Sequential catalytic asymmetric Heck-iminium ion cyclization: Enantioselective total synthesis of the Strychnos alkaloid minfiensine

Article abstract of DOI:10.1021/ja0533895

A catalytic asymmetric method for the chemical synthesis of alkaloids containing the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (1) moiety is reported and verified by the enantioselective total synthesis of (+)-minfiensine (4). The central step i

Full text of DOI:10.1021/ja0533895

Published on Web 07/01/2005
Sequential Catalytic Asymmetric Heck-Iminium Ion Cyclization:
Enantioselective Total Synthesis of the Strychnos Alkaloid Minfiensine
Amy B. Dounay,1 Larry E. Overman,* and Aaron D. Wrobleski
Department of Chemistry, UniVersity of California, 516 Rowland Hall, IrVine, California 92697-2025
Received May 24, 2005; E-mail: leoverma@uci.edu
Scheme 1 a
A variety of natural products containing the 1,2,3,4-tetrahydro-
9a,4a-(iminoethano)-9H-carbazole (1) ring have been isolated from
higher plants.2 These alkaloids, exemplified by 2-4, are comprised
of tryptamine and monoterpene units, presumably being derived
in nature by cyclization of corynantheine derivatives.3 Several
biological activities have been associated with these alkaloids,
including promising anticancer activity.2,4,5 A concise, enantiose-
a Reagents: (a) p-TsOH, PhH, 50 °C (95%); (b) ClCO2Me, NaHMDS,
THF, -78 °C (52-60%); (c) Comins' reagent, NaHMDS, THF, -78 °C
(82%); (d) 9-BBN, 13, THF; PdCl2(dppf)‚DCM, THF, rt; H2O2, 0 °C (72%);
(e) CsF, Cs2CO3, Comins’ reagent, DMF, rt (95%); (f) Pd(OAc)2, 14, PMP,
PhMe, 170 °C; CF3CO2H, CH2Cl2, 0 °C (75%).
only when the sodium salt of the secondary enamine was allowed
to react at -78 °C with methyl chloroformate, providing carbamate
8 in 52-60% yield. Elaboration of the enone functionality to a
dienyl carbamate and introduction of the aminoethyl side chain were
accomplished by initial enol triflation of 8 by reaction with sodium
hexamethyldisilazide (NaHMDS) and 2-[N,N-bis(trifluoromethyl-
sulfonyl)amino]-5-chloropyridine (Comins’ reagent).12 Suzuki cross-
coupling of this dienyl triflate with the alkyl borane generated by
hydroboration of N-vinyl-tert-butyl carbamate (13)13 provided 9 in
60% overall yield.14 In one step and 95% yield, the Heck cyclization
precursor, aryl triflate 10, was secured by reaction of silyl ether 9
at room temperature with CsF, Cs2CO3, and Comins’ reagent.
Initial survey experiments showed that the pivotal asymmetric
Heck cyclization of 10 could be realized with several chiral
enantiopure ligands.15 The Pfaltz ligand, (S)-4-tert-butyl-2-[2-
(diphenylphosphinyl)phenyl]-4,5-dihydrooxazole (14),16 proved
optimal, providing tricyclic dienyl carbamate 11 in ca. 85% yield
and 99% ee. However, asymmetric Heck cyclization of 10 was slow,
requiring more than 70 h at 100 °C to reach completion. Fortunately,
this conversion could be accomplished in 30 min with no erosion
in enantioselectivity at 170 °C in a microwave reactor.17 Upon
addition of excess trifluoroacetic acid to the crude Heck product,
the one-pot reaction sequence was completed to furnish (dihy-
droiminoethano)carbazole 12 in 75% overall yield.18,19
Figure 1. Representative alkaloids containing a 1,2,3,4-tetrahydro-9a,4a-
(iminoethano)-9H-carbazole ring system.
lective chemical synthesis entry to alkaloids, such as 2-4, would
allow further exploration of the pharmacology of this unique
structural motif.6
We saw (hydroiminoethano)carbazoles 1 having a 1,2 or 2,3
double bond as potentially versatile platforms for constructing
alkaloids of this type, as stitching an ethylideneethano unit between
the pyrrolidine nitrogen and C2 or C3 would form the pentacyclic
ring systems found in these alkaloids. We furthermore perceived
that the 4aR,9aR enantiomer 5 of these 3,4-dihydro-9a,4a-(imino-
ethano)-9H-carbazole intermediates might be directly assembled
by the domino catalytic asymmetric Heck-N-acyliminium ion
sequence posited in eq 1.7 The development of this chemistry and
its use to complete the first total synthesis of (+)-minfiensine (4)8
is the subject of this communication.
The elaboration of dihydrocarbazole 12 to the pentacyclic ring
system of minfiensine is summarized in Scheme 2. Epoxidation of
12 with m-chloroperoxybenzoic acid provided the corresponding
R-epoxide in 87% yield.20 Because of the propensity of the aminal
fragment to open under acidic conditions,21 the tert-butoxycarbonyl
(Boc) protecting group had to be exchanged for an allyloxycarbonyl
(Alloc) group prior to transforming the epoxide to an allylic
The asymmetric construction of 3,4-dihydro-9a,4a-(iminoethano)-
9H-carbazole 12 commenced with acid-catalyzed transamination9
of the morpholine enamine 710 of 1,2-cyclohexanedione with
2-siloxyaniline 611 (Scheme 1). Selective protection of the nitrogen
of the resulting enamine was complicated by competitive reaction
of the cyclohexenone functionality. Useful selectivity was realized
9
10186
J. AM. CHEM. SOC. 2005, 127, 10186-10187
10.1021/ja0533895 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole (12).
This intermediate and related intermediates containing a 2,3 double
bond should be versatile precursors for constructing a variety of
pentacyclic indole alkaloids containing the (hydroiminoethano)-
carbazole fragment. The enantioselective total synthesis of (+)-
minfiensine (4) reported herein provides the first verification of
this total synthesis strategy.
Acknowledgment. Financial support from the NIH Heart, Lung
and Blood Institute (HL-25854) and postdoctoral fellowship support
for A.B.D. (CA94471) and A.D.W. (CA108197) from the NIH
National Cancer Institute is gratefully acknowledged. We thank
Professor Georges Massiot for copies of NMR spectra of natural
minfiensine.
a Reagents: (a) m-CPBA, CH2Cl2, 0 °C f rt (87%); (b) CF3CO2H, 0
°C f rt (98%); (c) CH2dCHCH2OCOCl, K2CO3, rt (92%); (d) (PhSe)2,
NaBH4, THF/MeOH, 70 °C; H2O2, 0 f 70 °C (83%); (e) TESCl, imidazole,
CH2Cl2, rt (90%); (f) Pd(PPh3)4, pyrrolidine, THF, rt; (Z)-2-iodo-2-butenyl
tosylate, K2CO3, MeCN, 70 °C (96%); (g) Pd(OAc)2, K2CO3, Bu4NCl,
NaO2CH, DMF, 80 °C (80%).
Supporting Information Available: Experimental details for key
steps and 1H and 13C spectra of new compounds (48 pages). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
Scheme 3 a
(1) Current address: Pfizer Global Research and Development, 2800 Plymouth
Road, Ann Arbor, MI 48105.
(2) For a recent review, see: Anthoni, U.; Christophersen, C.; Nielsen, P. H.
In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Wiley: New York, 1999; Vol. 14, pp 163-236.
(3) Scott, A. I. Acc. Chem. Res. 1970, 3, 151-157.
(4) Ram´ırez, A.; Garcia-Rub´ıo, S. Curr. Med. Chem. 2003, 10, 1891-1915.
(5) For example, the antitumor potential of echitamine has received consider-
able study in India. See: Saraswathi, V.; Mathuram, V.; Subramanian,
S.; Govindasamy, S. Cancer Biochem. Biophys. 1999, 17, 79-88.
(6) No total syntheses in this area have been recorded.2,4
(7) Catalytic asymmetric Heck cyclizations have been proven to have wide
utility for constructing quaternary carbon stereocenters of natural products.
See: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363-5367. (b) Dounay, A. B.; Overman, L. E. Chem. ReV.
2003, 103, 2945-2963.
a Reagents: (a) TBAF, THF, rt (100%); (b) DMP, CH2Cl2, rt (99%);
(c) CNCO2Me, LiHMDS, THF, -78 °C (71%); (d) NaBH4, MeOH/THF,
0 °C (60%); (e) BzOTf, pyridine, CH2Cl2, 60 °C (100%); (f) KHMDS,
THF, -78 °C (83%); (g) LiAlH4, THF, -20 °C (89%); (h) NaOH, MeOH/
H2O, 100 °C (95%).
(8) Massiot, G.; The´penier, P.; Jacquier, M.; Le Men-Olivier, L.; Delaude,
C. Heterocycles 1989, 29, 1435-1438.
(9) Polozov, G. I.; Tishchenko, I. G. USSR Vestn. Belorus. Un-ta, Ser. 2 1986,
1, 67-69.
(10) Ohashi, M.; Takahashi, T.; Inoue, S.; Sato, K. Bull. Chem. Soc. Jpn. 1975,
48, 1892-1896.
alcohol.22 This former conversion was accomplished in standard
fashion to deliver N-Alloc derivative 15 in 78% overall yield from
precursor 12. Opening of epoxide 15 by reaction with sodium
phenylselenide, followed by hydrogen peroxide-induced elimina-
tion,23 formed the corresponding allylic alcohol, which upon silyl
protection, gave allylic silyl ether 16 in 75% overall yield. Alloc
deprotection, followed by alkylation of the resulting secondary
amine with (Z)-2-iodo-2-butenyl tosylate,24 then delivered vinyl
iodide 17 in 96% yield. Using Heck reaction conditions introduced
by Jeffery25 and a reductive trap (NaO2CH), iodide 17 was
converted to pentacyclic diamine 18 in 80% yield.
(11) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507-
6511.
(12) Comins, D.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299-6302.
(13) Hart, R. Bull. Soc. Chim. Belg. 1956, 65, 291-296.
(14) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743-8744.
(15) The use of BINAP as the ligand resulted in extensive double bond
migration to form the fully conjugated dienyl carbamate.
(16) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 200-202.
(17) For a review of microwave assisted synthesis, see: Lidstrom, P.; Tierney,
J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225-9283.
(18) Intermediate 11 can be isolated and converted to 12 in a separate step;
The conversion of pentacyclic intermediate 18 to (+)-minfiensine
(4) is adumbrated in Scheme 3. Using standard chemistry, â-ke-
toester 19 was secured in 70% overall yield.26 Transformation of
this intermediate to R,â-unsaturated ester 20 was accomplished by
reaction with NaBH4 to provide the corresponding â-hydroxyester
in 60% yield (70% based on consumed 19). Benzoylation of this
product27 and reaction with KHMDS in THF at -78 °C supplied
unsaturated ester 20 in 83% yield. Reduction of this R,â-unsaturated
ester with LiAlH4, and subsequent removal of the carbamate
the overall yield in this case was 74%.
(19) Absolute configuration was secured by single-crystal X-ray analysis of a
heavy atom derivative.
(20) The â-epoxide is isolated in 10% yield.
(21) Fritz, v. H.; Fischer, O. Tetrahedron 1964, 20, 1737-1753.
(22) Attempted acidic cleavage of the Boc protecting group at the allylic alcohol
stage led to fragmentation of the six-membered ring.
(23) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697-2699.
(24) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695-1698.
(25) (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667-2670. (b) Jeffery, T.
Tetrahedron 1996, 52, 10113-10130.
(26) Attempts to directly introduce the methyl ester by carbonylative trapping
of the alkylpalladium intermediate generated from Heck cyclization of
17 have proven unsuccessful thus far.
protecting group with NaOH, provided (+)-minfiensine (4), [R]23
D
+125 (c 0.82, CHCl3), in 85% overall yield.28
In summary, a concise catalytic asymmetric chemical synthesis
entry to alkaloids containing the 1,2,3,4-tetrahydro-9a,4a-(imino-
ethano)-9H-carbazole (1) moiety is reported. The central step in
this sequence is a sequential catalytic asymmetric Heck-N-
acyliminium ion cyclization of dienyl carbamate triflate 10 to deliver
(27) Brown, L.; Koreeda, M. J. Org. Chem. 1984, 49, 3875-3880.
(28) A rotation of [R]23 +134 (c 0.82, CHCl3) is reported for natural
D
minfiensine.8
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J. AM. CHEM. SOC. VOL. 127, NO. 29, 2005 10187