Preparation of optically active apoverbenone and verbenone from nopinone by use of the sulfenylation-dehydrosulfenylation method. Stability and reactivity attributable to absolute configuration at the sulfur atom in sulfoxides

Article abstract of DOI:10.1021/jo9807316

Apoverbenone (4) and verbenone (5) in optically active forms are potentially useful compounds as the chiral source in enantioselective synthesis. Starting with (+)-nopinone (1), readily available from (-)-β-pinene, (+)-apoverbenone (4a) and (+)-verbenone (5a) were prepared in synthetically satisfactory overall yields, using commonly the sulfenylation-dehydrosulfenylation method directed toward construction of an enone function. This methodology could be applicable to preparation of their enantiomers (-)-4b and (-)-5b on starting with (-)-nopinone. While configuration of the phenylsulfinyl group in sulfoxides 10a, b, and 18a, b were assigned by their NMR spectra and NOE correlations, absolute configurations at the sulfur atom were performed by comparison in 1H NMR spectra with their homologues whose absolute configurations are well-defined, that is, lOa with 13a, lOb with 13b, 18a with 19b, and 18b with 19a. As a result, it was proved that, in 3-(phenylsulfinyl)nopinones, thermodynamic stability of isomers is dependent on absolute configuration at the sulfur center; that is, the frans-isomer 10a possesses an R_s-phenylsulfinyl group and the a's-isomer 10b possesses an S_s-phenylsulfinyl group, and it was proved that, in (4R)-4methyl-3-(phenylsulfinyl)nopinones, both as-isomers 18a, b are stable, irrelevant with absolute configurations at the sulfur atom. In elimination of phenylsulfenic acid from sulfoxides 10 and 18, the use of purified sulfoxides was essential, because the competing Pummerer reaction proceeded to give 3-(phenylthio)verbenone (11) as a byproduct, when acidic contaminants were present. The sulfoxides 10a, b and 18a provided smoothly 4a and 5a, respectively, in a syn elimination manner, whereas 18b gave a mixture of decomposed products as a major part, probably because of instability of 18b to heat as well as because of its conformational requirement.

Full text of DOI:10.1021/jo9807316

J . Org. Chem. 1998, 63, 6939-6946
6939
P r ep a r a tion of Op tica lly Active Ap over ben on e a n d Ver ben on e
fr om Nop in on e by Use of th e Su lfen yla tion -Deh yd r osu lfen yla tion
Meth od . Sta bility a n d Rea ctivity Attr ibu ta ble to Absolu te
Con figu r a tion a t th e Su lfu r Atom in Su lfoxid es
Hiroshi Kosugi, J aseung Ku, and Michiharu Kato*
Institute for Chemical Reaction Science, Tohoku University, Katahira, Aoba-ku, Sendai 980-8577, J apan
Received April 20, 1998
Apoverbenone (4) and verbenone (5) in optically active forms are potentially useful compounds as
the chiral source in enantioselective synthesis. Starting with (+)-nopinone (1), readily available
from (-)-â-pinene, (+)-apoverbenone (4a ) and (+)-verbenone (5a ) were prepared in synthetically
satisfactory overall yields, using commonly the sulfenylation-dehydrosulfenylation method directed
toward construction of an enone function. This methodology could be applicable to preparation of
their enantiomers (-)-4b and (-)-5b on starting with (-)-nopinone. While configuration of the
1
phenylsulfinyl group in sulfoxides 10a ,b, and 18a ,b were assigned by their H NMR spectra and
1
NOE correlations, absolute configurations at the sulfur atom were performed by comparison in H
NMR spectra with their homologues whose absolute configurations are well-defined, that is, 10a
with 13a , 10b with 13b, 18a with 19b, and 18b with 19a . As a result, it was proved that, in
3-(phenylsulfinyl)nopinones, thermodynamic stability of isomers is dependent on absolute config-
uration at the sulfur center; that is, the trans-isomer 10a possesses an Rs-phenylsulfinyl group
and the cis-isomer 10b possesses an Ss-phenylsulfinyl group, and it was proved that, in (4R)-4-
methyl-3-(phenylsulfinyl)nopinones, both cis-isomers 18a ,b are stable, irrelevant with absolute
configurations at the sulfur atom. In elimination of phenylsulfenic acid from sulfoxides 10 and
18, the use of purified sulfoxides was essential, because the competing Pummerer reaction proceeded
to give 3-(phenylthio)verbenone (11) as a byproduct, when acidic contaminants were present. The
sulfoxides 10a ,b and 18a provided smoothly 4a and 5a , respectively, in a syn elimination manner,
whereas 18b gave a mixture of decomposed products as a major part, probably because of instability
of 18b to heat as well as because of its conformational requirement.
Ch a r t 1
In tr od u ction
(+)-Nopinone (1) (Chart 1) is readily available in large
quantities by ozonolysis of (-)-â-pinene. As part of
synthetic study on natural products starting with 1, we
have demonstrated that 4,4-disubstituted nopinones 2a 1
and their enantiomers 2b2 served as the versatile key
intermediates for the enantioselective syntheses of el-
emane1 and nardosinane sesquiterpenes3 and lobane4 and
clerodane diterpenes.5 In addition, (4R)-methylnopinone
(3)6 has been utilized as the key compound for the
enantioselective approach to the steroid-D ring.7 In all
preparations of these alkyl-substituted nopinones from
1, introduction of methyl and other alkyl groups at the
C(4) position was achieved by use of the stereoselective
conjugate addition of alkyl nucleophiles to an enone
(1) Kato, M.; Watanabe, M.; Vogler, B.; Awen, B. Z.; Masuda, Y.;
Tooyama, Y.; Yoshikoshi, A. J . Org. Chem. 1991, 56, 7071. Kato, M.;
Kido, F.; Watanabe, M.; Masuda, Y. Awen, B. Z. J . Chem. Soc., Perkin
Trans. 1. 1993, 2831.
(2) Watanabe, M.: Awen, B. Z.; Kato, M. J . Org. Chem. 1993, 58,
3923.
(3) Kato, M.; Watanabe, M.; Awen, B. Z. J . Org. Chem. 1993, 58,
5145.
(4) Kosugi, H.; Yamabe, O.; Kato, M. J . Chem. Soc., Perkin Trans.
1 1998, 217.
(5) Kato, M.; Kosugi, H.; Kodaira, A.; Hagiwara, H. Tetrahedron Lett.
1997, 38, 6845.
(6) Hobbs, P. D.; Magnus, P. D. J . Chem. Soc., Perkin Trans. 1 1973,
2870. Konopelski, J . P.; Sundararaman, P.; Barth, G.; Djerassi, C. J .
Am. Chem. Soc. 1980, 102, 2737.
function, that is, the conjugate addition of (1R,5R)-(+)-
6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (apoverbenone;
4a ) with lithium dimethylcuprate for the synthesis of 3
and that of (1R,5R)-(+)-4,6,6-trimethylbicyclo[3.1.1]hept-
3-en-2-one (verbenone; 5a ) with alkyl Grignard reagents
in the presence of copper(I) iodide for the synthesis of
2a . On the other hand, compound 2b was prepared from
4a by a sequence of reactions: (i) 1,2-addition of 4a with
(7) Kosugi, H.; Sugiura, J .; Kato, M. J . Chem. Soc., Chem. Commun.
1996, 2743.
S0022-3263(98)00731-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/15/1998

6940 J . Org. Chem., Vol. 63, No. 20, 1998
Kosugi et al.
MeLi; (ii) oxidative rearrangement of the resulting allyl
alcohol with pyridinium chlorochromate (PCC) with
formation of (1S,5S)-(-)-verbenone 5b; (iii) subsequent
stereoselective conjugate addition with alkyl Grignard
reagents to give 2b.2
From the reasons mentioned above, compounds 4a and
5a attracted considerable attention as potentially useful
synthetic intermediates, and substantial quantities of
these were required.
The early preparation of 4a consisted of bromination
of 1 followed by dehydrobromination with bases. First,
Grimshaw et al. employed NBS as a brominating reagent
to obtain a mixture of (3S)- and (3R)-bromo ketones 6
and 7, in which only the latter, 7, derivable from 6 by
epimerization on alumina, underwent dehydrobromina-
tion with Li2CO3 and LiBr to give 4a in more than 70%
overall yield (eq 1).8,9 Then, Nishino et al. reported a
expensive and toxic selenenyl compounds. Herein, we
wish to describe not only facile and efficient preparation
of 4a and 5a from (+)-nopinone (1) by use of the sul-
fenylation-dehydrosulfenylation method12 as the key
unit reaction but also a few attractive findings obtained
in the present study, that is, the relationship in thermo-
dynamic stability between configuration of a phenylsulfi-
nyl group at the C(3) position of nopinones and absolute
configuration at the sulfur atom. In addition, reactivity
resulting from absolute configuration at the sulfur center
in the dehydrosulfenylation reaction of (3R,4R)-3-(phen-
ylsulfinyl)-4-methylnopinones will be discussed.
Resu lts a n d Discu ssion
Previously, one (M.K.) of the authors has pointed out
that attempted syn elimination reaction of (3R)-3-(phen-
ylsulfinyl)nopinone (10), prepared from the sulfide 9 by
oxidation with MCPBA, proved to be unsuccessful, af-
fording 3-(phenylthio)apoverbenone (11) as the major
product (49% yield) along with a small amount of the
expected 4a (eq 3).2 Now, we reinvestigated the phenyl-
sulfenylation-dehydrosulfenylation method in some de-
tail, since formation of the compound 11 could be
accounted for by the Pummerer reaction of the sulfoxide
10 with some acidic contaminants, probably m-chlo-
robenzoic acid (MCBA) and/or MCPBA, which were
carelessly left unremoved on purification of a mixture of
oxidation products.
To avoid contamination of the sulfoxide with some
acidic compounds mentioned above, we employed, in the
present study, sodium periodate (NaIO4) as an oxidant
in place of MCPBA. The sulfides 8 and 9 were prepared
from 1 in a 85:15 ratio and 97% yield according to our
synthetic procedure established earlier.1 Treatment of
8 with DBU in boiling benzene led to an equilibrium
mixture from which the thermodynamically stable 9 was
obtained in 63% yield.1 The sulfide 9 was oxidized with
NaIO4 in aqueous methanol to give in 99% yield a
mixture of two diastereomeric sulfoxides 10a ,b (a 36:64
ratio) which are readily separable by silica gel chroma-
tography, while upon oxidation of the sulfide 8 under the
same reaction conditions a mixture of the same sulfoxides
10a ,b (a 72:28 ratio) was obtained in 99% yield (Scheme
1
1). Table 1 shows the H NMR data for the compounds
obtained in the present study. Stereochemistry of 10a ,b
was assigned by their 1H NMR data and NOE correla-
tions, in which the NOEs in 10a indicate stereochemistry
of the C(3)-phenylsulfinyl substituent as S, while those
in 10b indicate that as R. In addition, as seen in Table
1, the chemical shifts of the C(7)-Hb of 10a and C(6)-
Me(a) of 10b showed a deshielding effect (0.36 for the
former and 0.14 ppm for the latter) by the proximate
phenylsulfinyl group, as revealed when compared with
those of 10b and 10a , respectively. The findings support
the above configurational assignment.
sequence of reactions, bromination with bromine followed
by heating with DBU to give 4a , without any description
on the overall yield.10 Recently, we have shown an
alternate approach consisting of phenylselenenylation of
1 followed by selenoxide fragmentation (eq 2).2,11 Al-
though our synthesis provided 4a in good overall yield
(63%), it has its own disadvantages, such as the use of
Next, assignment of the absolute configuration at the
sulfur atom in 10a ,b was carried out by the synthesis of
their homologues, whose absolute configuration are well-
(8) Grimshaw, J .; Grimshaw, J . T.; J uneja, H. R. J . Chem. Soc.,
Perkin Trans. 1 1972, 50.
(9) In our repeated runs according to the reported procedures,
procurement of the bromo ketone 7 was not necessarily reproducible,
so that the reproducibility in the overall yield from 1 to 4a appeared
to be poor.
1
defined, followed by comparison of their H NMR spectra
with those of 10a ,b. The nucleophilic substitution reac-
tion of (-)-(S)-menthyl p-toluenesulfinate (12a )13 with 1
(10) Nishino, C.; Takayanagi, H. Agric. Biol. Chem. 1979, 43,
1957.
(11) Related synthesis: Siegel, C.; Gordon, D. H.; Vliss, D. B.;
Handrick, G. R. Dalzell, H. C.; Razdan, R. K. J . Org. Chem. 1991, 56,
6865.
(12) Trost, B. M.; Salzmann, T. N. J . Am. Chem. Soc. 1973, 95,
6840.
(13) Solladie, G. Synthesis 1981, 185.

Optically Active Apoverbenone and Verbenone
J . Org. Chem., Vol. 63, No. 20, 1998 6941
Sch em e 1
Ta ble 1. 1H NMR (400 MHz, CDCl3) Da ta (δ, Mu ltip licity, a n d J in Hz) of 8, 9, 10a ,b, 13a ,b, 17, 18a ,b, a n d 19a ,ba
1-H
(1H)
3-H
(1H)
4-Hb
(1H)
4-Ha
(1H)
5-H
(1H)
7-Ha
(1H)
7-Hb
(1H)
4-Me
(3H)
6-Me(a)
(3H)
6-Me(b)
(3H)
8
2.68
t
3.74
dd
2.23
m
2.14
ddd
2.5-2.60
(2H, m)
1.88
d
0.85
s
1.36
s
5.4
2.75
t
9.5, 2.2
4.18
dd
14.5, 3.6 2.4
2.56
ddd
10.7
1.72
d
9
1.95
ddd
2.25
dddd
2.51
ddd
0.82
s
1.34
s
5,4
2.67
t
5.6
2.74
t
5.1
2.73
t
10.9, 8,3
3.43
dd
10.5, 4.4
3.54
dd
10.5, 8.5
3.37
d
13.8, 10.9, 1.5
2.36
dt
14.4, 3.6
1.63
ddd
13.8, 5.5, 3.4
1.66
ddt
5.4, 5.4, 3.4, 1.5
2.20
ddt
10.7, 5.4, 5.4
2.56
ddt
11.0, 2.2, 5.6
2.30
dt
11.0, 5.1
2.15
ddd
10.7
1.91
d
11.0
1.55
d
11.0
1.70
d
10a
10b
17
0.85
s
1.35
s
14.4, 10.5, 2.2
5.6, 3.9, 2.2
2.49-2.55
0.99
s
1.33
s
(2H, m)
13.9, 10.5, 4.4
2.44
ddq
2.05
ddd
1.23
d
0.70
s
1.34
s
5.4
2.71
t
5.1
2.57
t
5.4
2.66
t
5.6
2.73
t
5.2
2.57
t
5.3
2.69
t
8.1
3.27
d
6.8
3.49
d
8.0
3.39
dd
10.3, 3.9
3.52
dd
10.5, 8.3
3.46
d
8.1, 1.5, 6.6
2.90
ddq
6.9, 1.9, 6.6
2.53
ddq
8.0, 1.9, 6.6
1.67
ddt
5.4, 5.1, 1.5
2.03
ddd
5.1, 5.0, 1.9
2.00
td
5.4, 1.9
2.20
ddt
11.0, 5.4, 5.1
2.46
ddd
11.2, 5.1, 5.0
2.42
ddd
11.0, 5.4, 5.1
2.55
ddt
11.2, 2.2, 5.6
2.30
dt
11.0, 5.1
2.42
ddd
11.0, 5.4, 5.1
2.46
ddd
11.0
1.59
d
11.2
1.63
d
11.0
1.92
d
11.2
1.54
d
11.0
1.62
d
11.0
1.58
d
6.6
0.70
d
6.6
1.12
d
18a
18b
13a
13b
19a
19b
1.02
s
1.34
s
0.65
s
1.27
s
6.6
2.36
dt
14.6, 3.9
1.64
ddd
0.84
s
1.35
s
14.6, 10.3, 2.2
5.6, 3.9, 2.2
2.49-2.56
(2H, m)
0.99
s
1.33
s
13.9, 10.5, 4.4
2.49
ddq
8.0, 1.9, 6.6
2.89
ddq
1.98
td
5.4, 1.9
2.02
ddd
1.10
d
6.6
0.73
d
0.65
s
1.27
s
7.6
3.25
d
1.02
s
1.34
s
5.2
8.0
8.0, 2.0, 6.6
5.3, 5.1, 2.0
11.1, 5.3, 5.1
11.1
6.6
a
Others: 8, 7.24-7.37 (3H, m), 7.50-7.55 (2H, m); 9, 7.22-7.32 (3H, m), 7.47-7.55 (2H, m); 10a , 7.45-7.56 (3H, m), 7.62-7.65 (2H,
m); 10b, 7.42-7.55 (3H, m), 7.61-7.65 (2H, m); 17, 7.21-7.30 (3H, m), 7.54-7.50 (2H, m); 18a , 7.46-7.55 (3H, m), 7.74-7.78 (2H, m);
18b, 7.46-7.54 (3H, m), 7.75-7.78 (2H, m); 13a , 2.40 (3H, s), 7.33 (2H, d, 8.6b), 7.52 (2H, d, 8.3b); 13b, 2.42 (3H, s), 7.31 (2H, d, 8.1b), 7.52
b
(2H, d, 8.0b); 19a , 2.41 (3H, s); 7.31 (2H, d,b 8.0), 7.65 (2H, d,b 8.3); 19b: 2.42 (3H, s), 7.32 (2H, d,b 8.0), 7.64 (2H, d,b 8.2). With fine
splittings.
in the presence of (diisopropylamino)magnesium bro-
mide14 provided in 65% yield (3S,Rs)-p-tolyl sulfoxide
(13a ), whose Rf value on TLC agreed very closely with
that of 10a (Scheme 2).15 Similarly, the reaction of (+)-
(R)-menthyl p-toluenesulfinate (12b)13 with the magne-
sium salt of 1 gave in 65% yield (3R,Ss)-13b,16 whose Rf
value agreed very closely with that of 10b. As seen in
(15) Attempted substitution reaction using LDA in place of (diiso-
propylamino)magnesium bromide proved to be unsuccessful, because
the reaction was sluggish and a large portion of 1 was recovered.
(14) Carreno, M. C.; Garcia Ruano, J . L.; Rubio, A. Tetrahedron Lett.
1987, 28, 4861.

6942 J . Org. Chem., Vol. 63, No. 20, 1998
Kosugi et al.
Sch em e 2
Sch em e 4
equiv) as the representative of weak organic acids, giving
4a and 11 in 41 and 7% and 53 and 14% yields,
respectively (Scheme 4). Contrary to these observations,
it is worth mentioning that, upon heating 2-(phenylsulfi-
nyl)-4-tert-butylcyclohexanone (14) under the same reac-
tion conditions, 4-tert-butylcyclohex-2-en-1-one (15) was
produced in nearly quantitative yield, and no Pummerer
reaction product could be detectable despite careful
inspection of the reaction mixture.
As a consequence of observations mentioned above,
while we have developed the efficient preparation of 4a
from 1 using the sulfenylation-dehydrosulfenylation
method, it was proved that transformation of sulfoxides
10 into apoverbenone (4a ) is affected by the presence of
acidic contaminants in the reaction media, probably by
the reason described in our preceding report;2 that is, the
bridges, especially, the gem-dimethyl bridge in 10, would
somewhat hinder formation of the cyclic transition state
necessary for the syn elimination between a phenylsulfi-
nyl function and a â-hydrogen atom, and thus, the
competing Pummerer reaction proceeds to give 11, when
acidic contaminants are present.
It is well-known that (-)-â-pinene, a synthetic precur-
sor of (-)-nopinone (mirror image of 1), is scarcely found
in nature.18 However, a 5-step chemical transformation
of (+)-R-pinene into (-)-nopinone in more than 70%
overall yield has been accomplished by Lavallee et al.19
This fact implies that (-)-apoverbenone (4b) could be
obtainable in more than 60% overall yield on application
of the present sequence of reactions to (-)-nopinone as
the starting material.
Sch em e 3
1
Table 1, the H NMR spectra of 13a ,b are very closely
similar in chemical shifts and coupling patterns to those
of 10a ,b, respectively, except for the aromatic part,
respectively, suggesting configuration at the sulfur center
in 10a ,b being R and S, respectively. The above findings
indicate that the initial products 10c,d , which would be
produced by NaIO4 oxidation of 8 and 9, respectively, are
thermodynamically unstable to lead readily to 10b and
10a , respectively, by concomitant epimerization, during
the time the oxidation reaction proceeds.
Each of the sulfoxides 10a ,b, obtained by purification
with silica gel chromatography, was subjected to the syn
elimination reaction under heating at 120 °C in toluene
in the presence of K2CO3 (5 equiv), thus giving 4a as the
sole product in 96 and 93% yields from 10a ,b, respec-
tively (Scheme 3).17 Finally, from the standpoint of the
practical preparation, a mixture of 10a ,b was heated to
provide 4a in 93% yield. This yield is equivalent to 89%
overall yield on starting from 1. In the syn elimination
reaction, it was proved that when the sulfoxide is
employed without purification, the reaction shows the
marked tendency to produce a mixture of 4a and the
Pummerer reaction product 11. Then, the elimination
reaction of the mixture of 10a ,b was carried out in boiling
CCl4 in the presence of MCBA (0.1 equiv) and PPTS (0.1
Verbenones 5a ,b are natural products and both avail-
able commercially. However, these compounds with high
optical purity are high in price. For the synthesis of (-)-
verbenone (5b), a few chemical transformations from (-)-
R-pinene have been reported,18 and we have recently
shown the efficient 2 step chemical transformation of 4a
into 5b, as aforementioned.2 Then, to synthesize its
enantiomer (+)-5a , the present sulfenylation-dehydro-
sulfenylation method was applied to (4R)-methylnopinone
(3). Phenylsulfenylation of the lithium enolate of 3 with
S-phenyl benzenethiosulfonate20 provided, in 93% com-
bined yield, sulfides 16 and 17 as an inseparable mixture
(a 4:6 ratio from the 1H NMR analysis) (Scheme 5).
Treatment of the mixture 16 and 17 with DBU in boiling
benzene resulted in smooth epimerization of 16, because
of a steric interaction between the phenylsulfenyl and
(16) The products 13b and 19a ,b are thermodynamically stable
compounds, and their production is attributable to concomitant
epimerization of a p-tolylsulfinyl group in the initial products, (3S,Ss)-,
(3S,Rs)-, and (3S, Ss)-p-tolyl sulfoxides, for the formation of 13b, 19a ,
and 19b, respectively.
(17) Attempted syn elimination under the mild reaction conditions;
heating in CCl4 containing pyridine proved to be impractical, because
the reaction was sluggish.
(18) Thomas, A. F.; Bessiere, Y. The Total Synthesis of Natural
Products; Apsimon, J ., Ed.; Wieley-Interscience: New York, 1988; Vol.
7, p 275. Banthorpe, D. V.; Ekundayo, O.; Njar, V. C. O. Phytochemistry
1984, 23, 291.
(19) Lavallee, P.; Gouthillier, G. J . Org. Chem. 1986, 51, 1362.
(20) Trost, B. M.; Massiot, G. S. J . Am. Chem. Soc. 1977, 99, 4405.

Optically Active Apoverbenone and Verbenone
J . Org. Chem., Vol. 63, No. 20, 1998 6943
Sch em e 5
(17% yield). Consequently, heating a mixture of 18a ,b,
which was carried out from the preparative point of view,
resulted in procurement of 5a only in 53% yield. After
considerable experimentation, the reaction conditions
with heating at 95 °C in toluene in the presence of K2-
CO3 (12 equiv) for 2 days was employed as optimum, thus
providing 5a in 92% from 18a , 40% from 18b, and 82%
yields from a mixture of 18a ,b. The last yield is
equivalent to 61% overall yield on starting from 1.
C(4)-methyl groups in the close neighborhood, to give the
thermodynamically stable 17 as the sole product in
nearly quantitative yield. On oxidation with NaIO4, the
compound 17 provided sulfoxides 18a ,b (a 68:32 ratio)
as a separable diastereomeric mixture in 98% combined
yield (Scheme 6). Stereochemical assignments of the
phenylsulfinyl group in 18a ,b were unambiguously es-
tablished by their 1H NMR data (Table 1) and NOE
correlations as shown in the structures of 18a ,b. With
respect to configuration at the sulfur center, (3R,Rs)-19a
and (3R,Ss)-19b were prepared from the nucleophilic
substitution reaction of (-)-(S)- and (+)-(R)-menthyl
p-toluenesulfinate 12a ,b13 with 3, respectively (Scheme
2).16 As seen in Table 1, a marked spectral resemblance
between 18b and 19a and 18a and 19b except for the
aromatic part indicates the absolute configuration at the
sulfur atom of 18a ,b as being S and R, respectively. It
is worth mentioning that oxidation of a mixture 16 and
17 afforded a mixture of the same sulfoxides 18a ,b (a
82:18 ratio) in nearly quantitative yield, and no other
configurational isomers were detected by careful inspec-
tion of the reaction mixture. The findings suggest that
the initial products of 16, (3S,Rs)-18c and (3S,Ss)-18d ,
easily isomerize to the stable 18b and 18a , respectively,
while the oxidation reaction proceeds.
The chemical shift (δ 0.70) of the C(4)-Me of 18a shows
a considerable upfield shift (ca. 0.4 ppm) by the shielding
effect of a benzene ring, in comparison with that of 18b
(δ 1.12). In addition, the C(4)-H(a) and the C(6)-Me(a)
protons in 18b occur at δ 2.53 and 0.65, respectively,
while those in 18a occur at δ 2.90 and 1.02, respectively,
probably because of the deshielding effect due to the
proximate phenylsulfinyl function. J udging from the
above findings as well as the repulsive behavior between
the polar carbonyl and sulfinyl functions, conformation
of the major product 18a was surmised as depicted in
20.
In conclusion, using the sulfenylation-dehydrosulfe-
nylation method, we have developed the convenient
preparation of (+)-apoverbenone (4a ) and (+)-verbenone
(5a ) from (+)-nopinone (1) as a common starting mate-
rial. As this methodology could be applicable to prepara-
tion of their enantiomers (-)-4a and (-)-5a on starting
with (-)-nopinone, the present synthetic approach may
be practically useful for a laboratory scale preparation
of 4 and 5 in optically active forms on account of its
simplicity of operation, safety in handling, and syntheti-
cally satisfactory overall yield.
A few interesting chemical behaviors characteristic of
the compounds possessing a 6,6-dimethylbicyclo[3.1.1]-
heptane skeleton were found in this study. With respect
to configuration of the substituent in 3-substituted no-
pinones, it is known that methylation,22 bromination,9
and phenylsulfenylation1 of 1 give exclusively the ther-
modynamically less stable trans-substituted products as
the initial product, which easily epimerize to the stable
cis-isomers with bases or acids.23 On the contrary,
phenylselenenylation provides a trans-substituted prod-
uct as a stable form.2 It is worth mentioning that, in
3-(phenylsulfinyl)nopinones, absolute configuration at the
sulfur center controls thermodynamic stability of isomers;
that is, the stable trans-isomer possesses a Rs-phenyl-
sulfinyl group, and the stable cis-isomer possesses a Ss-
phenylsulfinyl group, as seen in the oxidation reaction
of 8 and 9 (Scheme 1) and the nucleophilic substitution
reactions of 12a ,b with 1 (Scheme 2). On the other hand,
in the case of (4R)-4-methyl-3-(phenylsulfinyl)nopinones,
cis-isomers are thermodynamically stable, irrelevant of
the absolute configuration at the sulfur atom, as seen in
Schemes 2 and 6, probably because steric hindrance
between the phenylsulfinyl and methyl groups stimulates
a trans-isomer to a cis-isomer in isomerization. In the
phenylsulfenic acid elimination from the sulfoxids, the
bridges, especially the gem-dimethyl bridge, in 3-(phen-
ylsulfinyl)nopinones have a tendency to hinder formation
of the cyclic transition state between a phenylsulfinyl
function and a â-hydrogen atom, thus producing the
Pummerer reaction product 11 as a byproduct when
acidic contaminants are present, as seen in transforma-
tion of 10 into 4a (Scheme 4). In addition, the syn
elimination reactions of (4R)-4-methyl-3-(phenylsulfinyl)-
nopinones are affected by absolute configuration at the
sulfur center, as seen in heating of 18a ,b at 120 °C
(Scheme 7); that is, the former 18a provided 5a in high
yield, whereas the latter 18b gave mainly thermal
decomposition products which may be produced via the
phenylsulfinyl radical process, probably because of in-
stability of 18b to heat as well as the conformational
requirement.
It is of interest to note that, as shown in Scheme 7,
upon heating 18 under the same reaction conditions as
those for the conversion from 10 to 4a , phenylsulfenic
acid elimination reaction of the major diastereomer 18a
proceeded smoothly to give 5a in 76% yield, whereas that
of the minor 18b was not only sluggish but also some-
what affected by heat to give, after 11 h, a mixture of a
few decomposed products21 along with the desired 5a
(21) Among the products, thermal decomposition products 3, 4a , 17,
and 18a were identified by the spectral comparison with authentic
samples.
(22) Konopelski, J . P.; Djerassi, C. J . Org. Chem. 1980, 45, 2297.
(23) The terms trans and cis refer to whether the substituent points
away from (trans) or toward (cis) the gem-dimethyl bridge.

6944 J . Org. Chem., Vol. 63, No. 20, 1998
Kosugi et al.
Sch em e 6
Calcd for C15H18O2S: C, 68.67; H, 6.91; S, 12.22. Found: C,
68.57; H, 6.84;, S, 12.42.
Sch em e 7
Similarly, the compound 9 (260 mg, 1.06 mmol) was treated
with NaIO4 (338 mg, 1.58 mmol) in 50% methanol (12 mL) to
give 10a (99 mg, 36%) and 10b (175 mg, 63%).
(+)-Ap over ben on e (4a ). Meth od 1. F r om 10a ,b.
A
suspension of 10a (5.0 g, 19.06 mmol), K2CO3 (13.2 g, 95.5
mmol), and toluene (70 mL) was heated at 120 °C with stirring
for 4 h. After being cooled to room temperature, the reaction
mixture was charged on a silica gel column (SiO2, 300 g).25
Toluene was eluted off by use of hexane as an eluent, and then
the product was eluted with AcOEt-hexane (1:6), giving 4a
Exp er im en ta l Section
1
(2.50 g, 96%), [R]15D ) +288.4 (c 0.84, CHCl3). IR and H NMR
Gen er a l Meth od s. Melting points are uncorrected. 1H
NMR spectra were recorded at 400 MHz. All reactions were
carried out under dry N2 or Ar atmosphere. Na2SO4 was used
for drying of extracts. Column chromatography was performed
on 70-230 mesh silica gel (Merck). Medium-pressure chro-
matography (MPLC) utilized a 22 φ × 300 mm silica gel (10
µm) column. Solvent for elution are shown in parentheses.
Ether refers to diethyl ether.
P r epar ation of (1R,3S,5R)-6,6-Dim eth yl-3-(ph en ylth io)-
b icyclo[3.1.1]h ep t a n -2-on e (8) a n d (1R,3R,5R)-6,6-Di-
m eth yl-3-(p h en ylth io)bicyclo[3.1.1]h ep ta n -2-on e (9). The
compounds 8 and 9 were prepared from 124 in 82 and 14%
yields, respectively, according to our synthetic procedure
established earlier.1 Treatment of 8 with DBU in boiling
benzene provided an equilibrium mixture of 8 and 9 from
which 9 was isolated in 63% yield by silica gel chromatog-
raphy.
spectra of 4a were identical with those of the authentic
sample.2
Similarly, a mixture of 10b (4.80 g, 18.29 mmol) and
K2CO3 (12.65 g, 91.5 mmol) was heated in toluene (70 mL) to
give 4a (2.31 g, 93%).
Meth od 2. F r om a Mixtu r e of 10a ,b. A mixture (a 36:
64 ratio) of 10a ,b (10.5 g, 40 mmol), K2CO3 (17.29 g, 200 mmol),
and toluene (100 mL) was heated at 120 °C with stirring for
4 h. Aqueous workup followed by chromatography of a residue
on silica gel gave 4a (5.09 g, 93%).
(1R,3S,4S,5R)-4,6,6-Tr im et h yl-3-(p h en ylt h io)b icyclo-
[3.1.1]h ep t a n -2-on e (16) a n d (1R,3R,4S,5R)-4,6,6-Tr i-
m eth yl-3-(p h en ylth io)bicyclo[3.1.1]h ep ta n -2-on e (17). Ac-
cording to our synthetic procedure established earlier6 with a
slight modification, a solution of 1.05 M MeLi in ether (16.8
mL, 17.64 mmol) was added dropwise at 0 °C to a stirred
mixture of copper(I) iodide (1.68 g, 8.82 mmol) in ether (20
mL). Stirring was continued for an additional 1 h, after
which the reaction mixture was treated with a solution of 4a
(1.04 g, 7.67 mmol) in ether (5 mL). The reaction mixture
was stirred for an additional 2 h, quenched with aqueous NH4-
Cl, and extracted with ether. The combined extracts were
washed successively with water and brine and dried. Evapo-
ration of the extract followed by distillation of an oily resi-
due by use of the Kugelrohr apparatus (140 °C, 19 Torr)
(1R,3S,5R,Rs)- a n d (1R,3R,5R,Ss)-6,6-Dim eth yl-3-(p h en -
ylsu lfoxy)bicyclo[3.1.1]h ep ta n -2-on e (10a ,b). A mixture
of 8 (1.00 g, 4.06 mmol), NaIO4 (1.30 g, 6.09 mmol), and 50%
aqueous methanol (48 mL) was stirred at 0 °C for 1 d and
extracted with CH2Cl2. The combined extracts were washed
successively with water and brine and dried. Concentration
of the extract left a crystalline residue which was chromato-
graphed on silica gel (AcOEt-hexane, 1:5) to give 10a (756
mg, 71%) and 10b (294 mg, 28%).
gave
(1R,4R,5R)-4,6,6-trimethylbicyclo[3.1.1]heptan-2-one
10a : crystals; mp 97 °C; [R]15 ) +421.3 (c 0.56, CHCl3);
(3) (1.07 g, 92%), [R]15 ) +50.1 (c 0.99, CHCl3). IR and 1H
D
D
IR (KBr) 1709, 1086, 1048, 985, 749, 696 cm-1. Anal. Calcd
for C15H18O2S: C, 68.67; H, 6.91; S, 12.22. Found: C,68.27;
H,7.02; S, 12.16.
NMR spectra of 3 were identical with those of the authentic
sample.7
To a stirred solution of diisopropylamine (0.92 mL, 5.96
mmol) in THF (5 mL) was added dropwise at 0 °C a solution
of 1.66 M BuLi in hexane (3.6 mL, 5.98 mmol). After 30 min,
10b: crystals; mp 126-127 °C; [R]15 ) -315.3 (c 0.92,
D
CHCl3); IR (KBr) 1711, 1085, 1033, 760, 697 cm-1
. Anal.
(24) In the present study, (+)-nopinone, [R]15 ) +34.0 (c 1.10,
(25) As verbenone is volatile, evaporative removal of toluene from
the extract was avoided in the purification step.
D
CHCl3) and 98% ee, was used.

Optically Active Apoverbenone and Verbenone
J . Org. Chem., Vol. 63, No. 20, 1998 6945
a solution of 3 (750 mg, 4.97 mmol) in THF (5 mL) was added
dropwise at - 78 °C, and stirring was continued for an
additional 1 h. To the reaction mixture was added a solution
of S-phenyl benzenethiosulfonate20 (1.51 g, 5.47 mmol) in THF
(5 mL), and stirring was continued for an additional 6 h, during
which the reaction temperature rose slowly to room temper-
ature. The reaction mixture was quenched with aqueous NH4-
Cl and extracted with CH2Cl2, and the combined extracts were
washed successively with water and brine and dried. Evapo-
ration of the extract followed by purification of a residue with
silica gel chromatography (AcOEt-hexane, 1: 10) gave an oily
mixture of 16 and 17 (1.19 g, 93%, a 4:6 ratio), 1H NMR
(CDCl3): δ 0.70 (s, 1.8H) and 0.84 (s, 1.2H), 1.23 (s, 1.8H),
1.26 (s, 1.2H), 1.34 (s, 1.8H), 1.36 (s, 1.2H), 1.70 (d, J ) 11.0
Hz, 0.6H), 1.87 (d, J ) 11.0 Hz, 0.4H), 1.93 (dt, J ) 11.0, 5.4
Hz, 0.4H), 2.05 (ddd, J ) 5.4, 5.1, 1.5 Hz, 0.6H), 2.15 (ddd, J
) 11.0, 5.4, 5.1 Hz, 0.6H), 2.42-2.48 (m, 1H), 2.66-2.75 (m,
1.4H), 3.37 (d, J ) 8.1 Hz, 0.6H), 3.73 (d, J ) 8.6 Hz, 0.4H),
7.21-7.33 (m, 3H), 7.53-7.56 (m, 2H).
(15 mL) gave 5a (61 mg, 72%, 82% based on consumed 18a ,b)
and 18a ,b (16 mg).
Hea tin g of 10a ,b in th e P r esen ce of MCBA a n d P P TS.
A solution of 10a ,b (290 mg, 1.11 mmol) and MCBA (17 mg,
0.11 mmol) in CCl4 (7 mL) was gently refluxed for 7 h. After
being cooled to room temperature, the reaction mixture was
filtered through a short silica gel column (AcOEt). Concentra-
tion of the filtrate left an oily residue which was purified by
MPLC (AcOEt-hexane, 1:4) to give 4a (63 mg, 41%) and 11
(19 mg, 7%).
Similarly, heating a solution of 10a ,b (146 mg, 0.56 mmol)
and PPTS (14 mg, 0.06 mmol) in CCl4 (6 mL) gave 4a (41 mg,
53%) and 11 (19 mg, 14%).
H ea t in g of 2-(P h en ylsu lfoxy)-4-ter t-b u t ylcycloh ex-
a n on e (14) in t h e P r esen ce of MCBA a n d P P TS. The
compound 14 was prepared from 4-tert-butylcyclohexanone
according to the reported procedures.8 A solution of 14 (584
mg, 2.10 mmol) and MCBA (33 mg, 0.21 mmol) in CCl4 (10
mL) was gently refluxed for 1 h and cooled to room tempera-
ture. The reaction mixture was washed successively with
water and brine and dried. Concentration followed by chro-
matography of a residue on silica gel (benzene-ether, 10:1)
gave 15 (309 mg, 97%). IR and 1H NMR spectra of 15 were
identical with those of the authentic sample.
A mixture of 16 and 17 (520 mg, 2.00 mmol) was dissolved
in benzene (6 mL) containing DBU (321 mg, 2.0 mmol), and
the reaction mixture was heated at 85 °C for 2 h. Aqueous
workup followed by chromatography of a residue on silica gel
(AcOEt-hexane, 1: 10) gave 17 (513 mg, 99%) as an oil: [R]15
D
) +220.5 (c 0.41, CHCl3); IR (film) 1716, 1590, 1198, 1160,
1026, 746, 691 cm-1. Anal. Calcd for C16H20OS: C, 73.82; H,
7.74; S, 12.30. Found: C, 73.54; H, 7.61; S, 12.44.
Similarly, heating of a solution of 14 (216 mg, 0.78 mmol)
and PPTS (20 mg, 0.08 mmol) in CCl4 (10 mL) gave 15 (119
mg, quantitative).
(1R,3R,4S,5R,Ss)- a n d (1R,3R,4S,5R,Rs)-4,6,6-Tr im eth yl-
3-(ph en ylsu lfoxy)bicyclo[3.1.1]h eptan -2-on e (18a ,b). Meth -
od 1. F r om 17. A mixture of 17 (4.20 g, 16.10 mmol) and
NaIO4 (5.18 g, 24.15 mmol) in 50% aqueous methanol (52 mL)
was stirred at 0 °C for 1 d and extracted with CH2Cl2. The
combined extracts were washed successively with water and
brine and dried. Concentration of the extract followed by
chromatography of a residue on silica gel (AcOEt-hexane, 1:3)
gave 18a (2.97 g, 67%) and 18b (1.40 g, 31%).
(1R,3S,5R,Rs)-6,6-Dim eth yl- a n d (1R,3R,4S,5R,Rs)-4,6,6-
Tr im et h yl-3-(p -t olylsu lfoxy)b icyclo[3.1.1]h ep t a n -2-on e
(13a a n d 19a ). To a stirred 2.35 M solution of ethylmagne-
sium bromide in ether (1.7 mL, 4.0 mmol) was added diiso-
propylamine (0.56 mL, 4.0 mmol). After evaporation of ether
by N2 steam, toluene (10 mL) was added. To the resulting
suspension, a solution of 1 (415 mg, 3.0 mmol) in toluene (3
mL) was added dropwise at 0 °C, and stirring was continued
for an additional 1.5 h. A solution of (S)-menthyl-p-toluene-
sufinate 12a 13 (877 mg, 3.0 mmol) in toluene (3 mL) was added
to the reaction mixture, and stirring was continued for an
additional 15 h, during which the reaction temperature rose
slowly to room temperature. The reaction was quenched by
addition of aqueous NH4Cl. The organic layer was sepa-
rated, washed successively with water and brine, and dried.
Concentration followed by chromatography of a residue on
silica gel (AcOEt-hexane, 1:10) gave 13a (543 mg, 65%) as
18a : crystals, mp 131-133 °C; [R]15 ) -188.7 (c 0.48,
D
CHCl3); IR (KBr) 1711, 1086, 1030, 996, 744, 698 cm-1. Anal.
Calcd for C16H20OS: C, 69.54; H, 7.30; S, 11.58. Found: C,
69.53; H, 7.24; S, 11.30.
18b: crystals, mp 106-107 °C; [R]15 ) +180.2 (c 0.57,
D
CHCl3); IR (KBr) 1706, 1080, 1046, 1034, 990, 762, 696 cm-1
.
Anal. Calcd for
C16H20OS: C, 69.54; H, 7.30; S, 11.58.
Found: C, 69.43; H, 7.20; S, 11.38.
crystals: mp 125-126 °C; [R]16 ) +435.0 (c 1.12, CHCl3); IR
Meth od 2. F r om a Mixtu r e of 16 a n d 17. Similarly, a
mixture (a 4:6 ratio) of 16 and 17 (1.04 g, 4.0 mmol) was
treated with NaIO4 (1.28 g, 6.0 mmol) in 50% aqueous
methanol (12 mL) to give 18a (914 mg, 85%) and 18b (131
mg, 12%).
D
(KBr) 1713, 1594, 1039, 818 cm-1
.
Anal. Calcd for
C
16H20O2S: C, 69.53; H, 7.29; S, 11.60. Found: C, 69.13; H,
7.14; S, 11.36.
Similarly, treatment of 3 (457 mmg, 3.0 mmol) with (diiso-
propylamino)magnesium bromide, prepared from ethylmag-
nesium bromide (1.7 mL, 4.0 mmol) and diisopropylamine (0.56
mL, 4.0 mmol) in toluene (10 mL), followed by addition of a
solution of 12a (877 mg, 3.0 mmol) in toluene (3 mL) gave 19a
(407 mg, 47%) as crystals: mp 118 °C; [R]16D ) +186.8 (c 1.13,
(+)-Ver ben on e (5a ). Meth od 1. Hea tin g a t 120 °C. A
mixture of 18a (51 mg, 0.18 mmol), K2CO3 (1.28 g, 0.90 mmol),
and toluene (10 mL) was heated with stirring at 130 °C for 18
h. After cooling, the reaction mixture was chromatographed
on silica gel (AcOEt-hexane, 1:9) according to the manner
described for preparation of 4a from 10a , giving 5a (20 mg,
CHCl3); IR (KBr) 1706, 1597, 1048, 825 cm-1
. Anal. Calcd
1
76%), [R]15D ) +257.4 (c 0.47, CHCl3). IR and H NMR spectra
for C17H22O2S: C, 70.31; H, 7.64; S, 11.04. Found: C, 70.22;
H, 7.50; S, 10.92.
of 5a were identical with those of the authentic sample.
Similarly, heating a mixture of 18b (400 mg, 1.45 mmol),
K2CO3 (1.0 mg, 7.25 mmol), and toluene (10 mL) gave 5a (38
mg, 17%).
(1R,3R,5R,Ss)-6,6-Dim eth yl- a n d (1R,3R,4S,5R,Ss)-4,6,6-
Tr im et h yl-3-(p -t olylsu lfoxy)b icyclo[3.1.1]h ep t a n -2-on e
(13b a n d 19b). According to the procedure for the synthesis
of 13a from 1, treatment of 1 (276 mg, 2.0 mmol) with
(diisopropylamino)magnesium bromide, prepared from ethyl-
magnesium bromide (3 mL, 3.0 mmol) and diisopropylamine
(0.56 mL, 4.0 mmol) in toluene (10 mL), followed by addi-
tion of a solution of (R)-menthyl-p-toluenesufinate (12b )13
(585 mg, 2.0 mmol) in toluene (3 mL) gave 13b (361 mg,
Similarly, heating a mixture (a 68:32 ratio) of 18a ,b (250
mg, 0.91 mmol) with K2CO3 (413 mg, 4.55 mmol), in toluene
(10 mL) gave 5a (59 mg, 53%).
Meth od 2. Hea tin g a t 95 °C. A mixture of 18a (365 mg,
1.32 mmol), K2CO3 (2.19 g, 15.8 mmol), and toluene (27 mL)
was heated at 95 °C with stirring for 2 d and cooled to room
temperature. Aqueous workup followed by chromatography
of a residue on silica gel (AcOEt-hexane, 1:9) gave 5a (155
mg, 78%, 92% based on consumed 18a ) and 18a (55 mg).
Similarly, heating a mixture of 18b (226 mg, 0.82 mmol),
K2CO3 (1.357 g, 9.82 mmol) and toluene (22 mL) gave 5a (47
mg, 38%, 40% based on consumed 18b) and 18b(10 mg).
Similarly, heating a mixture (a 68:32 ratio) of 18a ,b (153
mg, 0.55 mmol) with K2CO3 (918 mg, 6.64 mmol), in toluene
65%) as crystals: mp 164-65 °C; [R]19 ) -348 (c 0.96,
D
CHCl3); IR (KBr) 1717, 1595, 1050, 816 cm-1
. Anal. Calcd
for C16H20O2S: C, 69.53; H, 7.29; S, 11.60. Found: C, 69.23;
H, 7.36; S, 11.38.
Similarly, treatment of 3 (152 mg, 1.0 mmol) with (diiso-
propylamino)magnesium bromide, prepared from ethylmag-
nesium bromide (1.5 mL, 1.5 mmol) and diisopropylamine (0.28
mL, 2.0 mmol) in toluene (6 mL), followed by addition of a

6946 J . Org. Chem., Vol. 63, No. 20, 1998
Kosugi et al.
solution of 12b13 (293 mg, 1.0 mmol) in toluene (2 mL) gave19b
Ack n ow led gm en t. We are grateful to a Grant-in-
Aid for Scientific Research (C) for financial support for
this study.
(134 mg, 46%) as crystals: mp 160 °C; [R]25 ) -207 (c 0.48,
D
CHCl3); IR (KBr) 1709, 1042, 819 cm-1
C
.
Anal. Calcd for
17H22O2S: C, 70.31; H, 7.64; S, 11.04. Found: C, 70.24; H,
7.62; S, 10.95.
J O9807316