Efficient and practical method for synthesizing optically active indan-2-ols by the Ti(O-i-Pr)4/2 i-PrMgCl-mediated metalative Reppe reaction

Article abstract of DOI:10.1021/jo034391m

An efficient and practical synthesis of optically active indan-2-ols 1 has been developed starting from readily accessible optically active 4-siloxy-1,6-alkadiynes 2 and ethynylp-tolyl sulfone, where the metalative Reppe reaction mediated by an economical divalent titanium reagent, Ti-(O-i-Pr)₄/2 i-PrMgCl, is a key step.

Full text of DOI:10.1021/jo034391m

SCHEME 1. P r ep a r a tion of 4,7-Disu bstitu ted
In d a n -2-ols via th e Meta la tive Rep p e Rea ction
Efficien t a n d P r a ctica l Meth od for
Syn th esizin g Op tica lly Active In d a n -2-ols
by th e Ti(O-i-P r )4/2 i-P r MgCl-Med ia ted
Meta la tive Rep p e Rea ction
Takeshi Hanazawa, Kousuke Sasaki,
Yuuki Takayama, and Fumie Sato*
Graduate School of Bioscience and Biotechnology,
Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama, Kanagawa 226-8501, J apan
fsato@bio.titech.ac.jp
SCHEME 2. P r ep a r a tion of 2 Sta r tin g fr om 3
Received March 26, 2003
Abstr a ct: An efficient and practical synthesis of optically
active indan-2-ols 1 has been developed starting from readily
accessible optically active 4-siloxy-1,6-alkadiynes 2 and
ethynyl p-tolyl sulfone, where the metalative Reppe reaction
mediated by an economical divalent titanium reagent, Ti-
(O-i-Pr)4/2 i-PrMgCl, is a key step.
The indan-2-ol skeleton exists in a number of organic
compounds and, thus, the construction of its structure
is important.1 However, its asymmetric synthesis is not
necessarily an easy process. The synthetic difficulty
becomes more and more marked with an increase in the
number of substituents on the aromatic ring, and as far
as we know, no general synthetic method is available for
preparing optically active indan-2-ols having two aro-
matic substituents.
Recently, we have reported a metalative Reppe reac-
tion mediated by an economical divalent titanium re-
agent, Ti(O-i-Pr)4/2 i-PrMgX, which realizes the direct
preparation of aryltitanium compounds from two acety-
lenes and ethynyl p-tolyl sulfone.2,3 We anticipated that
this reaction might allow the preparation of optically
active 4,7-disubstituted indan-2-ols of the type 1 from
optically active 4-siloxy-1,6-alkadiynes 2 and ethynyl
p-tolyl sulfone, as shown in Scheme 1.
and the following treatment of the resulting epoxide ring-
opening product with NaOH in CH2Cl2 afforded 4. The
compound 4 was then converted into 2 by the treatment
of R2-CtC-Li in the presence of BF3‚Et2O and the
silylation with TBSCl/imidazole.
The metalative Reppe reaction starting with 2 readily
proceeded as we expected to provide 1 after hydrolysis.
As can be seen from Table 1, which summarizes the
results of the reaction, a variety of 1 having two aromatic
substituents at the C-4 and C-7 positions can be prepared
in high isolated yields.
As both enantiomers of 3 with more than 99% enan-
tiometric excess (ee) are commercially available at low
price and in bulk, it can be said that an efficient and
practical method for preparing optically active 1 has now
been opened up. And we actually prepared several
optically active compounds 1, including one that was
utilized for the synthesis of biologically active compounds.
The reaction allows the preparation of both enanti-
omers of 1 starting from a single enantiomer of 3 by
changing the order of the two acetylenes that are reacted
with 3 in Scheme 2, as exemplified by the preparation of
both enantiomers of 1d (Scheme 3).
First, we investigated the feasibility of the transforma-
tion depicted in Scheme 1 by starting with racemic 2.
The starting 2 can be readily prepared from racemic
epichlorohydrin (3) according to the conventional reaction
sequence shown in Scheme 2. Thus, the reaction of 3 with
R1-CtC-Li in the presence of BF3‚Et2O4 and/or Et2AlCl5
The synthesis of optically active (S)-4-phenyl-indan-
2-ol [(S)-5] has attracted much interest because it can
be used as the alcohol moiety of (S)-4-phenyl-2-indanyl
(Z)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcy-
clopropanecarboxylate (6), a highly effective pyrethroid
derivative (Figure 1).6 However, the reported synthesis
of (S)-5 was not so efficient; the synthetic method
required multistep transformation and involved an op-
eration for refinement of enantiomeric purity by recrys-
* Author to whom correspondence should be addressed. Phone: +81-
45-924-5787. Fax: +81-45-924-5826.
(1) Ghosh, A. K.; Fidanze, S.; Senanayake, C. H. Synthesis 1998,
937.
(2) Suzuki, D.; Urabe, H.; Sato, F. J . Am. Chem. Soc. 2001, 123,
7925. See also: Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J . Am.
Chem. Soc. 2002, 124, 3518. Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe,
H.; Sato, F. J . Am. Chem. Soc. 2002, 124, 9682.
(3) Review for synthetic reactions mediated by a Ti(O-i-Pr)4/2 i-
PrMgCl reagent: Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000,
100, 2835. Sato, F.; Okamoto, S. Adv. Synth. Catal. 2001, 343, 759.
Sato, F.; Urabe, H. In Titanium and Zirconium in Organic Synthesis;
Marek, I., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 319-354.
(4) Yamaguchi, M.; Hirano, I. Tetrahedron Lett. 1983, 24, 391.
(5) Fried, J .; Lin, C.-H.; Ford, S. H. Tetrahedron Lett. 1969, 10, 1379.
Fried, J .; Sih, J . C.; Lin, C. H.; Dalven, P. J . Am. Chem. Soc. 1972, 94,
4343.
(6) Engel, J . F.; Staetz, C. A.; Young, S. T.; Crosby, G. A. Spec.
Publ.sR. Soc. Chem. 1985, 53, 162. Engel, J . F. U. S. Patent 4,429,-
149, 1984. For synthesis and biological activities of antificial pyethroid,
see: Scott, J . G.; Georghiou, G. P. Pestic. Sci. 1986, 17, 195.
10.1021/jo034391m CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/10/2003
4980
J . Org. Chem. 2003, 68, 4980-4983

SCHEME 3. P r ep a r a tion of Both En a n tiom er s of 1 Sta r tin g fr om a Sin gle En a n tiom er of 3a
a
Reaction conditions: (a) PhCtCH, n-BuLi, BF3‚Et2O, THF. (b) NaOH, CH2Cl2. (c) H13C6CtCH, n-BuLi, BF3‚Et2O, THF. (d) TBSCl,
imidazole, DMF. (e) Ti(O-i-Pr)4/2 i-PrMgCl, Et2O, then TolSO2CtCH.
SCHEME 5. Th e Syn th esis of Op tica lly Active
Ter p h en yl Der iva tives
F IGURE 1. A highly effective pyrethroid derivative.
TABLE 1. Syn th esis of a Va r iety of 1 by th e Meta la tive
Rep p e Rea ction
substrate
yield (%)
a : R1 ) TMS; R2 ) n-C6H13
b: R1 ) TMS; R2 ) Ph
76
82
86
63
88
75
c: R1 ) TMS; R2 ) O-c-C6H11
d : R1 ) Ph; R2 ) n-C6H13
e: R1 ) Ph; R2 ) O-c-C6H11
f: R1 ) n-C6H13; R2 ) n-C4H9
Terphenyl derivatives have attracted much interest in
recent years in the field of material10 and medicinal
sciences.11 The preparation of optically active terphenyl
derivatives, however, has been scarcely reported. The
present method can allow access to optically active
terphenyl derivatives as exemplified by the synthesis of
8 shown in Scheme 5. The easy and practical method for
synthesizing optically active terphenyl compounds de-
veloped here might find utility in the field of the sciences
mentioned above.
SCHEME 4. Th e Efficien t Syn th esis of th e Alcoh ol
Moiety of a P yr eth r oid Der iva tive
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Ti(II)-Med ia ted Meta la tive
Rep p e Rea ction . As a typical example, the synthesis of (R)-
1d is described as follows.
(R)-2-[(ter t-Bu t yl)d im et h ylsiloxy]-4-h exyl-7-p h en ylin -
d a n ((R)-1d , Sch em e 3). The titled compound was prepared
according to the literature.2 To a stirred solution of (R)-2d (0.191
(8) The metalative Reepe reaction of (R)-2b after protodesilylation
did not proceed efficiently.
(9) See Supporting Information.
tallization and tedious separation of byproduct(s) by
column chromatography or recrystallization. As shown
in Scheme 4, (S)-5 can be readily synthesized by treat-
ment of optically active (R)-1b with KI-TMSCl-H2O7 in
94% yield.8 The enantiomeric excess of (S)-5 thus ob-
tained was confirmed to be >99% ee by HPLC analysis.9
(10) Chaumeil, H.; Drian, C. L.; Defoin, A. Synthesis 2002, 757 and
references therein. Kiupel, B.; Niederalt, C.; Nieger, M.; Grimme, S.;
Vo¨gtle, F. Angew. Chem., Int. Ed. 1998, 37, 3031.
(11) Kutzki, O.; Park, H. S.; Ernst, J . T.; Orner, B. P.; Yin, H.;
Hamilton, A. D. J . Am. Chem. Soc. 2002, 124, 11838. Ernst, J . T.;
Kutzki, O.; Debnath, A. K.; J iang, S.; Lu, H.; Hamilton, A. D. Angew.
Chem., Int. Ed. 2002, 41, 278. Orner, B. P.; Ernst, J . T.; Hamilton, A.
D. J . Am. Chem. Soc. 2001, 123, 5382.
(7) Radner, F.; Wistrand, L.-G. Tetrahedron Lett. 1995, 36, 5093.
J . Org. Chem, Vol. 68, No. 12, 2003 4981

g, 0.500 mmol) and Ti(O-i-Pr)4 (0.177 mL, 0.600 mmol) in 2.50
mL of Et2O was added i-PrMgCl (0.706 mL, 1.77 M in Et2O,
1.25 mmol) at -78 °C under argon to give a yellow homogeneous
solution. The solution was warmed to -50 °C over 30 min, during
which period its color turned dark yellow. After the solution was
stirred at -50 °C for an additional 4 h, ethynyl p-tolyl sulfone
(0.180 g, 1.00 mmol) was added and the reaction mixture was
subsequently allowed to warm to 0 °C. After being stirred for 3
h at this temperature, the reaction was terminated by the
addition of H2O (0.090 mL) and stirred for 10 min. After the
addition of NaF (0.210 g) and Celite (0.200 g), the mixture was
stirred for 10 min and filtered through a pad of Celite with Et2O.
The filterate was concentrated and chromatographed on silica
gel (hexanes-Et2O) to give (R)-1d (0.129 g, 63%) as a colorless
the same temperature. After addition of saturated aqueous NH4-
Cl (20 mL), the mixture was extracted with Et2O (3 × 20 mL).
The combined organic layers were dried over MgSO4, concen-
trated, passed through a short silica gel column with 5% ether
in hexane for removing nonpolar products such as ethynylben-
zene, and then concentrated to provide a crude oil.
To a solution of the crude oil in CH2Cl2 (16.7 mL) was slowly
added NaOH (0.400 g, 10.0 mmol) at room temperature. The
mixture was stirred for 2 days. After addition of saturated
aqueous NH4Cl (20 mL), the mixture was extracted with CH2-
Cl2 (3 × 20 mL). The combined organic layers were dried over
MgSO4, concentrated, and chromatographed on silica gel (hex-
anes-Et2O) to give (S)-4a (0.623 g, 78%) as a colorless oil. 1H
NMR δ 7.39-7.45 (m, 2H), 7.27-7.32 (m, 3H), 3.15-3.21 (m,
1H), 2.80-2.88 (m, 2H), 2.64-2.74 (m, 2H); 13C NMR δ 131.4,
128.0, 127.8, 123.0, 84.0, 82.5, 49.9, 46.4, 23.1; IR (neat) 3060,
1
oil. H NMR δ 7.31-7.49 (m, 5H), 7.19 (d, J ) 7.8 Hz, 1H), 7.10
(d, J ) 7.8, 1H), 4.61-4.70 (m, 1H), 3.21 (dd, J ) 2.7, 6.9 Hz,
1H), 3.15 (dd, J ) 3.0, 6.9 Hz, 1H), 3.03 (dd, J ) 6.3, 15.9 Hz,
1H), 2.91 (dd, J ) 6.6, 15.9 Hz, 1H), 2.62 (dd, J ) 6.6, 8.4 Hz,
2H), 1.57-1.70 (m, 2H), 1.24-1.47 (m, 6H), 0.87-0.98 (m, 3H),
0.93 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR δ 141.2, 139.8,
138.4, 137.6, 135.6, 128.4, 128.1, 127.1, 126.9, 126.5, 73.8, 42.5,
41.0, 33.5, 31.9, 30.3, 29.4, 26.0, 22.7, 18.3, 14.2, -4.55, -4.60;
IR (neat) 3057, 3027, 2928, 1472, 1363, 1254, 1097, 896, 836,
2996, 1598, 1490, 1442, 1406, 1071, 959, 926, 840, 756 cm-1
;
[R]29 +32.4 (c 4.37, CHCl3).
D
(R)-4-[(ter t-Bu t yl)d im et h ylsiloxy]-1-p h en yl-1,6-t r id ec-
a d iyn e ((R)-2d , Sch em e 3). To a stirred solution of 1-octyne
(0.885 mL, 6.00 mmol) in THF (9.0 mL) was slowly added n-BuLi
(3.79 mL, 1.58 M in hexane, 6.00 mmol) at -78 °C and the
mixture was stirred for 1 h at this temperature. Then, to the
mixture was added boron trifluoride etherate (0.760 mL, 6.00
mmol). After the mixture was stirred for 1 h at -78 °C, a solution
of (S)-4a (0.475 g, 3.00 mmol) in THF (4.0 mL) was added. The
reaction mixture was stirred for 1 h at the same temperature
and warmed to room temperature over 30 min. After addition
of saturated aqueous NH4Cl (20 mL), the mixture was extracted
with Et2O (3 × 20 mL). The combined organic layers were dried
over MgSO4, concentrated, passed through a short silica gel
column with 5% ether in hexane for removing nonpolar products
such as 1-octyne, and then concentrated to provide a crude oil.
775, 700 cm-1; [R]29 -15.5 (c 6.69, CHCl3). Anal. Calcd for
D
C
27H40OSi: C, 79.35; H, 9.87. Found: C, 79.67; H, 9.79.
(S)-2-[(ter t-Bu t yl)d im et h ylsiloxy]-4-h exyl-7-p h en ylin -
d a n ((S)-1d , Sch em e 3). (S)-1d (0.123 g, 60%) was obtained
starting from (S)-2d (0.191 g, 0.500 mmol), Ti(O-i-Pr)4 (0.177
mL, 0.600 mmol), i-PrMgCl (1.88 M in Et2O, 0.670 mL, 1.26
mmol), and ethynyl p-tolyl sulfone (0.180 g, 1.00 mmol) under
similar reaction conditions as described for the synthesis of (R)-
1d . The spectral data (1H NMR, 13C NMR, IR) have been
described. [R]27 +14.9 (c 0.914, CHCl3).
D
(R)-2-[(ter t-Bu t yl)d im et h ylsiloxy]-4-p h en yl-7-(t r im et h -
ylsilyl)in d a n ((R)-1b, Sch em e 4). (R)-1b (0.163 g, 82%) was
obtained starting from (R)-2b (0.185 g, 0.500 mmol), Ti(O-i-Pr)4
(0.177 mL, 0.600 mmol), i-PrMgCl (1.88 M in Et2O, 0.670 mL,
1.26 mmol), and ethynyl p-tolyl sulfone (0.180 g, 1.00 mmol)
under similar reaction conditions as described for the synthesis
of (R)-1d . 1H NMR δ 7.35-7.52 (m, 6H), 7.24 (d, J ) 7.8 Hz,
1H), 4.57-4.70 (m, 1H), 3.28 (dd, J ) 6.9, 15.3 Hz, 1H), 3.16
(dd, J ) 6.6, 15.9 Hz, 1H), 3.05 (dd, J ) 6.6, 15.3 Hz, 1H), 3.00
(dd, J ) 6.0 Hz, 15.9 Hz, 1H), 0.93 (s, 9H), 0.37 (s, 9H), 0.12 (s,
3H), 0.10 (s, 3H); 13C NMR δ 147.0, 141.0, 139.0, 137.9, 134.1,
132.4, 128.4, 128.1, 126.8, 126.3, 73.8, 43.9, 41.8, 26.0, 18.3, -0.6,
-4.5, -4.6; IR (neat) 3057, 2954, 1472, 1363, 1250, 1110, 910,
837, 755, 700 cm-1; [R]27D +21.9 (c 1.01, CHCl3). Anal. Calcd for
C24H36OSi2: C, 72.66; H, 9.15. Found: C, 72.90; H, 9.24.
(S)-2-[(ter t-Bu t yl)d im et h ylsiloxy]-4-(3-b u t yl-4-m et h ox-
yp h en yl)-7-p h en ylin d a n (8, Sch em e 5). 8 (0.142 g, 58%) was
obtained starting from 7 (0.230 g, 0.500 mmol), Ti(O-i-Pr)4 (0.177
mL, 0.600 mmol), i-PrMgCl (1.88 M in Et2O, 0.670 mL, 1.26
mmol), and ethynyl p-tolyl sulfone (0.180 g, 1.00 mmol) under
similar reaction conditions as described for the synthesis of (R)-
1d . 1H NMR δ 7.43-7.51 (m, 4H), 7.28-7.39 (m, 5H), 6.94 (d, J
) 8.4 Hz, 1H), 4.53-4.63 (m, 1H), 3.90 (s, 3H), 3.06-3.25 (m,
4H), 2.70 (dt, J ) 2.7, 7.8 Hz, 2H), 1.59-1.70 (m, 2H), 1.36-
1.49 (m, 2H), 0.97 (t, J ) 7.2 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H);
13C NMR δ 156.8, 141.1, 139.3, 139.2, 137.4, 136.8, 132.9, 131.1,
130.2, 128.6, 128.4, 127.6, 127.5, 126.9, 126.8, 110.1, 74.1, 55.3,
42.5, 42.4, 31.9, 29.8, 25.8, 22.5, 18.1, 13.9, -4.9; IR (Nujol) 3052,
3022, 2926, 1464, 1374, 1248, 1146, 1083, 1038, 904, 837, 815,
To a mixture of the crude oil thus obtained and imidazole
(0.408 g, 6.00 mmol) in DMF (6.0 mL) was added TBSCl (0.543
g, 3.60 mmol) at 0 °C. After the solution was stirred for 12 h at
room temperature, the reaction was terminated by the addition
of saturated aqueous NaHCO3 (10 mL) at 0 °C. The mixture was
extracted with Et2O (3 × 10 mL). The combined organic layers
were dried over MgSO4, concentrated, and chromatographed on
silica gel (hexanes-Et2O) to give (R)-2d (0.967 g, 84%) as a
1
colorless oil. H NMR δ 7.39-7.43 (m, 2H), 7.26-7.31 (m, 3H),
3.95-4.04 (m, 1H), 2.75 (dd, J ) 5.7, 16.5 Hz, 1H), 2.60 (dd, J
) 6.3, 16.5 Hz, 1H), 2.42-2.50 (m, 2H), 2.13-2.20 (m, 2H), 1.24-
1.53 (m, 8H), 0.93 (s, 9H), 0.91 (t, J ) 7.2 Hz, 3H), 0.15 (s, 3H),
0.14 (s, 3H); 13C NMR δ 131.4, 128.0, 127.5, 123.8, 87.4, 82.4,
82.0, 76.6, 70.7, 31.5, 29.0, 28.7, 27.9, 27.6, 25.9, 22.9, 18.9, 18.2,
14.2, -4.45, -4.50; IR (neat) 3081, 2929, 1490, 1472, 1362, 1255,
1103, 937, 837, 777, 755, 691 cm-1; [R]28D -5.16 (c 2.52, CHCl3).
Anal. Calcd for C25H38OSi: C, 78.47; H, 10.01. Found: C, 78.68;
H, 9.70.
(S)-2-(2-Non yn yl)oxir a n e ((S)-4b, Sch em e 3). (S)-4b (1.38
g, 83%) was obtained starting from (S)-3 (0.782 mL, 10.0 mmol),
1-octyne (2.95 mL, 20.0 mmol), n-BuLi (12.6 mL, 1.58 M in
hexane, 20.0 mmol), boron trifluoride etherate (2.53 mL, 20.0
mmol), and NaOH (0.800 g, 20.0 mmol) under similar reaction
conditions as described for the synthesis of (S)-4a . 1H NMR δ
3.00-3.06 (m, 1H), 2.73 (dd, J ) 3.9, 4.8 Hz, 1H), 2.61 (dd, J )
2.4, 4.8 Hz, 1H), 2.55 (ddt, J ) 2.4, 4.5, 17.8 Hz, 1H), 2.39 (ddt,
J ) 2.4, 5.1, 17.8 Hz, 1H), 2.11 (tt, J ) 2.4, 7.2 Hz, 2H), 1.16-
1.50 (m, 8H), 0.85 (t, J ) 6.9 Hz, 3H); 13C NMR δ 82.7, 73.9,
50.2, 46.3, 31.3, 28.8, 28.5, 22.6, 22.5, 18.7, 14.0; IR (neat) 2930,
769, 705 cm-1; mp 89-91 °C; [R]27 +8.8 (c 0.96, CHCl3). Anal.
D
Calcd for C32H42O2Si: C, 78.96; H, 8.70. Found: C, 79.28; H,
9.07.
2858, 1466, 965, 844 cm-1; [R]29 +20.6 (c 4.88, CHCl3).
D
(S)-4-[(ter t-Bu t yl)d im et h ylsiloxy]-1-p h en yl-1,6-t r id ec-
a d iyn e ((S)-2d , Sch em e 3). (S)-2d (0.941 g, 82%) was obtained
starting from (S)-4b (0.498 g, 3.00 mmol), ethynylbenzene (0.659
mL, 6.00 mmol), n-BuLi (3.79 mL, 1.58 M in hexane, 6.00 mmol),
boron trifluoride etherate (0.760 mL, 6.00 mmol), imidazole
(0.408 g, 6.00 mmol), and TBSCl (0.543 g, 3.60 mmol) under
similar reaction conditions as described for the synthesis of (R)-
2d . The spectral data (1H NMR, 13C NMR, IR) have been
(S)-2-(3-P h en yl-2-p r op yn yl)oxir a n e ((S)-4a , Sch em e 3).
(S)-4a was prepared according to the literature.4 To a stirred
solution of ethynylbenzene (0.824 mL, 7.50 mmol) in THF (15.0
mL) was slowly added n-BuLi (4.75 mL, 1.58 M in hexane, 7.50
mmol) at -78 °C and the mixture was stirred for 10 min at this
temperature. Then, to the mixture was added boron trifluoride
etherate (0.950 mL, 7.50 mmol). After the solution was stirred
for 10 min at -78 °C, freshly distilled (S)-3 (0.391 mL, 5.00
mmol) was slowly added and the mixture was stirred for 1 h at
described. [R]28 +5.24 (c 2.52, CHCl3).
D
4982 J . Org. Chem., Vol. 68, No. 12, 2003

(S)-2-(3-Tr im eth ylsilyl-2-p r op yn yl)oxir a n e ((S)-4c, Sch -
em e 4). (S)-4c was prepared according to the literature.5,12 To
a stirred solution of ethynyltrimethylsilane (65.7 mL, 465 mmol)
in hexane (150 mL) was slowly added n-BuLi (296 mL, 1.57 M
in hexane, 465 mmol) at 0 °C under argon and the mixture was
stirred for 30 min. To the mixture was added Et2AlCl (500 mL,
0.93 M in hexane, 465 mmol) at 0 °C and the mixture was stirred
for 30 min. To this mixture was added freshly distilled (S)-3 (30.3
mL, 387 mmol) at 0 °C and the mixture was stirring for 1.5 h.
After addition of 1N HCl (500 mL) at 0 °C, the mixture was
extracted with Et2O (3 × 400 mL). The combined organic layers
were dried over MgSO4, concentrated, passed through a short
silica gel column with 20% ether in hexane, and then concen-
trated to provide a crude oil.
0.558 mmol) and trimethylsilyl chloride (0.0710 mL, 0.560 mmol)
in one portion at room temperature. After 12 h of stirring,
saturated aqueous NaHCO3 (4 mL) was added to the mixture.
The mixture was extracted with Et2O (3 × 4 mL). The combined
organic layers were dried over MgSO4, concentrated, and chro-
matographed on silica gel (hexanes-Et2O) to give (S)-5 (37.1
mg, 94%) as a white solid. The enantiomeric ratio was deter-
mined to be >99:<1 by HPLC analysis [CHIRALCEL OD-H
column (silica gel, 0.46 φ × 15.25 cm), i-PrOH/hexane (1/20 (v/
v)) at the rate of 1.5 mL/min: retention time ) 8.71 min for
(S)-5 and 18.31 min for (R)-5].9 1H NMR δ 7.21-7.45 (m, 8H),
4.63-4.70 (m, 1H), 3.30 (dd, J ) 2.1, 6.0 Hz, 1H), 3.25 (dd, J )
1.5, 6.0 Hz, 1H), 3.00 (dd, J ) 3.0, 3.0 Hz, 1H), 2.95 (dd, J )
3.0, 3.0 Hz, 1H), 1.69 (br s, 1H); 13C NMR δ 141.6, 141.0, 139.0,
138.6, 128.6, 128.4, 127.3, 127.2, 127.1, 124.1, 73.0, 42.7, 42.5;
IR (Nujol) 3370, 3057, 2941, 1591, 1467, 1424, 1339, 1207, 1033,
To a solution of the crude oil in CH2Cl2 (500 mL) was slowly
added NaOH (31 g, 775 mmol) at room temperature. The
mixture was stirred for 2 days. After addition of saturated
aqueous NH4Cl (500 mL), the mixture was extracted with CH2-
Cl2 (3 × 300 mL). The combined organic layers were dried over
MgSO4 and concentrated and the distillation of this crude (70-
943, 789, 754, 704 cm-1; mp 101-103 °C; [R]27 +21.7 (c 1.92,
D
CHCl3).
Com p ou n d 7 (Sch em e 5). 7 (0.667 g, 96%) was obtained
starting from (S)-4a (0.237 g, 1.50 mmol), 3-butyl-4-methoxy-
ethynylbenzene9 (0.564 g, 3.00 mmol), n-BuLi (1.92 mL, 1.56 M
in hexane, 3.00 mmol), and boron trifluoride etherate (0.380 mL,
3.00 mmol) under similar reaction conditions as described for
the synthesis of (R)-2d . 1H NMR δ 7.40-7.45 (m, 2H), 7.21-
7.33 (m, 5H), 6.75 (d, J ) 8.4 Hz, 1H), 4.09-4.18 (m, 1H), 3.82
(s, 3H), 2.82 (dd, J ) 6.0, 12.9 Hz, 1H), 2.77 (dd, J ) 6.0, 12.9
Hz, 1H), 2.70 (dd, J ) 4.8, 6.0 Hz, 1H), 2.65 (dd, J ) 4.5, 6.0 Hz,
1H), 2.58 (t, J ) 7.5 Hz, 2H), 1.51-1.62 (m, 2H), 1.30-1.44 (m,
2H), 0.96 (s, 9H), 0.96 (t, J ) 3.6 Hz, 3H), 0.18 (s, 6H); 13C NMR
δ 157.3, 133.1, 131.6, 131.3, 130.4, 128.2, 127.7, 123.9, 115.4,
110.0, 87.2, 84.8, 82.5, 82.3, 70.6, 55.2, 31.7, 29.5, 28.1, 28.0,
25.7, 22.4, 18.0, 13.9, -4.7; IR (neat) 3080, 3055, 2928, 1498,
1
72 °C, 12 mmHg) gave (S)-4c (48.7 g, 82%) as a colorless oil. H
NMR δ 3.05-3.11 (m, 1H), 2.77 (dd, J ) 3.9, 5.1 Hz, 1H), 2.65
(dd, J ) 4.5, 17.4 Hz, 1H), 2.64 (dd, J ) 2.4, 5.1 Hz, 1H), 2.47
(dd, J ) 5.4, 17.4 Hz, 1H), 0.13 (s, 9H); 13C NMR δ 100.6, 87.1,
49.8, 46.5, 23.6, 0.07; IR (neat) 2960, 2900, 2179, 1406, 1250,
1027, 952, 839, 760 cm-1; [R]27 +29.3 (c 1.36, CHCl3).
D
(R)-4-[(ter t-Bu t yl)d im et h ylsiloxy]-1-p h en yl-7-(t r im et h -
ylsilyl)-1,6-h ep ta d iyn e ((R)-2b, Sch em e 4). (R)-2b (7.26 g,
98%) was obtained starting from (S)-4c (3.08 g, 20.0 mmol),
ethynylbenzene (4.39 mL, 40.0 mmol), n-BuLi (25.3 mL, 1.58 M
in hexane, 40.0 mmol), boron trifluoride etherate (5.07 mL, 40.0
mmol), imidazole (2.72 g, 40.0 mmol), and TBSCl (3.62 g, 24.0
mmol) under similar reaction conditions as described for the
synthesis of (R)-2d . 1H NMR δ 7.26-7.43 (m, 5H), 3.98-4.10
(m, 1H), 2.56-2.74 (m, 3H), 2.48 (dd, J ) 6.6, 17.1 Hz, 1H), 0.93
(s, 9H), 0.17 (s, 9H), 0.15 (s, 6H); 13C NMR δ 131.4, 128.1, 127.6,
123.6, 104.0, 86.9, 86.4, 82.3, 70.3, 28.7, 28.2, 25.9, 18.2, 0.2,
-4.40, -4.41; IR (neat) 3057, 2957, 2178, 1491, 1472, 1250, 1107,
1464, 1362, 1240, 1105, 1037, 937, 837, 777, 755, 691 cm-1; [R]26
D
-0.86 (c 0.89, CHCl3); Anal. Calcd for C30H40O2Si: C, 78.21; H,
8.75. Found: C, 78.23; H, 8.58.
Ack n ow led gm en t. T.H. would like to thank the
J apan Society for the Promotion of Science for financial
support. Y.T. would like to thank the Grant of the 21st
Century COE Program, Ministry of Education, Culture,
Sports, Science and Technology for financial support.
1036, 934, 842, 755 cm-1; [R]27 +8.32 (c 1.36, CHCl3); Anal.
D
Calcd for C22H34OSi2: C, 71.28; H, 9.25. Found: C, 71.61; H,
9.51.
(S)-4-P h en yl-2-in d a n ol ((S)-5, Sch em e 4). To a stirred
solution of (R)-1b (73.7 mg, 0.186 mmol) in CH3CN (2.80 mL)
and H2O (0.0100 mL) were added potassium iodide (92.6 mg,
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
1a ,c,e,f and 2a ,c,e,f, and the HPLC data for (S)-5, (R)-5, and
rac-5. This material is available free of charge via the Internet
at http://pubs.acs.org.
(12) Takano, S.; Kamikubo, T.; Sugihara, T.; Ogasawara, K. Tetra-
hedron: Asymmetry 1992, 3, 853. Subburaj, K.; Okamoto, S.; Sato, F.
J . Org. Chem. 2002, 67, 1024 and references therein.
J O034391M
J . Org. Chem, Vol. 68, No. 12, 2003 4983