see Chart 1) bearing a two-carbon
appendage at C-20 (alkyl, alkylidene or oxygenated) and an
In the last decade, the Strychnan alkaloids have been the
subject of intensive synthetic investigation. Much of this
continuing interest has been focused on the synthesis of the
heptacyclic alkaloid strychnine,6-8 while the pentacyclic curan
alkaloids have received less attention. The synthetic efforts
made in this field, using the strategies outlined in Scheme 1,
have culminated in the total syntheses of the curan alkaloids
depicted in Chart 1 (which includes the alkaloids whose
synthesis is reported in this paper). The several different
strategies can be classified into those that form the crucial
quaternary center at C-7 in the last synthetic steps9-12 and those
in which the strategic bonds around C-7 are preformed at the
initial stages of the synthesis.13-14
X Abstract published in AdVance ACS Abstracts, July 1, 1997.
(1) For preliminary accounts of parts of this work, see: (a) Bonjoch, J.;
Sole´, D.; Bosch, J. J. Am. Chem. Soc. 1993, 115, 2064-2065. (b) Sole´, D.;
Bonjoch, J.; Bosch, J. J. Am. Chem. Soc. 1995, 117, 11017-11018. (c)
Sole´, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1996, 61, 4194-4195. (d)
Sole´, D.; Bonjoch, J.; Garc´ıa-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron
Lett. 1996, 37, 5213-5216.
(2) Reviews: (a) Sapi, J.; Massiot, G. In Monoterpenoid Indole Alkaloids;
Saxton, J. E., Ed. In The Chemistry of Heterocyclic Compounds; Taylor,
E. C., Ed.; Wiley: New York, 1994; Supplement to Vol. 25, Part 4, pp
279-355. (b) Bosch, J.; Bonjoch, J.; Amat, M. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1996; Vol. 48, pp 75-189.
(3) For a general classification of indole alkaloids, see: Kisaku¨rek, M.
V.; Leeuwenberg, A. J. M.; Hesse, M. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1983;
Vol. 1, pp 211-376. The Strychnan class includes the alkaloids in which
the unrearranged monoterpenoid unit is attached to the indole nucleus by
C-2/C-16 and C-7/C-3 bonds.4
(4) The numbering system and ring labeling (ABCDE) based on the
biogenetic interrelationship of indole alkaloids is used throughout this
paper: Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508-510.
(5) The curan alkaloids include the pentacyclic alkaloids of the akuam-
micine-group as well as the hexacyclic alkaloids of the diaboline and
spermostrychnine groups, in which there is an additional oxygenated ring
linking C-17 with the two-carbon chain at C-20. More than 125 alkaloids
with the curan skeleton have been isolated so far (nearly half of all the
Strychnos alkaloids).
Synthetic Plan. In this paper, we describe a new, general
and flexible synthetic entry to the Strychnos alkaloids with the
curan skeleton via 3a-(2-nitrophenyl)hexahydroindol-4-ones and
(6) Since the classical pioneering work by Woodward,7a five different
syntheses of strychnine have been completed, all of them in recent years,
either via isostrychnine7 or via Wieland-Gumlich aldehyde.8
(7) (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.;
Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749-4751.
Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.;
Schenker, K. Tetrahedron 1963, 19, 247-288. (b) Kuehne, M. E.; Xu, F.
J. Org. Chem. 1993, 58, 7490-7497. (c) Rawal, V. H.; Iwasa, S.; Michoud,
C. J. Org. Chem. 1994, 59, 2685-2686.
(8) (a) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.;
Merritt, A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403-4405. Magnus,
P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt,
A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116-8129. (b)
Stork, G. Reported at the Ischia Advanced School of Organic Chemistry,
Ischia Porto, Italy, September 21, 1992. (c) Knight, S. D.; Overman, L. E.;
Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293-9294. Knight, S. D.;
Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776-5788.
S0002-7863(97)00347-8 CCC: $14.00 © 1997 American Chemical Society

Synthetic Entry to Strychnos Alkaloids of the Curan Type
J. Am. Chem. Soc., Vol. 119, No. 31, 1997 7231
Scheme 1. Synthetic Strategies for the Synthesis of Curan
Chart 1. Structures of Curan Alkaloids Prepared by Total
Synthesis
Alkaloidsa
Scheme 2. Synthetic Strategy
a The numbers in boldface indicate the alkaloids (see Chart 1)
synthesized following each particular strategy.
report the total syntheses of (()- and (-)-tubifolidine (1), (()-
19,20-dihydroakuammicine (4), (()-norfluorocurarine (5), (()-
akuammicine (7), (()-echitamidine (9), and (()-20-epilochne-
ridine (10).
In planning our approach to curan alkaloids our aim was to
develop a unified strategy for the synthesis of these compounds.
As the main differences among the curan alkaloids are in the
nature of the appendages at C-16 and C-20, we adopted a
strategy in which these substituents are incorporated at advanced
stages of the synthesis from a common intermediate. The
cornerstone of our synthetic plan is the use of a non-indolic
starting material, such as 23, in which the crucial quaternary
center has already been formed, the A, C, and E rings of
Strychnos alkaloids have been incorporated, and the B ring is
present in a latent form (Scheme 2). The approach involves a
series of stepwise annelations from 1,3-cyclohexanedione, which
preforms the core carbocyclic E ring of the target alkaloids.
Once the nitrophenyl group (A ring) has been incorporated and
(9) (a) Dadson, B. A.; Harley-Mason, J.; Foster, G. H. J. Chem. Soc.,
Chem. Commun. 1968, 1233. (b) Dadson, B. A.; Harley-Mason, J. J. Chem.
Soc., Chem. Commun. 1970, 665. (c) Harley-Mason, J.; Taylor, C. G. J.
Chem. Soc., Chem. Commun. 1970, 812. (d) Crawley, G. C.; Harley-Mason,
J. J. Chem. Soc., Chem. Commun. 1971, 685-686. (e) Ban, Y.; Yoshida,
K.; Goto, J.; Oishi, T.; Takeda, E. Tetrahedron 1983, 39, 3657-3668. (f)
Amat, M.; Coll, M.-D.; Passarella, D.; Bosch, J. Tetrahedron: Asymmetry
1996, 7, 2775-2778. See also ref 8a.
the quaternary C-7 center has been formed, the crucial steps of
the synthesis are as follows: (i) the closure of the pyrrolidine
C ring from the symmetric 1,3-cyclohexanedione 15 through a
one-pot procedure that involves the ozonolysis of the allyl group
and a double (inter- and intramolecular) reductive amination;15
(ii) the closure of the piperidine D ring by formation of C-15/
C-20 bond from an appropriately substituted 3a-arylhexahy-
droindol-4-one (in Scheme 2, R and R′ represent, respectively,
the requisite cyclization promoter and the two-carbon C-20
substituent); and (iii) the formation of the indoline ring in the
last synthetic steps by reductive cyclization of the R-(2-
nitrophenyl) ketone moiety. In addition, the introduction of the
C-17 one-carbon appendage characteristic of curan alkaloids
can be achieved prior to the closure of B ring, taking advantage
of the activation exerted by the C-2 carbonyl group at C-16.
The versatility of our strategy lies in the fact that closure of D
ring can be brought about by different methodologies, leading
to azatricyclic compounds bearing different piperidine substit-
(10) Amat, A.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55, 6299-
6312.
(11) (a) Kuehne, M. E.; Frasier, D. A.; Spitzer, T, D. J. Org. Chem.
1991, 56, 2696-2700. (b) Kuehne, M. E.; Brook, C. S.; Frasier, D. A.;
Xu, F. J. Org. Chem. 1994, 59, 5977-5982.
(12) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem.
Soc. 1996, 118, 9804-9805.
(13) (a) Formation of C-20/C-21 bond: Kuehne, M. E.; Xu, F.; Brook,
C. S. J. Org. Chem. 1994, 59, 7803-7806. (b) Formation of C-15/C-20
bond: Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61,
7873-7881. See also ref 8b.
(14) (a) Closure of the indole ring either from protected anilines14b or
from nitro derivatives as reported in this work.1 (b) Angle, S. R.; Fevig, J.
M.; Knight, S. D.; Marquis, R. W., Jr.; Overman, L. E. J. Am. Chem. Soc.
1993, 115, 3966-3977. See also ref 8c.

7232 J. Am. Chem. Soc., Vol. 119, No. 31, 1997
Bonjoch et al.
Scheme 5. Closure of the Piperidine Ring by Michael
Scheme 3. Preparation of the Key
3a-(2-Nitrophenyl)hexahydroindol-4-one
Cyclization
Scheme 4. Conversion of trans-16 to cis-16
ether 20a, which, upon palladium diacetate-mediated dehy-
drosilylation,18 gave rise to the R,â-unsaturated ketone 22a.
However, attempts to remove the carbamate group led to
complex unidentifiable mixtures. So, we then decided to use
the carbamate 19b, bearing a more easily removable protecting
group.19 In this series, as direct oxidation of silyl enol ether
20b failed, the generation of the double bond was achieved
through the phenylseleno derivative 21. Oxidation of 21 gave
the corresponding selenoxide, which underwent a â-elimination
to give enone 22b in 50% overall yield from cis-16. Finally,
deprotection (MeOH, reflux) of the pyrrolidine nitrogen satis-
factorily gave the secondary amine 23.
The Intramolecular Michael Reaction Approach to Curan
Alkaloids. Synthesis of (()-Tubifolidine and (()-Echit-
amidine. The first methodology we explored for the closure
of the piperidine ring took advantage of an intramolecular
Michael addition.20 Conjugate addition of the secondary amine
23 to methyl vinyl ketone provided the alkylated hexahydroin-
dolone 24 in 74% yield (Scheme 5). Initially, the base-catalyzed
cyclization of 24 was effected by treatment with benzyltri-
methylammonium hydroxide (Triton B) to give a 1:3 mixture
of epimeric ketones 25 and 26 in 58% yield. This yield was
improved using R-methylbenzylamine21 as the cyclization
promoter: hydrolysis of the initially formed imine afforded the
azatricyclic derivatives 25 and 26, with the same stereoselec-
tivity as above, in 67% overall yield. The minor epimer 2522
was converted to 26 by treatment with KF-EtOH.
uents, which can be further elaborated into the variety of two-
carbon substituents present at C-20 in Strychnos alkaloids.
It is noteworthy that the above synthetic strategy is also
applicable to the enantiospecific synthesis of curan alkaloids,
because the key building block 23 can be prepared in both
enantiopure forms starting from the prochiral dione 15.
Results and Discussion
Synthesis of the Key Intermediate 23. The synthesis of
the key intermediate 23 starts from the multigram available
octahydroindolone 16, which was prepared in 62% yield from
dione 15 as a 1.5:1 mixture of cis and trans isomers (Scheme
3).15 Conversion of trans-16 to the cis isomer, which possesses
the required C/E ring junction, was accomplished in 87% yield
by the three-step sequence depicted in Scheme 4: oxidation of
trans-16 with m-CPBA afforded N-oxide 17, which, on treat-
ment with TFAA16 followed by reduction of the resulting
iminium salt 18 with tri-2-ethylhexanoyloxyborohydride,17 ste-
reoselectively gave cis-16. This efficient transformation of
trans-16 to cis-16 allows the cis-3a-(2-nitrophenyl)octahydroin-
dol-4-one system to be assembled in 24% overall yield from
1,3-cyclohexanedione.
Conversion of 26 into tubifolidine (1) required the reductive
cyclization of the R-(2-nitrophenyl) ketone moiety and the
reduction of the acetyl group. For this purpose, tricyclic
For the closure of the piperidine ring it was necessary to
activate the octahydroindole 6-position (C-15 biogenetic). This
was accomplished by generating an enone moiety. Initially,
ketone cis-16 was converted via carbamate 19a to silyl enol
(18) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-1013.
(19) Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T.
J. Org. Chem. 1984, 49, 2081-2082.
(20) Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J.
I. Org. React. 1995, 47, 315-552.
(15) Sole´, D.; Bosch, J.; Bonjoch, J. Tetrahedron 1996, 52, 4013-4028.
(16) Grierson, D. Org. React. 1990, 39, 85-295.
(17) Before the recent report about this reagent (McGill, J. M.; LaBell,
E. S.; Williams, M. Tetrahedron Lett. 1996, 37, 3977-3980) we had used
NaBH3CN, although with a lower stereoselectivity (2:1 cis/trans ratio).
(21) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J. J. Am. Chem. Soc.
1985, 107, 173-179.
(22) This epimer could give access to the alstogustine alkaloid series,
although this possibility was not explored.

Synthetic Entry to Strychnos Alkaloids of the Curan Type
J. Am. Chem. Soc., Vol. 119, No. 31, 1997 7233
Scheme 6. Ni(COD)2-Promoted Double Cyclization
diketone 26 was chemoselectively converted into dithioacetal
27. Reduction of 27 with Bu3SnH in the presence of catalytic
amounts of AIBN directly afforded (()-tubifolidine (1)23 in 50%
yield, in a one-pot process involving desulfurization24 and
simultaneous closure of the indoline ring by reductive cyclization
of the γ-nitro ketone unit.25
Next, we focused our attention on the alkaloid echitamidine
(9). Methoxycarbonylation of azatricyclic ketone 27 rendered
â-keto ester 28. This reaction was troublesome, and the best
results were obtained when the lithium enolate was generated
at -78 °C in the presence of HMPA, and methyl cyanoformate
was added to the mixture at room temperature. In this way,
â-keto ester 28 was obtained in 50% yield, with recovering of
the unreacted starting material.26 Deprotection of the dithio-
acetal group of 28 with red HgO afforded ketone 29 in 85%
yield. For the B ring closure, the best results were obtained
when hydrogenation was done from the hydrochloride27 derived
from 29 using Pd-C as the catalyst: the pentacyclic compound
30 was obtained in 80% yield. Finally, NaBH4 reduction of
the acetyl side chain of 30 stereoselectively afforded (()-
echitamidine (9) in 75% yield.28
Synthesis of (()-Akuammicine and (()-Norfluorocurarine
by Nickel(0)-Promoted Double Cyclization. Although the
pentacyclic derivative 30 contains all the carbon atoms and the
functionality necessary to undertake the synthesis of curan
alkaloids bearing a C-20 ethylidene chain, we decided to explore
an alternative procedure for the closure of the piperidine ring
with simultaneous introduction of the aforementioned substitu-
ent. We focused our attention on the intramolecular nickel(0)-
promoted cyclizations of vinyl halides with alkenes.29 It was
our original hope that this methodology might allow for both
the closure of the ethylidene-bearing piperidine ring and the
introduction of the one-carbon substituent present at C-16.
The required N-substituted 3a-arylhexahydroindol-4-one 31
was prepared by alkylation of 25 with (Z)-1-bromo-2-iodo-2-
butene30 (Scheme 6). Initial attempts to promote the tandem
cyclization-capture process from 31 under the usual conditions
(Ni(COD)2, 2 equiv, then TMSCN) failed, affording complex
unidentifiable mixtures. Initially, we attributed the failure of
the reaction to the lack of a suitable stabilization of the transient
σ-alkylnickel intermediate presumably formed in the process.
Consequently, we decided to trap this intermediate while it was
being generated. To our surprise, when 31 was treated with
Ni(COD)2 (6.6 equiv) in the presence of LiCN, 19,20-dehy-
drotubifoline (32)31 was obtained in 40% yield. This one-pot
transformation involves the Ni(0)-promoted cyclization of the
vinyl iodide upon the carbon-carbon double bond32 and the
controlled reductive cyclization of the R-(2-nitrophenyl) ketone
moiety to the imine functionality.
With dehydrotubifoline (32) in hand, the synthesis of curan
alkaloids simply required the introduction of the one-carbon
substituent at C-16. For this purpose we took advantage of the
known photochemical rearrangement of N-(methoxycarbonyl)-
enamines to vinylogous carbamates.33 Thus, treatment of 32
with methyl chloroformate in the presence of NaH gave (36%)
the N-methoxycarbonyl enamine 33, which was then photo-
isomerized (30%) to (()-akuammicine (pseudoakuammicine).34
A more straightforward method for the introduction of the
oxidized C-17 atom was the treatment of vinyl iodide 31 with
Ni(COD)2/LiCN, followed by trapping of the resulting inter-
mediate with (chloromethylene)dimethyliminium chloride in a
one-pot reaction. Under these conditions, the pentacyclic
N-formyl enamine 34 was directly obtained from 31 in 15%
yield. Probably, formylation occurs from a metalloenamine
intermediate because dehydrotubifoline (32) was recovered
unchanged after treatment with the above formylating agent
(DMF, 80 °C, 15 h).35 Photoisomerization36 of 34 gave (()-
norfluorocurarine (vinervidine)37 in 15% yield, the major product
(69%) formed in this process being the deformylated indolenine
32.
(23) (a) Isolation and structural elucidation: Kump, W. G.; Patel, M.
B.; Rowson, J. M.; Schmid, H. HelV. Chim. Acta 1964, 47, 1497-1503.
(b) NMR data: ref 10. (c) Previous syntheses: refs 9a,e and 10.
(24) Gutierrez, C. G.; Stringham, R. A.; Nitasaka, T.; Glasscock, K. G.
J. Org. Chem. 1980, 45, 3393-3395.
(25) We do not know examples of the generation of indolines by
reduction of R-(2-nitrophenyl) ketones with Bu3SnH. For the use of
2-nitrophenyl derivatives as precursors of the indoline nucleus in alkaloid
synthesis, see inter alia: Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K.
Chem. Pharm. Bull. 1982, 30, 2641-2643. Heathcock, C. H.; Norman, M.
H.; Dickman, D. A.; J. Org. Chem. 1990, 55, 798-811. Mittendorf, J.;
Hiemstra, H.; Speckamp, W. N. Tetrahedron 1990, 46, 4049-4062.
(26) This result contrasts with those reported by Overman14b for the
methoxycarbonylation of azatricyclic derivatives that differ from 27 in the
substituent on the aromatic ring and makes evident that the nitro group is
the cause of the different behavior. For an unusual reaction of nitro ketone
27 under basic conditions, see: Sole´, D.; Pare´s, A.; Bonjoch, J. Tetrahedron
1994, 50, 9769-9774.
(27) Catalytic hydrogenation of 29 under either basic (Li2CO3) or neutral
conditions afforded appreciable amounts of the corresponding carbinolamine.
(28) (a) Isolation and structural elucidation: Goodson, J. A. J. Chem.
Soc. 1932, 2626. Djerassi, C.; Nakagawa, Y.; Budzikiewicz, H.; Wilson, J.
M.; LeMen, J.; Poisson, J.; Janot. M.-M. Tetrahedron Lett. 1962, 653-
659. Ze`ches, M.; Ravao, T.; Richard, B.; Massiot, G.; LeMen-Olivier, L.;
Guilhem, J.; Pascard, C.; Tetrahedron Lett. 1984, 25, 659-662. (b) NMR
data: Keawpradub, N.; Takayama, H.; Aimi, N.; Sakai, S. Phytochemistry
1994, 37, 1745-1749. (c) Since our preliminary communication,1a a second
synthesis of (()-echitamidine has been reported.11b
When the above one-pot treatment [Ni(COD)2/LiCN/Me2-
N+dCHCl Cl-] was applied to the (E)-vinyl iodide 35 (Scheme
(31) Previous syntheses: (a) Takano, S.; Hirama, M.; Ogasawara, K.
Tetrahedron Lett. 1982, 23, 881-884. (b) Hugel, G.; Le´vy, J. Tetrahedron
Lett. 1993, 34, 633-634. See also refs 9d, 14b, and 30.
(32) Formation of 32 requires the protolysis of the transient alkylnickel
intermediate generated in the Ni(COD)2-promoted cyclization. For a related
example where an alkylnickel intermediate generated in such a process is
protonated during the workup, see: Mori, M.; Ban, Y. Tetrahedron Lett.
1976, 1807-1810.
(33) For the use of this photoisomerization in the synthesis of Strychnos
alkaloids, see: Gra`cia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org.
Chem. 1994, 59, 3939-3951. See also ref 10.
(34) (a) Isolation of (()-akuammicine (ψ-akuammicine): Edwards, P.
N.; Smith, G. F. Proc. Chem. Soc. (London) 1960, 215. (b) Isolation and
structural elucidation of (-)-akuammicine: Aghoramurthy, K.; Robinson,
R. Tetrahedron 1957, 1, 172-173. Edwards, P. N.; Smith, G. F. J. Chem.
Soc. 1961, 152-156 (c) NMR data: Hu, W.-L.; Zhu, J.-P.; Hesse, M. Planta
Med. 1989, 55, 463-466. See also refs 13a. (d) Synthesis: ref 12, 13a, and
14b.
(29) (a) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J. M.; Delgado, A.
J. Am. Chem. Soc. 1994, 116, 12133-12134. (b) Sole´, D.; Cancho, Y.;
Llebaria, A.; Moreto´, J. M.; Delgado, A. J. Org. Chem. 1996, 61, 5895-
5904.
(30) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030-3031.
(35) Formylation (POCl3, DMF, 50-60 °C) of dehydrotubifoline 32 to
the N-formyl derivative 34 has been previously reported (no yield
indicated): see ref 14b.
(36) Lenz, G. R. Synthesis 1978, 489-518.

7234 J. Am. Chem. Soc., Vol. 119, No. 31, 1997
Bonjoch et al.
Scheme 7
Scheme 10
Scheme 8
50% yield. This result seems to indicate that reduction of the
nitro group occurs prior to the nickel-induced C-C bond
formation.42
The controlled reductive cyclization of R-(2-nitrophenyl)
ketones using Ni(COD)2 is unprecedented and seems to be quite
general. It can be exploited to assemble the partially reduced
pyrrolo[2,3-d]carbazole unit, which is present in several groups
of indole alkaloids.43 Thus, treatment of octahydroindol-4-one
19a with Ni(COD)2 under the above conditions led either to
nitrone 41 (50% yield) or indolenine 42 (51% yield) depending
on the absence or presence of LiCN/DMF in the reaction
mixture.
Other methodologies were explored for the closure of the
piperidine ring from vinyl iodide 31 (Scheme 10). The use of
Ni(CO)4 to produce the tandem cyclization-carbonylation
process failed. Thus, treatment of vinyl iodide 31 under the
usual conditions44 afforded the uncyclized-carbonylated com-
pound 43 (27%). In this context, the Heck reaction45 was also
studied under a variety of conditions (catalytic or stoichiometric
on palladium). Cyclization was only observed on treatment of
vinyl iodide 31 with Pd(PPh3)4 (0.2 equiv) in the presence of
LiCN:46 the azatricyclic compound 44 was isolated in 26% yield,
the starting material being recovered in part.47 Although this
reaction was not improved, it could also receive further
application for the synthesis of curan alkaloids. On the other
hand, treatment of 31 with Bu3SnH and AIBN led to the D-nor
derivative 45 (45%) instead of the desired bridged azatricycle
44.48
Scheme 9
7), the pentacyclic N-formyl enamine 36 was isolated in 20%
yield. The constitution and relative configuration of 36 was
unambiguously established from its 1H and 13C NMR data, with
the aid of 2D-NMR experiments and ROESY. These data are
clearly different from those reported for bharhingine, an alkaloid
isolated from Rhazya stricta38 for which the structure 36 had
been proposed. Therefore, the structure of this natural product
awaits further investigation.
Interestingly, the outcome of the Ni(0)-promoted double
cyclization from vinyl iodide 31 was slightly different when
the process was carried out [6.6 equiv of Ni(COD)2] in the
absence of LiCN/DMF. Under these conditions nitrone 38 was
obtained in a single step in 40% yield. A further treatment of
nitrone 38 with Ni(COD)2, now in the presence of LiCN,
afforded the pentacyclic indoline 39 (19,20-didehydrotubifoli-
dine)39 in 40% yield. The different course of the reduction when
lithium cyanide is present in the medium could be attributed to
a decrease in the redox potential of the original Ni(0) com-
plex.40,41
(40) Cyanide species such as K4Ni(CN)4 and K2[Ni(CN)2(CO)2] have
been well-characterized: del Rosario, R.; Sthul, L. S. Organometallics 1986,
5, 1260-1262. del Rosario, R.; Sthul, L. S. J. Am. Chem. Soc. 1984, 106,
1160-1161. Moreover, cyanonickelate(0) species have been postulated as
intermediates in some reductions with cyanonickel complexes: Bingham,
D.; Burnett, M. G. J. Chem. Soc. (A) 1971, 1782.
(41) As a consequence of the great stability of the complex [Ni(CN)4]2-
the redox potential of Ni decreases in the presence of cyanide ions.
,
(42) The isolation of indolenine 40 when using decreasing amounts of
Ni(COD)2 in the presence of LiCN/DMF is in agreement with this
interpretation.
(43) Octahydropyrrolo[2,3-d]carbazoles are valuable intermediates in the
synthesis of Aspidosperma and ibophyllidine alkaloids: (a) Benchekroun-
Mounir, N.; Dugat, D.; Gramain, J.-C.; Husson, H.-P. J. Org. Chem. 1993,
58, 6457-6465. (b) Kuehne, M. E.; Pitner, J. B. J. Org. Chem. 1989, 54,
4553-4569.
On the other hand, when the amount of Ni(COD)2 was
reduced to 2.5 equiv, the tetracyclic nitrone 37 was obtained in
(44) Delgado, A.; Llebaria, A.; Camps, F.; Moreto´, J. M. Tetrahedron
Lett. 1994, 35, 4011-4014.
(45) Heck, R. F. Vinyl Substitution with Organopalladium Intermediates.
In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
New York, 1991; Vol. 4, pp 833-863.
(37) (a) Isolation of (()-norfluorocurarine: Rakhimov, D. A.; Malikov,
V. M.; Yusunov, C. Y. Khim. Prir. Soedin 1969, 5, 461-462; Chem. Abstr.
1970, 72, 67165n. (b) Isolation and structural elucidation of (-)-norfluo-
rocurarine: Stauffacher, D. HelV. Chim. Acta 1961, 44, 2006-2015. (c)
NMR data: Clivio, P.; Richard, B.; Deverre, J.-R.; Sevenet, T.; Zeches,
M.; Le Men-Oliver, L. Phytochemistry 1991, 30, 3785-3792. (d) For the
only previous synthesis of racemic norfluorocurarine, see ref 9d.
(38) Atta-ur-Rahman; Habib-ur-Rehman; Ahmad, Y.; Fatima, K.; Badar,
Y. Planta Med. 1987, 53, 256-259.
(46) Grigg, R.; Santhakumar, S.; Sridharan, V. Tetrahedron Lett. 1993,
34, 3163-3164.
(47) Formation of 44 requires the protolysis of the transient alkylpalla-
dium intermediate: Benhaddou, R.; Czernecki, S.; Ville, G. J. Org. Chem.
1992, 57, 4612-4616.
(48) The pyrrolidine ring is formed by a 1,5-hydrogen shift from the
initially formed vinylic radical, followed by a 5-exo-trig cyclization of the
resulting allylic radical: Lathbury, D. C.; Parsons, P. J.; Pinto, I. J. Chem.
Soc., Chem. Commun. 1988, 81-82.
(39) For a previous synthesis, see: Smith, G. F.; Wro´bel, J. T. J. Chem.
Soc. 1960, 792-795.

Synthetic Entry to Strychnos Alkaloids of the Curan Type
J. Am. Chem. Soc., Vol. 119, No. 31, 1997 7235
Synthesis of (()-19,20-Dihydroakuammicine and (()-20-
Epilochneridine via Intramolecular Cyclization of an Enone-
Propargylic Silane System. The third approach we have
explored for the formation of the crucial C15-C20 bond of curan
alkaloids from the key intermediate 23 is based on the
intramolecular conjugate addition of a propargylic silane to an
R,â-unsaturated ketone moiety49 (Scheme 11). Alkylation of
23 with 1-iodo-4-(trimethylsilyl)-2-butyne50,51 led to the pro-
pargylic silane 46, which, upon treatment with BF3‚Et2O,
underwent a smooth cyclization to give the bridged azatricyclic
compound 47 in 55% overall yield. The ketone 47 bears a
vinylidene side chain that can be further elaborated into the
variety of two-carbon substituents present at C-20 in the
Strychnos family.52
Scheme 11. Closure of the Piperidine Ring by Cyclization
of a Propargylic Silane
Catalytic hydrogenation of a methanolic solution of 47 using
Pd on charcoal as the catalyst in the presence of Na2CO3 brought
about both the reductive cyclization of the R-(2-nitrophenyl)
ketone unit and the hydrogenation of the vinylidene side chain,
which took place stereoselectively from the less hindered R-face
of the ethylidene intermediate, to give (()-tubifolidine1d,23 in
60% yield.53
The introduction of the oxidized one-carbon substituent at
the R-position of the carbonyl group in 47 entailed the same
problems as the methoxycarbonylation of the above related
azatricyclic ketone 27. Thus, treatment of 47 with LDA and
then with methyl cyanoformate gave â-ketoester 48 in 39%
yield. Palladium-catalyzed hydrogenation of 48 in the presence
of Na2CO3 afforded (()-19,20-dihydroakuammicine54 in 57%
yield. Interestingly, when the above hydrogenation was carried
out from 48‚hydrochloride at 100 psi for a short time, the
alkaloid (()-akuammicine (pseudoakuammicine)1d,34 was iso-
lated as the main product in 38% yield. The stereoselectivity
of the process is worth noting because only the natural (E)-
ethylidene isomer was isolated. The survival of the ethylidene
double bond under these reaction conditions can be accounted
for by the conjunction of several factors: (i) in the Pd-catalyzed
hydrogenation of terminal allenes, after the initial regioselective
reduction of the less substituted double bond, the resulting alkene
reacts slower,55 (ii) the protonation of the piperidine nitrogen
introduces an axial interaction on the less hindered R-face that
slows down the hydrogenation upon the remaining C-19/C-20
double bond, and (iii) under acidic conditions and a slight
pressure, the rate of the reductive cyclization (closure of B ring)
increases, thus allowing the reaction to be stopped after a shorter
reaction time.
yield. All attempts to chemoselectively oxidize the allylstannane
moiety after protection of the nitrogen atom as a BF3 adduct51
failed, and only traces of the desired allylic alcohol were
obtained. The problem was circumvented by treating stannane
49 with an excess of m-CPBA58 in the presence of an
equimolecular amount of TFA. The allylic alcohol 50, in which
the piperidine nitrogen is in the N-oxide oxidation level, was
stereoselectively formed in 76% yield. Catalytic hydrogenation
of 50 with Pd on charcoal in the presence of Na2CO3
simultaneously accomplished the reduction of the vinyl double
bond and the N-oxide functionality and the reductive cyclization
of the R-(2-nitrophenyl) ketone moiety to give (()-20-epiloch-
neridine59 in 48% yield.
Synthesis of (-)-Tubifolidine (1). Apart from the enantio-
selective syntheses of (-)-Wieland-Gumlich aldehyde8c and
tubifoline,9f the asymmetric synthesis of curan alkaloids has been
little explored and remains a challenge for synthetic organic
chemists.60
Following the schemes previously developed in the above
total syntheses in the racemic series, the enantioselective
synthesis of curan alkaloids simply requires the preparation of
appropriate enantiopure cis-3a-(2-nitrophenyl)octahydroindol-
Our next goal was the synthesis of the alkaloid 20-epiloch-
neridine. Palladium-catalyzed hydrostannation56,57 of allene 48
afforded regio- and stereoselectively allylstannane 49 in 68%
(49) Langkopf, E.; Schinzer, D. Chem. ReV. 1995, 95, 1375-1408.
(50) Klaver, W. J.; Moolenaar, M. J.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1988, 44, 3805-3818.
(51) Sole´, D.; Garc´ıa-Rubio, S.; Bosch, J.; Bonjoch, J. Heterocycles 1996,
43, 2415-2424.
(52) For model studies from 3-vinylidenepiperidines, see ref 51. Although
allenes have received extensive application in the synthesis of natural
products, they have mainly been used as precursors of carbonyl groups: (a)
Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Recl. TraV. Chim. Pays-Bas
1986, 105, 299-306. (b) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J.
Am. Chem. Soc. 1989, 111, 2588-2595.
(53) The use of PtO2 as the catalyst was less efficient from the synthetic
standpoint, and the best result (48% yield of isolated tubifolidine) was
obtained operating from 47‚hydrochloride using ethyl acetate as the solvent.
The complete reduction (PtO2) of the R-(2-nitrophenyl) ketone moiety of
47 was slower in ethanolic solution and, under these conditions, after longer
reaction times (≈40 h) Na-ethyltubifolidine was isolated as the major product
(20%).
(56) Mitchell. T. N.; Schneider, U. J. Organomet. Chem. 1991, 405, 195-
199.
(57) Hydroboration of allene 47 with 9-borabicyclo[3.3.1]nonane (Brown,
H. C.; Liotta, R.; Kramer, G. W. J. Am. Chem. Soc. 1979, 101, 2966-
2979) did not give satisfactory results because the initially formed
allylborane reacted with the ketone group.
(58) Ueno, Y.; Sano, H.; Okawara, M. Synthesis 1980, 1011-1013.
(59) (a) Isolation and structural elucidation: Lathuillie`re, P.; Olivier, L.;
Le´vy, J.; Le Men, J. Ann. Pharm. Fr. 1966, 24, 547-549. (b) 13C NMR
data and hemisynthesis from akuammicine: Mirand, C.; Masiot, G.; Le
Men-Olivier, L.; Le´vy, J. Tetrahedron Lett. 1982, 23, 1257-1258.
(60) For a recent synthesis of (-)-tubifolidine and (-)-19,20-dihy-
droakuammicine following the methodology reported in ref 9f, see: Amat,
M.; Coll, M.-D.; Bosch, J.; Espinosa, E.; Molins, E. Tetrahedron:
Asymmetry 1997, 8, 935-948.
(54) (a) Isolation and structural elucidation: ref 23a. (b) NMR data and
previous synthesis: ref 10. See also ref 11a.
(55) Schuster, H. E.; Coppola, G. M. Allenes in Organic Synthesis;
Wiley: New York, 1984; Chapter 3.

7236 J. Am. Chem. Soc., Vol. 119, No. 31, 1997
Bonjoch et al.
pentacyclic ABCDE ring system of Strychnos alkaloids. After
generation of an enone functionality, closure of the bridged
piperidine D ring (bond formed C15-C20) has been ac-
complished either by intramolecular Michael addition or by
nickel(0)-promoted cyclization of a vinyl halide or by intramo-
lecular addition of a propargylic silane to an enone. Subsequent
or concomitant reductive cyclization of the R-(2-nitrophenyl)
ketone moiety completes the pentacyclic Strychnos system. The
procedures reported here provide new solutions for the formation
of the crucial C15-C20 bond of Strychnos alkaloids that can be
applied to the synthesis of the most complex alkaloids of this
group. The strategy we have developed not only allows the
stereocontrolled synthesis of a variety of curan alkaloids in the
racemic series from a common advanced intermediate but also
can be extended to the enantiospecific synthesis of these
alkaloids.
Figure 1.
Scheme 12. Synthesis of Strychnos Alkaloids in
Enantiomerically Pure form: (-)-Tubifolidine
Experimental Section
General Methods. All reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhydrous
conditions. Unless otherwise noted, H and 13C NMR spectra were
1
4-ones. As the double reductive amination leading to the 3a-
(2-nitrophenyl)octahydroindole system takes place from a
symmetric dione (15), the use of a chiral nonracemic amine as
the aminocyclization agent in this step should afford the above-
mentioned crucial building blocks in enantiomerically pure form.
Thus, the use of R-(S)-methylbenzylamine in the sequence
of ozonolysis-double reductive amination from dione 15 afforded
(-)-51 in 37% yield and 78% of diastereoselectivity.61 Positive
diagnostic evidence for the (3aR, 7aS) configuration came from
a NOESY experiment on (-)-51. The resulting 2D spectrum
showed off-diagonal cross-peaks connecting H-7a and H-7eq
with a methyl proton, thus indicating their spacial proximity.
The distance between these protons would increase in the
alternative possible conformation62 or in the derivative with the
opposite configuration at the ring junction. The NOESY
spectrum also showed interactions between the benzylic proton
and the C-7 methylene and C-2 endo protons, thus corroborating
the absolute configuration of (-)-51.
recorded in CDCl3 solution, using Me4Si as internal standard. Chemical
shifts are reported in ppm downfield from Me4Si. NMR peak
assignments are given only when they are derived from definitive two-
dimensional NMR experiments. The 13C NMR spectra, when an
unambiguous assignment is not available, are reported as follows:
chemical shift (multiplicity determined from DEPT spectra). Only
noteworthy IR absorptions are listed. Melting points were determined
in a capillary tube and are uncorrected. TLC was carried out on SiO2
(silica gel 60 F254, Merck), and the spots were located with iodoplatinate
reagent. Chromatography refers to flash chromatography and was
carried out on SiO2 (silica gel 60, SDS, 230-400 mesh ASTM) unless
otherwise noted. Drying of organic extracts during workup of reactions
was performed over anhydrous Na2SO4. Evaporation of solvents was
accomplished with a rotatory evaporator. Microanalyses and HRMS
were performed by Centro de Investigacio´n y Desarrollo (CSIC),
Barcelona.
cis-1-Methyl-3a-(2-nitrophenyl)octahydroindol-4-one (cis-16). This
compound was prepared from 1,3-cyclohexanedione by the published
procedure.15 For the conversion of trans-16 to cis-16, see Supporting
Information.
Removal of the R-methylbenzyl substituent required more
drastic conditions than in the N-methyl series, presumably
because of the steric hindrance. Successful debenzylation was
achieved by refluxing a solution of (-)-51 in 1-chloroethyl
chloroformate for 48 h. From the resulting carbamate 19b
(mixture of epimers at the methine carbon of the carbamate
group), the alkaloid (-)-tubifolidine was synthesized as in the
above racemic series, following the sequence outlined in Scheme
12, by cyclization of the propragylic silane (-)-46 to allene
(-)-47, followed by hydrogenation. The resulting (-)-tubifo-
lidine ([RD]-56.6) had an ee of 84% determined by chiral
HPLC.
cis-1-[(1-Chloroethoxy)carbonyl]-3a-(2-nitrophenyl)octahydroin-
dol-4-one (19b). To a cooled (0 °C) solution of octahydroindole cis-
16 (8.46 g, 30.8 mmol) and 1,8-bis(dimethylamino)naphthalene (6.6
g, 30.8 mmol) in 1,2-dichloroethane (250 mL) was added dropwise
R-chloroethyl chloroformate (13.3 mL, 123 mmol). After 15 min at 0
°C, the mixture was heated at reflux for 3 h. The solvent was
evaporated, and the residue was partitioned between CH2Cl2 and 1 N
aqueous HCl. The organic layer was washed with 10% aqueous
NaHCO3, dried, and concentrated to give carbamate 19b (11.4 g,
quantitative):63 IR (CHCl3) 1709, 1530, 1350 cm-1 1H NMR (200
;
MHz) δ 1.60-1.85 (m, 3H), 1.86-2.05 (m, 1H), 2.15-2.65 (m, 7H),
3.60-4.05 (m, 2H), 4.27-4.55 (m, 1H), 6.35-6.50 (m, 1H), 7.25-
7.70 (m, 3H), 8.05 (d, J ) 8 Hz, 1H); 13C NMR (50.3 MHz) δ 19.2
(t), 24.7-24.9 (q), 26.6-27.7 (t), 31.1-32.3 (t), 36.0-36.2 (t), 43.2-
43.7 (t), 60.3-61.3 (s), 65.0-65.5 (d), 82.5-82.8 (d), 126.2-126.9
(d), 128.5-129.1 (d), 133.8-134.2 (d), 136.4-136.7 (s), 147.1-147.3
(s), 150.9-151.5 (s), 206.7 (s). Anal. Calcd for C17H19ClN2O5: C,
55.67; H, 5.22; N, 7.64. Found: C, 55.75; H, 5.34; N, 7.53.
cis-1-[(1-Chloroethoxy)carbonyl]-3a-(2-nitrophenyl)-5-(phenyl-
selanyl)octahydroindol-4-one (21). To a cooled (-20 °C) solution
of ketone 19b (11.4 g, 30.8 mmol) in 1:1 pentane-CH2Cl2 (700 mL)
were added hexamethyldisilazane (17.5 mL, 83.3 mmol) and Me3SiI
(8.4 mL, 61.7 mmol). The resulting solution was stirred at -20 °C
for 6 h and quenched by the addition of saturated aqueous NaHCO3.
The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic extracts were sequentially washed
Conclusion
cis-3a-(2-Nitrophenyl)octahydroindol-4-ones have proved to
be particularly useful building blocks for assembling the
(61) i-PrOH was the solvent of choise for the reductive amination. The
use of MeOH15 led to considerable amounts of 52 (four diastereomers). Its
formation can be rationalized as outlined in the following scheme, taking
into account that the hydride reduction of the iminium intermediate A is
slower than in the N-methyl series as a consequence of the larger size of
the N-substituent.
(62) Octahydroindolone (-)-51 is in a preferred conformation that locates
the 3a-aryl group in equatorial disposition with respect to the carbocyclic
ring. A related 3a-aryloctahydroindolone (aryl ) 3,4-methylenedioxyphenyl)
possessing the same relative stereochemistry as (-)-51 exists in a preferred
conformation in which the aryl group is axial: Overman, L. E.; Sugai, S.
HelV. Chim. Acta 1985, 68, 745-749. For the conformational behavior of
3a-aryloctahydroindoles, see: Bonjoch, J.; Sole´, D.; Cuesta, X. Heterocycles
1997, 45, 315-322. See also ref 15.
(63) In the description of the 13C NMR data of N-(R-chloroethoxycar-
bonyl) octahydroindoles a hyphen is used to indicate that the spectra are
complex due to the existence of diastereoisomers and rotamers.

Synthetic Entry to Strychnos Alkaloids of the Curan Type
J. Am. Chem. Soc., Vol. 119, No. 31, 1997 7237
with 10% aqueous sodium thiosulfate and saturated aqueous NaHCO3,
J ) 8, 7, 1.5 Hz, 1H), 7.83 (dd, J ) 8, 1.5 Hz, 1H); 13C NMR (50.3
MHz) δ 24.8 (t), 29.4 (q), 34.4 (t), 42.3 (t), 46.2 (t), 49.7 (t), 59.1 (s),
67.0 (d), 125.2 (d), 127.9 (2 d), 130.8 (d), 132.5 (d), 137.5 (s), 145.7
(d), 148.2 (s), 197.7 (s), 208.2 (s). Anal. Calcd for C18H20N2O4: C,
65.84; H, 6.14; N, 8.53. Found: C, 65.66; H, 6.12; N, 8.29.
dried, and concentrated to give silyl enol ether 20b (13.6 g, quantitative):
63
1H NMR (200 MHz) δ 0.03-0.16 (m, 9H), 1.60-2.70 (m, 9H),
3.40-3.95 (m, 2H), 4.50-4.75 (m, 1H), 4.80-5.05 (m, 1H), 6.45-
6.75 (m, 1H), 7.25-7.75 (m, 4H); 13C NMR (50.3 MHz) δ 0.26 (q),
20.8 (t), 23.1 and 23.8 (2 t), 25.2 (q), 32.3-34.6 (t), 44.5-45.1 (t),
53.0-54.0 (s), 62.7-63.4 (d), 82.7-83.1 (d), 102.9-104.4 (d), 124.6
(d), 127.9 (d), 129.9-130.6 (d), 130.9-131.2 (d), 134.4 (s), 149.4-
149.9 (s), 151.2-152.2 (s).
Cyclization of 24. Method A. To a solution of ketone 24 (0.98 g,
3 mmol) in THF (40 mL) were added dropwise (R)-R-methylbenzyl-
amine (0.8 mL, 6 mmol) and 3Å molecular sieves. The mixture was
stirred at rt for 4 days. After filtering through Celite, the solvent was
removed in Vacuo, the residue was dissolved in 20% aqueous AcOH
(100 mL), and the solution was stirred at rt for 4 h. The mixture was
basified with saturated aqueous Na2CO3 and extracted with CH2Cl2.
The organic extracts were dried and concentrated, and the resulting
residue was chromatographed. Elution with 98:2 CH2Cl2-MeOH gave
azatricycle 25 (167 mg, 17%), whereas elution with 97:3 CH2Cl2-
MeOH gave the C-2 epimer, (1RS,2SR,7RS,8SR)-2-acetyl-7-(2-nitro-
phenyl)-4-azatricyclo[5.2.2.04,8]undecan-11-one (26, 490 mg, 50%):
To a cooled (-35 °C) solution of 20b (5.56 g, 12.7 mmol) and
diphenyl diselenide (3.95 g, 12.7 mmol) in freshly distilled THF64 (325
mL) was added dropwise over a 90 min period a solution of
benzeneselenenyl chloride (2.42 g, 12.7 mmol) in THF (250 mL). The
resulting solution was slowly warmed to rt (3 h) and then concentrated.
Chromatography (Florisil, hexane-EtOAc from 7:3 to 1:1) yielded
ketone 2165 (4.63 g, 70% from cis-16):63 IR (CHCl3) 1714, 1694, 1530,
1
1350 cm-1; H NMR (200 MHz) δ 1.60-1.85 (m, 3H), 1.87-2.42
1
(m, 3H), 2.55-2.84 (m, 2H), 3.04-3.34 (m, 1H), 3.60-3.98 (m, 2H),
4.14 (br s, 1H), 4.18-4.55 (m, 1H), 6.40-6.55 (m, 1H), 7.20-7.74
(m, 8H), 8.06 (m, 1H); 13C NMR (50.3 MHz) δ 24.1-24.3 (t), 24.7-
25.2 (q), 26.0 (t), 33.8-35.0 (t), 43.8-44.2 (t), 45.1-45.4 (d), 60.5-
61.0 (s), 64.9-65.4 (d), 82.7-82.9 (d), 126.5-126.8 (d), 128.8 (d),
129.1 (d), 129.3 (d), 134.0-134.3 (d), 135.3 (d), 137.0 (s), 147.0 (s),
151.2-151.5 (s), 204.2-204.4 (s). Anal. Calcd for C23H23ClN2O5-
Se‚1/4H2O: C, 52.48; H, 4.50; N, 5.32. Found: C, 52.50; H, 5.03; N,
5.36.
IR (KBr) 1704-1698, 1530, 1366 cm-1; H NMR (200 MHz) δ 2.17
(s, 3H), 2.10-2.58 (m, 6H), 2.79 (br s, 1H), 2.75-3.25 (m, 5H), 3.78
(br s, 1H), 7.24 (dd, J ) 7.8, 1.7 Hz, 1H), 7.37 (m, 1H), 7.45-7.55
(m, 2H); 13C NMR (50.3 MHz) δ 26.5 (t), 28.2 (q), 29.1 (d), 39.5 (t),
41.9 (t), 45.7 (t), 52.1 (d), 54.8 (t), 61.8 (s), 65.0 (d), 125.5 (d), 128.1
(d), 129.9 (d), 132.0 (d), 134.2 (s), 151.2 (s), 208.0 (s), 212.3 (s). Anal.
Calcd for C18H20N2O4‚1/4H2O: C, 64.95; H, 6.20; N, 8.41. Found: C,
65.21; H, 6.21; N, 8.21.
Method B. To a cooled (-20 °C) solution of ketone 24 (0.42 g,
1.3 mmol) in DME (30 mL) was added dropwise Triton B (40% in
MeOH, 0.55 mL, 1.3 mmol). The mixture was stirred at -20 °C for
2.5 h and partitioned between Et2O and brine. The organic layer was
washed several times with brine, dried, and concentrated. Chroma-
tography of the residue yielded ketones 25 (59 mg, 14%) and 26 (186
mg, 44%).
cis-1-[(1-Chloroethoxy)carbonyl]-3a-(2-nitrophenyl)-1,2,3,3a,7,-
7a-hexahydroindol-4-one (22b). A stream of ozone gas was bubbled
through a cooled (-78 °C) solution of ketone 21 (4.63 g, 8.87 mmol)
in CH2Cl2 (350 mL) until it turned to the characteristic pale blue color.
The solution was purged with O2, and diisopropylamine (1.3 mL, 8.9
mmol) was added. The resulting mixture was stirred at rt for 15 min
and sequentially washed with 1 N aqueous HCl and 10% aqueous
NaHCO3. The organic extracts were dried and concentrated, and the
residue was chromatographed (Florisil, 1:1 hexane-EtOAc) to give
(1RS,2SR,7RS,8SR)-2-[2-(2-Methyl-1,3-dithiolanyl)]-7-(2-nitro-
phenyl)-4-azatricyclo[5.2.2.04,8]undecan-11-one (27). BF3‚Et2O (0.9
mL, 6.9 mmol) was added dropwise to a solution of ketone 26 (452
mg, 1.38 mmol) and 1,2-ethanedithiol (0.9 mL, 11 mmol) in glacial
AcOH (9 mL). After stirring at rt for 24 h, the mixture was diluted
with CH2Cl2 and basified with 2 N aqueous NaOH. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried, and
concentrated to give a residue. Chromatography (98:2 CH2Cl2-MeOH)
yielded dithioacetal 27 (435 mg, 80%): IR (CHCl3) 1696, 1529, 1350
ketone 22b (2.33 g, 72%):63 IR (KBr) 1721, 1673, 1521, 1348 cm-1
;
1H NMR (200 MHz) δ 1.60-1.85 (m, 3H), 2.30-2.60 (m, 2H), 2.65-
2.80 (m, 1H), 3.00-3.45 (m, 1H), 3.65-4.00 (m, 2H), 4,58-4.90 (m,
1H), 6.19 (d, J ) 10.5 Hz, 1H), 6.35-6.55 (m, 1H), 6.80-6.92 (m,
1H), 7.30-7.75 (m, 3H), 8.09 (m, 1H); 13C NMR (50.3 MHz) δ 24.9-
25.1 (q), 29.6-30.4 (t), 31.5-33.0 (t), 43.9-44.2 (t), 58.0-58.8 (s),
62.1-62.7 (d), 82.8-82.9 (d), 126.7-127.2 (d), 128.9-129.8 (d),
133.8-134.1 (d), 135.9-137.0 (s), 144.1-145.0 (d), 147.7 (s), 151.5
(s), 195.6-195.9 (s). Anal. Calcd for C17H17ClN2O5: C, 55.98; H,
4.70; N, 7.68. Found: C, 56.01; H, 5.10; N, 7.50.
1
cm-1; H NMR (200 MHz) δ 1.80 (s, 3H), 2.05-2.55 (m, 6H), 2.75
(br s, 1H), 2.82-3.44 (m, 9H), 3.81 (br s, 1H), 7.27 (d, J ) 7.8 Hz,
1H), 7.38 (m, 1H), 7.40-7.55 (m, 2H); 13C NMR (50.3 MHz) δ 28.8
(t), 31.0 (d), 33.7 (q), 38.3 (t), 38.7 (t), 40.9 (t), 42.2 (t), 48.8 (t), 49.6
(d), 54.5 (t), 61.9 (s), 64.6 (d), 68.3 (s), 125.6 (d), 128.1 (d), 129.6 (d),
131.7 (d), 133.2 (s), 151.4 (s), 212.4 (s). Anal. Calcd for C20H24N2-
O3S2: C, 59.38; H, 5.98; N, 6.92; 15.85. Found: C, 59.63; H, 5.89;
N, 6.71; S, 15.73.
Methyl (1RS,2RS,7SR,8RS)-2-[2-(2-Methyl-1,3-dithiolanyl)]-7-(2-
nitrophenyl)-11-oxo-4-azatricyclo[5.2.2.04,8]undecane-10-carboxy-
late (28). To a cooled (-78 °C) solution of diisopropylamine (0.33
mL, 2.39 mmol) in THF (10 mL) was added dropwise BuLi (1.6 M in
hexane, 1.43 mL). After 10 min at -78 °C, were added HMPA (1
mL, 5.7 mmol) and a solution of ketone 27 (460 mg, 1.14 mmol) in
THF (10 mL). After 30 min at -78 °C, the bath was removed, methyl
cyanoformate (0.27 mL, 3.42 mmol) was added dropwise, and the
mixture was stirred at rt for 3 h. The reaction was quenched by addition
of saturated aqueous NH4Cl (10 mL) and extracted with Et2O. The
organic layer was washed with brine, dried, and concentrated to give
a residue, which was chromatographed. On elution with EtOAc, ester
28 (260 mg, 50%)67 was obtained. IR (CHCl3) 1649, 1599, 1531, 1355
cis-3a-(2-Nitrophenyl)-1,2,3,3a,7,7a-hexahydroindol-4-one (23). A
solution of carbamate 22b (2.33g, 6.39 mmol) in MeOH (200 mL)
was heated at reflux for 3 h. The solvent was removed in Vacuo giving
crude hexahydroindole 23‚hydrochloride (1.65 g, quantitative), which
was used in the next step without purification: mp 171 °C (Et2O); 1H
NMR (200 MHz, DMSO-d6) δ 2.65-2.80 (m, 2H), 2.95-3.15 (m, 1H),
3.20-3.45 (m, 1H), 3.50-3.70 (m, 2H), 4.42 (t, J ) 7.5 Hz, 1H), 6.11
(d, J ) 10.5 Hz, 1H), 7.01 (ddd, J ) 10.5, 5, 3 Hz, 1H), 7.55-7.91
(m, 3H), 8.12 (d, J ) 7.5 Hz, 1H), 9.14 (br, 1H), 9.83 (br, 1H); 13C
NMR (50.3 MHz, DMSO-d6) δ 26.8 (t), 32.3 (t), 42.4 (t), 59.0 (s),
62.8 (d), 126.5 (d), 126.9 (d), 130.1 (d), 131.2 (d), 134.0 (s), 135.1
(d), 145.9 (d), 148.2 (s), 194.6 (s). Amine 23 could never be isolated
as the free base, probably due to its tendency to polymerization, and
had to be used as the hydrochloride salt.
cis-3a-(2-Nitrophenyl)-1-(3-oxobutyl)-1,2,3,3a,7,7a-hexahydroin-
dol-4-one (24). To a solution of crude amine 23‚hydrochloride (1.09
g, 4.23 mmol) and triethylamine (0.65 mL, 4.66 mmol) in MeOH (100
mL) was added dropwise methyl vinyl ketone (0.4 mL, 4.7 mmol).
The mixture was stirred at rt for 1 h 45 min. The solvent was removed
in Vacuo, and the residue was purified by chromatography (from EtOAc
to 98:2 EtOAc-diethylamine) to give amine 24 (1.02 g, 74%):66 IR
(CHCl3) 1708, 1669, 1524, 1354 cm-1; 1H NMR (200 MHz) δ 1.94 (s,
3H), 2.25-3.10 (m, 10H), 3.64 (t, J ) 6 Hz, 1H), 6.12 (dt, J ) 10, 2
Hz, 1H), 6.85 (dt, J ) 10, 4 Hz, 1H), 7.35-7.48 (m, 2H), 7.57 (ddd,
(65) When ketone 19b was treated with diphenyl diselenide (0.5 equiv)/
SeO2 (0.5 equiv)/H2SO4 (cat) the phenylseleno ketone 21 was obtained in
50% yield, with recovering of all the unreacted starting material. Increasing
the amount of diphenyl diselenide and SeO2 gave the same result.
(66) In some runs, tricycles 25 and 26 (3:1 ratio) were obtained together
with the alkylated product. These compounds were formed during purifica-
tion by column chromatography. All attempts to take advantage of this
spontaneous cyclization resulted in failure.
(64) When the THF used had been kept with Na, appreciable amounts
of the corresponding R-chloro ketone were formed: see Supporting
Information.
(67) In some runs, the corresponding carbonate was formed as a minor
byproduct: see Supporting Information.

7238 J. Am. Chem. Soc., Vol. 119, No. 31, 1997
Bonjoch et al.
cm-1; 1H NMR (200 MHz) δ 1.89 (s, 3H), 1.92 (dt, J ) 12.5, 3.5 Hz,
1H), 2.07 (ddd, J ) 12.5, 3.8, 2.5 Hz, 1H), 2.19 (dm, J ) 11.5 Hz,
1H), 2.37 (dd, J ) 15.3, 7 Hz, 1H), 2.54 (t, J ) 11.4 Hz, 1H), 2.84
(m, 1H), 3.00 (m, 1H), 3.10-3.33 (masked, 1H), 3.22 (m, 4H), 3.44
(br s, 1H), 3.47 (dd, J ) 11.5, 3 Hz, 1H), 3.76 (t, J ) 2.5 Hz, 1H),
3.84 (s, 3H), 7.20-7.50 (m, 4H), 12.92 (br s, 1H); 13C NMR (50.3
MHz) δ 27.4 (t), 27.5 (d), 31.9 (q), 36.4 (t), 38.9 (t), 41.4 (t), 49.2 (t),
51.0 (d), 51.5 (q), 55.0 (s), 56.0 (t), 65.6 (d), 68.4 (s), 101.2 (s), 124.8
(d), 127.7 (d), 131.1 (d), 132.0 (d), 134.5 (s), 150.9 (s), 172.5 (s), 174.9
(s). Anal. Calcd for C22H26N2O5S2: C, 57.12; H, 5.66; N, 6.06; S,
13.86. Found: C, 57.50; H, 5.68; N, 5.97; S, 13.53. On elution with
97:3 EtOAc-MeOH, unreacted ketone 27 (230 mg, 50%) was recovered.
Methyl (1RS,2RS,7SR,8RS)-2-Acetyl-7-(2-nitrophenyl)-11-oxo-4-
azatricyclo[5.2.2.04,8]undecane-10-carboxylate (29). A solution of
red HgO (0.28 g, 1.3 mmol) and BF3‚Et2O (0.3 mL, 2.6 mmol) in 85:
15 THF-H2O (23 mL) was stirred at rt for 5 min. A solution of
dithioacetal 28 (300 mg, 0.65 mmol) in THF (7.5 mL) was added
dropwise. After stirring at rt for 30 min, the mixture was partitioned
between Et2O and brine. The aqueous layer was extracted with CH2-
Cl2. The combined organic extracts were washed with brine, dried,
and concentrated. Chromatography (97:3 CH2Cl2-MeOH) of the
residue yielded ketone 29 (215 mg, 86%): IR (CHCl3) 1708, 1656,
in CH3CN (25 mL) were added anhydrous K2CO3 (1.1 g, 8 mmol) and
(Z)-1-bromo-2-iodo-2-butene30 (2.1 g, 8 mmol). The mixture was
stirred at rt for 3 h. The solvent was removed in Vacuo, and the residue
was partitioned between H2O and CH2Cl2. The dried organic extracts
were concentrated and chromatographed (8:2 hexane-EtOAc) to give
1
compound 31 (1.22 g, 70%): IR (film) 1670, 1525, 1360 cm-1; H
NMR (200 MHz) δ 1.73 (d, J ) 6.4 Hz, 3H), 2.30-2.70 (m, 4H),
2.90 (td, J ) 9.5, 3.5 Hz, 1H), 3.08 (m, 1H), 3.34 (s, 2H), 3.75 (t, J )
6 Hz, 1H), 5.77 (q, J ) 6.4 Hz, 1H), 6.15 (dt, J ) 9.6, 1.9 Hz, 1H),
6.89 (dt, J ) 9.6, 4.7 Hz, 1H), 7.42 (m, 1H), 7.60 (m, 2H), 7.90 (d, J
) 7.5 Hz, 1H); 13C NMR (50.3 MHz) δ 21.4 (q), 25.0 (t), 34.2 (t),
48.8 (t), 59.1 (s), 62.2 (t), 65.6 (d), 108.7 (s), 124.8 (d), 127.4 (d),
127.5 (d), 131.1 (d), 131.2 (d), 132.4 (d), 137.5 (s), 145.5 (d), 147.9
(s), 197.3 (s). Anal. Calcd for C18H19IN2O3: C, 49.33; H, 4.37; N,
6.39. Found: C, 49.81; H, 4.36; N, 5.99.
(()-19,20-Didehydrotubifoline (32). A solution of vinyl iodide 31
(47 mg, 0.11 mmol), LiCN in DMF (2.15 mL, 0.5 M, 1.1 mmol), and
Et3N (45 µl, 0.32 mmol) in CH3CN (5 mL) was added at rt to Ni-
(COD)2 (195 mg, 0.71 mmol). The resulting mixture was stirred at rt
for 2.5 h and filtered through Celite, washing carefully with Et2O. The
filtrate was sequentially washed with saturated aqueous Na2CO3 and
brine. The dried organic phase was concentrated and chromatographed
(Florisil, 95:5 CH2Cl2-MeOH) to give dehydrotubifoline (32,11 mg,
40%). The 1H and 13C NMR spectra of dehydrotubifoline were identical
with those reported in the literature.14b,30
1
1604, 1532, 1357 cm-1; H NMR (200 MHz) δ 1.99 (dt, J ) 13.4, 3
Hz, 1H), 2.11 (dt, J ) 13.4, 3 Hz, 1H), 2.25 (s, 3H), 2.35 (dd, J )
15.2, 6.5 Hz, 1H), 2.60-2.91 (m, 4H), 2.99 (m, 1H), 3.14 (dd, J ) 11,
7 Hz, 1H), 3.40 (br s, 1H), 3.70 (s, 3H), 3.71 (br s, 1H), 7.25-7.52
(m, 4H); 13C NMR (50.3 MHz) δ 25.7 (t), 28.5 (d), 29.1 (q), 37.0 (t),
45.9 (t), 50.8 (d), 51.3 (q), 54.9 (s), 55.8 (t), 65.4 (d), 98.3 (s), 124.5
(d), 127.5 (d), 130.9 (d), 131.7 (d), 134.1 (s), 150.5 (s), 171.4 (s), 175.5
(s), 208.2 (s). Anal. Calcd for C20H22N2O6‚3/4H2O: C, 60.06; H, 5.92;
N, 7.00. Found: C, 60.17; H, 5.67; N, 6.91. HRMS calcd for
C20H22N2O6 386.1478, found 386.1488.
Methyl (()-19-Oxo-2,16-didehydro-17-curanoate (30). To a
solution of the nitro derivative 29 (100 mg, 0.26 mmol) in MeOH (25
mL) was added dropwise an excess of Et2O solution of dry HCl. The
solvent and the excess of acid were removed in Vacuo, and the resulting
residue was dissolved in MeOH (25 mL). The mixture was hydroge-
nated at rt and atmospheric pressure in the presence of 10% Pd-C (50
mg) for 2 h. After filtration through Celite and removal of the solvent,
the residue was partitioned between CH2Cl2 and 10% aqueous Na2-
CO3. The dried extracts were concentrated and chromatographed (95:5
CH2Cl2-MeOH) to give pentacyclic ketone 30 (70 mg, 80%): IR
(CHCl3) 3380, 1708, 1675 cm-1; 1H NMR (200 MHz) δ 1.49 (dt, J )
13, 3 Hz, 1H), 1.80-2.15 (m, 3H), 2.16 (dt, J ) 13, 3.5 Hz, 1H), 2.30
(s, 3H), 2.60-2.90 (m, 2H), 2.98 (dd, J ) 15.5, 6 Hz, 1H), 3.05-3.15
(m, 1H), 3.49 (br s, 1H), 3.69 (s, 3H), 3.93 (br s, 1H), 6.81 (d, J ) 7.5
Hz, 1H), 6.91 (t, J ) 7.5 Hz, 1H), 7.08-7.20 (m, 2H), 8.94 (br s, 1H);
13C NMR (50.3 MHz) δ 29.2 (q), 30.4 (d), 31.2 (t), 42.8 (t), 45.5 (t),
49.4 (d), 51.0 (q), 53.5 (t), 56.1 (s), 60.5 (d), 96.5 (s), 109.9 (d), 119.7
(d), 121.3 (d), 127.9 (d), 134.6 (s), 144.1 (s), 167.5 (s), 171.4 (s), 208.0
(s). Anal. Calcd for C20H22N2O3‚1/2H2O: C, 69.14; H, 6.67; N, 8.06.
Found: C, 68.98; H, 6.53; N, 7.77. HRMS calcd for C20H22N2O3
338.1630, found 338.1623.
Methyl (()-(19E)-2,16,19,20-Tetradehydro-17-norcuran-1-car-
boxylate (33). To a suspension of NaH (27 mg, 60% oil dispersion,
0.65 mmol), previously washed with hexane, in DME (20 mL) were
added a solution of dehydrotubifoline (32, 87 mg, 0.33 mmol) in DME
(5 mL) and methyl chloroformate (0.13 mL, 1.7 mmol). The mixture
was warmed at 60 °C for 4 h. After cooling, the mixture was poured
into saturated aqueous NaHCO3 and extracted with CH2Cl2. The
organic extracts were washed with brine, dried, and concentrated.
Chromatography (95:5 Et2O-diethylamine) of the residue yielded
compound 33 (38 mg, 36%): IR (film) 1717, 1469, 1441, 1378, 1317,
1
1208 cm-1; H NMR (300 MHz) δ 1.37 (dt, J ) 13.2, 2.3 Hz, 1H),
1.70 (d, J ) 6.6 Hz, 3H), 1.80 (ddd, J ) 12.6, 9.3, 6.9 Hz, 1H), 2.09
(ddd, J ) 12.9, 6.0, 4.4 Hz, 1H), 2.15 (dt, J ) 10.1, 3.2 Hz, 1H), 2.77
(td, J ) 9.7, 6.2 Hz, 1H), 2.92 (d, J ) 14.9 Hz, 1H), 2.98 (ddd, J )
10.3, 6.6, 3.8 Hz, 1H), 3.31 (dm, J ) 8.3 Hz, 1H), 3.70 (d, J ) 15.6
Hz, 1H), 3.92 (s, 3H), 4.10 (t, J ) 1.7 Hz, 1H), 5.34 (q, J ) 6.8 Hz,
1H), 6.50 (d, J ) 8.8 Hz, 1H), 7.05 (td, J ) 7.4, 1 Hz, 1H), 7.18 (d,
J ) 6.9 Hz, 1H), 7.21 (td, J ) 7.6, 1.3 Hz, 1H), 7.77 (d, J ) 8.2 Hz,
1H); 13C NMR (75 MHz) δ 13.0 (q), 27.0 (t), 30.2 (d), 41.6 (t), 51.6
(t), 52.7(q), 52.8 (t), 53.8 (s), 58.5 (d), 115.1 (d), 115.4 (d), 120.3 (d),
120.7 (d), 123.5 (d), 127.5 (d), 135.0 (s), 136.0 (s), 141.2 (s), 144.2
(s), 153.1 (s); HRMS calcd for C20H22N2O2 322.1685, found 322.1681.
(()-(19E)-2,16,19,20-Tetradehydro-17-norcuran-1-carboxalde-
hyde (34). A solution of vinyl iodide 31 (200 mg, 0.46 mmol), LiCN
in DMF (9.1 mL, 0.5 M, 4.55 mmol), and Et3N (190 µL, 1.37 mmol)
in CH3CN (20 mL) was added at rt to Ni(COD)2 (830 mg, 3 mmol).
After 2.5 h at room temperature, N,N-dimethyl(chloromethylene)-
iminium chloride (1.17 g, 9.1 mmol) was added, and the mixture was
stirred at rt for 2 h. The reaction mixture was poured into saturated
aqueous NaHCO3 and extracted with Et2O. The organic extracts were
washed with brine, dried, and concentrated to give a residue that was
purified by chromatography. On elution with 96:4 CH2Cl2-MeOH,
pentacycle 34 (20 mg, 15%) was obtained: 1H NMR (acetone-d6, 300
MHz) δ 1.38 (dm, J ) 12.3 Hz, 1H), 1.71 (d, J ) 6.8 Hz, 3H), 1.76
(ddd, J ) 12.4, 8.9, 7.1 Hz, 1H), 2.11 (m, 1H), 2.22 (dt, J ) 13.3, 3.3
Hz, 1H), 2.75 (m, 1H), 2.88 (d, J ) 15 Hz, 1H), 2.94 (m, 1H), 3.40
(m, 1H), 3.71 (d, J ) 14.9 Hz, 1H), 4.10 (s, 1H), 5.35 (q, J ) 6.7 Hz,
1H), 6.32 (d, J ) 6.2 Hz, 2/3H), 6.95 (br, 1/3H), 7.19 (t, J ) 7.5 Hz,
1H), 7.29 (t, J ) 7.6 Hz, 1H), 7.38 (d, J ) 7.4 Hz, 1H), 7.50 and 8.06
(2 br, 1H), 8.96 and 9.30 (2 br, 1H); 13C NMR (acetone-d6, 75 MHz,
major rotamer) δ 13.2 (q), 28.0 (t), 30.8 (d), 41.9 (t), 52.3 (t), 53.4 (t),
54.3 (s), 58.8 (d), 114.0 (d), 116.2 (d), 120.7 (d), 121.7 (d), 125.6 (d),
128.3 (d), 137.6 (s), 141.2 (s), 145.4 (s), 157.9 (d); HRMS Calcd for
C19H20N2O 292.1580, found 292.1576.
(()-Echitamidine (9). To a cooled (0 °C) solution of ketone 30
(20 mg, 0.059 mmol) in MeOH (3 mL) was added NaBH4 (5 mg, 0.13
mmol). After 15 min at 0 °C and 2.5 h at room temperature, the
reaction was quenched by the addition of water (3 mL). The mixture
was partitioned between Et2O and H2O, and the organic extracts were
dried and concentrated to give a residue. Chromatography (92:8 CH2-
1
Cl2-MeOH) yielded (()-echitamidine (9, 15 mg, 75%). The H and
13C NMR spectral data were identical with those reported for the natural
product:28b 1H NMR (200 MHz) δ 1.16 (d, J ) 6.2 Hz, 3H), 1.41
(ddd, J ) 13.1, 3.9, 1.9 Hz, 1H), 1.70-2.10 (m, 3H), 2.03 (ddd, J )
13, 3, 2 Hz, 1H), 2.70-3.30 (m, 4H), 3.30 (br s, 1H), 3.87 (br s, 1H),
3.88 (s, 3H), 4.50 (br s, 1H), 6.84 (d, J ) 7.5 Hz, 1H), 6.93 (td, J )
7.6, 1 Hz, 1H), 7.15 (td J ) 7.6, 1.3 Hz, 1H,), 7.19 (d, J ) 7.3 Hz,
1H), 8.65 (br s, 1H); 13C NMR (50.3 MHz) δ 19.8 (q), 28.8 (d), 31.1
(t), 43.6 (t), 45.9 (d), 48.2 (t), 51.9 (t), 54.1 (t), 57.2 (s), 60.9 (d), 68.4
(d), 96.9 (s), 109.6 (s), 119.8 (d), 121.4 (d), 127.6 (d), 135.6 (s), 143.7
(s), 168.8 (s), 172.5 (s).
(()-Norfluorocurarine (5). A solution of 34 (16 mg, 0.055 mmol)
in MeOH (75 mL) was photolyzed under argon with a 125-W medium-
pressure mercury lamp for 10 min. Evaporation of the solvent gave a
cis-1-[(Z)-2-Iodo-2-butenyl]-3a-(2-nitrophenyl)-1,2,3,3a,7,7a-hexahy-
droindol-4-one (31). To a solution of crude amine 23 (1 g, 4 mmol)

Synthetic Entry to Strychnos Alkaloids of the Curan Type
J. Am. Chem. Soc., Vol. 119, No. 31, 1997 7239
residue, which was chromatographed (95:5 Et2O-diethylamine) yielding
(()-norfluorocurarine (5, 2.5 mg, 15%) and 19,20-didehydrotubifoline
(32, 10 mg, 69%). The 1H NMR spectral data of synthetic (()-
norfluorocurarine were identical with those reported for the natural
product.37c
tubifolidine (1, 19 mg, 60%), which exhibited spectral data identical
to those previously reported.10
(b) From Allene 47. To a solution of allene 47 (26 mg, 0.084 mmol)
and anhydrous Na2CO3 (27 mg, 0.26 mmol) in MeOH (5 mL) was
added 10% Pd-C (10 mg). The mixture was hydrogenated at rt and
atmospheric pressure for 18 h. After filtration through Celite and
removal of the solvent, the residue was partitioned between CH2Cl2
and H2O. The organic extracts were dried and concentrated. Chro-
matography of the residue yielded (()-tubifolidine (1, 14 mg, 60%).
Methyl (1RS,7SR,8RS)-7-(2-Nitrophenyl)-11-oxo-2-vinylidene-4-
azatricyclo[5.2.2.04,8]undecane-10-carboxylate (48). Operating as in
the preparation of 28, from allene 47 (152 mg, 0.49 mmol) were
obtained ester 48 (78 mg, 39%, 53% based on the consumed 47) and
starting allene 47 (43 mg, 28%) after chromatography (from hexane to
9:1 hexane-EtOAc).67 48: IR (film) 1650, 1611, 1530, 1363, 1246
(()-(19Z)-2,16,19,20-Tetradehydro-17-norcuran-1-carboxalde-
hyde (36). Operating as in the preparation of 34, from vinyl iodide
35 (47 mg, 0.11 mmol) was obtained pentacycle 36 (6.5 mg, 20%)
after chromatography (96:4 CH2Cl2-MeOH): IR (film) 1685, 1656,
1
1462, 1385 cm-1; H NMR (acetone-d6, 300 MHz) δ 1.43 (dm, J )
11.8 Hz, 1H, H-14), 1.64 (d, J ) 7.7 Hz, 3H, H-18), 1.72 (ddd, J )
12.8, 6.9, 5.9 Hz, 1H, H-6), 2.12 (m, 1H, H-14), 2.75 (dt, J ) 10.7,
6.6 Hz, 1H, H-6), 2.84-3.04 (m, 1H, H-5), 3.02 (dt, J ) 11.2, 7 Hz,
1H, H-5), 3.13 (m, 1H, H-15), 3.18 (d, J ) 14.6 Hz, 1H, H-21), 3.63
(d, J ) 14.6 Hz, 1H, H-21), 4.03 (m, 1H, H-3), 5.49 (qd, J ) 6.8, 1.2
Hz, 1H, H-19), 6.07 (dm, J ) 6 Hz, 2/3H, H-16), 6.73 (br, 1/3H, H-16),
7.18 (td, J ) 7.5, 1.1 Hz, 1H, H-10), 7.28 (td, J ) 7.7, 1.4 Hz, 1H,
H-11), 7.39 (d, J ) 7.7 Hz, 1H, H-9), 7.50 and 8.06 (2 br, 1H, H-12),
8.92 and 9.26 (2 br, 1H, CHO); 13C NMR (acetone-d6, 75 MHz, major
rotamer) δ 13.0 (C-18), 29.1 (C-14), 36.2 (C-15), 41.8 (C-6), 46.7 (C-
21), 53.4 (C-5), 54.2 (C-7), 59.7 (C-3), 114.4 (C-16), 116.3 (C-12),
120.3 (C-9), 121.4 (C-19), 125.7 (C-10), 128.2 (C-11), 137.0 (C-20),
141.3 (C-13), 146.2 (C-2), 157.8 (C-17); HRMS calcd for C19H20N2O
292.1582, found 292.1577.
1
cm-1; H NMR (500 MHz) δ 2.00 (dt, J ) 13.5, 3.5 Hz, 1H, H-9),
2.04 (dt, J ) 13.5, 3.5 Hz, 2H, H-9), 2.37 (ddd, J ) 15, 7.5, 3.5 Hz,
1H, H-6), 2.67 (ddd, J ) 15, 8.75, 7.75 Hz, 1H, H-6), 2.91 (ddd, J )
11.75, 7.75, 3.5 Hz, 1H, H-5), 3.11 (dt, J ) 13, 4 Hz, 1H, H-3), 3.13
(ddd, J ) 12, 8.5, 7.75 Hz, 1H, H-5), 3.48 (d, J ) 13 Hz, 1H, H-3),
3.58 (t, J ) 2.75 Hz, 1H, H-1), 3.79 (s, 3H, OCH3), 3.83 (t, J ) 3 Hz,
1H, H-8), 4.64 (dd, J ) 10, 3.25 Hz, 1H, dCH), 4.71 (dd, J ) 10, 3
Hz, 1H, dCH), 7.31-7.35 (m, 2H, H-4′ and H-5′), 7.43-7.47 (m, 2H,
H-3′ and H-6′), 12.51 (s, 1H, OH); 13C NMR (75 MHz) δ 24.1 (C-9),
30.5 (C-1), 36.4 (C-6), 48.3 (C-3), 52.0 (OCH3), 54.8 (C-5), 55.3 (C-
7), 65.2 (C-8), 75.2 (dCH2), 97.1 (C-2), 102.5 (C-10), 124.8 (C-3′),
127.8 (C-4′), 131.1 (C-6′), 132.0 (C-5′), 133.6 (C-1′), 150.9 (C-2′),
172.2 (C-11), 172.8 (COO), 203.2 (dCd). Anal. Calcd for C20H20-
N2O5‚1/3H2O: C, 64.06; H, 5.57; N, 7.47. Found: C, 64.06; H, 5.75;
N, 7.45.
cis-3a-(2-Nitrophenyl)-1-[4-(trimethylsilyl)-2-butynyl]-1,2,3,3a,7,-
7a-hexahydroindol-4-one (46). To a solution of crude amine 23 (167
mg, 0.69 mmol) in 2-butanone (10 mL) were added 4-iodo-1-
(trimethylsilyl)-2-butyne51 (260 mg, 1.03 mmol) and anhydrous K2-
CO3 (140 mg, 1.03 mmol). The mixture was heated at reflux for 5 h.
The solvent was removed in Vacuo, and the residue was partitioned
between H2O and CH2Cl2. The organic extracts were dried and
concentrated, and the resulting residue was purified by chromatography.
On elution with 1:1 hexane-EtOAc, hexahydroindole 46 (340 mg,
65%) was obtained: IR (KBr) 1673, 1529, 1358, 1250, 850 cm-1; 1H
NMR (200 MHz) δ 0.02 (s, 9H), 1.38 (t, J ) 2.4 Hz, 2H), 2.44-2.56
(m, 3H), 2.80 (dq, J ) 19, 3 Hz, 1H), 2.99-3.18 (m, 2H), 3.48 (t, J )
2.4 Hz, 2H), 3.63 (ddd, J ) 5, 2.5, 1Hz, 1H), 6.18 (ddd, J ) 10, 1.5,
1 Hz, 1H), 6.85 (m, 1H), 7.39 (t, J ) 8 Hz, 1H), 7.51 (m, 2H), 7.78
(dd, J ) 8, 1 Hz, 1H); 13C NMR (50.3 MHz) δ -2.3 (q), 6.6 (t), 26.4
(t), 36.4 (t), 40.0 (t), 49.8 (t), 58.5 (s), 65.1 (d), 72.3 (s), 83.0 (s), 124.8
(d), 127.5 (d), 127.9 (d), 130.0 (d), 132.4 (d), 136.8 (s), 146.3 (d),
148.8 (s), 196.9 (s). Anal. Calcd for C21H26N2O3Si: C, 65.93; H, 6.85;
N, 7.32. Found: C, 65.67; H, 6.87; N, 7.04.
(()-19,20-Dihydroakuammicine (4). Operating as in the conver-
sion of allene 47 to (()-tubifolidine, from ester 48 (10 mg, 0.03 mmol)
was obtained (()-19,20-dihydroakuammicine (4, 5 mg, 57%) after
chromatography (97:3 Et2O-diethylamine). The NMR spectra were
identical in all respects with those previously reported.10
(()-Akuammicine (7). (a) From Carbamate 33. A solution of
33 (15 mg, 0.047 mmol) in MeOH (75 mL) was photolyzed under
argon with a 125-W medium-pressure mercury lamp for 30 min.
Evaporation of the solvent gave a residue which was chromatographed
(95:5 Et2O-diethylamine) yielding (()-akuammicine (7, 4.5 mg, 30%),
1
which was identical with an authentic sample by H NMR and TLC
comparison.34c
(b) From Allene 48. To a solution of ester 48 (10 mg, 0.03 mmol)
in MeOH (10 mL) was added dropwise an excess of Et2O solution of
dry HCl. The solvent and the excess of acid were removed in Vacuo,
and the resulting residue was dissolved in MeOH (50 mL). The mixture
was hydrogenated in the presence of 10% Pd-C (6 mg) at rt and 100
psi for 1 h 15 min. After filtration through Celite and removal of the
solvent, the residue was partitioned between CH2Cl2 and 10% aqueous
Na2CO3. The organic extracts were dried and concentrated, and the
residue was chromatographed (from Et2O to 96:4 Et2O-diethylamine)
to give (()-19,20-dihydroakuammicine (4, 1 mg, 12%) and (()-
akuammicine (7, 3.5 mg, 38%).
(1RS,7RS,8SR)-7-(2-Nitrophenyl)-2-vinylidene-4-azatricyclo-
[5.2.2.04,8]undecan-11-one (47). To a cooled solution (0 °C) of
propargylic silane 46 (340 mg, 0.89 mmol) in CH2Cl2 (34 mL) was
added dropwise BF3‚Et2O (0.45 mL, 3.55 mmol). The mixture was
stirred at 0 °C for 10 min and at rt for 6 h. After cooling to 0 °C,
BF3‚Et2O (0.23 mL, 1.78 mmol) was added dropwise, and the mixture
was stirred at rt overnight. The reaction was quenched by addition of
H2O, basified with 10% aqueous Na2CO3, and extracted with CH2Cl2.
The dried extracts were concentrated and chromatographed (Al2O3, 1:1
hexane-EtOAc) to give allene 47 (234 mg, 85%): IR (film) 1950,
Methyl (1RS,7SR,8RS)-7-(2-Nitrophenyl)-11-oxo-2-[(Z)-2-(tribu-
tylstannyl)ethylidene]-4-azatricyclo[5.2.2.04,8]undecane-10-carboxy-
late (49). To a solution of allene 48 (300 mg, 0.81 mmol) and
Pd(PPh3)4 (47 mg) in THF (20 mL) was added dropwise Bu3SnH (0.26
mL, 0.98 mmol). After 24 h at room temperature, the mixture was
concentrated, and the residue was chromatographed (from hexane to
2:8 hexane-EtOAc) to give stannane 49 (363 mg, 68%): IR (film)
1
1699, 1532, 1366 cm-1; H NMR (500 MHz) δ 2.21 (dm, J ) 14.5
Hz, 1H, H-9), 2.20-2.30 (masked, 1H, H-6), 2.30 (dt, J ) 14.5, 2.8
Hz, 1H, H-9), 2.61 (d, J ) 4.5 Hz, 2H, H-10), 2.85-2.92 (m, 2H, H-5
and H-6), 2.95-3.12 (masked, 1H, H-1), 2.97 (dt, J ) 14.5, 2.5 Hz,
1H, H-3), 3.14-3.22 (m, 1H, H-5), 3.58 (dt, J ) 14.5, 2.5 Hz, 1H,
H-3), 3.89 (br s, 1H, H-8), 4.67 (dd, J ) 5, 2.5 Hz, 2H, dCH2), 7.28-
7.33 (m, 2H, H-4′ and H-6′), 7.42-7.47 (m, 2H, H-3′ and H-5′); 13C
NMR (50.3 MHz) δ 25.4 (C-9), 31.8 (C-1), 38.9 (C-6), 46.5 (C-10),
49.7 (C-3), 54.9 (C-5), 62.2 (C-7), 65.0 (C-8), 76.1 (dCH2), 99.8 (C-
2), 125.1 (C-3′), 127.9 (C-4′), 129.1 (C-6′), 132.0 (C-5′), 133.8 (C-1′),
150.9 (C-2′), 203.5 (dCd), 210.1 (C-11); HRMS calcd for C18H18N2O3
310.1325, found 310.1317.
1
2920-2960, 1649, 1609, 1531, 1363 cm-1; H NMR (500 MHz) δ
0.75-0.95 (m, 14H), 1.20-1.65 (m, 14H), 1.84 (ddd, J ) 13, 3.7, 3
Hz, 1H, H-9), 2.03 (dt, J ) 13, 3 Hz, 1H, H-9), 2.12 (t, J ) 11.5 Hz,
1H, CH2Sn), 2.33 (dd, J ) 15, 7 Hz, 1H, H-6), 2.78 (ddd, J ) 15.5,
11, 8 Hz, 1H, H-6), 2.91 (dd, J ) 12, 8 Hz, 1H, H-5), 3.11 (td, J ) 11,
7.5 Hz, 1H, H-5), 3.15-3.20 (m, 2H, H-3), 3.78 (s, 3H, OCH3), 3.76-
3.82 (m, 2H, H-1 and H-8), 5.47 (m, 1H, dCH), 7.29-7.36 (m, 2H,
H-4′ and H-5′), 7.42-7.48 (m, 2H, H-3′ and H-6′), 12.45 (s, 1H, OH);
13C NMR (75 MHz) δ 9.2 (C3H7CH2Sn), 9.4 (CH2Sn), 13.7 (CH3),
25.4 (C-9), 27.3 (CH2), 27.6 (C-1), 29.1 (CH2), 37.3 (C-6), 51.8 (OCH3),
54.6 (C-3), 55.2 (C-7), 55.9 (C-5), 66.7 (C-8), 102.1 (C-10), 122.8
(dCH), 124.6 (C-3′), 127.4 (C-4′), 129.1 (C-2), 130.9 (C-6′), 132.0
(()-Tubifolidine (1). (a) From Dithioacetal 27. To a solution of
dithioacetal 27 (50 mg, 0.12 mmol) in C6H6 (3 mL) were added Bu3-
SnH (0.5 mL, 1.8 mmol) and AIBN (7.5 mg). After stirring at 80 °C
for 16 h, the mixture was partitioned between C6H6 and 2 N aqueous
NaOH. The organic extracts were dried and concentrated, and the
residue was chromatographed (98:2 Et2O-diethylamine) to give (()-

7240 J. Am. Chem. Soc., Vol. 119, No. 31, 1997
Bonjoch et al.
(C-5′), 134.7 (C-1′), 151.0 (C-2′), 172.2 (C-11), 173.8 (CO); HRMS
calcd for C32H48N2O5Sn 660.2585, found 660.2552.
1.5 equiv) was added, and the stirring was continued for 48 h. The
solvent was removed under reduced pressure, and the residue was
partitioned between CH2Cl2 and 10% aqueous NaHCO3. The organic
extracts were dried and concentrated, and the resulting oil was
chromatographed (from hexane to 7:3 hexane-EtOAc) to give cis-
octahydroindole (-)-51 (2.47 g, 37%) and a mixture (1:3 ratio) of the
two trans-octahydroindoles (0.53 g, 8%). (-)-51: IR (CHCl3) 1697,
(1RS,2RS,7RS,8SR)-2-Hydroxy-11-(methoxycarbonyl)-7-(2-nitro-
phenyl)-11-oxo-2-vinyl-4-azatricyclo[5.2.2.04,8]undecane 4-Oxide (50).
To a solution of stannane 49 (130 mg, 0.2 mmol) in CH2Cl2 (15 mL)
was added TFA (15 µL, 0.2 mmol). After 2 min at room temperature,
m-CPBA (94 mg, 0.46 mmol) was added, and the stirring was
maintained for 2 h. The mixture was poured into H2O, the pH of the
solution was adjusted to 7 by addition of 10% aqueous Na2CO3, and
the mixture was extracted with CH2Cl2. The dried extracts were
concentrated and chromatographed (95:5 CH2Cl2-MeOH) to give
N-oxide 50 (61 mg, 76%): IR (film) 3000-3200, 1648, 1605, 1530,
1
1527, 1356 cm-1; H NMR (500 MHz) δ 1.16 (d, J ) 6.5 Hz, 3H,
CH3), 1.64 (dddd, J ) 16.5, 13.5, 10.5, 3.5 Hz, 1H, H-7), 2.01 (dm, J
) 13.5 Hz, 1H, H-6), 2.09 (dm, J ) 13.5 Hz, 1H, H-7), 2.13-2.30
(m, 3H, H-3 and H-6), 2.42-2.54 (m, 2H, H-5), 2.63 (td, J ) 10, 5
Hz, 1H, H-2), 2.83 (td, J ) 9, 6.5 Hz, 1H, H-2), 3.64 (q, J ) 6.5 Hz,
1H, NCH), 3.75 (dd, J ) 10.5, 5 Hz, 1H, H-7a), 7.15 (d, J ) 7 Hz,
2H, H-o), 7.21 (tm, J ) 7 Hz, 1H, H-4′), 7.26 (tm, J ) 7.5 Hz, 2H,
H-m), 7.41-7.46 (m, 2H, and H-p and H-6′), 7.63 (td, J ) 8, 1.5 Hz,
1H, H-5′), 7.97 (dd, J ) 8.5, 1.5 Hz, 1H, H-3′); 13C NMR (50 MHz)
δ 19.5 (C-6), 20.7 (C-7), 22.2 (CH3), 33.5 (C-3), 36.7 (C-5), 47.4 (C-
2), 59.0 (NCH), 62.0 (C-3a), 66.1 (C-7a), 125.0 (C-3′), 126.8 (o-C),
127.0 (C-4′), 127.7 (p-C), 128.4 (m-C), 131.6 (C-6′), 132.5 (C-5′), 139.3
1
1365 cm-1; H NMR (300 MHz) δ 1.86 (ddd, J ) 14.6, 3.4, 2 Hz,
1H), 2.52-2.74 (m, 2H), 3.05 (ddd, J ) 14.6, 4.2, 2.8 Hz, 1H), 3.13
(br s, 1H), 3.24 (d, J ) 12.8 Hz, 1H), 3.60 (d, J ) 12.8 Hz, 1H),
3.64-3.78 (m, 2H), 3.83 (s, 3H), 4.46 (br s, 1H), 5.14 (dd, J ) 10.8,
1.1 Hz, 1H), 5.24 (dd, J ) 17.4, 1.1 Hz, 1H), 5.65 (dd, J ) 17.4, 10.8
Hz, 1H), 7.33 (dd, J ) 7.9, 1.4 Hz, 1H), 7.48 (td, J ) 7.6, 1.4 Hz,
1H), 7.57 (td, J ) 7.8, 1.8 Hz, 1H), 7.61 (dd, J ) 7.7, 1.6 Hz, 1H); 13
C
25
NMR (75 MHz) δ 17.1 (t), 32.4 (t), 34.6 (d), 51.1 (s), 52.1 (q), 63.9
(t), 70.3 (t), 71.9 (s), 77.4 (d), 103.3 (s), 114.0 (t), 125.5 (d), 129.2 (d),
131.5 (s), 131.8 (d), 131.9 (d), 139.0 (d), 150.6 (s), 171.3 (s), 171.9
(C-1′), 145.9 (ipso-C), 148.0 (C-2′), 209.4 (C-4); [R]D ) -30.2 (c
0.01, MeOH). Anal. Calcd for C22H24N2O3: C, 72.17; H, 6.65; N,
7.68. Found: C, 72.01; H, 6.58; N, 7.63.
.
(s). Anal. Calcd for C20H22N2O7 H2O: C, 57.14; H, 5.75; N, 6.66.
(3aR,7aS)-3a-(2-Nitrophenyl)-1-[4-(trimethylsilyl)-2-butinyl]-1,2,3,-
3a,7,7a-hexahydroindol-4-one [(-)-46]. A solution of octahydroin-
dole (-)-51 (5 g, 13.72 mmol) in R-chloroethyl chloroformate (20 mL,
185 mmol) was heated at 135 °C for 2 days. The mixture was diluted
with CH2Cl2 and sequentially washed with 4 N aqueous HCl and 10%
aqueous NaHCO3. The organic extract was dried and concentrated to
give the nonracemic carbamate 19b (3.62 g, 72%). Operating as in
the racemic series, this carbamate was converted to propargylic silane
Found: C, 56.76; H, 5.78; N, 6.47.
(-)-20-Epilochneridine (9). To a solution of alcohol 50 (26 mg,
0.065 mmol) and anhydrous Na2CO3 (21 mg, 0.19 mmol) in MeOH (8
mL) was added 10% Pd-C (10 mg). The mixture was hydrogenated at
rt and atmospheric pressure for 24 h. After filtration through Celite
and removal of the solvent, the residue was partitioned between CH2-
Cl2 and H2O. The organic extracts were dried and concentrated, and
the residue was chromatographed. Elution with 94:6 CH2Cl2-MeOH
gave 20-epilochneridine (9, 10 mg, 48%): IR (film) 3000-3400, 1671,
25
(-)-46: [R]D ) -74.7 (c 0.01, CHCl3).
(-)-Tubifolidine [(-)-1]. Operating as in the racemic series,
cyclization of (-)-46 afforded allene (-)-47: [R]D25 ) -111.9 (c 0.01,
CHCl3). Reduction of (-)-47, following the procedure above described
for the racemic series, yielded (-)-tubifolidine [(-)-1]: [R]D25 ) -56.6
1
1595, 1462, 1240 cm-1; UV, (EtOH) λmax 326, 296, 231, 203 nm; H
NMR (500 MHz) δ 0.96 (t, J ) 7.2 Hz, 3H, H-18), 1.18 (dt, J ) 14,
3 Hz, 1H, H-14), 1.37 (dq, J ) 14.5, 7 Hz, 1H, H-19), 1.60 (dq, J )
14.5, 7 Hz, 1H, H-19), 1.89 (dd, J ) 13, 7 Hz, 1H, H-6), 2.38 (d, J )
12.5 Hz, 1H, H-21), 2.69 (dt, J ) 13.5, 3.2 Hz, 1H, H-14), 2.80-2.90
(m, 3H, H-5, H-6 and H-21), 3.03 (s, 1H, H-15), 3.10-3.20 (m, 1H,
H-5), 3.73 (s, 3H, OCH3), 3.95 (s, 1H, H-3), 6.79 (d, J ) 7.5 Hz, 1H,
H-12), 6.88 (td, J ) 7.5, 1 Hz, 1H, H-10), 7.11 (td, J ) 7.5, 1 Hz, 1H,
H-11), 7.15 (dd, J ) 7.5, 1 Hz, 1H, H-9), 9.03 (s, 1H, NH); 13C NMR
(75 MHz) δ 6.7 (C-18), 25.7 (C-14), 32.3 (C-19), 36.4 (C-15), 42.4
(C-6), 51.2 (OCH3), 53.7 (C-5), 54.5 (C-21), 56.2 (C-7), 60.6 (C-3),
71.0 (C-20), 101.4 (C-16), 109.8 (C-12), 119.7 (C-9), 121.2 (C-10),
127.8 (C-11), 135.1 (C-8), 144.2 (C-13), 168.5 (C-2), 170.9 (C-17).
HRMS Calcd for C20H24N2O3 340.1787, found 340.1787. IR, UV and
13C NMR data were identical with those reported for the natural
product.59
(3aR,7aS)-N-[(S)-r-Methylbenzyl]-3a-(2-nitrophenyl)octahydroin-
dol-4-one [(-)-51]. A stirred solution of 15 (5 g, 18.3 mmol) in CH2-
Cl2 (400 mL) at -78 °C was charged with a constant stream of ozone.
After 3 h, the solution turned pale blue and was purged with oxygen.
The solvent was removed with a rotatory evaporator without warming,
and the residue was dissolved in i-PrOH (750 mL). To this solution
were added first L-(-)-R-methylbenzylamine hydrochloride (11.5 g,
73.2 mmol) and then NaBH3CN (0.58 g, 9.15 mmol, 0.5 equiv). After
30 min of stirring, an additional portion of NaBH3CN (0.58 g, 9.15
mmol, 0.5 equiv) was added, and the stirring was continued for 1 h.
At this time, an additional portion of NaBH3CN (1.74 g, 27.4 mmol,
23
(c 0.01, CHCl3); lit.23a [R]D ) -67 (c 0.61, CHCl3). The ee (89%)
was determined by HPLC using a chiral column (Chiralcel OD, 75:
25:0.1 hexane-i-PrOH-diethylamine, 0.5 cm3 min-1, 254 nm) and
racemic tubifolidine as reference.
Acknowledgment. Financial support from the DGICYT,
Spain (Projects PB91-0800, PB94-0214, and PB94-0858) is
gratefully acknowledged. We are grateful to Prof. G. Massiot
(University of Reims) for a sample of akuammicine and to Prof.
Atta-ur-Rahman (University of Karachi) for sending us detailed
spectroscopic data of bharhingine. We thank Dr. Daniele
Passarella (Universita` degli Studi di Milano) for the chiral HPLC
measurements.
Supporting Information Available: Experimental details
for the conversion of trans-16 to cis-16 and 25 to 26, preparation
and characterization data for 17, 19a, 20a, 22a, 35, 37-39, and
41-45, NMR data for 25, 34, 36, 40, and 53-55, and copies
of NMR spectra and a plot of the NOESY experiment for (-)-
51 (14 pages). See any current masthead page for ordering
information and Internet access instructions.
JA970347A