Stereocontrolled tandem radical cyclization: A new and facile route to syntheses of (±)-α-biotol and (±)-β-biotol

Full text of DOI:10.1021/jo951955g

2536
J . Org. Chem. 1996, 61, 2536-2539
Notes
of the nitro group8 in Diels-Alder reactions, ionic ni-
Ster eocon tr olled Ta n d em Ra d ica l
troaldol reactions, and free radical cyclizations, have also
been demonstrated. In continuation of our synthetic
studies in this series, we describe here new and facile
total syntheses of (()-R-biotol (1) and (()-â-biotol (2) via
a stereocontrolled tandem radical cyclization.
Cycliza tion : A New a n d F a cile Rou te to
Syn th eses of (()-r-Biotol a n d (()-â-Biotol
Yao-J ung Chen* and Wen-Hsin Chang
Department of Chemistry, National Chung Hsing
University, Taichung, Taiwan 40227, Republic of China
Resu lts a n d Discu ssion
Our approach is based on the following hypotheses: (1)
A tandem radical cyclization reaction is an efficient
method to construct the cedrene skeleton. (2) The
4-hydroxyl group and the 2-methyl substituent in the
cedrene molecule could be introduced before the cycliza-
tion. (3) The stereochemistry of the radical cyclization
must be affected by the 4-hydroxyl substituent, based on
the studies of 1,5-stereochemistry controlled by the
configuration of the C4 center of the radical in hex-5-enyl
radical cyclizations by Beckwith,9 Houk,10 and Rajan-
Babu.11 A directed synthetic design involving these three
strategic features is outlined below.
Received November 3, 1995
In tr od u ction
R-Biotol (1) and â-biotol (2), isolated from the essential
oil of the wood of Biota orientalis,1 are one kind of
cedranoid sesquiterpenes containing the tricyclo[5.3.1.01,5]-
undecane skeleton and a hydroxyl substituent at the C4
position. From a synthetic standpoint, the efficiency of
constructing a cedrane skeleton and exo-4-hydroxyl group
is a challenge. Although a number of strategies for the
syntheses of R-cedrene and its analogs have been studied2
and briefly summarized,3 relatively little attention has
been directed to the syntheses of biotols. To date, the
total synthesis of biotols has only been reported once4
while a few partial syntheses5 have been recorded. The
approach by Yates et al. included the photosensitized
oxadi-π-methane rearrangement4 of bicyclo[2.2.2]octenone
and required more than 20 steps.
Scheme 1 presents our synthetic routes to the target
molecules. The starting material 3 was readily prepared
by a method that we have previously used in the
synthesis of R-cedrene. The Michael adduct of compound
3 and crotonaldehyde treated with DBU in acetonitrile
at 0 °C gave nitro aldehyde 4 in 66% yield. The Grignard
reaction of compound 4 was carried out with isobutenyl-
magnesium bromide in THF at 0 °C to give a 1:1 mixture
of diastereomers 5 and 6 in 60% total yield. Although
the pairs of diastereomers 5 and 6 could not be fully
separated, the removal of the nitro group would generate
the same radical during the cyclization reaction. There-
fore, the diastereomers could be used directly without
further purification. However, in order to obtain spec-
troscopic data for each of the four diastereomers of 5 and
6 a pair of diastereomers 4 was separated. Each of the
Recently, intramolecular radical cyclizations have re-
ceived considerable attention and are widely applied to
organic synthesis.6 From our previous studies3b on the
synthesis of R-cedrene, we have successfully developed
a new method involving a tandem radical cyclization7
through an addition/elimination mechanism to build up
a cedrene skeleton. Moreover, the synthetic versatility
(1) Tomita, B.; Hirose, Y.; Nakatsuka, T. Tetrahedron Lett. 1968,
9, 843.
(2) ApSimon, J . The Total Synthesis of Natural Products; J ohn Wiley
& Sons: New York, 1973,1982.
(3) (a) Chen, Y. J .; Lin, W. Y. Tetrahedron Lett. 1992, 33, 1749 and
references cited therein. (b) Chen, Y. J .; Chen, C. M.; Lin, W. Y. Ibid.
1993, 34, 2961.
(4) (a) Grewal, R. S.; Hayes, P. C.; Sawyer, J . F.; Yates, P. J . Chem.
Soc., Chem. Commun. 1987, 1290. (b) Yates, P.; Grewal, R. S.; Hayes,
P. C.; Sawyer, J . F. Can. J . Chem. 1988, 66, 2805.
(5) (a) Trifilieff, E.; Luu, B.; Ourisson, G. Tetrahedron Lett. 1975,
16, 4307. (b) Luu, B.; Ourisson, G. Ibid. 1975, 16, 1881. (c) Brun, P.
Ibid. 1977, 18, 2269. (d) Shiao, M. J .; Lin, J . L.; Kuo, Y. H.; Shih, K.
S. Ibid. 1986, 27, 4059.
(6) For reviews, see: (a) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Pergamon Press: New York, 1986.
(b) Ramaiah, M. Tetrahedron 1987, 43, 3541. (c) Curran, D. P.
Synthesis 1988, 417 and 489. (d) J asperse, C. P.; Curran, D. P.; Fevig,
T. L. Chem. Rev. 1991, 91, 1237.
(8) (a) Ono, N.; Kaji, A. Synthesis 1986, 693. (b) Feuer, H.; Nielsen,
A. T. Nitro Compounds: Recent Advances in Synthesis and Chemistry;
VCH Publishers, Inc.: New York, 1990.
(9) (a) Beckwith, A. L. J .; Blair, I.; Phillipou, G. J . Am. Chem. Soc.
1974, 96, 1613. (b) Beckwith, A. L. J .; Easton, C. J .; Serelis, A. K. J .
Chem. Soc., Chem. Commun. 1980, 482. (c) Beckwith, A. L. J .;
Lawrence, T.; Serelis, A. K. Ibid. 1980, 484. (d) Beckwith, A. L. J .;
Easton, C. J .; Lawrence, T.; Serelis, A. K. Aust. J . Chem. 1983, 36,
545. (e) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41, 3925.
(10) (a) Houk, K. N.; Paddon-Row, M. N.; Spellmeyer, D. C.; Rondan,
N. G.; Nagase, S. J . Org. Chem. 1986, 51, 2874. (b) Spellmeyer, D. C.;
Houk, K. N. J . Org. Chem. 1987, 52, 959 and references cited therein.
(11) (a) RajanBabu, T. V.; Fukunaga, T.; Reddy, G. S. J . Am. Chem.
Soc. 1989, 111, 1759 and references cited therein. (b) RajanBabu, T.
V. Acc. Chem. Res. 1991, 24, 139 and references cited therein.
(7) (a) Curran, D. P.; Chen, M. H.; Kim, D. J . Am. Chem. Soc. 1989,
111, 6265. (b) Schwartz, C. E.; Curran, D. P. J . Am. Chem. Soc. 1990,
112, 9272. (c) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1992,
31, 1332.
0022-3263/96/1961-2536$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 7, 1996 2537
Sch em e 1
observations, the stereochemistry of the 2-methyl and
4-hydroxyl substituents in the cyclization precursor 5
could be deduced as syn while the stereochemistry in
compound 6 was assigned as anti. Finally, the direct
isomerization of the exo double bond in â-biotol 2 and its
epimer 7 was effected by treatment with a catalytic
amount of HI in benzene at 30 °C to provide (()-R-biotol
(1) (93% yield) and (()-2-epi-R-biotol (8) (94% yield).
In consideration of the stereochemistry of the ring
closure in diastereomers 5 and 6, our results show that
the 4-hydroxyl group assumes a cis orientation with the
hydrogen at the C5 position in both cases. Evidently, the
4-hydroxyl substituent plays a more important role in
controlling the stereoselectivity of radical cyclizations
than the 2-methyl group. To rationalize these observa-
tions, we propose that the radical cyclization reactions
might proceed through a cyclohexane-like transition state
9, where the conformation is determined by both steric
and stereoelectronic effects of the substituent groups,
especially at the C4 position. This kind of chairlike
transition state has been well studied and proposed by
Beckwith9 in studies of the stereochemistry of hex-5-enyl
radical cyclizations. The use of transition state models
to rationalize the stereochemistry of hex-5-enyl radical
cyclizations has been reviewed by RajanBabu.11b As
pointed out by them, a chairlike conformation for the
transition states with substituents in a quasiequatorial
orientation, and with the least allylic strain13 (and the
possible stereoelectronic effect) in the local allylic con-
formation (C3-C6), is more favorable.11b On the basis of
these considerations, we believe that the predominant
formation of â-biotol (2) in the radical cyclization of 5
proceeds through the lower energy transition state 9a ,
in which both the 4-hydroxyl and the 2-methyl groups
assume equatorial orientations. The former is also in the
most favorable allylic conformation for the C3-C6 portion
of the transition state 9a . In the case of 6, unexpectedly,
only one predominant stereoisomer of 7 was observed. It
appears to be formed through the more favorable transi-
tion state 9c exclusively instead of 9d . This result shows
that the local conformation of the allylic alcohol portion
of 9c is more important in controlling the stereochemistry
than the equatorial conformation of the 2-methyl group.
To rationalize this observation, we evaluated the results
of 1,5-ring closure of the 2- or 4-methylhex-5-enyl radicals
in Beckwith’s studies.9c He found that the kcis/ktrans ratio
for both cases were 0.56 and 0.21, respectively. He also
pointed out that the degree of stereoselectivity should be
more pronounced with bulky groups. On the basis of his
observations, the different degree of stereoselectivity of
1,5-ring closure with the methyl group at different
positions probably could be accounted for by assuming
that the 4-substituent more effectively controls stereo-
chemistry than the 2-substituent. However, we doubt
that steric factors alone account for the observed selectiv-
ity. We believe that the conformational preference of the
substituent in a chairlike transition state should be
determined by both steric and stereoelectronic effects, in
agreement with RajanBabu’s observations.11a
diastereomers 4 was individually reacted with isobuten-
ylmagnesium bromide to give two separable diastereo-
mers of 5 and 6. Unfortunately, the stereochemistry of
the 2-methyl and 4-hydroxyl substituents in these iso-
1
mers still could not be determined directly from their H
NMR data. Since the stereochemistry at C2 and C4 does
not change during the radical cyclization reactions, the
relative configurations could be assigned from the prod-
ucts after cyclization.
The tandem radical cyclization of a mixture of 5 was
effected by treatment with Bu3SnH in the presence of
20 mol % of azobisisobutyronitrile (AIBN) in refluxing
benzene. Surprisingly, only one product (2) was isolated
in 55% yield. The structure of compound 2 was assigned
as (()-â-biotol on the basis of mp, H NMR, 13C NMR,
1
IR, and HRMS studies, compared with the reported
values by Yates.4 Moreover, diastereomers 6 were sub-
jected to the same reaction conditions to afford 7 as a
single product in 61% yield. The relative stereochemistry
of 7 was determined by single-crystal X-ray diffraction12
of its p-nitrobenzoate 10. The structure of 7 was verified
as (()-2-epi-â-biotol, an epimer of 2. From the above
In conclusion, the target molecules 2 and 1 have been
synthesized in three and four steps from the starting
material 3 with a total yield of 11% and 10%, respectively.
A new and facile route to 2 and 1 through a stereocon-
trolled tandem radical cyclization has been successfully
(12) Compound 10 crystallizes in the triclinic P1h space group with
a ) 7.669(3) Å, b ) 13.700(4) Å, c ) 18.802(5) Å, V ) 1907.0(10) Å3,
and Z ) 4. The asymmetric unit contains two independent molecules.
The final coordinates were solved by direct methods and refined by
full-matrix least-squares methods with R ) 5.15%, Rw ) 6.33%, and
GOF ) 1.04 for 487 variables. The atomic coordinates for this work
are available, on request, from the Director, Cambridge Crystal-
lographic Data Center, University Chemical Laboratory, Lensfield
Road, Cambridge CB2 1EW, UK. Any request should be accompanied
by the full literature citation for this communication.
(13) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841 and references cited
therein.

2538 J . Org. Chem., Vol. 61, No. 7, 1996
Notes
45 min. The magnesium almost completely disappeared, and
another 4 mL of THF was added. To 397 mg (1.24 mmol) of the
mixture of 4a and 4b in 12 mL of THF was added 1.2 mL of the
Grignard solution at 0 °C. After the mixture was stirred for 2
h, the reaction was monitored and found to be incomplete. After
a further addition of 0.6 mL of the Grignard solution was added,
the mixture was allowed to stir for 2 more h and then was
quenched by adding 15 mL of 1 N HCl. The product was
extracted with ether. The combined organic layers were rinsed
with water, dried over MgSO4, and evaporated in vacuo. The
crude product was purified by column chromatography (5:1
hexane/EtOAc) and followed by MPLC (10:1 hexane/EtOAc) to
provide two pale yellow liquids of 278 mg (0,74 mmol, 60% yield)
of 5 and 6 with a ratio of about 1:1. To obtain the spectroscopic
data for each of the four diastereomers of 5 and 6, each
diastereomer of 4 was reacted individually with Grignard
reagents by the same method mentioned above to give two
separable diastereomers 5 and 6.
demonstrated. Furthermore, the conformation of the
hydroxyl substituent at the C4 position was a more
important factor in controlling the stereochemistry of the
radical cyclizations than that of the methyl substituent
at the C2 position in this study. The reason is probably
that the conformation of the transition state 9 is mainly
determined by the local conformation of the allyl alcohol
portion of the molecular due to both steric and stereo-
electronic effects.
5a : IR (neat) 3400, 1524 cm-1 1H NMR δ 0.97 (d, J ) 6.6
;
Hz, 3H), 1.27 (br s, 1H), 1.38-1.48 (m, 2H), 1.69 (s, 3H), 1.74 (s,
3H), 1.84 (ddd, J ) 13.5, 11.1, 6.0 Hz, 1H), 1.91-2.03 (m, 1H),
2.03-2.18 (m, 1H), 2.18-2.35 (m, 2H), 2.35-2.45 (m, 1H), 2.84
(br d, J ) 18.6 Hz, 1H), 3.36 (d, J ) 13.5 Hz, 1H), 3.47 (d, J )
13.5 Hz, 1H), 4.31-4.41 (m, 1H), 4.98-5.05 (m, 1H), 5.38-5.43
(m, 1H), 7.16-7.34 (m, 5H);13C NMR: δ 15.0 (q), 18.2 (q), 24.1
(t), 25.8 (q), 29.0 (t), 38.6 (d), 39.0 (t), 41.4 (t), 67.2 (d), 93.8 (s),
121.3 (d), 126.6 (d), 127.1 (d), 128.8 (d), 130.7 (d), 133.0 (s), 136.0
(s), 137.2 (s); HRMS: m/z 375.1861 (M+, calcd for C21H29O3NS
375.1868).
Exp er im en ta l Section
Melting points were uncorrected. Solvents and reagents were
dried prior to use as required. Reactions were monitored by
analytical thin-layer chromatography using silica gel 60 F-254,
layer thickness 0.2 mm. Column chromatography was per-
formed on silica gel 60 (70-230 mesh). Medium-pressure liquid
chromatography was carried out by using Merck Lobar pre-
packed silica gel columns with elution of gradients of EtOAc and
hexane. The starting material 3 was prepared by our previously
reported method.3b
5b: IR (neat) 3368, 1528 cm-1 1H NMR δ 0.90 (d, J ) 6.6
;
Hz, 3H), 1.30-1.46 (m, 2H), 1.53-1.62 (m, 1H), 1.70 (s, 3H),
1.76 (s, 3H), 1.83-2.02 (m, 2H), 2.02-2.45 (m, 4H), 2.91 (br d,
J ) 17.7 Hz, 1H), 3.36 (d, J ) 13.5 Hz, 1H), 3.48 (d, J ) 13.5
Hz, 1H), 4.34-4.46 (m, 1H), 5.03-5.11 (m, 1H), 5.37-5.44 (m,
1H), 7.16-7.34 (m, 5H);13C NMR δ 14.9 (q), 18.3 (q), 24.1 (t),
25.8 (q), 29.1 (t), 29.2 (t), 38.7 (d), 39.1 (t), 41.3 (t), 67.2 (d), 93.8
(s), 121.3 (d), 126.5 (d), 127.0 (d), 128.8 (d), 130.7 (d), 132.9 (s),
135.9 (s), 137.5 (s); HRMS m/z 375.1866 (M+, calcd for C21H29O3-
NS 375.1868). Anal. Calcd for C21H29O3NS: C, 67.17; H, 7.78;
N, 3.73; S, 8.54. Found: C, 67.05; H, 7.85; N, 4.11; S, 8.84.
4-(2′-F or m yl-1′-m et h ylet h yl)-1-((p h en ylt h io)m et h yl)-4-
n itr ocycloh exen e (4). To a mixture of 840 mg (3.37 mmol) of
the starting material 3 and 514 mg (3.37 mmol) of DBU in 7
mL of acetonitrile at 0 °C was added dropwise 234 mg (3.33
mmol) of crotonaldehyde in 7 mL of acetonitrile within 5 min.
After being stirred for another hour at the same temperature,
the solution was poured into 30 mL of water and then acidified
with 1 N HCl until the pH value reached ∼2. The aqueous layer
was extracted with ether. The combined organic layers were
rinsed with an additional 50 mL of water, separated, dried over
MgSO4, and evaporated in vacuo. The crude product was
purified by column chromatography (15:1 hexane/EtOAc) to give
a pale yellow liquid of 700 mg (2.19 mmol, 66% yield) of the
mixture of 2. Further purification by MPLC was carried out
with 20:1 hexane/EtOAc to afford two diastereomers. 4a : IR
6a : IR (neat) 3420, 1526 cm-1 1H NMR δ 1.00 (d, J ) 6.9
;
Hz, 3H), 1.09 (ddd, J ) 13.8, 10.8, 3.0 Hz, 1H), 1.18 (br d, J )
4.2 Hz, 1H), 1.48-1.63 (m, 1H), 1.67 (s, 3H), 1.70 (s, 3H), 1.80-
1.93 (m, 1H), 2.05-2.40 (m, 4H), 2.42-2.53 (m, 1H), 2.88 (br d,
J ) 19.5 Hz, 1H), 3.36 (d, J ) 13.5 Hz, 1H), 3.48 (d, J ) 13.5
Hz, 1H), 4.29-4.41 (m, 1H), 5.11-5.19 (m, 1H), 5.37-5.45 (m,
1H), 7.16-7.35 (m, 5H);13C NMR δ 14.0 (q), 18.1(q), 24.1 (t), 25.6
(q), 29.0 (t), 29.8 (t), 37.4 (d), 38.9 (t), 41.3 (t), 65.8 (d), 93.5 (s),
121.3 (d), 126.5 (d), 128.0 (d), 128.8 (d), 130.7 (d), 133.0 (s), 135.2
(s), 135.9 (s); HRMS m/z 375.1866 (M+, calcd for C21H29O3NS
375.1868).
(neat) 1720, 1526 cm-1 1H NMR δ 0.97 (d, J ) 7.2 Hz, 3H),
;
6b: IR (neat) 3428, 1526 cm-1 1H NMR δ 0.97 (d, J ) 6.9
;
1.79-1.92 (m, 1H), 2.05-2.38 (m, 4H), 2.40-2.51 (m, 1H), 2.57-
2.72 (m, 2H), 2.91 (br d, J ) 17.4 Hz, 1H), 3.37 (d, J ) 13.8 Hz,
1H), 3.48 (d, J ) 13.8 Hz, 1H), 5.36-5.43 (m, 1H), 7.18-7.33
(m, 5H), 9.71 (br s, 1H); 13C NMR δ 15.1 (q), 24.0 (t), 29.4 (t),
29.9 (t), 35.3 (d), 41.3 (t), 45.7 (t), 92.4 (s), 120.9 (d), 126.7 (d),
128.8 (d), 130.8 (d), 133.1 (s), 135.7 (s), 199.9 (d); HRMS m/z
319.1244 (M+, calcd for C17H21O3NS 319.1242). 4b: IR (neat)
1716, 1522 cm-1; 1H NMR δ 0.97 (d, J ) 6.6 Hz, 3H), 1.77-1.89
(m, 1H), 2.12-2.38 (m, 4H), 2.44-2.54 (m, 1H), 2.58-2.71 (m,
2H), 2.92 (br d, J ) 16.5 Hz, 1H), 3.37 (d, J ) 13.8 Hz, 1H), 3.47
(d, J ) 13.8 Hz, 1H), 5.35-5.41 (m, 1H), 7.16-7.32 (m, 5H), 9.72
(br s, 1H); 13C NMR δ 15.1 (q), 24.1 (t), 28.7 (t), 30.7 (t), 35.2 (d),
41.2 (t), 45.9 (t), 92.1 (s), 120.6 (d), 126.7 (d), 128.8 (d), 130.8
(d), 133.2 (s), 135.7 (s), 199.9 (d); HRMS m/z 319.1245 (M+, calcd
for C17H21O3NS 319.1242). Anal. Calcd for C17H21O3NS: C,
63.92; H, 6.63; N, 4.39; S, 10.04. Found: C, 63.82; H, 6.66; N,
4.62; S, 10.27.
Hz, 3H), 1.05 (ddd, J ) 14.1, 10.8, 3.3 Hz, 1H), 1.25 (br s, 1H),
1.54-1.66 (m, 1H), 1.67 (s, 3H), 1.71 (s, 3H), 1.82-1.95 (m, 1H),
2.07-2.36 (m, 4H), 2.44-2.54 (m, 1H), 2.96 (br d, J ) 19.2 Hz,
1H), 3.36 (d, J ) 13.5 Hz, 1H), 3.48 (d, J ) 13.5 Hz, 1H), 4.32-
4.44 (m, 1H), 5.13-5.20 (m, 1H), 5.36-5.44 (m, 1H), 7.15-7.32
(m, 5H);13C NMR δ 14.0 (q), 18.1(q), 24.1 (t), 25.7 (q), 29.2 (t),
29.8 (t), 37.6 (d), 39.0 (t), 41.3 (t), 66.0 (d), 93.5 (s), 121.3 (d),
126.5 (d), 128.0 (d), 128.8 (d), 130.7 (d), 132.9 (s), 135.3 (s), 136.0
(s); HRMS m/z 375.1874 (M+, calcd for C21H29O3NS 375.1868).
Anal. Calcd for C21H29O3NS: C, 67.17; H, 7.78; N, 3.73; S, 8.54.
Found: C, 66.92; H, 7.87; N, 4.04; S, 8.80.
(()-â-Biotol (2). To a solution of 5a and 5b (126 mg, 0.34
mmol) in dry benzene (14 mL) at 80 °C was added by a syringe
pump a solution of Bu3SnH (0.25 mL, 0.9 mmol) and AIBN (30
mg, 0.18 mmol) in dry benzene (33 mL). After the addition was
complete (14 h), the reaction mixture was refluxed for another
6 h and then cooled and evaporated in vacuo. The crude product
was purified by chromatography using hexane and then hexane/
EtOAc (2:1) as eluent to remove the byproduct tin compounds.
After further purification by MPLC with hexane/EtOAc (50:1)
as eluent, a colorless solid 2 (41 mg, 55% yield) was obtained:
mp 97-99 °C (recrystalized from acetone, lit.4b mp 95-97 °C);
4-(3′-Hyd r oxy-1′,5′-d im eth yl-4′-h exen yl)-1-((p h en ylth io)-
m eth yl)-4-n itr ocycloh exen e (5 a n d 6). A THF solution of
isobutenylmagnesium bromide was prepared as follows. Several
drops of a THF (2 mL) solution of 1.186 g (8.78 mmol) of 1-bromo-
2-methylpropene were added by an addition funnel to 240 mg
(9.88 mmol) of activated magnesium in 2 mL of THF, followed
by adding a few drops of 1,2-dibromoethane with a syringe. The
mixture was warmed by hand until the THF refluxed and the
rest of the solution of 1-bromo-2-methylpropene was added
dropwise. This solution was kept at reflux by heating for about
1
IR (CCl4) 3356 cm-1; H NMR δ 0.92 (d, J ) 6.9 Hz, 3H), 1.03
(s, 3H), 1.13 (s, 3H), 1.27 (d, J ) 11.4 Hz, 1H), 1.30-1.64 (m,
4H), 1.71 (d, J ) 8.1 Hz, 1H), 1.68-1.83 (m, 2H), 2.10 (dt, J )
11.4, 5.4 Hz, 1H), 2.21 (d, J ) 4.5 Hz, 1H), 2.31-2.38 (m, 2H),

Notes
J . Org. Chem., Vol. 61, No. 7, 1996 2539
4.15 (ddd, J ) 9.6, 8.7, 5.4 Hz, 1H), 4.52 (br s, 1H), 4.60 (br s,
1H); 13C NMR δ 14.9 (q), 26.1 (q), 26.2 (q), 29.0 (t), 33.7 (t), 39.5
(d), 41.1 (s), 45.5 (t), 46.6 (t), 53.2 (s), 61.1 (d), 65.2 (d), 73.6 (d),
mg, 94% yield): mp 80-82 °C (recrystallized from acetone); IR
1
(CCl4) 3348 cm-1; H NMR δ 0.91 (d, J ) 6.9 Hz, 3H), 0.95 (s,
3H), 1.13 (d, J ) 10.5 Hz, 1H), 1.14 (s, 3H), 1.49-1.82 (m, 6H),
1.68 (d, J ) 1.5 Hz, 3H), 1.92-2.06 (m, 1H), 2.41 (dt, J ) 16.8,
2.1 Hz, 1H), 4.06 (d, J ) 4.5 Hz, 1H), 5.26 (br s, 1H); 13C NMR:
δ 13.4 (q), 24.7 (q), 25.2 (q), 27.9 (q), 33.5 (t), 37.7 (d), 41.6 (t),
43.6 (t), 48.2 (s), 53.9 (d), 54.6 (s), 70.1 (d), 73.0 (d), 120.0 (d),
140.5 (s); HRMS m/z 220.1823 (M+, calcd for C15H24O 220.1827).
Anal. Calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 81.43;
H, 10.96.
108.1 (t), 151.1 (s); HRMS m/z 220.1828 (M+, calcd for C15H24
O
220.1827).
(()-r-Biotol (1). Two drops of 57% HI aqueous solution were
added to a solution of 2 (72 mg, 0.33 mmol) in benzene (25 mL)
at 30 °C, and the mixture was stirred for 24 h. Saturated
aqueous NaHCO3 was added, and the mixture was extracted
with EtOAc. The combined extracts were dried over MgSO4,
and the solvent was evaporated. The residue was purified by
liquid chromatogrphy with hexane/EtOAc (20:1) as eluent to give
a colorless solid 1 (66.8 mg, 93% yield): mp 73-74 °C (recrystal-
lized from acetone, lit.4b mp 68-70 °C); IR (CCl4) 3384 cm-1; 1H
NMR δ 0.94 (d, J ) 6.9 Hz, 3H), 1.08 (s, 3H), 1.12 (s, 3H), 1.25
(br s, 1H), 1.46 (d, J ) 11.1 Hz, 1H), 1.52-1.69 (m, 3H), 1.67 (d,
J ) 2.1 Hz, 3H), 1.74-1.93 (m, 2H), 1.77 (d, J ) 4.2 Hz, 1H),
2.10 (dt, J ) 11.7, 5.4 Hz, 1H), 2.22 (dt, J ) 16.8, 2.4 Hz, 1H),
4.10 (ddd, J ) 8.7, 7.8, 5.4 Hz, 1H), 5.22 (br s, 1H); 13C NMR δ
15.8 (q), 24.6 (q), 25.7 (q), 27.8 (q), 38.7 (t), 39.5 (d), 40.9 (t),
46.5 (t), 46.6 (t), 52.5 (s), 55.5 (d), 68.8 (d), 73.7 (d), 118.6 (d),
140.4 (s); HRMS m/z 220.1832 (M+, calcd for C15H24O 220.1827).
(()-2-epi-â-Biotol (7). After a mixture of 6a and 6b (87 mg,
0.23 mmol) was subjected to the same procedure as 2, a colorless
4-((4′-Nit r ob en zoyl)oxy)-2,6,6-t r im et h yl-8-m et h ylen e-
tr icyclo[5.3.1.01,5]u n d eca n e (10). To a solution of 7 (109 mg,
0.5 mmol) in benzene (5 mL) was added pyridine (0.2 mL, 2.5
mmol) and 4-nitrobenzoyl chloride (150 mg, 0.8 mmol). The
solution was refluxed for 5 h, and the mixture was diluted with
EtOAc. The mixture was filtered and the filtrate was evapo-
rated. The residue was purified by chromatography with 100:1
hexane/EtOAc to give a colorless solid 10 (128 mg, 70% yield).
The derivative of (()-2-epi-â-biotol (7) was recrystallized from
ethyl acetate to provide a crystal for X-ray examination: mp
181-183 °C; IR (KBr) 1698, 1506 cm-1; 1H NMR δ 0.95 (d, J )
6.6 Hz, 3H), 1.01 (d, J ) 12.0 Hz, 1H), 1.08 (s, 3H), 1.12 (s, 3H),
1.32-1.43 (m, 1H), 1.66-1.86 (m, 3H), 1.91 (br s, 1H), 1.94-
2.09 (m, 2H), 2.23 (d, J ) 4.5 Hz, 1H), 2.25-2.45 (m, 2H), 4.56-
4.61 (m, 1H), 4.61-4.65 (m, 1H), 5.28 (d, J ) 4.8 Hz, 1H), 8.15-
8.20 (m, 2H), 8.26-8.31 (m, 2H); 13C NMR: δ 13.7 (q), 25.6 (q),
26.1 (q), 30.2 (t), 36.8 (t), 37.0 (t), 39.4 (d), 40.4 (t), 43.1 (s), 55.9
(s), 58.9 (d), 64.2 (d), 78.7 (d), 108.8 (t), 123.5 (d), 130.6 (d), 136.4
(s), 150.4 (s), 150.5 (s), 164.3 (s); HRMS m/z 369.1936 (M+, calcd
for C22H27O4N 369.1940).
solid
7
(31 mg, 61% yield) was obtained: mp 82-83 °C
(recrystallized from acetone); IR (CCl4) 3360 cm-1
;
1H NMR δ
0.89 (d, J ) 6.9 Hz, 3H), 0.92 (d, J ) 11.7 Hz, 1H), 0.97 (s, 3H),
1.03 (s, 3H), 1.24 (br s, 1H), 1.36-1.45 (m, 1H), 1.50-1.66 (m,
1H), 1.68-1.81 (m, 4H), 1.89-2.04 (m, 1H), 2.15 (d, J ) 4.8 Hz,
1H), 2.34-2.42 (m, 2H), 4.15 (d, J ) 4.2 Hz, 1H), 4.56 (br s,
1H), 4.61 (br s, 1H); 13C NMR δ 13.9 (q), 26.1 (q), 26.2 (q), 30.4
(t), 37.0 (t), 37.2 (t), 38.4 (d), 42.8 (s), 44.0 (t), 55.8 (s), 59.2 (d),
66.5 (d), 72.8 (d), 108.4 (t), 151.1 (s); HRMS m/z 220.1826 (M+,
calcd for C15H24O 220.1827). Anal. Calcd for C15H24O: C, 81.76;
H, 10.98. Found: C, 81.54; H, 10.93.
Ack n ow led gm en t. We thank the National Science
Council of the Republic of China for financial support
under Grant No. NSC83-0208-M005-011 and Professor
H. M. Gau for X-ray crystallography.
(()-2-epi-r-Biotol (8). Treatment of 7 (27.6 mg, 0.13 mmol)
with the same procedure as 1 generated a colorless solid 8 (26.0
J O951955G