A New Synthesis of the Central Substructure of Botryococcenes

Full text of DOI:10.1021/jo9721397

2392
J . Org. Chem. 1998, 63, 2392-2396
bond, the C-13 methyl group, and the C-10 quaternary
carbon center of the central substructure, which are
common to all members of botryococcenes.
A New Syn th esis of th e Cen tr a l
Su bstr u ctu r e of Botr yococcen es
We now describe the synthesis of the central substruc-
tures such as 5 and 6 in a diastereomerically pure form.
Our synthetic route to 6 is tactically different from those
reported by White,10 and Lee and Maxwell.11
The known allylic alcohol 8,12 readily prepared in 83%
overall yield from methyl (R)-3-hydroxy-2-methylpropi-
onate 7, was epoxidized by means of Sharpless asym-
metric epoxidation to yield 2,3-epoxy alcohol 913 in 83%
yield (98% ee). The optical purity of the epoxide 9 was
also confirmed at the latter stage. Subsequent standard
tosylation of 9 gave the 2,3-epoxy alcohol tosylate 10 in
74% yield.
Although a number of groups have contributed to
methodology for the transformation of type 9 and 10
compounds into the allylic alcohol of type 11,14 some of
these methods are still impractical in cases where the
protective groups in the substrate tosylate are rather
acid-labile and/or if research quantities of the allylic
alcohol 11 are needed. Recently, Williams and co-
workers reported the first total synthesis of (+)-breyno-
lide via the MEM ether of allylic alcohol 11 which, in
turn, was synthesized from 2,3-epoxy alcohol 9 in high
yield by iodination with triphenylphosphine-iodine-
imidazole followed by reductive elimination with tert-
butyllithium.13 Synthesis of some allylic alcohols from
the corresponding 2,3-epoxy-1-iodoalkanes by treatment
with n-butyllithium in place of tert-butyllithium was also
reported by Marshall and co-workers.14e We recently
developed a convenient and simple procedure for the
transformation of the 2,3-epoxy alcohol tosylates into the
corresponding allylic alcohols of type 11 by one-pot
treatment with potassium iodide, followed by zinc dust
and ammonium chloride, under mild reaction condi-
tions.15 Following this protocol, the tosylate 10 was
converted into the allylic alcohol 11 in 92% isolated yield
(de >98%; Mosher’s ester). Acetylation of 11 followed by
ozonolysis gave an aldehyde which, without purification,
was treated with [(methoxycarbonyl)ethylidene]triphen-
Hiromu Habashita, Takeshi Kawasaki,
Yoshiji Takemoto, Nobutaka Fujii, and Toshiro Ibuka*
Graduate School of Pharmaceutical Sciences,
Kyoto University, Sakyo-ku, Kyoto 606-01, J apan
Received November 21, 1997
The green, freshwater alga, Botryococcus braunii, is
well-known for its ability to produce large quantities of
hydrocarbons termed botryococcenes with the general
formula CnH2n-10 (n ) 30-37).1 Concentrations in the
senescent phase of B. braunii are reported in the 70-
90% range of its dry weight.1-3 The alga, B. braunii, has
received considerable interest because of its high poten-
tial to be a liquid fuel in the future. Botryococcene
terpenoids are frequently found in many petroleum-rich
deposits. In addition, botryococcane (perhydrobotryococ-
cene) has been also discovered in the crude petroleum
oils of Duri and Minas (Sumatra).4 Botryococcane was
also identified in a suite of coastal bitumens from 10
different stranding sites between Kingston, South Aus-
tralia and Portland, Victoria.5 The plain structure of the
natural product C34-botryococcene 1 was suggested by
Cox and co-workers on the basis of chemical, spectral,
and biosynthetic evidence.6 The absolute stereochemistry
of the two chiral centers in the methylenecyclohexane
ring of braunicene 2 was elucidated by Poulter and co-
workers.7 The most influential reports on the structural
elucidation of C34-botryococcene 1 by chemical and spec-
troscopic means were White’s 1986 and 1992 publica-
tions.8 Recently, a new compound, 1,6,17,21-octahydro-
botryococcene (3), has also been identified in sediment
from Sacred Lake, Mount Kenya.9
Two independent syntheses of C34-botryococcene 1 by
White10 and C30-botryococcene 4 by Lee and Maxwell11
have also appeared recently.
A key to the synthesis of botryococenes lies in the
efficient and stereoselective construction of the E-double
(1) Metzger, P.; Casadevall, E.; Pouet, M. J .; Pouet, Y. Phytochem-
istry 1985, 24, 2995. Metzger, P.; Casadevall, E. Tetrahedron Lett.
1983, 24, 4013. Galbraith, M. N.; Willen, L. W.; Wake, L. V. Phy-
tochemistry 1983, 22, 1441.
(2) Maxwell, J . R.; Douglas, A. G.; Eglinton, G.; McCormick, A.
Phytochemistry 1968, 7, 2157.
(3) Knights, R. A.; Brown, A. C.; Conway, E.; Niddleditch, B. S.
Phytochemistry 1970, 9, 1317.
(4) Moldowan, J . M.; Seifert, W. K. J . Chem. Soc., Chem. Commun.
1980, 912.
(5) McKirdy, D. M.; Cox, R. E.; Volkman, J . K.; Howell, V. J . Nature
1986, 320, 57.
(6) Cox, R. E.; Burlingame, A. L.; Wilson, D. M. J . Chem. Soc., Chem.
Commun. 1973, 284.
(7) Huang, Z.; Poulter, C. D. J . Org. Chem. 1988, 53, 4089. See also,
Huang, Z.; Poulter, C. D.; Wolf, F. R.; Somers, T. C.; White, J . D. J .
Am. Chem. Soc. 1988, 110, 3959.
(8) White, J . D.; Somers, T. C.; Reddy, G. N. J . Am. Chem. Soc. 1986,
108, 5352. White, J . D.; Somers, T. C.; Reddy, G. N. J . Org. Chem.
1992, 57, 4991.
(12) Mulzer, J .; Kattner, L.; Strecker, A. R.; Schro¨der, C.; Bus-
chmann, J .; Lehmann, C.; Luger, P. J . Am. Chem. Soc. 1991, 113, 4218.
(13) Williams, D. R.; J ass, P. A.; Tse, H.-L. A.; Gaston, R. D. J . Am.
Chem. Soc. 1990, 112, 4552.
(14) Various allylic alcohols have been synthesized from 2,3-epoxy
alcohols or related substrates by reduction. (a) Telluride(II)-mediated
or metallic sodium-mediated reduction: Xu, Q.; Chao, B.; Wang, Y.;
Dittmer, D. C. Tetrahedron 1997, 53, 12131 and references cited.
Yasuda, A.; Yamamoto, H.; Nozaki, H. Bull. Chem. Soc. J pn. 1979,
52, 1757. (b) Titanocene(III)-induced deoxygenation: Yadav, J . S.;
Srinivas, D.; Shekharam, T. Tetrahedron Lett. 1994, 35, 3625 and
references cited. (c) Reduction with a zinc-copper couple: Balmer, E.;
Germain, A.; J ackson, W. P.; Lygo, B. J . Chem. Soc., Perkin Trans. 1
1993, 399. Nishigaichi, Y.; Kuramoto, H.; Takuwa, A. Tetrahedron Lett.
1995, 36, 3353. Sarandeses, L. A.; Mourino, A.; Luche, J .-L. J . Chem.
Soc., Chem. Commun. 1991, 818. (d) Reduction with activated zinc:
Rao, A. V. R.; Reddy, E. R.; J oshi, B. V.; Yadav, J . S. Tetrahedron Lett.
1987, 28, 6497. (e) Reduction with n-butyllithium: Marshall, J . A.;
Sedrani, R. J . Org. Chem. 1991, 56, 5496. Marshall, J . A.; Garofalo,
A. W. J . Org. Chem. 1993, 58, 3675. (f) Reduction of iodides with
triphenylphosphine in the presence of iodine: Fujii, N.; Habashita,
H.; Akaji, M.; Nakai, K.; Ibuka, T.; Fujiwara, M.; Tamamura, H.;
Yamamoto, Y. J . Chem. Soc., Perkin Trans. 1 1996, 865.
(9) Huang, Y.; Murray, M. J . Chem. Soc., Chem. Commun. 1995,
335.
(10) White, J . D.; Reddy, G. N.; Spessard, G. O. J . Am. Chem. Soc.
1988, 110, 1624. White, J . D.; Reddy, G. N.; Spessard, G. O. J . Chem.
Soc., Perkin Trans. 1 1993, 759.
(11) Hird, N. W.; Lee, T. V.; Leigh, A. J .; Maxwell, J . R.; Peakman,
T. M. Tetrahedron Lett. 1989, 30, 4867.
(15) A preliminary communication for the synthesis of the allylic
alcohol 11 from the tosylate 10 in a one-pot manner, see Habashita,
H.; Kawasaki, T.; Akaji, M.; Tamamura, H.; Kimachi, T.; Fujii, N.;
Ibuka, T. Tetrahedron Lett. 1997, 38, 8307.
S0022-3263(97)02139-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/06/1998

Notes
J . Org. Chem., Vol. 63, No. 7, 1998 2393
Sch em e 1
ylphosphorane to afford the R,â-(E)-unsaturated ester 14
in 79% yield from 11. Although the stereochemistry and
configuration of the R,â-enoate 14 was inferred from H
1
NMR analysis, the structure was unequivocally ascer-
tained by a single-crystal X-ray analysis. Selective
hydrolysis of the acetyl group in 14 with sodium carbon-
ate in methanol gave the alcohol 15 in 83% yield which,
on treatment with methanesulfonyl chloride and pyridine
in the presence of a catalytic amount of 4-(dimethylami-
no)pyridine, yielded the rather labile mesylate 16 in 86%
yield. Although the mesylate 16 could be synthesized in
two steps from the mesylate 13 by exposure to ozone
followed by [(methoxycarbonyl)ethylidene]triphenylphos-
phorane, the isolated yield of 16 was very low due to loss
of the product during chromatographic purification.
Next, regio- and stereoselective transformation of the
mesylate 16 into the desired R-vinyl-â,γ-enoate 21 was
examined. Extensive stereochemical and mechanistic
studies by the present authors,16 Corey,17 Trost,18 Flem-
ing,19 Goering,20 Marshall,21 and Marino22 on the substi-
tution reaction of acetates, benzoates, and mesylates of
allylic alcohols and of vinyloxiranes with organocopper
and organocopper-Lewis acid reagents have shown that
an anti SN2′ pathway is highly favored for substitution.
In addition, as shown in Scheme 3, it has been well
documented by the present authors that the highly anti
SN2′-selective nature of the reaction of γ-(mesyloxy)-R,â-
enoates such as 17 with alkylcopper reagents (sp3 carbon
reagents) can be used to relay the stereochemistry at the
γ-position to an R-position to yield alkylation products
such as 18 via preferred conformation B in acyclic
systems.23
Sch em e 2
While seemingly straightforward, it was found that the
conversion of the mesylate 16 into 21 by the use of
ordinary sp2 carbon organocopper reagents was rather
more difficult than first envisioned.24 In conjunction with
the optimization process, the solvent, metal (Cu- and Zn-
salts), vinyllithium, and vinylmagnesium halide were
screened to maximize the expected anti SN2′ reaction.
Some results are summarized in Table 1.
(16) Ibuka, T.; Yamamoto, Y. In Organocopper Reagents: A Practical
Approach; Taylor, R. J . K, Ed.; Oxford University Press: Oxford, 1994;
part 7, p 143.
(17) Corey, E. J .; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.
(18) Schmuff, N. R.; Trost, B. M. J . Org. Chem. 1983, 48, 1404. Trost,
B. M.; Klun, T. P. J . Org. Chem. 1980, 45, 4256.
(19) Fleming, I.; Thomas, A. P. J . Chem. Soc., Chem. Commun. 1985,
411. Fleming, I.; Thomas, A. P. J . Chem. Soc., Chem. Commun. 1986,
1456.
(20) Underiner, T. L.; Goering, H. L. J . Org. Chem. 1990, 55, 2757.
Goering, H. L.; Kantner, S. S.; Seitz, E. P., J r. J . Org. Chem. 1985, 50,
5495.
Sch em e 3
(21) Marshall, J . A. Chem. Rev. 1989, 89, 1503. Marshall, J . A.;
Blough, B. E. J . Org. Chem. 1991, 56, 2225. Marshall, J . A.; Blough,
B. E. J . Org. Chem. 1990, 55, 1540. Marshall, J . A.; Crute, T. D., III.;
Hsi, J . D. J . Org. Chem. 1992, 57, 115.
(22) Marino, J . P.; Ferna`ndez de la Pradilla, R.; Laborde, E. J . Org.
Chem. 1987, 52, 4898. Ferna`ndez de la Pradilla, R.; Rubio, M. B.;
Marino, J . P. Tetrahedron Lett. 1992, 33, 4985. Marino, J . P.; Viso, A.;
Ferna`ndez de la Pradilla, R.; Ferna`ndez, P. J . Org. Chem. 1991, 56,
1349. Marino, J . P.; Anna, L. J .; Ferna`ndez de la Pradilla, R.; Martinez,
M. V.; Monteero, C. Viso, A. Tetrahedron Lett. 1996, 37, 8031.
(23) Ibuka, T.; Nakao, T.; Nishii, S.; Yamamoto, Y. J . Am. Chem.
Soc. 1986, 108, 7420. Ibuka, T.; Tanaka, M.; Nishii, N.; Yamamoto, Y.
J . Am. Chem. Soc. 1989, 111, 4864. Ibuka, T.; Akimoto, N.; Tanaka,
M.; Nishii, S.; Yamamoto, Y. J . Org. Chem. 1989, 54, 4055. Ibuka, T.;
Habashita, H.; Funakoshi, S.; Fujii, N.; Oguchi, Y.; Uyehara, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1990, 29, 801. Ibuka, T.;
Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.; Uyehara, T.; Yamamoto,
Y. J . Org. Chem. 1991, 56, 4370. Ibuka, T.; Nakai, K.; Habashita, H.;
Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. Engl. 1994, 33, 652.
The reaction of the mesylate 16 with ordinary vinyl-
copper reagents or their Lewis acid complexes in THF
at -78 °C yielded only the reduction product 19 as a 50:
50 mixture of diastereomers (Scheme 4 and entries 1 and
2, Table 1). Similarly, the treatment of the mesylate 16
with a vinylcopper reagent, prepared from vinylzincate
and cuprous cyanide, afforded exclusively the reduction
product 19 (entry 3, Table 1). The drawback in these
reactions has been remedied partially by the use of
(24) Ibuka, T.; Nakai, K.; Habashita, H.; Bessho, K.; Fujii, N.;
Chounan, Y.; Yamamoto, Y. Tetrahedron 1993, 49, 9479.

2394 J . Org. Chem., Vol. 63, No. 7, 1998
Ta ble 1. Vin ylcop p er -Med ia ted Rea ction s of γ-(Mesyloxy)-r,â-en oa te 16
Notes
product ratio
19:20:21
combined isolated
entry
reagent
conditionsa
yield, %
1
2
3
4
5
6
(vinyl)2CuMgBr‚Mg(Br)I‚BF3
b
b
c
d
d
e
100:0:0
100:0:0
100:0:0
0:24:27
0:19:81
0:24:76
63
63
92
51
70
98
(vinyl)2Cu(CN)(MgBr)2
(vinyl)3ZnMgBr‚2Mg(Br)Cl‚2LiCl + 0.5CuCN
(vinyl)2Cu(CN)(ZnCl)2‚2Mg(Br)Cl‚4LiCl
(vinyl)2Zn‚2LiCl + 0.5 CuCN
(vinyl)2Cu(CN)(ZnCl)2‚4LiCl
a
b
d
All reactions were carried out in THF under a positive pressure of argon. -78 °C, 2 h. c -78 °C, 3 h. -78 °C, 1 h, and then 0 °C,
5 h. e -78 °C, 0.5 h, and then 0 °C, 5 h.
(2R,3R,4S)-5-(ter t-Bu tyldiph en ylsiloxy)-2,3-epoxy-4-m eth -
yl-1-p en ta n ol (9). To a stirred suspension of diisopropyl
D-tartrate (3.05 g, 13 mmol), Ti(OiPr)4 (2.84 g, 10 mmol), and
4A molecular sieves (500 mg, activated powder) in CH2Cl2 (15
mL) at -20 °C under argon was added 13.3 mL (40 mmol) of a
3.0 M solution of tBuOOH in isooctane, and the whole was stirred
for 30 min at -20 °C. To the above mixture was added allyl
alcohol 8 (3.546 g, 10 mmol) in CH2Cl2 (10 mL) at -20 °C and
the mixture was allowed to stand for 26 h at -20 °C. The
mixture was poured into a cold mixture of FeSO4‚7H2O (16.68
g, 60 mmol), citric acid monohydrate (12.608 g, 60 mmol), and
H2O (120 mL). The mixture was extracted with Et2O, and the
extract was washed with 5% citric acid, 5% NaHCO3, and brine
and dried over MgSO4. Concentration under reduced pressure
gave an oily residue. To a vigorously stirred solution of the
above residue in Et2O (20 mL) at 0 °C was added 30 mL of 30%
NaOH. The mixture was stirred for 1 h at 0 °C and extracted
with Et2O. The extract was washed with H2O and dried over
MgSO4. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica
gel with n-hexane-AcOEt (5:1) to afford the epoxy alcohol 9
Sch em e 4
(3.088 g, 83% yield) as a colorless oil. Kugelrohr distillation,
1
170 °C (1 mmHg); [R]22 +11.4 (c 0.666, CHCl3); H NMR (270
D
MHz, CDCl3) δ 0.99 (d, J ) 6.9 Hz, 3 H), 1.06 (s, 9 H), 1.62-
1.78 (m, 2 H), 3.67 (dd, J ) 9.9, 5.0 Hz, 1 H), 3.72 (dd, J ) 9.9,
5.0 Hz, 1 H), 3.91 (ddd, J ) 12.9, 5.6, 2.3 Hz, 1 H), 7.34-7.46
(m, 6 H), 7.64-7.69 (m, 4 H). Anal. Calcd for C22H30O3Si: C,
71.31; H, 8.16. Found: C, 71.33; H, 8.30.
(3R,2S,4S)-5-(ter t-Bu tyldiph en ylsiloxy)-2,3-epoxy-4-m eth -
yl-[1-(4-m eth ylben zen esu lfon yl)oxy]p en ta n e (10). To a
stirred solution of the epoxy alcohol 9 (371 mg, 1.0 mmol) in
CH2Cl2 (10 mL) at -78 °C were added pyridine (2.24 mL, 33
mmol), 4-(dimethylamino)pyridine (12 mg, 0.10 mmol), and TsCl
(210 mg, 4.4 mmol), and the mixture was stirred for 40 h at room
temperature. To the stirred mixture was added 10 mL of 5%
NaHCO3 at 0 °C. After 1 h, the mixture was extracted with a
mixed solvent of Et2O and CH2Cl2 (4:1). The extract was washed
with 5% citric acid, 5% NaHCO3 and brine and dried over
MgSO4. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica
gel with n-hexane-AcOEt (5:1) to afford the tosylate (387 mg,
copper-catalyzed vinylzinc chloride giving the SN2 and
SN2′ substitution products 20 and 21 in rather low yield
(entry 4, Table 1). Finally, the substrate 16 yielded the
separable substitution products 20 and 21 in acceptable
yields by treatment with either divinylzinc in the pres-
ence of 0.5 equiv of CuCN or “higher order” vinylzinc
cuprate (entries 5 and 6, Table 1). By the use of a reagent
shown in entry 6, the desired anti SN2′ product 21 could
be obtained in 75% isolated yield after flash chromato-
graphic separation from a small amount of the SN2
product 20.
Conversion of 21 into the target bis-tosylate 6 via the
alcohol 22 and the tosylate 23 was achieved in a direct
way. The 1H and 13C NMR spectra of synthesized 6 were
found to be superimposable to the authentic spectra
kindly provided by Professor White.10 Since bis-tosylate
6 has been converted into C34-botryococcene 1 in an
elegant manner by White,10 synthesis of 6 constitutes a
formal synthesis of C34-botryococcene 1.
74% yield) as a colorless oil. [R]25 +11.75 (c 0.511, CHCl3); 1H
D
NMR (270 MHz, CDCl3) δ 0.94 (d, J ) 6.9 Hz, 3 H), 1.04 (s, 9
H), 1.66 (m, 1 H), 2.44 (s, 3 H), 2.84 (dd, J ) 6.6, 2.3 Hz, 1 H),
3.04 (ddd, J ) 6.3, 3.6, 2.3 Hz, 1 H), 3.61 (dd, J ) 10.2, 4.2 Hz,
1 H), 3.66 (dd, J ) 10.2, 4.2 Hz, 1 H), 3.95 (dd, J ) 11.2, 6.3 Hz,
1 H), 4.20 (dd, J ) 11.2, 3.6 Hz, 1 H), 7.59-7.67 (m, 4 H), 7.30-
7.48 (m, 8 H), 7.80 (d, J ) 8.3 Hz, 2 H); LRMS (FAB), m/z, 525
(MH+), 467, 437, 353 (base peak), 333, 293, 269, 239, 197, 165,
135, 97, 91, 75. HRMS (FAB), m/z, calcd for C29H37O5SSi
(MH): 525.2131; found: 525.2113.
In summary, synthesis of the key intermediate 6 for
botryococcene terpenoids has been accomplished starting
from methyl (R)-3-hydroxy-2-methylpropionate (7).
(2S,3S)-1-(ter t-Bu tyld ip h en ylsiloxy)-3-h yd r oxy-2-m eth -
yl-4-p en ten e (11). A mixture of the tosylate 10 (5.16 g, 9.85
mmol), KI (4.90 g, 30 mmol), and DMF (60 mL) was heated at
55 °C under stirring for 1.5 h. The mixture was cooled to 0 °C,
where zinc powder (6.14 g, 98.5 mmol) and NH4Cl (2.63 g, 49.3
mmol) were added with stirring, and the whole was stirred at 0
°C for 30 min. The mixture was diluted with 200 mL of Et2O,
and inorganic precipitates were removed by filtration. The
filtrate was successively washed with 5% citric acid, 5% NaH-
CO3, and water and dried over MgSO4. The usual workup
followed by flash chromatography over silica gel with n-hex-
ane-EtOAc (4:1) gave 3.22 g (92% yield) the title compound
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
positive pressure of argon. All glassware and syringes were
dried in an electric oven at 100 °C prior to use. All melting
points are uncorrected. For flash chromatographies, silica gel
60 H (silica gel for thin-layer chromatography, Merck) or silica
gel 60 (finer than 230 mesh, Merck) was employed.

Notes
J . Org. Chem., Vol. 63, No. 7, 1998 2395
as a colorless oil. Kugelrohr distillation, 140 °C (1 mmHg); [R]22
MHz, CDCl3) δ 0.79 (d, J ) 7.3 Hz, 3 H), 1.07 (s, 9 H), 1.90 (d,
J ) 1.6 Hz, 3 H), 1.83-1.98 (m, 1 H), 3.67 (dd, J ) 10.2, 7.3 Hz,
1 H), 3.73 (d, J ) 3.3 Hz, 1 H), 3.75 (s, 3 H), 3.83 (dd, J ) 10.2,
4.0 Hz, 1H), 4.50 (ddd, J ) 9.2, 7.9, 3.3 Hz, 1 H), 6.72 (dq, J )
9.2, 1.6 Hz, 1 H), 7.37-7.52 (m, 6 H), 7.63-7.72 (m, 4 H); LR-
MS (FAB), m/z, 427 (MH+), 409, 379, 339, 269, 251, 239, 229,
213, 199 (base peak), 197, 165, 153, 135. HR-MS (FAB), m/z,
calcd for C25H35O4Si: 427.2304; found 427.2286. Anal. Calcd
for C25H34O4Si: C, 70.39; H, 8.03. Found: C, 70.12; H, 8.07.
Met h yl (4S,5R,2E)-6-(ter t-Bu t yld ip h en ylsiloxy)-2,5-d i-
m eth yl-4-[(m eth a n esu lfon yl)oxy]-2-h exen oa te (16). To a
stirred solution of alcohol 15 (1.0 g, 2.34 mmol) in CH2Cl2 (30
mL) were added pyridine (1.90 mL, 23.44 mmol), 4-(dimethyl-
amino)pyridine (29 mg, 0.23 mmol), and methanesulfonyl chlo-
ride (0.90 mL, 11.72 mmol) at -78 °C, and the mixture was
stirred for 24 h at 0 °C. To the stirred mixture was added 10
mL of 5% NaHCO3 at 0 °C, and the whole was stirred for 30
min. The mixture was extracted with Et2O, and the extract was
washed with 5% citric acid, 5% NaHCO3, and H2O and dried
over MgSO4. Concentration under reduced pressure followed
by recrystallization from cold hexane-Et2O (3:1) gave 1.01 g
(86% yield) of the title compound 16 as colorless crystals. Mp
D
-21.2 (c 0.179, CHCl3); de ) >98% (Mosher’s ester); 1H NMR
(270 MHz, CDCl3) δ 0.85 (d, J ) 7.0 Hz, 3 H), 1.06 (s, 9 H), 1.84
(m, 1 H), 3.62 (m, 2 H), 3.80 (dd, J ) 10.2, 4.3 Hz, 1 H), 4.10 (m,
1H), 5.17 (ddd, J ) 10.2, 2.0, 1.3 Hz, 1 H), 5.30 (ddd, J ) 16.8,
1.7, 1.3 Hz, 1 H), 5.87 (ddd, J ) 16.8, 10.2, 6.3 Hz, 1 H), 7.36-
7.48 (m, 6 H), 7.66-7.70 (m, 4 H). Anal. Calcd for C22H30O2Si:
C, 74.53; H, 8.53. Found: C, 74.81; H, 8.75.
(2S,3S)-3-Acetoxy-1-(ter t-bu tyld ip h en ylsiloxy)-2-m eth yl-
4-p en ten e (12). To a stirred solution of the alcohol 11 (266 mg,
0.75 mmol) in CH2Cl2 (10 mL) were added pyridine (0.36 mL,
4.5 mmol), 4-(dimethylamino)pyridine (9 mg, 0.08 mmol), and
acetic anhydride (0.17 mL, 2.25 mmol) at 0 °C, and the mixture
was stirred for 2 h at room temperature. To the stirred mixture
was added 10 mL of 5% NaHCO3 at 0 °C. After 30 min, the
mixture was extracted with Et2O, and the extract was washed
with 5% citric acid, 5% NaHCO3, and brine and dried over
MgSO4. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica
gel with n-hexane-AcOEt (20:1) to afford the acetate 12 (294
mg, 99% yield) as a colorless oil. Kugelrohr distillation, 150 °C
(1 mmHg); [R]22 -6.17 (c 0.486, CHCl3); 1H NMR (200 MHz,
D
CDCl3) δ 0.94 (d, J ) 6.9 Hz, 3 H), 1.05 (s, 9 H), 1.99 (s, 3 H),
2.06-1.94 (m, 1 H), 3.57 (d, J ) 5.6 Hz, 2 H), 5.20 (ddd, J )
10.2, 1.7, 1.0 Hz, 1 H), 5.25 (ddd, J ) 17.2, 1.7, 1.0 Hz, 1 H),
5.35 (dd, J ) 6.9, 6.9 Hz, 1 H), 5.73 (ddd, J ) 17.2, 10.2, 6.6 Hz,
1 H), 7.33-7.48 (m, 6 H), 7.59-7.70 (m, 4 H). Anal. Calcd for
C24H32O3Si: C, 72.68; H, 8.13. Found: C, 72.52; H, 8.01.
(2S,3S)-1-(ter t-Bu tyldiph en ylsiloxy)-3-[(m eth an esu lfon yl)-
oxy]-2-m eth yl-4-p en ten e (13). To a stirred solution of the
alcohol 11 (20 mg, 0.0565 mmol) in THF (0.5 mL) were added
pyridine (0.1 mL) and methanesulfonyl chloride (0.02 mL) at
-78 °C, and the mixture was stirred for 3 h at room temperature.
To the above mixture was added 10 mL of 5% NaHCO3 at 0 °C.
After 30 min, the mixture was extracted with Et2O-AcOEt (4:
1), and the extract was washed with 5% citric acid, 5% NaHCO3,
and brine and dried over MgSO4. Concentration under reduced
pressure gave the title compound 13 (24 mg, 98%) as a rather
87-88 °C; [R]20 -6.15 (c 0.156, CHCl3); 1H NMR (270 MHz,
D
CDCl3) δ 0.91 (d, J ) 7.0 Hz, 3 H), 1.07 (s, 9 H), 2.00 (d, J ) 1.3
Hz, 3 H), 2.11 (m, 1 H), 2.88 (s, 3 H), 3.52 (dd, J ) 10.5, 5.9 Hz,
1 H), 3.69 (dd, J ) 10.5, 4.6 Hz, 1 H), 3.77 (s, 3 H), 5.63 (dd, J
) 9.7, 6.5 Hz, 1 H), 6.68 (dd, J ) 9.7, 1.4 Hz, 1 H), 7.26-7.44
(m, 6 H), 7.61-7.69 (m, 4 H). Anal. Calcd for C26H36O6SSi: C,
61.88; H, 7.19. Found: C, 61.60; H, 7.29.
Meth yl (5S,3E)-6-(ter t-Bu tyldiph en ylsiloxy)-2,5-dim eth yl-
3-h exen oa te (19). To a stirred suspension of CuCN (105 mg,
1.17 mmol) in dry THF (15 mL) at -78 °C under argon was
added a 1.0 M THF solution of vinylmagnesium bromide (2.34
mL, 2.34 mmol). After 10 min, to the stirred mixture was added
the mesylate 16 (148 mg, 0.293 mmol) in dry THF (2 mL) at
-78 °C, and the mixture was stirred for 30 min at -78 °C. The
reaction was quenched with a 1:1 mixed solution of sat. NH4Cl
(2 mL) and 28% NH4OH (2 mL) at -78 °C. The mixture was
extracted with Et2O, and the extract was washed with H2O and
dried over MgSO4. Concentration under reduced pressure gave
an oily residue, which was purified by flash chromatography over
silica gel. Elution with n-hexane-AcOEt (20:1) gave 76 mg (63%
labile oil. [R]23 -5.58 (c 0.203, CHCl3); 1H NMR (270 MHz,
D
CDCl3) δ 0.91 (d, J ) 7.0 Hz, 3 H), 0.89 (s, 9 H), 2.15 (m, 1 H),
2.95 (s, 3 H), 3.54 (dd, J ) 10.0, 6.5 Hz, 1 H), 3.64 (dd, J ) 10.0,
5.1 Hz, 1 H), 5.25 (dd, J ) 7.5, 6.5 Hz, 1 H), 5.35-5.46 (m, 3 H),
5.85 (ddd, J ) 18.0, 10.5, 8.4 Hz, 1 H), 7.3-7.5 (m, 6 H), 7.6-
7.7 (m, 4 H). Due to its instability, the mesylate 13 was used
directly for the next step.
yield) of the â,γ-unsaturated ester 19 as a colorless oil. [R]30
D
-4.1 (c 0.13, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.02 (d, J )
6.9 Hz, 3 H), 1.04 (s, 9 H), 1.23 (d, J ) 6.9 Hz, 3 H), 2.35 (m, 1
H), 3.10 (m, 1 H), 3.50 (m, 2 H), 3.65 (s, 1.5 H), 3.66 (s, 1.5 H),
5.44-5.59 (m, 2 H), 7.25-7.45 (m, 6 H), 7.63-7.24 (m, 4 H).
LRMS (FAB) m/z, 411 (MH+), 409, 353, 333, 243, 213 (base
peak), 199, 135, 95. HRMS (FAB) m/z, calcd for C25H35O3Si
(MH+) 411.2355; found: 411.2362.
Meth yl (4S,5R,2E)-4-Acetoxy-6-(ter t-bu tyldiph en ylsiloxy)-
2,5-d im eth yl-2-h exen oa te (14). Ozone was bubbled through
a solution of the vinyl acetate 12 (3.0 g, 8.47 mmol) in 20 mL of
n-hexane-CHCl3 (1:1) at -78 °C until a blue color persisted.
Zinc powder (1 g, 16 mmol) was added to the mixture, and the
mixture was stirred for 30 min during which time it was allowed
to warm to 0 °C. To the mixture at 0 °C was added [(methoxy-
carbonyl)ethylidene]triphenylphosphorane (19 g, 54.4 mmol),
and the mixture was stirred for 18 h. The mixture was
concentrated under reduced pressure to leave a semisolid, which
was purified by flash chromatography over silica gel eluting with
n-hexane-EtOAc (5:1) to give the enoate 14 (2.83 g, 80% yield).
Met h yl (4S,5S,2E)-6-(ter t-Bu t yld ip h en ylsiloxy)-2,5-d i-
m eth yl-4-eth en yl-2-h exen oa te (20) a n d Meth yl (2S,5S,3E)-
6-(ter t-Bu tyld ip h en ylsiloxy)-2,5-d im eth yl-2-eth en yl-3-h ex-
en oa te (21). To a stirred solution of LiCl (81 mg, 9.36 mmol)
in dry THF (15 mL) at -78 °C under argon were successively
added a 1.0 M ethereal solution of ZnCl2 (9.35 mL, 9.36 mmol),
a 0.6 M THF solution of vinyllithium (15.6 mL, 9.36 mmol), and
CuCN (419 mg, 4.68 mmol). After 10 min, to the stirred mixture
was added the mesylate 16 (1.18 g, 2.34 mmol) in dry THF (10
mL) at -78 °C, and the mixture was stirred for 30 min at -78
°C and for 5 h at 0 °C. The reaction was quenched with a 1:1
mixed solution of sat. NH4Cl (20 mL) and 28% NH4OH (20 mL)
at -78 °C. The mixture was extracted with Et2O, and the
extract was washed with H2O and dried over MgSO4. Concen-
tration under reduced pressure gave an oily residue, which was
purified by flash chromatography over silica gel. Elution with
n-hexane-AcOEt (20:1) gave 775 mg (75% yield) of the â,γ-
unsaturated ester 21 as a colorless oil and further elution
afforded 243 mg (23% yield) of the R,â-unsaturated ester 20 as
mp 90 °C (colorless crystals from n-hexane:Et2O ) 3:1); [R]16
D
-22.1 (c 0.797, CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.94 (d, J
) 6.8 Hz, 3 H), 1.05 (s, 9 H), 1.95 (s, 3 H), 1.99 (d, J ) 1.4 Hz,
3 H), 3.55 (dd, J ) 10.0, 5.4 Hz, 1 H), 3.62 (dd, J ) 10.0, 5.1 Hz,
1 H), 3.74 (s, 3 H), 5.64 (dd, J ) 9.5, 7.6 Hz, 1 H), 6.53 (dd, J )
9.5, 1.4 Hz, 1 H), 7.25-7.46 (m, 6 H), 7.62-7.66 (m, 4 H). Anal.
Calcd for C27H36O5Si: C, 69.20; H, 7.74. Found: C, 68.98; H,
7.77.
Met h yl (4S,5R,2E)-6-(ter t-Bu t yld ip h en ylsiloxy)-2,5-d i-
m eth yl-4-h yd r oxy-2-h exen oa te (15). A mixture of the acetate
14 (1.0 g, 2.14 mmol), powdered Na2CO3 (900 mg, 8.56 mmol),
and MeOH (60 mL) was stirred at room temperature for 8 h.
The inorganic precipitates were removed by filtration. The
filtrate was concentrated under reduced pressure to leave an
oily residue. Water (10 mL) was added to the residue, and the
whole was extracted with EtOAc-Et2O (2:1). The extract was
washed with water and dried over MgSO4. Usual workup
followed by flash chromatography over silica gel with n-hex-
ane-EtOAc (1:4) gave 756 mg (83% yield) of the title compound
15 as a colorless oil. [R]16D -37.8 (c 0.880, CHCl3); 1H NMR (270
a colorless oil. 20: [R]24 -33.1 (c 0.324, CHCl3); 1H NMR (270
D
MHz, CDCl3) δ 0.92 (d, J ) 6.9 Hz, 3 H), 1.05 (s, 9 H), 1.76 (m,
1 H), 1.85 (d, J ) 1.7 Hz, 3 H), 3.29 (m, 1 H), 3.49 (dd, J ) 9.9,
5.6 Hz, 1 H), 3.52 (dd, J ) 9.9, 5.9 Hz, 1 H), 3.73 (s, 3 H), 5.03
(d, J ) 16.2 Hz, 1 H), 5.04 (d, J ) 10.3 Hz, 1 H), 5.66 (ddd, J )
16.2, 11.2, 8.2 Hz, 1 H), 6.74 (dd, J ) 10.3, 1.7 Hz, 1 H), 7.32-
7.45 (m, 6 H), 7.60-7.67 (m, 4 H); LR-MS (FAB), m/z, 437 (MH+),
435, 405, 379, 359, 213 (base peak), 199, 183, 135. HR-MS

2396 J . Org. Chem., Vol. 63, No. 7, 1998
Notes
(FAB), m/z, calcd for C27H37O3Si: 437.2512; found: 437.2537.
Anal. Calcd for C27H36O3Si: C, 74.27; H, 8.31. Found: C, 74.13;
7.25-7.45 (m, 8 H), 7.75 (m, 2 H); LR-MS (FAB), m/z, 563 (MH+),
561, 505, 391, 353, 333, 293, 269, 239, 197, 165, 135 (base peak),
93, 91, 55, 41. HR-MS, m/z calcd for C33H43O4SiS: 563.2651;
found: 563.2654.
H, 8.26. 21: Kugelrohr distillation, 150 °C (1 mmHg); [R]20
D
-1.57 (c 0.510, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.02 (d, J
) 6.9 Hz, 3 H), 1.04 (s, 9 H), 1.39 (s, 3 H), 2.42 (m, 1 H), 3.51
(m, 2 H), 3.66 (s, 3 H), 5.10 (dd, J ) 17.5, 0.7 Hz, 1 H), 5.12 (dd,
J ) 10.9, 1.0 Hz, 1 H), 5.51 (dd, J ) 15.8, 6.9 Hz, 1 H), 5.70 (dd,
J ) 15.8, 1.0 Hz, 1 H), 6.06 (dd, J ) 17.5, 10.9 Hz, 1 H), 7.33-
7.47 (m, 6 H), 7.64-7.67 (m, 4 H). Anal. Calcd for C27H36O3Si:
C, 74.27; H, 8.31. Found: C, 74.19; H, 8.53.
(2S,5S,3E)-1,6-Bis[(4-m et h ylb en zen esu lfon yl)oxy]-2,5-
d im eth yl-2-eth en yl-3-h exen e (6). To a stirred solution of the
silyl ether 23 (93 mg, 0.17 mmol) in THF (3 mL) were added
0.18 mL (0.18 mmol) of a 1.0 M THF solution of tetrabutylam-
monium fluoride at 0 °C, and the mixture was stirred for 7 h at
room temperature. To the mixture was added 10 mL of H2O,
and the mixture was extracted with CHCl3. The extract was
washed with water and dried over MgSO4. Concentration under
reduced pressure gave an oily residue, which was dissolved in 4
mL of CH2Cl2. To a stirred CH2Cl2 solution were added pyridine
(0.50 mL, 6.18 mmol), 4-(dimethylamino)pyridine (10 mg, 0.08
mmol), and 4-methylbenzenesulfonyl chloride (157 mg, 0.83
mmol) at 0 °C. After 14 h, to the stirred mixture was added 5
mL of 5% NaHCO3 at 0 °C, and the whole was stirred for 1 h.
The mixture was extracted with Et2O-CH2Cl2 (1:4), and the
extract was washed with 5% citric acid, 5% NaHCO3, and H2O
and dried over MgSO4. Concentration under reduced pressure
gave an oily residue, which was purified by flash chromatogra-
phy over silica gel with n-hexane-AcOEt (2:1) to give the title
(2S,5S,3E)-6-(ter t-Bu tyld ip h en ylsiloxy)-2,5-d im eth yl-2-
eth en yl-3-h exen -1-ol (22). To a stirred solution of the ester
21 (655 mg, 1.5 mmol) in CH2Cl2 (15 mL) at -78 °C under argon
was added a 1.02 M solution of DIBAL in toluene (3.09 mL, 3.15
mmol), and the mixture was stirred for 30 min at -78 °C. The
mixture was poured into a cold solution of saturated NH4Cl (10
mL) at 0 °C. The mixture was made acidic with 30 mL of
saturated citric acid and extracted with Et2O-CH2Cl2 (4:1). The
extract was washed with 5% NaHCO3 and water and dried over
MgSO4. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica
gel with n-hexane-AcOEt (15:1) to give the alcohol 22 (505 mg,
82% yield) as a colorless oil. Kugelrohr distillation, 150 °C (1
mmHg); [R]20 -6.95 (c 1.09, CHCl3); IR (CHCl3) 3600, 3060,
compound 6 (69 mg, 87% yield) as a colorless oil: [R]20 +5.94
D
D
1
2960, 2930, 2850, 1460, 1415, 1380, 1360, 1105, 1025, 980, 920,
(c 1.310, CHCl3); H NMR (300 MHz, CDCl3) δ 0.95 (d, J ) 6.8
800, 610 cm-1
;
1H NMR (270 MHz, CDCl3) δ 1.00 (d, J ) 6.9
Hz, 3 H), 1.06 (s, 3 H), 2.45 (s, 6 H), 2.46 (m, 1 H), 3.77 (s, 2 H),
3.78 (dd, J ) 9.5, 6.7 Hz, 1 H), 3.84 (dd, J ) 9.4, 6.4 Hz, 1 H),
4.97 (dd, J ) 17.5, 0.9 Hz, 1 H), 5.06 (dd, J ) 10.7, 0.9 Hz, 1 H),
5.21 (dd, J ) 15.9, 7.0 Hz, 1 H), 5.34 (dd, J ) 15.9, 0.8 Hz, 1 H),
5.64 (dd, J ) 17.5, 10.8 Hz, 1 H), 7.35 (m, 4 H), 7.76 (m, 4 H);
13C NMR (75 MHz, CDCl3) δ 16.52, 21.18, 21.65, 36.35, 42.81,
73.97, 75.63, 114.96, 127.89, 129.86, 130.78, 132.95, 133.16,
134.10, 140.63, 144.81. The 1H and 13C NMR spectra were found
to be identical with those of authentic spectra of Professor White.
Hz, 3 H), 1.05 (s, 9 H), 1.12 (s, 3 H), 1.37 (t, J ) 6.6 Hz, 1 H),
2.40 (m, 1 H), 3.39 (m, 2 H), 3.50 (m, 2 H), 5.09 (dd, J ) 17.5,
1.3 Hz, 1 H), 5.13 (dd, J ) 10.9, 1.3 Hz, 1 H), 5.42 (d, J ) 16.2
Hz, 1 H), 5.49 (dd, J ) 16.2, 5.6 Hz, 1 H), 5.81 (dd, J ) 17.5,
10.9 Hz, 1 H), 7.33-7.46 (m, 6 H), 7.63-7.72 (m, 4 H). Anal.
Calcd for C26H36O2Si: C, 76.42; H, 8.88. Found: C, 76.12; H,
9.08.
(2S,5S,3E)-6-(ter t-Bu tyld ip h en ylsiloxy)-2,5-d im eth yl-2-
eth en yl-1-[(4-m eth ylben zen esu lfon yl)oxy]-3-h exen e (23).
To a stirred solution of the alcohol 22 (347 mg, 0.85 mmol) in
CH2Cl2 (5 mL) were added pyridine (0.96 mL, 11.87 mmol),
4-(dimethylamino)pyridine (30 mg, 0.25 mmol), and 4-methyl-
benzenesulfonyl chloride (1.06 g, 5.54 mmol) at -78 °C, and the
mixture was stirred for 16 h at room temperature. The reaction
was quenched with 5% NaHCO3 (30 mL) at 0 °C, and the whole
was stirred for 1 h at room temperature. The mixture was
extracted with Et2O, and the extract was washed with 5% citric
acid, 5% NaHCO3, and H2O and dried over MgSO4. Concentra-
tion under reduced pressure gave an oily residue, which was
purified by flash chromatography over silica gel with n-hexane-
AcOEt (15:1) to give 464 mg (97% yield) of the title compound
23 as a colorless oil. [R]20D -3.12 (c 0.961, CHCl3);1H NMR (270
MHz, CDCl3) δ 0.96 (d, J ) 6.6 Hz, 3 H), 1.02 (s, 9 H), 1.10 (s,
3 H), 2.33 (m, 1 H), 2.42 (s, 3 H), 3.44 (dd, J ) 9.9, 6.3 Hz, 1 H),
3.47 (dd, J ) 9.9, 6.3 Hz, 1 H), 3.78 (d, J ) 9.2 Hz, 1 H), 3.81 (d,
J ) 9.2 Hz, 1 H), 4.99 (dd, J ) 17.5, 1.0 Hz, 1 H), 5.05 (dd, J )
10.9, 1.0 Hz, 1 H), 5.30 (d, J ) 15.8 Hz, 1 H), 5.41 (dd, J ) 15.8,
6.6 Hz, 1 H), 5.70 (dd, J ) 17.5, 10.9 Hz, 1 H), 7.63 (m, 4 H),
Ack n ow led gm en t. We thank Professor J . D. White,
Oregon State University, for providing us with the
1
authentic H and 13C NMR spectra of 9. The authors
thank Dr. N. Hamanaka and Mr. T. Inohara, Ono
Pharmaceutical Co., Ltd., for determining the X-ray
crystal structure of compound 14. Financial support
from a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture,
J apan, is gratefully acknowledged.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of compounds 6, 10, 13, 19, 20, and 23 and 13C NMR
spectrum of 6 (7 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; see
any current masthead page for ordering information.
J O9721397