A preliminary approach to nonenolizable β,β-tricarbonyls: Assembly of a hyperevolutin prototype

Article abstract of DOI:10.1021/jo010884k

A synthetic approach to the hyperevolutin A acylated phloroglucinol ring system is described. Thus, intramolecular allene-nitrile oxide cycloaddition of 10 was used to construct the bicyclic framework and vicinal quaternary centers in cycloadduct 20 in the key bond-forming step. Treatment of 20 with Raney nickel and hydrogen gas produced primary enamine 21 which contains a nonenolizable β,β-tricarbonyl group in latent form.

Full text of DOI:10.1021/jo010884k

3134
J . Org. Chem. 2002, 67, 3134-3137
A P r elim in a r y Ap p r oa ch to Non en oliza ble
â,â-Tr ica r bon yls: Assem bly of a
Hyp er evolu tin P r ototyp e1
David G. J . Young* and Dongxiang Zeng
Department of Chemistry, University of Tennessee,
Knoxville, Knoxville, Tennessee 37996
dgjyoung@utk.edu
Received August 29, 2001
Abstr a ct: A synthetic approach to the hyperevolutin A
acylated phloroglucinol ring system is described. Thus,
intramolecular allene-nitrile oxide cycloaddition of 10 was
used to construct the bicyclic framework and vicinal qua-
ternary centers in cycloadduct 20 in the key bond-forming
step. Treatment of 20 with Raney nickel and hydrogen gas
produced primary enamine 21 which contains a nonenoliz-
able â,â-tricarbonyl group in latent form.
F igu r e 1. Biologically active structures from guttiferae.
cleavage strategy. Examination of the potential cyclo-
adducts (4 f 5 + 6) suggested that 6 should be favored
thermodynamically due to the bridgehead double bond
present in 5. Intramolecular nitrile oxide-allene cyclo-
additions had not been reported prior to the studies
described here, however, and it was not clear whether 6
or an analogous structure could be acquired using the
chemistry.13,14 Reduction of the N-O bond in 6 was
expected to produce â,â-tricarbonyl 7, or a surrogate.15
Prenyl groups were removed for the pilot study, which
led to the selection of 8 as a synthetic target (Scheme 2).
Application of the proposed allene-nitrile oxide discon-
nection to 8 led to isoxazoline tricycle 9, which was
disconnected to gem-dimethylcyclohexanone 10, a struc-
tural relative of 4 in which it was not possible for the
exocyclic allene π-bond to migrate.
The “hyperforins” are a family of natural products
isolated from various sources of guttiferae (clusia) that
have recently attracted attention from medicinal and
synthetic chemists.2 As shown in Figure 1, hyperevolutin
A (1), garsubellin A (2), and sampsonione J (3) as well
as other members of the hyperforin family are structur-
ally related by virtue of an acylated phloroglucinol A-ring
and a prenylated bicyclo[3.3.1]nonanone core.3-5
From a synthetic standpoint 1-3 and other family
members contain asymmetric vicinal quaternary centers
(C1-C2 in 1, for example) and a densely functionalized
tetracarbonyl array. No total synthesis has been de-
scribed for any of the more than 50 members of the class;
however, a single report on an approach to 2 was recently
described.6,7 Nonetheless, antitumor, antibiotic, anti-
depressant, antiHIV, and potential anti-neurodegenera-
tive properties have been associated with the hyperforins
for a number of years.8-12
Efforts toward 10 were initiated from benzylidene
ketone 11 as shown in Scheme 3.16 Thus, 11 was treated
with the cerate derived from propynylmagnesium bro-
mide, which afforded a quantitative yield of the propargyl
alcohol (not pictured).17 Alkene-selective ozonolysis of the
Scheme 1 outlines a hypothetical approach to the â,â-
tricarbonyl cluster following a cycloaddition-reductive
(8) (a) Hu, L.-H.; Sim, K.-Y. Tetrahedron Lett. 1998, 39, 7999. (b)
Decosterd, L. A.; Stoeckli-Evans H.; Chapuis, J . C.; Sordat, B.;
Hostettmann, K. Helv. Chim. Acta 1989, 72, 1833. (c) Hu, L. H.; Sim,
K. Y. Org. Lett. 1999, 1, 879. (d) Hu, L. H.; Sim, K.-Y. Tetrahedron
2000, 56, 1379.
(9) (a) Bystrov, N. S.; Chernov, B. K.; Dobrynin, V. N.; Kolosov, M.
N. Tetrahedron Lett. 1975, 32, 2791. (b) Brondz, I.; Greibrokk, T.;
Groth, P. A.; Aasen, A. J . Tetrahedron Lett. 1978, 1299. (c) Winkel-
mann, K.; Heilmann, J .; Zerbe, O.; Rali, T.; Sticher, O. J . Nat. Prod.
2000, 63, 104.
(10) Barnes, J .; Anderson, L. A.; Phillipson, J . D. J . Pharm.
Pharmacol. 2001, 53, 5, 583 and references therein.
(11) (a) Gustafson, K. R.; Blunt, J . W.; Munro, M. H. G.; Fuller, R.
W.; McKee, T. C.; Cardellina, J . H., II; McMahon, J . B.; Cragg, G. M.;
Boyd, M. R. Tetrahedron 1992, 42 10093. (b) Bokesch, H. R.; Groweiss,
A.; McKee, T. C.; Boyd, M. R. J . Nat. Prod. 1999, 62, 1197.
(12) (a) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm.
Bull. 1997, 45, 947. (b) Hefti, F. J . Neurobiol. 1994, 1418. (c) Hefti, F.
Annu. Rev. Pharmacol. Toxicol. 1997, 37, 239. (d) Verotta, L.; Appen-
dino, G.; J akupovic, J .; Bombardelli, E. J . Nat. Prod. 2000, 63, 412.
(e) Fuller, R. W.; Blunt, J . W.; Boswell, J . L.; Cardellina, II, J . H.; Boyd,
M. R. J . Nat. Prod. 1999, 62, 130.
(1) Presented at the 222nd American Chemical Society National
Meeting in Chicago, IL, August 26-30, 2001.
(2) Medical interest in hypericum species was described as early as
1943: Osborn, E. M. Brit. J . Exp. Path. 1943, 24, 227.
(3) Decosterd, L. A.; Stoeckli-Evans H.; Chapuis, J . C.; Msonthi, J .
D.; Sordat, B.; Hostettmann, K. Helv. Chim. Acta 1989, 72, 464.
(4) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull.
1997, 45, 947.
(5) Hu, L.-H.; Sim, K.-Y. Tetrahedron 2000, 56, 1379.
(6) a. Grossman, R. B.; J acobs, H. Tetrahedron Lett. 2000, 41, 5165;
b. Henry, G. E.; J acobs, H.; Carrington, C. M. S.; McLean, S.; Reynolds,
W. F. Tetrahedron 1999, 55, 1581; c. de Oliveira, C. M. A.; Porto, A. L.
M.; Bittrich, V.; Marsaioli, A. J . Phytochemistry 1999, 50, 1073; d. Hu,
L.-H.; Sim, K. Y. Tetrahedron Lett. 1999, 40, 759; e. de Oliveira, C. M.
A.; Porto, A. M.; Bittrich, V.; Vencato, I.; Marsaioli, A. J . Tetrahedron
Lett. 1996, 6427; f. Henry, G. E.; J acobs, H.; Carrington, C. M. W.;
McLean, S.; Reynolds, W. F. Tetrahedron Lett. 1996, 37, 8663; g.
Krishnamurthy N.; Ravindranath, B.; Row, T. N. G.; Venkatesan, K.
Tetrahedron Lett. 1982, 23, 2233; h. Krishnamurthy, N.; Lewis, Y. S.;
and Ravindranath, B. Tetrahedron Lett. 1981, 22, 793; I. Rao, A. V.
R.; Venkatswamy, G.; Pendse, A. D. Tetrahedron Lett. 1975, 21, 1975;
j. Blount, J . F.; Williams, T. H. Tetrahedron Lett. 1976, 34, 2921; k.
Karanjgoakar, C. G.; Rao, A. V. R.; Venkataraman, K.; Yemul, S. S.;
Palmer, K. J . Tetrahedron Lett. 1973, 50, 4977.
(13) Bruche, L.; Gelmi, M. L.; Zecchi, G. J . Org. Chem. 1985, 50,
3206.
(14) Zecchi, G. J . Org. Chem. 1979, 44, 2796.
(15) See: Rubinov, D. B.; Rubinova, I. L.; Akhrem, A. A. Chem. Rev.
1999, 99, 1047.
(7) (a) Nicolaou, K. C.; Pfefferkorn, J . A.; Kim, S.; Wei, H. X. J . Am.
Chem. Soc. 1999, 121, 4724. (b) Nicolaou, K. C.; Pfefferkorn, J . A.; Cao,
G.-Q., Sanghee, K.; Kessabi, J . Org. Lett. 1999, 1, 807.
(16) J ohnson, W. S. J . Am. Chem. Soc. 1943, 65, 1317.
(17) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
10.1021/jo010884k CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/05/2002

Notes
J . Org. Chem., Vol. 67, No. 9, 2002 3135
Sch em e 1. Nitr ile Oxid e-Allen e Cycloa d d ition
Sch em e 2. Retr osyn th etic An a lysis of 8
21 in quantitative yield via N-O bond reduction and
tautomerization of the resulting imine (Scheme 5).24
Bicyclo[3.3.1]nonanone 21 embodies requisite vicinal
quaternary centers of the natural product family and is
functionalized at all appropriate locations for hyperevo-
lutin A.
In conclusion, a synthetic approach to the hyperevo-
lutin A framework has been achieved, starting from a
known readily available ketone. The current route re-
quires ten steps and proceeds in 9% overall yield. The
key bond-forming step occurs in modest yield (40%), but
is the first example of an intramolecular allene-nitrile
oxide [3 + 2] cycloaddition. Studies toward the synthesis
of analogues and the preparation of hyperevolutin A are
underway.
product afforded R-hydroxyketone 13 that was subjected
to lithium aluminum hydride reduction to yield the
expected diols 14 as a mixture of diastereomers.18 After
initial attempts to convert 13 or 14 to the propargyl
acetate led to decomposition, carbonate 15 was prepared
and subjected to displacement by Gilman’s reagent to
yield alcohol 16.19 This material was oxidized under
Swern’s conditions to yield allenyl ketone 17.20 Aldol
condensation between 17 and 3-nitropropanal was the
initial plan for introducing the nitro side chain. This
approach was abandoned, however, when material ten-
tatively identified as a pyrone was isolated, presumably
formed via Michael addition of the aldol hydroxyl group
to the central carbon of the allene. Accordingly, the
dimethylacetal derived from 3-nitropropanal (19) was
employed in a Lewis acid-catalyzed Mukaiyama aldol
condensation with silylenol ether 18.21 The reaction of
18 and 19 in the presence of titanium tetrachloride
produced methoxy diastereomers 10a ,b in 44% yield
(Scheme 4).22 In the key event, 10 was exposed to phenyl
isocyanate in refluxing benzene to produce 20 as a single
diastereomer in 40% yield.23
Although structural assignments were not possible via
1H NMR data, X-ray diffraction showed that the methoxy
and carbonyl groups in 20 reside on opposite faces of the
cycloadduct. The “syn” diastereomeric cycloadduct was
not produced, indicating that although two diastereomers
entered the cycloaddition, only one emerged. Moreover,
if one assumes that epimerization did not occur under
the reaction conditions, it is evident that one isomer
cyclized in 80% yield while the other disintegrated.
Treatment of 10a ,b with triethylamine in benzene at
reflux did not lead to decomposition, however, which
suggests â-elimination of the methoxy group did not occur
during the cycloaddition.
Exp er im en ta l Section
6-Ben zyliden e-2,2-dim eth ylpr op-1-yn ylcycloh exan ol (12).
Cerous chloride heptahydrate (3.90 g, 10.5 mmol) was dried
using the slow dry method, and then cooled to room temperature.
To the resulting white powder was added a solution of 2.14 g
(10 mmol) of 11 in 180 mL of THF all at once. The resulting
slurry was stirred at room temperature for 4 h and then cooled
to 0 °C, and 23 mL of a 0.5 M solution (11.5 mmol) of
1-propynylmagnesium bromide in THF was added. The resulting
mixture was gradually warmed to room temperature and stirred
overnight. The reaction was quenched with 50 mL of saturated
aqueous NH4Cl. The aqueous layer was extracted with three 25-
mL portions of ether. The combined organic layers were washed
with 100 mL of brine, dried (MgSO4), and concentrated in vacuo.
The residue was flash chromatographed over 50 g of silica gel
(eluted with hexanes-ethyl acetate, 10:1) to afford 2.40 g of 12
as a pale viscous oil (95%): IR (neat) 3472, 3056,3023,2969, 2929,
2864, 2235, 1599, 1457 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.18-
7.35 (m, 5H), 6.93 (s, 1H), 2.50-2.60 (m, 2H), 2.20 (s, 1H), 1.91
(s, 3H), 1.51-1.68 (m, 4H), 1.12 (s, 3H), 1.08 (s, 3H); 13C NMR
(63 MHz, CDCl3) δ 144.99 (s), 137.99 (s), 128.80 (d), 127.86 (d),
126.04 (d), 123.22 (d), 82.83 (s), 80.31 (s), 77.85 (s), 40.58 (s),
35.98 (t), 25.26 (t), 24.59 (q), 22.56 (q), 22.24 (t), 3.48 (q); exact
mass calcd for C18H22O m/z 254.1671; found m/z 254.1670.
2-Hydr oxy-3,3-dim eth yl-2-pr op-1-yn ylcycloh exan on e (13).
A solution of 2.18 g (8.59 mmol) of alcohol 12 in 150 mL of
dichloromethane was cooled to -78 °C. Ozone was passed
through the solution until a light blue color persisted. The
solution was then purged with nitrogen until the blue color
disappeared. Dimethyl sulfide (4 mL) was added, and the
resulting solution was warmed to room temperature and stirred
overnight. The solvent was removed in vacuo, and the residue
was chromatographed over 80 g of silica gel (eluted with
hexanes-ethyl acetate, 40:1) to afford 1.17 g (76%) of 13 as a
yellow oil which solidified at room temperature: mp 38-39 °C
(from diethyl ether); IR (neat) 3464, 2964, 2923, 2876, 2227, 1720
Reductive cleavage was briefly investigated through
the exposure of 20 to methanolic Raney nickel which gave
(18) (a) Pryor, W. A.; Govindan, C. K.; Church, D. F. J . Am. Chem.
Soc. 1982, 104, 7563. (b) J ackson, W. R.; Zurqiyah, A. J . Chem. Soc.
1965, 5280.
(19) (a) Kutney, J . P.; Ratcliffe, A. H. Synth. Commun. 1975, 5, 47.
(b) Gilman, H.; J ones, R. G.; Woods, L. A. J . Org. Chem. 1952, 17,
1630.
(20) Swern, D.; Mancuso, A. J . Synthesis 1981, 165.
(21) Griesser, H.; Ohrlein, W.; Schwab, W.; Ehrler, R.; J ager, V. Org.
Synth. 1999, 77, 236.
1
cm-1; H NMR (250 MHz, CDCl3) δ 4.05 (s, 1H), 2.95-3.09 (m,
1H), 2.36-2.44 (m, 1H), 2.06-2.14 (m, 1H), 1.94 (s, 3H), 1.70-
1.92 (m, 2H), 1.40-1.47 (m, 1H), 1.19 (s, 3H), 0.70 (s, 3H); 13C
NMR (63 MHz, CDCl3) δ 209.02 (s), 84.01 (s), 79.36 (s), 77.78
(s), 44.00 (s), 35.96 (t), 35.69 (t), 24.85 (q), 21.76 (t), 19.27 (q),
3.61 (q); exact mass calcd for C11H16O2 m/z 180.1150; found m/z
(22) Mukaiyama T.; Banno, H.; Narasaka, K.J . Am. Chem. Soc.
1974, 96, 7503.
(23) Mukaiyama, T.; Hoshino, T. J . Am. Chem. Soc. 1960, 82, 5339.
Sharma, S. C.; Torssell, K. B. G. Acta Chem. Scand. 1979, B33, 379.
(24) (a) Curran, D. P. J . Am. Chem. Soc. 1982, 104, 4024. (b)
Kozikowski, A. P.; Stein, P. D. J . Am. Chem. Soc. 1982, 104, 4023. (c)
Ko, S.; Confalone, P. N. Tetrahedron 1985, 41, 3511.

3136 J . Org. Chem., Vol. 67, No. 9, 2002
Sch em e 3. P r ep a r a tion of Allen yl Keton e 16
Notes
Sch em e 4. Assem bly of Tr icycle 20
were washed with 40 mL of water, dried (MgSO4), and concen-
trated in vacuo. The residue was chromatographed over 8 g of
silica gel (eluted with hexanes-ethyl acetate, 5:1) to afford 633
mg of 15a as a white solid (99%): mp 91-92 °C (Et2O); 1H NMR
(250 MHz, CDCl3) δ 4.59 (t, J ) 6.6 Hz, 1H), 2.11-2.19 (m, 1H),
1.87 (s, 3H), 1.36-1.56 (m, 5H), 1.14 (s, 3H), 1.07 (s, 3H); 13C
NMR (63 MHz, CDCl3) δ 154.46 (s), 84.86 (s, 2C), 80.71 (d), 75.35
(s), 36.39 (s), 33.18 (t), 27.51 (t), 25.50 (q), 25.26 (q), 16.49 (t),
3.47 (q); exact mass calcd for C12H16O3 m/z 208.1099; found m/z
208.1095. Anal. Calcd for C12H16O3: C, 69.23; H, 7.69. Found:
C, 69.35; H, 7.80. Single-crystal structure showed a cis relation-
ship.
Sch em e 5. Red u ction of th e Isoxa zolin e N-O
Bon d in 20
180.1155. Anal. Calcd for C11H16O2 : C, 73.33; H, 8.89. Found:
C, 73.30; H, 8.99.
4,4-Dim eth yl-3a -p r op -1-yn ylh exa h yd r oben zo[1,3]d ioxol-
2-on e (15b). A solution of 36.4 mg (0.20 mmol) of diol 14b and
130 mg (0.80 mmol) of carbonyldiimidazole were heated in 2.5
mL of refluxing benzene for 18 h. The mixture was cooled to
room temperature, and 3 mL of water was added. The aqueous
layer was extracted with four 4-mL portions of ether and four
4-mL portions of ethyl acetate. The combined organic layers were
washed with 4 mL of water, dried (MgSO4), and concentrated
in vacuo. The residue was chromatographed over 4 g silica gel
(eluted with hexanes-ethyl acetate, 5:1) to afford 40.0 mg of
15b as a colorless oil which crystallized on standing (96%): mp
74-75 °C (diethyl ether); 1H NMR (250 MHz, CDCl3) δ 4.40 (dd,
J ) 9.0, 7.05 Hz, 1H), 2.09-2.13 (m, 2H), 2.08 (s, 3H), 1.41n˜1.91
(m, 4H), 1.19 (s, 3H), 1.08 (s, 3H); 13C NMR (63 MHz, CDCl3) δ
154.83 (s), 89.41 (s), 88.34 (s), 80.29 (d), 72.97 (s), 38.14 (s), 36.45
(t), 26.59 (q), 25.98 (t), 19.71 (t), 19.59 (q), 3.59 (q); exact mass
calcd for C12H16O3 m/z 208.1099; found m/z 208.1098. Anal. Calcd
for C12H16O3: C, 69.23; H, 7.69. Found: C, 69.15; H, 7.73.
3,3-Dim et h yl-2-(2-m et h ylp r op en ylid en e)cycloh exa n ol
(16). To a suspension of 237 mg (1.24 mmol) of cuprous iodide
in 5 mL of ether at ice-salt temperature was added methyl-
lithium (1.4 M in ether) such that a yellow precipitate formed
and redissolved. To the resulting colorless solution was added a
solution of 215 mg (1.04 mmol) of carbonates 15 in 9 mL of ether,
and the resulting mixture was stirred at 0 °C for 5 h followed
by quenching with 15 mL of saturated aqueous NH4Cl. The
aqueous layer was extracted with four 20-mL portions of ether,
and the combined organic layers were dried (MgSO4) and
concentrated in vacuo. The residue was chromatographed over
10 g of silica gel (eluted with hexanes-ethyl acetate, 10:1) to
afford 151.4 mg of 16 as a colorless oil (81%): IR (neat) 3456,
6,6-Dim eth yl-1-p r op -1-yn ylcycloh exa n e-1,2-d iol (14). Ke-
tone 13 (450 mg, 2.5 mmol) was added at room temperature to
a slurry of 474 mg (12.5 mmol) of LiAlH4 in 7 mL of THF. The
mixture was stirred at room temperature for 16 h, quenched
with 50 mL of 1 N HCl, and extracted with 100 mL of ether.
The combined organic layers were washed with brine, dried
(MgSO4), and concentrated in vacuo, and the residue was
chromatographed over 80 g of silica gel (eluted with hexanes-
ethyl acetate, 5:1) to afford 245 mg of 14a as a colorless oil which
crystallized on standing: mp 64-65 °C (diethyl ether); 1H NMR
(250 MHz, CDCl3) (3.80 (t, J ) 5.7, 1H), 2.65 (s, 1H), 2.37 (s,
1H), 1.88 (s, 3H), 1.73 (m, 1H), 1.45-1.57 (m, 4H), 1.12-1.17
(m, 1H), 1.09 (s, 3H), 1.03 (s, 3H); 13C NMR (63 MHz, CDCl3)
(81.43 (s), 80.12 (s), 76.35 (s), 72.39 (d), 38.48 (s), 32.94 (t), 27.65
(t), 25.78 (q), 23.47 (q), 19.31 (t), 3.50 (q); exact mass calcd for
C11H18O2 m/z 182.1307; found m/z 182.1305. Anal. Calcd for
C11H18O2: C, 72.53; H, 9.89. Found: C, 72.62; H, 10.06.
Continued elution using the same solvent produced 132 mg
1
of 14b as a white solid: mp 91-92 °C (diethyl ether); H NMR
(250 MHz, CDCl3) δ 3.66 (m, 1H), 2.80 (s, 1H), 1.95 (s, 1H), 1.90-
1.99 (m, 1H), 1.90 (s, 3H), 148-1.58 (m, 4H), 1.23-1.27 (m, 1H),
1.12 (s, 3H), 0.98 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 84.18 (s),
79.49 (s), 78.24 (s), 73.05 (d), 39.16 (s), 37.02 (t), 32.39 (t), 26.68
(q), 19.93 (q), 19.76 (t), 3.59 (q); exact mass calcd for C11H18O2
m/z 182.1307; found m/z 182.1307. Anal. Calcd for C11H18O2: C,
72.53; H, 9.89. Found: C, 72.74; H, 10.08.
4,4-Dim eth yl-3a -p r op -1-yn ylh exa h yd r oben zo[1,3]d ioxol-
2-on e (15a ). A solution of 0.558 g (3.07 mmol) of diol 14a and
1.99 g (12.3 mmol) of carbonyldiimidazole in 45 mL of benzene
was heated under reflux for 18 h. The mixture was cooled to
room temperature, and 30 mL of water was added. The aqueous
layer was extracted with four 15-mL portions of ether and four
15-mL portions of ethyl acetate. The combined organic layers
1
2957, 2930, 2864, 1813, 1448, 1391, 1361, 1081, 1021 cm-1; H
NMR (250 MHz, CDCl3) δ 4.10 (dd, J ) 10.8, 4.5 Hz, 1H), 2.15
(m, 1H), 1.92 (s, 1H), 1.75 (s, 3H), 1.74 (s, 3H), 1.43-1.68 (m,

Notes
J . Org. Chem., Vol. 67, No. 9, 2002 3137
3H), 1.09-1.31 (m, 2H), 1.05 (s, 3H), 1.01 (s, 3H); 13C NMR (63
MHz, CDCl3) δ 192.15 (s), 115.58 (s), 103.18 (s), 66.10 (d), 40.31
(t), 36.76 (t), 35.64 (s), 30.51 (q), 26.55 (q), 21.56 (q), 21.14 (q),
20.17 (t); exact mass calcd for C12H20O m/z 180.1514; found m/z
180.1515.
cm-1
;
1H NMR (250 MHz, CDCl3) δ 4.47 (t, J ) 6.8 Hz, 2H),
4.01-4.04 (m, 1H), 3.83-3.90 (m, 1H), 3.28 (s, 3H), 2.71-2.75
(m, 1H), 2.08-2.24 (m, 2H), 1.90-1.92 (m, 1H), 1.78 (s, 3H), 1.76
(s, 3H), 1.48-1.53 (m, 1H), 1.25-1.37 (m, 2H), 1.11 (s, 3H), 1.08
(s, 3H); 13C NMR (63 MHz, CDCl3) δ 205.31 (204.98) (s), 201.90
(201.27) (s), 113.98 (s), 101.29 (101.05) (s), 77.51 (76.49) (d), 73.27
(72.75) (t), 59.28 (57.08) (s), 52.89 (49.98) (d), 37.27 (36.82) (t),
36.00 (35.79) (s), 31.03 (28.94) (t), 30.57 (q), 29.70 (q), 19.63
3,3-Dim e t h yl-2-(2-m e t h ylp r op e n ylid e n e )c yc loh e xa -
n on e (17). To a solution of 132 mg (1.04 mmol) of oxalyl chloride
in 2.5 mL of methylene chloride at -78 °C was added 172 mg
(2.20 mmol) of dimethyl sulfoxide. The resulting mixture was
stirred for 30 min, and a solution of 149 mg (0.83 mmol) of
alcohol 16 in 1.5 mL of methylene chloride was added. The
resulting slurry was stirred at -78 °C for an additional 1.5 h,
and 0.6 mL of triethylamine was then added. The mixture was
stirred at -78 °C for 30 min, warmed to room temperature, and
stirred for 1.5 h, and then 5 mL of water was added. The aqueous
layer was extracted with four 10-mL portions of methylene
chloride. The combined organic layers were washed with 30 mL
of brine, dried (MgSO4), and concentrated in vacuo. The residue
was flash chromatographed over 8 g of silica gel (eluted with
pentane-methylene chloride, 1:1) to afford 131 mg of 17 as a
pale yellow oil (89%): IR (neat) 2958, 2868, 1949, 1679, 1451,
(19.35) (q, 2C), 18.78 (18.62) (t); exact mass calcd for C16H25
NO4 m/z 295.1784; found m/z 295.1776.
-
2-Isop r op ylid en e-7-m eth oxy-11,11-d im eth yl-3-oxa -4-a za -
tr icyclo[6.3.1.0.1.5]d od ec-4-en -12-on e (20). To a solution of
29.0 mg (0.098 mmol) of nitro-allene 10a ,b and 32.2 mg (0.147
mmol) di-tert-butyl carbonate in 2 mL of benzene and 1 mL of
acetonitrile at room temperature was added 1 mg of 4-(dimeth-
ylamino)pyridine. The mixture was stirred for 10 min, heated
to 80 °C, and stirred for 18 h. Saturated aqueous NH4Cl (2 mL)
was added, and the aqeuous layer was extracted with three 10-
mL portions of ethyl acetate. The combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was chromatographed over 2 g of silica gel (eluted with hexanes-
ethyl acetate, 10:1) to afford 11 mg of 20 as a white solid (40%):
mp 148-150 °C (MeOH); 1H NMR (250 MHz, CDCl3) δ 3.59 (m,
1H), 3.36 (s, 3H), 3.22 (dd, J ) 16.5, 7.4 Hz, 1H), 2.95-2.98 (m,
1H), 2.79 (dd, J ) 16.5, 10.5 Hz, 1H), 2.30-2.34 (m, 1H), 1.99-
2.03 (m, 2H), 1.82 (s, 3H), 1.80 (m, 3H), 1.46-1.50 (m, 1H), 1.07
(s, 3H), 0.96 (m, 3H); 13C NMR (63 MHz, CDCl3) δ 203.57 (s),
156.88 (s), 144.54 (s), 110.90 (s), 77.87 (d), 73.82 (s), 56.71 (q),
50.25 (d), 48.39 (t), 36.49 (t), 31.75 (q), 26.44 (q), 25.89 (t), 22.29
(q), 22.13 (q), 19.13 (q); exact mass calcd for C16H23NO3 m/z
277.1678; found m/z 277.1673. Anal. Calcd for C16H23NO3: C,
69.31; H, 8.30; N, 5.05. Found: C, 69.40; H, 8.38; N, 4.98.
2-Am in o-1-isob u t yr yl-4-m et h oxy-8,8-d im et h ylb icyclo-
[3.3.1]n on -2-en -9-on e (21). A solution of 25.2 mg (0.09 mmol)
of 20 and 5 mg of Raney nickel in 3 mL of methanol was stirred
under hydrogen for 24 h. The mixture was filtered and concen-
trated in vacuo to afford 25 mg of 21 as a white solid (100%):
mp 135-137 °C (MeOH); 1H NMR (250 MHz, CDCl3) δ 5.17 (d,
J ) 2.2 Hz, 1H), 4.15 (dd, J ) 6.5, 2.4 Hz, 1H), 3.34 (s, 3H), 31.2
(s, 2H), 2.93 (t, J ) 5.6 Hz, 1H), 2.59 (m J ) 6.5 Hz, 1H), 1.92-
2.08 (m, 2H), 1.73-1.81 (m, 1H), 1.60 (m, 1H), 1.33 (s, 3H), 1.17
(d, J ) 6.5 Hz, 3H), 1.13 (d, J ) 6.5 Hz, 1H), 1.09 (s, 3H); 13C
NMR (63 MHz, CDCl3) δ 214.78 (s), 209.87 (s), 139.04 (d), 101.84
(s), 76.48 (d), 72.84 (s), 56.01 (q), 48.95 (d), 43.79 (s), 39.99 (d),
37.11 (t), 27.62 (q), 23.41(t), 22.19 (q, 2C), 20.84 (q); exact mass
calcd for C16H25NO3 m/z 279.1834; found m/z 279.1827. Anal.
Calcd for C16H25NO3 C, 68.82; H, 8.96; N, 5.02. Found: C, 68.95;
H, 9.08; N, 5.03.
1
1383, 1180 cm-1; H NMR (250 MHz, CDCl3) δ 2.41 (t, J ) 6.6
Hz, 2H), 1.85-1.89 (m, 2H), 1.76 (s, 6H), 1.62-1.67 (m, 2H),
1.07 (s, 6H); 13C NMR (63 MHz, CDCl3) δ 204.86 (s), 201.95 (s),
113.85 (s), 100.89 (s), 40.33 (t), 37.99 (t), 35.94 (s), 30.18 (q, 2C),
19.58 (q, 2C), 19.30 (t); exact mass calcd for C12H18O m/z
178.1358; found m/z 178.1355.
[5,5-Dim eth yl-6-(2-m eth ylp r op en ylid en e)cycloh ex-1-en -
yloxy]tr im eth ylsila n e (18). A solution of 0.165 mL (0.119 g,
1.18 mmol) of diisopropylamine in 3 mL of THF at -78 °C was
treated with 0.71 mL of a 1.6 M solution of n-BuLi in hexane
(1.13 mmol). The resulting solution was stirred at -78 °C for
10 min warmed to 0 °C, stirred 30 min, and recooled to -78 °C.
To the resulting solution of LDA was added a solution of 0.175
g (0.98 mmol) of ketoallene 17 in 2 mL of THF. The mixture
was stirred at -78 °C for 1 h, and 0.150 mL (0.128 g, 1.18 mmol)
of chlorotrimethylsilane was added. The reaction was allowed
to warm to room temperature over 3 h and then stirred for an
additional 18 h. The solvent was removed in vacuo. The residue
was dissolved in hexane and filtered through 1.5 g of Florisil to
afford 232 mg (95%) of 18 as an unstable colorless oil: IR (neat)
2959, 2871, 1951, 1699, 1452, 1386, 1364, 1251, 844 cm-1 1H
;
NMR (250 MHz, CDCl3) δ 5.00 (t, J ) 4.2 Hz, 1H), 2.14 (pt, J )
6.1 Hz, 2H), 1.73 (s, 6H), 1.44 (t, J ) 6.2 Hz, 2H), 1.03 (s, 6H),
0.14 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 198.59 (s), 145.19 (s),
109.96 (s), 107.26 (d), 99.37 (s), 36.23 (t), 34.15 (s), 28.23 (q, 2C),
21.40 (t), 20.69 (q, 2C), -0.03 (q, 3C).
6-(1-Met h oxy-3-n it r op r op yl)-3,3-d im et h yl-2-(2-m et h yl-
p r op en ylid en e)cycloh exa n on e (10a ,b). To a solution of 87.1
mg of nitropropanal dimethylacetal 19 (0.59 mmol) in 5 mL of
methylene chloride at -78 °C was added 63.7 µL (110 mg, 0.59
mmol) of titanium(IV) chloride. The resulting yellow solution
was stirred for 10 min before a solution of 0.121 g (0.48 mmol)
of enol ether 18 in 1 mL of methylene chloride was added. The
mixture was stirred at -78 °C for 2 h and then quenched with
10 mL of aqueous K2CO3. The aqueous layer was extracted with
three 15-mL portions of ethyl acetate. The combined organic
layers were washed with 20 mL of brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over
2 g of silica gel (eluted with hexanes-ethyl acetate, 10:1) to
afford 62.5 mg of 10a ,b as a 1:1 mixture of diastereomers
(44%): IR (neat) 2959, 1948, 1667, 1553, 1448, 1383, 1156, 1093
Ack n ow led gm en t. The author thanks the Univer-
sity of Tennessee for providing research funds, and
Tianniu Chen for X-ray crystallography. The crystal
structure and associated atomic coordinates have been
deposited with the Cambridge Structural Database.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds and X-ray structural data for
20 and 15 is available free of charge via the Internet at
http://pubs.acs.org.
J O010884K