The rearrangement of 2,3-epoxysulfonates and its application to natural products syntheses: Formal synthesis of (-)-aphanorphine and total syntheses of (-)-α-herbertenol and (-)-herbertenediol

Article abstract of DOI:10.1021/jo034573g

The Lewis acid treatment of 2,3-epoxysulfonates with 2,3-dialkyl substituents or 2-alkyl-3-aryl substituents produced the rearrangement products via C3-cleavage of the oxirane ring in high yields. On the other hand, 2-aryl-3-alkyl-2,3-epoxysulfonates produced the products via C2-cleavage of the oxirane ring. The sulfonyloxy groups of the α-sulfonyloxy ketones, having a chiral benzylic quaternary carbon center obtained by the rearrangement of 2-alkyl-3-aryl-2,3-epoxysulfonates, were reductively eliminated to give the ketones with a chiral benzylic quaternary carbon center. The method was applied to the formal synthesis of (-)-aphanorphine and total syntheses of (-)-α-herbertenol and (-)-herbertenediol.

Full text of DOI:10.1021/jo034573g

Th e Rea r r a n gem en t of 2,3-Ep oxysu lfon a tes a n d Its Ap p lica tion to
Na tu r a l P r od u cts Syn th eses: F or m a l Syn th esis of
(-)-Ap h a n or p h in e a n d Tota l Syn th eses of (-)-r-Her ber ten ol a n d
(-)-Her ber ten ed iol
Yasuyuki Kita,* J unko Futamura, Yusuke Ohba, Yoshinari Sawama,
J naneshwara K. Ganesh, and Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita,
Osaka 565-0871, J apan
kita@phs.osaka-u.ac.jp
Received May 2, 2003
The Lewis acid treatment of 2,3-epoxysulfonates with 2,3-dialkyl substituents or 2-alkyl-3-aryl
substituents produced the rearrangement products via C3-cleavage of the oxirane ring in high yields.
On the other hand, 2-aryl-3-alkyl-2,3-epoxysulfonates produced the products via C2-cleavage of
the oxirane ring. The sulfonyloxy groups of the R-sulfonyloxy ketones, having a chiral benzylic
quaternary carbon center obtained by the rearrangement of 2-alkyl-3-aryl-2,3-epoxysulfonates, were
reductively eliminated to give the ketones with a chiral benzylic quaternary carbon center. The
method was applied to the formal synthesis of (-)-aphanorphine and total syntheses of (-)-R-
herbertenol and (-)-herbertenediol.
In tr od u ction
We have studied the rearrangements of epoxides with
adjoining electron-withdrawing functional groups such
as 2,3-epoxy acylates.1-3 Epoxides with 2,3-dialkyl sub-
stituents react through cleavage of the oxirane ring at
the C3-position due to the electron-withdrawing nature
of the acyloxyalkyl group. A similar reaction course is
observed for epoxides with a C3-aryl substituent (eq 1).1,2
On the other hand, the reactions of epoxides with a C2-
aryl substituent occur through the cleavage of the oxirane
ring at the C2-position due to the cation-stabilizing
ability of the aromatic ring (eq 2).3 In these cases, the
relationship between the epoxide and the acyloxy group
sometimes played an important role. Namely, the trans-
epoxy acylates with an acetyl or benzoyl group sometimes
involved neighboring group participation and led to the
formation of diols and enones, rather than rearranged
products (eq 3).
(1) (a) Fujioka, H.; Kitagaki, S.; Imai, R.; Kondo, M.; Okamoto, S.;
Yoshida, Y.; Akai, S.; Kita, Y. Tetrahedron Lett. 1995, 36, 3219-3222.
(b) Kita, Y.; Kitagaki, S.; Yoshida, Y.; Mihara, S.; Fang, D.-F.; Fujioka,
H. Tetrahedron Lett. 1997, 38, 1061-1064. (c) Kita, Y.; Kitagaki, S.;
Yoshida, Y.; Mihara, S.; Fang, D.-F.; Kondo, M.; Okamoto, S.; Imai,
R.; Akai, S.; Fujioka, H. J . Org. Chem. 1997, 62, 4991-4997. (d) Kita,
Y.; Yoshida, Y.; Kitagaki, S.; Mihara, S.; Fang, D.-F.; Furukawa, A.;
Higuchi, K.; Fujioka, H. Tetrahedron 1999, 55, 4979-4998.
(2) Kita, Y.; Furukawa, A.; Futamura, J .; Ueda, K.; Sawama, Y.;
Hamamoto, H.; Fujioka, H. J . Org. Chem. 2001, 66, 8779-8786.
(3) (a) Kita, K.; Kitagaki, S.; Imai, R.; Okamoto, S.; Mihara, S.;
Yoshida, Y.; Akai, S.; Fujioka, H. Tetrahedron Lett. 1996, 37, 1817-
1820. (b) Kita, Y.; Furukawa, A.; Futamura, J .; Higuchi, K.; Ueda, K.;
Fujioka, H. Tetrahedron Lett. 2000, 41, 2133-2136. Quite recently we
found that the reaction of acyclic 2-aryl-2,3-epoxy acylates proceeded
via the C3-cleavage of the oxirane ring. However, the intermediates
are phenonium ions, which are completely different from the inter-
mediates of eqs 1 and 2 due to the flexibility of the substrates. Kita,
Y.; Furukawa, A.; Futamura, J .; Higuchi, K.; Ueda, K.; Fujioka, H.
Tetrahedron 2001, 57, 815-825.
To overcome neighboring group participation, a stron-
ger electron-withdrawing group than an acyloxy group
was explored. We found that the rearrangements of
epoxysulfonates provide a useful method for synthesizing
many kinds of compounds. We report on the reactions of
2,3-epoxysulfonates and the application of the rearrange-
ment of 2,3-epoxysulfonates to the formal synthesis of
(-)-aphanorphin (11) and total syntheses of (-)-R-her-
bertenol (19a ) and (-)-herbertenediol (19b) (Scheme 1,
Figure 1).4
(4) We have recently reported the asymmetric synthesis of (-)-
herbertenediol through the rearrangement of 3-aryl-2-methyl-2,3-epoxy
tosylate. See: Kita, Y.; Futamura, J .; Ohba, Y.; Sawama, Y.; Ganesh,
J . K.; Fujioka, H. Tetrahedron Lett. 2003, 44, 411-413.
10.1021/jo034573g CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/25/2003
J . Org. Chem. 2003, 68, 5917-5924
5917

Kita et al.
TABLE 1. Rea r r a n gem en t of
3-Meth yl-2-p en tyl-2,3-ep oxy Su lfon a tes
BF3‚Et2O
yield
(%)
F IGURE 1. Natural products synthesized by the rearrange-
ment of 2,3-epoxysulfonates.
entry
substrate
RSO2
(equiv)
1
2
3
4
5
6
7
8
cis-1a
cis-1b
cis-1c
cis-1d
cis-1e
cis-1c
cis-1c
trans-1c
Ms
1.0
1.0
1.0
1.0
1.0
0.1
10
40a
43a
48a
40a
45a
4b
PhSO2
SCHEME 1
Ts
p-F-C6H4SO2
p-MeO-C6H4SO2
Ts
Ts
Ts
83
87
10
a
Other products, enones 3 and 4, were obtained in 20-40%
b
yield. Other products, enones 3 and 4, were obtained in 75%
combined yield.
TABLE 2. Rea r r a n gem en t of
2-Meth yl-3-p h en yl-2,3-ep oxy Su lfon a tes
Resu lts a n d Discu ssion
Rea r r a n gem en ts of 2,3-Ep oxysu lfon a tes.5
Rea r r a n gem en ts via C3-ca r boca tion : The treat-
ment of cis-2,3-epoxysulfonates (1a -e) with 1 equiv of
BF3‚Et2O afforded the desired products (2a -e) in moder-
ate yields with enones 3 and 4 as byproducts (Table 1,
entries 1-5).6 The use of other Lewis acids such as SnCl4,
SnBr4, Al(OC6F5)3,7 and InCl5 did not produce better
yields of the desired products (2a -e) than reactions with
BF3‚Et2O. We studied the amount of BF3‚Et2O using
epoxy tosylate cis-1c (entries 6 and 7) and found that 10
equiv of BF3‚Et2O resulted in a high yield of the rear-
ranged product cis-2c, whereas the use of 0.1 equiv of
BF3‚Et2O afforded enones 3 and 4 as the major products.
A similar high yield was obtained from trans-2,3-ep-
oxysulfonate trans-1c to give the rearranged product
trans-2c (entry 8). These results showed that the rela-
tionship between the epoxide ring and sulfonyloxy group
(cis or trans) is not very significant.
The rearrangement via the C3-carbocation was also
observed in the reaction of the 2,3-epoxysulfonates with
the C3-phenyl group (Table 2). The reaction of cis-5
afforded the rearranged product cis-6 in high yields with
1 equiv of EtAlCl2, whereas the use of 1 equiv of BF3‚
Et2O afforded enone 7, not the rearranged product
(entries 1 and 2). The results from cis-5 and trans-5 were
consistent with the prior finding that there was a
stereochemical relationship between the oxirane ring and
the sulfonyloxy group (entries 2 and 3). This ability of
EtAlCl2 to give better results than BF3‚Et2O may be
rationalized as the outcome of the ionic nature of the
O-metal bond to aluminum metal, as previously dis-
cussed in the reactions of the epoxy acylates with a C3-
aryl substituent.2
Rea r r a n gem en ts via C2-ca r boca tion : In our study
of the rearrangement of 2,3-epoxyacylates with the C2-
aromatic substituent, the reaction proceeded as expected
through a C2-carbocation.3 The reaction of the 2,3-
epoxysulfonates 8 with the C2-phenyl group proceeded
in the same manner, although a sulfonyloxy group has a
stronger electron-withdrawing ability than an acyloxy
group. The reaction of cis-8 or trans-8 smoothly produced
the rearranged products cis-9 or trans-9, respectively, in
almost the same high yields with 1 equiv of BF3‚Et2O.
The relationships between the epoxide and sulfonyloxy
group (cis or trans) did not effect the desired rearrange-
ment reaction (Scheme 2).
(5) In this section, racemic epoxysulfonates were used to examine
their reactivity under Lewis acid treatment.
(6) The reaction mechanism for compounds 3 and 4 will be discussed
elsewhere.
(7) For synthetic applications of (C6F5O)3Al, see: (a) Ishihara, K.;
Hanaki, N.; Yamamoto, H. J . Am. Chem. Soc. 1991, 113, 7074-7075.
(b) Ishihara, K.; Hanaki, N.; Yamamoto, H. Synlett 1993, 127-129.
Na tu r a l P r od u cts Syn th eses.
F or m a l syn th esis of (-)-a p h a n or p h in e (11): (-)-
Aphanorphine 11 was isolated from Aphanizomenon flas-
5918 J . Org. Chem., Vol. 68, No. 15, 2003

earrangement of 2,3-Epoxysulfonates
SCHEME 2
SCHEME 4
SCHEME 3
SCHEME 5
aquae by Gulavita et al. in 1988.8 Three asymmetric total
syntheses and manyformalsyntheses havebeen reported.9-12
Among them, we focused on Ogasawara’s intermediate
10 as a target compound with a chiral quaternary carbon
center on the cyclopentanone ring.9 Scheme 3 shows
Ogasawara’s asymmetric synthesis of 11. The asym-
metric synthesis of 10 would constitute a formal enan-
tioselective synthesis of 11, and our plan for the synthesis
of 10 would take advantage of the stereoselective rear-
rangement of 2,3-epoxysulfonates followed by reductive
elimination of the R-tosyloxyketone as shown in Scheme
4.
Optically active epoxytosylate 17 was synthesized as
shown in Scheme 5. 2-Methylcyclopentane-1,3-dione (12)
was converted to 3-isobutoxy-2-methyl-2-cyclopenten-1-
one (13) following a literature procedure.13 The nucleo-
philic addition of 2-methoxyphenylmagnesium bromide
to 13 followed by acidic treatment gave enone 14. The
asymmetric reduction of enone 14 with Corey’s reagent14
gave the optically active allylic alcohol 15 with 98% ee.
The stereoselective epoxidation15 and tosylation gave cis-
epoxysulfonate 17.
SCHEME 6
(8) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J .
Tetrahedron Lett. 1988, 29, 4381-4384.
(9) Takano, S.; Inomata, K.; Sato, T.; Takahashi, M.; Ogasawara,
K. J . Chem. Soc., Chem. Commun. 1990, 290-292.
(10) (a) Shiotani, S.; Okada, H.; Nakamura, K.; Yamamoto, T.;
Sekino, F. Heterocycles 1996, 43, 1031-1047. (b) Shimizu, M.; Ka-
mikubo, T.; Ogasawara, K. Heterocycles 1997, 44, 21-26.
(11) Asymmetric synthesis of unnatural (+)-aphanorphine, see:
Takano, S.; Inomata, K.; Sato, T.; Ogasawara, K. J . Chem. Soc., Chem.
Commun. 1989, 1591-1592.
(12) For formal sythesis of (-)-aphanorphine, see: (a) Tanaka, K.;
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 1049-1052.
(b) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 6, 371-374. (c)
Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1995, 6, 893-900. (d)
Hulme, A. N.; Henry, S. S.; Meyers, A. I. J . Org. Chem. 1995, 60, 1265-
1270. (e) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 45, 12211-
12216. (f) Node, M.; Imazato, H.; Kurosaki, R.; Kawano, Y.; Inoue, T.;
Nishide, K.; Fuji, K. Heterocycles 1996, 42, 811-819.
(13) Crisan, C.; Normant, H. Bull. Soc. Chim. Fr. 1957, 1451-1453.
(14) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V.
K. J . Am. Chem. Soc. 1987, 109, 7925-7926. The absolute configura-
tion of the secondary alcohol was deduced by referring to the literature
and our previous study (refs 1-3). This deduction was consequently
determined by agreement of the synthesized 10 to the authentic one.
(15) Sharpless, K. B.; Michaelson, R. C. J . Am. Chem. Soc. 1973,
95, 6136-6137.
The treatment of 17 with 1 equiv of EtAlCl2 gave the
rearranged product 18 in 93% yield. The tosyloxyl group
of 18 was removed under reductive condition to give
Ogasawara’s intermediate 10 in good yield (Scheme 6).
Our asymmetric synthesis of Ogasawara’s intermedi-
ate 10 from the commercially available starting material
12 in 47% overall yield required a 7-step sequence (5
steps shorter than Ogasawara’s procedure for 10), and
completed a formal asymmetric synthesis of (-)-apha-
norphine (11).
J . Org. Chem, Vol. 68, No. 15, 2003 5919

Kita et al.
SCHEME 7
SCHEME 8
Tota l Syn th eses of (-)-r-Her ber ten ol ((-)-19a )
a n d (-)-Her ber ten ed iol ((-)-19b). The herbertane
group of sesquiterpenes are chemical markers for the
liverworts belonging to the genus Herbertus.16 (-)-R-
Herbertenol ((-)-19a ), one of the simplest herbertanes
isolated from liverwort Herberta adunca, has anti-fungal
activity.16 There are several racemic syntheses and two
asymmetric syntheses of 19a .17,18 (-)-Herbertenediol
((-)-19b)16 has also been isolated from the same source
as (-)-19a and it is postulated that the phenolic coupling
of two molecules of (-)-19b leads to the dimers, masti-
gophorenes A and B, since both co-occur in the same
source as (-)-19b.19,20 The promising antilipid peroxida-
tion activity of (-)-19b21a and the activities of mastigo-
phorenes that promote neuronral outgrowth and enhance
choline acetyltransferase activity22 make (-)-19b an
attractive synthetic target. In addition to the racemic
syntheses of (()-19b ,21 a few groups, Mayers et al.,20b
Bringmann et al.,20c Fukuyama et al.,20d and our own
group,4 have reported the asymmetric syntheses of (-)-
19b.
sulfonyloxy goups as described in aphanorphin synthesis
(see above). Conversion of the ketones 25 to gem-dimethyl
functions and cleavage of the methyl ether would afford
(-)-19a and (-)-19b.
(i) Con str u ction of Ch ir a l Ben zylic Qu a ter n a r y
Ca r bon Cen ter s in Op tica lly Active F or m s. The
chiral benzylic quaternary carbon centers of (-)-19a and
(-)-19b were synthesized by a method similar to that
for the intermediate of (-)-aphanorphine described above.
The nucleophilic addition of the 2-methoxy-5-methyl-
phenyllithium or cerium reagent of 2,3-dimethoxy-5-
methylphenyllithium23 to the isobutyl ether13 of 2-meth-
ylcyclopentane-1,3-dione (12) followed by acidic workup
afforded enones 20a and 20b. The asymmetric reduction
of enones 20a ,b with Corey’s reagent14 gave the optically
active allyl alcohols 21a ,b. The enantiomeric excesses (ee)
of 21a ,b were determined by HPLC analysis to be 94%
ee for 21a and >98%ee for 21b. Enantiomeric enhance-
ment to optically pure 21a was unsuccessful at this stage.
The stereoselective epoxidation15 of 21a ,b followed by
tosylation gave cis-epoxytosylates 23a ,b. The treatment
of 23a ,b with 1 equiv of EtAlCl2 gave the rearranged
products 24a ,b in high yields. At this stage, compound
24a (94% ee) was recrystallized to give optically pure 24a
(>99% ee). The removal of the tosyloxy groups of 24a ,b
afforded ketones 25a ,b with chiral benzylic quaternary
carbon centers (Scheme 8).
Scheme 7 shows our synthetic plan. The benzylic
quaternary carbon centers of 19a and 19b would be
constructed by rearrangement of the optically active 2,3-
epoxysulfonates 23 followed by reductive removal of the
(16) (a) Matsuo, A.; Nakayama, M.; Maeda, T.; Noda, Y.; Hayashi,
S. Phytochemistry 1975, 14, 1037-1040. (b) Matsuo, A.; Yuki, S.;
Nakayama, M.; Hayashi, S. Chem. Lett. 1982, 463-466. (c) Matsuo,
A.; Yuki, S.; Nakayama, M. Chem. Lett. 1983, 1041-1042. (d) Matsuo,
A.; Yuki, S.; Nakayama, M. J . Chem. Soc., Perkin Trans. 1 1986, 701-
710. (e) Irita, H.; Hashimoto, T.; Fukuyama, Y.; Asakawa, Y. Phy-
tochemistry 2000, 55, 247-253.
(17) For racemic synthesis, see ref 21f and references therein.
(18) For asymmetric synthesis, see: Adad, A.; Agullo´, C.; Cun˜at, A.
C.; Perni, R. H. J . Org. Chem. 1999, 64, 1741-1744 and ref 20d.
(19) Chau, P.; Mo, W.-L. Proc. Natl. Sci. Counc. ROC(A) 1987, 43,
124-128.
(20) (a) Bringmann, G.; Pabst, T.; Rycroft, D. S.; Connolly, J . D.
Tetrahedron Lett. 1999, 40, 483-486. (b) Degnan, A. P.; Meyers, A. I.
J . Am. Chem. Soc. 1999, 121, 2762-2769. (c) Bringmann, G.; Pabst,
T.; Henschel, P.; Kraus, J .; Peters, K.; Peters, E. M.; Rycroft, D. S.;
Connolly, J . D. J . Am. Chem. Soc. 2000, 122, 9127-9133. (d) Fuku-
yama, Y.; Matsumoto, K.; Tonoi, Y.; Yokoyama, R.; Takahashi, H.;
Minami, H.; Okazaki, H.; Mitsumoto, Y. Tetrahedron 2001, 57, 7127-
7135.
(21) (a) Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett.
1996, 37, 1261-1264. (b) Harrawven, D. C.; Hannam, J . C. Tetrahedron
Lett. 1998, 39, 9573-9574. (c) Gupta, P. D.; Pal, A.; Roy, A.; Mukherjee,
D. Tetrahedron Lett. 2000, 41, 7563-7566. (d) Srikrishna, A.; Rao, M.
S. Tetrahedron Lett. 2001, 42, 5781-5782. (e) Abad, A.; Agullo´, C.;
Cun˜at, A. C.; J ime´nez, D.; Perni, R. H. Tetrahedron 2001, 57, 9727-
9735. (f) Srikrishna, A.; Rao, M. S. Synlett 2002, 340-342.
(22) Fukuyama, Y.; Asakawa, Y. J . Chem. Soc., Perkin Trans. 1
1991, 2737-2741.
(ii) Con ver sion of Keton es 25a ,b to (-)-r-Her -
ber ten ol ((-)-19a ) a n d (-)-Her ber ten ed iol ((-)-19b).
Me2TiCl2 tr ea tm en t: The use of Me2TiCl2, a common
reagent for the dimethylation of carbonyl compounds,
(23) Tomita, M.; Bessho, K. Yakugaku Zasshi 1959, 79, 1097-1099.
5920 J . Org. Chem., Vol. 68, No. 15, 2003

earrangement of 2,3-Epoxysulfonates
SCHEME 9
SCHEME 10
failed.24 The desired trimethyl compound 26 was obtained
from 25a in moderate yield, but to our surprise, its ee
value proved to be zero (Scheme 9). The first mono-
methylation of ketone 25a probably occurred from the
same side as the aromatic group through chelation-
controlled addition. The migration of the benzylic methyl
group, driven by the preferable formation of the benzylic
carbocation, led to racemization. The possibility of the
mechanism via the phenonium ion intermediate i was
excluded for the following reasons: (1) the formation of
a bicyclo[3.1.0] ring system i is sterically unfavorable,
and (2) in the case of compound 25b, the oxacyclic
compound 27 is the major product, which is very difficult
to obtain from the phenonium ion intermediate ii and
supports the mechanism through the carbocation inter-
mediate (see Scheme 10).25
SCHEME 11
In the case of 25b, the oxacyclic compound 27 was
obtained as the major product through nucleophilic
attack of the methoxy group and demethylation. The
formation of 31b (see Scheme 11) was not observed with
TLC. In fact, the treatment of 28b (see Scheme 11),
obtained by the MeLi-CeCl3 treatment of 25b , with
Me2TiCl2 gave the same oxacyclic compound 27 as the
major product and no 31b. The mechanism via the
phenonium ion intermediate ii was excluded for the
reasons described above (Scheme 10).
The difference between 25a and 25b is the absence or
presence of one methoxy group on the aromatic ring. The
reasons for the difference in the reactivity between the
two are not clear at the present time.
Rou te via cyclop r op a n e r in g: On the basis of the
above results, a route involving reductive cyclopropana-
tion was next examined (Scheme 11). The methylation
of 25a ,b with MeCeCl2 (prepared in situ from MeLi-
CeCl3) gave the products 28a ,b in high yields, respec-
tively. Their stereochemistries were determined by NOE
experiments. Presumably, the attack occurred from the
same side as the phenyl group by chelation between the
reagent and the methoxy groups. The treatment of 28a ,b
with Burgess reagent26 gave olefins 29a ,b, which were
cyclopropanated in the usual way27 to afford the products
30a ,b as a diastereomeric mixture, respectively. The
reductive opening of the cyclopropane ring of 30a ,b gave
the trimethyl compounds 31a ,b, whose ee values were
determined by HPLC analysis, respectively. Acidic cleav-
age of the methyl ether bond of 31a ,b with BBr3 led to
(24) Reetz, M. T.; Westermann, J .; Steinbach, R. Angew. Chem., Int.
Ed. 1980, 19, 900-901.
(25) The same tendency in the formation of the phenonium ion
intermediate, i.e., the difference between the cyclic system not forming
the phenonium ion and the acyclic system forming the phenonium ion,
was observed in our previous study; see: Kita, Y.; Furukawa, A.;
Futamura, J .; Higuchi, K.; Ueda, K.; Fujioka, H. Tetrahedron 2001,
57, 815-825.
(26) Burgess, E. M.; Penton, H. R., J r.; Taylor, E. A. J . Org. Chem.
1973, 38, 26-31. For a successful result, see: Kita, Y.; Higuchi, K.;
Yoshida, Y.; Iio, K.; Kitagaki, S.; Ueda, K.; Akai, S.; Fujioka, H. J .
Am. Chem. Soc. 2001, 123, 3214-3222.
(27) Furukawa, J .; Kawabata, N.; Nishimura, J . Tetrahedron 1968,
24, 53-58.
J . Org. Chem, Vol. 68, No. 15, 2003 5921

Kita et al.
in THF, 12.5 mL, 12.5 mmol) was added dropwise to a solution
of (S)-5,5-diphenyl-2-methyl-3,4-propan-1,3,2-oxazaborolidine
(3.5 g, 12.5 mmol) in THF (130 mL) at 0 °C under N2. After
being stirred for 30 min, a solution of enone 20a (2.70 g, 12.5
mmol) in THF (150 mL) was added slowly to the resulting
mixture. After being stirred for 5 min, MeOH was added to
the mixture. The solvent was removed in vacuo. The residue
was purified by SiO2 column chromatography with hexane-
AcOEt (2/1) as the eluent to give 21a (2.68 g, 12.3 mmol, 98%,
94% ee by HPLC analysis). 21a : Colorless oil; IR (KBr) 3287,
(-)-19a and (-)-19b, respectively, whose physical data
were in agreement with reported values.
Asymmetric syntheses of (-)-R-herbertenol ((-)-19a )
and (-)-herbertenediol ((-)-19b) from commercially avail-
able 12 were completed in 12 steps with a 48.5% total
yield for (-)-19a and with a 49.9% total yield for (-)-
19b. The method described here is short compared with
other asymmetric syntheses, and the yield of each step
is very high.
1
1495, 1242, 1034, 741 cm-1; H NMR (CDCl3) δ 1.70 (s, 3H),
1.69-1.79 (m, 1H), 2.29 (s, 3H), 2.36-2.43 (m, 1H), 2.54-2.78
(m, 2H), 3.77 (s, 3H), 4.73 (br s, 1H), 6.80 (d, 1H, J ) 8.1 Hz),
6.91 (d, 1H, J ) 2.1 Hz), 7.04 (dd, 1H, J ) 8.1, 2.1 Hz); 13C
NMR (CDCl3) δ 12.5, 20.5, 33.1, 34.3, 55.5, 81.2, 110.8, 126.8,
128.4, 129.3, 130.5, 136.8, 137.1, 154.6. HPLC analysis: 94%
ee (CHIRAL CEL OJ ; hexane/iPrOH ) 99/1; flow rate 0.5 mL/
Con clu sion
We have developed a rearrangement reaction of 2,3-
epoxysulfonates and succeeded in applying this reaction
to the formal synthesis of (-)-aphanorphine and total
syntheses of of (-)-R-herbertenol and (-)-herbertenediol.
This method provides a reliable way to construct the
optically pure chiral quaternary carbon centers next to
a carbonyl function and may find application in the
synthesis of many natural products.
min); [R]26 +4.63 (c 1.63, CHCl3). Anal. Calcd for C14H18O2:
D
C, 77.03; H, 8.31. Found: C, 76.97; H, 8.34.
In the same procedure as for 21a , 21b (1.10 g, 4.5 mmol,
100%) was obtained from BH3‚Me2S (1 M in THF, 4.5 mL, 4.5
mmol), (S)-5,5-diphenyl-2-methyl-3,4-propan-1,3,2-oxazaboro-
lidine (1.2 g, 4.5 mmol), 20b (1.1 g, 4.5 mmol), THF (20 mL+
25 mL), and SiO2 column (hexane-AcOEt (1/1)). 21b: Color-
less oil; IR (KBr) 3354, 1481, 1229, 1126, 1012 cm-1; 1H NMR
(CDCl3) δ 1.71 (s, 3H), 1.78 (m, 1H), 2.21 (br s, 1H), 2.30 (s,
3H), 2.38 (m, 1H), 2.60 (m, 1H), 2.73 (m, 1H), 3.68 (s, 3H),
3.85 (s, 3H), 4.73 (br s, 1H), 6.52 (s, 1H), 6.66 (s, 1H); 13C NMR
(CDCl3) δ 12.2, 21.2, 33.1, 34.6, 55.6, 60.7, 80.9, 111.9, 122.0,
132.0, 133.2, 136.5, 137.6, 144.4, 152.3. HPLC analysis: 98%
ee (CHIRAL CEL OD; hexane/iPrOH ) 99/1; flow rate 1 mL/
Exp er im en ta l Section
2-Met h yl-3-(2-m et h oxy-5-m et h yl)p h en yl-2-cyclop en -
ten on e (20a ) a n d 2-Meth yl-3-(2,3-d im eth oxy-5-m eth yl)-
p h en yl-2-cyclop en ten on e (20b). n-BuLi (n-hexane solution,
29 mL, 45.2 mmol) was added slowly to a solution of 2-bromo-
4-methylanisole (8.98 g, 44.7 mmol) in THF (100 mL) at -78
°C under N2 and the resulting mixture was stirred for 1 h at
-40 °C. A solution of isobutyl ether of 12 (3.01 g, 18.1 mmol)
in THF (30 mL) was added dropwise to the resulting solution
at -78 °C. The mixture was allowed to warm to room
temperature and stirred for 20 h. The mixture was quenched
by 10% aq HCl and extracted with Et2O. The organic layer
was washed with saturated NaHCO3 aq and brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified
by SiO2 column chromatography with hexane-AcOEt (4/1-
3/1) as the eluent to give 20a (3.13 g, 14.5 mmol, 80%). 20a :
min); [R]25 +4.77 (c 1.02, CHCl3). Anal. Calcd for C15H20O3:
D
C, 72.55; H, 8.12. Found: C, 72.20; H, 8.15.
(-)-(1R,2R,5R)-1-Meth yl-5-(2-m eth oxy-5-m eth yl)ph en yl-
6-oxa bicyclo[3.1.0]h exa n -2-ol (22a ) a n d (-)-(1R,2R,5R)-
1-Meth yl-5-(2,3-dim eth oxy-5-m eth yl)ph en yl-6-oxabicyclo-
[3.1.0]h exa n -2-ol (22b). A solution of t-BuOOH (dried over
molecular sieves 4A before use, 68%, 1.50 g, 11.3 mmol) in
benzene (7.0 mL) was added dropwise to a solution of 21a (770
mg, 3.77 mmol) and 0.1 equiv of VO(acac)2 in benzene (20 mL)
at 0 °C under N2. After being stirred for 1.5 h at room
temperature, the mixture was poured into the mixture of
saturated Na2S2O3 aq and saturated NaHCO3 aq. The result-
ing solution was extracted with AcOEt. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by SiO2 column chromatog-
raphy with hexane-AcOEt (2/1) as the eluent to give 22a (830
mg, 3.77 mmol, 100%). 22a : Colorless oil; IR (KBr) 3385, 1504,
Colorless oil; IR (KBr) 1697, 1499, 1258, 743 cm-1; H NMR
1
(CDCl3) δ 1.70 (s, 3H), 2.32 (s, 3H), 2.49-2.53, (m, 2H), 2.86-
2.89 (m, 2H), 3.80 (s, 3H), 6.87 (d, 1H, J ) 8.4 Hz), 6.96 (d,
1H, J ) 2.2 Hz), 7.16 (dd, 1H, J ) 2.2, 8.4 Hz); 13C NMR
(CDCl3) δ 9.5, 20.4, 30.5, 34.3, 55.4, 111.0, 125.5, 129.0, 129.5,
130.3, 138.0, 153.9, 167.4, 209.8. Anal. Calcd for C14H16O2: C,
77.75; H, 7.46. Found: C, 77.91; H, 7.58.
n-BuLi (1.5 M hexane soluution, 2.0 mL, 3.0 mmol) was
added slowly to a solution of 2-bromo-4-methyl-6-methoxy-
anisole (692 mg, 3.0 mmol) in THF (6.0 mL) at -78 °C under
N2 and the resulting mixture was stirred for 1 h. The mixture
was added dropwise to a solution of CeCl3, dried from CeCl3‚
7H2O (1.12 g, 3.0 mmol) before use, and stirred in THF (6.0
mL) for 1 h, at -78 °C under N2, and the mixture was stirred
for 1 h. A solution of isobutyl ether of 12 (100 mg, 0.60 mmol)
in THF (4.0 mL) was added dropwise to the resulting solution
at -78 °C and stirred for 3 h. The mixture was quenched by
10% aq HCl and extracted with AcOEt. The organic layer was
washed with saturated NaHCO3 aq and brine, dried over Na2-
SO4, and evaporated in vacuo. The residue was purified by
SiO2 column chromatography with hexane-AcOEt (5/1) as the
eluent to give 20b (148 mg, 0.60 mmol, 100%). 20b: Colorless
1
1242, 1035 cm-1; H NMR (CDCl3) δ 1.20 (s, 3H), 1.26-1.39
(m, 1H), 1.97-2.16 (m, 3H), 2.29 (s, 3H), 3.79 (s, 3H), 4.21 (dd,
1H, J ) 17.3, 7.9 Hz), 6.76 (d, 1H, J ) 9.0 Hz), 7.07 (br d, 1H,
J ) 9.0 Hz), 7.13 (br s, 1H); 13C NMR (CDCl3) δ 12.8, 20.5,
29.1, 29.6, 55.4, 70.2, 70.5, 76.4, 110.0, 125.0, 129.0, 129.3,
129.6, 154.3; [R]27D -35.6 (c 1.29, CHCl3). HPLC analysis: 94%
ee (CHIRAL CEL AD-H; hexane/iPrOH ) 95/5; flow rate 1 mL/
min, 15 °C). Anal. Calcd for C14H18O3: C, 71.77; H, 7.74.
Found: C, 71.67; H, 7.66.
In the same procedure as for 22a , 22b (820 mg, 3.10 mmol,
99%) was obtained from 21b (776 mg, 3.13 mmol), 0.1 equiv
of VO(acac)2, t-BuOOH (1.2 g, 9.4 mmol), benzene (15 mL),
and SiO2 column (hexane-AcOEt (4/1)). 22b: Colorless oil; IR
1
(KBr) 3443, 1589, 1219, 1126, 772 cm-1; H NMR (CDCl3) δ
crystals; mp 111-112 °C; IR (KBr) 1697, 1466, 1352, 743 cm-1
;
1.24 (s, 3H), 2.03-2.16 (m, 5H), 2.31 (s, 3H), 3.82 (s, 3H), 3.85
(s, 3H), 4.22 (br s, 1H), 6.70 (s, 1H), 6.73 (s, 1H); 13C NMR
(CDCl3) δ 13.0, 21.1, 28.7, 29.9, 55.6, 60.6, 70.2, 70.6, 76.3,
1H NMR (CDCl3) δ 1.73 (s, 3H), 2.34 (s, 3H), 2.53 (m, 2H),
2.87 (m, 2H), 3.69 (s, 3H), 3.89 (s, 3H), 6.55 (s, 1H), 6.76 (s,
1H); 13C NMR (CDCl3) δ 9.2, 21.2, 30.6, 34.3, 55.6, 61.0, 113.5,
120.2, 130.3, 133.8, 138.2, 143.7, 152.5, 167.5, 209.9. Anal.
Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.10; H,
7.32.
113.0, 120.7, 129.8, 133.4, 144.4, 151.8; [R]24 -36.6 (c 1.08,
D
CHCl3). HPLC analysis: 98% ee (CHIRAL CEL AD-H; hexane/
iPrOH ) 99/1; flow rate 1 mL/min, 25 °C). Anal. Calcd for
C
15H20O4: C, 68.16; H, 7.63. Found: C, 67.91; H, 7.60.
(1R)-2-Meth yl-3-(2-m eth oxy-5-m eth yl)p h en yl-2-cyclo-
p r op en -1-ol (21a ) a n d (1R)-2-Meth yl-3-(2,3-d im eth oxy-5-
m eth yl)p h en yl-2-cyclop r op en -1-ol (21b). BH3‚Me2S (1 M
(1R,2R,5R)-1-Met h yl-5-(2-m et h oxy-5-m et h yl)p h en yl-
6-oxa b icyclo[3.1.0]h ex-2-yl 4-Met h ylb en zen esu lfon a t e
(23a) an d (1R,2R,5R)-1-Meth yl-5-(2,3-dim eth oxy-5-m eth yl)-
5922 J . Org. Chem., Vol. 68, No. 15, 2003

earrangement of 2,3-Epoxysulfonates
p h en yl-6-oxa bicyclo[3.1.0]h ex-2-yl 4-Meth ylben zen esu l-
fon a te (23b). p-Methylbenzenesulfonyl chloride (2.44 g, 12.81
mmol) was added to a solution of 22a (2.00 g, 8.54 mmol) in
pyridine (8.0 mL) at 0 °C, and the resulting solution was
stirred for 3 h at room temperature. The excess reagent was
quenched by addition of water, and the mixture was extracted
with EtOAc. The organic layer was washed with water and
brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2 column chromatography with hexane-
AcOEt (5/1-4/1) as the eluent to give 23a (3.25 g, 8.37 mmol,
98%). 23a : Colorless oil; IR (KBr) 1504, 1365, 1176, 914, 740
cm-1; 1H NMR (CDCl3) δ 1.08 (s, 3H), 1.51-1.61 (m, 1H), 1.79-
1.88 (m, 1H), 1.94-2.17 (m, 2H), 2.26 (s, 3H), 2.45 (s, 3H), 3.77
(s, 3H), 5.01 (t, 1H, J ) 8.3 Hz), 6.74 (d, 1H, J ) 8.3 Hz), 7.06
(d, 1H, J ) 8.3 Hz), 7.09 (s, 1H), 7.34 (d, 1H, J ) 8.4 Hz), 7.84
(d, 1H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 12.8, 20.5, 21.7, 25.4,
29.1, 55.4, 67.9, 68.1, 85.1, 109.9, 123.9, 127.7, 129.4, 129.5,
129.6, 129.7, 134.1, 144.5, 154.4. HPLC analysis: 94% ee
(CHIRAL CEL OD; hexane/iPrOH ) 99/1; flow rate 1 mL/min,
25 °C); HRMS calcd for C21H24O5S 388.1344, found 388.1358.
1; flow rate 1 mL/min, 25 °C). Anal. Calcd for C22H26O6S: C,
63.14; H, 6.26; S, 7.66. Found: C, 63.14; H, 6.24; S, 7.58.
(2R)-2-Meth yl-2-(2-m eth oxy-5-m eth yl)p h en ylcyclop en -
t a n on e (25a ) a n d (2R)-2-Met h yl-2-(2,3-d im et h oxy-5-
m eth yl)p h en ylcyclop en ta n on e (25b). Zn powder (951 mg,
14.6 mmol) was added to a solution of 24a (113 mg, 0.29 mmol)
in glacial AcOH (4 mL) under N2 and the mixture was refluxed
for 6 h. After removal of AcOH in vacuo, the mixture was
poured into saturated aqueous NaHCO3 and extracted with
CH2Cl2. The organic layer was washed with water and brine,
dried over Na2SO4, and evaporated in vacuo. The residue was
purified by SiO2 column chromatography with hexane-AcOEt
(7/1) as the eluent to give 25a (55 mg, 0.254 mmol, 87%). 25a :
Colorless crystals; mp 95-96 °C; IR (KBr) 1738, 1450, 1238,
1030, 735 cm-1 1H NMR (CDCl3) δ 1.37 (s, 3H), 1.77-2.10
;
(m, 3H), 2.29 (s, 3H), 2.33-2.65 (m, 3H), 3.71 (s, 3H), 6.76 (d,
1H, J ) 8.1 Hz), 7.02 (d, 1H, J ) 8.1 Hz), 7.09 (br s, 1H); 13C
NMR (CDCl3) δ 19.9, 20.4, 20.8, 36.8, 38.4, 50.5, 55.1, 111.5,
128.0, 128.1, 129.7, 132.8, 153.6, 222.0; [R]25 +25.3 (c 0.89,
D
CHCl3). HPLC analysis: >99% ee (CHIRAL CEL AD-H;
hexane/iPrOH ) 99/1; flow rate 1 mL/min, 25 °C). Anal. Calcd
for C14H18O2: C, 77.03; H, 8.31. Found: C, 77.02; H, 8.44.
In the same procedure as for 23a , 23b (1.27 g, 3.03 mmol,
100%) was obtained from 22b (800 mg, 3.03 mmol), TsCl (870
mg, 4.55 mmol), pyridine (3.0 mL), and SiO2 column (hexane-
AcOEt (4/1)). 23b: Amorphous; IR (KBr) 1589, 1177, 1339, 957
In the same procedure as for 25a , 25b (73 mg, 0.29 mmol,
91%) was obtained from 24b (134 mg, 0.32 mmol), Zn powder
(1.01 g, 15.4 mmol), glacial AcOH (4.5 mL), and SiO2 column
(hexane-AcOEt (5/1)). 25b: Colorless oil; IR (KBr) 1736, 1487,
1
cm-1; H NMR (CDCl3) δ 1.12 (s, 3H), 1.52 (m, 1H), 1.85 (m,
1H), 2.09 (m, 2H), 2.28 (s, 3H), 2.45 (s, 3H), 3.80 (s, 3H), 3.84
(s, 3H), 4.97 (t, 1H, J ) 8.1 Hz), 6.69 (s, 2H), 7,32 (d, 2H, J )
8.1 Hz), 7.83 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 13.1,
21.3, 21.7, 25.3, 29.7, 55.7, 60.8, 68.0, 68.3, 84.9, 113.3, 120.6,
127.7, 128.7, 129.6, 133.5, 134.0, 144.3, 144.6, 151.6. HPLC
analysis: 98% ee (CHIRAL CEL OD; hexane/iPrOH ) 99/1;
flow rate 1 mL/min, 25 °C); HRMS calcd for C22H26O6S
418.1450, found 418.1456.
1
1329, 1146, 1997 cm-1; H NMR (CDCl3) δ 1.35 (s, 3H), 1.92
(m, 2H), 2.02 (m, 1H), 2.30 (s, 3H), 2.42 (m, 2H), 2.56 (m, 1H),
3.67 (s, 3H), 3.81 (s, 3H), 6.65 (s, 1H), 6.70 (s, 1H); 13C NMR
(CDCl3) δ 19.7, 20.9, 21.5, 36.8, 40.0, 50.7, 55.6, 58.6, 112.4,
119.7, 132.6, 138.3, 143.1, 151.0, 221.6; [R]25 +86.0 (c 1.05,
D
CHCl3). HPLC analysis: >98% ee (CHIRAL CEL AD-H;
hexane/iPrOH ) 99/1; flow rate 1 mL/min, 25 °C). Anal. Calcd
for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.53; H, 8.00.
(1R,3R)-3-Meth yl-3-(2-m eth oxy-5-m eth yl)p h en yl-2-oxo-
cyclopen tyl 4-Meth ylben zen esu lfon ate (24a) an d (1R,3R)-
3-Meth yl-3-(2,3-d im eth oxy-5-m eth yl)p h en yl-2-oxo-cyclo-
p en t yl 4-Met h ylb en zen esu lfon a t e (24b ). EtAlCl2 (0.9 M
n-hexane solution, 0.83 mL, 0.75 mmol) was added to a
solution of 23a (282 mg, 0.75 mmol) in CH2Cl2 (7.5 mL) at 0
°C under N2. The mixture was stirred at 0 °C (the reaction
was checked by TLC). After having been diluted with CH2Cl2,
10% HCl was added to the mixture. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2.
The combined organic layer was washed with saturated
NaHCO3 aq. and brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by SiO2 column chroma-
tography with hexane-AcOEt (4/1) as the eluent to give 24a
(263 mg, 0.70 mmol, 93%), which was recrystalized by hexane-
AcOEt to give the optically pure 24a . 24a : Colorless crystals;
(1R,2R)-1,2-Dim et h yl-2-(2-m et h oxy-5-m et h yl)p h en yl-
cyclop en t a n ol (28a ) a n d (1R,2R)-1,2-Dim et h yl-2-(2,3-
d im eth oxy-5-m eth yl)p h en ylcyclop en ta n ol (28b). THF (5
mL) was added to dry CeCl3 {obtained by drying of CeCl3‚7H2O
(1.30 g, 3.49 mmol) at 140 °C under 0.3 mmHg} under N2 and
the mixture was stirred for 2 h. MeLi (Et2O solution, 3.1 mL,
3.53 mmol) was added dropwise slowly to the mixture at -78
°C. After being stirred for 2 h at room temperature, a solution
of 25a (76 mg, 0.348 mmol) in THF (4 mL) was added dropwise
slowly to the resulting mixture at -78 °C. The reaction
mixture was allowed to warm to 0 °C over 3 h and the excess
reagent was quenched by saturated NH4Cl aq. The mixture
was extracted with Et2O. The organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2 column chromatography with hexane-
AcOEt (8/1) as the eluent to give 28a (79 mg, 0.338 mmol,
97%). 28a : Colorless oil; IR (KBr) 3506, 1496, 1232, 1030, 912,
738 cm-1; 1H NMR (CDCl3) δ 1.33 (s, 3H), 1.36 (s, 3H), 1.66-
1.90 (m, 5H), 2.30 (s, 3H), 2.65-2.72 (m, 1H), 2.87 (br s, 1H),
3.82 (s, 3H), 6.82 (d, 1H, J ) 8.1 Hz), 7.02 (dd, 1H, J ) 8.1,
2.1 Hz), 7.23 (d, 1H, J ) 2.1 Hz); 13C NMR (CDCl3) δ 20.4,
20.9, 24.4, 25.0, 38.6, 40.8, 52.7, 55.2, 83.5, 111.8, 127.7, 129.8,
mp 123-125 °C; IR (KBr) 1759, 1499, 1364, 1177, 741 cm-1
;
1H NMR (CDCl3) δ 1.39 (s, 3H), 1.79-1.83 (m, 1H), 2.27 (s,
3H), 2.44 (s, 3H), 2.26-2.39 (m, 3H), 3.66 (s, 3H), 4.99 (t, 1H,
J ) 8.1 Hz), 6.73 (d, 1H, J ) 8.0 Hz), 6.99 (s, 1H), 7.00 (d, 1H,
J ) 8.0 Hz), 7.34 (d, 2H, J ) 8.2 Hz), 7.89 (d, 2H, J ) 8.2 Hz);
13C NMR (CDCl3) δ 20.8, 21.8, 23.9, 27.0, 35.3, 47.6, 55.4,-
79.1, 111.6, 127.5, 128.0, 128.4, 129.7, 129.9, 132.9, 133.4,
144.7, 153.2, 211.9; [R]21 -15.6 (c 0.55, CHCl3). HPLC
D
129.9, 132.7, 155.8; [R]26 -24.2 (c 0.23, CHCl3). HPLC
analysis: >99% ee (CHIRAL CEL AS; hexane/iPrOH ) 99/1;
flow rate 1.0 mL/min). Anal. Calcd for C21H24O5S: C, 64.93;
H, 6.23; S, 8.25. Found: C, 64.85; H, 6.15; S, 8.18.
D
analysis: >99% ee (CHIRAL CEL OD; hexane/iPrOH ) 99/1;
flow rate 1 mL/min, 25 °C). Anal. Calcd for C15H22O2: C, 76.88;
H, 9.46. Found: C, 76.89; H, 9.36.
In the same procedure as for 24a , 24b (988 mg, 2.55 mmol,
99%) was obtained from 23b (1.00 g, 2.58 mmol), EtAlCl2 (0.98
M n-hexane solution, 2.6 mL, 2.58 mmol), CH2Cl2 (20 mL), and
SiO2 column (hexane-AcOEt (3/1)). 24b: Colorless oil; IR
(KBr) 1751, 1487, 1177, 764 cm-1; 1H NMR (CDCl3) δ 1.39 (s,
3H), 1.77 (m, 1H), 2.18 (m, 3H), 2.32 (s, 3H), 2.43 (s, 3H), 3.55
(s, 3H), 3.80 (s, 3H), 5.03 (t, 1H, J ) 9.6 Hz), 6.60 (s, 1H), 6.61
In the same procedure as for 28a , 28b (50 mg, 0.189 mmol,
92%) was obtained from 25b (51 mg, 0.205 mmol), CeCl3‚7H2O
(765 mg, 2.05 mmol), MeLi (1.5 mL, 2.05 mmol), THF (2 mL-2
mL), and SiO2 column (hexane-AcOEt (5/1)). 28b: Colorless
oil; IR (KBr) 3501, 1462, 1232, 1059 cm-1; 1H NMR (CDCl3) δ
1.32 (s, 3H), 1.36 (s, 3H). 1.83 (m, 5H), 2.30 (s, 3H), 2.59 (m,
1H), 2.74 (br s, 1H), 3.82 (s, 3H), 3.85 (s, 3H), 6.65 (d, 1H, J )
1.8 Hz), 6.85 (d, 1H, J ) 1.8 Hz); 13C NMR (CDCl3) δ 20.2,
21.7, 24.2, 25.5, 38.6, 40.4, 52.9, 55.7, 60.6, 83.4, 111.9, 121.2,
(s, 1H), 7.33 (d, 2H, J ) 8.1 Hz), 7.87 (d, 2H, J ) 8.1 Hz); 13
C
NMR (CDCl3) δ 21.5, 21.7, 24.8, 26.5, 36.2, 47.2, 55.6, 59.0,
79.5, 112.4, 118.8, 127.9, 129.6, 133.0, 133.7, 138.5, 142.6,
144.6, 151.9, 210.9; [R]26 +26.5 (c 1.04, CHCl3). HPLC
132.4, 137.3, 146.0, 152.9; [R]27 -13.8 (c 1.05, CHCl3). HPLC
D
D
analysis: >98% ee (CHIRAL CEL AD-H; hexane/iPrOH ) 99/
analysis: >98% ee (CHIRAL CEL OD; hexane/iPrOH ) 99/1;
J . Org. Chem, Vol. 68, No. 15, 2003 5923

Kita et al.
flow rate 1 mL/min, 25 °C). Anal. Calcd for C16H24O3: C, 72.69;
H, 9.15. Found: C, 72.95; H, 9.06.
(1S)-1,2,2-Tr im eth y-1-(2-m eth oxy-5-m eth yl)p h en ylcy-
clop en ta n e (31a ) a n d (1S)-1,2,2-Tr im eth y-1-(2,3-d im eth -
oxy-5-m eth yl)p h en ylcyclop en ta n e (31b). Compound 30a
(50 mg, 0.22 mmol), AcONa (142 mg, 1.74 mmol), and PtO2
(195 mg, 0.87 mmol) in AcOH (1.0 mL) were hydrogenated with
H2 under 3 atm. After completion of the reaction (TLC check),
the reaction mixture was filtered through Celite pad with CH2-
Cl2. The filtrate was washed with water and brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified
by SiO2 column chromatography with hexane as the eluent to
give 31a (47 mg, 0.20 mmol, 94%). 31a : Colorless oil; IR (KBr)
(3S)-2,3-Dim eth yl-3-(2-m eth oxy-5-m eth yl)p h en ylcyclo-
p en t-1-en e (29a ) a n d (3S)-2,3-Dim eth yl-3-(2,3-d im eth oxy-
5-m eth yl)p h en ylcyclop en t-1-en e (29b). A solution of Bur-
gess reagent (90 mg, 16.8 mmol) and 28a (500 mg, 2.14 mmol)
in THF (21 mL) was refluxed for 0.5 h under N2. The mixture
was poured into water and extracted with Et2O. The organic
layer was washed with brine, dried over Na2SO4, and evapo-
rated in vacuo. The residue was purified by SiO2 column
chromatography with hexane as the eluent to give 29a (360
mg, 1.67 mmol, 78%). 29a : Colorless oil; IR (KBr) 1497, 1242,
1
1497, 1242, 1034, 804 cm-1; H NMR (CDCl3) δ 0.68 (s, 3H),
1
912, 743 cm-1; H NMR (CDCl3) δ 1.45 (s, 3H), 1.59 (dd, 3H,
1.14 (s, 3H), 1.33 (s, 3H), 1.50-1.73 (m, 5H), 2.28 (s, 3H), 2.50-
2.54 (m, 1H), 3.74 (s, 3H), 6.75 (d, 1H, J ) 8.1 Hz), 6.96 (br d,
1H, J ) 8.1 Hz), 7.11 (br s, 1H); 13C NMR (CDCl3) δ 20.5, 20.9,
23.1, 26.0, 27.6, 39.8, 42.0, 44.1, 51.1, 54.8, 111.4, 127.0, 128.7,
J ) 3.7, 2.0 Hz), 1.76-1.84 (m, 1H), 2.18-2.25 (m, 2H), 2.27
(s, 3H), 2.31-2.40 (m, 1H), 3.76 (s, 3H), 5.45 (d, 1H, J ) 1.5
Hz), 6.76 (d, 1H, J ) 8.3 Hz), 6.92 (d, 1H, J ) 2.2 Hz), 6.98
(dd, 1H, J ) 8.3, 2.2 Hz); 13C NMR (CDCl3) δ 13.7, 20.8, 25.1,
29.9, 40.0, 52.6, 55.3, 111.5, 124.5, 127.2, 128.7, 128.9, 135.3,
146.4, 156.3. HPLC analysis: >99% ee (CHIRAL CEL ODH;
129.6, 135.9, 156.7; [R]25 -50.2 (c 1.37, CHCl3). HPLC
D
analysis: >99% ee (CHIRAL CEL OD-H; hexane only; flow
rate 0.5 mL/min); HRMS calcd for C16H24: 232.1827, found
232.1813 (31a is slight volatile).
hexane only; flow rate 0.5 mL/min); HRMS calcd for C15H20
O
In the same procedure as for 31a , 31b (37 mg, 0.14 mmol,
93%) was obtained from 30b (40 mg, 0.15 mmol), AcONa (101
mg, 1.23 mmol), PtO2 (136 mg, 0.61 mmol) in AcOH (1.5 mL),
and SiO2 column (hexane-benzene (1/1)). 31b: Colorless oil;
216.1514, found 216.1518 (29a is volatile).
In the same procedure as for 29a , 29b (47 mg, 0.19 mmol,
100%) was obtained from 28b (50 mg, 0.19 mmol), Burgess
reagent (8.0 mg, 1.51 mmol), THF (2 mL), and SiO2 column
(hexanes-Et2O (1/3)). 29b: Colorless oil; IR (KBr) 1464, 1313,
1059 cm-1; 1H NMR (CDCl3) δ 1.39 (s, 3H), 1.50 (m, 3H), 1.82
(m, 1H), 2.24 (s, 3H), 2.25 (s, 3H), 3.68 (s, 3H), 3.76 (s, 3H),
5.37 (br s, 1H), 6.52 (br s, 1H), 6.56 (br s, 1H); 13C NMR (CDCl3)
δ 13.5, 21.5, 26.1, 30.2, 41.2, 53.6, 55.6, 60.1, 111.4, 120.5,
124.5, 124.7, 132.0, 140.8, 146.9, 153.0. HPLC analysis: >98%
ee (CHIRAL CEL OD-H; hexane only; flow rate 0.5 mL/min,
10 °C); HRMS calcd for C16H22O2 246.1620, found 246.1618
(29b is volatile).
1
IR (KBr) 1479, 1234, 1058, 1011, 831 cm-1; H NMR (CDCl3)
δ 0.70 (s, 3H), 1.13 (s, 3H), 1.36 (s, 3H), 1.47-1.82 (m, 5H),
2.30 (s, 3H), 2.62 (m, 1H), 3.78 (s, 3H), 3.83 (s, 3H), 6.62 (s,
1H), 6.75 (s, 1H); 13C NMR (CDCl3) δ 20.3, 21.7, 24.2, 25.2,
26.8, 38.9, 40.8, 45.9, 51.5, 55.6, 60.4, 111.0, 121.6, 131.6, 140.1,
146.6, 153.0; [R]24D -32.3 (c 0.54, CHCl3). HPLC analysis: 98%
ee (CHIRAL CEL OD-H; hexane/iPrOH ) 99/1; flow rate 1 mL/
min, 10 °C). Anal. Calcd for C17H26O2: C, 77.82; H, 9.99.
Found: C, 72.80; H, 9.94.
(-)-r-Her ber ten ol ((-)-19a ) a n d (-)-Her ber ten ed iol
((-)-19b). BBr3 (1 M CH2Cl2 solution, 0.44 mL, 0.44 mmol)
was added dropwise to a solution of 31a (41 mg, 0.178 mmol)
in CH2Cl2 (1.8 mL) under N2. After being stirred for 0.5 h at
room temperature, saturated NaHCO3 aq was added to the
mixture, which was extracted with CH2Cl2. The organic layer
was washed with brine, dried over Na2SO4, and evaporated
in vacuo. The residue was purified by SiO2 column chroma-
tography with hexane-AcOEt (20/1) as the eluent to give (-)-
19a (37 mg, 0.17 mmol, 95%). (-)-19a : Colorless oil; IR (KBr)
2-(2-Met h oxy-5-m et h yl)p h en yl-1,2-d im et h ylb icyclo-
[3.1.0]h exa n e (30a ) a n d 2-(2,3-Dim et h oxy-5-m et h yl)-
p h en yl-1,2-d im eth ylbicyclo[3.1.0]h exa n e (30b). CH2I2 (2.6
mL, 32.0 mmol) was added dropwise to a solution of Et2Zn (1
M n-hexane solution, 32 mL, 32 mmol) in CH2Cl2 (10 mL) at
0 °C under N2, and the mixture was stirred for 0.5 h at the
same temperature. A solution of 29a (360 mg, 1.67 mmol) in
CH2Cl2 (11 mL) was added dropwise to the resulting solution,
and the mixture was stirred for 30 h at room temperature.
Excess reagent was quenched by saturated NH4Cl aq at 0 °C.
The mixture was extracted with Et2O. The organic layer was
dried over Na2SO4 and evaporated in vacuo. The residue was
purified by SiO2 column chromatography with hexane as the
eluent to give 30a (345 mg, 1.50 mmol, 90%, ca. 2:1 mixture
of two isomers). 30a : Colorless oil; IR (KBr) 1497, 1242, 1036,
1
3535, 1506, 1165, 808 cm-1; H NMR (CDCl3) δ 0.76 (s, 3H),
1.18 (s, 3H), 1.41 (s, 3H), 1.46-1.79 (m, 5H), 2.26 (s, 3H), 2.31-
2.66 (m, 1H), 4.58 (s, 1H), 6.57 (d, 1H, J ) 7.9 Hz), 6.86 (dd,
1H, J ) 7.9, 2.1 Hz), 7.69 (d, 1H, J ) 2.1 Hz); 13C NMR (CDCl3)
δ 20.3, 20.9, 22.9, 25.6, 26.9, 39.4, 41.2, 44.6, 50.9, 116.7, 127.2,
129.0, 130.0, 133.0, 152.2; [R]25 -56.3 (c 1.28, CHCl3) (lit.1c
D
1
804 cm-1; H NMR (CDCl3) (major product) δ 0.14-0.18 (m,
[R]D -55.0). HPLC analysis: >99% ee (CHIRAL CEL OD-H;
1H), 0.46-0.47 (m, 1H), 1.07 (s, 3H), 1.26-1.70 (m, 4H), 1.70
(s, 3H), 1.81-1.98 (m, 1H), 2.29 (s, 3H), 3.77 (s, 3H), 6.77 (d,
1H, J ) 8.1 Hz), 6.97 (dd, 1H, J ) 8.1, 2.1 Hz), 7.19 (d, 1H, J
) 2.1 Hz), (minor product) δ 0.46-0.52 (m, 2H), 1.07 (s, 3H),
1.26-1.70 (m, 4H), 1.70 (s, 3H), 2.17-2.31 (m, 1H), 2.31 (s,
3H), 3.76 (s, 3H), 6.77 (d, 1H, J ) 8.1 Hz), 6.97 (dd, 1H, J )
hexane/iPrOH ) 98/2; flow rate 0.5 mL/min); HRMS calcd for
C
15H22O 218.1671, found 218.1704.
In the same procedure as for 19a , 19b (29 mg, 0.125 mmol,
93%) was obtained from 31b (35 mg, 0.134 mmol), BBr3 (1 M
CH2Cl2 solution, 0.40 mL, 0.40 mmol), CH2Cl2 (1.3 mL), and
SiO2 column (hexane-AcOEt (5/1)). 19b: Colorless crystal; mp
8.1, 2.1 Hz), 7.38 (d, 1H, J ) 2.1 Hz). HRMS calcd for C16H22
230.1671, found 230.1669.
O
1
89-90 °C; IR (KBr) 3508, 2959, 1302 cm-1; H NMR (CDCl3)
δ 0.76 (s, 3H), 1.18 (s, 3H), 1.41 (s, 3H), 1.52-1.76 (m, 5H),
2.22 (s, 3H), 2.60-2.61 (m, 1H), 5.34 (s, 1H), 5.40 (s, 1H), 6.55
(s, 1H), 6.67 (s, 1H); 13C NMR (CDCl3) δ 20.3, 21.1, 22.8, 25.4,
26.8, 39.2, 40.9, 44.8, 51.1, 113.4, 121.8, 128.2, 133.4, 141.0,
143.3; [R]28 -57.0 (c 0.78, CHCl3) {lit.7b [R]25 -53.8 (c 1.0,
In the same procedure as for 30a , 30b (23 mg, 0.089 mmol,
72%, ca. 5:2 mixture of two isomers) was obtained from 29b
(30 mg, 0.12 mmol), CH2I2 (30 µL, 0.365 mmol × 4), Et2Zn (1
M n-hexane solution, 0.37 mL, 0.365 mmol × 4) in CH2Cl2 (0.8
mL), and SiO2 column (hexane-AcOEt (20/1)). Cyclopropana-
tion of 29b was very slow and the reagents were added to the
reaction mixture 4 times. 30b: IR (KBr) 1462, 1317, 1061, 743
D
D
CHCl3)}. HPLC analysis: >98% ee (CHIRAL CEL OD-H;
hexane/iPrOH ) 99/1; flow rate 1 mL/min, 25 °C).
1
cm-1; H NMR (CDCl3) (major product) δ 0.14-0.19 (m, 1H),
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for cis- and trans-2,3-epoxysul-
fonates 1a -e, 5, and 8, the rearranged products 2a -e, 6, and
9, and the compounds in the formal synthesis of (-)-aphan-
orphine 14, 15, 16, 17, 18, and 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
0.47-0.48 (m, 1H), 1.10 (s, 3H), 1.15-1.61 (m, 4H), 1.61 (s,
3H), 1.85-1.87 (m, 1H), 2.32 (s, 3H), 3.79 (s, 3H), 3.84 (s, 3H),
6.61 (br s, 1H), 6.83 (br s, 1H), (minor product) δ 0.50-0.52
(m, 2H), 1.10 (s, 3H), 1.15-1.61 (m, 4H), 1.61 (s, 3H), 2.10-
2.12 (m, 1H), 2.30 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 6.62 (br s,
1H), 7.26 (br s, 1H). HRMS calcd for C17H24O2 260.1802, found
260.1776.
J O034573G
5924 J . Org. Chem., Vol. 68, No. 15, 2003