Direct stereo- and enantiocontrolled synthesis of vicinal stereogenic quaternary carbon centers. Total syntheses of meso- and (-)-chimonanthine and (+)-calycanthine [4]

Full text of DOI:10.1021/ja991714g

7702
J. Am. Chem. Soc. 1999, 121, 7702-7703
Scheme 1
Direct Stereo- and Enantiocontrolled Synthesis of
Vicinal Stereogenic Quaternary Carbon Centers.
Total Syntheses of meso- and (-)-Chimonanthine and
(+)-Calycanthine
Larry E. Overman,* Daniel V. Paone, and Brian A. Stearns
Department of Chemistry, 516 Rowland Hall
UniVersity of California
IrVine, California 92697-2025
ReceiVed May 24, 1999
Among the most demanding challenges encountered in the
synthesis of complex molecules is enantioselective formation of
vicinal stereogenic quaternary carbon centers.1,2 This problem
typically has been addressed by constructing the quaternary
centers sequentially,3 often using a sigmatropic rearrangement to
form the second center.4 In this disclosure, we report that vicinal
stereogenic carbon centers can be constructed in a single step
and with excellent control of relative and absolute stereochemistry
using an intramolecular Heck reaction cascade. We have addressed
this problem in the context of the total synthesis of polypyrrolo-
indoline alkaloids whose signature structural motif is the hexa-
cyclic 3a,3a′-bispyrrolo[2,3-b]indoline ring system.5 All possible
stereoisomers of the simplest members of this indole alkaloid
family, the chimonanthines, are found in Nature: (-)-chimonan-
thine (1)6,7 and meso-chimonanthine (2)8 in plants, (+)-chimon-
anthine in a dendrobatid frog9 and in plants.10 Absolute config-
uration assignments for the chiral chimonanthine enantiomers
derive from circular dichroism studies11 of (+)-calycanthine (3),12
which under acidic conditions is in equilibrium with 1.12c Chiral
C2-symmetric chimonanthines and their analogues have previously
been prepared only as racemates through nonstereocontrolled
routes.5,12c-14 Herein we describe the first stereo- and enantio-
controlled total synthesis of (-)-chimonanthine (1) and (+)-
calycanthine (3), and a second stereocontrolled route to meso-
chimonanthine (2).14
We envisaged pentacyclic bisoxindole 4 as a precursor of the
chimonanthines and conjectured that this intermediate could be
accessed by palladium-catalyzed cyclization of 6 (Scheme 1).
Although we have previously utilized intramolecular Heck
reactions to fashion various sterically congested quaternary carbon
centers,15 the projected conversion of 6 f 4 was expected to be
particularly challenging since insertion of a tetrasubstituted double
bond would be required in the first Heck reaction, while the
second insertion would form adjacent quaternary centers. At the
outset, we entertained the possibility that the stereochemistry of
the trans oxygen substituents of 6 might regulate stereoselection
in the generation of 4.
Synthesis of the C2-symmetric cyclization substrate began with
double alkylation16 of the lithium dienolate of dimethyl succinate
(7) and tartrate-derived diiodide 8,17 followed by oxidation18 of
the resulting diastereomeric mixture of saturated diesters with
LDA and I2 to form 9 in 33% overall yield (Scheme 2). Although
the efficiency of the initial dialkylation was low, this sequence
could be performed conveniently on large scale to provide
multigram quantities of enantiomerically pure 9. Aminolysis of
9 with the dimethylaluminum amide of 2-iodoaniline19 and
conventional N-benzylation of the product generated 11. Removal
of the benzyl ethers with BCl3, followed by silylation with tert-
butyldimethylsilyl chloride (TBDMSCl) gave cyclization substrate
13. Heck cyclization of 13 at 100 °C in N,N-dimethylacetamide
(DMA) in the presence of 10% (Ph3P)2PdCl2 and excess Et3N
provided bisoxindole 14 in 71% yield.20 Only a single pentacyclic
bisoxindole, which ultimately proved to have the meso relation-
ship of the two oxindole groups, was isolated. Cleavage of the
(12) (a) Woodward, R. B.; Yang, N. C.; Katz, T. J.; Clark, V. M.; Harley-
Mason, J.; Ingleby, R. F. J.; Sheppard, N. Proc. Chem. Soc. 1960, 76-78.
(b) Hamor, T. A.; Robertson, J. M.; Shrivastava, H. N.; Silverton, J. V. Proc.
Chem. Soc. 1960, 78-80. (c) Hendrickson, J. B.; Go¨schke, R.; Rees, R.
Tetrahedron 1964, 20, 565-579.
(13) (a) Hino, T.; Yamada, S. Tetrahedron Lett. 1963, 4, 1757-1760. (b)
Hall, E. S.; McCapra, F.; Scott, A. I. Tetrahedron 1967, 23, 4131-4141. (c)
Hino, T.; Kodata, S.; Takahashi, K.; Yamaguchi, H.; Nakagawa, M.
Tetrahedron Lett. 1978, 4913-4916. (d) Nakagawa, M.; Sugumi, H.; Kodato,
S.; Hino, T. Tetrahedron Lett. 1981, 22, 5323-5326. (e) Fang, C.-L.; Horne,
S.; Taylor, N.; Rodrigo, R. J. Am. Chem. Soc. 1994, 116, 9480-9486.
(14) For the first stereocontrolled total synthesis of a 3a,3a′-bispyrro[2,3-
b]indoline alkaloid, see: Link, J. T.; Overman, L. E. J. Am. Chem. Soc. 1996,
118, 8166-8167.
(15) For a recent review of the use of intramolecular Heck reactions in
natural products total synthesis, see: Link, J. T.; Overman, L. E. In Metal-
Catalyzed Cross-Coupling Reactions; Stang, P. J., Diederich, F., Eds.; Wiley-
VCH: Weinheim; 1998, Chapter 6.
(16) Misumi, A.; Iwanaga, K.; Furata, K.; Yamamoto, H. J. Am. Chem.
Soc. 1985, 107, 3343-3345.
(17) Raeppel, S.; Toussaint, D.; Suffert, J. Synlett 1997, 1061-1062.
(18) Wilkening, D.; Mundy, B. P. Synth. Commun. 1984, 14, 227-238.
(19) Basha, A.; Lipton, M. F.; Weinreb, S. M. Org. Synth. 1979, 59, 49-
53.
(20) (a) The stereochemistry of the siloxy substituent of 14 has not yet
been established. (b) Due to slow conformational equilibration on the NMR
time scale, NMR spectra of this intermediate are highly complex.
(1) That no general methods exist is apparent in the lack of examples in
recent reviews of asymmetric synthesis of quaternary carbon centers.2
(2) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388-401. (b) Fuji, K. Chem. ReV. 1993, 93, 2037-2066.
(3) Examples can be found, inter alia, in asymmetric syntheses of
diterpenes. For recent reviews, see: (a) Hanson, J. R. Nat. Prod. Rep. 1999,
209-219, and earlier reviews in this series.
(4) For a recent example of forming both quaternary centers by a
sigmatropic rearrangement, see: Lemieux, R. M.; Meyers, A. I. J. Am. Chem.
Soc. 1998, 120, 5453-5457.
(5) For recent reviews that briefly discuss this indole alkaloid family, see:
(a) Hino, T.; Nakagawa, M. In The Alkaloids; Brossi, A., Ed.; Academic:
San Diego, 1989; Vol. 34, pp 1-75. (b) Wrobel, J. T. In The Alkaloids; Brossi,
A., Ed.; Academic: New York, 1985; Vol. 26, pp 53-87.
(6) Hodson, H. F.; Robinson, B.; Smith, G. F. Proc. Chem. Soc. 1961,
465-466.
(7) Duke, R. K.; Allan, R. D.; Johnston, G. A. R.; Mewett, K. N.; Mitrovic,
A. D.; Duke, C. C.; Hambley, T. W. J. Nat. Prod. 1995, 58, 1200-1208.
(8) Adjibade, Y.; Weniger, B.; Quirion, J. C.; Kuballa, B.; Cabalion, P.;
Anton, R. Phytochemistry 1992, 31, 317-319.
(9) Tokuyama, T.; Daly, J. W. Tetrahedron 1983, 39, 41-47.
(10) (a) Lajis, N. H.; Mahmud, Z.; Toia, R. F. Planta Med. 1993, 59, 383-
384. (b) Verotta, L.; Pilati, T.; Tato`, M.; Elisabetsky, E.; Amador, T. A.; Nunes,
D. S. J. Nat. Prod. 1998, 61, 392-396.
(11) Mason, S. F.; Vane, G. W. J. Chem. Soc. (B) 1966, 370-374.
10.1021/ja991714g CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/06/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 33, 1999 7703
Scheme 2a
Scheme 3a
a Reaction conditions: (a) LDA, THF/HMPA, -78 °C, 46%; LDA,
THF, I2, -78 °C, 72%; (b) 2-iodoaniline, Me3Al, toluene, rt, 92%; (c)
NaH, BnBr, DMF, 87%; d) BCl3, -78 °C, 70%; (e) TBDMSCl,
imidazole, CH2Cl2, 86%; (f) 10% (Ph3P)2PdCl2, Et3N, DMA, 100 °C,
71%; (g) HF, MeCN; NaBH4, MeOH; Pb(OAc)4, PhH, then NaBH4,
MeOH, 88% overall; (h) Red-Al, THF, rt f reflux; HN3, Ph3P,
EtO2CNdNCO2Et, THF, 78%.
a Reaction conditions: (a) camphorsulfonic acid monohydrate (CSA),
2,2-dimethoxypropane, 80%; (b) 10% (Ph3P)2PdCl2, Et3N, DMA, 100
°C, 90%; (c) CSA, THF; NaBH4, MeOH; Pb(OAc)4, PhH, then NaBH4,
MeOH, 88% overall; (d) Red-Al, THF, rt f reflux; (e) (PhO)2P(O)N3,
Ph3P, EtO2CNdNCO2Et, THF, 92% over two steps; (f) H2, 10% Pd/C,
EtOH, 100%; (g) MeOH, 110 °C, sealed tube; (h) CH2O, NaBH(OAc)3,
MeOH, 75% over two steps; Na, NH3/THF, 98%; (i) AcOH, reflux, 60%.
silyl ethers of 14 with HF in acetonitrile and reduction of the
R-hydroxy ketone product with NaBH4 provided the correspond-
ing cyclohexanediol. This diol was cleaved with Pb(OAc)4, and
the resulting labile dialdehyde was immediately reduced to furnish
diol 15 in 88% overall yield from 14. Reduction of 15 with sodium
bis(2-methoxyethoxy)aluminum hydride (Red-Al) in refluxing
THF provided a delicate pentacyclic diol which was immediately
converted to its diazide derivative 16, an intermediate in our earlier
synthesis of meso-chimonanthine.14
The outcome of the double Heck cyclization was dramatically
altered when the cyclohexanediol was protected as an acetonide
(Scheme 3).21 Thus, Heck cyclization of acetonide 1720b under
identical conditions occurred efficiently to give bisoxindole 18
in 90% yield; the relative stereochemistry of 18 was secured by
single-crystal X-ray analysis.22 Processing of 18 to 19 and
reduction of the latter with Red-Al in refluxing THF gave unstable
pentacyclic diol 20, which was immediately converted into diazide
21. Stereoselection in the cascade Heck cyclization of 17 was
extremely high, since no trace of the meso stereoisomer 15 was
seen in the 500 MHz 1H NMR spectrum of diol 19. Transforma-
tion of diazide 21 to the corresponding C2-symmetric bispyrrolo-
indoline proved challenging due to facile fragmentation of the
3a-3a′ bond. We eventually discovered that heating a methanol
solution of diamine 22 at 110 °C in a sealed tube generated
bispyrroloindoline 23 in high yield. Reductive methylation of this
product and discharge of the benzyl groups of 24 using Na/NH3
gave (-)-chimonanthine (1), [R]23D -310° (c 0.5 EtOH), in 67%
overall yield from diazide 21.23,24 Finally, exposure of 1 to hot
acetic acid provided (+)-calycanthine (3)12 in 60% yield.25,26 Due
to an error in drawing11 the enantiomer of chimonanthine that
would lead to (+)-calycanthine upon equilibration in acid, the
absolute configuration of (-)-chimonanthine has been represented
incorrectly in the literature and should be revised to be as depicted
in this paper.27
In summary, the first stereo- and enantioselective route for
preparing chiral 3a,3a′-bispyrrolo[2,3-b]indolines and their caly-
canthine isomers has been developed. The central step in this
sequence is a double Heck cyclization that forges vicinal
quaternary carbon centers in high yield (up to 90%) and with
complete stereocontrol.
Acknowledgment. This research was supported by NIH grant GM-
12389 and through a graduate fellowship to B.A.S. from Bristol-Myers
Squibb Pharmaceuticals. We particularly thank Drs. J. T. Link and Robert
J. Hinkle for their early investigations in this area. We are also grateful
to Professor Everly B. Fleischer and Dr. John Greaves for X-ray and
mass spectrometric analyses.
Supporting Information Available: Experimental procedures, spec-
troscopic and analytical data for compounds 9, 14, 18, 21, and 24 (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA991714G
(23) (a) Synthetic 1, mp 184-185 °C (lit.6 mp 188-189 °C) exhibited 1H
and 13C NMR spectra identical to those described.10b,24 (b) Optical rotations
at the sodium D line of varying magnitudes in alcohol solvents have been
reported for the chiral chimonanthine enantiomers: (-)-chimonanthine:
-329,6 -328;7 (+)-chimonanthine: +224,10a +280,9 +264.10b
(24) Libot, F.; Kunesch, N.; Poisson, J.; Kaiser, M.; Duddeck, H.
Heterocycles 1988, 27, 2381-2385.
(25) Synthetic (+)-calycanthine (3) was recrystallized from EtOH to give
colorless crystals: mp 244-245 °C, [R]23D +664° (c 0.7, EtOH); comparison
data for natural 3 are: mp 243-245 °C, [R]23 +684° (EtOH).26
(26) Spa¨th, E.; Stroh, W. Chem. Ber. 1925,D58, 2131-2132.
(27) The total synthesis of (+)-calycanthine recorded herein confirms the
absolute configuration of calycanthine originally assigned by Mason and Vane11
using the coupled oscillator CD method.
(21) The trans vicinal siloxy groups of 13 preferentially adopt diaxial
orientations, while the oxygen substituents are locked diequatorial in 17.
(22) The authors have deposited coordinates for this compound with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, U.K.