9044
J. Am. Chem. Soc. 2000, 122, 9044-9045
Scheme 1
Enantioselective Total Synthesis of Nicandrenones
Brian M. Stoltz, Taichi Kano, and E. J. Corey*
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed July 10, 2000
The nicandrenone (NIC) family of structurally complex, steroid-
derived natural products includes the active principals of Nicandra
physaloides (the Pyruvian “shoofly” plant) which give rise to its
insect repellent and antifeedant properties.1 The novel structures
of the nicandrenones were elucidated independently by groups
in the US2 and UK3 almost 30 years ago. The NIC family is
structurally related to another and even larger class of plant
products, the withanolides.4 No member of either group has been
made by total synthesis. We describe herein the first syntheses
of nicandrenones, specifically NIC-1 lactone (1), NIC-1 (2), and
NIC-10 (3), by an approach which is both enantio- and diaste-
reoselective.
The synthesis of the tetracyclic nicandrenone nucleus (Scheme
1) commenced with a highly unusual exo-selective Diels-Alder
reaction to generate all four rings in a stereocontrolled way.
Addition of diene 55 (1.05 equiv) to a mixture of the chiral R,â-
enone 46 and methylaluminum dichloride (1.05 equiv) in CH2Cl2
at -78 °C over 2.5 h resulted in formation of the exo adduct 6
1
(85%, exo-endo selectivity >15:1 by H NMR analysis). The
a MeAlCl2,CH2Cl2,-78°C.b LiAlH4,Et2O,-78°C.c C6H5CH2OCH2Cl,
EtN(i-Pr)2, CH2Cl2, 23 °C. d p-TsOH, MeOH, 23 °C. e LDA, TMSCl,
mechanistic basis of the high exo selectivity in the reaction leading
to 6 has recently been analyzed in detail.7,8 Conversion of 6 to
the benzyloxymethyl (BOM) ether 79 was accomplished in 82%
overall yield by reduction with LiAlH4 (1.05 equiv) in Et2O at
-78 °C for 20 min and subsequent reaction with BOM-Cl (2
equiv) and EtN(i-Pr)2 in CH2Cl2 at 23 °C for 46 h. The R,â-
enone 89 was obtained from 7 in 64% overall yield by the
following sequence: (1) TES cleavage with 0.6 equiv of p-
toluenesulfonic acid in MeOH-CH2Cl2 at 23 °C for 5 min, (2)
trimethylsilyl enol ether formation with LDA-TMSCl in THF
at -78 °C, and (3) R,â-enone formation with 10 mol % Pd(OAc)2
and O2 in dimethyl sulfoxide (DMSO) in the presence of 2,6-di-
tert-butyl-4-methylpyridine at 23 °C for 12 h. The carbonyl group
of 8 was reduced (L-selectride, THF, -78 °C, 20 min) and the
resulting allylic alcohol was subjected to cis epoxidation (t-
BuOOH, 0.3 equiv of VO(acac)2, CH2Cl2, 0 °C, 20 h) and
subsequent acetylation to give 99 (71% from 8). Deallylation of
9 (5 mol % Pd(Ph3P)4, excess Et2NH, CH2Cl2, 3 h at 40 °C) and
g
-78 °C. f Pd(OAc)2, O2, DMSO, 23 °C. L-selectride, THF, -78 °C.
h t-BuOOH, VO(acac)2, CH2Cl2, 0 °C. i Ac2O, Et3N, DMAP, -25 °C.
j Pd(Ph3P)4, Et2NH, CH2Cl2, 40 °C. k C4F9SO2F, Et3N, CH2Cl2, 23 °C.
l H2, Pd-C, 23 °C. m Dess-Martin periodinane, CH2Cl2, 23 °C. n K2CO3,
MeOH, 23 °C. o MgI2, NaI, CH2Cl2-CH3CN, 0 °C. p CH3SO2Cl, Et3N,
-60 to 23 °C. q t-BuOOH, VO(acac)2, CH2Cl2, 0 °C.
reaction with nonafluorobutanesulfonyl fluoride (NfF) and Et3N
in CH2Cl2 for 18 h at 23 °C produced the nonaflate 109 (93%
from 9). Epoxy ketone 119 was accessed from 10 in 86% overall
yield by the following sequence: (1) BOM ether cleavage (1 atm
H2, Pd-C, EtOAc-HOAc, 23 °C, 7 h), (2) Dess-Martin
periodinane oxidation of the resulting alcohol (in CH2Cl2 at 23
°C for 2 h), and (3) deacetylation (K2CO3 in CH3OH at 23 °C).
The oxiranyl carbinol subunit of 11 was unusually reactive as
demonstrated by transformation to the corresponding 6â-iodo-
5,7-diol structure upon treatment with 6 equiv of MgI2 and 6 equiv
of NaI in CH3CN-CH2Cl2 at 0 °C for 10 min. Reaction of this
diol with CH3SO2Cl-Et3N (2 equiv, 3 equiv) at -66 °C to +23
°C over 1.5 h resulted in elimination to form 129 in 72% overall
yield.10,11 Epoxidation of 12 with t-BuOOH and 0.1 equiv of VO-
(acac)2 in CH2Cl2 at 0 °C for 44 h gave 139 in 76% yield.
The enantioselective synthesis of the NIC-1 side chain fragment
is outlined in Scheme 2, the starting point being the known lactone
14.12 Amidation with a reagent from 2.5 equiv of trimethylalu-
minum and 2.5 equiv of N,O-dimethylhydroxylamine hydrochlo-
(1) (a) Nalbandov, O.; Yamamoto, R. T.; Fraenkel, G. S. J. Agric. Food
Chem. 1964, 12, 55. (b) Fraenkel, G.; Nayer, J.; Nalbandov, O.; Yamamoto,
R. T. Int. Kongr. Entomol. Verh., 11th 1960, 3, 122.
(2) (a) Bates, R. B.; Eckert, D. J. J. Am. Chem. Soc. 1972, 94, 8258. (b)
Bates, R. B.; Morehead, S. R. J. Chem. Soc., Chem. Commun. 1974, 125.
(3) (a) Begley, M. J.; Crombie, L.; Ham, P. J.; Whiting, D. A. J. Chem.
Soc., Chem. Commun. 1972, 1108. (b) Begley, M. J.; Crombie, L.; Ham, P.
J.; Whiting, D. A. J. Chem. Soc., Chem. Commun. 1972, 1250. (c) Begley,
M. J.; Crombie, L.; Ham, P. J.; Whiting, D. A. J. Chem. Soc., Perkin Trans.
1 1976, 304.
(4) (a) Ray, A. B. J. Indian Chem. Soc. 1998, 75, 672. (b) Kirson, I.; Glotter,
E. J. Nat. Prod. 1981, 44, 633.
(5) Diene 5 was synthesized from 6-allyloxy-1-tetralone by the following
sequence: (1) addition of 1-ethoxyvinyllithium, (2) dehydration of the resulting
tertiary alcohol, (3) hydrolysis of vinyl ether to methyl ketone, and (4)
triethylsilyl (TES) enol ether formation using triethylsilyltriflate and triethy-
lamine in CH2Cl2 at 0 °C.
(10) The formation of 12 from the 6â-iodo-5,7R-diol precursor is considered
to occur via the 7R-mesylate by solvolysis to the 6,7-â-iodonium ion which
undergoes I+ transfer to Et3N forming Et3NI+. The transfer of positve halogen
to amines is well-known. For a similar elimination see: Corey, E. J.; Marfat,
A.; Falck, J. R.; Albright, J. O. J. Am. Chem. Soc. 1980, 102, 1433.
(11) (a) Attempts to generate 12 by a Wharton elimination of 5,6-R-epoxy-
7-keto intermediate with hydrazine were completely unsuccessful. See: Dupuy,
C.; Luche, J. L. Tetrahedron 1989, 45, 3437. (b) For epoxidation reactions
catalyzed by VO(acac)2 see: Sharpless, K. B.; Michaelson, R. C. J. Am. Chem.
Soc. 1973, 95, 6136.
(12) Lactone 14 was synthesized in two steps from 2,3-dimethylbutadiene
as described by Aumann et al. (Aumann, R.; Ring, H.; Kru¨ger, C.; Goddard,
R. Chem. Ber. 1979, 112, 3644) using sequential monoepoxidation and Pd-
catalyzed carbonylation.
(6) Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 811.
(7) Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett. 2000, 2, 1927.
(8) The structure of adduct 6 (a racemic sample) was confirmed by reaction
with CuCl2 in dimethylformamide at 60 °C to form the corresponding ∆(8)-
1,7-diketone (steroid numbering, mp 172-3 °C) and subsequent X-ray
crystallographic analysis. Detailed X-ray crystallographic data are available
from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge,
CB2 1EZ, U.K.
(9) This product was purified by column chromatography on silica gel.
10.1021/ja0024892 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/02/2000