Asymmetric total synthesis of the Caribbean fruit fly pheromone (+)-epianastrephin

Article abstract of DOI:10.1021/jo960568j

An asymmetric total synthesis of (+)-epianastrephin (1) from the chiral benzamide 2 (15 steps, 9.5% overall yield) is described. Birch reduction-alkylation of 2 with methyl iodide gave 3 in 91% yield as a single diastereomer. Cyclohexadiene 3 was converted to olefinic carboxylic acid 6b, and a tandem iodolactenization-radical reduction sequence provided lactone 8 with three contiguous stereogenic centers. Chiral HPLC comparison of diol 12b, the immediate precursor to (+)-epianastrephin (1), with 12b prepared from racemic epianastrephin demonstrated that 1 had been prepared with > 98% ee.

Full text of DOI:10.1021/jo960568j

5626
J . Org. Chem. 1996, 61, 5626-5630
Asym m etr ic Tota l Syn th esis of th e Ca r ibbea n F r u it F ly
P h er om on e (+)-Ep ia n a str ep h in
Arthur G. Schultz* and Steven J . Kirincich
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180-3590
Received March 26, 1996X
An asymmetric total synthesis of (+)-epianastrephin (1) from the chiral benzamide 2 (15 steps,
9.5% overall yield) is described. Birch reduction-alkylation of 2 with methyl iodide gave 3 in 91%
yield as a single diastereomer. Cyclohexadiene 3 was converted to olefinic carboxylic acid 6b, and
a tandem iodolactonization-radical reduction sequence provided lactone 8 with three contiguous
stereogenic centers. Chiral HPLC comparison of diol 12b, the immediate precursor to (+)-
epianastrephin (1), with 12b prepared from racemic epianastrephin demonstrated that 1 had been
prepared with >98% ee.
The Tephritidae (true fruit fly) family contains about
sources are 55:45 mixtures of enantiomers. Herein, we
report the asymmetric synthesis of (+)-epianastrephin
(1) via Birch reduction-alkylation of the chiral benza-
mide 2.
4000 species organized into 500 genera and represents
one of the largest families of Diptera (true flies). Within
the subfamily Trypetinae, the genus Anastrepha contains
about 180 species of tropical and subtropical flies. Two
such species, the Caribbean fruit fly, Anastrepha sus-
pensa (Loew) and the Mexican fruit fly, Anastrepha
ludens (Loew) are responsible for substantial loss of
citrus, tropical fruits, and nuts in the Caribbean, Florida,
Mexico, and the Southwestern United States. With the
growing pressure to eliminate the use of often effective
but indiscriminate insecticides, significant research ef-
forts have been directed toward the use of the insect’s
own signaling agents (pheromones) for monitoring and
controlling their numbers and distribution.1
Resu lts a n d Discu ssion
The chiral benzamide 2 was prepared in two steps from
3,4-dihydro-5-methyl-2(1H)-benzopyran-1-one7 as de-
scribed in the Experimental Section. The conversion of
2 to (+)-epianastrephin (1) is shown in Scheme 1. Birch
reduction-alkylation of 2 with methyl iodide gave the
1,4-cyclohexadiene 3 in 91% yield as what appeared to
be a single diastereomer by 1H NMR analysis. It is
significant that Birch reduction-methylation of related
chiral 2-alkylbenzamides provided diastereoselectivities
ranging from 18:1 to >99:1 with the same sense of
diastereoselection as that resulting from the 2,3-dialky-
lbenzamide 2.8,9 Hydrogenation of 1,4-cyclohexadiene 3
gave the 1-cyclohexene 4 in 95% yield.
Nation reported the isolation of a mixture of four
biologically active components from whole male A. sus-
pensa.2,3 This blend consists of two alcohols and two
lactones and was found to be more attractive to female
flies than any of the four individual components. Further
studies identified the alcohols as (Z)-3-nonen-1-ol and
(Z,Z)-3,6-nonadien-1-ol and the lactones as anastrephin
and epianastrephin (1). The structures of the two
lactones were determined by X-ray crystallographic
analysis4 and synthesis.5,6 It is noteworthy that both
anastrephin and epianastrephin obtained from natural
Protiolactonization or iodolactonization10 of 4 was
expected to provide an opportunity to introduce the
remaining two stereogenic centers required for prepara-
tion of 1; however, the tetrasubstituted double bond in 4
resisted such electrophilic addition reactions. The chiral
auxiliary was removed by an internal transesterifica-
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) For a current review of the chemistry of fruit flies, see: Fletcher,
M. T.; Kitching, W. Chem. Rev. 1995, 95, 789-828.
(2) (a) Nation, J . L. Ann. Entomol. Soc. Am. 1972, 65, 1364. (b)
Perdemo, A. J .; Nation, J . L.; Baronowski, R. M. Environm. Entomol.
1976, 5, 1208.
(3) For the earlier isolation of anastrephin and epianastrephin from
the Mexican fruit fly (A. ludens), see: Gaxiola, R. E. Thesis, Technical
University of Monterrey, Mexico, 1975.
(4) Stokes, J . B.; Uebel, E. C.; Warthen, J . D., J r.; J acobsen, M.;
Flippen-Anderson, J . L.; Gilardi, R.; Spishakoff, L. M.; Wilzer, K. R.
J . Agric. Food Chem. 1983, 31, 1162-1167.
(7) (a) 3,4-Dihydro-5-methyl-2(1H)-benzopyran-1-one has been pre-
pared in 77% overall yield from o-tolylacetic acid; see: Schultz, A. G.;
Kirincich, S. J . J . Org. Chem. 1996, 61, 5631-5634. (b) For the first
preparation of 3,4-Dihydro-5-methyl-2(1H)-benzopyran-1-one, see: Bhide,
B. H.; Shah, K. K. Ind. J . Chem. 1980, 19b, 9-12.
(5) Battiste, M. A.; Strekowski, L.; Vanderbilt, D. P.; Visnick, M.;
King, R. W.; Nation, J . L. Tetrahedron Lett. 1983, 24, 2611-2614 and
references cited therein.
(6) For additional syntheses of anastrephin and epianastephin,
see: (a) Visnick, M. Ph.D. Dissertation, University of Florida, 1983.
(b) Strekowski, L.; Visnick, M.; Battiste, M. A. J . Org. Chem. 1986,
51, 4836-4839. (c) Saito, A.; Matsushita, H.; Kaneko, H. Chem. Lett.
1984, 729-730. (d) For a recent report of the stereoselective rear-
rangement of suspensolide to bicyclic lactones, see: Battiste, M. A.;
Strekowski, L.; Coxon, J . M.; Wydra, R. L.; Harden, D. B. Tetrahedron
Lett. 1991, 32, 5303-5304. (e) Mori, K.; Nakazono, Y. Liebigs Ann.
Chem. 1988, 167-174. (f) For the first enantioselective syntheses of
(-)-anastrephin and (-)-epianastrephin, see: Tadano, K.; Isshiki, Y.;
Minami, M.; Ogawa, S. J . Org. Chem. 1993, 58, 6266-6279. (g) Irie,
O.; Shishido, K. Chem. Lett. 1995, 53-54.
(8) Schultz, A. G.; Green, N. J . J . Am. Chem. Soc. 1991, 113, 4931-
4936.
(9) Birch reduction-methylation of the 2,3-dimethylbenzamide cor-
responding to 2 gave little if any diastereoselectivity (unpublished
observations of S. J . Kirincich); the same process with the 2-methyl-
benzamide gave a diastereomer distribution >99:1. Aggregation effects
may play a significant role in the stereoselectivity of these and related
alkylations as noted earlier: Schultz, A. G.; Macielag, M.; Sundarara-
man, P.; Taveras, A. G.; Welch, M. J . Am. Chem. Soc. 1988, 110, 7828-
7841.
(10) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J . Am. Chem.
Soc. 1993, 115, 7904-7905.
S0022-3263(96)00568-3 CCC: $12.00 © 1996 American Chemical Society

Asymmetric Synthesis of (+)-Epianastrephin
J . Org. Chem., Vol. 61, No. 16, 1996 5627
stereoselectivities.14,15 With regard to the conversion of
7 to 8, it is clear that an axial approach of Bu3SnH to
the C(8) radical derived from oxabicyclo[3.2.1]octan-7-one
7 would encounter 1,3-interactions with the axial hydro-
gen atoms at C(2) and C(4); the equatorial approach of
Bu3SnH appears to be relatively unobstructed.
Sch em e 1a
Cleavage of the methyl ether group in 8 was found to
be problematic. Consequently, 8 was oxidized to methyl
ester 9a , and 9a was saponified to give carboxylic acid
9b in 83% overall yield. Reduction of the acid chloride
prepared from 9b with Li(t-BuO)3AlH gave alcohol 10a ,
which was converted to the more labile SEM derivative
10b. Reduction of 10b with diisobutylaluminum hydride
(DIBAL) provided lactol 11 in 70% overall yield from 9b.
Wittig olefination of 11 using conventional reaction
conditions failed to give 12a . However, addition of a
solution of methylenetriphenylphosphorane in DMSO
prepared by the method of Corey and co-workers16 to
lactol 11 in DMSO followed by heating this mixture in a
sealed tube under an argon atmosphere at 70 °C for 23
h gave the desired olefin 12a in 85% yield. Cleavage of
the SEM ether gave 12b, and oxidation of 12b with
tetrapropylammonium perruthenate(VII)17 gave (+)-epi-
anastrephin (1).
The 1H NMR and 13C NMR spectra, TLC, and [R]D
obtained from synthetic 1 compared favorably with data
reported in the literature. In addition, a sample of
racemic epianastrephin, obtained from Professor J ames
Nation to determine the enantiomeric purity of synthetic
1, was reduced to diol 12b, and chiral HPLC comparison
of this material to synthetic 12b demonstrated that (+)-
epianastrephin had been prepared with an enantiomeric
excess of >98%.
a
Reaction conditions: (a) K, NH3, THF, t-BuOH (1 equiv) -78
°C; piperylene; MeI (3 equiv) -78 to 25 °C; (b) 10% Pd/C, H2,
EtOAc; (c) H2SO4, MeOH, H2O, reflux; (d) HC(OMe)3, MeOH,
H2SO4, 50 °C; (e) KOH, MeOH, H2O, reflux; (f) NaHCO3, H2O,
THF, I2, KI; (g) AIBN, Bu3SnH, PhH, reflux; (h) RuO4, NaIO4,
CCl4, MeCN, H2O; (i) KOH, MeOH, H2O, reflux; (j) (COCl)2, PhH,
reflux; Li(t-BuO)3AlH, THF, 0 °C; (k) SEMCl, DIPEA; (l) DIBAL,
CH2Cl2, -78 °C; (m) Ph3P)CH2, DMSO, 70 °C; (n) HOAc, MeOH,
MeCN; (o) TPAP, NMO, CH2Cl2, MeCN.
tion,11 realized by treatment of 4 with aqueous acid at
reflux to give lactone 5 (84%). To avoid the occurrence
of competing cycloetherification reactions in a subsequent
iodolactonization, 5 was directly converted to methyl
ester-methyl ether 6a by utilization of King’s procedure
for alcoholysis of lactones.12 Saponification of 6a gave
carboxylic acid 6b in 86% overall yield from 5.
Iodolactonization of 6b occurred slowly but efficiently
to give 7 in 85% yield. Reduction of the tertiary iodide
in 7 with AIBN and Bu3SnH in benzene gave 8 in 94%
yield. The stereoselectivity for this reaction was estab-
lished by an X-ray determination of structure for the
anilide derivative 13.13 The exclusive equatorial delivery
of a hydrogen atom from Bu3SnH to the tertiary radical
generated from 7 is remarkable but is not without
precedent in the literature of radical substitution reac-
tions of bridged halocyclohexanes.14 Various factors have
been considered in attempts to explain the observed
Con clu sion
A practical asymmetric synthesis of (+)-epianastrephin
(1) has been achieved. The synthesis of 1 required 15
steps from the readily available chiral benzamide 2 with
an overall yield of 9.5%. A key step in the synthesis is
the completely regio- and stereoselective functionalization
of the double bond in 6b by a tandem iodolactonization-
radical reduction sequence to provide overall cis addition.
The highly stereoselective Birch reduction-alkylation of
the chiral 2,3-disubstituted benzamide 2 convincingly
demonstrates that this substitution pattern can be
utilized for the asymmetric synthesis of 1,2,6,6-tetrasub-
stituted 1,4-cyclohexadienes.
Exp er im en ta l Section
Gen er a l P r oced u r es. Tetrahydrofuran (THF) was dis-
tilled from benzophenone sodium ketyl under nitrogen. Ben-
zene, dimethylformamide (DMF), triethylamine, acetonitrile,
(11) Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett.
1992, 33, 6611-6614.
(12) King, S. A. J . Org. Chem. 1994, 59, 2253-2256.
(15) It has been suggested that the stereoselectivities observed in
ref 14 may be the result of a stereoelectronic effect that involves
stabilization of an equatorial radical by the nonbonding orbital of the
oxygen atom in the lactone bridge; see: Ramaiah, M. Tetrahedron
1987, 43, 3541-3676.
(16) Greenwald, R.; Chaykovsky, M.; Corey, E. J . J . Org. Chem.
1963, 28, 1128-1129.
(17) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(13) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(14) (a) Chuang, C.-P.; Gallucci, J . C.; Hart, D. J . J . Org. Chem.
1988, 53, 3210-3218. (b) Keck, G. E.; Yates, J . B. J . Org. Chem. 1982,
47, 3590-3591. (c) Coblens, K. E.; Muralidharan, V. B.; Ganem, B. J .
Org. Chem. 1982, 47, 5041-5042.

5628 J . Org. Chem., Vol. 61, No. 16, 1996
Schultz and Kirincich
and tert-butyl alcohol were distilled from CaH2. Dimethyl
sulfoxide (DMSO) was azeotroped with heptane and distilled
from CaH2. Solutions were concentrated by rotary evapora-
tion. Analytical TLC was performed on 0.25 mm E. Merck
silica gel (60F-254) plates using UV light and iodine as
visualizing agents. Purifications by flash column chromatog-
raphy used Baker silica gel (40 µm). High-resolution mass
spectra were obtained from the mass spectrometry laboratory
at the University of Illinois at Urbana/Champaign. Elemental
analyses were performed by Quantitative Technologies, Inc.,
Whitehouse, NJ , and Atlantic Microlab, Inc., Norcross, GA.
(S)-2-[2-(Meth oxym eth oxy)eth yl]-1-[[2′-(m eth oxym eth -
yl)p yr r olid in yl]ca r bon yl]-3-m eth ylben zen e (2). A solu-
tion of triethylamine (12.7 mL, 92 mmol) in methylene chloride
(50 mL) was added to a stirred slurry of aluminum chloride
(1.5 g, 78 mmol) in methylene chloride (250 mL) at 0 °C. After
15 min, a solution of 3,4-dihydro-5-methyl-2(1H)-benzopyran-
1-one7 (10.6 g, 65 mmol) and (S)-prolinol methyl ether (9.8 g,
85 mmol) in methylene chloride (100 mL) was added dropwise
to the cooled TEA-AlCl3 mixture, and this was warmed to
room temperature. After 40 h, the reaction was quenched with
crushed ice and the aqueous layer was acidified with 10%
aqueous HCl. The organic layer was collected, and the
remaining aqueous layer was washed with methylene chloride
(2 × 100 mL). The combined organic phases were dried,
filtered, and evaporated to give a brown oil. Flash chroma-
tography (100% ethyl acetate) afforded (S)-2-(2-hydroxyethyl)-
1-[[2-(methoxymethyl)pyrrolidinyl]carbonyl]-3-methylben-
zene (15.6 g, 86%) as an amber oil: 1H NMR (CDCl3) δ 7.17-
7.20 (m, 1 H), 7.12 (overlapping dd, J ) 7.6, 7.3 Hz, 1 H), 7.04
(d, J ) 7.6 Hz, 1 H), 4.38-4.43 (m, 1 H), 3.81-3.87 (m, 1 H),
3.75-3.80 (m, 2 H), 3.60 (dd, J ) 9.4, 2.8 Hz, 1 H), 3.41 (s, 3
H), 2.80-3.30 (m, 5 H), 2.36 and 2.37 (s, 3 H, rotamers), 1.96-
2.08 (m, 2 H), 1.86-1.96 (m, 2 H), 1.57-1.76 (m, 1 H); 13C NMR
(CDCl3) δ 137.55, 131.35, 126.18, 73.12, 72.24, 61.04, 59.07,
58.66, 57.98, 56.40, 50.05, 33.48, 33.34, 27.84, 24.51, 19.50;
3 H), 1.68-1.71 (m, 1 H), 1.30 (s, 3 H); 13C NMR (CDCl3) δ
172.07, 129.87, 128.27, 126.35, 122.82, 96.02, 72.14, 66.18,
58.82, 57.94, 54.97, 49.40, 46.50, 32.95, 29.30, 26.77, 26.58,
24.73, 18.96; IR (film) 2940, 2870, 1630, 1380 cm-1; CIMS m/ z
(relative intensity) 338 (M+ + 1, 100), 306 (19), 236 (4); HRMS
(CI, CH4) calcd for C19H32NO4 (M+ + 1) 338.2331, found
338.2332.
(2′S,6S)-2,6-Dim eth yl-1-[2-(m eth oxym eth oxy)eth yl]-6-
[[2′-(m eth oxym eth yl)p yr r olid in yl]ca r bon yl]-1-cycloh ex-
en e (4). A solution of 3 (3.0 g, 8.09 mmol) and 10% Pd/C (0.4
g) in ethyl acetate (300 mL) was shaken under a hydrogen
atmosphere (60 psi, room temperature) for 72 h. The solution
was filtered through Celite, evaporated, and flash chromato-
graphed (hexane/ethyl acetate, 1:1) to provide 4 (2.89 g, 95%)
as a colorless oil: 1H NMR (CDCl3) δ 4.55 (s, 2 H), 4.24-4.27
(m, 1 H), 3.52 (dd, J ) 9.3, 3.1 Hz, 1 H), 3.30 (s, 3 H), 3.29 (s,
3 H), 3.25-3.48 (m, 5 H), 2.45-2.48 (m, 1 H), 1.64 (s, 3 H),
1.54-1.99 (m, 11 H), 1.27 (s, 3 H); 13C NMR (CDCl3) δ 175.63,
131.24, 128.09, 96.15, 72.32, 66.78, 58.87, 57.72, 55.05, 49.06,
46.70, 32.87, 31.83, 31.33, 26.40, 25.21, 25.19, 19.76, 18.89;
IR (film) 2940, 1620, 1380 cm-1; CIMS m/ z (relative intensity)
340 (M+ + 1, 100), 308 (20), 279 (3); HRMS (CI, CH4) calcd for
C19H34NO4 (M+ + 1) 340.2488, found 340.2482.
(8a S)-5,8a -Dim eth yl-3,4,6,7,8,8a -h exa h yd r o-2(1H)-ben -
zop yr a n -1-on e (5). A solution of 4 (3.0 g, 9.0 mmol) and concd
sulfuric acid (0.5 mL) in methanol (100 mL) and water (30 mL)
was refluxed for 72 h. The reaction was neutralized with
aqueous sodium bicarbonate and extracted with methylene
chloride (3 × 100 mL). The combined organic phases were
dried, filtered, evaporated, and flash chromatographed (hex-
ane/ethyl acetate, 4:1) to give 5 (1.35 g, 84%) as a pale yellow
oil:
1H NMR (CDCl3) δ 4.49 (ddd, J ) 11.0, 6.5, 5.1 Hz, 1 H),
4.21 (ddd, J ) 11.0, 7.6, 5.3 Hz, 1 H), 2.65-2.71 (m, 1 H), 2.46-
2.51 (m, 1 H), 1.95-2.02 (m, 3 H), 1.68-1.79 (m, 3 H), 1.63 (s,
3 H), 1.42 (s, 3 H);
13C NMR (CDCl3) δ 176.94, 129.24, 125.76,
66.97, 43.26, 32.97, 31.08, 35.58, 25.17, 19.18, 17.92; IR (film)
2920, 1720, 1125, 1050 cm-1; CIMS m/ z (relative intensity)
181 (M+ + 1, 100); [R]28D +169.55° (c 2.89, CHCl3); HRMS (CI,
CH4) calcd for C11H17O2 (M+ + 1) 181.1229, found 181.1229.
(1S)-1,3-Dim eth yl-2-(2-m eth oxyeth yl)-2-cycloh exen e-1-
ca r boxylic Acid Meth yl Ester (6a ). A solution of 5 (3.15 g,
18 mmol), trimethyl orthoformate (4.65 g, 2.5 equiv), and concd
sulfuric acid (1 drop) in dry methanol (60 mL) was heated at
50 °C for 12 h. The reaction was diluted with water and
extracted with methylene chloride (3 × 100 mL). The com-
bined organic phases were dried, filtered, evaporated, and flash
chromatographed (hexane/ethyl acetate, 4:1) to provide 6a (3.4
g, 86%) as a clear, colorless oil: 1H NMR (CDCl3) δ 3.66 (s, 3
H), 3.32 (s, 3 H), 3.30-3.35 (m, 2 H), 2.44-2.50 (m, 1 H), 2.10-
2.16 (m, 1 H), 1.93-2.05 (m, 3 H), 1.69 (s, 3 H), 1.51-1.67 (m,
3 H), 1.29 (s, 3 H); 13C NMR (CDCl3) δ 178.03, 131.98, 127.72,
71.85, 58.32, 51.74, 47.77, 35.71, 31.96, 30.99, 23.75, 20.10,
19.12; IR (film) 2920, 1730, 1430 cm-1; CIMS m/ z (relative
IR (film) 3410 (br), 2880, 1610, 1590 (shoulder), 1410 cm-1
;
CIMS m/ z (relative intensity) 278 (M+ + 1, 100); HRMS (CI,
CH4) calcd for C16H24NO3 (M+ + 1) 278.1756, found 278.1752.
A solution of (S)-2-(2-hydroxyethyl)-1-[[2-(methoxymethyl)-
pyrrolidinyl]carbonyl]-3-methylbenzene (10.0 g, 36 mmol),
chloromethyl methyl ether (3.6 mL, 1.3 equiv), and N,N-
diisopropylethylamine (8.2 mL, 1.3 equiv) in methylene chlo-
ride (500 mL) was stirred at room temperature for 24 h. The
solution was washed with 10% hydrochloric acid, and the
organic layer was dried, filtered, evaporated, and flash chro-
matographed (hexane/ethyl acetate, 2:1) to provide 2 (9.4 g,
81%) as a pale-yellow oil: 1H NMR (CDCl3) δ 7.11-7.26 (m, 2
H), 7.02-7.04 (m, 1 H), 4.59 (s, 2 H), 4.40-4.44 (m, 1 H), 3.58-
3.75 (m, 4 H), 3.40 (s, 3 H), 3.31 (s, 3 H), 2.80-3.20 (bm, 4 H),
2.38 (s, 3 H), 1.88-2.05 (m, 3 H), 1.70-1.80 (m, 1 H); IR (film)
3500 (br), 2900, 1620, 1405 cm-1; CIMS m/ z (relative inten-
sity) 322 (M+ + 1, 100), 290 (20).
intensity) 227 (M+ + 1, 100), 195, (24), 167 (25); [R]27 -60.0°
Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47. Found: C,
67.10; H, 8.53.
D
(c 1.55, CHCl3).
Anal. Calcd for C13H22O3: C, 68.99; H, 9.80. Found: C,
69.12; H, 9.85.
(2′S,6S)-2,6-Dim eth yl-1-[2-(m eth oxym eth oxy)eth yl]-6-
[[2′-(m et h oxym et h yl)p yr r olid in yl]ca r b on yl]-1,4-cyclo-
h exa d ien e (3). A solution of 2 (8.9 g, 28 mmol), and tert-
butyl alcohol (2.6 mL, 1 equiv) in THF (200 mL) was cooled to
-78 °C, and ammonia (∼1500 mL) was added. Potassium (2.4
g, 2.2 equiv) was added in small pieces, and after 30 min the
excess metal was quenched with piperylene (1 mL) and methyl
iodide (5.2 mL, 3 equiv) was added. The solution was stirred
at -78 °C for 1 h, the ammonia was allowed to evaporate, and
water was added. The residue was diluted with water (100
mL) and methylene chloride (100 mL) and extracted with
methylene chloride (3 × 300 mL). The combined organic
phases were washed with 10% aqueous sodium thiosulfate,
dried, filtered, evaporated, and flash chromatographed (hex-
ane/ethyl acetate, 2:1) to provide 3 (8.5 g, 91%) as an amber
oil (single diastereomer by 1H NMR): 1H NMR (CDCl3) δ 5.70
(dm, J ) 10.1 Hz, 1 H), 5.50 (dm, J ) 10.1 Hz, 1 H), 4.57 (s,
2 H), 4.24-4.29 (m, 1 H), 3.59 (dd, J ) 9.2, 3.2 Hz, 1 H), 3.46-
3.51 (m, 1 H), 3.34 (s, 3 H), 3.33 (s, 3 H), 3.24-3.42 (m, 4 H),
2.70 (d, J ) 23.0 Hz, 1 H), 2.55 (d, J ) 23.0 Hz, 1 H), 2.38-
2.46 (m, 1 H), 2.25-2.31 (m, 1 H), 1.75-1.89 (m, 3 H), 1.72 (s,
(1S)-1,3-Dim eth yl-2-(2-m eth oxyeth yl)-2-cycloh exen e-1-
ca r boxylic Acid (6b). A solution of 6a (3.4 g, 15 mmol) and
sodium hydroxide (6.0 g, 10 equiv) in methanol (100 mL) and
water (10 mL) was refluxed for 48 h. The solution was
acidified with 10% aqueous hydrochloric acid and extracted
with methylene chloride (3 × 100 mL). The combined organic
phases were dried, filtered, and evaporated to provide 6b (3.3
g, 100%) as a yellow oil. For analytical purposes, flash chroma-
tography (CH2Cl2/MeOH, 20:1) was performed on a 50 mg
portion of the crude acid: 1H NMR (CDCl3) δ 3.34-3.43 (m, 2
H), 3.33 (s, 3 H), 2.50-2.57 (m, 1 H), 2.18-2.24 (m, 1 H), 1.92-
2.06 (m, 3 H), 1.70 (s, 3 H), 1.66-1.72 (m, 1 H), 1.54-1.61 (m,
2 H), 1.31 (s, 3 H); 13C NMR (CDCl3) δ 183.55, 132.79, 127.24,
71.88, 58.28, 47.62, 35.95, 32.02, 30.94, 23.64, 20.15, 19.16;
IR 3500-2900 (br), 1690, 1100 cm-1; CIMS m/ z (relative
intensity) 213 (M+ + 1, 90), 167 (100); IR 3500-2800 (br), 2940,
1690, 1100 cm-1; [R]27 -66.84° (c 1.9, CHCl3).
D
Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found: C,
67.99; H, 9.57.

Asymmetric Synthesis of (+)-Epianastrephin
J . Org. Chem., Vol. 61, No. 16, 1996 5629
(1R,5R,8R)-1,5-Dim eth yl-8-iod o-8-(2-m eth oxyeth yl)-6-
oxa bicyclo[3.2.1]octa n -7-on e (7). A solution of 6b (3.3 g,
15 mmol), iodine (11.4 g, 3 equiv), potassium iodide (14.9 g, 6
equiv), and sodium bicarbonate (1.9 g, 1.5 equiv) in water (40
mL) and THF (40 mL) was stirred at room temperature for
10 days. The excess iodine was reduced with aqueous sodium
thiosulfate, and the solution was diluted with water and then
extracted with methylene chloride (3 × 100 mL). The com-
bined organic phases were dried, filtered, evaporated, and flash
chromatographed (hexane/ethyl acetate, 10:1) to provide 7
(4.33 g, 85%) as a white solid (mp 54-56 °C): 1H NMR (CDCl3)
δ 3.45-3.50 (m, 1 H), 3.31-3.37 (m, 1 H), 3.28 (s, 3 H), 2.64-
2.68 (m, 2 H), 2.50-2.57 (m, 1 H), 1.91-2.03 (m, 2 H), 1.79-
1.83 (m, 1 H), 1.58-1.68 (m, 2 H), 1.50 (s, 3 H), 1.20 (s, 3 H);
13C NMR (CDCl3) δ 174.21, 71.15, 64.90, 58.63, 51.90, 42.37,
38.03, 35.84, 29.65, 19.93, 17.39, 16.43; IR (KBr) 2920, 1765,
1095 cm-1; CIMS m/ z (relative intensity) 339 (M+ + 1, 100),
layers were dried, filtered, and evaporated to provide 10a
(0.39g, 82%). A sample of the crude reaction product was flash
chromatographed (hexane/ethyl acetate, 1:1) to provide the
alcohol as a white solid (mp 63-65 °C): 1H NMR (CDCl3) δ
3.66-3.74 (m, 2 H), 1.95 (overlapping dd, J ) 6.1 Hz, 1 H),
1.48-1.78 (m, 7 H), 1.40 (s, 3 H), 1.39-1.43 (m, 1 H), 1.14 (s,
3 H); 13C NMR (CDCl3) δ 180.52, 85.46, 61.09, 50.56, 46.49,
27.87, 27.67, 26.14, 24.15, 19.80, 18.41; IR (KBr) 3500-3250
(br), 2940, 1755 cm-1; CIMS m/ z (relative intensity) 199 (M+
+ 1, 100), 181 (18), 153 (14); [R]25 -7.88° (c 3.68, CHCl3).
D
Anal. Calcd for C11H18O3: C, 66.64; H, 9.15. Found: C,
66.52; H, 9.13.
(1S,5R,8R)-1,5-Dim eth yl-8-[2-[[2-(tr im eth ylsilyl)eth oxy]-
m et h oxy]et h yl]-6-oxa b icyclo[3.2.1]oct a n -7-on e (10b ). A
solution of 10a (280 mg, 1.4 mmol), [2-(trimethylsilyl)ethoxy]-
methyl chloride (SEMCl, 0.75 mL, 3 equiv), and N,N-diiso-
propylethylamine (DIPEA, 0.86 mL, 3.5 equiv) was stirred at
room temperature for 5 h. The reaction was quenched with
10% aqueous HCl and extracted with CH2Cl2 (3 × 20 mL). The
combined organic phases were dried, filtered, evaporated, and
flash chromatographed (hexane/ethyl acetate, 4:1) to provide
10b (410 mg, 91%) as a clear, colorless oil: 1H NMR (CDCl3)
δ 4.66 (s, 2 H), 3.59-3.63 (m, 2 H), 3.54-3.58 (m, 2 H), 1.95
(t, J ) 6.2 Hz, 1 H), 1.46-1.79 (m, 8 H), 1.39 (s, 3 H), 1.14 (s,
3 H), 0.91-0.96 (m, 2 H), 0.02 (s, 9 H); 13C NMR (CDCl3) δ
180.18, 94.82, 85.19, 66.10, 65.27, 50.86, 46.46, 27.70, 26.15,
25.20, 24.22, 19.88, 18.43, 18.04, -1.49; IR (film) 2960, 1770
cm-1; CIMS m/ z (relative intensity) 329 (M+ + 1, 2), 271 (100),
211 (80), 167 (29); [R]25 -72.13° (c 1.22, CHCl3).
D
Anal. Calcd for C12H19IO3: C, 42.62; H, 5.66. Found: C,
42.66; H, 5.67.
(1S ,5R ,8R )-1,5-Dim e t h yl-8-(2-m e t h oxye t h yl)-6-oxa -
bicyclo[3.2.1]octa n -7-on e (8). A solution of 7 (2.2 g, 6.5
mmol), tri-n-butyltin hydride (2.1 mL, 1.2 equiv), and azobi-
sisobutyronitrile (0.1 g, 0.1 equiv) in benzene (100 mL) was
refluxed for 2 h. The cooled solution was evaporated, and the
crude oil was flash chromatographed (hexane/ethyl acetate,
3:1) to provide 8 (1.3 g, 94%) as a yellow oil that partially
solidified upon standing: 1H NMR (CDCl3) δ 3.32-3.41 (m, 2
H), 3.33 (s, 3 H), 1.93 (t, J ) 6.0 Hz, 1 H), 1.46-1.76 (m, 7 H),
1.39 (s, 3 H), 1.36-1.42 (m, 1 H), 1.13 (s, 3 H); 13C NMR
(CDCl3) δ 180.19, 85.22, 71.01, 58.53, 50.91, 46.45, 27.68, 26.13,
211 (16), 181 (7); [R]26 -8.30° (c 2.17, CHCl3). An acceptable
D
elemental analysis could not be obtained.
(1S,5R,7R*,8R)-1,5-Dim et h yl-8-[2-[[2-(t r im et h ylsilyl)-
et h oxy]m et h oxy]et h yl]-7-h yd r oxy-6-oxa b icyclo[3.2.1]-
oct a n e (11). To a solution of 10b (245 mg, 0.75 mmol) in
CH2Cl2 at -78 °C was added diisobutylaluminum hydride (2.2
mL, 3 equiv, CH2Cl2 solution). After 1 h at -78 °C, the
reaction was quenched with H2O and warmed to room tem-
perature. The resulting suspension was diluted with water
(50 mL) and CH2Cl2 (50 mL), and the pH was adjusted to 4
with 10% aqueous HCl. The organic layer was removed, and
the aqueous phase was reextracted with CH2Cl2 (30 mL). The
combined organic layers were dried, filtered, evaporated, and
flash chromatographed (hexane/ethyl acetate, 4:1) to provide
11 (230 mg, 93%) as a clear, colorless oil: 1H NMR (CDCl3) δ
5.01 (s, 1/8 × 1 H), 4.95 (s, 7/8 × 1 H), 4.67 (s, 2 H), 3.61-3.67
(m, 2 H), 3.55-3.59 (m, 2 H), 1.62-1.68 (m, 2 H), 1.27 (s, 7/8
× 3 H), 1.23 (s, 1/8 × 3 H), 1.20-1.64 (m, 8 H), 0.95 (s, 3 H),
0.90-1.02 (m, 2 H), 0.02 (s, 9 H); IR (film) 3500-3200 (br),
1250 cm-1; CIMS m/ z (relative intensity) 255 (M+ -75, 90),
183 (100).
25.10, 24.15, 19.81, 18.43; IR (film) 2940, 1770, 1120 cm-1
;
CIMS m/ z (relative intensity) 213 (M+ + 1, 100), 167 (22);
[R]26 -10.66° (c 3.66, CHCl3).
D
Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found: C,
68.06; H, 9.44.
(1S,5R,8R)-8-[(Meth oxyca r bon yl)m eth yl]-1,5-d im eth yl-
6-oxa bicyclo[3.2.1]octa n -7-on e (9a ). A solution of 8 (0.50
g, 2.4 mmol), ruthenium dioxide (20 mg, 4 mol %), and sodium
periodate (2.0 g, 4 equiv) in carbon tetrachloride (12 mL),
acetonitrile (12 mL), and water (18 mL) was stirred at room
temperature for 48 h. The reaction was quenched with
methanol (5 mL), filtered through Celite, and extracted with
methylene chloride (3 × 50 mL). The combined organic phases
were washed with aqueous sodium thiosulfate, dried, filtered,
and evaporated to provide 9a (0.47g) as a yellow oil: 1H NMR
(CDCl3) δ 3.70 (s, 3 H), 2.35-2.46 (m, 3 H), 1.41-1.73 (m, 6
H), 1.36 (s, 3 H), 1.10 (s, 3 H); 13C NMR (CDCl3) δ 179.35,
171.96, 84.52, 52.01, 50.02, 46.08, 29.81, 27.67, 26.13, 23.66,
19.24, 18.29; IR (film) 2955, 2880, 1770, 1730 cm-1; CIMS m/ z
(relative intensity) 227 (M+ + 1, 100) 181 (11). An acceptable
elemental analysis could not be obtained.
Anal. Calcd for C17H28O4: C, 61.77; H, 10.37. Found: C,
61.61; H, 10.27.
(1R,2R,3R)-1,3-Dim eth yl-3-eth en yl-[2-[[2-(tr im eth ylsi-
lyl)eth oxy]m eth oxy]eth yl]cycloh exa n ol (12a ). A stock
solution of methylenetriphenylphosphorane in DMSO (0.66 M)
was prepared according to the Corey procedure.16 A sealed
tube fitted with a rubber septum and a stir bar was flame-
dried under a stream of argon. A solution of 11 (370 mg, 1.1
mmol) in DMSO (6 mL) was added via syringe to the sealed
tube followed by addition of the ylide solution (8.5 mL, 5 equiv).
Under an argon stream, the septum was quickly removed and
replaced with the gasket and Teflon screw cap. The tube was
heated at 70 °C (bath reading) for 23 h and cooled. The
contents were added to a separatory funnel and diluted with
water (150 mL) and CH2Cl2 (75 mL). The organic layer was
collected, washed with water (3 × 50 mL), dried, filtered,
evaporated, and flash chromatographed (hexane/ethyl acetate,
4:1) to provide 12a (306 mg, 85%) as a clear, colorless oil: 1H
NMR (CDCl3) δ 5.66 (dd, J ) 17.6, 10.7 Hz, 1 H), 4.96 (dd, J
) 10.7, 1.0 Hz, 1 H), 4.94 (dd, J ) 17.6, 1.0 Hz, 1 H), 4.64-
4.68 (m, 2 H), 3.66 (ddd, J ) 9.6, 9.6, 4.8 Hz, 1 H), 3.60 (t, J
) 8.3 Hz, 2 H), 3.44 (ddd, J ) 9.6, 9.6, 4.8 Hz, 1 H), 1.80 (dm,
J ) 12.5 Hz, 1 H), 1.30-1.72 (m, 9 H), 1.22 (s, 3 H), 0.95 (s, 3
H), 0.90-0.93 (m, 1 H), -0.07 (s, 9 H); 13C NMR (CDCl3) δ
150.21, 111.27, 94.62, 71.69, 68.99, 65.33, 52.90, 42.01, 26.47,
24.37, 19.95, 18.03, -0.07; IR (film) 3500-3250 (br), 2930, 1250
cm-1; CIMS m/ z (relative intensity) 329 (M+ + 1, 25), 255 (94),
(1S,5R,8R)-8-Ca r boxy-1,5-d im eth yl-6-oxa bicyclo[3.2.1]-
octa n -7-on e (9b). A solution of 9a (0.47 g, 2.1 mmol) and
potassium hydroxide (1.3 g, 10 equiv) in methanol (10 mL) and
water (10 mL) was refluxed for 10 h. The cooled solution was
acidified and extracted with methylene chloride (3 × 50 mL).
The combined organic layers were dried, filtered, and evapo-
rated to provide 9b (0.42 g, 83%, two steps) as a pale-yellow
solid (mp 99-101 °C): 1H NMR (CDCl3) δ 2.38-2.50 (m, 3 H),
1.49-1.76 (m, 5 H), 1.43-1.48 (m, 2 H), 1.39 (s, 3 H), 1.13 (s,
3 H); 13C NMR (CDCl3) δ 179.36, 177.23, 84.54, 46.69, 46.15,
29.66, 27.70, 26.17, 23.69, 19.28, 18.25; IR (film) 3500-2800
(br), 1695 (br) cm-1; CIMS m/ z (relative intensity) 213 (M+
+
1, 100), 195 (5), 167 (15); [R]26 -16.66° (c 1.02, CHCl3).
D
Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C,
62.16; H, 7.63.
(1S ,5R ,8R )-1,5-Dim e t h yl-8-(2-h yd r oxye t h yl)-6-oxa -
bicyclo[3.2.1]octa n -7-on e (10a ). A solution of 9b (0.52 g,
2.0 mmol) and oxalyl chloride (0.44 mL, 2.5 equiv) in benzene
(10 mL) was refluxed for 100 min. The solvent was evapo-
rated, and the residue was dissolved in THF (20 mL) and
cooled to 0 °C. Lithium tri-tert-butoxyaluminohydride (1.5 g,
3 equiv) was added, and after 45 min, the reaction was
quenched with aqueous HCl. The solution was extracted with
methylene chloride (3 × 50 mL), and the combined organic

5630 J . Org. Chem., Vol. 61, No. 16, 1996
Schultz and Kirincich
163 (100); [R]25D -13.5° (c 1.63, CHCl3). Acceptable elemental
and high resolution mass spectrometry analyses could not be
obtained.
racemic-
12
synthetic-12
(1R,2R,3R)-1,3-Dim eth yl-3-eth en yl-2-(2-h yd r oxyeth yl)-
cycloh exa n ol (12b). A solution of 12a (54 mg, 0.61 mmol)
and acetic acid (0.5 mL) in CH3CN (1 mL) and MeOH (1 mL)
was stirred at room temperature for 36 h. The solution was
neutralized with aqueous NaHCO3, extracted with CH2Cl2 (3
× 20 mL), dried, filtered, evaporated, and flash chromato-
graphed (hexane/ethyl acetate, 1:1) to provide 12b (16.6 mg,
51%) as an oil that solidified upon standing (mp 85-87 °C).
Chiral HPLC analysis (Chiralcel OD column, 10:1 hexane/2-
propanol) indicated that the enantiomeric ratio exceeded 70:
1: 1H NMR (CDCl3) δ 5.65 (dd, J ) 17.5, 10.6 Hz, 1 H), 4.97
(dd, J ) 10.8, 1.0 Hz, 1 H), 4.94 (dd, J ) 17.3, 1.0 Hz, 1 H),
3.74 (ddd, J ) 10.5, 4.4, 4.4 Hz, 1 H), 3.46-3.52 (m, 1 H), 3.09
(bs, 2 H), 1.83-1.86 (m, 1 H), 1.58-1.65 (m, 3 H), 1.40-1.57
(m, 3 H), 1.32-1.38 (m, 2 H), 1.29 (s, 3 H), 0.95 (s, 3 H); 13C
NMR (CDCl3) δ 150.28, 111.45, 72.43, 63.62, 53.41, 42.84,
42.19, 39.44, 29.15, 24.19, 20.13, 16.92; IR (KBr) 3000-3400
(br), 2920 cm-1; CIMS m/ z (relative intensity) 199 (M+ + 1,
7), 181 (100), 163 (31), 137 (21); [R]26 -18.0° (c 2.44, CHCl3).
D
1.81-1.87 (m, 1 H), 1.59-1.70 (m, 2 H), 1.52-1.58 (m, 1 H),
1.42-1.50 (m, 1 H), 1.38 (s, 3 H), 1.06 (s, 3 H); 13C NMR
(CDCl3) δ 176.17, 147.76, 111.63, 86.04, 53.46, 38.46, 37.91,
37.01, 29.46, 20.88, 20.42, 16.35; [R]25D +69.8° (c 0.80, hexanes);
(lit.6e [R]25 +87.9° (c 0.27, n-hexane; (lit.6b [R]25 +74.7° (c 4,
Anal. Calcd for C12H22O2: C, 72.68; H, 11.18. Found: C,
72.41; H, 11.06.
(3a R,4R,7a R)-4,7a -Dim eth yl-3a ,4,5,6,7,7a -h exa h yd r o-4-
eth en ylben zofu r a n -2(3H)-on e. (+)-Ep ia n a str ep h in (1).
Solid tetrapropylammonium perruthenate(VII) (TPAP, 3.5 mg,
10 mol %) was added to a solution of 12b (20 mg, 0.10 mmol)
and 4-methylmorpholine N-oxide (NMO, 31 mg, 2.5 equiv) in
CH2Cl2 (1 mL) and CH3CN (0.5 mL). After being stirred at
room temperature for 40 min, the solvent was evaporated and
the residue was flash chromatographed (hexane/ethyl acetate,
4:1) to provide (+)-epianastrephin (1) (13 mg, 68%) as a white
solid: 1H NMR (CDCl3) δ 5.68 (dd, J ) 17.6, 11.5 Hz, 1 H),
4.98 (dd, J ) 11.5, 1.0 Hz, 1 H), 4.95 (dd, J ) 17.6, 1.0 Hz, 1
H), 2.38 (dd, J ) 16.4, 14.7 Hz, 1 H), 2.24 (dd, J ) 16.5, 6.5
Hz, 1 H), 2.10 (dd, J ) 14.9, 6.6 Hz, 1 H), 2.00-2.03 (m, 1 H),
D
D
hexanes)).
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM 26568). We thank
Dr. Fook S. Tham for the X-ray structure determination
of 13, Degussa AG for a generous gift of L-proline, and
Professor J ames Nation for a sample of racemic
epianastrephin.
J O960568J