Lewis acid-activated chiral leaving group: Enantioselective electrophilic addition to prochiral olefins

Article abstract of DOI:10.1021/jo020165l

A new strategy using a BINOL derivative as a chiral leaving group and Lewis acid has been developed for enantioselective alkylation of prochiral olefins. (R)-2,2′-Bis[2-(trimethylsilyl)ethoxy- methyl]-1,1′-binaphthol is demonstrated to be an effective reagent for enantioselective hydroxymethylation of silyl enol ethers and trisubstituted alkenes. Electrophilic addition to prochiral olefins is accompanied by cleavage of an acetal that is dual activated by SnCl₄ and the δ-effect of silicon through the SN2 substitution process. Enantioselective synthesis of cyclic terpenes is also described using this strategy.

Full text of DOI:10.1021/jo020165l

Lew is Acid -Activa ted Ch ir a l Lea vin g Gr ou p : En a n tioselective
Electr op h ilic Ad d ition to P r och ir a l Olefin s
Hiroko Nakamura, Kazuaki Ishihara, and Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, SORST, J apan Science and Technology Corporation
(J ST), Chikusa, Nagoya 464-8603, J apan
yamamoto@cc.nagoya-u.ac.jp
Received March 8, 2002
A new strategy using a BINOL derivative as a chiral leaving group and Lewis acid has been
developed for enantioselective alkylation of prochiral olefins. (R)-2,2′-Bis[2-(trimethylsilyl)ethoxy-
methyl]-1,1′-binaphthol is demonstrated to be an effective reagent for enantioselective hydroxy-
methylation of silyl enol ethers and trisubstituted alkenes. Electrophilic addition to prochiral olefins
is accompanied by cleavage of an acetal that is dual activated by SnCl4 and the δ-effect of silicon
through the SN2 substitution process. Enantioselective synthesis of cyclic terpenes is also described
using this strategy.
SCHEME 1
In tr od u ction
Enantioselective alkylation of prochiral olefins is an
effective way to construct stereogenic carbons, especially
quaternary carbon centers. Numerous examples have
been presented:1 using a chiral leaving group is one of
the most attractive methods since it does not require the
additional steps for removal of a chiral auxiliary and
affords the desired enantiomer directly. However, chiral
leaving group-induced enantioselective alkylation has
been less investigated than other methods, which include
chiral ligand/metal-catalyzed reactions and chiral aux-
iliary-induced diastereoselective reactions. One difficulty
of the system using a chiral leaving group is that a
leaving group should not be released before asymmetric
addition, but simultaneous cleavage of a leaving group
after addition is required. Fuji et al. presented highly
enantioselective nitroolefination of prochiral enolates
derived from R-substituted lactones with chiral nitro
enamines based on the addition-elimination strategy,2h,i
and this is one of the few successful examples2 that
overcame this difficulty. The addition-elimination strat-
egy, which was first introduced by Wilson and Cram,2c,f
is an effective method for high asymmetric induction
because initial enantioselective addition and the following
elimination proceed completely stepwise manner. Tamu-
ra et al. developed asymmetric synthesis of 3-substituted
2-exo-methylenecyclohexanones via allylic SN2′ substitu-
tion of chiral amine auxiliary by organocuprates.2j,l
Denmark and Marble also reported asymmetric SN2′
substitution of chiral carbamates derived from an achiral
allylic alcohol.2k In these SN2′ reactions, alkylation oc-
curred on one of the two possible diastereotopic faces to
give an enantiomer. An example of the SN2 substitution
process, which is the asymmetric synthesis of monocyclic
terpenes, was developed in our laboratory.2e,g
We have developed a new and effective method of
enantiotopic face-selective alkylation of prochiral olefins
using BINOL derivatives as a chiral leaving group under
acidic conditions. In our strategy, a Lewis acid-activated
O-C bond is cleaved at the moment of electrophilic
addition and the chiral auxiliary is released (Scheme 1).
This reaction should proceed by an SN2 mechanism to
construct a chiral center on an achiral olefin. The reagent
(1) (a) Seyden-Penen, J . Chiral Auxiliaries and Ligands in Asym-
metric Synthesis; J ohn Wiley: New York, 1995. (b) Comprehensive
Asymmetric Catalysis, J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds;
Springer-Verlag: New York, 1999; Vol. 3.
(2) (a) Duggan, P. G.; Murphy, W. S. J . Chem. Soc., Chem. Commun.
1974, 263. (b) Duggan, P. G.; Murphy, W. S. J . Chem. Soc., Perkin
Trans. 1 1976, 634. (c) Wilson, J . M.; Cram, D. J . J . Am. Chem. Soc.
1982, 104, 881. (d) Duhamel, P.; Valnet, J . Y.; Eddine, J . J . Tetrahedron
Lett. 1982, 23, 2863. (e) Sakane, S.; Fujiwara, J .; Maruoka, K.;
Yamamoto, H. J . Am. Chem. Soc. 1983, 105, 6154. (f) Wilson, J . M.;
Cram, D. J . J . Org. Chem. 1984, 49, 4930. (g) Sakane, S.; Fujiwara,
J .; Maruoka, K.; Yamamoto, H. Tetrahedron 1986, 42, 2193. (h) Fuji,
K.; Node, M.; Nagasawa, H.; Naniwa, Y.; Terada, S. J . Am. Chem. Soc.
1986, 108, 3855. (i) Fuji, K.; Node, M.; Abe, H.; Ito, A.; Masaki, Y.;
Shiro, M. Tetrahedron Lett. 1990, 31, 2419. (j) Tamura, R.; Watabe,
K.; Katayama, H.; Suzuki, H.; Yamamoto, Y. J . Org. Chem. 1990, 55,
408. (k) Denmark, S. E.; Marble, L. K. J . Org. Chem. 1990, 55, 1984.
(l) Tamura, R.; Watabe, K.; Ono, N.; Yamamoto, Y. J . Org. Chem. 1992,
57, 4895. (m) Baker, R. W.; Pocock, G. R.; Sargent, M. V. J . Chem.
Soc., Chem. Commun. 1993, 1489. (n) Ogata, M.; Yoshimura, T.; Fujii,
H.; Ito, Y.; Katsuki, T. Synlett 1993, 728. (o) Yanagisawa, A.; Nomura,
N.; Yamada, Y.; Hibino, H.; Yamamoto, H. Synlett, 1995, 841. (p) Yang,
X.; Wang, R. Tetrahedron: Asymmetry 1997, 31, 3275.
10.1021/jo020165l CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/28/2002
5124
J . Org. Chem. 2002, 67, 5124-5137

Enantioselective Electrophilic Addition to Prochiral Olefins
TABLE 1. En a n tioselective Alk oxym eth yla tion of 4
could be thought of as a cation synthon, which has a
chiral atmosphere. The idea of a Lewis acid-activated
cationic alkyl group took a hint from Lewis acid-assisted
chiral Brønsted acid (LBA), which is a reagent developed
in our laboratory for enantioselective protonation pre-
pared from SnCl4 and an optically pure BINOL deriva-
tive.3 On the basis of this concept, an intermolecular
hydroxymethylating reagent (R)-1d ,4a,b an achiral deriva-
tive 2, and a reagent for intramolecular cyclization (R)-
3d 4c have been developed. Herein we report three topics
based on the new concept in which a chiral leaving group
is used: (1) alkoxymethylation of silyl enol ethers; (2)
alkoxymethylation of trisubstituted alkenes; (3) and
intramolecular cyclization of terpenes.
a
w ith 1 a n d Sn Cl4
T, time
(°C, h)
yield
(%)
eec,d
(%)
entry
reagent (CH2OR1, R2)b
1e
2
3
4
5
1a (MOM, MOM)
1b (BOM, BOM)
1c (SEM, Me)
1d (SEM, SEM)
1e (TBSEM, TBSEM)
1f (DMPSEM, DMPSEM)
SEMClf
-78, 3
-78, 3
-78, 2
-78, 1
-78, 1
-78, 1
-78, 0.5
56
55
79
91
79
90
90
51
43
71
75
76
68
6
7
a
b
For details, see the Experimental Section. 1.1 equiv of
reagent was used. c Determined by HPLC analysis. Configura-
d
tion was all (R)-(+). e Reaction was run in toluene. f SEMCl was
used in place of 1.
TABLE 2. Effects of Lew is Acid s on SEM Ad d ition of 4
Resu lts a n d Discu ssion
w ith (R)-1d a ,b
En a n tioselective Alk oxym eth yla tion of Silyl En ol
Eth er s. First, we chose to investigate the enantioselec-
tive alkylation of silyl enol ethers using a chiral leaving
group (eq 1).5,6 Silyl enol ethers, which are synthetic
entry
Lewis acid
yield (%)
eec,d (%)
1
2
3
4
5
ZrCl4
HfCl4
TiCl4
GaCl3
B(C6F5)3
49
84
59
26
34
42
55
28
58
0
a
b
Reactions were carried out at -78 °C for 1 h. 1.1 equiv of
(R)-1d was used. c Determined by HPLC analysis. Configuration
d
was all (R)-(+).
better yield, 91%, and with 75% ee (Table 1, entry 4).
This result can be explained by assuming an interaction
between silicon and a γ-positive charge (the γ-effect).7 The
terminal silyl group would stabilize the γ-oxonium cation,
and therefore, the cleavage of acetal would be accelerated.
The disubstituted, C2-symmetric reagent (1d ), only one
alkyl group of which was transferred to a substrate, was
more reactive than the monomethyl substituted reagent
(1c). This reagent seems uneconomical at first sight;
however, 1d can be synthesized in one step from optically
pure BINOL and SEMCl. Furthermore, mono(SEM)-
protected BINOL can be collected and recycled. The
corresponding racemic products could be synthesized in
the reaction of silyl enol ethers with SEMCl and SnCl4
(Table 1, entry 7).8 While other terminal silyl groups were
examined, they did not give significantly better reactivity
or enantioselectivity (Table 1, entries 5 and 6). This result
indicated that there was no appreciable steric effect from
bulkiness of terminal silyl groups and the increase in
enantioselectivity could be due to the increase in reactiv-
ity by an electronic effect of the silyl groups.
equivalents of enols or enolates, are more stable than the
corresponding metal enolates and can be isolated. Shown
in Table 1 are results from the reaction of various alkyl
ethers of BINOL with the trimethylsilyl enol ether
derived from 2-phenylcyclohexanone in the presence of
SnCl4. p-Methoxybenzyl ether of BINOL gave the racemic
product, methoxymethyl or benzyloxymethyl ether of
BINOL, while 1a or 1b gave products in moderate yields
and ees (Table 1, entries 1 and 2). These reactions
proceeded in toluene more slowly than in dichloromethane,
and addition of excess SnCl4 or an increase in the reaction
temperature promoted the decomposition of substrate.
When the trimethylsilylethoxymethyl (SEM) ether of
BINOL 1d was used, the product was obtained in much
(3) (a) Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997,
411 and references therein. (b) Taniguchi, T.; Ogasawara, K. Tetra-
hedron Lett. 1997, 38, 6429. (c) Ishihara, K.; Ishida, Y.; Nakamura,
S.; Yamamoto, H. Synlett 1997, 758. (d) Ishihara, K.; Nakamura, H.;
Nakamura, S.; Yamamoto, H. J . Org. Chem. 1998, 63, 6444. (e)
Ishihara, K.; Nakamura, S.; Yamamoto, H. J . Am. Chem. Soc. 1999,
121, 4906. (f) Nakamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto,
H. J . Am. Chem. Soc. 2000, 122, 8120. (g) Nakamura, S.; Ishihara K.;
Yamamoto, H. J . Am. Chem. Soc. 2000, 122, 8131. (h) Ishihara, K.;
Ishibashi, H.; Yamamoto, H. J . Am. Chem. Soc. 2001, 123, 1505.
(4) (a) Ishihara, K.; Nakamura, H.; Yamamoto, H. J . Am. Chem.
Soc. 1999, 121, 7720. (b) Ishihara, K.; Nakamura, H.; Yamamoto, H.
Synlett 2000, 1245. (c) Ishihara, K.; Nakamura, H.; Yamamoto, H.
Synlett 2001, 1113.
(5) While far from efficient, there is nevertheless a report on the
enantioselective hydroxymethylation. Fujii, M.; Sato, Y.; Aida, T.;
Yoshihara, M. Chem. Express 1992, 7, 309.
(6) For the diastereoselective aldol-type reactions of chiral enolates
with SEMCl, see: Suzuki, S.; Narita, H.; Harada, K. J . Chem. Soc.,
Chem. Commun. 1979, 29.
Different kinds of Lewis acids were then examined in
place of SnCl4 (Table 2). ZrCl4 and HfCl4 acted similarly
to SnCl4, but they did not exceed SnCl4 in enantioselec-
(7) Lambert, J . B. Tetrahedron 1990, 46, 2677.
(8) Lithium enolates/SEMCl: (a) Crich, D.; Davies, J . W. J . Chem.
Soc., Chem. Commun. 1989, 1418. (b) Crich, D.; Lim, L. B. L. Synlett
1990, 117. (c) Paquette, L. A.; Ra, C. S., Silvestri, T. W. Tetrahedron
1989, 45, 3099. Lithium enolates/BOMCl: (d) Wa¨gner, J .; Vogel, P. J .
Chem. Soc., Chem. Commun. 1989, 1634. Trialkylsilyl enol ethers/
MOMCl/B(C6F5)3: (e) Ishihara, K.; Hanaki, N.; Yamamoto, H. Synlett
1993, 577. Trialkylsilyl enol ethers/RSCH2Cl/TiCl4 or ZnBr2: Paterson,
I. Tetrahedron 1988, 44, 4207, and references therein.
J . Org. Chem, Vol. 67, No. 15, 2002 5125

Nakamura et al.
TABLE 3. Effects of Solven ts on SEM Ad d ition of 4
TABLE 4. En a n tioselective
2-(Tr im eth ylsilyl)eth oxym eth yla tion a
a
w ith (R)-1d a n d Sn Cl4
yield eeb,c
entry
solvent
hexane
toluene
Et2O
tBuOMe
EtNO2
chlorobenzene
CHCl3
1,2-dichloropropane -78, 1
1,2-dichloropropane -100, 3
1,3-dichloropropane -78, 1
1-chloropropane
1-chloropropane
1-chloropropane
2-chloropropane
CH2BrCl
T, time (°C, h)
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
(16
-78, 1
d
65
d
-78, 1
56
-78, 1
-78 to -40, 1
-78, 1
71
38
91
82
76
82
97
78
94
55
85
94
91
55
52
45
69
77
81
66
73
81
94
70
70
75)e
-40, 0.5
-50, 0.5
-78, 2.5
-125, 1 to -78, 1
-125, 47
-78, 1
-78, 1
-78, 1
CH2Cl2
a
b
1.1 equiv of (R)-1d and SnCl4 were used. Determined by
HPLC analysis. c Configuration was all (R)-(+). No reaction was
d
observed. e These data appear in Table 1 (entry 4).
tivity (Table 2, entries 1 and 2). We considered their low
solubility in dichloromethane to be the reason that ZrCl4
and HfCl4 did not lead to better results than SnCl4. While
GaCl3 and TiCl4 had high solubility in dichloromethane,
they did not afford satisfactory results (Table 2, entries
3 and 4).
We next examined the solvent effects on the reaction
of 4 with (R)-1d and SnCl4 (Table 3). No reaction was
observed in hexane, because of its low solubility, and
diethyl ether promoted the decomposition of SnCl4.
Halogenated solvents tended to give the product with
high enantiomeric excess, with 1,2-dichloropropane, 1-
chloropropane, and dichloromethane showing the best
results. Although enantioselectivity in 1,2-dichloropro-
pane at -78 °C was higher than that in 1-chloropropane
at -78 °C, the latter is cheaper and can be cooled to lower
temperature than the former, and the highest ee value
was achieved by performing the reaction in 1-chloropro-
pane at -125 °C for an extended time (Table 3, entry
13). The reaction of 1 equiv of 4 and 1d with 0.5 equiv of
SnCl4 or 0.5 equiv of 1d with 1 equiv of 4 and SnCl4
afforded 5d in 50% yield. These results led us to
understand that SnCl4 does not act as a catalyst, prob-
ably due to formation of a stable complex with a released
chiral auxiliary, and the second SEM group on 1d is not
consumed. It should be added that tert-butyldimethylsilyl
enol ether and dimethylhydrosilyl enol ether derived from
2-phenylcyclohexanone treated with 1d and SnCl4 in CH2-
Cl2 at -78 °C led to the adducts in quantitative yields
with 32% and 69% ee, respectively.
a
b
For details, see the Experimental Section. Determined by
HPLC or GC analysis. c 1-Chloropropane was used. Dichlo-
d
romethane was used. e E/Z ) 83:17. f >99% Z.
were observed in the reaction of silyl enol ethers derived
from 2-phenylcyclopentanone and 2-alkylcyclohexanones.
Notice that the absolute stereochemical course in the case
of 4 is opposite that in 6f, and reactions proceeded
smoothly in 1-chloropropane in the case of aromatic silyl
enol ethers including 4, while no desired reaction was
observed in the aliphatic silyl enol ethers including 6f.
The 2-(trimethylsilyl)ethyl group was easily removed in
quantitative yield without racemization by treatment
with hydrogen fluoride-pyridine at room temperature (eq
2).
In view of these results, we believe that the highly
enantioselective SN2 SEM-addition mechanism could be
materialized with an exquisite balance between the
nucleophilicity of a trimethylsilyl enol ether and the
electrophilicity of acetal dual activated by SnCl4 and the
γ-effect of silicon.7
The generality and scope of the SnCl4-mediated SEM
addition explored using several trimethylsilyl enol ethers
are shown in Table 4. Good enantioselectivities were
observed in the reaction of aromatic silyl enol ethers
(Table 4, entries 1-4) and aliphatic silyl enol ethers
(Table 4, entries 5-7), whereas low enantioselectivities
To demonstrate the effectiveness of the present reac-
tion, optically active ketone 7f obtained in the reaction
of Heathcock’s silyl enol ether 6f 6 (Table 4, entry 7) was
converted to synthetically more useful aldehyde 9 in high
yield according to their protocol (eq 3).
5126 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Electrophilic Addition to Prochiral Olefins
F IGURE 2. Optimized geometry of a 2,2′-dimethoxy-1,1′-
diphenyl-SnCl4 complex. Selected bond distances (Å), bond
angles (deg), and dihedral angles (deg): O4-C5 ) 1.456, C5-
O6 ) 1.386, Sn-Clap ) 2.397, Sn-Cleq ) 2.376, O4-Sn )
2.328, C2-O4-C5 ) 111.4, Sn-O4-C5 ) 122.1, C5-O6-C7
) 116.4, C1-C2-O4-C5 ) -85.7, C3-C2-O4-C5 ) 92.4,
Clap-Sn-O4-C5 ) 33.0, Cleq-Sn-O4-C5 ) -61.5, C2-O4-
C5-O6 ) -64.0, O4-C5-O6-C7 ) -90.6.
F IGURE 1. Changes in the chemical shifts of the chiral
reagents 1. 13C NMR (75 MHz, CD2Cl2, -78 °C) assignments
(δ (ppm)) for a 1:1 1-SnCl4 complex.
Str u ctu r e of 1-Sn Cl4 Com p lex. While the chiral
reagent 1 has four oxygens that could be coordinated by
SnCl4, we believe that the bidentate complex A is
probably formed of 1 and SnCl4 (Figure 1). Because an
amount of SnCl4 equivalent to a chiral reagent gave the
best result in these transformations, a n:n complex10 of
reagent and SnCl4 would be the most effective species.
The regioselective cleavage of acetals in these transfor-
mations indicates that SnCl4 predominantly coordinates
with the OAr oxygen atoms. In addition, a 13C NMR study
established that the addition of 1 equiv of SnCl4 to 1a
gave rise to a symmetrical complex, and changes in the
chemical shifts also supported the existence of complex
A.11
A stable conformation of complex A was predicted by
theoretical calculations of a 2,2′-di(methoxymethoxy)-1,1′-
biphenyl and SnCl4 complex B, which was optimized at
the partial PM3 calculation of the MOM units on the
basis of a 2,2′-dimethyl-1,1′-biphenyl and SnCl4 complex
optimized at the B3LYP/LANL2DZ level12 using Gauss-
ian 9813 (Figure 2).4a These calculations indicated that
the di(MOM) ether with SnCl4 occurs at an equatorial
site on tin. It is noteworthy that the C5-O4 bond is
F IGURE 3. Proposed extended transition states for the
enantioselective SEM addition to silyl enol ethers. (R: CH2-
CH2SiMe3).
almost perpendicular to the C1-C3 axis, presumably due
to the steric repulsive interactions with apical and
equatorial chlorines. Also of interest is the finding that
the C5-O6 bond is shorter than the O4-C5 bond which
is perpendicular to the C5-O6-C7 plane. This indicates
that the C5-O6 bond has a partial double-bond character
due to the stereoelectronic effect.14 From these studies,
we assumed that a stable conformation of the reagent
was C (Figure 3).
(9) Mori, I.; Ishihara, K.; Heathcock, C. H. J . Org. Chem. 1990, 55,
1114.
(10) We have no evidence that the complex is consisted of one chiral
reagent and one SnCl4. There is a possibility that a 2:2, 4:4, or n:n
complex exists.
(11) The possibility of an unsymmetrical structure, in which two
oxygen atoms in a single MOM group of 2a are coordinated to the tin
atom, was clearly denied. Santelli, M.; Pons, J .-M. Lewis Acids and
Selectivity in Organic Synthesis; CRC Press: Boca Raton, 1996;
Chapter 4.
The observed absolute stereochemistries are explained
in terms of the acyclic extended transition-state mecha-
nism that was a kind postulated by Noyori et al.15 We
considered that there could be two different routes
(Figure 3). First in the reaction of 4, TS D, which is
stabilized by π-π attractive interaction between phenyl
and naphthyl groups, is favored over the alternative TS
E, which is destabilized due to steric repulsion between
(12) (a)Dunning, T. H., J r. J . Chem. Phys. 1970, 53, 2823. (b) Wadt,
W. R.; Hay, P. J . J . Chem. Phys. 1985, 82, 284.
(13) Gaussian 98 (Revision A.6): Frisch, M. J .; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.;
Zakrzewski, V. G.; Montgomery, J . A.; Stratmann, R. E.; Burant, J .
C.; Dapprich, S.; Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J .;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J . B.; Cioslowski, J .; Ortiz,
J . V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.
M. W.; J ohnson, B. G.; Chen, W.; Wong, M. W.; Andres, J . L.; Head-
Gordon, M.; Replogle, E. S.; Pople, J . A. Gaussian, Inc., Pittsburgh,
PA, 1998.
(14) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, 1983.
(15) Murata, S.; Suzuki, M.; Noyori, R. J . Am. Chem. Soc. 1980,
102, 3248.
J . Org. Chem, Vol. 67, No. 15, 2002 5127

Nakamura et al.
TABLE 5. Regioselective Deh yd r och lor in a tion of 13a to
12a
SCHEME 2
entry
base
Ph3CLi
DBU
DBN
i-Pr2EtN
2,4,6-collidine
T (°C), time (h)a yieldb (%) (12a /14a )c
1
2
3
4
5
40, 1d
130, 3
120, 1
170, 3
180, 3
e
84
87
e
89:11
86:14
96
97:3
a
Unless otherwise noted, the reaction was carried out under
b
reflux conditions using a base as a solvent. Isolated yield.
c Determined by 1H NMR analysis. Diethyl ether was used as a
d
solvent. e No reaction.
TABLE 6. En a n tioselective P r in s Rea ction of P r och ir a l
a
2-(trimethylsilyl)ethyl and phenyl groups. Second in the
reaction of 7f, TS G is preferable to TS F , which is
destabilized due to steric repulsion between the tert-alkyl
group and an apical chlorine. In other words, 4 favored
TS D because of the positive cause while 7f disfavored
TS F because of the negative cause. The stereoselection
observed for other silyl enol ethers can also be understood
in a similar fashion. These two different mechanisms can
explain the observed difference between aromatic and
aliphatic substrates in stereochemistry and solvent ef-
fects, which has been described above.
Alk en es w ith (R)-1d a n d Sn Cl4
En a n tioselective Hyd r oxym eth yla tion of Tr isu b-
stitu ted Alk en es. We have demonstrated above an
enantioselective SEM addition to silyl enol ethers using
1d and SnCl4. The chiral reagent 1d and SnCl4-induced
enantioselective Prins-type reaction16 of trisubstituted
alkenes was then developed.17,18 Simple olefins are com-
mon and easily available substrates; however, with them
it is harder than with silyl enol ethers to control regio-
selection and enantioselection because they have two or
more possible reacting points and no heteroatom that can
interact with reagents and metals. First, we examined
an enantioselective SEM addition to 2-methyl-2-pentene
with 1d and SnCl4 (Scheme 2). Electrophilic SEM addi-
tion occurred rapidly and site selectively at the less
substituted carbon of the double bond in olefin 11a at
-78 °C in dichloromethane, and a mixture of the desired
product 12a and the 3-chloroalkyl ether 13a was ob-
tained. Although it was difficult to separate the product
mixture by column chromatography on silica gel,19 the
chlorinated byproduct 13a could be converted into the
desired product by regioselective dehydrochlorination. No
reaction was observed when the mixture of 12a and 13a
was treated with a bulky anionic base such as triphenyl-
methyllithium,20 and KO(t-Bu)/t-BuLi resulted in decom-
position of substrate, whereas the mixture could be
transformed into 12a and 14a by heating in amines
(Table 5). Especially in 2,4,6-collidine was the product
a
Reactions were run with 1.1 equiv of 1d and SnCl4 at -97 °C
for 12 h in dichloromethane. Isolated yield. c Determined by GC
b
analysis. Determined by GC or HPLC analysis. e The mixture
d
of 12 and 13, which was obtained by SEM addition, was treated
with 2,4,6-collidine. f The ratio of 12/13 was 74:26 (1H NMR
g
h
analysis). Total yield in two steps. 3 equiv of 11a was used.
Isolated yield based on (R)-1d . The ratio of 12:13 was 85:15 (1H
i
NMR analysis). 13 was not detected by 1H NMR analysis.
j
k
Stirred for 5 h.
12a obtained in high regioselectivity (Table 5, entry 5)
and with 60% ee. The enantiomeric excess of 12a was
improved to 81% by carrying out the SEM addition at
-97 °C in dichloromethane. The higher concentration of
the reaction mixture raised the reactivity without reduc-
ing the enantioselectivity. The reaction of 11a in toluene
at -78 °C and 1-chloropropane at -125 to -78 °C led to
12a with 54% and 74% ee, respectively.
The representative results are summarized in Table
6. For acyclic or exocyclic trisubstituted alkenes 11a -d ,
the reaction with 1d proceeded smoothly even at -97 °C
and afforded the corresponding homoallylic ethers 12a -d
in good enantioselectivities and good yields. The dehy-
drochlorination condition using collidine was applied to
11b in 99% regioselectivity. Other substrates did not give
significant amounts of chlorinated byproduct. In one
particular case, cyclization occurred with SEM addition
(16) For reviews on the Prins reaction, see: (a) Adams, D. R.;
Bhatnagar, S. P. Synthesis 1977, 661. (b) Snyder, B. B. Compr. Org.
Synth. 1991, 2, 527.
(17) Enantioselective reaction of prochiral alkenes with formalde-
hyde: Mikami, K.; Yoshida, A. Synlett 1995, 29.
(18) For the diastereoselective Prins reaction of chiral acetals, see:
Snider, B. B.; Burbaum, B. W. Synth. Commun. 1986, 16, 1451.
(19) The % ee of chloride 5a could not be determined by chiral HPLC
and GC analyses.
(20) For the successful use of triphenylmethyllithium, see: Kenneth,
J . B.; Grundon, M. F.J . Chem. Soc., Perkin Trans. 1 1980, 1820.
5128 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Electrophilic Addition to Prochiral Olefins
(eq 4).21,22,4e,g,h One additional remark should be made:
A Prins-type SEM addition generally did not proceed well
when SEMCl-SnCl4 or SEM phenyl ether-SnCl4 was
used instead of the chiral reagent 1d , in contrast with
the case of a SEM addition to silyl enol ethers. Racemic
homoallylic ethers 12a -d , which were required as au-
thentic samples, were quantitatively prepared according
to the SEM-addition to 11a -d with 2 (Scheme 1) at -78
°C. Therefore, a bidentate chelation system is necessary
and would be particularly effective for introducing SEM
to alkenes.
F IGURE 4. Proposed transition-state assemblies of enanti-
oselective Prins-type SEM addition.
En a n tioselective In tr a m olecu la r Cycliza tion of
Ter p en es. In 1983, we reported the first biomimetic
asymmetric synthesis of (R)-(+)-limonene (up to 77% ee)
from (R)-BINOL mononeryl ether with bulky organo-
aluminum reagents.2e,g This was one of the successful
examples of a chiral leaving group inducing intramolecu-
lar cyclization of terpenes.24 We decided to apply our
strategy using BINOL derivatives as a chiral leaving
group and SnCl4 to synthesis of cyclic terpenes (eq 7).
The 2-(trimethylsilyl)ethyl group of 12 was cleanly
removed by treatment of hydrogen fluoride-pyridine in
acetonitrile in most cases (eq 5). A careful quench at low
temperature was required to avoid decomposition of
substrates. The HSiEt3/catalytic B(C6F5)3 system23 was
also effective for the site-selective reductive cleavage of
12, especially in the case of unstable substrates, to afford
the corresponding homoallylic triethylsilyl ether (eq 6).
The subsequent deprotection of alkoxysilanes was un-
necessary in the reductive cleavage with HSiEtMe2/cat-
B(C6F5)3 to give the corresponding homoallylic alcohol
directly after mild acidic quench.
The absolute stereochemistry observed in the Prins
reaction can be explained in terms of the acyclic extended
transition-state (TS) mechanism, which has been postu-
lated in the enantioselective SEM addition to silyl enol
ethers with 1d (Figure 4). In the reaction of 11a with
1d , TS H is preferable to TS I, which is destabilized due
to steric repulsion between the ethyl group of 11a and
the adjacent naphthyl group of 1d .
To investigate effects of leaving groups on enantio-
selectivity, various neryl-protected (R)-BINOL deriva-
tives (R)-3a -e were treated with SnCl4 in toluene (Table
7). The reactions of 3a -c gave (S)-(-)-limonene with only
moderate asymmetric induction (Table 7, entries 1-3),
whereas the reaction of 3d gave (R)-(+)-limonene with
87% ee (Table 7, entry 4). This remarkable change could
be explained as follows: In the case of 3e and 3f, SnCl4
probably coordinates to the carbonyl oxygen predomi-
nantly, thus the conformation of a 3-SnCl4 complex
would be quite different from that in the case of 3a -c.
While the reactivity in toluene at -78 °C was very low,
cyclization completed within 12h in dichloromethane
even at -97 °C and (R)-(+)-limonene was obtained in 93-
94% ee (Table 7, entries 5 and 10). Enantioselectivity
observed in 1-chloropropane at -78 °C was equal to that
in dichloromethane at -97 °C (Table 7, entry 6). Com-
pound 3d led to results similar to those of 3e except for
the generation of R-terpinene in 1-chloropropane (Table
7, entry 6). R-Terpinyl chloride (17) was obtained together
with 16 as a single byproduct regardless of reaction
(21) For the nonasymmetric cyclization of polyprenoids using chlo-
romethyl methyl ether and AgBF4, see: Krimer, M. Z.; Smit, V. A.;
Semenovskii, A. V.; Kucherov, V. F. Izv. Akad. Nauk SSSR, Ser. Khim.
1968, 1352; Chem. Abstr. 1968, 69, 87212s.
(22) For examples of bicyclic sesquiterpenes including chiral tertiary
methyl group, see: (a) Goldsmith, D. J .; Deshpande, R. Synlett 1995,
495. (b) San Feliciano, A.; Gordaliza, M.; Miguel del Corral, J . M.; de
la Puente, M. L. Garc´ıa-Granda, S.; Salvado, M. A. Tetrahedron 1993,
49, 9067. (c) Tokoroyama, T.; Kanazawa, R.; Yamamoto, S.; Kakikawa,
T.; Suenaga, H.; Miyabe, M. Bull. Chem. Soc. J pn. 1990, 63, 1720. (d)
Kushlan, D. M.; Faulkner, D. J .; Parkanyi, L.; Clardy, J . Tetrahedron
1989, 45, 3307. (e) Capon, R. J .; Macleod, J . K.; Coote, S. J .; Davies, S.
G.; Gravatt, G. L.; Dordor-Hedgecock, I. M.; Whittaker, M. Tetrahedron
1988, 44, 1637. (f) Piers, E.; Wai, J . S. M. J . Chem. Soc., Chem.
Commun. 1987, 1342.
(24) For the intermolecular version in terpene biosynthesis, see: (a)
Coates, R. M. Fortschr. Chem. Org. Naturst. 1976, 33, 73. (b) Poulter,
C. D.; Rilling, H. C. Acc. Chem. Res. 1978, 11, 307. (c) Poulter, C. D.;
Rilling, H. C. In Biosynthesis of Isoprenoid Compounds; Porter, J . W.,
Ed.; Wiley: New York, 1981; Vol. 1, p 161.
(23) (a) Gevorgyan, V.; Liu, J .-X.; Rubin, M.; Benson, S.; Yamamoto,
Y. Tetrahedron Lett. 1999, 40, 8919. (b) Blackwell, J . M.; Foster, K.
L.; Beck, V. H.; Piers, W. E. J . Org. Chem. 1999, 64, 4887.
J . Org. Chem, Vol. 67, No. 15, 2002 5129

Nakamura et al.
TABLE 7. In tr a m olecu la r Cycliza tion of 3 P r om oted by
Lew is Acid a
eeb (%)
(config)
yieldc (%)
entry
3
solvent
T, time (°C, h)
16/17d
1
2
3
4
5
3a
3b
3c
3d
3d
3d
3d
3e
3e
3e
3e
toluene
toulene
toluene
toluene
CH2Cl2
PrCl
toluene
toluene
toluene
CH2Cl2
PrCl
-78, 12
-78, 12
-78, 12
-78, 6
18 (S)
52 (S)
25 (S)
87 (R)
93 (R)
92 (R)
48 (R)
89 (R)
92 (R)
94 (R)
92 (R)
e
-97, 4
40:51
37f:47
6
-78, 12
-78, 12
-78, 12
-97, 6
-97, 6
-78, 12
7g
8
24:33
e
38:62
40:48
9
10
11
a
Unless otherwise noted, the reaction proceeded with >99%
conversion. Ee of 16. Determined by GC analysis. c Isolated
b
yields. The ratio was estimated by GC and 1H NMR spectral
d
analyses. e Some of the starting material 3 remained. f R-Ter-
g
pinene was produced in 6% yield. TiCl4 was used in place of
SnCl4.
conditions (see the Experimental Section); nonetheless,
desired product 16 could be isolated by column chroma-
tography on silica gel. 17 was transformed to an 81:19
mixture of 16 and terpinolene (18) in 90% yield by
heating in 2,4,6-collidine under reflux conditions without
reducing the optical purity (eq 8). Therefore, (R)-16 was
obtained with 93% ee in 77% overall yield from 3d in
two steps (entry 5, Table 7 f eq 8).
F IGURE 5. Proposed transition-state model for the enantio-
selective intramolecular cyclization of (R)-3d .
isolated from termite,27 tree28a and soft coral,29 has been
shown to be a highly active trail pheromone of the
Australian termite Nasuititermis exitiosus. The geo-
As described previously, we believe that the chiral
auxiliary could discriminate one of two possible enan-
tiotopic faces in enantioselective SEM addition. In the
case of intramolecular cyclization, the mechanism could,
however, be a little different from the previous case
because a new chiral center is constructed on a chiral
compound. Shown in Figure 5 is a proposed transition-
state model. The isoprenyl group can approach the
activated carbon center from two possible faces, anti-endo
J and anti-exo K without chiral auxiliary. The topologi-
cally related linalyl system is known to cyclize preferen-
tially from an anti-endo conformation,25 and a similar
preference is expected for its allylic isomer.26 Then, anti-
endo J has two possible enantiomeric transition-state
structures, L and M, the former of which is sterically
more favorable than the latter. The complex 3 has a
cavity between binaphthyl group and SnCl4, and six-
membered limonene seems to fit in there.
metrical structure of 20 has been confirmed to be 3E,7E,-
11E, and the absolute configuration has been determined
to be 1R. Attempts to synthesize 20 have used a variety
of methodologies;30 however, as far as we know, there has
been only one report on its enantioselective synthesis.30e
The reaction of (R)-19 in the presence of 1 equiv of SnCl4
gave the desired cyclic compound 20 with many isomers
and byproducts that were generated by intermolecular
reaction. The ratio of 20 and other byproducts was greatly
(27) (a) Moore, B. P. Nature (London) 1966, 211, 746. (b) Birch, A.
J .; Brown, M. W. V.; Corrie, J . E. T.; Moore, B. P. J . Chem. Soc., Perkin
Trans. 1 1972, 2653.
(28) (a)Patil, V. D.; Nayak, V. R.; Dev, S. Tetrahedron 1973, 29, 341.
(b) Kato, T.; Suzuki, M.; Kobayashi, T.; Moore, B. P. J . Org. Chem.
1980, 45, 1126.
(29) (a) Patil, V. D.; Nayak, V. R.; Dev, S. Tetrahedron 1972, 28,
2341. (b) Vanderah, D. J .; Rutedge, N.; Schnitz, F. J .; Cierezko, L. S.
J . Org. Chem. 1978, 43, 1614.
(30) (a) Kodama, M.; Matsuki, Y.; Ito, S. Tetrahedron Lett. 1975,
16, 3065. (b) Kitahara, Y.; Kato, T.; Kobayashi, T. Chem. Lett. 1976,
219. (c) Vig, O. P.; Nanda, R.; Cauba, R.; Puri, S. K. Ind. J . Chem.
1985, 24B, 918. (d) Schwabe, R.; Farkas, I.; Pfander, H. Helv. Chim.
Acta 1988, 71, 292. (e) Farkas, I.; Pfander, H. Helv. Chim. Acta 1990,
73, 1980. (f) Pattenden, G.; Smithies, A. J . Synlett 1992, 577. (g) Li,
W. D.; Li, Y.; Li, Y. L. Chin. J . Chem. 1992, 10, 92. (h) Li, W. D.; Li,
Y.; Li, Y. L. Science in China 1993, 36, 1161; Chem. Abstr. 1994, 120,
218236z. (i) Yue, X. J .; Li, Y. L. Bull. Soc. Chim. Belg. 1995, 104, 69.
(j) Pattenden, G.; Smithies, A. J . J . Chem. Soc., Perkin Trans. 1 1995,
57. (k) Yue, X.; Li, Y. Synthesis 1996, 736.
We next examined synthesis of a 14-membered cyclic
diterpene, cembrene A (20) by macrocyclization of all-E-
geranylgeranyl ether 19 derived from monobenzoate of
(R)-BINOL (eq 9). A cembranoid 20, which has been
(25) Godtfredsen, S.; Obrecht, J . P.; Arigoni, D. Chimia 1977, 31,
62.
(26) Poulter, C. D.; King, C.-H. R. J . Am. Chem. Soc. 1982, 104,
1420, 1422.
5130 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Electrophilic Addition to Prochiral Olefins
TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.38; IR (KBr) 2835,
1622, 1510, 1381, 1148, 756 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 4.34 (s, 4H), 5.10 (d, J ) 7.2 Hz, 2H), 5.20 (d, J ) 7.2 Hz,
2H), 7.05-7.38 (m, 16H), 7.66 (d, J ) 9.0 Hz, 2H), 7.90 (d, J
) 8.2 Hz, 2H), 7.98 (d, J ) 9.0 Hz, 2H); 13C NMR (CDCl3, 75
MHz) δ 69.7, 92.7, 117.1, 121.1, 124.2, 125.6, 126.5, 127.7,
127.9, 128.0 (2C), 128.4 (2C), 129.5, 129.9, 134.1, 137.3, 152.6;
influenced by the solvent effect. Toluene, dichloromethane,
chlorobenzene, and other solvents were examined, use
of 1-chloropropane resulted in the best purity in these
solvents, and 20 could be isolated with >95% purity.
When the reaction was carried out in dichloromethane,
20 was obtained with better ee, 32%. The absolute
configuration of its major enantiomer was determined to
be 1S by comparing the specific rotation with data for
natural (R)-20. The absolute stereochemistry of 20 was
opposite to that of 16, although the same chiral leaving
group derived from (R)-BINOL was used for both reac-
tions. Limitations of yield and ee in this reaction are
believed to be due to a disproportion between the 14-
membered ring and reacting space on the complex of 19
and SnCl4. Although six-membered limonene could fit in
a cavity between the binaphthyl group and SnCl4, the
14-membered ring was too big to fit in. Despite the low
optical yield and low chemical yield of 20, the macro-
cyclization is a very attractive alternative to the multi-
step synthesis from naturally occurring chiral synthons.
[R]24.5 ) +39.8 (c ) 3.44, CHCl3). Anal. Calcd for C36H30O4:
D
C, 82.11; H, 5.74. Found: C, 82.10; H, 5.76.
(R)-2-Met h oxy-2′-[2-(t r im et h ylsilyl)et h oxym et h oxy]-
1,1′-bin a p h th yl (1c). Compound 1c was prepared from 2-(tri-
methylsilyl)ethoxymethyl chloride and (R)-BINOL-Me32 as
described above for the preparation of 1d : TLC (hexanes-
ethyl acetate ) 4:1) Rf ) 0.50; IR (KBr) 2951, 1593, 1509, 1252,
1084, 1017, 810 cm-1; 1H NMR (CDCl3, 300 MHz) δ -0.10 (s,
9H), 0.72-0.80 (m, 2H), 3.35-3.42 (m, 2H), 3.77 (s, 3H), 5.03
(d, J ) 7.0 Hz, 1H), 5.14 (d, J ) 7.0 Hz, 1H), 7.10-7.38 (m,
6H), 7.46 (d, J ) 9.0 Hz, 1H), 7.60 (d, J ) 9.0 Hz, 1H), 7.87
(dd, J ) 3.6, 8.2 Hz, 2H), 7.96 (t, J ) 9.3 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) δ -1.3, 18.0, 56.9, 66.0, 93.7, 114.1, 117.6,
123.6, 124.0, 125.5, 125.6, 126.3, 126.5, 128.0, 128.1, 128.3,
129.2, 129.4, 129.5, 130.0, 134.1, 152.9, 155.0; [R]24.2D ) +54.7
(c ) 3.06, CHCl3). Anal. Calcd for C27H30O3Si: C, 75.31; H,
7.02. Found: C, 75.37; H, 7.05.
Con clu sion s
(R)-2,2′-Bis[2-(ter t-bu tyldim eth ylsilyl)eth oxym eth oxy]-
1,1′-bin a p h th yl (1e). (a) To a stirred solution of ethylvinyl
ether (8.8 mL, 92 mmol) in THF (35 mL) was added a 1.59 M
solution of tert-butyllithium (48 mL, 77 mmol) in pentane
dropwise under argon atmosphere at -78 °C. The mixture was
slowly warmed to 0 °C by removal of the solid dry ice from
the bath and then cooled to -78 °C again, and tert-butyldi-
methylsilyl trifluoromethanesulfonate (13.8 mL, 60 mmol) was
added to the mixture. After being stirred for 1 h at room
temperature, the mixture was quenched with ice and a
saturated NaHCO3 solution, extracted with pentane, and
washed with water six times. The combined organic layers
were dried over anhydrous MgSO4, concentrated, and distilled.
Obtained tert-butyldimethyl(R-ethoxyvinyl)silane (6.3 g, 33.6
mmol) was then added to a 1.06 M solution of BH3‚THF (78
mL, 83 mmol) in dry THF. After 2 h at reflux temperature,
NaOH solution was added followed by the dropwise addition
of 30% H2O2 (30 mL), and the mixture was refluxed for 1.5 h.
The aqueous phase was extracted with ether, and the com-
bined organic layers were washed with water, dried with K2-
CO3, concentrated, and distilled to give 2-(tert-butyldimeth-
ylsilyl)ethanol.33 (b) Compound 1e was prepared as described
above for the preparation of 1d from (R)-BINOL and 2-(tert-
butyldimethylsilyl)ethoxymethyl chloride, which was prepared
from 2-(tert-butyldimethylsilyl)ethanol with paraformaldehyde
and gaseous hydrogen chloride:34 TLC (hexanes-ethyl acetate
) 4:1) Rf ) 0.57; IR (film) 2953, 1509, 1472, 1235, 1015, 828,
We have developed a new chiral hydroxymethylation
reagent that has a chiral leaving group and demonstrated
that this reagent can introduce a functionalized carbon
directly to prochiral silyl enol ethers and trisubstituted
alkenes with high enantioselectivities. The electrophilic
addition proceeds through the SN2 substitution mecha-
nism with cleavage of an acetal, which is dual activated
by SnCl4 and the γ-effect of silicon. The present protocol
is highly effective for the asymmetric construction of not
only tertiary but also quaternary carbon stereocenters.
Our chiral leaving group-Lewis acid system is also
effective for enantioselective synthesis of cyclic terpenes,
which has no remarkable functional group.
Exp er im en ta l Section
(R)-2,2′-Bis[2-(t r im et h ylsilyl)et h oxym et h oxy]-1,1′-b i-
n a p h th yl (1d ). To a solution of (R)-2,2′-dihydroxy-1,1′-bi-
naphthyl (2.86 g, 10 mmol) in dry THF (100 mL) was added
sodium hydride (60% dispersion in mineral oil, 880 mg, 22
mmol) portionwise at 0 °C. After being stirred for 1 h,
2-(trimethylsilyl)ethoxymethyl chloride (3.89 mL, 22 mmol)
was added dropwise, and the reaction mixture was allowed to
warm to room temperature. After being stirred for 2 h at the
same temperature, the mixture was quenched with brine and
extracted with ether. The combined organic layers were dried
over anhydrous MgSO4, concentrated, and purified by column
chromatography on silica gel using hexanes-ethyl acetate
(50:1 to 35:1) as eluent to give 1d (5.45 g, >99% yield) as a
viscous oil: TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.56; IR
1
758 cm-1; H NMR (CDCl3, 300 MHz) δ -0.19 (s, 12H), 0.79
(s, 18H), 0.87-1.08 (m, 4H), 3.51-3.57 (m, 4H), 5.19 (d, J )
7.1 Hz, 2H), 5.35 (d, J ) 7.1 Hz, 2H), 7.30-7.54 (m, 6H), 7.78
(d, J ) 9.0 Hz, 2H), 8.05 (d, J ) 8.1 Hz, 2H), 8.14 (d, J ) 9.0
Hz, 2H); 13C NMR (CDCl3, 75 MHz) δ -6.0 (2C), 13.9, 16.4,
26.5, 66.3, 93.7, 117.6, 121.4, 124.1, 125.7, 126.4, 128.0, 129.4,
129.9, 134.1, 152.9; [R]26.6 ) +56.5 (c ) 4.30, CHCl3). Anal.
D
(film) 2953, 1509, 1248, 1034, 1015, 860, 835 cm-1; H NMR
1
Calcd for C42H46O4Si2: C, 75.18; H, 6.91. Found: C, 75.18; H,
7.10.
(CDCl3, 300 MHz) δ -0.11 (s, 18H), 0.65-0.82 (m, 4H), 3.29-
3.42 (m, 4H), 5.00 (d, J ) 6.9 Hz, 2H), 5.15 (d, J ) 6.9 Hz,
2H), 7.11-7.35 (m, 6H), 7.59 (d, J ) 9.0 Hz, 2H), 7.59 (d, J )
7.8 Hz, 2H), 7.94 (d, J ) 8.7 Hz, 2H); 13C NMR (CDCl3, 75
MHz) δ -1.2, 18.2, 66.3, 94.0, 117.8, 121.6, 124.3, 125.9, 126.6,
(R)-2,2′-Bis[2-(d im et h ylp h en ylsilyl)et h oxym et h oxy]-
1,1′-bin a p h th yl (1f). (a) Ethyl triphenylsilyl acetate, which
was prepared following the procedure described by Fes-
senden,35 was reduced by lithium aluminum hydride to give
128.2, 129.6, 130.1, 134.3, 153.1; [R]31.0 ) +71.5 (c ) 1.86,
D
CHCl3). Anal. Calcd for C32H42O4Si2: C, 70.28; H, 7.74.
Found: C, 70.32; H, 7.69.
(31) Qian, C.; Huang, T.; Zhu, C.; Sun, J . J . Chem. Soc., Perkin
(R)-2,2′-Di(m et h oxym et h oxy)-1,1′-b in a p h t h yl (1a ).31
Compound 1a was prepared from chloromethyl methyl ether
and (R)-BINOL as described above for the preparation of 1d .
(R)-2,2′-Di(b en zyloxym et h oxy)-1,1′-b in a p h t h yl (1b ).
Compound 1b was prepared from benzyloxymethyl chloride
and (R)-BINOL as described above for the preparation of 1d :
Trans. 1 1998, 2097.
(32) Takahashi, M.; Ogasawara, K. Tetrahedron: Asymmetry 1997,
8, 3125.
(33) Soderquist, J . A.; Rivera, I.; Negron, A. J . Org. Chem. 1989,
54, 4051.
(34) Pyne, S. G.; Hensel, M. J .; Fuchs, P. L. J . Am. Chem. Soc. 1982,
104, 5719.
J . Org. Chem, Vol. 67, No. 15, 2002 5131

Nakamura et al.
2-(dimethylphenylsilyl)ethanol. (b) Compound 1f was prepared
as described above for the preparation of 1d from (R)-BINOL
and 2-(dimethylphenylsilyl)ethoxymethyl chloride, which was
prepared from 2-(dimethylphenylsilyl)ethanol with paraform-
aldehyde and gaseous hydrogen chloride:34 TLC (hexanes-
ethyl acetate ) 4:1) Rf ) 0.49; IR (film) 2955, 1507, 1235, 1034,
temperature. After being stirred for 2-3 h, the solution was
quenched with water and extracted with ether twice, and the
combined extracts were dried over MgSO4, filtered, and
concentrated. The crude product was purified by column
chromatography on silica gel to give the desired R-hydroxy-
methyl ketone in quantitative yield.
The physical properties and analytical data of R-[2-(tri-
methylsilyl)ethoxymethyl] ketones and R-hydroxymethyl ke-
tones thus are listed below.
820, 752 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.16 (s, 12H),
;
0.88-1.06 (m, 4H), 3.32-3.38 (m, 4H), 4.91 (d, J ) 6.9 Hz,
2H), 5.08 (d, J ) 6.9 Hz, 2H), 7.08-7.40 (m, 16H), 7.53 (d, J
) 8.7 Hz, 2H), 7.85 (d, J ) 7.8 Hz, 2H), 7.91 (d, J ) 9.3 Hz,
2H); 13C NMR (CDCl3, 75 MHz) δ -2.7, -2.6, 17.1, 65.8, 93.7,
117.5, 121.3, 124.0, 125.7, 126.3, 127.9, 128.0, 129.1, 129.4,
(R )-(+)-2-P h e n yl-2-m e t h oxym e t h ylc yc loh e xa n on e
(5a ): TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.46; HPLC
(Chiralpak AD, hexane-i-PrOH ) 200:1, flow rate ) 1.0 mL/
min) tR ) 7.76 (minor), 9.36 (major) min; IR (film) 2938, 1705,
1449, 1105, 702 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.68-1.80
(m, 3H), 1.90-2.09 (m, 2H), 2.26-2.32 (m, 2H), 2.70-2.78 (m,
1H), 3.24 (s, 3H), 3.29 (d, J ) 9.4 Hz, 1H), 3.74 (d, J ) 9.4 Hz,
1H), 7.22-7.39 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 21.3,
27.8, 32.2, 40.3, 58.4, 59.6, 79.1, 127.1 (2C), 127.2, 129.0 (2C),
129.9, 133.5, 134.1, 138.6, 152.9; [R]26.8 ) +48.1 (c ) 4.27,
D
CHCl3). Anal. Calcd for C38H54O4Si2: C, 72.33; H, 8.63.
Found: C, 72.45; H, 8.79.
13C NMR Assign m en ts for a 1:1 2a -Sn Cl4 Com p lex.
(R)-2,2′-Bis(m eth oxym eth oxy)-1,1′-bin a p h th yl (1a ): 13C
NMR (75 MHz, CD2Cl2, -78 °C) δ 57.9, 95.6, 117.7, 121.5,
126.1, 126.9, 128.6, 130.1, 131.2, 131.4, 135.5, 154.0.
1a -Sn Cl4: 13C NMR (75 MHz, CD2Cl2, -78 °C) δ 60.1,
102.2 (br), 123.3 (br), 126.0 (br), 128.2 (2C), 129.3, 130.4, 132.6,
133.2, 134.7, 150.8 (br).
138.8, 212.2; [R]26.0 ) +52.3 (c ) 0.34, CHCl3) for 23% ee.
D
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 76.91;
H, 8.43.
(R)-(+)-2-P h e n yl-2-b e n zyloxym e t h ylcycloh e xa n on e
(5b): TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.48; HPLC
(Chiralpak AD, hexane-i-PrOH ) 200:1, flow rate ) 1.0 mL/
min) tR ) 9.86 (minor), 10.98 (major) min; IR (film) 2938, 1705,
1453, 1100, 700 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.68-1.80
(m, 3H), 1.84-2.10 (m, 2H), 2.24-2.32 (m, 2H), 2.77-2.84 (m,
1H), 3.41 (d, J ) 9.2 Hz, 1H), 3.81 (d, J ) 9.2 Hz, 1H), 4.35 (d,
J ) 12.3 Hz, 1H), 4.46 (d, J ) 12.3 Hz, 1H), 7.17-7.36 (m,
10H); 13C NMR (CDCl3, 75 MHz) δ 21.3, 27.8, 32.4, 40.2, 58.5,
73.3, 76.5, 127.1, 127.2 (2C), 127.3, 127.4 (2C), 128.3, 128.9,
138.7 (2C), 138.9 (2C), 212.3; [R]26.0D ) +34.8 (c ) 1.30, CHCl3)
for 18% ee. Anal. Calcd for C20H22O2: C, 81.60; H, 7.53.
Found: C, 81.56; H, 7.64.
(R)-2-Meth oxy-2′-m eth oxym eth oxy-1,1′-bin aph th yl (1g):
13C NMR (75 MHz, CD2Cl2, -78 °C) δ 57.8, 58.0, 95.3, 114.7,
117.7, 119.7, 121.6, 125.5, 126.1, 126.7, 126.9, 128.5, 128.6,
130.1, 130.5, 131.2, 131.3, 131.5, 135.5, 135.6, 153.8, 156.3.
1g-Sn Cl4: 13C NMR (75 MHz, CD2Cl2, -78 °C) δ 60.1, 66.9
(br), 103.0 (br), 122.7 (br), 123.7 (br), 124.9 (br), 126.3 (br),
128.1, 128.3, 129.4, 130.4, 130.5, 132.5, 133.0, 133.2, 133.3,
134.5 134.7 150.0 (br), 154.2.
(R)-2,2′-Dim eth oxy-1,1′-bin a p h th yl (1h ): 13C NMR (75
MHz, CD2Cl2, -78 °C) δ 58.2, 114.8, 119.8, 125.5, 126.6, 128.5,
130.1, 130.5, 131.5, 135.4, 156.3.
1h -Sn Cl4: 13C NMR (75 MHz, CD2Cl2, -78 °C) δ 68.6,
124.6, 125.3, 128.6, 128.9, 129.6, 130.6, 133.3, 133.9, 134.3,
153.7.
(R)-(+)-2-P h en yl-2-[2-(tr im eth ylsilyl)eth oxym eth yl]cy-
cloh exa n on e (5d ). TLC (hexane-diethyl ether ) 10:1) Rf )
0.25; HPLC (Chiralpak AD, hexane-i-PrOH ) 100:1, flow rate
) 0.25 mL/min) tR ) 17.29 (minor), 18.19 (major) min; IR (film)
P r ep a r a tion of Silyl En ol Eth er s 4 a n d 6a -f. Com-
pounds 4, 6a , and 6b were prepared as described in the
literature.3f Compounds 6c,36 6d ,37 6e,38 and 6f 6 were prepared
by treating the corresponding ketones with LDA in THF,
followed by silylation (TMSCl, Et3N).
2951, 1709, 1105, 860, 837, 702 cm-1 1H NMR (CDCl3, 300
;
MHz) δ -0.07 (s, 9H), 0.82 (t, J ) 8.1 Hz, 2H), 1.65-1.80 (m,
3H), 1.88-2.10 (m, 2H), 2.25-2.32 (m, 2H), 2.75 (dd, J ) 3.0,
15.0 Hz, 1H), 3.26-3.35 (m, 1H), 3.30 (d, J ) 9.3 Hz, 1H),
3.38-3.50 (m, 1H), 3.75 (d, J ) 9.3 Hz, 1H), 7.20-7.36 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ -1.1 (3C), 18.1, 21.6, 28.0,
32.5, 40.5, 58.6, 69.1, 76.8, 127.3, 127.4 (2C), 129.1 (2C), 139.3,
Rep r esen ta tive P r oced u r e for th e En a n tioselective
2-(Tr im eth ylsilyl)eth oxym eth ylation of Silyl En ol Eth er s
w ith (R)-1d in th e P r esen ce of Tin Tetr a ch lor id e a n d
th e Su bsequ en t Dep r otection of th e 2-(Tr im eth ylsilyl)-
eth yl Gr ou p . To a solution of a silyl enol ether (0.5 mmol)
and (R)-1d (0.55 mmol) in dichloromethane or 1-chloropropane
(2.5 mL) was added a 1 M solution of SnCl4 (0.55 mmol) in
dichloromethane over 30 min under argon atmosphere at the
temperature indicated in Table 1 or 3 (a pentane-nitrogen
liquid bath, -125 °C; a hexane-nitrogen liquid bath, -97 °C;
an acetone-dry ice bath, -78 °C). After being stirred under
the conditions indicated in Table 1 or 3, the reaction was
quenched with triethylamine (0.55 mmol) and a saturated
NaHCO3 solution. Then the mixture was warmed to room
temperature and extracted with ether. The combined organic
layers were dried over anhydrous MgSO4, concentrated, and
purified by column chromatography on silica gel to give the
desired a-[2-(trimethylsilyl)ethoxymethyl] ketone. The ee of the
ketone was determined by HPLC or GC analysis or by
subsequent conversion to the corresponding a-hydroxymethyl
ketone or its trifluoroacetate and GC analysis.
212.5; [R]26.1 ) +163.1 (c ) 3.09, CHCl3) for 93% ee. Anal.
D
Calcd for C18H28O2Si: C, 71.00; H, 9.27. Found: C, 70.93; H,
9.28. This compound was converted to (R)-2-hydroxymethyl-
2-phenylcyclohexanone: TLC (hexanes-ethyl acetate ) 4:1)
Rf ) 0.18; HPLC (Chiralpak OD-H, hexane-i-PrOH ) 9:1, flow
rate ) 1.0 mL/min) tR ) 6.51 (major), 7.28 (minor) min; IR
1
(film) 3400 (br), 2938, 1701, 1032, 702 cm-1;Å@ H NMR
(CDCl3, 300 MHz) δ 1.63-1.83 (m, 3H), 1.92-2.03 (m, 1H),
2.13-2.47 (4H), 2.54-2.64 (m, 1H), 3.36 (dd, J ) 8.7, 11.4 Hz,
1H), 3.88 (dd, J ) 6.3, 11.4 Hz, 1H), 7.17-7.42 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 21.4, 28.6, 32.2, 40.7, 60.3, 70.4, 127.2
(2C), 127.7, 129.4 (2C), 138.5, 216.2. Anal. Calcd for C13
16O2: C, 76.44; H, 7.89. Found: C, 76.47; H, 7.88.
(R)-(+)-2-P h en yl-2-[2-(ter t-bu tyld im eth ylsilyl)eth oxy-
-
H
m eth yl]cycloh exa n on e (5e): TLC (hexane-diethyl ether )
20:1) Rf ) 0.20; IR (film) 2951, 1709, 1125, 828, 702 cm-1; 1H
NMR (CDCl3, 300 MHz) δ -0.15 (s, 3H), -0.13 (s, 3H), 0.81
(s, 9H), 0.82-0.90 (m, 2H), 1.69-1.79 (m, 3H), 1.88-2.10 (m,
2H), 2.26-2.31 (m, 2H), 2.72-2.78 (m, 1H), 3.25-3.48 (m, 2H),
3.30 (d, J ) 9.6 Hz, 1H), 3.76 (d, J ) 9.6 Hz, 1H), 7.22-7.39
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ -6.0, -5.9, 13.9, 16.5,
21.3, 26.5 (3C), 27.7, 32.3, 40.3, 58.4, 69.1, 76.6, 127.1 (2C),
To a solution of R-[2-(trimethylsilyl)ethoxymethyl] ketone
(0.5 mmol), obtained in the above reaction, in THF (1.5 mL)
was added hydrogen fluoride (70%)-pyridine (1.5 mL) at -78
°C. The reaction mixture was allowed to warm to room
127.1, 128.9 (2C), 139.0, 212.2; [R]26.8 ) +109.58 (c ) 3.45,
(35) Fessenden, R. J .; Fessenden, J . S. J . Org. Chem. 1967, 32, 3535.
(36) Bonafoux, D.; Bordeau, M.; Biran, C.; Cazeau, P.; Dunogues,
J . J . Org. Chem. 1996, 61, 5532.
(37) Rubottom, G. M.; J uve, H. D., J r. J . Org. Chem. 1989, 54, 4051.
(38) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066.
D
CHCl3) for 76% ee. Anal. Calcd for C21H34O2Si: C, 72.78; H,
9.89. Found: C, 72.68; H, 10.03.
(R )-(+)-2-P h e n yl-2-[2-(d im e t h ylp h e n ylsilyl)e t h oxy-
m eth yl]cycloh exa n on e (5f): TLC (hexanes-ethyl acetate )
5132 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Electrophilic Addition to Prochiral Olefins
4:1) Rf ) 0.51; IR (film) 2951, 1709, 1118, 822, 758, 702 cm-1
;
6H), 2.64 (br, 1H), 3.78 (d, J ) 11.1 Hz, 1H), 3.51 (d, J ) 11.1
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 17.8, 22.7, 27.3, 27.4,
35.1, 40.0, 45.3, 49.6, 70.7, 223.3. The trifluoroacetate: GC
(γ-TA, column temperature ) 100 °C, 50 kPa) tR ) 11.31
(minor), 12.01 (major) min; 1H NMR (CDCl3, 300 MHz) δ 1.08
(s, 3H), 1.18 (s, 3H), 1.20 (s, 3H), 1.62-1.80 (m, 4H), 1.84-
1.96 (m, 2H), 4.03 (d, J ) 10.2 Hz, 1H), 4.62 (d, J ) 10.2 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 17.6, 22.8, 27.4, 27.7, 34.6,
39.5, 44.9, 48.0, 73.3, 112.9, 217.3. Other resonances for the
trifluoroacetate could not be discerned. Anal. Calcd for
1H NMR (CDCl3, 300 MHz) δ 0.20 (s, 3H), 0.21 (s, 3H), 1.06 (t,
J ) 8.0 Hz, 2H), 1.67-1.76 (m, 3H), 1.86-2.03 (m, 2H), 2.24-
2.30 (m, 2H), 2.67-2.74 (m, 1H), 3.26-3.36 (m, 1H), 3.28 (d,
J ) 9.4 Hz, 1H), 3.42-3.51 (m, 1H), 3.72 (d, J ) 9.4 Hz, 1H),
7.20-7.47 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ -2.7 (2C),
17.0, 21.2, 27.6, 32.2, 40.1, 58.2, 68.5, 76.7, 127.0, 127.1 (2C),
127.7 (2C), 128.7 (2C), 128.8, 133.5 (2C), 138.9, 139.0, 212.0;
[R]23.6 ) +93.7 (c ) 2.77, CHCl3) for 67% ee. Anal. Calcd for
D
C
23H30O2Si: C, 75.36; H, 8.25. Found: C, 75.36; H, 8.44.
C
10H18O2: C, 70.55; H, 10.66. Found: C, 70.61; H, 10.63.
(+)-2,4,4-Tr im eth yl-1-[2-(tr im eth ylsilyl)eth oxym eth oxy]-
(+)-2-(4-Met h oxyp h en yl)-2-[2-(t r im et h ylsilyl)et h oxy-
m eth yl]cycloh exa n on e (7a ). TLC (hexane-diethyl ether )
10:1) Rf ) 0.23; HPLC (Chiralpak AD, hexane-i-PrOH ) 40:
1, flow rate ) 0.5 mL/min) tR ) 10.2 (minor), 11.1 (major) min;
p en ta n -3-on e (7e): TLC (hexane-diethyl ether ) 10:1) Rf )
0.38; GC (γ-TA, column temperature ) 100 °C, 50 kPa) tR
)
IR (film) 2951, 1707, 1512, 1250, 860, 831 cm-1 1H NMR
;
18.55 (minor), 19.35 (major) min; IR (film) 2957, 1707, 11250,
1107, 860, 837 cm-1; H NMR (CDCl3, 300 MHz) δ -0.01 (s,
1
(CDCl3, 300 MHz) δ -0.06 (s, 9H), 0.83 (t, J ) 8.4 Hz, 2H),
1.64-1.79 (m, 3H), 1.86-2.09 (m, 2H), 2.28 (t, J ) 5.2 Hz, 2H),
2.67 (dd, J ) 3.4, 15.2 Hz, 1H), 3.25 (d, J ) 9.4 Hz, 1H), 3.28-
3.37, (m, 1H), 3.40-3.50 (m, 1H), 3.73 (d, J ) 9.4 Hz, 1H),
3.80 (s, 3H), 6.88 (d, J ) 8.7 Hz, 2H), 7.15 (d, J ) 8.7 Hz, 2H);
9H), 0.86 (t, J ) 8.4 Hz, 2H), 1.01 (d, J ) 6.6 Hz, 3H), 1.15 (s,
9H), 3.24-3.38 (m, 2H), 3.42 (t, J ) 8.4 Hz, 2H), 3.52 (t, J )
7.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ -1.1 (3C), 15.8, 18.4,
16.3 (3C), 40.4, 45.0, 68.6, 73.6, 218.7; [R]27.6 ) +20.0 (c )
D
[R]27.1 ) +163.0 (c ) 1.68, CHCl3) for 82% ee. Anal. Calcd for
3.00, CHCl3) for 74% ee. Anal. Calcd for C13H28O2Si: C, 63.88;
H, 11.54. Found: C, 63.89; H, 11.51. This compound was
converted to 1-hydroxy-2,4,4-trimethylpentan-3-one: TLC (hex-
anes-ethyl acetate ) 4:1) Rf ) 0.08; IR (film) 3400 (br), 2973,
1701, 1030, 992 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.09 (d, J
) 7.2 Hz, 3H), 1.18 (s, 9H), 2.10 (s, 1H), 3.21-3.31 (m, 1H),
3.58-3.62 (m, 1H), 3.71-3.78 (m, 1H); 13C NMR (CDCl3, 75
MHz) δ 15.3, 26.2 (3C), 42.0, 45.1, 65.7, 220.7. Anal. Calcd for
C8H16O2: C, 66.63; H, 11.18. Found: C, 66.71; H, 11.11.
(R)-(+)-3,3,5-Tr im eth yl-6-[2-(tr im eth ylsilyl)eth oxy]h ex-
1-en -4-on e (7f): TLC (hexane-diethyl ether ) 10:1) Rf ) 0.38;
D
C
19H30O3Si: C, 68.22; H, 9.04. Found: C, 68.19; H, 9.07.
(+)-2-P h en yl-2-[2-(t r im et h ylsilyl)et h oxym et h yl]cyc-
loh ep ta n on e (7b): TLC (hexane-diethyl ether ) 10:1) Rf )
0.38; IR (film) 2951, 1701, 1107, 860, 837, 700 cm-1; 1H NMR
(CDCl3, 300 MHz) δ -0.10 (s, 9H), 0.78 (t, J ) 8.4 Hz, 2H),
1.34-1.58 (m, 3H), 1.75-2.04 (m, 4H), 2.27-2.34 (m, 1H),
2.46-2.54 (m, 1H), 2.72 (dd, J ) 9.2, 14.7 Hz, 1H), 3.22-3.44
(m, 2H), 3.62 (d, J ) 10.4 Hz, 1H), 3.70 (d, J ) 10.4 Hz, 1H),
7.20-7.35 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ -1.1 (3C),
18.1, 24.7, 27.1, 31.1 (2C), 42.1, 60.2, 69.1, 75.0, 127.2, 127.4
IR (film) 2973, 1713, 1250, 1107, 860, 837 cm-1 1H NMR
;
(2C), 128.7 (2C), 141.6, 214.5; [R]27.5 ) +103.4 (c ) 1.58,
D
(CDCl3, 300 MHz) δ -0.01 (s, 9H), 0.87 (t, J ) 8.4, 2H), 0.98
(d, J ) 6.3 Hz, 3H), 1.22 (s, 6H), 3.19-3.32 (m, 2H), 3.42 (t, J
) 8.4 Hz, 2H), 3.42-3.53 (m, 1H), 5.13-5.24 (m, 2H), 5.95 (dd,
J ) 10.5, 17.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ -1.1 (3C),
16.0, 18.4, 23.3 (2C), 41.2, 51.6, 68.6, 73.4, 114.9, 142.2, 215.8;
CHCl3) for 86% ee. Anal. Calcd for C19H30O2Si: C, 71.64; H,
9.49. Found: C, 71.73; H, 9.47. The ee was determined by
conversion to 2-(hydroxymethyl)-2-phenylcycloheptanone and
HPLC analysis: HPLC (Chiralcel OD-H, hexane-i-PrOH )
9:1, flow rate ) 0.5 mL/min) tR ) 15.25 (major), 17.12 (minor)
min; IR (film) 3400 (br), 2932, 1698, 1057, 700 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.36-1.60 (m, 3H), 1.76-1.86 (m, 2H),
1.95-2.11 (m, 2H), 2.33-3.57 (m, 4H), 3.69 (dd, J ) 5.7, 10.8
Hz, 1H), 3.82 (d, J ) 10.8 Hz, 1H), 7.15-7.39 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 25.2, 26.9, 30.9, 32.6, 42.3, 61.0, 70.3,
127.2 (2C), 127.6, 129.1 (2C), 140.9, 217.2. Anal. Calcd for
[R]28.1 ) +35.6 (c ) 2.79, CHCl3) for 79% ee. Anal. Calcd for
D
C
14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.52; H, 11.04. The
ee was determined by conversion to 6-hydroxy-3,3,5-trimeth-
ylhex-1-en-4-one, trifluoroacetylation, and GC analysis. 6-hy-
droxy-3,3,5-trimethylhex-1-en-4-one: IR (film) 3400 (br), 2977,
1710, 1011, 992 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.05 (d, J
) 7.2 Hz, 3H), 1.24 (s, 3H), 1.25 (s, 3H), 1.90 (br, 1H), 3.13-
3.24 (m, 1H), 3.56 (dd, J ) 3.9, 10.8 Hz, 1H), 3.64-3.73 (m,
1H), 51.8-5.24 (m, 2H), 5.93 (dd, J ) 10.5, 17.4 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 15.4, 23.3, 23.4, 42.8, 51.7, 65.5,
115.3, 141.8, 217.5. Anal. Calcd for C9H16O2: C, 69.19; H,
10.32. Found: C, 69.21; H, 10.29. The trifluoroacetate: GC
(γ-TA, column temperature ) 80 °C, 100 kPa) tR ) 6.13
C
14H18O2: C, 77.03; H, 8.31. Found: C, 77.06; H, 8.30.
(+)-2,4-Dip h en yl-1-[2-(t r im et h ylsilyl)et h oxy]-3-b u t a -
n on e (7c): TLC (hexane-diethyl ether ) 10:1) Rf ) 0.25;
HPLC (Chiralcel OB-H, hexane-i-PrOH ) 50:1, flow rate )
0.5 mL/min) tR ) 13.2 (major), 18.5 (minor) min; IR (film) 1717,
1248, 1103, 860, 837, 700 cm-1; 1H NMR (CDCl3, 300 MHz) δ
0.04 (s, 9H), 0.86 (t, J ) 8.4 Hz, 2H), 3.38-3.55 (m, 3H), 3.71
(s, 2H), 4.01 (t, J ) 8.6 Hz, 1H), 4.06-4.11 (m, 1H), 7.05-7.35
(m, 10H); 13C NMR (CDCl3, 300 MHz) δ -1.1 (3C), 18.3, 49.9,
58.1, 68.8, 71.7, 127.2, 127.9, 128.8 (4C), 129.2 (2C), 130.0 (2C),
1
(minor), 7.05 (major) min; H NMR (CDCl3, 300 MHz) δ 1.07
(d, J ) 6.9 Hz, 3H), 1.23 (s, 3H), 1.26 (s, 3H), 3.37-3.51 (m,
1H), 4.24 (dd, J ) 5.4, 10.2 Hz, 1H), 4.45 (t, J ) 10.2 Hz, 1H),
5.22-5.28 (m, 2H), 5.88 (dd, J ) 10.5, 17.4 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 15.5, 23.0, 23.1, 49.3, 51.7, 69.8, 114.7 (q,
J CF ) 284 Hz), 116.1, 141.2, 213.3. Other resonances for the
trifluoroacetate could not be discerned.
134.1, 136.1, 206.8; [R]29.6 ) +60.7 (c ) 1.00, CHCl3) for 64%
D
ee. Anal. Calcd for C21H28O2Si: C, 74.07; H, 8.29. Found: C,
74.02; H, 8.31.
(+)-2,6,6-Tr im eth yl-2-[2-(tr im eth ylsilyl)eth oxym eth yl]-
cycloh exa n on e (7d ): TLC (hexane-diethyl ether ) 10:1) Rf
) 0.30; IR (film) 2951, 1701, 1109, 860, 839 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ -0.01 (s, 9H), 0.87 (t, J ) 7.8 Hz, 2H),
1.07 (s, 3H), 1.08 (s, 3H), 1.12 (s, 3H), 1.55-1.86 (m, 5H), 2.00-
2.09 (m, 1H), 3.10 (d, J ) 8.9 Hz, 1H), 3.41-3.53 (m, 2H), 3.57
(d, J ) 8.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ -1.0 (3C),
18.1, 18.2, 23.7, 27.3, 28.1, 35.0, 29.7, 44.7, 49.0, 68.8, 77.1,
219.4; [R]28.5D ) +4.25 (c ) 2.84, CHCl3) for 71% ee. Anal. Calcd
for C15H30O2Si: C, 66.61; H, 11.18. Found: C, 66.59; H, 11.21.
The ee was determined by conversion to 2,6,6-trimethyl-2-
(hydroxymethyl)cyclohexanone, trifluoroacetylation, and GC
analysis. 2,6,6-Tr im et h yl-2-(h yd r oxym et h yl)cycloh ex-
a n on e: TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.18; IR (film)
Deter m in a tion of th e Absolu te Con figu r a tion of
2-P h e n y l-2-[(2-t r im e t h y ls ily l)e t h o x y m e t h y l]c y c lo -
h exa n on e (5d ). To a solution of 2-hydroxymethyl-2-phenyl-
cyclohexanone (122.6 mg, 0.6 mmol, 81% ee) derived from 5d
and N,N-diisopropylethylamine (127 mL, 0.73 mmol) in dichlo-
romethane (5 mL) was added methanesulfonyl chloride (57 mL,
0.73 mmol) at -78 °C, and the reaction mixture was allowed
to warm to room temperature. After being stirred for 2 h, the
reaction mixture was quenched with saturated ammonium
1
3500 (br), 2932, 1692, 1466, 1051 cm-1; H NMR (CDCl3, 300
MHz) δ 1.07 (s, 3H), 1.18 (s, 3H), 1.19 (s, 3H), 1.51-1.97 (m,
J . Org. Chem, Vol. 67, No. 15, 2002 5133

Nakamura et al.
chloride and extracted with ether twice, and the combined
extracts were dried over MgSO4, filtered, and concentrated.
The crude product was purified by column chromatography
on silica gel using hexanes-ethyl acetate (4:1) as eluent to
give the corresponding methanesulfonate (168.7 mg, 0.54
mmol, 90% yield): TLC (hexanes-ethyl acetate ) 4:1) Rf )
3.40-3.58 (m, 3H), 4.98-5.05 (m, 2H), 5.98 (dd, J ) 10.2, 18.1
Hz, 1H).
To a solution of a diastereomeric mixture (191 mg, 0.74
mmol) of 4,4-dimethyl-2-[(2-trimethylsilyl)ethoxymethyl]hex-
5-en-3-ol in dichloromethane (5 mL) was added lead tetra-
acetate (443.4 mg, 1 mmol) at -78 °C. The reaction mixture
was allowed to warm to room temperature. After being stirred
at room temperature for 2 h, ca. 0.5 g of silica gel was added
(for filtration aid), the mixture was filtered, and the filtrate
was concentrated to obtain 2-[2-(trimethylsilyl)ethoxymethyl]-
propionaldehyde (9) as an oil. The crude aldehyde was used
in the next step without purification. 9: TLC (hexanes-ethyl
acetate ) 4:1) Rf ) 0.29; 1H NMR (CDCl3, 300 MHz) δ 0.01 (s,
9H), 0.85-0.95 (m, 2H), 1.11 (d, J ) 6.9 Hz, 3H), 2.54-2.67
(m, 1H), 3.45-3.60 (m, 4H), 9.71 (s, 1H).
1
0.11; H NMR (CDCl3, 300 MHz) δ 1.65-1.87 (m, 3H), 1.93-
2.13 (m, 2H), 2.28-2.40 (m, 2H), 2.73-2.82 (m, 1H), 2.84 (s,
3H), 4.07 (d, J ) 10.5 Hz, 1H), 4.49 (d, J ) 10.5 Hz, 1H), 7.22-
7.45 (m, 5H).
To a solution of the methanesulfonate (156.2 mg, 0.5 mmol)
in dry THF (1 mL) was added Superhydride (0.75 mL, 0.75
mmol, 1 M in THF). After being stirred at room temperature
for 6 h, the reaction mixture was quenched with ice-1 N HCl,
extracted with ether twice, and the combined extracts were
dried over MgSO4, filtered, and concentrated. The crude
product was purified by column chromatography on silica gel
using hexane-diethyl ether (10:1) as eluent to give a diaster-
eomeric mixture of 2-methyl-2-phenylcyclohexanol (87.5 mg,
0.46 mmol, 92% yield): TLC (hexanes-ethyl acetate ) 4:1) Rf
) 0.43; 1H NMR (CDCl3, 300 MHz) δ 1.00-1.04 (m, 1H), 1.27
(s, 3H), 1.36-1.92 (m, 7H), 2.12-2.29 (m, 1H), 3.91-4.14 (m,
1H), 7.19-7.50 (m, 5H).
To a solution of 2-methyl-2-phenylcyclohexanol (78.7 mg,
0.41 mmol) in dichloromethane were added pyridinium chlo-
rochromate (221 mg, 1.03 mmol) and sodium acetate (202 mg,
2.46 mmol) at room temperature. After the mixture was stirred
for 7 h, magnesium sulfate (500 mg) was added. After being
stirred for 0.5 h, the reaction mixture was filtered and
concentrated. The crude product was purified by column
chromatography on silica gel using hexane-diethyl ether (30:
1-25:1) as eluent to give 2-methyl-2-phenylcyclohexanone
(70.2 mg, 0.37 mmol, 91% yield): TLC (hexanes-ethyl acetate
) 4:1) Rf ) 0.50; [R]D ) +155.9 (c ) 2.16, cyclohexane) [lit.39
[R]D ) -163 (cyclohexane) for the (S)-enantiomer];1H NMR
(CDCl3, 300 MHz) δ 1.27 (s, 3H), 1.61-1.82 (m, 4H), 1.89-
2.01 (m, 1H), 2.25-2.43 (m, 2H), 2.61-2.76 (m, 1H), 7.14-
7.40 (m, 5H).
The crude aldehyde 9 was dissolved in dry THF (1 mL) was
added lithium aluminum hydride (34.2 mg, 0.90 mmol) at 0
°C, and the reaction mixture was allowed to warm to room
temperature. After being stirred for 2 h, the reaction mixture
was quenched with ice-1 N HCl, extracted with ether twice,
and the combined extracts were dried over MgSO4, filtered,
and concentrated. The crude product was purified by column
chromatography on silica gel using hexanes-ethyl acetate (20:
1) as eluent to give 2-[(2-trimethylsilyl)ethoxymethyl]-1-pro-
panol (10) (121.6 mg, 0.64 mmol, 84% yield). 10: TLC (hexanes-
1
ethyl acetate ) 4:1) Rf ) 0.23; H NMR (CDCl3, 300 MHz) δ
0.02 (s, 9H), 0.86 (d, J ) 6.9 Hz, 3H), 0.94 (t, J ) 8.3 Hz, 2H),
1.97-2.12 (m, 1H), 2.87 (dd, J ) 4.6, 8.1 Hz, 1H), 3.34 (t, J )
8.1 Hz, 1H), 3.46-3.68 (m, 5H).
To a solution of 10 (118.3 mg, 0.62 mmol) in dry THF (1.4
mL) and DMF (0.5 mL) was added sodium hydride (60%
dispersion in mineral oil, 32 mg, 0.80 mmol) portionwise at 0
°C, and the reaction mixture was allowed to warm to room
temperature. After being stirred for 1 h, benzyl bromide (80
mL, 0.65 mmol) was added. After being stirred for 1 h, the
reaction mixture was quenched with brine and extracted with
ether, and the combined extracts were dried over MgSO4,
filtered, and concentrated. The crude product was purified by
column chromatography on silica gel using hexanes-ethyl
acetate (50:1) as eluent to give 1-benzyloxy-2-methyl-3-[(2-
trimethylsilyl)ethoxy]propane (158.3 mg, 0.56 mmol, 91%
yield): TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.60; 1H NMR
(CDCl3, 300 MHz) δ 0.01 (s, 9H), 0.92 (t, J ) 7.9 Hz, 2H), 0.97
(d, J ) 6.9 Hz, 3H), 2.06 (octet, J ) 6.8 Hz, 1H), 3.23-3.53
(m, 6H), 4.51 (s, 2H), 7.22-7.39 (m, 5H).
Benzyloxy-2-methyl-3-[(2-trimethylsilyl)ethoxy]propane was
converted to the known (-)-(S)-1-benzyloxy-3-hydroxy-2-me-
thylpropane by treatment with hydrogen fluoride-pyridine in
THF (see the above general procedure): >95% yield; TLC
Deter m in a tion of th e Absolu te Con figu r a tion of (+)-
7f.10 To a solution of (+)-6f (197 mg, 0.77 mmol, 79% ee) in
dry THF (1 mL) was added lithium aluminum hydride (35.1
mg, 0.92 mmol) at 0 °C, and the reaction mixture was allowed
to warm to room temperature. After being stirred for 2 h, the
reaction mixture was quenched with ice-1 N HCl and ex-
tracted with ether twice, and the combined extracts were dried
over MgSO4, filtered, and concentrated. The crude product was
purified by column chromatography on silica gel using hex-
anes-ethyl acetate (20:1) as eluent to give a diastereomeric
mixture of 4,4-dimethyl-2-[(2-trimethylsilyl)ethoxymethyl]hex-
5-en-3-ol (191 mg, 0.74 mmol, 96% yield). Minor diastere-
omer: TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.52; 1H NMR
(CDCl3, 300 MHz) δ 0.00 (s, 9H), 0.80-1.00 (m, 2H), 1.03 (s,
3H), 1.04 (d, J ) 6.9 Hz, 3H), 1.06 (s, 3H), 1.85-1.95 (m, 1H),
3.23 (dd, J ) 4.6, 6.9 Hz, 1H), 3.32-3.53 (m, 3H), 3.59 (dd, J
) 4.6, 9.2 Hz, 1H), 3.75 (d, J ) 6.9 Hz, 1H), 4.95-4.99 (m,
1H), 4.99-5.04 (m, 1H), 5.98 (dd, J ) 10.0, 16.7 Hz, 1H); Major
diastereomer: TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.48;
1H NMR (CDCl3, 300 MHz) δ 0.01 (s, 9H), 0.90-0.10 (m, 2H),
0.95 (d, J ) 6.9 Hz, 3H), 1.05 (s, 3H), 1.07 (s, 3H), 1.90-2.02
(m, 1H), 2.44 (d, J ) 4.4 Hz, 1H), 3.37 (d, J ) 5.7 Hz, 2H),
(hexanes-ethyl acetate ) 4:1) Rf ) 0.12; [R]31.0 ) -15.6 (c )
D
2.21, CHCl3) [lit.40 [R]D ) +17.2 (c ) 3.24, CHCl3) for the (R)-
enantiomer]; 1H NMR (CDCl3, 300 MHz) δ 0.88 (d, J ) 6.9
Hz, 3H), 2.00-2.17 (m, 1H), 2.55 (br, 1H), 3.43 (t, J ) 8.4 Hz,
1H), 3.50-3.70 (m, 3H), 4.52 (s, 2H), 7.26-7.40 (m, 5H).
Gen er a l P r oced u r e for th e En a n tioselective SEM
Ad d ition to P r och ir a l Alk en es w ith (R)-1d a n d Sn Cl4
(See Ta ble 5 for Rea ction Con d ition s). To a solution of (R)-
1d (0.55 or 0.5 mmol) in dichloromethane (0.5 or 3 mL) was
added a 1 M solution of SnCl4 in dichloromethane (0.55 or 0.5
mL) dropwise at -78 °C. The solution was cooled to -97 °C,
and then substrate 11 (0.5 or 2.5 mmol) was added dropwise.
The reaction mixture was stirred at the same temperature for
5-12 h and quenched with excess triethylamine and saturated
aqueous sodium hydrogen carbonate successively. After being
allowed to warm to room temperature, the resultant mixture
was extracted with hexane twice. The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated
in vacuo to yield the crude product. Column chromatography
of the crude product on silica gel (eluting with hexanes-ethyl
acetate) gave 12 including 0-26% of 13 as a minor product.
(39) Paquette, L. A.; Gilday, J . P.; Maynard, G. D. J . Org. Chem.
1983, 48, 422.
(40) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
5134 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Electrophilic Addition to Prochiral Olefins
Regioselective Deh yd r och lor in a tion of 13. A mixed solu-
tion of 12 and 13 obtained in the above SEM addition in 2,4,6-
collidine (0.5 mL) was heated with reflux conditions for 3 h.
After being cooled to room temperature, the resultant mixture
was washed with 1 M hydrogen chloride and brine andex-
tracted with hexane. The combined organic layers were dried
over magnesium sulfate, filtered, and concentrated in vacuo
to yield the crude product. Column chromatography on silica
gel (eluting with hexanes-ethyl acetate) gave 12 including
with less than 3% of 14 in good yield. Enantiopurities of 12a -d
were determined by GC or HPLC analysis.
8.3 Hz, 2H), 1.68 (s, 3H), 1.70 (s, 3H), 2.05-2.11 (m, 1H), 2.68
(dd, J ) 10.5, 13.5 Hz, 1H), 3.08 (dd, J ) 3.0, 13.5 Hz, 1H),
3.28-3.42 (m, 4H), 7.13-7.31 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ -1.2 (3C), 18.3, 31.0, 32.2, 34.2, 53.8, 66.1, 68.1, 68.7,
126.0, 128.4 (2C), 129.3 (2C), 141.4. By the regioselective
dehydrochlorination described above, the mixture of 12b and
13b was converted to 12b and 1% of 14b: GC (PEG, column
temperature ) 140 °C, 100 kPa) tR ) 7.3 min; 1H NMR (CDCl3,
300 MHz) δ 1.82 (s, 6H), 3.85 (s, 2H). Other resonances could
not be discerned for this minor isomer.
2-Cycloh exyl-3-m eth yl-1-[2-(tr im eth ylsilyl)eth oxy]-3-
bu ten e (12c): GC (γ-TA column, column temperature ) 80
°C, 30 kPa) for the corresponding homoallyl trifluoroacetate
tR ) 40.5 (minor enantiomer), 42.1 (major enantiomer) min;
TLC (hexanes-EtOAc ) 15:1, Rf ) 0.46; IR (neat) 2923, 2853,
1248, 1111, 860 cm-1; 1H NMR (CDCl3, 300 MHz) δ -0.01 (s,
9H), 0.83-1.00 (m, 4H), 1.10-1.35 (m, 4H), 1.60-1.79 (m, 5H),
1.66 (s, 3H), 2.08 (dt, J ) 5.1, 8.7 Hz, 1H), 3.39 (t, J ) 8.7 Hz,
2H), 3.44-3.53 (m, 2H), 4.68 (s, 1H), 4.80 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ -1.3 (3C), 18.1, 20.2, 26.7 (2C), 26.8, 31.3,
2-E t h y l-3-m e t h y l-1-[2-(t r i m e t h y ls i ly l)e t h o x y ]-3-
bu ten e (12a ): GC (PEG, column temperature ) 80 °C, 100
kPa) tR ) 2.9 min; HPLC (Daicel OD-H column, hexane-i-
PrOH ) 9:1, flow rate ) 1.0 mL/min) for the R-naphthylure-
thane of the corresponding homoallylic alcohol tR ) 18.2 (minor
enantiomer), 21.6 (major enantiomer) min; TLC (hexanes-
EtOAc ) 15:1) Rf ) 0.55; IR (neat) 2959, 1248, 1111, 860, 837
cm-1; 1H NMR (CDCl3, 300 MHz) δ -0.01 (s, 9H), 0.84 (t, J )
7.5 Hz, 3H), 0.92 (t, J ) 8.3 Hz, 2H), 1.22-1.37 (m, 1H), 1.46-
1.56 (m, 1H), 1.65 (s, 3H), 2.19-2.28 (m, 1H), 3.29 (dd, J )
6.8, 9.3 Hz, 1H), 3.37 (dd, J ) 7.5, 9.3 Hz, 1H), 3.48 (t, J ) 8.3
Hz, 2H), 4.73 (s, 1H), 4.81 (s, 1H); 13C NMR (CDCl3, 75 MHz)
δ -1.2 (3C), 11.8, 18.2, 19.5, 22.9, 49.0, 68.2, 73.1, 112.1, 145.8;
31.5, 37.6, 53.0, 68.1, 71.0, 112.5, 146.1; [R]26.8 ) -1.3 (c )
D
3.14, CHCl3) for 77% ee. Anal. Calcd for C16H32OSi: C, 71.57;
H, 12.01. Found: C, 71.34; H, 12.32.
1-[1-[[2-(Tr im eth ylsilyl)eth oxy]m eth yl]p en tyl]-1-cyclo-
h exen e (12d ): GC (γ-TA column, column temperature ) 80
°C, 50 kPa) for the corresponding homoallylic trifluoroacetate
tR ) 42.3 (minor enantiomer), 45.0 (major enantiomer) min;
TLC (hexanes-EtOAc ) 15:1) Rf ) 0.53; IR (neat) 2928, 2857,
1248, 1120, 858, 837 cm-1; 1H NMR (CDCl3, 300 MHz) δ -0.01
(s, 9H), 0.85-0.94 (m, 5H), 1.15-1.33 (m, 5H), 1.34-1.46 (m,
1H), 1.50-1.54 (m, 4H), 1.82-1.90 (m, 2H), 1.94-2.03 (m, 2H),
2.11-2.22 (m, 1H), 3.24 (dd, J ) 7.1, 9.3 Hz, 1H), 3.33 (dd, J
) 7.2, 9.3 Hz, 1H), 3.47 (dt, J ) 2.1, 8.4 Hz, 2H), 5.42 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ -1.2 (3C), 14.3, 18.2, 22.9, 23.0,
[R]26.9 ) -12.0 (c ) 3.00, CHCl3) for 81% ee. Anal. Calcd for
D
C
17H28OSi: C, 67.22; H, 12.22. Found: C, 67.10; H, 12.44.
The absolute configuration of 12a was determined to be R
by comparison of optical rotation values with data in the
literature41 after conversion to the known a-naphthylurethan
with hydrogenation (Pd/C, H2, EtOH, rt, 12 h), deprotection
of 2-(trimethylsilyl)ethyl group (hydrogen fluoride-pyridine,
CH3CN, rt, 3 h), and addition of 1-naphthyl isocyanate (cat.
DMAP, pentane, rt, 2 h): [R]25.7D ) +1.6 (c ) 2.42, CHCl3) [lit.41
[R]24D ) -3.5 (CHCl3) for the (S)-enantiomer]; 1H NMR (CDCl3,
300 MHz) δ 0.91-0.97 (m, 9H), 1.24-1.54 (m, 3H), 1.74-1.92
(m, 1H), 4.14-4.26 (m, 2H), 6.91(s, 1H), 7.45-7.55 (m, 3H),
7.67 (d, J ) 8.4 Hz, 1H), 7.84-7.92 (m, 3H); 13C NMR (CDCl3,
300 MHz) δ 12.2, 19.6 (2C), 21.0, 28.2, 45.3, 66.4, 119.2, 120.6,
125.1, 125.9, 126.0, 126.2, 128.8, 132.7, 134.2, 154.9.
23.2, 25.4, 25.5, 29.7, 29.8, 47.7, 68.1, 73.6, 122.9, 138.0; [R]25.9
D
) -14.3 (c ) 3.00, CHCl3) for 73% ee. Anal. Calcd for C17H34
-
OSi: C, 72.27; H, 12.13. Found: C, 72.04; H, 12.47.
tr a n s-2,3,4,4a,9,9a-Hexah ydr o-1,1,4a-tr im eth yl-2-[2-(tr i-
m eth ylsilyl)eth oxym eth yl]-1H-xan th en e (12e): HPLC (hex-
ane-i-PrOH ) 400:1, flow rate ) 1.0 mL/min, Daicel OD-H
column) tR ) 5.5 (major enantiomer), 7.6 (minor enantiomer)
min; TLC (hexanes-EtOAc ) 15:1) Rf ) 0.33; IR (neat) 2867,
The product of SEM addition reaction 12a included 26% of
13a : TLC (hexanes-EtOAc ) 15:1) Rf ) 0.55; 1H NMR (CDCl3,
300 MHz) δ -0.01 (s, 9H), 0.92 (t, J ) 8.1 Hz, 2H), 1.00 (t, J
) 7.5 Hz, 3H), 1.25-1.54 (m, 2H), 1.60 (s, 3H), 1.62 (s, 3H),
1.65-1.75 (m, 1H), 3.42-3.58 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ -1.3 (3C), 13.2, 18.3, 21.5, 31.2, 31.6, 53.2, 65.0, 68.2,
70.1. By the regioselective dehydrochlorination described
above, the mixture of 12a and 13a was converted to 12a and
3% of 14a : GC (PEG, column temperature ) 80 °C, 100 kPa)
1586, 1489, 1456, 1248, 1100, 860, 837, 752 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ -0.01 (s, 9H), 0.77 (s, 3H), 0.95 (t, J )
8.3 Hz, 2H), 1.10 (s, 3H), 1.20 (s, 3H), 1.20-1.36 (m, 1H), 1.45-
1.55 (m, 1H), 1.64-1.75 (m, 2H), 1.98-2.04 (m, 2H), 2.59-
2.77 (m, 2H), 3.10 (t, J ) 9.0 Hz, 1H), 3.41-3.54 (m, 2H), 3.61
(dd, J ) 3.3, 9.0 Hz, 1H), 6.74-6.84 (m, 2H), 7.04-7.10 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ -1.2 (3C), 16.4, 18.4, 19.9,
23.0, 24.1, 28.6, 35.7, 39.6, 48.1, 49.1, 68.4, 71.8, 77.1, 117.1,
1
tR ) 3.5 min; H NMR (CDCl3, 300 MHz) δ 1.70 (s, 3H), 1.73
(s, 3H), 2.13 (q, J ) 5.6 Hz, 2H), 3.92 (s, 2H). Other resonances
could not be discerned for this minor isomer.
119.8, 122.5, 127.3, 129.8, 153.2; [R]33.2 ) +10.4 (c ) 2.57,
D
2-B e n zy l-3-m e t h y l-1-[2-(t r im e t h y ls ily l)e t h o x y ]-3-
bu ten e (12b): GC (PEG, column temperature ) 140 °C, 100
kPa) tR ) 6.3 min; HPLC (Daicel OD-H column, hexane-i-
PrOH ) 400:1, flow rate ) 0.25 mL/min) tR ) 17.7 (major
enantiomer), 20.2 (minor enantiomer) min; TLC (hexanes-
EtOAc ) 15:1, Rf ) 0.50; HPLC (hexane-i-PrOH ) 400:1, flow
rate ) 0.25 mL/min, Daicel OD-H column) tR ) 17.7 (major
enantiomer), 20.2 (minor enantiomer) min; IR (neat) 2867,
1248, 1111, 837, 699 cm-1; 1H NMR (CDCl3, 300 MHz) δ -0.01
(s, 9H), 0.92 (t, J ) 8.2 Hz, 2H), 1.69 (s, 3H), 2.58-2.67 (m,
2H), 2.79-2.88 (m, 1H), 3.30-3.39 (m, 2H), 3.47 (t, J ) 8.2
Hz, 2H), 4.66 (s, 1H), 4.76 (s, 1H), 7.13-7.28 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ -1.2 (3C), 18.2, 20.5, 37.0, 48.8, 68.3, 72.3,
CHCl3) for 54% ee. Anal. Calcd for C22H36O2Si: C, 73.28; H,
10.06. Found: C, 73.30; H, 10.19.
Gen er a l P r oced u r e for t h e Dep r ot ect ion of 2-(Tr i-
m eth ylsilyl)eth yl Gr ou p of 12a -d . To a solution of 12a -d
(0.4 mmol) in acetonitrile (0.8 mL) was added 70% hydrogen
fluoride‚pyridine (0.4 mL) dropwise at -40 °C, and the mixture
was stirred at room temperature for 3 h. After being cooled to
-40 °C, the resultant mixture was carefully neutralized with
triethylamine (3.5 mL) to prevent the decomposition of homo-
allyl alcohols with hydrogen fluoride aqueous solution, and
subsequently, the saturated aqueous sodium hydrogen carbon-
ate was poured into the mixture. After being allowed to warm
to room temperature, the mixture was extracted with ether,
dried over magnesium sulfate, filtered, and concentrated in
vacuo to yield the crude product. Column chromatography on
silica gel (eluting with hexanes-ethyl acetate) gave the
corresponding optically active homoallylic alcohol in good yield.
112.3, 125.9, 128.2 (2C), 129.2 (2C), 140.7, 145.6; [R]27.6
)
D
-13.5 (c ) 3.19, CHCl3) for 84% ee. Anal. Calcd for C17H28
-
OSi: C, 73.85; H, 10.21. Found: C, 73.58; H, 10.50.
The product of SEM addition reaction 12b included 15% of
13b: 1H NMR (CDCl3, 300 MHz) δ -0.02 (s, 9H), 0.85 (t, J )
1
2-Eth yl-3-m eth yl-3-bu ten ol (15a ): H NMR (CDCl3, 300
MHz) δ 0.88 (t, J ) 6.6 Hz, 3H), 1.20-1.50 (m, 3H), 1.67 (s,
3H), 2.14-2.24 (m, 1H), 3.45-3.56 (m, 2H), 4.83 (s, 1H), 4.95
(s, 1H). Th e cor r esp on d in g R-n a p h th ylu r eth a n e: TLC
(41) (a) Fuji, K.; Tanaka, F.; Node, M. Tetrahedron Lett. 1991, 32,
7281. (b) Tsuda, K.; Kishida, Y.; Hayatsu, R. J . Am. Chem. Soc. 1960,
82, 3396.
J . Org. Chem, Vol. 67, No. 15, 2002 5135

Nakamura et al.
(hexanes-EtOAc ) 4:1) Rf ) 0.41, HPLC (hexane-i-PrOH )
9:1, flow rate ) 1.0 mL/min, Daicel OD-H) tR ) 18.2 (minor
enantiomer), 21.6 (major enantiomer) min; IR (neat) 3312
(R)-2-Ner yloxy-2′-h yd r oxy-1,1′-bin a p h th yl (3a ). To a
solution of (R)-2,2′-dihydroxy-1,1′-binaphthyl (8.59 g, 30 mmol),
triphenylphosphine (7.87 g, 30 mmol), and nerol (7.9 mL, 45
mmol) in dry THF (240 mL) was added diethyl azodicarboxy-
late (14.5 mL, 33 mmol) dropwise. The reaction mixture was
stirred for 12 h and then evaporated under reduced pressure.
The crude product was purified by column chromatography
on silica gel using hexanes-ethyl acetate (30:1) as eluent to
give 3a (7.76 g, 61% yield) as a viscous oil: TLC (hexanes-
ethyl acetate ) 4:1) Rf ) 0.49; IR (film) 2928, 1592, 1507, 1208,
814, 749 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.54 (s, 3H), 1.61
(s, 3H), 1.64 (s, 3H), 1.92 (s, 4H), 4.47-4.59 (m, 2H), 4.93-
5.00 (m, 2H), 5.13-5.18 (m, 1H), 7.05 (d, J ) 8.7 Hz, 1H),
7.14-7.39 (m, 6H), 7.46 (d, J ) 9.0 Hz, 1H), 7.83-7.91 (m,
3H), 8.01 (d, J ) 9.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
17.8, 23.4, 25.8, 26.4, 32.3, 66.5, 115.3, 116.6, 117.1, 117.7,
120.9, 123.2, 123.8, 124.3, 125.1, 125.2, 126.4, 127.2, 128.1,
128.2, 129.2, 129.7, 129.8, 130.7, 132.1, 133.9, 134.2, 141.0,
(NH), 1710 (CdO), 1539, 1499, 1215, 772 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.88 (t, J ) 7.4 Hz, 3H), 1.30-1.55 (m,
2H), 1.70 (s, 3H), 2.34-2.45 (m, 1H), 4.12-4.23 (m, 2H), 4.80
(s, 1H), 4.89 (s, 1H), 6.94 (s, 1H), 7.43-7.54 (m, 3H), 7.66 (d,
J ) 8.1 Hz, 1H), 7.84-7.87 (m, 3H); 13C NMR (CDCl3, 75 MHz)
δ 11.7, 19.2, 22.5, 48.2, 67.3, 113.3, 120.7, 125.1, 125.9, 126.1
(2C), 126.3 (2C), 128.8, 132.6, 134.2, 144.5, 154.6; [R]26.3
)
D
-5.9 (c ) 2.00, CHCl3) for 73% ee; HRMS (EI+) calcd for C18H21
-
NO2 283.1572, found 283.1570.
2-Ben zyl-3-m eth yl-3-bu ten ol (15b): TLC (hexanes-EtOAc
) 4:1) Rf ) 0.22; IR (neat) 3650-3300 (br, OH), 2928, 1456,
1
1040, 891, 698 cm-1; H NMR (CDCl3, 300 MHz) δ 1.40 (br,
1H), 1.73 (s, 3H), 2.50-2.63 (m, 1H), 2.71 (d, J ) 6.9 Hz, 2H),
3.50-3.62 (m, 2H), 4.19 (s, 1H), 4.94 (s, 1H), 7.16-7.28 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ 20.1, 36.3, 51.2, 63.2, 113.9,
126.2, 128.4 (2C), 129.0 (2C), 140.1, 145.0; HRMS (EI+) calcd
for C12H14 (M - H2O) 158.1096, found 158.1079.
151.4, 155.3; [R]25.8 ) -31.7 (c ) 3.15, CHCl3). Anal. Calcd
D
for C30H30O2: C, 85.27; H, 7.16. Found: C, 85.28; H, 7.29.
(R)-2-Ner yloxy-2′-m eth oxy-1,1′-bin a p h th yl (3b). To a
stirred suspension of potassium carbonate (415 mg, 3 mmol)
in acetone were added 3a (423 mg, 1 mmol) and iodomethane
(190 mL, 3 mmol). The reaction mixture was heated at reflux
for 12 h, quenched with saturated NH4Cl in an ice bath, and
concentrated in vacuo. The resulting residue was diluted with
ether, washed with H2O, dried over MgSO4, and concentrated.
The crude product was purified by column chromatography
on silica gel using hexanes-ethyl acetate (35:1) as eluent to
give 3b (352 mg, 81% yield) as a viscous oil: TLC (hexanes-
ethyl acetate ) 4:1) Rf ) 0.45; IR (film) 2932, 1593, 1509, 1263,
806, 749 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.54 (s, 3H), 1.59
(s, 3H), 1.64 (s, 3H), 1.89 (s, 4H), 3.77 (s, 3H), 4.48 (d, J ) 6.3
Hz, 2H), 4.93-5.00 (m, 1H), 5.10-5.15 (m, 1H), 7.09-7.46 (m,
8H), 7.86 (d, J ) 8.4 Hz, 2H), 4.91-7.98 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 17.8, 23.4, 25.9, 26.5, 32.3, 56.9, 66.8, 114.1,
117.0, 119.7, 121.1, 121.7, 123.5, 123.7, 123.9, 125.5, 125.6,
126.2, 126.3, 127.9, 128.0, 129.2 (2C), 129.4, 129.5, 132.0,
2-Cycloh exyl-3-m eth yl-3-bu ten ol (15c): TLC (hexanes-
EtOAc ) 4:1) Rf ) 0.20; GC (80 °C (column temperature), 30
kPa, γ-TA) for the corresponding homoallylic trifluoroacetate
tR ) 40.5 (minor enantiomer), 42.1 (major enantiomer) min;
IR (neat) 3600-3200 (br, OH), 2924, 1449, 1089, 1067, 1053,
1
1013, 889 cm-1; H NMR (CDCl3, 300 MHz) δ 0.86-0.98 (m,
2H), 1.13-1.39 (m, 5H), 1.60-1.78 (m, 5H), 1.68 (s, 3H), 2.05
(dt, J ) 4.5, 9.8 Hz, 1H), 3.46 (dt, J ) 3.0, 10.2 Hz, 1H), 3.69-
3.77 (m, 1H), 4.83 (s, 1H), 4.99 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 19.2, 26.4, 26.5, 26.7, 31.0, 31.8, 36.9, 56.2, 61.6, 115.0,
145.0; [R]25.9D ) -1.9 (c ) 1.62, CHCl3) for 77% ee; HRMS (EI+)
calcd for C11H18 (M - H2O) 150.1409, found 150.1404.
2-(Cycloh ex-1-en -1-yl)h exa n -1-ol (15d ): TLC (hexanes-
EtOAc ) 4:1) Rf ) 0.30, GC (80 °C (column temperature), 50
kPa, γ-TA) for the trifluoroacetate tR ) 42.3 (minor enanti-
omer), 45.0 (major enantiomer) min; IR (neat) 3550-3100 (br,
OH), 2928, 1466, 1055, 1017 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.88 (t, J ) 6.9 Hz, 3H), 1.16-1.37 (m, 7H), 1.54-1.67 (m,
4H), 1.84-1.90 (m, 2H), 2.01-2.08 (m, 2H), 2.09-2.18 (m, 1H),
3.39-3.51 (m, 2H), 5.55 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
14.2, 22.8, 22.9, 23.0, 24.4, 25.4, 28.9, 29.7, 50.4, 64.1, 125.6,
134.1, 134.2, 139.9, 154.5, 155.0; [R]26.5 ) +27.7 (c ) 3.15,
D
CHCl3). Anal. Calcd for C31H32O2: C, 85.28; H, 7.39. Found:
C, 85.19; H, 7.46.
(R)-2-Ner yloxy-(1,1′-bin a p h th a len )-2′-yl p-tolu en esu l-
fon a te (3c). To a stirred solution of 3a (423 mg, 1 mmol) and
triethylamine (420 mL, 3 mmol) in ether at -78 °C was added
tosyl chloride (190 mg, 1 mmol). The reaction mixture was
allowed to warm to room temperature. After being stirred for
5 h, the mixture was poured into saturated NaHCO3 solution,
extracted with ether, dried over MgSO4, and concentrated. The
crude product was purified by column chromatography on
silica gel using hexanes-ethyl acetate (15:1) as eluent to give
3c (508 mg, 88% yield) as a viscous oil. TLC (hexanes-ethyl
acetate ) 4:1) Rf ) 0.34; IR (film) 1593, 1509, 1372, 1173, 967,
137.1; HRMS (EI+) calcd for
C12H22NO 182.1671, found
182.1686.
Rep r esen ta tive P r oced u r e for th e En a n tioselective
In tr a m olecu la r Cycliza tion of (R)-3 (or 19) a n d Sn Cl4
(See Ta ble 7 for Rea ction Con d ition s). To a solution of
(R)-3 (or 19) (0.5 mmol) in 1-chloropropane (2.5 mL) was added
a 1 M solution of SnCl4 in hexane (0.5 mL), which was distilled
before preparation of its solution, dropwise at -78 °C. The
reaction mixture was stirred at the same temperature for 4-12
h and quenched with a saturated NaHCO3 solution. After
being allowed to warm to room temperature, the resultant
mixture was extracted with pentane twice. The combined
organic layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo to yield the crude product. Column
chromatography of the crude product on silica gel (eluting with
pentane) gave limonene (16) including 30∼40% of 1742 as a
minor product (or 20). 16: GC (CHIRALDEX B-DM, column
temperature ) 90 °C, 7 kPa) tR ) 56.3 [(S)-16], tR ) 59.7 [(R)-
16] min; [R]30.8 ) 103.5 (c ) 0.87, pentane) for 92% ee [[R]20
1
824 cm-1; H NMR (CDCl3, 300 MHz) δ 1.56 (s, 3H), 1.60 (s,
3H), 1.66 (s, 3H), 1.95 (s, 4H), 2.20 (s, 3H), 4.44-4.56 (m, 2H),
4.96-5.05 (m, 1H), 5.15-5.19 (m, 1H), 6.65-6.73 (m, 3H),
6.96-7.45 (m, 8H), 7.73-7.99 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 17.7, 21.6, 23.3, 25.8, 26.4, 32.3, 66.2, 115.5, 117.7,
121.3, 121.7, 123.2, 123.8, 125.6, 125.8, 125.9, 126.3, 126.6,
126.9, 127.2 (2C), 127.6, 128.1, 128.7, 128.9 (2C), 129.4, 129.8,
132.0, 132.1, 132.9, 133.5, 133.7, 140.1, 144.0, 145.8, 154.5;
D
D
[R]27.3 ) -0.53 (c ) 2.50, CHCl3). Anal. Calcd for C37H36O4S:
D
) +123 (neat) for (R)-limonene]. 20: GC (CHIRALDEX B-DM,
C, 77.05; H, 6.29. Found: C, 76.98; H, 6.37.
column temperature ) 150 °C, 25 kPa) tR ) 42.1 (major), tR
)
43.1 (minor) min; [R]26.4 ) +4.9 (c ) 0.86, CHCl3) for 19% ee
(R)-2-Ner yloxy-(1,1′-bin a p h th a len )-2′-yl Ben zoa te (3d ).
Compound 3d was prepared as previously described by use of
benzoyl chloride (85% yield): TLC (hexanes-ethyl acetate )
D
[lit.28 [R]D ) -19.7 (c ) 0.35) for natural (R)-neocembrene];
TLC (hexanes-ethyl acetate ) 15:1) Rf ) 0.67; 1H NMR
(CDCl3, 300 MHz) δ 1.31-1.42 (m, 1H), 1.57 (s, 6H), 1.59 (s,
3H), 1.66 (s, 3H), 1.75-2.30 (m, 14H), 4.65-4.66 (m, 1H),
4.70-4.72 (m, 1H), 4.98 (t, J ) 5.9 Hz, 1H), 5.06 (t, J ) 6.3
Hz, 1H), 5.19 (t, J ) 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 15.5, 15.7, 18.2, 19.5, 23.9, 25.0, 28.3, 32.6, 34.1, 39.1,
39.6, 46.1, 110.3, 121.9, 124.2, 126.1, 133.6, 134.1, 135.0,
149.4.
4:1) Rf ) 0.42; IR (film) 1738, 1266, 1215, 1088, 750, 708 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.52 (s, 3H), 1.55 (s, 3H), 1.63
(s, 3H), 1.90 (s, 4H), 4.46(d, J ) 6.6 Hz, 2H), 4.93-5.00 (m,
1H), 5.08-5.13 (m, 1H), 7.19-7.66 (m, 13H), 7.80 (d, J ) 7.8
Hz, 1H), 7.87 (d, J ) 9.0 Hz, 1H), 7.96 (d, J ) 8.4 Hz, 1H),
8.03 (d, J ) 8.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 17.7,
23.3, 25.8, 26.4, 32.3, 66.2, 115.5, 118.6, 121.4, 122.0, 123.6,
5136 J . Org. Chem., Vol. 67, No. 15, 2002

Enantioselective Electrophilic Addition to Prochiral Olefins
123.8, 125.2, 125.4 (2C), 126.3, 126.4, 126.5, 127.8, 128.1 (3C),
128.9, 129.0, 129.6, 129.7 (3C), 131.7, 131.9, 133.0, 133.8,
geranylgeraniol43 followed by esterification: TLC (hexanes-
ethyl acetate ) 15:1) Rf ) 0.20; IR (film) 1740, 1266, 1215,
1088, 754, 708 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 3H),
1.53 (s, 3H), 1.57 (s, 3H), 1.59 (s, 3H), 1.67 (s, 3H), 1.81-2.09
(m, 12H), 4.40-4.54 (m, 2H), 4.94-5.15 (m, 4H), 7.20-7.66
(m, 13H), 7.79 (d, J ) 7.5 Hz, 1H), 7.86 (d, J ) 9.0 Hz, 1H),
7.96 (d, J ) 8.1 Hz, 1H), 8.03 (d, J ) 8.7 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 16.0, 16.1, 16.4, 17.7, 25.7, 26.1, 26.6, 26.8,
39.3, 39.7, 39.8, 66.3, 115.4, 118.4, 120.4, 122.0, 123.5, 123.8,
124.2, 124.4, 125.2, 125.4 (2C), 126.3, 126.4, 126.5, 127.8, 128.1
(3C), 128.8, 128.9, 129.5, 129.6 (3C), 131.1, 131.7, 132.9, 133.7,
133.9, 134.8, 135.1, 139.7, 147.0, 154.2, 164.5; [R]24.3D ) +1.26
(c ) 3.39, CHCl3). Anal. Calcd for C47H50O3: C, 85.16; H, 7.60.
Found: C,85.16; H, 7.72.
133.9, 139.8, 147.0, 154.3, 164.6; [R]27.4 ) -2.79 (c ) 3.79,
D
CHCl3). Anal. Calcd for C37H34O3: C, 84.38; H, 6.51. Found:
C, 84.40; H, 6.58.
(R)-2-Ner yloxy-(1,1′-b in a p h t h a len )-2′-yl p -Tr iflu or o-
m eth ylben zoa te (3e). Compound 3e was prepared as previ-
ously described by use of p-trifluoromethylbenzoyl chloride
(85% yield): TLC (hexanes-ethyl acetate ) 4:1) Rf ) 0.50; IR
(film) 1744, 1325, 1267, 1215, 1088, 1017, 806 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.52 (s, 3H), 1.54 (s, 3H), 1.62 (s, 3H),
1.90 (s, 4H), 4.45 (d, J ) 6.3 Hz, 2H), 4.91-4.99 (m, 1H), 5.05-
5.10 (m, 1H), 7.15-7.51 (m, 9H), 7.62-7.66 (m, 3H), 7.81 (d,
J ) 8.0 Hz, 1H), 7.88 (d, J ) 8.8 Hz, 1H), 7.97 (d, J ) 8.0 Hz,
1H), 8.04 (d, J ) 8.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
17.7, 23.4, 25.8, 26.5, 32.4, 66.3, 115.6, 118.4, 121.3, 121.6,
123.8 (2C), 125.25, 125.30, 125.34, 125.4, 125.7, 126.6 (2C),
126.7, 128.0, 128.2, 129.0, 129.1, 130.0, 130.2 (2C), 131.9,
132.1, 133.0, 133.8, 133.9, 134.2, 134.7, 140.1, 146.8, 154.4,
Ack n ow led gm en t. H.N. acknowledges a J SPS Fel-
lowship for J apanese J unior Scientists. We also thank
Dr. Shingo Nakamura for his helpful discussions re-
garding the calculations.
163.6; [R]25.5 ) -0.52 (c ) 3.85, CHCl3). Anal. Calcd for
D
J O020165L
C
38H33F3O3: C, 76.75; H, 5.59. Found: C, 76.73; H, 5.77.
(R)-2-(a ll-E-ger a n ylger a n yloxy)(1,1′-bin a p h th a len )-2′-
yl Ben zoa te (19). Compound 19 was prepared using a method
similar to that for 3d by Mitsunobu reaction with (E,E,E)-
(42) Bellesia, F.; Grandi, R.; Pagnoni, U. M.; Trave, R. J . Chem. Soc.,
Perkin Trans. 1 1979, 851.
(43) Eis, K.; Schmalz, H.-G. Synthesis 1997, 202.
J . Org. Chem, Vol. 67, No. 15, 2002 5137