A general strategy to Aspidosperma alkaloids: Efficient, stereocontrolled synthesis of tabersonine [6]

Full text of DOI:10.1021/ja983198k

J. Am. Chem. Soc. 1998, 120, 13523-13524
13523
Scheme 1
A General Strategy to Aspidosperma Alkaloids:
Efficient, Stereocontrolled Synthesis of Tabersonine
Sergey A. Kozmin and Viresh H. Rawal*
Department of Chemistry, The UniVersity of Chicago
5735 South Ellis AVenue, Chicago, Illinois 60637
ReceiVed September 8, 1998
The Aspidosperma family comprises the largest group of indole
alkaloids, with more than 250 compounds.1 These alkaloids
possess a complex pentacyclic skeleton that is conformationally
rigid due to the cis relationship of the three contiguous stereo-
centers at C(7), C(21), and C(20) in the cyclohexenyl ring. The
structural challenge posed by these alkaloids in conjunction with
the potent pharmacological properties exhibited by several
members has stimulated considerable effort directed toward their
synthesis.1 We describe here a conceptually new strategy to the
Aspidosperma family of alkaloids,1c illustrated through a concise,
highly stereocontrolled synthesis of tabersonine.
Isolated in 1954 from Amsonia tabernaemontana, tabersonine
(1)2 plays a central role in the biosynthesis of Aspidosperma
alkaloids, serving as the biogenetic1,3 (as well as synthetic)4
predecessor of other members of the Aspidosperma familysmost
notably of vindoline, a key component of the clinically important
antitumor agents vinblastine and vincristine.5
was expected to give exclusively the endo cycloadduct 3, in which
the enol ether is poised for regioselective introduction of the
required indole unit.6a What would be needed was the develop-
ment of effective chemistry for the conversion of 3 to the
Aspidosperma pentacycle.
The N-allyl-N-carbomethoxy diene 6 was chosen for the pivotal
Diels-Alder reaction (Scheme 1). The carbomethoxy group was
selected to temper the reactivity of the amino group, and the allyl
group was chosen to provide a means to construct the piperidine
ring. The condensation of commercially available acetylacetal-
dehyde dimethylacetal (4) with methyl N-(2-propenyl)carbamate
in the presence of a catalytic amount of p-toluenesulfonic acid7
in refluxing chloroform afforded vinylogous imide 5 in 90% yield.
The treatment of a slight excess of the imide with KHMDS
followed by quenching of the resulting enolate with TBSCl gave
the desired diene (6) in quantitative yield, even on a multigram
scale.8 The cycloaddition reaction between diene 6 and ethacrolein
proceeded with complete regiocontrol and excellent endo selectiv-
ity to yield adduct 7 in 97% yield.
Having achieved the cis relative stereochemistry required for
Aspidosperma alkaloids, we then proceeded to construct the
hexahydroquinoline ring system of these alkaloids using a ring-
closing metathesis reaction.9 The aldehyde was first converted
into the desired vinylated compound 8 via a Wittig olefination
(Ph3PCH3Br, n-BuLi, THF, 0 °C; 85% yield). The critical ring-
closing metathesis reaction was examined using both Grubbs’s
ruthenium10 catalyst and Schrock’s molybdenum11 catalyst.
Whereas both catalysts promoted the desired metathesis, the latter
gave a cleaner, higher-yielding conversion to the product 9, which
was isolated in 88% yield.12,13 It is worth noting that, despite its
presence adjacent to the enol silyl ether, the amino group has
remained intact.
Our strategy to the Aspidosperma pentacycle is based on the
recognition that control of the cis relationship between the amino
group and C(15) on ring C is tantamount to solving all the
stereochemical problems for these alkaloids. A particularly
attractive solution for this stereocontrol was possible through a
Diels-Alder reaction using our recently developed amino siloxy
dienes.6 Thus, the cycloaddition between ethacrolein and diene 2
(1) (a) Saxton, J. E. Indoles, Part 4: The Monoterpenoid Indole Alkaloids;
Wiley: Chichester, 1983. (b) Herbert, R. B. In The Monoterpenoid Indole
Alkaloids; Supplement to Vol. 25, part 4 of The Chemistry of Heterocyclic
Compounds; Saxton J. E., Ed.; Wiley: Chichester, 1994; Chapter 1. (c) Saxton,
J. E. In ref 1b, Chapter 8. (d) Saxton, J. E. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1998; Vol. 50, Chapter 9. (e) Saxton, J. E.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998;
Vol. 51, Chapter 1.
(2) Isolation: Janot, M.-M.; Pourrat, H.; Le Men, J. Bull. Soc. Chim. Fr.
1954, 707. Synthetic studies: (a) Ziegler, F. E.; Bennett, G. B. J. Am. Chem.
Soc. 1973, 95, 7458. (b) Takano, S.; Hatakeyama, S.; Ogasawara, K. J. Am.
Chem. Soc. 1979, 101, 6414. (c) Le´vy, J.; Laronze, J.-Y.; Laronze, J.; Le
Men, J. Tetrahedron Lett. 1978, 1579. (d) Kuehne, M. E.; Okuniewitcz, F. J.;
Kirkemo, C. L.; Bohnert, J. C. J. Org. Chem. 1982, 47, 1335. Kuehne, M. E.;
Podhorez, D. E.; Mulamba, T.; Bornmann, W. G. J. Org. Chem. 1987, 52,
347. Kuehne, M. E.; Bornmann, W. G.; Earley, W. G.; Marko, I. J. Org.
Chem. 1986, 51, 2913. Kuehne, M. E.; Wang, T.; Seaton, P. J. J. Org. Chem.
1996, 61, 6001. (e) Kalaus, G.; Greiner, I.; Kajtar-Peredy, M.; Brlik, J.; Szabo,
L.; Szantay, C. J. Org. Chem. 1993, 58, 1434. For 16-methoxytabersonine:
(f) Overman, L. E.; Sworin, M.; Burk, R. M. J. Org. Chem. 1983, 48, 2685.
(g) Cardwell, K.; Hewitt, B.; Ladlow, M.; Magnus, P. J. Am. Chem. Soc.
1988, 110, 2242.
(3) (a) Scott, A. I. Acc. Chem. Res. 1970, 3, 151. (b) Atta-Ur-Rahman,
Basha, A. Biosynthesis of Indole Alkaloids; Clarendon Press: Oxford, 1983.
(4) Danieli, B.; Lesma, G.; Palmisano, G.; Riva, R. J. Chem. Soc., Perkin
Trans. 1 1987, 155.
(5) (a) Potier, P.; Langlois, N.; Langlois, Y.; Gueritte, G. J. Chem. Soc.,
Chem. Commun. 1975, 670. (b) Kutney, J. P.; Ratcliffe, A. H.; Treasurywala,
A. M.; Wunderly, S. Heterocycles 1975, 3, 639. (c) Langlois, N.; Gueritte,
G.; Langlois, Y.; Potier, P. J. Am. Chem. Soc. 1976, 98, 7017. (d) Danieli,
B.; Lesma, G.; Palmisano, G.; Riva, R. J. Chem. Soc., Chem. Commun. 1984,
909.
(6) (a) Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252. (b)
Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1997, 119, 7165. (c) Full
paper on amino siloxy dienes: Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J.
Org. Chem., in press. (d) Manuscript on the kinetics of these dienes: Kozmin,
S. A.; Green, M. T.; Rawal, V. H., submitted for publication.
(7) Khokhlov, P. S.; Savenkov, N. F.; Sokolova, G. D.; Strepikheev, Yu.
A.; Kolesova, V. A. J. Org. Chem. USSR 1982, 875.
(8) It was found that the use an excess of KHMDS (1.1 equiv), according
to the general protocol described in ref 6a, resulted in partial isomerization of
the double bond of the allyl group into an internal position.
(9) Recent reviews on olefin metathesis: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans.
1 1998, 371. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037. (d) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446.
(10) For recent examples, see: (a) Birman, V. B.; Rawal, V. H. J. Org.
Chem. 1998, 63, 9146. (b) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1997, 119, 3887. (c) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J.
Am. Chem. Soc. 1996, 118, 100. (d) Holder, S.; Blechert, S. Synlett 1996,
505. (e) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192. (f)
Garro-Helion, F.; Guibe, F. J. Chem. Soc., Chem. Commun. 1996, 641. (g)
Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942. (h) Fu, G.;
Nguyen, S. T.; Grubbs, R. R. J. Am. Chem. Soc. 1993, 115, 9856.
(11) (a)Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875. (b) Bazan, G. C.; Oskam,
J. H.; Cho, H.-N.; Park, L. Y.; Schrock, R. R. J. Am. Chem. Soc. 1991, 113,
6899.
(12) Use of the Grubbs catalyst (7 mol %, CH2Cl2, 40 °C, 2 h) afforded 9
in 75% isolated yield.
10.1021/ja983198k CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/08/1998

13524 J. Am. Chem. Soc., Vol. 120, No. 51, 1998
Communications to the Editor
Scheme 2
Scheme 3
The regiocontrolled installation of the indole unit on bicycle 9
proved challenging. Most of the available methods for indole
synthesis involve the reaction of a ketone with a suitable aryl
partner and, consequently, do not always provide predictable
control of the regiochemistry. Having unsuccessfully examined
a few of these procedures,14-17 we decided to develop an indole
synthesis that took advantage of the regiospecifically formed enol
silyl ether present in 9. Building on the precedent provided by
Chen and Koser,18 we prepared o-nitrophenylphenyliodonium
fluoride (NPIF),19 with the expectation that the more electron
deficient nitrophenyl group would react with the enol silyl ether.
In the event, treatment of a solution of enol ether 9 with NPIF
cleanly generated the desired R-arylated ketone 15 in 94% yield,
as the single diastereomer shown (Scheme 2). Reduction20 of the
nitro group using TiCl3 gave the desired, regiospecifically
generated indole 16 in 89% yield.
The final cyclization required the conversion of the hydroxy
group in 18 into a leaving group, followed by a base-mediated
intramolecular nucleophilic displacement by the indole anion.21
Interestingly, activation of the alcohol of 18 using mesyl chloride
gave not the expected mesylate but the corresponding chloride
(19), presumably arising via the aziridinium ion.25 On reaction
with t-BuOK in THF, chloride 19 was efficiently converted to
didehydroaspidospermidine 20,26 a common late-stage intermedi-
ate to several Aspidosperma alkaloids.1 Deprotonation of 20 with
LDA in THF followed by acylation with Mander’s reagent27 gave
cleanly the C-acylated product, tabersonine (1), in 70-80%
yield.28,29
In summary, we have described here a novel, highly stereo-
controlled route to Aspidosperma alkaloids. The strategy was
illustrated through the total synthesis of (()-tabersonine, which
was achieved in 12 steps and ca. 30% overall yield, the highest
reported to date. The synthesis illustrates (a) the complete
regioselectivity and excellent endo selectivity possible with
1-amino-3-siloxy-1,3-butadienes, which have been developed in
our laboratory, (b) the use of an olefin metathesis reaction to
construct the cis-hexahydroquinoline ring system, having the
double bond correctly positioned for these alkaloids, and (c) a
novel indole synthesis based on the regiospecific ortho-nitro-
phenylation of an enol silyl ether.
What was required for the end game leading to the Aspi-
dosperma skeleton was introduction of the two carbons for the
pyrrolidine ring that is in a spiro arrangement to the indole.
Although this construction is precedented in the Aspidosperma
alkaloids area,21 the yields for this transformation have been
variable. The methyl carbamate group was first removed by the
reaction of 16 with trimethylsilyl iodide in refluxing CH2Cl2,
followed by a methanol quench to hydrolyze the labile silyl
carbamate.22,23 Alkylation of the resulting secondary amine with
a 10-fold excess of bromoethanol in the presence of sodium
carbonate in refluxing ethanol for 18 h afforded the desired tertiary
amine 18 in quantitative yield (Scheme 3).24
(13) The structure of 9 was established by a combination of the DQF COSY
and NOESY experiments. The cis stereochemistry of the hexahydroquinoline
system was confirmed by the strong NOE cross-peaks between the proton
adjacent to the nitrogen and the methylene unit of the ethyl group.
(14) For example, see: (a) Chen, C.; Lieberman, D. R.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676. (b) Gassman,
P. G.; van Bergen, T. J.; Gilbert, D. P.; Berkeley, W. C. J. Am. Chem. Soc.
1974, 96, 5495.
(15) Recent reviews of indole synthesis: (a) Sundberg, R. J. Indoles;
Academic Press: London, 1996. (b) Gribble, G. W. Contemp. Org. Synth.
1994, 3, 145.
(16) Fischer Indole synthesis: Robinson, B. The Fischer Indole Synthesis;
J. Wiley & Sons: New York, 1982.
(17) For example, when ketone 10, obtained from hydrolysis of 9 (1.2 M
HCl, THF/H2O, 96%), was subjected to Fischer indolization procedure ((a)
PhNHNH2‚HCl, Na2CO3, EtOH; (b) AcOH, 95 °C), it produced both
regioisomeric tetracycles in 96% yield in approximately a 1:1 ratio.
Acknowledgment. This work was supported by the National Institutes
of Health (R01-GM-55998). Additional financial support from Pfizer Inc.
is gratefully acknowledged. Vladimir B. Birman is thanked for valuable
input on the ortho-nitrophenylation chemistry (see ref 19).
Supporting Information Available: Experimental procedures and
compound characterization data, including copies of NMR spectra for
all new compounds (36 pages, print/PDF). See any current masthead page
for ordering information and Web access instructions.
(18) Chen, K.; Koser, G. F. J. Org. Chem. 1991, 56, 5764 and references
therein.
JA983198K
(19) Birman, V. B.; Kozmin, S. A., unpublished results. NPIF was prepared
according to the scheme shown below. The full details of this preparation
and its application to indole synthesis will be reported separately.
(25) Similar observations have been reported: (a) Lee, J. W.; Son, H. J.;
Lee, J. H.; Yoon, G. J.; Park, M. H. Synth. Commun. 1996, 26, 89. (b) Springer,
C. J.; Antoniw, P.; Bagshawe, K. D.; Searle, F.; Bisset, G. M. F.; Jarman, M.
J. Med. Chem. 1990, 33, 677.
(26) This two-step process was also carried out in one step, albeit less
reproducibly, using Rubiralta’s recently reported conditions (ref 22). Thus,
simply treating alcohol 18 with TsCl and t-BuOK in THF at room temperature
gave directly the desired didehydroaspidospermidine 20 in up to 51% isolated
yield, with ca. 70% conversion of the starting material.
(20) Moody, C. J.; Rahimtoola, K. F. J. Chem. Soc., Perkin Trans. 1 1990,
673.
(27) (a) Mander, L. N. Encyclopedia of Reagents for Organic Synthesis;
Wiley: New York, 1995; Vol. 5, p 3465. (b) Crabtree, S. R.; Mander, L. N.;
Sethi, S. P. Org. Synth. 1991, 70, 256 and references therein.
(28) Acylation using methyl chloroformate gave the C-acylated product in
37% isolated yield, along with an appreciable amount of the N-acylated
compound. For a precedent, see ref 2f.
(21) (a) Ziegler, F. E.; Spitzner, E. B. J. Am. Chem. Soc. 1973, 95, 7146.
(b) Natsume, M.; Utsunomiya, I. Heterocycles 1982, 17, 111. (c) Ogawa, M.;
Kitagawa, Y.; Natsume, M. Tetrahedron Lett. 1987, 28, 3985. (d) Forns, P.;
Diez, A.; Rubiralta, M. J. Org. Chem. 1996, 61, 7882 and references therein.
(22) Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225.
(23) (a) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030. (b) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
(24) Rubiralta, M.; Diez, A.; Bosch, J.; Solans, S. J. Org. Chem. 1989, 54,
5591.
(29) The 500-MHz 1H NMR and 125-MHz 13C NMR spectra of our
synthetic sample of tabersonine were identical to those previously reported
in the literature. See: (a) refs 2d and 2e. (b) Wen, R.; Laronze J.-Y.; Le´vy,
J. Heterocycles 1984, 22, 1061.