Enantioselective total syntheses of the 5,11-methanomorphanthridine Amaryllidaceae alkaloids (-)-pancracine and (-)-coccinine

Full text of DOI:10.1021/ja963900h

2050
J. Am. Chem. Soc. 1997, 119, 2050-2051
Communications to the Editor
Scheme 1a
Enantioselective Total Syntheses of the
5,11-Methanomorphanthridine Amaryllidaceae
Alkaloids (-)-Pancracine and (-)-Coccinine
Jian Jin and Steven M. Weinreb*
Department of Chemistry
The PennsylVania State UniVersity
UniVersity Park, PennsylVania 16802
ReceiVed NoVember 12, 1996
The 5,11-methanomorphanthridine alkaloids are a small
subclass of compounds of the Amaryllidaceae type first isolated
by Wildman and co-workers over four decades ago.1 These
natural products, produced by plants of various Pancratium,
Narcissus, and BrunsVigia species, have a unique pentacyclic
structural framework exemplified by the alkaloids (-)-mon-
tanine (1), (-)-coccinine (2), (-)-pancracine (3), and (-)-
brunsvigine (4). In general, the alkaloids of this group are
identical except for the oxygen substitution (i.e., methoxyl Vs
hydroxyl) and stereochemistry at C-2 and C-3.2,3 Despite
extensive synthetic effort in the area of Amaryllidaceae alka-
loids,3 the construction of the 5,11-methanomorphanthridines
has received little attention. Overman and Shim have described
an elegant approach to both racemic and (-)-pancracine (3).4
In a nice series of papers, Hoshino and co-workers reported
total syntheses of alkaloids 1-4 in racemic form.5 In this
communication, we describe the application of our recently
discovered stereospecific intramolecular allenylsilane imino ene
chemistry6 as the pivotal step in enantioselective total syntheses
of (-)-coccinine (2) and (-)-pancracine (3).
a (a) PhCH2Br, NaH, TBAI, THF, -20 °C to room temperature (rt),
96%; (b) KCN, MeOH, ∆, 93%; (c) TBSCl, imidazole, DMF, 0 °C-
rt, 94%; (d) disiamylborane, THF, 0 °C-rt/NaOH, H2O2, 88%; (e)
Swern ox, 96%; (f) HCCMgBr, CH2Cl2, -78 to 0 °C, 89%; (g) Ac2O,
TEA, DMAP, CH2Cl2, 98%; (h) DEAD, Ph3P, HOAc, pyr, THF, -45
°C-rt, 86%; (i) (Me2PhSi)2CuCNLi2, THF, -96 °C, 84%; (j) DIBALH,
PhMe, -78 to 0 °C, 78%.
to yield nitrile 6 having differentially functionalized C-2,3
oxygen atoms (methanomorphanthridine numbering) (Scheme
1). The vinyl group of 6 was then hydroborated and the
intermediate primary alcohol oxidized to afford aldehyde 7.
Addition of ethynylmagnesium bromide to 7 produced a 2:1
mixture of (S)- and (R)-propargyl alcohols 8 and 9, respectively.
Each of these chromatographically separable epimers could be
efficiently processed to the desired S-acetate 10. Thus, alcohol
8 was directly acetylated, whereas 9 could be transformed
cleanly to 10 via a Mitsunobu inversion.8 Subjection of
propargyl acetate 10 to the silyl cuprate conditions of Fleming
and Terrett9 stereospecifically afforded the desired (R)-allenyl-
silane nitrile, which was reduced to aldehyde 11.
Aldehyde 11 was then condensed with iminophosphorane 12
to afford the corresponding imine 13 (Scheme 2).10,11 Upon
heating this imine/allenylsilane in mesitylene at 162 °C, a
stereospecific cyclization occurred to afford, after alkyne
desilylation, a single amino acetylene 14. No other stereoisomer
was detected in this reaction. We believe that this transforma-
tion occurs via a concerted thermal imino ene reaction.6 This
pericyclic process can, in principle, proceed through two imine
conformations 13a and/or 13b. Inspection of models indicates
that the two conformers are capable of undergoing a concerted
Our synthesis commenced with enantiomerically pure hy-
droxy epoxide 5, readily available by Sharpless asymmetric
epoxidation of divinylcarbinol.7 This compound was first
O-benzylated, the epoxide was regioselectively opened with
cyanide, and the resulting secondary alcohol was O-silylated
(1) Wildman, W. C.; Kaufman, C. J. J. Am. Chem. Soc. 1955, 77, 1249.
Inubushi, Y.; Fales, H. M.; Warnhoff, E. W.; Wildman, W. C. J. Org. Chem.
1960, 25, 2153. Wildman, W. C.; Brown, C. L. J. Am. Chem. Soc. 1968,
90, 6439.
(2) For an apparent exception, see: Viladomat, F.; Bastida, J.; Codina,
C.; Campbell, W. E.; Mathee, S. Phytochemistry 1995, 40, 307.
(3) For reviews, see: (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.;
Academic Press: The Amaryllidaceae Alkaloids. San Diego, CA, 1987,
30, 252. (b) Lewis, J. R. Nat. Prod. Rep. 1993, 10, 291. (c) Southon, I. W.;
Buckingham, J. Dictionary of the Alkaloids; Chapman Hall: New York,
1989; pp 229, 735, 817.
(4) (a) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005. (b)
Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662.
(5) (a) Ishizaki, M.; Hoshino, O.; Iitaka, Y. J. Org. Chem. 1992, 57,
7285. (b) Ishizaki, M.; Kurihara, K.; Tanazawa, E.; Hoshino O. J. Chem.
Soc., Perkin Trans. 1 1993, 101 and references cited therein.
(6) Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. J. Am. Chem. Soc.
1995, 117, 10905. Jin, J.; Smith, D. T.; Weinreb, S. M. J. Org. Chem.
1995, 60, 5366. See also: Weinreb, S. M. J. Heterocycl. Chem. 1996, 33,
1429.
(8) Wovkulich, P. M.; Shankaran, K.; Kiegel, J.; Uskokovic, M. R. J.
Org. Chem. 1993, 58, 832.
(9) Fleming, I.; Terrett, N. K. J. Organomet. Chem. 1984, 264, 99. This
reaction has been shown to proceed via an SN2′-anti process.
(10) Prepared from the corresponding azide and triphenylphosphine. Cf.:
Lambert, P. H.; Vaultier, M.; Carrie, R. J. Chem. Soc., Chem. Commun.
1982, 1224 and references cited therein.
(11) Direct reaction of aldehyde 11 with o-bromopiperonylamine to
produce the imine failed. Under forcing conditions, only the R,â-unsaturated
aldehyde from â-elimination of the siloxy group was formed.
(7) Schreiber, S. L.; Schreiber, T. L.; Smith, D. B. J. Am. Chem. Soc.
1987, 109, 1525. Babine, R. E. Tetrahedron Lett. 1986, 27, 5791.
S0002-7863(96)03900-5 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 8, 1997 2051
Scheme 2
Scheme 3a
ene reaction, but this has no consequence for the synthesis since
both lead to the same stereoisomeric cyclization product 14.
To continue the synthesis, alkyne 14 was partially hydroge-
nated using Lindlar catalyst to generate the terminal olefin. We
were pleased to find that this bromo alkene cyclizes under Heck
conditions12 to form the desired exocyclic seven-membered ring
alkene, subsequently N-protected as the sulfonamide 15 (Scheme
3). A number of attempts were made to hydroborate 15 to
produce the corresponding R-hydroxymethyl compound, but in
general, these reactions produced mixtures of the R- and
â-stereoisomers. An alternative strategy for stereoselectively
functionalizing the exocyclic methylene group was explored
using a sequence applied by Danishefsky and McClure in the
FR 900482 system.13 Therefore, oxidation of 15 was effected
with dimethyldioxirane14 to yield a 2:1 mixture of stereoisomeric
epoxides. Exposure of this epoxide mixture to anhydrous ferric
chloride at low temperature led to aldehyde 16, which was
immediately reduced15 with DIBALH to afford R-hydroxy-
methyl compound 17 as a single stereoisomer. It seems
probable that this transformation occurs via initial epoxide
opening to a benzylic carbonium ion which subsequently
undergoes a highly stereoselective 1,2-hydride migration from
the less congested convex face of the molecule.
a (a) Lindlar catalyst, H2, quinoline, MeOH, 93%; (b) Pd(PPh3)4,
TEA, MeCN, Me3BuNCl, 120 °C, 74%; (c) TsCl, pyr, DMAP, 100
°C, 92%; (d) Me2CO2; Me2CO, -20 °C, 89%; (e) FeCl3, CH2Cl2, -78
°C/DIBALH, 88%; (f) H2, 10% Pd-C, MeOH; (g) Na, naphthalene,
DME, -78 °C; (h) PPh3, I2, imidazole, Et2O, MeCN, 0 °C, 82% from
18; (i) TPAP, NMO, CH2Cl2, 96%; (j) LDA, TMSCl, THF, -78 °C/
Pd(OAc)2, MeCN, rt, 81%; (k) TBAF, THF, 0 °C-rt, 98%; (l)
(MeO)3CH, MeOH, p-TsOH, rt, 91%; (m) DIBALH, PhMe, rt, 81%.
to afford enone 19. Removal of the TBS group of 19 led to
1
hydroxy enone 20, having H and 13C NMR spectra identical
with those of material prepared by Overman and Shim,4,19 which
they found could be reduced to (-)-pancracine (3) with sodium
triacetoxyborohydride. In addition, it was possible to convert
enone 19 to the dimethyl ketal 21, which upon treatment with
DIBALH5 underwent reduction and cleavage of the TBS group
to afford (-)-coccinine (2) having a 1H NMR spectrum identical
with that of authentic alkaloid.20-22
Acknowledgment. We thank the National Institutes of Health (CA-
34303) for generous support of this research and Dr. Stephen P.
Fearnley and Professor R. L. Funk for helpful discussions.
The O-benzyl group of 17 was removed by hydrogenolysis,
followed by N-tosyl group cleavage to give an amino diol which
could be efficiently cyclized in a single step by treatment with
triphenylphosphine/iodine16 to yield the desired pentacyclic
alcohol 18. This compound was then oxidized to the ketone,
converted to a TMS enol ether under kinetically controlled
conditions,17 and dehydrogenated by the Saegusa methodology18
Supporting Information Available: Spectral data and experimental
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JA963900H
(18) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
1
(12) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Cf.: Cornec, O.;
Joseph, B.; Merour, J. Tetrahedron Lett. 1995, 36, 8587.
(13) McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115,
6094.
(14) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(15) Aldehyde 16 epimerizes readily to the more stable â-stereoisomer
upon attempted chromatographic purification.
(16) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979,
978.
(17) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(19) We thank Professor Larry Overman for H and 13C NMR spectra
of intermediate 20 and a sample of (-)-pancracine.
1
(20) We are grateful to Professor O. Hoshino for the H NMR spectra
of racemic montanine, coccinine and some synthetic intermediates.
(21) A small amount (<10%) of montanine (1) is also produced in this
reaction, possibly due to silyl group cleavage prior to hydride reduction of
the ketal. DIBALH reduction of the hydroxy ketal corresponding to 21
affords about a 1:1 mixture of coccinine (2) and montanine (1).
(22) Presented at the 212th National Meeting of the American Chemical
Society, Orlando, FL, August 25, 1996; ORGN 47.