Synthesis of both antipodal forms of 7,7-dimethylbicyclo[2.2.2]oct-2-en-5-one by enantiomer interconversion

Article abstract of DOI:10.1021/jo951552g

An enantioselective synthesis of both enantiomers of the title ketone 5 from a common achiral β-diketone is reported. Bakers' yeast reduction of 6 cleanly differentiates between the two carbonyl groups to deliver (+)-9 in >90% yield, and with an ee exceed

Full text of DOI:10.1021/jo951552g

142
J . Org. Chem. 1996, 61, 142 145
Syn th esis of Both An tip od a l F or m s of
7,7-Dim eth ylbicyclo[2.2.2]oct-2-en -5-on e by En a n tiom er
In ter con ver sion
Leo A. Paquette* and Hon-Chung Tsui
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received August 23, 1995X
An enantioselective synthesis of both enantiomers of the title ketone 5 from a common achiral
â-diketone is reported. Bakers’ yeast reduction of 6 cleanly differentiates between the two carbonyl
groups to deliver ( )-9 in 90% yield, and with an ee exceeding 98%. Direct xanthate elimination
leads to ( )-5. To arrive at the levorotatory antipode, the OH group in the â-hydroxy ketone is
transformed into the tetrahydropyranyl ether and the carbonyl group is subsequently reduced in
advance of formal dehydration. Oxidation of the deprotected alcohol ultimately reestablishes the
carbonyl functionality and delivers ( )-5 of equally high optical purity.
3
The anionic oxy-Cope rearrangement1 constitutes a
as in 1 or carry an exocyclic â,γ-olefinic substituent. The
13
powerful and definitive means for constructing polycyclic
ring systems with complete control over the several
stereogenic centers resident in the framework. The
outstanding stereoselectivity and utmost brevity provided
by this central reaction emerge in notably serviceable
fashion when the electrophilic reaction partner is a
bicyclic â,γ-unsaturated ketone. In the illustrated ex-
ample, the addition of lithiated dihydropyran to 1,
subsequent generation of the potassium salt of 2, and
direct trapping of the regiospecifically generated enolate
anion with benzeneselenenyl chloride provides direct
entry to a forskolin prototype.4
latter variant provides considerable added versatility.11
In such isomerization reactions, the emerging inter-
relationship of the stereogenic centers is controlled by
the particular transition state that is adopted. Beyond
this, absolute configuration can be traced directly to the
dissymmetric elements present in the ketone reactant.
Insofar as these considerations apply to projected enan-
tioselective syntheses of enmein (3)14,15 and other kau-
rane-related diterpenoid targets such as rabdokaurin C
(4a ),16 megathyrin A (4b),17 and oridorin (4c),18 the
sigmatropic mechanistic model contemplates initial con-
densation of an appropriate cyclohexenyl anion with the
(1S,4S) enantiomer of 7,7-dimethylbicyclo[2.2.2]oct-2-en-
5-one, viz. 5. This paper describes experiments which
Other important examples of the strategic adaptation
of this tactic can be found in the syntheses of coronafacic
acid,5 cannivonine,6 ( )-ikarugamycin,7 dimethyl secolo-
ganoside O-methyl ether,8a 9-isocyanopupukeanane,8b
reserpine intermediates,9 and ambergris-type odorants.10
cleanly deliver both 5 and its enantiomer 5′ from the
common 1,3-diketone precursor 6. Since the reduction
(8) (a) Chang, N.-C.; Day, H.-M.; Lu, W.-F. J . Org. Chem. 1989, 54,
4083. (b) Hsieh S.-L.; Chiu, C.-T.; Chang, N.-C. J . Org. Chem. 1989,
54, 3820.
(9) J ung, M. E.; Light, L. A. J . Am. Chem. Soc. 1984, 106, 7614.
(10) (a) Paquette, L. A.; Maleczka, R. E., J r. J . Org. Chem. 1991,
56, 912. (b) Maleczka, R. E., J r.; Paquette, L. A. J . Org. Chem. 1991,
56, 6538.
(11) (a) Martin, S. F.; White, J . B.; Wagner, R. J . Org. Chem. 1982,
47, 3190. (b) Martin, S. F.; Assercq, J .-M.; Austin, R. E.; Dau-
tauarayana, A. P.; Fishpaugh, J . R.; Gluchowski, C.; Guinn, D. E.;
Hartmann, M.; Tanaka, T.; Wagner, R.; White, J . B. Tetrahedron 1995,
51, 3455.
The bicyclic ketones may possess internal double bonds
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) (a) Hill, R. K. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: London, 1984; Vol. 3A, 503 ff. (b) Hill, R. K. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 5, Chapter 7.1.
(2) Wilson, S. R. Org. React. (NY) 1993, 43, 93.
(3) (a) Paquette, L. A. Synlett 1990, 67. (b) Paquette, L. A. Angew.
Chem., Int. Ed. Engl. 1990, 29, 609.
(4) (a) Oplinger, J . A.; Paquette, L. A. Tetrahedron Lett. 1987, 28,
5441. (b) Paquette, L. A.; Oplinger, J . A. Tetrahedron 1989, 45, 107.
(5) J ung, M. E.; Hudspeth, J . P. J . Am. Chem. Soc. 1980, 102, 2463.
(6) Evans, D. A.; Golob, A. M.; Mandel, N. S.; Mandel, G. S. J . Am.
Chem. Soc. 1978, 100, 8170.
(7) (a) Paquette, L. A.; Macdonald, D.; Anderson, L. G.; Wright, J .
J . Am. Chem. Soc. 1989, 111, 8037. (b) Paquette, L. A.; Macdonald,
D.; Andreson, L. G. J . Am. Chem. Soc. 1990, 112, 9292.
(12) (a) Paquette, L. A.; Poupart, M.-A. J . Org. Chem. 1993, 58, 4245.
(b) Paquette, L. A.; Lassalle, G. Y.; Lovely, C. J . J . Org. Chem. 1993,
58, 4254. (c) Paquette, L. A.; Deaton, D. M.; Endo, Y.; Poupart, M.-A.
J . Org. Chem. 1993, 58, 4262. (d) Paquette, L. A.; Hormuth, S.; Lovely,
C. J . J . Org. Chem. 1995, 60, 4813.
(13) (a) Paquette, L. A.; Zhao, M. J . Am. Chem. Soc. 1993, 115, 354.
(b) Paquette, L. A.; Thompson, R. C. J . Org. Chem. 1993, 58, 4952. (c)
Elmore, S. W.; Paquette, L. A. J . Org. Chem. 1993, 58, 4963. (d)
Paquette, L. A.; Huber, S. K.; Thompson, R. C. J . Org. Chem. 1993,
58, 6874 and relevant earlier references cited therein.
0022-3263/96/1961-0142$12.00/0 © 1996 American Chemical Society

Synthesis of Bicyclooctenones
J . Org. Chem., Vol. 61, No. 1, 1996 143
Sch em e 1
of prochiral 6 with bakers’ yeast is amenable to producing
only one highly optically enriched keto alcohol, reliance
had necessarily to be placed as well on chemical means
for distinguishing between the two oxidized ethano
bridges in this intermediate.
Resu lts a n d Discu ssion
The simplest approach to 6 consisted of adapting the
Sakurai reaction19 to readily available 4,4-dimethyl-2-
cyclohexenone (7).20 The titanium tetrachloride-pro-
moted conjugate allylation21 afforded 8 (82%), thereby
setting the stage for ozonolytic cleavage of the double
bond and intramolecular aldolization to give 9 under
catalysis by 20% phosphoric acid in THF22 (Scheme 1).
The racemic hydroxy ketone was obtained as colorless
needles in 84% yield. The most reproducible and effective
means uncovered for the oxidation of this aldol to 6
involved the solid oxidant KMnO4 CuSO4(H2O)5 devel-
oped by Menger and Lee.23 The mildness of this reagent
appears to obviate the substantive fluctuations in yield
noted with chromium-based oxidants.
As noted above, the role of 6 was to serve as a substrate
for asymmetric reduction by fermenting bakers’ yeast.24
Several substituted bicyclo[2.2.2]octane-2,6-diones had
previously been subjected to comparable biocatalytic
reduction, most notably in the laboratories of Mori25 and
Frejd.26 In all instances, the endo hydroxy ketone
predominated heavily and the optical purity of this
product was very high. In line with these prior develop-
ments, 6 was transformed within 24 h in water into ( )-
9, which was isolated in 91% yield and shown to be 98%
ee by Mosher ester analysis.27
The regioselectivity associated with the conversion of
6 into ( )-9 was initially assigned by analogy.25,26 De-
rivatization of this keto alcohol as its xanthate and
thermal elimination in refluxing 2-methoxyethyl ether
for 2 days gave rise to the powerfully dextrorotatory
product 5′. Comparison with closely related bicyclo[2.2.2]-
octenones10b was reason to believe 5′ to be the (1R,4R)
form.
From among a variety of options available for the
transformation of ( )-9 into ( )-5, the decision was made
to pursue in Scheme 2 a reaction sequence closely related
to that which worked so well in Scheme 1. Thus, the
hydroxyl group was protected as its tetrahydropyranyl
ether derivative in advance of 1,2-reduction of the ketone
with sodium borohydride, formation of the xanthate, and
pyrolysis of the latter intermediate. Adherence to this
route delivered 12 in very good overall yield. The
deprotection and oxidation of 12 proceeded smoothly to
make ( )-5 available without event. This enone proved
to be strongly levorotatory and was characterized by a
large Cotton effect with the following circular dichroic
characteristics: [æ]295 3611°, [θ]max 5420° and [æ]305
-3578°, [θ]max 5371°. The octant rule for such systems28
is uniquely consistent with formulation of this ketone as
the (1S,4S) enantiomer.
(14) Review: Fujita, E.; Node, M. Progress in the Chemistry of
Natural Products; Springer Verlag: New York, 1984; Vol. 46, pp 77
157.
(15) Synthesis: Fujita, E.; Shibuya, M.; Nakamura, S.; Okada, Y.;
Fujita, T. J . Chem. Soc., Perkin Trans. 1 1974, 165.
(16) Takeda, Y.; Futatsuishi, Y.; Ichihara, T.; Matsumoto, T.; Terao,
H.; Terada, H.; Otsuka, H. Chem. Pharm. Bull. 1993, 41, 685.
(17) Sun, H.-D.; Lin, Z.-W.; Niu, F.-D.; Lin, L.-Z.; Chai, H.; Pezzuto,
J . M.; Cordell, G. A. J . Nat. Prod. 1994, 57, 1424.
(18) (a) Yang, Y.-W.; Xu, X.-I.; Wang, D.-H.; Qian, B.-G.; Zhao, Q.-
Z. Huaxue Xuebao 1992, 50, 498. (b) Zhou, W.-S.; Chen, Y.-X. Sci.
China, Ser. B 1992, 35, 194.
(19) Hosomi, A.; Sakurai, H. J . Am. Chem. Soc. 1977, 99, 1673.
(20) Flaugh, M. E.; Crowell, T. A.; Farlow, D. S. J . Org. Chem. 1980,
45, 5399.
(21) Review: Fleming, I.; Dunogue´s, J .; Smithers, R. Org. React.
1989, 37, 57.
(22) Paquette, L. A.; Maleczka, R. E., J r.; Qiu, F.-Y. J . Org. Chem.
1991, 56, 2455.
(23) Menger, F. M.; Lee, C. J . Org. Chem. 1979, 44, 3446.
(24) Csuk, R.; Glanzer, B. I. Chem. Rev. 1991, 91, 49.
(25) (a) Kitahara, T.; Miyake, M.; Kido, M.; Mori, K. Tetrahedron:
Asymmetry 1990, 1, 775. (b) Mori, K.; Nagano, E. Biocatalysis 1990,
3, 25. (c) Watanabe, H.; Mori, K. J . Chem. Soc., Perkin Trans. 1 1991,
2919. (d) Mori, K. Bull. Soc. Chim. Belg. 1992, 101, 393. (e) Mori, K.;
Matsushima, Y. Synthesis 1993, 406. (f) Mori, K.; Matsushima, Y.
Synthesis 1994, 417. (f) Mori, K.; Matsushima, Y. Synthesis 1995, 845.
(26) (a) Almquist, F.; Eklund, L.; Frejd, T. Synth. Commun. 1993,
23, 1499. (b) Almquist, F.; Frejd, T. Tetrahedron: Asymmetry 1995, 6,
957.
In summary, the synthetic undertaking described
herein was quite successful in that reasonable quantities
of either antipode of 5 can be obtained in high optical
(27) (a) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543. (b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512. (c) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165.
(28) Crabbe´, P. Optical Rotatory Dispersion and Circular Dichroism
in Organic Chemistry; Holden-Day: San Francisco, 1965; pp 232 237.

144 J . Org. Chem., Vol. 61, No. 1, 1996
Paquette and Tsui
concentrated in vacuo. The white precipitate was separated
by filtration and washed with ether. The combined filtrates
were evaporated, and the residue was purified by chromatog-
raphy on silica gel (elution with 3:1 petroleum ether ether)
to give the keto aldehyde as a colorless oil (17.0 g, 75%): 1H
Sch em e 2
NMR (300 MHz, CDCl3) δ 9.71 (dd, J
2.1, 1.1 Hz, 1 H), 2.60
14.7, 1.1 Hz, 1 H), 2.44 2.06 (m, 6 H), 1.77 1.60 (m,
(dt, J
2 H), 1.02 (s, 3 H), 0.99 (s, 3 H); 13CNMR (75 MHz, CDCl3)
ppm 210.2, 201.0, 45.5, 43.5, 41.4, 39.6, 38.0, 32.3, 28.5, 19.9;
MS m/z (M ) calcd 168.1150, obsd 168.1152.
A solution of the above product (2.5 g, 0.015 mol) in THF
(20 mL) was treated with 20% phosphoric acid in water (20
mL) and heated at reflux overnight. The cooled reaction
mixture was extracted with ether (1 × 50 mL, 2 × 25 mL),
and the combined organic phases were dried and concentrated.
The residue was purified by chromatography on silica gel
(elution with 2:1 ether petroleum ether) and recrystallization
from this solvent system. There was obtained 2.1 g (84%) of
9 as colorless needles: mp 112 113 °C; IR (KBr, cm 1) 3416,
1
1724; H NMR (300 MHz, CDCl3) δ 4.14 (dt, J
8.8, 3.3 Hz,
6.4, 3.3
1 H), 3.66 (s, 1 H), 2.50 2.39 (m, 3 H), 2.31 (dd, J
Hz, 1 H), 2.08 (dd, J
19.1, 2.4 Hz, 1 H), 1.49 1.34 (m, 3 H),
0.99 (s, 3 H), 0.91 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
216.9, 67.8, 52.4, 41.4, 38.9, 36.9, 33.0, 29.8, 29.7, 29.2; MS
m/z (M ) calcd 168.1150, obsd 168.1149. Anal. Calcd for
C10H16O2: C, 71.38; H, 9.59. Found: C, 71.49; H, 9.56.
8,8-Dim eth ylbicyclo[2.2.2]octa n e-2,6-d ion e (6). A solu-
tion of ( )-9 (15.0 g, 0.089 mol) in benzene (300 mL) was
purity within a relatively short time frame. The syn-
thetic regimen is such that several consecutive steps can
easily be dovetailed without need for the isolation or
purification of reaction intermediates. This merging of
steps, in combination with the exceptional efficacy of the
biosynthetic transformation, allows for rewarding utiliza-
tion of 5 and 5′ as key reactants in various extensions of
oxy-Cope chemistry. The progress made along these lines
will be recorded in due course.
23
treated with KMnO4 CuSO4(H2O)5 (105 g, 2:1 w/w), and the
suspension was heated to reflux overnight. After being cooled,
the solid was removed by filtration through a pad of silica gel
and rinsed thoroughly with ether. Following concentation of
the filtrate, the residue was chromatographed on silica gel
(elution with 2:1 petroleum ether ether) to provide 11.6 g
1
(78%) of 6 as colorless needles, mp 153 155 °C; IR (KBr, cm
)
1
1716; H NMR (300 MHz, CDCl3) δ 3.09 (t, J
2.84 (ddd, J 21.2, 3.2, 2.8 Hz, 2 H), 2.28 2.10 (m, 3 H), 1.88
(d, J
3.0 Hz, 2 H), 1.15 (s, 6 H); 13C NMR (75 MHz, CDCl3)
3.0 Hz, 1 H),
ppm 207.0, 65.3, 41.6, 39.5, 39.1, 31.2, 29.5; MS m/z (M ) calcd
166.0994, obsd 166.0993. Anal. Calcd for C10H14O2: C, 72.25;
H, 8.49. Found: C, 71.95; H, 8.44.
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded at the indicated field strengths. High-resolution
mass spectra were recorded at The Ohio State University
Chemical Instrumentation Center. Elemental analyses were
performed at the Scandinavian Microanalytical Laboratory,
Herlev, Denmark. All separations were effected under flash
(
)-(1R,4S,7S)-7-H yd r oxy-5,5-d im et h ylb icyclo[2.2.2]-
octa n -2-on e (9). A mixture of 6 (3.0 g, 0.018 mol), D-glucose
(46 g), and bakers’ yeast (type II, 46 g) in water (30 mL) was
rapidly stirred at rt for 24 h. Following extraction with ethyl
acetate (6 × 100 mL), the combined organics were dried,
filtered, and evaporated. Chromatography of the residue on
silica gel (elution with 2:1 ether petroleum ether) gave ( )-9
as colorless needles: mp 112 113 °C (2.5 g, 82%). The spectra
chromatography conditions on Merck silica gel HG254
. The
organic extracts were dried over anhydrous magnesium sul-
fate. Solvents were reagent grade and in many cases dried
before use.
for ( )-9 were identical to those of the racemate: [ ]23
(c 0.69, CHCl3).
17.5
D
3-Allyl-4,4-d im eth ylcycloh exa n on e (8).29 4,4-Dimethyl-
cyclohexenone (20.0 g, 0.16 mol) in CH2Cl2 (100 mL) was added
dropwise to a cold ( 78 °C), magnetically stirred solution of
titanium tetrachloride (26.3 mL, 0.24 mol) in CH2Cl2 (240 mL)
under N2. After 15 min, allyltrimethylsilane (28 mL, 0.18 mol)
was introduced, and the mixture was stirred a further 3 h prior
to quenching the reaction mixture with water (150 mL). The
mixture was allowed to warm to rt, and the separated aqueous
phase was extracted with CH2Cl2 (50 mL). The combined
organic layers were dried, filtered, and evaporated to leave
an oil which upon distillation afforded 22.0 g (82%) of 8 as a
colorless liquid: IR (neat, cm 1) 1714, 1640; 1H NMR (300
MHz, CDCl3) δ 5.68 5.54 (m, 1 H), 4.97 (s, 1 H), 4.94 4.90
(m, 1 H), 2.41 2.28 (m, 3 H), 2.25 2.16 (m, 1 H), 1.98 (ddd, J
14.9, 11.9, 0.9 Hz, 1 H), 1.73 1.49 (m, 4 H), 1.00 (s, 3 H),
0.96 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 211.6, 136.6,
116.4, 46.2, 42.4, 40.2, 38.1, 35.2, 32.6, 28.6, 19.4; MS m/z (M )
calcd 166.1358, obsd 166.1356.
(
)-(1R,4R)-8,8-Dim eth ylbicyclo[2.2.2]oct-5-en -2-on e (5′).
A solution of ( )-9 (610 mg, 3.63 mmol) in carbon disulfide (5
mL) was added to a stirred suspension of sodium hydride (871
mg, 36.3 mmol) in CS2 (15 mL) at rt. The suspension was
refluxed overnight, cooled to rt, and treated dropwise with
methyl iodide (2.3 mL, 36.3 mmol). After 15 min, the mixture
was poured into iced water (100 mL) and extracted with ether
(1 × 50 mL, 1 × 20 mL). The combined organics were dried
and concentrated to leave xanthate ( )-10 (769 mg, 85%),
which was obtained as white needles, mp 70 71 °C, upon
1
recrystallization from petroleum ether ether: IR (KBr, cm
1731; H NMR (300 MHz, CDCl3) δ 5.86 (dt, J
1 H), 2.75 2.60 (m, 3 H), 2.47 (s, 3 H), 2.19 (dd, J
)
1
9.0, 3.3 Hz,
19.0, 2.4
Hz, 1 H), 1.84 (t, J
2.9 Hz, 1 H), 1.71 1.55 (m, 3 H), 1.11 (s,
3 H), 1.03 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 214.4, 212.6,
79.5, 48.4, 41.6, 39.1, 36.9, 31.2, 30.1, 29.9, 29.2, 18.7; MS m/z
(M ) calcd 258.0748, obsd 258.0747; [ ]25
4.6 (c 0.35,
D
(
)-(1R*,4S*,7S*)-7-Hydr oxy-5,5-dim eth ylbicyclo[2.2.2]-
CHCl3). Anal. Calcd for C12H18O2S2: C, 55.80; H, 7.03.
Found: C, 55.95; H, 7.06. Racemic 10 exhibits a melting point
of 52 53 °C.
A solution of ( )-10 (621 mg, 2.41 mmol) in 2-methoxyethyl
ether (10 mL) was refluxed under N2 for 15 h, cooled to rt,
and diluted with water (100 mL) and petroleum ether (100
mL). The separated organic phase was washed further with
water (5 × 20 mL), dried, and concentrated by bulb-to-bulb
octa n -2-on e (9). A solution of 8 (22.0 g, 0.13 mol) in CH2Cl2
(250 mL) was ozonolyzed at 78 °C until a blue color persisted.
After the introduction of triphenylphosphine (51 g), the reac-
tion mixture was allowed to stir at rt for 30 min and
(29) (a) Koft, E. R. Tetrahedron 1987, 43, 5775. (b) Neunert, D.;
Klein, H.; Welzel, P. Tetrahedron 1989, 45, 661.

Synthesis of Bicyclooctenones
J . Org. Chem., Vol. 61, No. 1, 1996 145
distillation. The concentrate was passed through a column of
silica gel (elution with 8:1 petroleum ether ether) to give 260
mg (72%) of ( )- 5′ as a waxy white solid which was further
purified by sublimation, mp 98 99 °C; IR (KBr, cm 1) 1722;
36.3 mmol). After 15 min, the workup described above was
implemented to give the xanthate (33 g, 90%) as white
needles: mp 82 83 °C (from ether petroleum ether); 1H NMR
(300 MHz, CDCl3) δ 5.68 5.60 (m, 1 H), 4.68 and 4.59 (t, J
3.4 and 2.4 Hz, respectively, 1 H), 4.06 3.90 (m, 1 H), 3.89
3.79 (m, 1 H), 3.48 3.39 (m, 1 H), 2.53 (s, 3 H), 2.51 2.29 (m,
3 H), 1.90 1.24 (series of m, 11 H), 0.99 (s, 6 H); 13C NMR (75
MHz, CDCl3) ppm (214.9, 214.7), (96.5, 96.4), (81.9, 81.2), (71.0,
70.6), (62.7, 61.9), (38.3, 37.9), (36.4, 36.1), 33.0, (32.6, 32.1),
(31.6, 31.3), (31.2, 30.9), 30.3, 30.2, (29.9, 29.8), (25.6, 25.5),
(19.9, 19.2), (18.5, 18.3); MS m/z (M ) calcd 344.1480, obsd
344.1499. Anal. Calcd for C17H28O3S2: C, 59.28; H, 8.20.
Found: C, 59.26; H, 8.20.
1H NMR (300 MHz, CDCl3) δ 6.51 (t, J
7.2 Hz, 1 H), 2.95 (t, J
7.2 Hz, 1 H), 6.10 (t,
3.1 Hz, 1 H), 2.42 2.40 (m, 1 H),
J
2.30 (dd, J
11.7, 2.2 Hz, 1 H), 1.86 (dd, J
18.7, 3.0 Hz, 1
H), 1.57 (dd, J
13.2, 2.1 Hz, 1 H), 1.40 (dd, J 13.2, 3.4 Hz,
1 H), 1.05 (s, 3 H), 0.94 (s, 3 H); 13C NMR (75 MHz, CDCl3)
ppm 212.9, 138.5, 126.8, 50.0, 44.3, 39.0, 36.5, 33.7, 31.6, 28.6;
MS m/z (M ) calcd 150.1044, obsd 150.1033; [ ]26
536 (c
D
0.46, CHCl3). The racemic ketone, accessed in a very different
manner, has been reported previously.30
A solution of this xanthate (33.0 g, 0.096 mol) in 2-meth-
oxyethyl ether (100 mL) was heated to reflux under N2 for 2
days and processed in the predescribed manner. Chromatog-
raphy on silica gel (elution with 7:1 petroleum ether ether)
gave 20.0 g (80%) of 12 as a colorless oil: IR (neat, cm 1) 1465,
1452; 1H NMR (300 MHz, CDCl3) δ 6.49 6.41 (m, 1 H), 6.13
5.99 (m, 1 H), 4.70 4.58 (m, 1 H), 4.03 3.83 (m, 2 H), 3.51
3.44 (m, 1 H), 2.76 2.70 (m, 1 H), 2.37 2.27 (m, 1 H), 2.05
2.02 (m, 1 H) 1.82 1.43 (m, 6 H), 1.26 1.00 (m, 3 H), 0.99 (s,
3 H), 0.82 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm (136.7,
136.1), (129.1, 128.3), 99.7, (97.7, 96.6), (74.9, 73.1), 62.9, (42.3,
42.2), (39.7, 39.4), (38.0, 35.4), (32.6, 32.3), 31.6, (31.3, 31.1),
(29.7, 29.6), 25.5, 20.1; MS m/z (M ) calcd 236.1777, obsd
236.1773. Anal. Calcd for C15H24O2: C, 76.21; H, 10.24.
Found: C, 76.24; H, 10.33.
(1R,4S,7S)-5,5-Dim eth yl-7-[(tetr a h yd r o-2H-p yr a n -2-yl)-
oxy]bicyclo[2.2.2]octa n -2-on e (11). A solution of ( )-9 (21.6
g, 0.13 mol), p-toluenesulfonic acid monohydrate (20 mg), and
dihydropyran (78 mL, 0.19 mol) in CH2Cl2 (200 mL) was
stirred at rt for 2 h, filtered through a short pad of silica gel,
and freed of solvent. Chromatography of the residue on silica
gel (elution with 3:1 petroleum ether ether) gave 11 as a
colorless oil (29.0 g, 90%): IR (neat, cm 1) 1730; 1H NMR (300
MHz, CDCl3) δ 4.66 (br d, J
23.0 Hz, 1 H), 3.82 3.75 (m, 1 H), 3.46 3.43 (m, 1 H), 2.53
2.37 (m, 3 H), 2.13 (br d, J 18.7 Hz, 1 H), 1.79 1.37 (m, 10
23.0 Hz, 1 H), 4.12 (dm, J
H), 1.04 1.02 (m, 3 H), 0.96 (s, 3 H); 13H MR (75 MHz, CDCl3)
ppm 215.0, (96.6, 95.8), (72.3, 71.0), (62.7, 61.6), (50.6, 48.2),
(41.6, 41.5), (39.1, 39.0), (37.5, 37.0), (31.8, 31.4), (30.8, 30.7),
(30.3, 30.1), 29.9, (29.2, 29.0), (25.4, 25.3), (19.5, 18.7); MS m/z
(M ) calcd 252.1726, obsd 252.1734. Anal. Calcd for
C15H24O3: C, 71.38; H, 9.59. Found: C, 70.97; H, 9.61.
(
)-(1S,4S)-8,8-Dim eth ylbicyclo[2.2.2]oct-5-en -2-on e (5).
A solution of 12 (20.0 g, 0.085 mol) in methanol (50 mL) was
treated with a catalytic amount of p-toluenesulfonic acid,
stirred at rt for 1 h, and filtered through a pad of silica gel.
Solvent evaporation followed by chromatography on silica gel
(elution with 1:1 ether petroleum ether) gave the alcohol as
a white solid: mp 61 61.5 °C, after sublimation at 65 °C and
0.5 Torr (11.0 g, 85%); IR (film, cm 1) 3300, 1445; 1H NMR
Sod iu m Bor oh yd r id e Red u ction of 11. A cold (0 °C),
magnetically stirred solution of 11 (29.0 g, 0.12 mol) in
methanol (200 mL) was treated in small portions with sodium
borohydride (4.4 g, 0.12 mol). The reaction mixture was stirred
at 0 °C for 1 h and diluted with CH2Cl2 (200 mL) and water
(200 mL). The separated aqueous phase was extracted with
CH2Cl2 (2 × 100 mL), and the combined organic layers were
dried and evaporated. Purification of the residue by chroma-
(300 MHz, CDCl3) δ 6.50 (dt, J
6.2, 0.9 Hz, 1 H) 3.92 (ddt, J
2.60 (m, 1 H), 2.39 (ddd, J
6.9, 1.1 Hz, 1 H), 6.06 (dt, J
8.3, 3.1, 1.0 Hz, 1 H), 2.65
8.3, 4.0, 2.7 Hz, 1 H), 2.07 2.03
tography on silica gel (elution with 1:1 ether petroleum ether)
(m, 1 H), 1.38 (s, 1 H), 1.19 (ABX, J AB
Hz, 1 H), 1.14 (ABX, J AB 13.0 Hz, J BX 3.6 Hz, 1 H), 0.97
(s, 3 H), 0.90 (dt, J
14.0, 3.1 Hz, 1 H), 0.83 (s, 3 H); 13C
13.0 Hz, J AX 2.4
1
gave the alcohol as a colorless oil (27.0 g, 95%): IR (neat, cm
3534; 1H NMR (300 MHz, CDCl3) δ 4.73 4.71 (m, 1 H), 4.12
4.01 (m, 1 H), 3.91 3.81 (m, 2 H), 3.65 3.58 (br s, 1 H), 3.53
3.45 (m, 2 H), 2.49 2.20 (m, 2 H), 2.08 2.01 (m, 1 H), 1.83
)
NMR (75 MHz, CDCl3) ppm 138.0, 127.9, 69.6, 42.5, 40.0, 39.2,
35.2, 32.2, 31.5, 29.5; MS m/z (M ) calcd 152.1200, obsd
1.34 (series of m, 8 H), 1.31 1.11 (m, 3 H), 0.93 0.90 (m, 6
H); 13C NMR (75 MHz, CDCl3) ppm (97.3, 95.7), (74.6, 73.0),
(69.2, 68.9), (62.5, 62.0), 38.31, (38.26, 38.1), (36.5, 36.1), (36.4,
36.3), 33.0, 32.0, (30.9, 30.8), 30.2, 29.2, 25.3, (19.3, 19.1); MS
m/z (M ) calcd 254.1882, obsd 254.1909. Anal. Calcd for
C15H26O3 : C, 70.81; H, 10.31. Found: C, 70.87; H, 10.36.
2-[[(1S,2S,4S)-8,8-Dim eth ylbicyclo[2.2.2]oct-5-en -2-yl]-
oxy]tetr a h yd r o-2H-p yr a n (12). A solution of the preceding
alcohol (27.0 g, 0.11 mol) in carbon disulfide (50 mL) was added
to a stirred suspension of sodium hydride (29.0 g, 1.2 mol) in
CS2 at rt, and the mixture was heated at reflux overnight,
cooled to rt, and treated dropwise with methyl iodide (2.3 mL,
152.1206; [ ]23
77.6 (c 0.62, CHCl3).
D
The above alcohol was dissolved in CH2Cl2 (10 mL), treated
with 4 Å molecular sieves (500 mg) and pyridinium chloro-
chromate (134 mg, 0.62 mmol), and stirred at rt for 2 h. After
petroleum ether (20 mL) was introduced, the solid was
separated by filtration and the filtrate was concentrated. The
residue was purified by chromatography on silica gel and
sublimation as before (24 mg, 52%). The colorless solid
exhibited mp 95 98 °C and [ ]25
544 (c 0.33, CHCl3).
D
Ack n ow led gm en t. We are grateful to the National
Institutes of Health for their financial support by means
of Grant CA-12115.
(30) Geribaldi, S.; Torri, G.; Azzaro, M. Bull. Soc. Chim. Fr. 1973,
2836.
J O951552G