Stereoselective total synthesis of dihydrocorynantheol.

Article abstract of DOI:10.1021/ol026470a

[reaction: see text] A stereoselective synthesis of the indole alkaloid dihydrocorynantheol (1) from indole-3-acetic acid has been achieved by a sequence involving 9 as a key intermediate. The synthesis of the unsaturated lactam ring in 9 highlights a series of catalytic organometallic reactions featuring two ring-closing metatheses and a zirconocene-catalyzed carbomagnesation. Since no protecting groups were used, the present synthesis of 1 is exceedingly concise, consisting of only eight distinct operations.

Full text of DOI:10.1021/ol026470a

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3243-3245
Stereoselective Total Synthesis of
Dihydrocorynantheol
Alexander Deiters and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received July 4, 2002
ABSTRACT
A stereoselective synthesis of the indole alkaloid dihydrocorynantheol (1) from indole-3-acetic acid has been achieved by a sequence involving
9 as a key intermediate. The synthesis of the unsaturated lactam ring in 9 highlights a series of catalytic organometallic reactions featuring
two ring-closing metatheses and a zirconocene-catalyzed carbomagnesation. Since no protecting groups were used, the present synthesis of
1 is exceedingly concise, consisting of only eight distinct operations.
We have had a longstanding interest in applying ring-closing
metathesis (RCM) as a key reaction for the construction of
nitrogen heterocycles and the frameworks of alkaloid natural
products.1 Indeed, our use of an RCM reaction to fabricate
the ABCE ring system of manzamine A represents one of
the first applications of such processes to complex molecule
synthesis.1a That RCM is a powerful reaction in natural
product synthesis is amply evident from the numerous
applications of this general transformation that have appeared
since Grubbs first showed that functionalized R,ω-dienes
served as substrates for such ring closures.2,3
We now report the use of RCM reactions in an exceedingly
short synthesis of the archetypal corynantheine alkaloid di-
hydrocorynantheol (1). Indole alkaloids of the corynantheine
group have attracted interest over the years because members
exhibit antiparasitic, antiviral, and analgesic activity.4 Di-
hydrocorynantheol (1) was first isolated from the bark of
Aspidosperma marcgraVianum Woodson (Apocynaceae) in
1962.5 Since its discovery, 1 has been a popular target for
the application of new synthetic methods, and there are a
number of partial6 and total syntheses of 1.7 Syntheses of
enantiomerically pure 1 have employed either an intermediate
(1) (a) Martin, S. F.; Liao, Y.; Chen, H.-J.; Paetzel, M.; Ramser, M. N.
Tetrahedron Lett. 1994 35, 6005. (b) Martin, S. F.; Wagman, A. S.
Tetrahedron Lett. 1995, 36, 1169. (c) Martin, S. F.; Chen, H.-J.; Courtney,
A. K.; Liao, Y.; Patzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron
1996, 52, 7251. (d) Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C.
J. Am. Chem. Soc. 1999, 121, 866. (e) Fellows, I. M.; Kaelin, D. E., Jr.;
Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781. (f) Neipp, C. E.; Martin,
S. F. Tetrahedron Lett. 2002, 43, 1779.
(2) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324.
(3) For recent reviews of olefin metathesis, see: (a) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (b) Grubbs, R.
H.; Chang, S. Tetarhedron 1998, 54, 4413. (c) Armstrong, S. K. J. Chem.
Soc., Perkin Trans. 1 1998, 371. (d) Schrock, R. R. Tetrahedron 1999, 55,
8141. (e) Wright, D. L. Curr. Org. Chem. 1999, 3, 211. (f) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012. (g) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18.
(4) (a) Takayama, H.; Iimura, Y.; Kitayama, M.; Aimi, N.; Konno, K.;
Inoue, H.; Fujiwara, M.; Mizuta, T.; Yokota, T.; Shigeta, S.; Tokushida,
K.; Hanasaki, Y.; Katsuura, K. Bioorg. Med. Chem. Lett. 1997, 7, 3145.
(b) Yamamoto, L. T.; Horie, S.; Takayama.; H, Aimi.; N, Sakai, S.; Yano,
S.; Shan, J.; Pang, P. K.; Ponglux, D.; Watanabe, K. Gen. Pharmacol. 1999,
33, 73. (c) Staerk, D.; Lemmich, E.; Christensen, J.; Kharazmi, A.; Olsen,
C. E.; Jaroszewski, J. W. Planta Med. 2000, 66, 531.
(5) (a) Gilbert, B.; Antonaccio, L. D.; Djerassi, C. J. Org. Chem. 1962,
27, 4702. Reviews: (b) Brown, R. T. In Indoles; Saxton, J. E., Ed.; Wiley-
Interscience: New York, 1983; Part 4 (The Monoterpenoid Indole
Alkaloids), Chapter 3. (c) Sza´ntay, C.; Blasko´, C.; Honty, K.; Do¨rnyei, G.
In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1986; Vol.
27, p 131. (d) Lounasmaa, M.; Tolvanen, A. In Monoterpenoid Indole
Alkaloids; Saxton, J. E., Ed.; Wiley-Interscience: New York, 1994;
Supplement to Vol. 25, Part 4, Chapter 3.
10.1021/ol026470a CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/23/2002

derived from the chiral pool,7f a chiral auxiliary,7g or a
resolution step.7h
Scheme 1
The key bond disconnections in our retrosynthetic analysis
of dihydrocorynantheol (1) are summarized in Figure 1. We
Figure 1. Dihydrocorynantheol (1): key bond disconnections.
planned to use a Bischler-Napieralski cyclization to form
the tetracyclic skeleton from a suitable ABD precursor. To
complement this classical ABD f ABCD approach, we
envisioned a novel strategy for constructing the functional-
ized piperidine D-ring by a conjugate addition of an
organocuprate to an R,â-unsaturated lactam that would in
turn be prepared by a RCM reaction. The substrate for this
RCM would be assembled via a zirconocene-catalyzed
carbomagnesation of a double bond,8,9 a reaction that has
only once been applied in natural product synthesis,10
although not to the synthesis of an alkaloid. Because this
reaction sets the stereocenter at C(20), use of a chiral catalyst
would enable a facile enantioselective synthesis of 1.11
The synthesis of 1 commenced with an EDCI coupling of
indole-3-acetic acid (2) with diallylamine to give the amide
3 in 88% yield (Scheme 1). Compound 3 was then converted
into the homoallylic amide 6 in a novel one-pot sequence in
which 3 was first cyclized via a RCM reaction employing
Grubbs’ catalyst 4 (0.5 mol %) in THF at room temperature
to provide the amide 5. Zirconocene dichloride (15 mol %)
and EtMgBr (4 equiv) were then simply added to the mixture
to induce the requisite carbomagnesation9 of 5 and a
subsequent elimination to deliver 6 in 71% yield from 3.
Significantly, it was not necessary to protect the indole-NH
during this conversion. It is possible to perform enantio-
selective carbomagnesations of cyclic allyl amides using the
chiral catalyst (EBTHI)Zr-binol,11 so there is an opportunity
to prepare 6 in enantiomerically pure form although we have
not yet examined this possibility. The amide 6 was then
reduced to the amine 7 (LiAlH4, Et2O, rt, 87%), acylation
of which with acryloyl chloride in CH2Cl2 at room temper-
ature gave 8 (73%) to set the stage for the second RCM
reaction. In the event, cyclization of 8 using 5 mol % of 4
delivered lactam 9 in 91% yield.12
(6) (a) Vamvacas, C.; van Philipsborn, W.; Schlittler, E.; Schmid, H.;
Karrer, P. HelV. Chim. Acta 1957, 40, 1793. (b) Dastoor, N. J.; Gorman,
A. A.; Schmid, H. HelV. Chim. Acta 1967, 50, 213. (c) Sawa, Y. K.;
Matsumura, H. Tetrahedron 1969, 25, 5329. (d) van Tamelen, E. E.;
Webber, J.; Schiemenz, G. P.; Barker, W. Bioorg. Chem. 1976, 5, 283; (e)
Le Men, J.; Ze`ches, M.; Sigaut, F. Heterocycles 1982, 19, 1807. (e)
Brillanceau, M. H.; Kan-Fan, C.; Kan, S. K.; Husson, H.-P. Tetrahedron
Lett. 1984, 25, 2767.
(7) Synthesis of rac-1: (a) Ziegler, F. E.; Sweeny, J. G. Tetrahedron
Lett. 1969, 14, 1097. (b) Kametani, T.; Kanaya, N.; Honda, T.; Ihara, M.
Heterocycles 1981, 16, 1937. (c) Ihara, M.; Taniguchi, N.; Fukumoto, K.;
Kametami, T. J. Chem. Soc., Chem. Commun. 1987, 1438. (d) Lounasmaa,
M.; Jokela, R.; Tirkonnen, B.; Miettinen, J.; Halonen, M. Heterocycles 1992,
34, 321. (e) Diez, A.; Villa, C.; Sinibaldi, M.-E.; Troin, Y.; Rubiralta, M.
Tetrahedron Lett. 1993, 34, 733. Synthesis of (-)-1: (f) Suzuki, T.; Sato,
E.; Unno, K.; Kametani, T. Heterocycles 1985, 23, 835. (g) Beard, R. L.;
Meyers, A. I. J. Org. Chem. 1991, 56, 2091. (h) Ohba, M.; Ohashi, T.;
Fuji, T. Heterocycles 1991, 32, 319.
The lactam 9 is potentially a versatile intermediate for the
syntheses of corynantheoid and other indole alkaloids
because the R,â-unsaturated carbonyl moiety should enable
introduction of a variety of substituents onto the D-ring at
C(15) via conjugate addition. However, R,â-unsaturated
(8) (a) Lehmkuhl, H. Bull. Soc. Chim. Fr., Part 2 1981, 87. (b)
Dzhemilev, U. M.; Vostrikova, O. S. J. Organomet. Chem. 1986, 304, 17
and references therein. (c) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J.
Am. Chem. Soc. 1989, 111, 366.
(9) For a review of Zr-catalyzed carbomagnesations, see: Geis, O.;
Schmalz, H.-G. In Organic Synthesis Highlights IV; Schmalz, H.-G., Ed.;
Wiley-VCH: Weinheim, 2000; p 83.
(10) Houri, A. F.; Xu, Z.-M.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1995, 117, 2943.
(11) Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda,
A. H. J. Am. Chem. Soc. 1996, 118, 4291.
(12) For other examples of the synthesis of R,â-unsaturated lactams by
RCM, see: (a) Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 65.
(b) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677.
See also ref 2.
3244
Org. Lett., Vol. 4, No. 19, 2002

lactams are notoriously poor Michael acceptors13 and there
are relatively few examples of 1,4-additions of organo-
metallic reagents to unsaturated piperidinones.14 In most of
these cases, there is an additional electron withdrawing group
on the nitrogen atom and/or in conjugation with the double
bond.
After surveying a number of reagents and conditions, we
discovered that organocuprates derived from Grignard re-
agents were superior nucleophiles in conjugate additions to
9.15 The reaction of 9 with vinylmagnesium bromide in the
presence of stoichiometric amounts of CuCN and trimethyl-
silyl chloride (TMSCl) proceeded in 91% yield to give an
inseparable mixture (dr ) 92:8) of 10 and its C(15) epimer
(Scheme 2). It is again noteworthy that no protection of the
The final assembly of the indoloquinolizidine skeleton was
achieved by a Bischler-Napieralski reaction of 10 (POCl3,
toluene, 100 °C) followed by stereoselective hydride reduc-
tion (NaBH4, CH3OH, 0 °C) to furnish 11 in 87% yield as
the only diastereomer. The relative configurations at C(3),
C(15), and C(20) were confirmed by NOE experiments.
Regioselective hydroboration of the pendant vinyl group in
11 with 9-BBN in THF at room temperature followed by an
oxidative workup (NaOH, H2O2, THF, 0 °C) delivered
dihydrocorynantheol (1) in 66% yield [mp 175-177 °C (lit.7a
1
mp 178-180 °C)]. The H and 13C NMR spectra of 1 thus
obtained were consistent with those previously reported.7d,g,h
In summary, an efficient (19% overall yield), eight-step
stereoselective synthesis of dihydrocorynantheol (1) has been
completed. The synthesis was conducted without any pro-
tecting groups and features the extensive application of
catalytic organometallic transformations, including two RCM
reactions and the first application of an olefin carbo-
magnesation reaction to alkaloid synthesis. Indeed, the
synthesis could be rendered enantioselective by using a chiral
catalyst for the carbomagnesation step.
Scheme 2
The use of RCM and other organometallic transformations
as key steps in the synthesis of alkaloids is being actively
pursued in our laboratory, and the results of these studies
will be reported in due course.
Acknowledgment. We thank the National Institutes of
Health, The Robert A. Welch Foundation, Merck Research
Laboratories, and Pfizer, Inc., for their generous support of
this research. A.D. gratefully acknowledges a Feodor-Lynen
postdoctoral fellowship from the Alexander von Humboldt
Foundation.
Supporting Information Available: Experimental pro-
cedures, analytical data, and H NMR spectra for 1, 6, and
11. This material is available free of charge via the Internet
at http://pubs.acs.org.
indole-NH is required. Use of TMSCl in the 1,4-addition
prevented the occurrence of side reactions, presumably by
trapping the transient copper enolate generated upon addition
of the vinyl cuprate to 9.
1
OL026470A
(13) Najashima, H.; Ozaki, N.; Washiayama, M.; Hoh, K. Tetrahedron
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Chem., Int. Ed. Engl. 1986, 25, 947. (b) Lipshutz, B. H. Synlett 1990, 119.
(c) Nakamura, E. Synlett 1991, 539. (d) Lipshutz, B. H.; Sengupta, S. Org.
React. 1992, 41, 135. (e) Lipshutz, B. H. In Organometallics in Synthesis;
Schlosser, M., Ed.; Wiley: Chichester, 1994. (f) Organocopper Reagents;
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N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186. (h) Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002.
(14) (a) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989, 111,
300. (b) Herdeis, C.; Kaschinski, C.; Karla, R. Tetrahedron: Asymmetry
1996, 7, 867. (c) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.;
Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem.
2000, 65, 3074. (d) Cossy, J.; Mirguet, O.; Pardo, D. G.; Desmurs, J.-R.
Tetrahedron Lett. 2001, 42, 78705. (e) Amat, M.; Pe´rez, M.; Llor, N.; Bosch,
J.; Lago, E.; Molins, E. Org. Lett. 2001, 3, 611. See also ref 13.
Org. Lett., Vol. 4, No. 19, 2002
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