Application of the stereoselective Diels-Alder reaction of enantiopure 2-sulfinyl dienes: Synthesis of (-)-(1S,5R)-Karahana ether

Full text of DOI:10.1021/jo961347g

J . Org. Chem. 1996, 61, 9049-9052
9049
Starting from (+)-(R)-4-methyl-2-(p-tolylsulfinyl)-1,3-
pentadiene (2), we devised a different approach outlined
in the retrosynthetic Scheme 1, which highlights some
features of the sulfoxide group chemistry, namely, chiral
auxiliary in asymmetric Diels-Alder reaction3 and acti-
vating group in heteroatom addition.10,11
Ap p lica tion of th e Ster eoselective
Diels-Ald er Rea ction of En a n tiop u r e
2-Su lfin yl Dien es: Syn th esis of
(-)-(1S,5R)-Ka r a h a n a Eth er †
Pascal Gosselin,* Eric Bonfand, and Christian Maignan*
Laboratoire de Synthe`se Organique associe´ au CNRS,
Universite´ du Maine, Avenue O. Messiean, BP 535,
F-72017 Le Mans cedex, France
Sch em e 1
Received J uly 16, 1996
Although a number of methods for the preparation of
enantiopure sulfinyl dienes have been reported to date,1
investigation of their reactivity has received little atten-
tion, even with racemic systems.2 Nevertheless, prelimi-
nary results showed a promising synthetic potential for
these novel chiral dienes, regarding their ability to
promote high endo and facial diastereoselectivities in [4
+ 2] cycloadditions.3 For instance, we obtained a single
diastereomer (among four) by reacting (+)-(E)-(R)-2-(p-
tolylsulfinyl)-1,3-pentadiene with N-methylmaleimide at
ambient temperature and without a catalyst.3e
We wish to describe herein the first application of our
methodology in the field of natural product chemistry.
Karahana ether (1) is a volatile monoterpenoid with a
pleasant camphor-like odor, which has been isolated from
Japanese hop “Shinshu Wase”.4 It contains a 6-oxabicyclo-
[3.2.1]octane skeleton, which is also encountered in some
recently isolated sesqui- and diterpenoids.5-7 Compound
1 has already been the subject of a few racemic8 and two
enantioselective9 syntheses, which generally involve an
intramolecular displacement of a sulfonate by an alkoxide
ion for the construction of the ethereal cycle.
Stereoselective Diels-Alder reaction of enantiopure
sulfinyl diene 21i,k with maleic anhydride was performed
in refluxing THF for 3 days. After basic hydrolysis and
acidification, both crystalline dicarboxylic acids 4 and 5
were easily isolated in a 90% yield by a simple filtration
(Scheme 2). The stereoisomer ratio was shown to be 4:1
by 1H NMR. According to our previous results in a
similar case,3e the major cycloadduct is probably the
diacid 4 resulting from hydrolysis of the corresponding
anhydride whose preferred conformation is of the “folded”
boat type.12 All attempts to reduce directly the mixture
of diacids 4 and 5 into diols 3 and 10 failed.13 Using the
procedure of Soa¨ı slightly modified by Martinez,14 reduc-
tion of diacids 4 and 5 gave “folded” 6, 7 and “extended”
8, 9 lactones in 76% and 20% yields, respectively, after
chromatographic separation. In both cases, the regioi-
someric ratio 6:7 and 8:9 were shown to be 7:3 by 1H
NMR in accordance with the integration and multiplici-
ties of H-3a and H-7a. Further reduction with in situ-
generated calcium borohydride15 afforded diols 3 and 10
in nearly quantitative yields.
† Presented in part at the First Electronic Conference on Trends in
Organic Chemistry (ECTOC 1), 1995, http://www.ch.ic.ac.uk/ectoc/
papers/.
(1) 1-Sulfinyl dienes: (a) Solladie´, G.; Colobert, F.; Ruiz, P.; Ham-
douchi, C.; Carren˜o, M. C.; Garcia-Ruano, J . L. Tetrahedron Lett. 1991,
32, 3695. (b) Solladie´, G.; Ruiz, P.; Colobert, F.; Carren˜o, M. C.; Garcia-
Ruano, J . L. Synthesis 1991, 1011. (c) Solladie´, G.; Maugein, N.;
Morreno, I.; Almario, A.; Carren˜o, M. C.; Garcia-Ruano, J . L. Tetra-
hedron Lett. 1992, 33, 4561. (d) Paley, R. S.; de Dios, A.; Ferna´ndez
de la Pradilla, R. Tetrahedron Lett. 1993, 34, 2429. (e) Paley, R. S.;
Lafontaine, J . A.; Ventura, M. P. Tetrahedron Lett. 1993, 34, 3663. (f)
Arce, E.; Carren˜o, M. C.; Cid, M. B.; Garcia-Ruano, J . L. Tetrahedron:
Asymmetry 1995, 6, 1757. 2-Sulfinyl dienes: (g) Bonfand, E.; Gosselin,
P.; Maignan, C. Tetrahedron Lett. 1992, 33, 2347. (h) Aversa, M. C.;
Bonaccorsi, P.; Giannetto, P.; J afari, S. M. A.; J ones, D. N. Tetrahe-
dron: Asymmetry 1992, 3, 701. (i) Bonfand, E.; Gosselin, P.; Maignan,
C. Tetrahedron: Asymmetry 1993, 4, 1667. (j) Paley, R. S.; Weers, H.
L.; Ferna´ndez, P. Tetrahedron Lett. 1995, 36, 3605. (k) Gosselin, P.;
Bonfand, E.; Maignan, C. Synthesis 1996, 1079.
(2) (a) Evans, D. A.; Bryan, C. A.; Sims, C. L. J . Am. Chem. Soc.
1972, 94, 2891. (b) Inomata, K.; Kinoshita, H.; Takemoto, H.; Muruta,
Y.; Kotake, H. Bull. Chem. Soc. J pn. 1978, 51, 3341. (c) Posner, G. H.;
Harrison, W. J . Chem. Soc., Chem. Commun. 1985, 1786. (d) Fisher,
M. J .; Overman,L. E. J . Org. Chem. 1988, 53, 2630.
(3) 1-Sulfinyl dienes: (a) Arce, E.; Carren˜o, M. C.; Bele´n Cid, M.;
Garcia Ruano, J . L. J . Org. Chem. 1994, 59, 3421. (b) Carren˜o, M. C.;
Cid, M. B.; Colobert, F.; Garcia Ruano, J . L.; Solladie´, G. Tetrahe-
dron: Asymmetry 1994, 5, 1439. (c) Carren˜o, M. C.; Cid, M. B.; Garcia
Ruano, J . L. Tetrahedron: Asymmetry 1996, 7, 2151. 2-Sulfinyl
dienes: (d) Adams, H.; J ones, D. N.; Aversa, M. C.; Bonaccorsi, P.;
Gianetto, P. Tetrahedron Lett. 1993, 34, 6481. (e) Gosselin, P.; Bonfand,
E.; Hayes, P.; Retoux, R.; Maignan, C. Tetrahedron: Asymmetry
1994, 5, 781. (f) Aversa, M. C.; Bonaccorsi, P.; Gianetto, P.; J ones, D.
N. Tetrahedron: Asymmetry 1994, 5, 805. (g) Yang, T. K.; Chu, H. Y.;
Lee D. S.; J iang, Y. Z.; Chou, T. S. Tetrahedron Lett. 1996, 37, 4537.
(4) Naya, Y.; Kotake, M. Tetrahedron Lett. 1968, 1645.
A key step of our synthesis was the construction of the
tetrahydrofuran moiety, which corresponds to a favorable
5-exo-trig cyclization16 by taking advantage of the sul-
foxide activating influence (Scheme 3). One intramo-
lecular conjugate addition of an alkoxide ion onto an R,â-
ethylenic sulfoxide has already been achieved in spiroketal
(8) (a) Coates, R. M.; Melvin, L. S. J . Org. Chem. 1970, 35, 865. (b)
Mukaiyama, T.; Iwasawa, N.; Tsuji, T.; Narasaka, K. Chem. Lett. 1979,
1175. (c) Yamada, Y.; Sanjoh, H.; Iguchi, K. Tetrahedron Lett. 1979,
20, 1323. (d) Armstrong, R. J .; Weiler, L. Can. J . Chem. 1986, 64, 584.
(e) Barrero, A. F.; Alvarez-Manzaneda, E. J .; Linares Palomino, P.
Tetrahedron 1994, 50, 13239.
(9) (a) Mori, K.; Mori, H. Tetrahedron 1985, 41, 5487. (b) Honda,
T.; Satoh, M.; Kobayashi, Y. J . Chem. Soc., Perkin Trans 1 1992, 1557.
(10) Imanishi, T.; Iwata, C. In Studies in Natural Products Chem-
istry; Atta-ur-Rahman, Ed.; Elsevier Science BV: New York, 1994; Vol.
14, pp 517-550.
(11) Guillot, C.; Maignan, C. Tetrahedron Lett. 1991, 32, 4907.
(12) Danishefsky, S.; Yan, C.; Singh, R. K.; Gammill, R. B.; Mc-
Murry, P. M.; Fritsch, N.; Clardy, J . J . Am. Chem. Soc. 1979, 101,
7001.
(13) LiAlH4 reduction afforded only degradation products. NaBH4/
MeOH reduction of an in situ generated bis(mixed carbonic anhydride)
resulted in the formation of either stereo- and regioisomeric lactones
6-9 or epimeric diols.
(14) (a) Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647.
(b) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J .
Tetrahedron Lett. 1991, 32, 923.
(5) Nidifocene: Waraszkiewicz, S. M.; Erickson, K. L.; Finer, J .;
Clardy, J . Tetrahedron Lett. 1977, 18, 2311.
(6) Pinnatifenol: Ahmad, V. U.; Ali, M. S. Phytochemistry 1991, 30,
4172.
(7) (+)-Kahukuene A: Brennan, M. R.; Kim, I. K.; Erickson, K. L.
J . Nat. Prod. 1993, 56, 76.
(15) Brown, H. C.; Narasimhan, S. J . Org. Chem. 1982, 47, 1606.
(16) Baldwin, J . E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J .
Org. Chem. 1977, 42, 3846.
S0022-3263(96)01347-3 CCC: $12.00 © 1996 American Chemical Society

9050 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
Sch em e 2a
Sch em e 4a
a
Reagents and conditions: (a) i-PrONa, i-PrOH, 70 °C, 15 h;
(b) Raney Ni, MeOH, rt, 14 h; (c) (1) o-NO2PhSeCN, n-Bu3P, THF,
rt, 2 h, (2) aqueous 30% H2O2, 0 °C to rt, 1.5 h; (d) 70% m-CPBA,
CH2Cl2, rt, 12 h; (e) EtONa, rt, 44 h; (f) Mg, cat. HgCl2, EtOH, rt,
2 h.
a
Reagents and conditions: (a) (1) maleic anhydride, THF,
reflux, 3 d, (2) aqueous Na2CO3, rt, 2 h, (3) aqueous HCl; (b) (1)
ClCO2Et, Et3N, DME, -7 °C, 0.5 h, (2) NaBH4, H2O, rt, 0.5 h, (3)
chromatographic separation; (c) NaBH4, CaCl2, EtOH, 45 °C, 30
min.
KH and prolonged reaction times. Cyclization of 13 was
achieved by exposure to sodium ethoxide in ethanol for
12 h at ambient temperature. A 92:8 mixture was thus
obtained, from which all-syn bicyclic product 14 was
isolated in 86% yield.
Sch em e 3
Next, the sulfoxide group of 11 was cleanly removed
using Raney nickel in methanol to give 12 (97% yield).
Unfortunately, all attempts to obtain 12 from the sulfone
14 using electron transfer agents, such as classical 6%
sodium amalgam (with or without NaH2PO4 buffer) or
magnesium with catalytic mercuric chloride,18 gave un-
satisfactory results. In each case, desired 12 was formed
together with a significant amount of cyclohexenediol 15
(up to 90%), which resulted from a J ulia-type elimination.
Consequently, although less effective in the cyclization
step, the sulfoxide route was preferred.
Final one-pot dehydration of primary alcohol 12 via
its o-nitrophenyl selenide19 followed by in situ oxidation
into the corresponding unstable selenoxide20 afforded (-)-
karahana ether (1) in 61% yield after purification.21
This constitutes the first utilization of enantiopure
2-sulfinyl dienes in natural product stereoselective syn-
thesis. We are currently investigating further applica-
tions of these promising chiral intermediates.
synthesis by using alkali hydrides in tetrahydrofuran.10
But, this procedure proved to be unsuccessful when
applied to the diol 3, even upon heating. We then turned
to the use of some protic media, among which 2-propanol
furnished the best result. Thus, treatment of 3 with
sodium isopropoxide at 65-70 °C for 15 h led to a mixture
of desired ether 11 and starting material in a 82:18 ratio
(Scheme 4). That the same ratio was observed after a
longer reaction time (36 h) suggested a thermodynamic
equilibrium between both anionic intermediates (Scheme
3).
Exp er im en ta l Section
Gen er a l Meth od s. THF was distilled from Na/benzophe-
none, i-PrOH from CaO, and triethylamine from KOH. Melting
points are uncorrected. NMR spectra were recorded at 400 MHz
for 1H and 100 MHz for 13C. Multiplicities in the 13C spectra
were determined by DEPT experiments. IR spectra were
recorded in KBr dispersion for solids and thin films on NaCl
The all-syn geometry of bicyclic alcohol 11 was deduced
1
from its 400 MHz H NMR spectrum, which exhibits no
coupling constant between H-1, H-2 and H-4, H-5. In
order to eventually improve the efficiency of this cycliza-
tion, sulfoxide 3 was converted into the corresponding
sulfone 13 in a nearly quantitative yield by treatment
with metachloroperbenzoic acid. Although such a strat-
egy has already been applied to substituted tetrahydro-
furan synthesis using a catalytic amount of potassium
hydride in THF,17 this led to a mixture of desired product
14 and starting material in a 1:2 ratio, even with excess
(17) Auvray, P.; Knochel, P.; Normant, J . F. Tetrahedron Lett. 1985,
26, 4455.
(18) Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. Tetrahedron Lett.
1993, 34, 4541.
(19) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485.
(20) Sharpless, K. B.; Young, M. W. J . Org. Chem. 1975, 40, 947.
(21) (+)-Karahana ether (+)-1 was also prepared from 10 by using
the same reaction sequence as for (-)-1 (see Experimental Section).

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9051
plates for liquids. High-resolution mass measurements were
obtained by electron impact at 70 eV. Flash chromatography
was run on silica gel 60 (230-400 mesh).
was washed with brine, dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed with acetone-cyclo-
hexane 1:1 to give 3 (2.76 g, 96%) as a white solid: mp 131-
134 °C (toluene); [R]D -1.2 (c 1.26, Me2CO); IR (neat) 3396, 1365,
1035, 809 cm-1; 1H NMR δ 1.14 (s, 3H), 1.19 (s, 3H), 1.64 (ddd,
J ) 17.6, 10.9, 2.0 Hz, 1H), 1.76 (m, 1H), 2.14 (dd, J ) 17.6, 4.9
Hz, 1H), 2.26 (m, 1H), 2.40 (s, 3H), 3.33 (dd, J ) 11.1, 8.6 Hz,
1H), 3.64 (m, 3H), 6.32 (s, 1H), 7.28-7.41 (AA′BB′ system, J )
8.1 Hz, 4H); 13C NMR δ 18.5 (t), 21.3 (q), 26.5 (q), 30.3 (q), 35.7
(d), 36.6 (s), 47.4 (d), 58.8 (t), 64.3 (t), 124.4 (d), 129.9 (d), 138.6
(s), 140.6 (s), 141.2 (s), 142.4 (d). Anal. Calcd for C17H20O5S:
C, 66.18; H, 7.86; S, 10.38. Found: C, 65.95; H, 7.75; S, 10.25.
(-)-(1R,2R,RS)-[[6-(Hydr oxym eth yl)-5,5-dim eth yl-3-p-tolyl-
su lfin yl]cycloh ex-3-en yl]m eth a n ol (10). Following the same
procedure as described above, 10 was obtained in 95% yield as
a white solid: [R]D -0.7 (c 0.7, Me2CO); 1H NMR δ 1.16 (s), 1.72
(ddd, J ) 17.5, 4.5, <1 Hz, 1H), 1.77 (m, 1H), 2.01 (ddd, J )
17.5, 10.0, 1.7 Hz, 1H), 2.25 (m, 1H), 2.41 (s, 3H), 2.85 (m, 1H),
3.25 (m, 1H), 3.51 (dd, J ) 11.0, 8.8 Hz, 1H), 3.63 (m, 2H), 3.74
(dd, J ) 11.0, 4.0 Hz, 1H), 6.33 (s, 1H), 7.29-7.43 (AA′BB′
system, J ) 8.2 Hz, 4H).
(1S,2S,RS)- a n d (1R,2R,RS)-3,3-Dim eth yl-5-(p-tolylsu lfi-
n yl)cycloh ex-4-en e-1,2-d ica r boxylic Acid s (4) a n d (5).
A
solution of 21i,k (3.30 g, 15 mmol) and maleic anhydride (3.00 g,
30 mmol) in dry THF (15 mL) was heated under reflux for 3 d.
The resulting dark brown mixture was poured into a 5% Na2-
CO3 aqueous solution (200 mL) and stirred for 2 h at rt. After
removal of the THF under reduced pressure, the aqueous layer
was washed with Et2O and saturated with NaCl and acidified
with concentrated HCl until pH ) 1. The resulting precipitate
was isolated by filtration and washed with cold water. Drying
under vacuum gave 4 and 5 (4.50 g, 4:1, 90%) as a beige solid,
which was used directly in the next step: mp 180-190 °C (THF/
H2O); IR (KBr) 3407, 1743, 1710, 1594, 1263, 1209, 1022, 987,
815 cm-1; 1H NMR (DMSO-d6) δ 1.16 (s, 3H), 1.19 (s, 3H), 2.10
(ddd, J ) 17.2, 11.2, 1.9 Hz, 1H), 2.22 (dd, J ) 17.2, 5.8 Hz,
1H), 2.38 (s, 3H), 2.73 (d, J ) 3.8 Hz, 1H), 2.94 (m, 1H), 6.27
and 6.40 (2s, 1H), 7.36-7.42 and 7.38-7.50 (2 AA′BB′ systems,
J ) 8.2 Hz, 4H). Anal. Calcd for C17H20O5S: C, 60.68; H, 6.01;
S, 9.52. Found: C, 60.51; H, 6.19; S, 9.51.
(+)-(1S,2S,4R,5S,SS)-[8,8-Dim eth yl-4-(p-tolylsu lfin yl)-6-
oxa bicyclo[3.2.1]oct-2-yl]m eth a n ol (11). Na (230 mg, 10
mmol) was dissolved in dry i-PrOH (50 mL) at 50 °C under Ar.
A solution of 3 (2.60 g, 8.4 mmol) in i-PrOH (50 mL) was then
added and the resulting mixture heated at 65-70 °C for 15 h.
After cooling and quenching with H2O, i-PrOH was evaporated
under reduced pressure and the residue extracted with AcOEt.
The organic phase was washed with H2O and brine, dried
(MgSO4), and concentrated in vacuo. The crude solid was
purified by chromatography (CH2Cl2-THF-EtOH 90:9:1) to
afford starting material 3 (0.40 g, 15%) and 11 (1.95 g, 75%) as
a white solid: Rf 0.58 (CH2Cl2-THF 1:1); [R]D +123 (c 1.05,
EtOH); 1H NMR δ 1.02 (t, J ) 9.0 Hz, 2H), 1.10 (s, 3H), 1.19 (s,
3H), 1.91 (dd, J ) 4.4, 2.1 Hz, 1H), 2.07 (m, 1H), 2.41 (s, 3H),
2.83 (t, J ) 9.0 Hz, 1H), 3.41 (m, 2H), 3.84 (d, J ) 8.8 Hz, 1H),
3.97 (dd, J ) 8.8, 4.4 Hz, 1H), 4.39 (s, 1H), 7.31-7.54 (AA′BB′
system, J ) 8.0 Hz, 4H); 13C NMR δ 19.4 (q), 20.2 (t), 21.4 (q),
26.2 (q), 36.5 (d), 42.3 (s), 44.0 (d), 65.0 (t), 67.1 (t), 66.5 (d),
78.6 (d), 125.4 (d), 129.9 (d), 139.0 (s), 142.2 (s). Anal. Calcd
for C17H24O3S: C, 66.18; H, 7.86. Found: C, 66.24; H, 7.87.
(-)-(1S,2S,5R)-(8,8-Dim eth yl-6-oxa bicyclo[3.2.1]oct-2-yl)-
m eth a n ol ((-)-12). A mixture of 11 (1.75 g, 5.67 mmol) and
Raney Ni (8 g, from Acros) in dry MeOH (175 mL) was stirred
at rt for 14 h. After filtration on Celite and removal of the MeOH
under reduced pressure, the residual oil was dissolved in Et2O,
washed with H2O and brine, dried (MgSO4), and filtered.
Concentration in vacuo yielded (-)-12 (0.93 g, 97%) as a colorless
oil, which was used directly in the next step (purity >98%
according to GC): Rf 0.40 (ethyl acetate); [R]D -15.2 (c 1.15,
(3a S,7a S,RS)-4,4-Dim et h yl-6-(p -t olylsu lfin yl)-3a ,4,7,7a -
t et r a h yd r o-3H -isob en zofu r a n -1-on e (6), (3a S,7a S,RS)-
7,7-Dim et h yl-5-(p -t olylsu lfin yl)-3a ,4,7,7a -t et r a h yd r o-3H -
isoben zofu r a n -1-on e (7), (3a R,7a R,RS)-4,4-Dim eth yl-6-(p-
t olylsu lfin yl)-3a ,4,7,7a -t et r a h yd r o-3H -isob en zofu r a n -1-
on e (8), a n d (3a R,7a R,RS)-7,7-Dim eth yl-5-(p-tolylsu lfin yl)-
3a ,4,7,7a -t et r a h yd r o-3H -isob en zofu r a n -1-on e (9). To a
solution of 4 and 5 (4.30 g, 12.8 mmol) and Et3N (4.0 mL, 28.7
mmol) in dry DME (100 mL) at -7 °C was added ClCO2Et (4.2
mL, 43.9 mmol) dropwise. After being stirred for 30 min, the
resulting mixture was filtered and placed in a 1 L Erlenmeyer
flask. NaBH4 (1.50 g) in H2O (15 mL) was slowly added before
the mixture was stirred for an additional 30 min. After
quenching with a 20% HCl aqueous solution and extraction with
CH2Cl2, the organic phase was washed with H2O, dried (MgSO4),
and concentrated in vacuo. Chromatographic separation (Et2O)
of the residue gave a first fraction (Rf 0.29, ether) which
contained 8 and 9 (0.80 g, 20%, 7:3) as a white solid: IR (neat)
1772, 1596, 1153, 1043, 811 cm-1. 8: 1H NMR δ 1.05 (s, 3H),
1.18 (s, 3H), 2.06 (ddd, J ) 18.4, 6.2, 2.3 Hz, 1H), 2.27 (ddd, J
) 18.4, 10.3, 1.3 Hz, 1H), 2.41 (s, 3H), 2.48 (q, J ) 7.4 Hz, 1H),
2.82 (ddd, J ) 10.3, 7.9, 6.2 Hz, 1H), 4.30 (dd, J ) 9.2, 7.0 Hz,
1H), 6.55 (s), 7.30-7.46 (AA′BB′ system, J ) 8.1 Hz, 4H); 13C
NMR δ 18.3 (t), 21.4 (q), 23.9 (q), 29.4 (q), 33.5 (s), 35.7 (d), 44.8
(d), 68.9 (t), 125.1 (d), 130.2 (d), 137.9 (d), 138.8 (s), 140.2 (s),
142.2 (s), 178.5 (s). 9: 1H NMR δ 1.28 (s), 1.38 (s), 1.91 (ddd, J
) 18.4, 6.4, 2.1 Hz, 1H), 2.13 (ddd, J ) 18.4, 9.0, 1 Hz, 1H), 2.41
(s, 3H), 2.44 (d), 2.85 (m), 3.83 (dd, J ) 9.0, 5.4 Hz, 1H), 4.04
(dd, J ) 9.2, 7.4 Hz, 1H), 4.25 (dd, J ) 9.0, 6.5 Hz, 1H), 6.55 (s),
7.30-7.45 (AA′BB′ system, J ) 8.3 Hz, 4H); 13C NMR δ 20.4 (t),
21.4 (q), 25.1 (q), 31.1 (q), 33.2 (d), 34.0 (s), 47.9 (d), 71.7 (t),
125.0 (d), 130.0 (d), 139.8 (d), 141.9 (s), 175.5 (s); HRMS calcd
for C17H20O3S 304.1133, found 304.1127. The second fraction
(Rf 0.21, ether) contained 6 and 7 (2.96 g, 76%, 7:3) as a white
solid: IR (neat) 1772, 1596, 1153, 1045, 970, 811 cm-1. 6: 1H
NMR δ 1.01 (s, 3H), 1.20 (s, 3H), 1.95 (ddd, J ) 18.5, 5.4, 2.3
Hz, 1H), 2.41 (s, 3H), 2.49 (q, J ) 7 Hz, 1H), 2.58 (ddd, J )
18.5, 10.5, 1.3 Hz, 1H), 2.87 (ddd, J ) 10.5, 8.0, 5.4 Hz, 1H),
4.30 (dd, J ) 9.4, 6.9 Hz, 1H), 6.56 (m, 1H), 7.30-7.43 (AA′BB′
system, J ) 8.2 Hz, 4H); 13C NMR δ 16.7 (t), 21.4 (q), 23.6 (q),
29.1 (q), 33.6 (s), 35.7 (d), 44.5 (d), 68.9 (t), 124.6 (d), 130.1 (d),
138.5 (s), 140.0 (d), 140.9 (s), 141.8 (s), 178.7 (s). 7: 1H NMR δ
1.31 (s), 1.40 (s) 1.54 (ddd, J ) 18.0, 7.2, 2.2 Hz, 1H), 2.41 (s,
3H), 2.47 (d, J ) 7.7 Hz, 1H), 2.89 (m, 1H), 3.77 (dd, J ) 9.0,
3.9 Hz, 1H), 4.04 (dd, J ) 9.4, 6.3 Hz, 1H), 4.22 (dd, J ) 9.0, 5.8
Hz, 1H), 6.56 (m, 1H), 7.30-7.41 (AA′BB′ system, J ) 8.4 Hz,
4H); 13C NMR δ 19.3 (t), 21.4 (q), 24.7 (q), 31.1 (q), 32.9 (d), 34.2
(s), 48.0 (d), 71.8 (t), 124.4 (d), 130.0 (d), 138.5 (s), 140.4 (s), 141.4
(s), 141.9 (d), 175.2 (s)
1
EtOH); IR (thin film) 3392, 1058 cm-1; H NMR δ 1.05 (s, 3H),
1.11 (s, 3H), 1.18 (m, 1H), 1.52 (m, 1H), 1.65 (m, 2H), 1.86 (d, J
) 4.4 Hz, 1H), 2.14 (m, 1H), 3.39 (dd, J ) 10.4, 8.2 Hz, 1H),
3.47 (dd, J ) 10.4, 5.9 Hz, 1H), 3.69 (d, J ) 3.7 Hz, 1H), 3.81 (d,
J ) 8.6 Hz, 1H), 3.85 (dd, J ) 8.6, 4.7 Hz, 1H); 13C NMR δ 19.8
(t), 19.9 (q), 26.5 (q), 27.1 (t), 36.7 (d), 41.5 (s), 44.5 (d), 66.0 (t),
66.6 (t), 82.1 (d); EIMS m/z (relative intensity) 170 (14, M•+),
152 (13, M - H2O•+), 96 (61), 95 (65), 81 (100), 69 (94), 55 (84),
43 (73), 41 (73), 28 (67); HRMS calcd for C10H18O2 170.1307,
found 170.1311.
(+)-(1R,2R,5S)-(8,8-Dim eth yl-6-oxa bicyclo[3.2.1]oct-2-yl)-
m eth a n ol ((+)-12). According to the procedure described for
11, 10 (1.10 g, 3.56 mmol) gave an unseparable 1:4 mixture of
starting material and desired bicyclic alcohol, which was used
directly in the next step: 1H NMR δ 0.98 (s, 3H), 1.03 (s, 3H),
1.60 (q, J ) 12.5 Hz, 1H), 1.95 (m, 1H), 2.06 (dt, J ) 13.7, 6.0
Hz, 1H), 2.23 (m, 1H), 2.43 (s, 3H), 2.86 (dd J ) 11.4, 6.3 Hz,
1H), 3.44 (s, 1H), 3.50 (dd, J ) 10.6, 8.2 Hz, 1H), 3.60 (dd, J )
10.6, 5.8 Hz, 1H), 3.91 (m, 2H), 7.33-7.55 (AA′BB′ system, J )
8.1 Hz, 4H). According to the procedure described for (-)-12,
hydrogenolysis of the crude product (1.05 g, 3.4 mmol) with
Raney Ni (4 g) in dry MeOH (100 mL) yielded (+)-12 (0.37 g,
60%) after chromatography (CH2Cl2 containing 5-10% THF) as
a colorless oil: [R]D +15.0 (c 0.3, ethanol).
(-)-(1S,2S,RS)-[[6-(Hydr oxym eth yl)-5,5-dim eth yl-3-p-tolyl-
su lfin yl]cycloh ex-3-en yl]m eth a n ol (3). To a solution of 6 and
7 (2.76 g, 9.0 mmol) in EtOH (125 mL) were successively added
CaCl2 (1.35 g, 12.0 mmol) and NaBH4 (0.80 g, 21.0 mmol). The
mixture was stirred at 45 °C for 30 min and quenched with a
10% HCl aqueous solution. After removal of the EtOH under
reduced pressure and extraction with AcOEt, the organic phase
(+)-(1S,2S)-[[6-(Hyd r oxym eth yl)-5,5-d im eth yl-3-p-tolyl-
su lfon yl]cycloh ex-3-en yl]m eth a n ol (13). To a solution of 3
(523 mg, 1.69 mmol) in CH2Cl2 (15 mL) was added solid 70%
m-CPBA (550 mg, 1.7 mmol) in portions. After being stirred

9052 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
for 12 h at rt, the reaction mixture was diluted with CH2Cl2,
washed twice with a solution made up of equal volumes of a
10% Na2SO3 solution and a saturated NaHCO3 solution, dried
(MgSO4), and concentrated in vacuo. The residue was chro-
matographed (cyclohexane-acetone 7:3 to 6:4) to yield 13 (530
mg, 96%) as a white solid: [R]D +24.5 (c 0.53, Me2CO); IR (KBr)
3232, 1596, 1311, 1297, 1147, 1043 cm-1; 1H NMR δ 1.16 (s, 3H),
1.17 (s, 3H), 1.76 (ddd, J ) 8.8, 4.4, 4.4 Hz, 1H), 2.15 (m, 2H),
2.27 (m, 1H), 2.44 (s, 3H), 3.42 (dd, J ) 11.0, 8.8 Hz, 1H), 3.68
(m, 3H), 6.72 (s, 1H), 7.32-7.71 (AA′BB′ system, J ) 8.1 Hz,
4H).
(+)-(1S ,2S ,4R ,5S )-[8,8-Dim e t h yl-4-(p -t olylsu lfon yl)-6-
oxa bicyclo[3.2.1]oct-2-yl]m eth a n ol (14). To dry EtOH (4 mL)
was added Na (92 mg, 4 mmol) under a N2 atmosphere. After
dissolution was complete, 13 (584 mg, 1.8 mmol) in dry EtOH
(3 mL) was added. The reaction mixture was stirred for 44 h at
rt and quenched with H2O. After solvent removal under reduced
pressure, the residue was dissolved in CH2Cl2, washed with H2O,
dried (MgSO4), and concentrated in vacuo. Chromatography
(ethyl acetate-cyclohexane 7:3) of the crude product yielded 14
(505 mg, 86%) as a white solid: [R]D +51 (c 1.09, Me2CO); 1H
NMR δ 1.09 (s, 3H), 1.11 (s, 3H), 1.38 (ddd, J ) 13.3, 12.5, 12.2
Hz, 1H), 1.87 (d, J ) 4.0 Hz, 1H), 1.92 (ddd, J ) 13.3, 6.0, 5.6
Hz, 1H), 2.17 (m, 1H), 2.45 (s, 3H), 3.26 (dd, J ) 12.2, 5.6 Hz,
1H), 3.41 (m, 1H), 3.49 (m, 1H), 3.62 (d, J ) 8.9 Hz, 1H), 3.81
(dd, J ) 8.9, 4.5 Hz, 1H), 4.22 (s, 1H), 7.34-7.75 (AA′BB′ system,
J ) 8.2 Hz, 4H); 13C NMR δ 19.3 (q), 21.1 (t), 21.6 (q), 26.0 (q),
36.2 (d), 43.1 (s), 43.9 (d), 64.2 (d), 65.0 (t), 67.2 (t), 79.4 (d),
129.3 (d), 129.6 (d), 134.8 (s), 144.5 (s).
pentane),9a -47.5 (c 0.3, pentane)9b];22 1H NMR δ 0.96 (s, 3H),
1.08 (s, 3H), 1.65 (m, 1H), 1.74 (ddd, J ) 13.7, 8.3, 4.0 Hz, 1H),
2.12 (dd, J ) 15.6, 7.0 Hz, 1H), 2.32 (d, J ) 4.6 Hz, 1H), 2.41
(m, 1H), 3.76 (d, J ) 4.0 Hz, 1H), 3.81 (d, J ) 8.1 Hz, 1H), 4.03
(dd, J ) 8.1, 4.6 Hz, 1H), 4.55 (dd, J ) 2.4, 2.3 Hz, 1H), 4.64
(dd, J ) 2.4, 2.3 Hz, 1H); 13C NMR δ 20.9 (q), 25.5 (q), 25.8 (t),
28.6 (t), 42.2 (s), 54.0 (d), 71.2 (t), 82.4 (d), 107.5 (t), 149.0 (s).
(+)-(1R,5S)-8,8-Dim eth yl-2-m eth ylen e-6-oxabicyclo[3.2.1]-
octa n e ((+)-Ka r a h a n a Eth er (+)-1)). According to the above
procedure, dehydration of (+)-12 (320 mg, 1.88 mmol) gave (+)-1
(175 mg, 62%) after purification as a colorless oil: [R]D +64.0 (c
0.27, pentane).
(+)-(1S,2S)-[6-(Hyd r oxym eth yl)-5,5-d im eth yl-cycloh ex-
3-en yl]m eth a n ol (15). A mixture of 14 (65 mg, 0.2 mmol),
powdered Mg (15 mg, 0.60 mmol), and a few crystals of HgCl2
in dry EtOH was stirred for 2 h at rt. The reaction mixture
was poured into a cold 5% HCl aqueous solution and extracted
with Et2O. The organic layer was washed with a saturated
aqueous NaHCO3 and brine, dried (MgSO4), filtered, and
concentrated in vacuo to give a 9/1 mixture of 15 and (-)-12
(crude yield: 99%) as a colorless oil. 15: 1H NMR δ 1.03 (s,
3H), 1.10 (s, 3H), 1.73 (ddd, J ) 8.4, 4.2, 4.2 Hz, 1H), 1.93 (ddd,
J ) 18.0, 4.5, 4.5 Hz, 1H), 2.03 (dddd, J ) 18.0, 10.5, 2.7, 2.5
Hz, 1H), 2.31 (m, 1H), 3.63 (dd, J ) 11.1, 8.4 Hz, 1H), 3.72 (dd,
J ) 11.1, 5.0 Hz, 1H), 3.77 (dd, J ) 11.1, 6.7 Hz, 1H), 3.79 (dd,
J ) 11.1, 3.8 Hz, 1H), 5.35 (d, J ) 10.0Hz, 1H), 5.56 (ddd, J )
10.0, 4.5, 2.7 Hz, 1H); 13C NMR δ 24.6 (t), 27.4 (q), 31.4 (q), 35.0
(s), 35.5 (d), 47.5 (d), 59.7 (t), 65.4 (t) 123.7 (d), 136.7 (d).
(-)-(1S,5R)-8,8-Dim eth yl-2-m eth ylen e-6-oxabicyclo[3.2.1]-
octa n e ((-)-Ka r a h a n a Eth er ((-)-1)). To a solution of (-)-
12 (445 mg, 2.64 mmol) and o-NO2PhSeCN (805 mg, 3.55 mmol)
in dry THF (8.5 mL) was slowly added n-Bu3P (0.90 mL) under
an Ar atmosphere. After being stirred for 2 h at rt, the reaction
mixture was cooled at 0 °C, and a 30% H2O2 aqueous solution
(3.1 mL, 26.4 mmol) was added. After 1.5 h at rt, the mixture
was diluted with Et2O, washed with H2O, dried (MgSO4),
filtered, and gently concentrated under atmospheric pressure.
The residue was chromatographed (pentane containing 0-1%
ether) and distilled under 100 mm Hg to give (-)-1 (243 mg,
61%, purity >96%) as a colorless oil: Rf 0.60 (pentane-ether
9:1); [R]D -65.5 (c 0.44, pentane) [lit. [R]D -70.3 (c 1.02,
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra (400 MHz) of compounds 1, 6 + 7, 8 + 9, and 12-14
(6 pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; ordering informa-
tion is given on any current masthead page.
J O961347G
(22) The optical purity of 93%9a was found to be identical to the
enantiomeric excess that was determined by chiral GC on Chiraldex
G-TA.