Asymmetric synthesis of the Lycopodium alkaloid, N(a)-acetyl-N(b)- methylphlegmarine

Full text of DOI:10.1021/jo990192k

2184
J . Org. Chem. 1999, 64, 2184-2185
Sch em e 1
Asym m etr ic Syn th esis of th e Lycopod iu m
Alk a loid , Na -Acetyl-Nb-m eth ylp h legm a r in e
Daniel L. Comins,* Adam H. Libby,
Rima S. Al-awar, and Christopher J . Foti
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
Received February 2, 1999
The plentiful and structurally interesting Lycopodium
alkaloids provide challenging targets for total synthesis.1
The phlegmarines are a C16N2 skeletal group of Lycopodium
alkaloids discovered by Braekman and co-workers in 1978.2
The members of this group (1a -d ) differ from one another
by their substituent pattern on the two nitrogen atoms.
Unlike most other perhydroquinoline containing Lycopodium
alkaloids, the phlegmarines possess a trans-decahydroquino-
line unit in their skeleton rather than the usual cis arrange-
ment. Racemic NR-methyl-Nâ-acetylphlegmarine (1e) was
Sch em e 2
synthesized by MacLean and co-workers, an accomplishment
that defined the relative stereochemistry of the phlegma-
rines.3 The absolute sense of chirality of the phlegmarine
alkaloids had not been determined. We now report the first
asymmetric synthesis of a naturally occurring phlegmarine
alkaloid, (-)-NR-acetyl-Nâ-methylphlegmarine (1d ).
.
Our synthetic plan followed the retrosynthetic analysis
depicted in Scheme 1. The strategy involves enantioselective
preparation of key fragment 2, which after conversion to an
organometallic is added to chiral 1-acylpyridinium salt 3 to
give phlegmarine precursor 4 with control of stereochemistry
at C-2′. We chose the enantiomer depicted in structure 1d
as our target based on analogy to other related Lycopodium
alkaloids, i.e., lycodine, of known absolute stereochemistry.1b
The Grignard of (R)-5-chloro-4-methylpentene4 was added
to chiral 1-acylpyridinium salt 3, prepared in situ from
4-methoxy-3-(triisopropylsilyl)pyridine5 and the chlorofor-
mate of (-)-trans-2-(R-cumyl)-cyclohexanol (TCC),6 to give
the crude N-acyldihydropyridone 5 in 90% yield and 88%
de (Scheme 2). Purification by recrystallization from ethanol
provided a 76% yield of the major diastereomer 5 as a white
solid. A one-pot reaction of 5 with NaOMe/MeOH followed
by aqueous 10% HCl furnished dihydropyridone 6 in 95%
yield with 95% recovery of the chiral auxiliary, (-)-TCC.
N-Acylation of 6 with n-BuLi and phenyl chloroformate gave
(1) (a) Ayer, W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A., Brossi,
A., Eds.; Academic Press: San Diego, 1994; Vol. 45, pp 233-274. (b)
Blumenkopf, T. A.; Heathcock, C. H. Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp 185-
240. (c) Schumann, D.; Naumann, A. Liebigs Ann. Chem. 1984, 1519. (d)
Szychowski, J .; MacLean, D. B. Can. J . Chem. 1979, 57, 1631. (e) Tori, M.;
Shimoji, T.; Takaoka, S.; Nakashima, K.; Sono, M.; Ayer, W. A. Tetrahedron
Lett. 1999, 40, 323.
(2) Nyembo, L.; Goffin, A.; Hootele, C.; Braekman, J .-C. Can. J . Chem.
1978, 56, 851.
(3) (a) Leniewski, A.; Szychowski, J .; MacLean, D. B. Can. J . Chem. 1981,
59, 2479. (b) Leniewski, A.; MacLean, D. B.; Saunders, J . K. Ibid. 1981, 59,
2695.
(5) Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem. Soc. 1994,
116, 4719.
(6) (a) Comins, D. L.; Salvador, J . M. J . Org. Chem. 1993, 58, 4656. (b)
The (+)- and (-)-TCC alcohols are available from Aldrich Chemical Co.
(4) The chloride was prepared (NCS, Ph3P, CH2Cl2) from the known
enantiopure alcohol; see: Evans, D. A.; Bender, S. L.; Morris, J . J . Am.
Chem. Soc. 1988, 110, 2506.
10.1021/jo990192k CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/06/1999

Communications
J . Org. Chem., Vol. 64, No. 7, 1999 2185
Sch em e 3
Sch em e 4
a quantitative yield of enantiopure carbamate 7. Conjugate
reduction of the endocyclic double bond with L-Selectride
in the presence of BF3‚OEt2 afforded ketone 8 in 86% yield.
In the absence of BF3‚OEt2, a significant amount of 1,2-
reduction was observed.7 Ozonolysis of the teminal alkene
of 8 provided a 91% yield of aldehyde 9, which underwent
an acid-mediated cyclization to the bicyclic enone 10 (84%).
The copper-mediated reaction of Grignard 11 with enone
10 and enolate trapping with N-5-(chloro-2-pyridyl)triflim-
ide8 gave a high yield (96%) of 12 with complete stereose-
lectivity. The selectivity was anticipated on the basis of
model studies that indicated stereoelectronically controlled
axial attack at C-5 would occur.9 The vinyl triflate was
smoothly reduced to alkene 13 in 95% yield using Cacchi’s
procedure10 (Scheme 3). Hydrolysis of the carbamate group
in 13 was effected with KOH in refluxing 2-propanol to
provide amine 14 in 91% yield. Hydrogenation of 14 gave a
mixture of crude amines that were isolated as carbamate
derivative 15 and the corresponding cis C-10 epimer. HPLC
analysis of this mixture showed a ratio of 89/11 favoring the
trans diastereomer 15. The trans selectivity is due to
significant shielding of the bottom face of the alkene in 14
by the axial (phenyldimethylsilyl)methyl group. Purification
by chromatography provided a 78% yield of pure 15. Oxida-
tion of the phenyldimethylsilyl group using Fleming’s pro-
cedure11 and subsequent reduction with lithium aluminum
hydride gave amino alcohol 16 (93%), which was converted
to the iodide 2 (86%) on treatment with 1,2-bis(triph-
enylphospino)ethane tetraiodide.12 Organometallics pre-
pared from 2 (R-MgX, R-Li, R-CuX) were added to
1-acylpyridinium salt 3 with little or no success (0-13%
yield).13 After several attempts, the mixed Grignard reagent
17 and 2 equiv of 3 afforded the desired dihydropyridone 4
in moderate yield (50%, Scheme 4) along with the corre-
sponding methyl addition product (50%).14 A single-crystal
X-ray structure of 4 confirmed that all five stereogenic
centers were correctly installed with respect to the target
alkaloid. One-pot removal of the TIPS group and TCC
auxiliary provided a 73% yield of dihydropyridone 18, which
was acylated to give 19 (88%). The synthesis was completed
by formation of vinyl triflate 208a and subsequent catalytic
reduction (90%) to provide NR-acetyl-Nâ-methylphlegmarine
(1d ), which exhibited spectral data in agreement with
reported data for authentic material.2,3 The optical rotation
[[R]D -18.5 (c 0.33, CHCl3)] is also in agreement with the
literature value [[R]D -11 (c 0.7, CHCl3)].2
In summary, the first asymmetric synthesis of a phleg-
marine alkaloid, (-)-NR-acetyl-Nâ-methylphlegmarine (1d ),
has been accomplished in 18 steps with a high degree of
stereocontrol.15 Our asymmetric synthesis of 1d has estab-
lished the absolute stereochemistry of this alkaloid as
2′S,5S,7R,9R,10R. The stereochemical relationship (5S,7R,-
10R) corresponds to several other Lycopodium alkaloids.
This determination strengthens the postulate that phleg-
marine may serve as an intermediate for the biosynthesis
of a variety of related Lycopodium compounds.2
Ack n ow led gm en t. We express appreciation to the
National Institutes of Health (Grant GM 34442) for finan-
cial support of this research. R.A. also thanks the Bur-
roughs Wellcome Fund for a graduate fellowship. We are
grateful to Dr. J .-C. Braekman for copies of a mass
spectrum and an 1H NMR spectrum of natural NR-acetyl-
Nâ-methylphlegmarine. NMR and mass spectra and X-ray
analysis of 4 were obtained at NCSU instrumentation
laboratories, which were established by grants from the
North Carolina Biotechnology Center and the National
Science Foundation (Grant CHE-9121380, CHE-9509532).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for 1d , 2, 4, 5-10, 12-16, and 18-
(7) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1989, 30, 5053.
(8) (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299. (b)
Comins, D. L.; Dehghani, A.; Foti, C. J .; J oseph, S. P. Org. Synth. 1996, 74,
77.
1
20, H and/or 13NMR spectra of 1d , 2, 4, 6, 9, 14-16, and 18-20,
and X-ray data of compound 4.
(9) Comins, D. L.; Al-awar, R. S. J . Org. Chem. 1995, 60, 711.
(10) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821.
(11) Fleming, I.; Sanderson, P. E. Tetrahedron Lett. 1987, 28, 4229.
(12) Schmidt, S. P.; Brooks, D. W. Tetrahedron Lett. 1987, 28, 767.
(13) Comins, D. L.; Foti, C. J .; Libby, A. H. Heterocycles 1998, 48, 1313.
(14) Comins, D. L.; Goehring, R. R.; J oseph, S. P.; O’Connor, S. J . Org.
Chem. 1990, 55, 2574.
J O990192K
(15) The structure assigned to each new compound is in accord with its
IR, 1H and 13C NMR spectra, and elemental analysis or high-resolution mass
spectra.