Catalytic highly enantioselective alkylation of aldehydes with deactivated grignard reagents and synthesis of bioactive intermediate secondary arylpropanols

Article abstract of DOI:10.1021/jo101351t

Because of the high reactivity of Grignard reagents, a direct, highly enantioselective Grignard reaction with aldehydes has rarely been disclosed. In this report, Grignard reagents were introduced with bis[2-(N,N′- dimethylamino)ethyl] ether (BDMAEE) to effectively deactivate their reactivity; thus, a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(OⁱPr)₂. It is thought that BDMAEE chelates the in situ generated salts MgBr₂ from a Schlenk equilibrium of RMgBr and Mg(OⁱPr)Br from transmetalation of RMgBr with Ti(OⁱPr)₄. The Mg salts can actively promote the undesired background reaction to give the racemate. The chelation definitely inhibits the catalytic activity of the Mg salts, suppresses the unwanted background reaction, and enables the highly enantioselective addition catalyzed by (S)-BINOL-Ti(OⁱPr)₂. Consequently, the Mg salt byproducts were not removed, less Ti(OⁱPr)₄ than RMgBr was used, and extremely low temperature was avoided in this catalytic asymmetric reaction in comparison with the research disclosed before. Various alkyl Grignard reagents were investigated in the asymmetric addition, and ⁱBuMgBr resulted in the highest enantioselectivity, >99%. Furthermore, important intermediate secondary arylpropanols for chiral drug synthesis were effectively synthesized with high enantioselectivity, up to 97%, in one step.

Full text of DOI:10.1021/jo101351t

pubs.acs.org/joc
Catalytic Highly Enantioselective Alkylation of Aldehydes with
Deactivated Grignard Reagents and Synthesis of Bioactive Intermediate
Secondary Arylpropanols
Yi Liu,† Chao-Shan Da,*,†,‡ Sheng-Li Yu,† Xiao-Gang Yin,† Jun-Rui Wang,†
Xin-Yuan Fan,† Wei-Ping Li,§ and Rui Wang†
†Institute of Biochemistry & Molecular Biology, School of Life Sciences, and ‡State Key Laboratory of
Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China, and
§Department of Biology, Shantou University, Shantou 515063, People’s Republic of China
dachaoshan@lzu.edu.cn
Received July 8, 2010
Because of the high reactivity of Grignard reagents, a direct, highly enantioselective Grignard reaction
with aldehydes has rarely been disclosed. In this report, Grignard reagents were introduced with
bis[2-(N,N0-dimethylamino)ethyl] ether (BDMAEE) to effectively deactivate their reactivity; thus, a
highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-
BINOL-Ti(OiPr)2. It is thought that BDMAEE chelatesthe in situ generated salts MgBr2 from a Schlenk
equilibrium of RMgBr and Mg(OiPr)Br from transmetalation of RMgBr with Ti(OiPr)4. The Mg salts
can actively promote the undesired background reaction to give the racemate. The chelation definitely
inhibits the catalytic activity of the Mg salts, suppresses the unwanted background reaction, and enables
the highly enantioselective addition catalyzed by (S)-BINOL-Ti(OiPr)2. Consequently, the Mg salt
byproducts were not removed, less Ti(OiPr)4 than RMgBr was used, and extremely low temperature was
avoided in this catalytic asymmetric reaction in comparison with the research disclosed before. Various
i
alkyl Grignard reagents were investigated in the asymmetric addition, and BuMgBr resulted in the
highest enantioselectivity, >99%. Furthermore, important intermediate secondary arylpropanols for
chiral drug synthesis were effectively synthesized with high enantioselectivity, up to 97%, in one step.
1. Introduction
their synthesis has attracted significant attraction. The current
procedures to synthesize these alcohols include asymmetric
addition of expensive diorganozinc reagents to aldehydes1
and enantioselective reduction of prochiral ketones.2 The
Grignard reaction with aldehydes is an ideal method to prepare
the optically active secondary alcohols, because the easily
Enantioenriched secondary alcohols are very important
intermediates for asymmetric synthesis of medications and
(1) (a) Pu, L.; Yu, H. Chem. Rev. 2001, 101, 757. (b) Da, C.-S.; Ni, M.;
Han, Z.-J.; Yang, F.; Wang, R. J. Mol. Catal. A: Chem. 2006, 245, 1. (c) Da,
C.-S.; Han, Z.-J.; Ni, M.; Yang, F.; Liu, D.-X.; Zhou, Y.-F.; Wang, R.
Tetrahedron: Asymmetry 2003, 14, 659. (d) Nugent, W. A. Org. Lett. 2002, 4,
2133. (e) Chen, Y. K.; Costa, A. M.; Walsh, P. J. J. Am. Chem. Soc. 2001, 123,
5378. (f ) Huang, W. S.; Hu, Q. S.; Pu, L. J. Org. Chem. 1998, 63, 1364.
(g) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109,
7111. (h) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028.
(2) (a) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (b) Cho,
B. T. Chem. Soc. Rev. 2009, 38, 443. (c) Ikariya, T.; Blacker, A. J. Acc. Chem.
Res. 2007, 40, 1300. (d) Genet, J.-P. Acc. Chem. Res. 2003, 36, 908. (e) Tang,
W.; Zhang, X. M. Chem. Rev. 2003, 103, 3029. (f ) Corey, E. J.; Helal, C. J.
Angew. Chem., Int. Ed. 1998, 37, 1986.
DOI: 10.1021/jo101351t
r
Published on Web 09/13/2010
J. Org. Chem. 2010, 75, 6869–6878 6869
2010 American Chemical Society

Liu et al.
JOCArticle
SCHEME 1. Procedures of Asymmetric Alkylation of Aldehydes with Grignard Reagents
prepared Grignard reagents are among the least expensive
and most commonly used organometallic reagents in both
laboratory and industry.3 In comparison with those two
forementioned asymmetric procedures, however, catalytic
asymmetric Grignard additions to aldehydes have rarely
been reported because of the high reactivity of Grignard
reagents with these substrates. Therefore, the previous ob-
servations on asymmetric Grignard reactions were mainly
focused on the use of superstoichiometric enantioenriched
auxiliaries4 or even chiral solvents.5
The recent procedures using Griganrd reagents as starting
materials in addition to aldehydes were focused on trans-
metalation to form less reactive intermediates (i.e., ZnR2, R-Ti-
(OiPr)3). For example, Seebach and co-worker prepared salt-
free diorganozinc reagents from Grignard reagents via precip-
itation and filtration and used enantioenriched TADDOL as
an effective chiral ligand in combination with Ti(OiPr)4 to
realize a high enantioselectivity up to 99% (eq 1, Scheme 1).6
Later, Soai and co-workers employed PhMgBr to prepare
diphenylzinc in situ. The salt byproduct was removed by
filtration after introduction of 1,4-dioxane into the mixture.
They achieved enantioselectivities up to 82% using (1R,2S)-
(þ)-N,N-dibutylnorephedrine (DBNE) as a chiral ligand (eq 2).7
^ ꢀ
More recently, Charette and Cote employed Zn(MeO)2 and
alkyl Grignard reagents to generate dialkyl zinc reagents and
achieved enantioselecitivity as high as 98% (eq 3).8 Like
Seebach, they also needed salt-free orgonametallic inter-
mediates, which were obtained by centrifugation and filtration.
Another fascinating intermediate organometallic reagent is
R-Ti(OiPr)3, which has also been successfully used in the asym-
metric addition to aldehydes.9 Seebach and Weber prepared
salt-free R-Ti(OiPr)3 by direct transmetalation of Grignard
reagents and Ti(OiPr)3Cl at -78 °C with centrifugation and
filtration. R-Ti(OiPr)3 was then used to highly enantioselec-
tively add to aldehydes in the catalysis of in situ generated
TADDOL-Ti(OiPr)2 (eq 4).10 A significant improvement was
reported by Harada and coauthors. They used the chiral
ligand DPP-binol (2%) and R-Ti(OiPr)3 in their protocol.
R-Ti(OiPr)3 was prepared in situ from the Grignard reagent
RMgCl and 2-fold Ti(OiPr)4 at -78 °C, and then the mixture
containing R-Ti(OiPr)3 and Mg salts was very slowly intro-
duced into another mixture at 0 °C. The second mixture
contained the aldehyde and the in situ pregenerated catalyst
from DPP-binol and a large excess of Ti(OiPr)4. As high as
97% enantioselectivity was realized regardless of whether or
not Mg salts were removed (eq 5).11
(3) (a) Wakefield, B. J., Ed. Organomagnesium Methods in Organic
ꢀ
Synthesis; Academic Press: San Diego, CA, 1995. (b) Franzen, R. G. Tetra-
hedron 2000, 56, 685. (c) Richey, H. G., Ed. New Developments: Grignard
ꢀ
Reagents; Wiley: Chichester, U.K., 2000. (d) Lopez, F.; Minnaard, A. J.;
Feringa, B. L. Acc. Chem. Res. 2007, 40, 179. (e) Luderer, M. R.; Bailey,
W. F.; Luderer, M. R.; Fair, J. D.; Dancer, R. J.; Sommer, M. B. Tetra-
hedron: Asymmetry 2009, 20, 981.
On the basis of the Schlenk equilibrium (Scheme 2), the
Grignard reagent RMgX (X = Cl, Br) is believed to produce
(4) (a) Weber, B.; Seebach, D. Angew. Chem., Int. Ed. 1992, 31, 84.
(b) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117. (c) Mukaiyama, T.;
Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J. Am. Chem. Soc. 1979, 101, 1455.
(d) Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 9751.
(e) Yong, K. H.; Taylor, N. J.; Chong, J. M. Org. Lett. 2002, 4, 3553.
(f ) Rozema, M. J.; Fickes, M.; McLaughlin, M.; Rohde, B.; McDermotte, T.
Tetrahedron Lett. 2006, 47, 8767. (g) Pritchett, S.; Woodmansee, D. H.;
Gantzel, P.; Walsh, P. J. J. Am. Chem. Soc. 1998, 120, 6423.
(7) (a) Soai, K.; Kawase, Y.; Oshio, A. J. Chem. Soc., Perkin Trans. 1
1991, 1613. (b) Soai, K.; Kawase, Y. J. Chem. Soc., Perkin Trans. 1 1990, 3214.
^ ꢀ
(8) Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771.
(9) (a) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807. (b) Yang,
X.-W.; Shen, J.-H.; Da, C.-S.; Wang, H.-S.; Su, W.; Wang, R.; Chan, A. S. C.
J. Org. Chem. 2000, 65, 295. (c) Wu, K.; Gau, H. J. Am. Chem. Soc. 2006, 128,
14808. (d) Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc.
2002, 124, 10336.
(5) (a) Cohen, H. L.; Wright, G. F. J. Org. Chem. 1953, 18, 432. (b) Seebach,
D.; Dorr, H.; Bastani, B.; Ehrig, V. Angew. Chem., Int. Ed. 1969, 8, 982.
(c) Seebach, D.; Langer, W. Helv. Chim. Acta 1979, 62, 1701.
(6) (a) Seebach, D.; Behrendt, L.; Felix, D. Angew. Chem., Int. Ed. 1991,
€
30, 1008. (b) Von Dem Bussche-Hunnefeld, J. L.; Seebach, D. Tetrahedron
1992, 48, 5719.
(10) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473.
(11) (a) Muramatsu, Y.; Harada, T. Angew. Chem., Int. Ed. 2008, 47,
1088. (b) Muramatsu, Y.; Harada, T. Chem. Eur. J. 2008, 14, 10560.
6870 J. Org. Chem. Vol. 75, No. 20, 2010

Liu et al.
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SCHEME 2. Schlenk Equilibrium
R2Mg and the strong Lewis acid MgX2. Both RMgX and
R2Mg can readily add to aldehydes.12 The solvated MgX2
can activate the aldehyde and promote formation of the
racemate. Therefore, the presence of the Lewis acid Mg salts
in the catalytic asymmetric reaction system is a central reason
why the asymmetric Grignard reaction of aldehydes usually
results in poor enantioselectivity, in spite of the presence of a
chiral catalyst.
FIGURE 1. Intermediates for bioactive compounds.
Despite the recent successful use of Grignard reagents in
enantioselective additions to aldehydes, there are still con-
siderable limitations. Less reactive and salt-free organome-
tallic reagents from Grignard reagents must be prepared in
advance. The procedures to remove the salt byproduct are
normally laborious. The organometallic intermediates thus
prepared were then employed to add to aldehydes. In many
cases, extreme temperature was unavoidable. In some cases,
a great excess of Ti(OiPr)4 with respect to Grignard reagents
was used. These situations make it more important, challeng-
ing, and interesting to develop a catalytic, highly enantio-
selective alkylation of aldehydes using Grignard reagents
with use of a smaller amount of Ti(OiPr)4 and no exclusion of
the salts from the reaction system under mild conditions.
In 2007, we used these guidelines to start this work: no
removal of any salt byproduct from the reaction mixture, use
of less Ti(OiPr)4 than Grignard reagent, and no use of extremely
low temperature. The preliminary communication of this
work has recently been published.13a Herein we disclose the
full results of this study.
FIGURE 2. Ligands used in the study.
with expensive diphenylzinc by Bolm and co-workers16 and
the asymmetric conjugate reduction of chalcone by Xiao and
co-workers.17 In addition, reports of chiral arylpropanol
synthesis include asymmetric alkylation,18 vinylation,19 allyla-
tion of phenylpropionaldehyde,20 and asymmetric reduction
by biocatalytic21 and chemical protocols.22
On the basis of our preliminary work, we examined the
enantioselective synthesis of various secondary arylpropanols
via Grignard additions to aldehydes with ee’s up to 97% in
one step.
Enantioenriched secondary arylpropanols are important
intermediates to bioactive molecules, such as the optically
active secondary alcohols I-1 and I-2 (Figure 1), which were
used to prepare artificial immunosuppressors,14 the high-
affinity ligands of FKBP (FK 506 binding protein).15 The
ligands potentially inhibit the cis-trans-peptidylprolyl iso-
merase (rotamase) catalyzed by FK 506 (the immnosup-
pressor). Previously, the chiral alcohols were afforded by three
steps, including a racemic Grignard reaction. As an example,
we will discuss I-1. First, the reaction of benzaldehyde with
PhCH2CH2MgBr gave the racemic secondary alcohol I-1.
Second, the alcohol was then oxidized to the corresponding
prochiral ketone. Third, the ketone was enantioselectively
reduced back to the chiral alcohol by stoichiometric (þ)-B-
chlorodiisopinocamphenyl-borane.14,15 Finally, the enan-
tiopure I-1 was realized by recrystallization. Other methods
to obtain I-1 include phenylation of phenylpropionaldehyde
2. Results and Discussion
2.1. Selection of Chiral Ligands. We started this work with
study of nBuMgBr asymmetric addition to benzaldehyde
catalyzed by a series of documented enantioenriched C2-
symmetrical ligands (Figure 2). We did not have a plan to
prepare salt-free nBu-Ti(OiPr)3 to add to benzaldehyde. We
only wanted to observe what would happen if the in situ
generated nBu-Ti(OiPr)3 was allowed to directly react with
aldehydes on the conditions of no salt removal, less Ti(OiPr)4
(17) Wu, X.; Li, X.; Zanotti-Gerosa, A.; Pettaman, A.; Liu, J.; Mills,
A. J.; Xiao, J. Chem. Eur. J. 2008, 14, 2209.
ꢀ
´
(18) (a) Martınez, R.; Zoli, L.; Cozzi, P. G.; Ramon, D. J.; Yus, M.
Tetrahedron: Asymmetry 2008, 19, 2600. (b) Muramatsu, Y.; Harash, T.
Angew. Chem., Int. Ed. 2008, 47, 1088. (c) Ukon, T.; Harada, T. Eur. J. Org.
Chem. 2008, 4405. (d) Mata, Y.; Dieguez, M.; Pamies, O.; Woodward, S.
J. Org. Chem. 2006, 71, 8159. (e) Biswas, K.; Prieto, O.; Goldmith, P. J.;
Woodward, S. Angew. Chem., Int. Ed. 2005, 44, 2232.
(19) (a) Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7, 5417.
(b) Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031.
(12) (a) Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521. (b) Ashby,
E. C.; Laemmle, J.; Neumann, H. M. Acc. Chem. Res. 1974, 7, 272.
(13) (a) Da, C.-S.; Wang, J.-R.; Yin, X.-G.; Fan, X.-Y.; Liu, Y.; Yu,
S.-L. Org. Lett. 2009, 11, 5578. (b) Fan, X.-Y.; Yang, Y.-X.; Zhou, F.-F.; Yu,
S.-L.; Li, X.; Guo, Q.-P.; Du, Z.-X.; Da, C.-S. Chem. Eur. J. 2010, 16, 7968.
(14) (a) Holt, D. A.; Luengo, J. I.; Yamashita, D. S.; Oh, H.-J.; Konialian,
A. L.; Yen, H.-K.; Rozamus, L. W.; Brandt, M.; Bossard, M. J.; Levy, M. A.;
Egglestone, D. S.; Liang, J.; Schultz, L. W.; Stout, T. J.; Clardy, J. J. Am.
Chem. Soc. 1993, 115, 9925. (b) Ko, H. M.; Lee, D. J.; Kim, M. A.; Park, J.;
Lah, M. S.; Lee, E. Org. Lett. 2007, 9, 141.
(15) (a) Steiner, J. P.; Hamilton, G. S. Rotamase Enzyme Activity
Inhibitors, U.S. Patent 0,052,410, May 2, 2002. (b) Hamilton, G. S.; Steiner,
J. P. Small Molecular Inhibitors of Rotamase Enzyme Activity, U.S. Patent
6,509,477, Jan. 21, 2003.
(16) Bolm, C.; Kesselgruber, M.; Hermanns, N.; Hildbrand, J. P.; Raabe,
G. Angew. Chem., Int. Ed. 2001, 40, 1488.
(20) (a) Massa, A.; Acocella, M. R.; De Sio, U.; Villano, R.; Scettri, A.
Tetrahedron: Asymmetry 2009, 20, 202. (b) Simonini, V.; Benaglia, M.;
Benincori, T. Adv. Synth. Catal. 2008, 350, 561. (c) McManus, H. A.; Cozzi,
P. G.; Guiry, P. J. Adv. Synth. Catal. 2006, 348, 551. (d) Rauniya, V.; Zhai,
H.; Hall, D. G. J. Am. Chem. Soc. 2008, 130, 8481. (e) Xia, G.; Yamamoto, H.
J. Am. Chem. Soc. 2006, 128, 2554. (f ) Miller, J. J.; Sigman, M. S. Angew.
Chem., Int. Ed. 2008, 47, 771.
(21) (a) Voss, C. V.; Gruber, C. C.; Kroutil, W. Angew. Chem., Int. Ed.
2008, 47, 741. (b) Voss, C. V.; Gruber, C. C.; Faber, K.; Knaus, T.;
Matheroux, P.; Kroutil, W. J. Am. Chem. Soc. 2008, 130, 13969. (c) Musa,
M. M.; Zieglmann-Fjeld, K. I.; Vieille, C.; Zeikus, J. G.; Philipps, R. S.
Angew. Chem., Int. Ed. 2007, 46, 3091.
(22) (a) Mikhailine, A.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc.
2009, 131, 1394. (b) Bogliotti, N.; Dalko, P. I.; Cossy, J. Tetrahedron Lett.
2005, 46, 6915.
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TABLE 1. Catalyzed Asymmetric Addition of nBuMgBr to PhCHOa
TABLE 2. Selection of the Optimal Deactivating Additivea
amt of
Ti(OiPr)4
(equiv)
amt of
nBuMgBrb
(equiv)
amt of
amt of
b
b
Ti(OiPr)4 nBuMgBrb
ligand
(amt (mol %))
ligand
entry (amt (mol %))
additivec ee (%)d
entry
ee (%)c
(equiv)
(equiv)
1
2
3
4
5
6
7
8
9
L1 (10)
L2 (10)
L3 (10)
L4 (10)
L5 (10)
L1 (40)
L1 (40)
L1 (40)
L1 (40)
2.8
2.8
2.8
2.8
2.8
2.8
2.8
2.8
2.8
3.85
3.85
3.85
3.85
3.85
3.58
3.58
3.58
3.58d
69
60
5
33
6
50
75
80
55
1
2
3
4
5
6
7
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (40)
0.7
0.7
0.7
0.7
0.7
0.7
0.7
1.9
1.9
1.9
1.9
1.9
1.9
2.5
NMM
TMEDA
DMAP
hexamine
BDMAEE
BDMAEE
BDMAEE
54
50
45
48
70
68
98
anBuMgBr was introduced into Ti(OiPr)4 at the temperature of an
ice-salt bath; the reaction mixture was then naturally warmed to ambient
temperature. The amount used relative to benzaldehyde. Conditions
and abbreviations: additive/nBuMgBr = 1:1; NMM, N-methylmorpholine;
TMEDA, N,N,N0,N0-tetramethylethelenediamine; DMAP, 4-(dimethyl-
amino)pyridine; hexamine, hexamethylenetetramine (also called urotropine).
dDetermined by chiral HPLC.
a nBuMgBr was introduced into Ti(OiPr)4 on the condition of ice-salt
bath, and then the reaction temperature was naturally warmed to be
ambient. The amount used relative to benzaldehyde. Determined by
chiral HPLC. The configuration was assigned by comparison of the
optical rotation of the alcohol with the reported data.23 dThe Grignard
reagent is nBuMgCl.
b
c
b
c
transmetalation of aryllithium to ZnCl and rapidly promoted
the undesired background reaction. As a consequence, addi-
tion of TEEDA successfully improved the enantioselectivity
regardless of the presence of LiCl in the reaction system.
These reports gave us some indication that we could select
a chelating reagent to coordinate to Lewis acidic Mg salts.
This chelation could decrease the activity of Mg salts and
inhibit background reactions promoted by these Mg salts
accordingly. Therefore, this chelation could deactivate the
reactivity of Grignard reagents in part. A series of commer-
cially available ligands were screened (additive/nBuMgBr =
1:1), and the results are included in Table 2. It was found that
only BDMAEE with three coordinating atoms improved the
enantioselectivity (entries 1-5). Additionally, with BDMAEE,
the enantioselecitivity could be reproduced easily (entries 5-6).
While 40% (S)-BINOL was used, the enantioselectivity was
markedly enhanced to 98% (entry 7). This result indicated
that the reactivity of the Grignard reagent was effectively
inhibited with the addition of BDMAEE.
than the Grignard reagent, and mild reaction conditions.
The results are included in Table 1.
It could be concluded that (S)-BINOL (L1) formed the
best catalyst among the five chiral ligands examined (Table 1).
(S)-H8-BINOL (L2) exhibited lower enantioselectivity than
(S)-BINOL (entry 2). The least enantioselective ligands were
(S)-3,30-Me2BINOL (L3) and tosylated (1R,2R)-cyclohex-
anediamine (L5), both generating nearly racemic secondary
alcohols (entries 3 and 5). Unfortunately, it was very difficult
to reproduce the enantioselectivity of this transformation
(entries 6-8). Replacing nBuMgBr with nBuMgCl did not
give any improvement in enantioselectivity (entry 9). We
ascribed this phenomenon to the intermediate salts MgBr2
and MgBr(OiPr), which promote the racemic background
reaction.
2.2. Selection of the Deactivator of the Grignard Reagent.
We found that the research groups of Bolm and Walsh had
met with similar problems in their works about arylation of
aldehydes with arylzinc reagents.24,25 Neither group removed
the salt byproducts, however. In their study of the asym-
metric addition of diphenylzinc to aldehydes,24 Bolm and co-
workers found that diphenylzinc and ZnBr2 could actively
promote a racemic background reaction and lead to low
enantioselectivity. When they added dimethyl(polyethylene
glycol) (DiMPEG, Mw 2000) to the reaction mixture, the
additive effectively suppressed the catalytic activity of Ph2Zn
and ZnBr2 and the enantioselectivity was then remarkably
increased. Later, Walsh and co-workers demonstrated a cost-
effective protocol starting from inexpensive aryl bromides
and butyllithium to prepare arylzinc reagents for asymmetric
addition to aldehydes.25 They similarly used N,N,N0,N0-
tetraethylethylenediamine (TEEDA) as another potent in-
hibitor of the Lewis acidic LiCl, which was formed on the
2.3. Generality of Grignard Reagents. Further optimiza-
tion experiments revealed that the THF/TBME (tBuOMe)
solvent system and 0.84 equiv of Ti(OiPr)4 with respect to the
aldehyde were optimal in terms of the enantioselectivity.13a
With these optimized reaction conditions, we then observed
the generality of varieties of commonly used Grignard reagents
in this protocol, and the results are included in Table 3. The
results revealed that iBuMgBr achieved the highest enantio-
selectivity. A high enantioselectivity of 94% with benzalde-
hyde was the result of using 10% L1 (entry 13). The enantio-
selectivity could be clearly raised to the highest value, 98%,
with 15% L1 (entries 14 and 15). As a result, the optimized
reaction conditions were finally selected: 15% L1, 1:1 ratio of
BDMAEE to Grignard reagents (2.0 equiv to aldehyde), 0.89
equiv of Ti(OiPr)4, TBME/THF solvent system, and a mild
reaction temperature (ice-salt bath and then room tempera-
ture). It was found that much less Ti(OiPr)4 could be used
than was the case in previously reported works.
(23) Qin, Y.-C.; Liu, L.; Sabat, M.; Pu, L. Tetrahedron 2006, 62, 9335.
(24) (a) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69,
3997. (b) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc.
Rev. 2006, 35, 454.
i
2.4. BuMgBr. Under these optimal reaction conditions,
(25) (a) Kim, J. G.; Walsh, P. J. Angew. Chem., Int. Ed. 2006, 45, 4175.
(b) Salvi, L.; Jeon, S.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2007, 129, 16119. (c) Salvi, L.; Kim, J. G.; Walsh, P. J. J. Am. Chem. Soc.
2009, 131, 12483.
we checked the generality of the reaction of various alde-
hydes with iBuMgBr. The results are shown in Table 4. All
cases realized g90% enantioselectivities, and aromatic aldehydes
6872 J. Org. Chem. Vol. 75, No. 20, 2010

Liu et al.
JOCArticle
TABLE 3. Investigation on Generality of Grignard Reagents
TABLE 5. Catalytic Asymmetric Addition of Alkyl RMgBr to Aldehydesa
entry
R1
Ar
amt of L1 (mol %) yield (%) ee (%)a
entry
R2
R1
yield (%)
ee (%)b
1
Me
Me
Me
Et
Et
Et
Ph
Ph
1-Naphth
Ph
Ph
1-Naphth
Ph
2-Naphth
2-Naphth
1-Naphth
Ph
10
40
40
10
40
30
20
10
40
40
10
40
10
15
20
33
45
78
39
46
54
68
44
58
75
46
26
65
76
76
35
51
72
70
81
93
92
34
54
58
48
33
94
98
97
1
2
3
4
5
6
7
8
Ph
nBu
68
60
23
53
77
79
52
46
50
62
36
92c
91d
88e
90
2b
3b
4
1-Naphth
phenylethyl
Ph
2-Naphth
1-Naphth
1-Naphth
2-Naphth
4-MeO-C6H4
1-Naphth
2-Naphth
nBu
nBu
n-pentyl
n-pentyl
n-pentyl
n-heptyl
n-heptyl
Me2CdCHCH2CH2
Me2CdCHCH2CH2
Me2CdCHCH2CH2
5b
6c
7d
8
90d
90
nBu
Ph
Ph
Ph
Bn
87d
88d
92d
91
9b
10b
11
9
10
11
90
12b,e vinyl 1-Naphth
aConditions: 2.0 equiv of BDMAEE, 2.0 equiv of Grignard reagent,
13
14f
iBu
iBu
iBu
Ph
Ph
Ph
and 0.89 equiv of Ti(OiPr)4. Measured by chiral HPLC. Conditions:
20% of L1, 2.1 equiv of BDMAEE, 2.1 equiv of Grignard reagent, and
0.94 equiv of Ti(OiPr)4. dConditions: 20% of L1, 2.3 equiv of BDMAEE,
2.3 equiv of Grignard reagent, and 1.04 equiv of Ti(OiPr)4. eConditions:
30% of L1, 2.1 equiv of BDMAEE, 2.1 equiv of Grignard reagent, and
0.94 equiv of Ti(OiPr)4.
b
c
15d
aMeasured by chiral HPLC. The configuration was assigned by com-
parison of the alcohol’s optical rotation with reported data.26 bCondi-
tions: 2.5 equiv of BDMAEE, 2.5 equiv of Grignard reagent, and 1.14
equiv of Ti(OiPr)4. Conditions: 2.3 equiv of BDMAEE, 2.3 equiv of
c
Grignard reagent, and 1.04 equiv of Ti(OiPr)4. dConditions: 2.1 equiv of
BDMAEE, 2.1 equiv of Grignard reagent, and 0.94 equiv of Ti(OiPr)4.
eL3 was used. fConditions: 2.0 equiv of BDMAEE, 2.0 equiv of Grignard
reagent, and 0.89 equiv of Ti(OiPr)4.
Table 5. With n-butyl, n-pentyl, and n-heptyl Grignard reagents,
87%-92% enantioselectivity was observed, even with an
alkyl aldehyde (Table 5, entries 1-8). It was found that the
enantioselectivity slowly dropped with the gradual elonga-
tion of the alkyl chain of the Grignard reagent (entry 1 vs 4
and entry 2 vs 6 vs 7). Furthermore, a functional Grignard
reagent with a remote carbon-carbon double bond (CdC)
was also observed, and it achieved g90% enantioselectivity
(entries 9-11).
TABLE 4. Catalytic Asymmetric Addition of iBuMgBr to Aldehydesa
2.6. Optimization of Conditions of PhCH2CH2MgBr Re-
action with Aldehydes. As outlined in the Introduction, the
enantioenriched secondary arylpropanols are important in-
termediates for the synthesis of medications. Their published
preparative procedure includes three synthetic steps and a
further recrystallization of the final synthetic alcohols (eq 6,
Scheme 3). Our protocol of catalytic asymmetric alkylation
of aldehydes with Grignard reagents gave us the opportunity
to prepare these important alcohols in one straightforward
step (eq 7). Direct use of the previously optimized reaction
conditions did not gave satisfactory enantioselectivity.
Therefore, we optimized the reaction again and obtained
the optimal reaction conditions. The amount of each reagent
used with respect to the aldehyde was 20 mol % (S)-BINOL,
1.35 equiv of Ti(OiPr)4, 2.4 equiv of PhCH2CH2MgBr, and
2.4 equiv of BDMAEE. The optimized solvent system was
still THF/TBME. The aldehyde was introduced at -15 °C,
and then the reaction was allowed to continue at room
temperature. The optimized experimental results are shown
in the Tables S1 and S2 in the Supporting Information.
2.7. Ar(CH2)2MgBr. Under the optimized reaction condi-
tions, the catalytic asymmetric reaction of PhCH2CH2MgBr
and an array of aromatic and aliphatic aldehydes were first
investigated (Table 6, entries 1-14). Benzaldehyde achieved
as high as 96% enantioselectivity (entry 1). Two naphthal-
dehydes resulted in yields higher than for other aryl aldehydes
(entries 1-10), and 1-naphthaldehyde and 2-naphthal-
dehyde achieved 93% and 90% enantioselectivity, respectively
(entries 2). The meta-substituted substrates generated
higher enantiomeric excess than para- and ortho-substituted
entry
R2
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
1-Naphth
2-Naphth
4-tolyl
3-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
thiophene-2
PhCHdCH
cyclohexyl
86
63
75
93
86
81
91
82
69
35
70
27
97
97
97
98
97
97
>99
98
9
>99
94
90
10
11
12
98c
aConditions: 2.0 equiv of BDMAEE, 2.0 equiv of Grignard reagent,
and 0.89 equiv of Ti(OiPr)4. Measured by chiral HPLC. cConditions:
30% L1, 2.3 equiv of BDMAEE, 2.3 equiv of Grignard reagent and 1.04
b
equiv of Ti(OiPr)4.
resulted in g97% enantioselectivity (entries 1-9). Two cases
reached more than 99% enantioselecivity in this transforma-
tion (entries 7 and 9). The heteroaromatic aldehyde (entry
10) and R,β-unsaturated aldehyde (entry 11) also afforded
94% and 90% enantioselectivity, respectively. The alkyl
aldehyde cyclohexanecarboxaldehyde gave high enantio-
selctivity (98%) but also a low yield (entry 12). The low yield
might be ascribed to the low reactivity of the alkyl aldehyde
and the strongly basic mixture, which reduced the aldehyde
into the checked primary alcohol.
2.5. Other Alkyl Grignard Reagents with High Enantio-
selectivity. The other alkyl Grignard reagents were investi-
gated with this procedure, and the results are included in
J. Org. Chem. Vol. 75, No. 20, 2010 6873

Liu et al.
JOCArticle
SCHEME 3. Different Synthetic Methods of I-1 or I-2
TABLE 6. Catalytic Asymmetric Arylethylation of Aldehydesa
afforded a high enantioselectivity of 96%. It is noteworthy
that the interesting chiral drug intermediates I-1 and I-2
(Figure 1) could be readily enriched into >99% ee by a
simple recrystallization from hexane (entries 1 and 13).
Additionally, other three ArCH2CH2MgBr were also ob-
served to extend the versatility of the protocol (Table 6,
entries 15-25). With regard to 2-MeO-C6H4-CH2CH2MgBr,
aryl and alkyl aldehydes nearly resulted in similarly high
enantioselectivity(entries 15-17). 1-NapthMgCH2CH2MgBr
afforded higher enantioselectivity with cyclohexanecarboxal-
dehyde than with the aromatic aldehyde (entries 18-20). In
comparison to other arylethyl Grignard reagents, interest-
ingly, the heteroatom-containing Grignard reagent (2-
thienylethyl)magnesium bromide obviously afforded the high-
est enantioselectivity among these Grignard reagents (entries
21-25). All cases with it gave >90% enatioselectivities
except for the heteroatom-containing aldehyde, which also
resulted in a 90% high enantioselectivity, and 1-naphthal-
dehyde yielded the highest enantioselectivity, 97%, among
the all investigated cases with ArCH2CH2MgBr (entry 21).
2.8. Mechanism. We observed that the nBuMgBr-BDMAEE
complex rapidly reacted with benzaldehyde in the absence of
Ti(OiPr)4. It was also indeed the case that nBuMgBr-Ti(OiPr)4
rapidly reacted with benzaldehyde in the absence of BDMAEE.
Interestingly, however, the nBuMgBr-BDMAEE-Ti(OiPr)4
combination did not react with benzaldehyde within 4 h in
the absence of BINOL. After MgBr2 was additionally added,
the addition rapidly proceeded. This result revealed that the
two reagents BDMAEE and Ti(OiPr)4 cooperated to de-
crease the reactivity of nBuMgBr. On the basis of the Schlenk
equilibrium, transmetalation of the Grignard reagents and
Ti(OiPr)4, and the investigations of Bolm and Walsh, the
mechanism is thought to occur as shown in Scheme 4.
BDMAEE coordinates to the Grignard reagent to generate
the three intermediates I-11, I-12, and I-13. Importantly, the
salt MgBr2 is well chelated by BDMAEE and partly loses its
catalytic activity. With the introduction of Ti(OiPr)4, the
chelated I-11 and I-12 are converted into the two chelated
salts I-21 and I-22, and one additional reactive intermediate,
nBu-Ti(OiPr)3 (I-23). Naturally, I-22 is a less reactive Lewis
acid than I-13, and I-23 is much less reactive than the Grignard
reagent itself (I-11 or I-12). This might be the reason the
three-component species nBuMgBr-BDMAEE-Ti(OiPr)4
does not react with benzaldehyde in the absence of the chiral
catalyst. Then, I-23 can coordinate with the chiral catalyst
(S)-BINOL-Ti(OiPr)2 and successively with benzaldehyde to
entry
Ar
R2
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
62
86
88
63
65
68
63
60
80
75
52
70
43
46
77
43
53
80
40
56
78
42
51
81
53
96 (>99)
93
90
88
89
77
90
82
92
88
88
79
96 (>99)
90
85
84
82
83
91
81
97
93
93
93
90
1-napth
2-napth
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-MeC6H4
o-ClC6H4
m-F3CC6H4
p-F3CC6H4
2-thienyl
PhCHdCH
c-hex
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
n-Pr
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
1-napth
1-napth
1-napth
2-thienyl
2-thienyl
2-thienyl
2-thienyl
2-thienyl
1-napth
c-hex
Ph
1-napth
c-hex
Ph
1-napth
c-hex
Ph
2-napth
2-thienyl
aConditions: BINOL (20 mol %), Ti(OiPr)4 (1.35 equiv), BDMAEE
(2.4 equiv), and Grignard reagents (2.4 equiv) in TBME-THF, room
temperature. bDetermined by chiral HPLC. Data in parentheses are the
ee values after a simple recrystallization with hexane. The configuration
was assigned by comparison of the sign of the optical rotation with the
reported data.28
benzaldehydes (entries 4-6 and 9-10). The heteroatom-
containing arylaldehyde also resulted in a high enantioselec-
tivity (entry 11), while the R,β-unsaturated aldehyde achieved
a good enantioselectivity (entry 12). In comparison with the
aryl aldehydes, however, the two alkyl aldehydes cyclohex-
anecarbaldehyde and butyraldehyde both resulted in high
enantioselectivity (entries 13 and 14): cyclohexanecarbaldehyde
(26) (a) Homman, M. J.; Vail, R. B.; Previte, E.; Tamarez, M.; Morgan,
B.; Dodds, D. R.; Zaks, A. Tetrahedron 2004, 60, 789. (b) Huang, W.-S.; Hu,
Q.-S.; Pu, L. J. Org. Chem. 1998, 63, 1364. (c) Xie, J.-H.; Wang, L.-X.; Fu, Y.;
Zhu, S.-F.; Fan, B.-M.; Duan, H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003,
125, 4404. (d) Huang, W. S.; Pu, L. J. Org. Chem. 1999, 64, 4222.
6874 J. Org. Chem. Vol. 75, No. 20, 2010

Liu et al.
JOCArticle
SCHEME 4. Proposed Reaction Mechanism
form the bimetallic nuclear complexes I-3 and I-4, separately.9d,27
Owing to steric effects, the phenyl group of benzaldehyde
should be positioned far away from the three bulky isopro-
poxy groups of nBu-Ti(OiPr)3 coordinated to the chiral
catalyst (S)-BINOL-Ti(OiPr)2. This location will favor the
Si-face addition of the nBu group to benzaldehyde and
predominantly result in an S alcohol.
reaction was performed under mild reaction conditions in
this work. This protocol is particularly effective for alkyl
Grignard reagents. A variety of alkyl Grignard reagents were
i
investigated, and BuMgBr results in the highest enantios-
electivity, up to 99%, among the investigated Grignard
reagents. In addition, this protocol enables the synthesis of
a variety of biologically interesting enantioenriched second-
ary arylpropanols in one step. Several arylethyl Grignard
reagents were successfully used to add to aldehydes to
prepare these valuable secondary alcohols, and aromatic
and aliphatic aldehydes both afforded high enantioselectiv-
ities. The heteroatom-containing Grignard reagent (2-
thienylethyl)magnesium bromide showed the highest enantio-
selectivity among the four observed arylethyl Grignard
reagents. This protocol gives us a promising clue to apply a
variety of more useful Grignard reagents in this catalytic
asymmetric reaction to synthesize an array of interesting
enantioselectively pure secondary alcohols, and such works
are underway in our laboratory at present.
3. Conclusions and Outlook
In conclusion, we have successfully developed a protocol
of highly catalytic enantioselective alkylation of aldehydes
with Grignard reagents. In this protocol, the high reactivity
of Grignard reagents is effectively deactivated by the additive
BDMAEE. BDMAEE chelates MgBr2 from a Schlenk equi-
librium of RMgBr and Mg(OiPr)Br from transmetalation
between RMgBr and Ti(OiPr)4. These two salts can rapidly
promote the racemic background reaction and consequently
result in low enantioselectivity. The chelation of the Mg salts
effectively inhibits this background reaction. Simultaneously
the transmetalation of the Grignard reagent RMgBr with
Ti(OiPr)4 generates in situ the intermediate R-Ti(OiPr)3. As a
result, the chiral catalyst (S)-BINOL-Ti(OiPr)2 catalyzes the
addition of R-Ti(OiPr)3 to aldehydes with high enantioselec-
tivity. In comparison to previously reported procedures,
reactive Mg salts were not removed from the reaction system,
less Ti(OiPr)4 than the Grignard reagent was used, and the
4. Experimental Section
For details on the synthesis and characterization of com-
pounds 1-32, see the reported results.13a
4.1. General Procedure for Catalytic Asymmetric Addition of
(Arylethyl)magnesium Bromide to Aldehydes. In flask A, (191.8
mg, 0.675 mmol) of Ti(OiPr)4 was added dropwise into a
solution of 28.6 mg (0.1 mmol) of (S)-BINOL in 1.0 mL of
dry TBME under an argon atmosphere at ambient temperature,
and the mixture was stirred for a further 0.5 h. In flask B, 1.14
mL (1.2 mmol, 1.05 mmol/mL in THF) of phenethylmagnesium
bromide was slowly added to 192.3 mg (1.2 mmol) of BDMAEE
in 2.0 mL of dry MTBE in an ice-water bath under argon within
(27) (a) Davis, T. J.; Balsells, J.; Carroll, P. J.; Walsh, P. J. Org. Lett. 2001,
3, 699. (b) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739.
(28) (a) Belzecki, C.; Panfil, I. J. Org. Chem. 1979, 44, 1212. (b) Hayashi,
T.; Konishi, M.; Okamoto, Y.; Kabeta, K.; Kumada, M. J. Org. Chem. 1986,
51, 3772.
J. Org. Chem. Vol. 75, No. 20, 2010 6875

Liu et al.
JOCArticle
5 min and then the mixture was stirred for 30 min. Mixture A
was introduced into the mixture B in an ice-water bath. After
the solution reached ambient temperature, the combined yellow
mixture was stirred for 1.0 h. The solution was cooled with an
ice-salt bath, and 0.5 mmol of aldehyde was added dropwise.
The mixture was warmed to ambient temperature and stirred
until the aldehyde was consumed (by TLC). The reaction
mixture was quenched with 5% cold aqueous HCl and extracted
three times with 50 mL of ether. The combined organic layers
were dried with anhydrous Na2SO4 and evaporated in vacuo,
and the residue was purified by flash column chromatography to
give the product. The ee was determined by chiral HPLC. The
absolute configuration of the alcohol was assigned by compar-
ison of the optical rotation to the reported value.
(400 MHz) δ 1.80-1.86 (m, 1H), 1.95-2.15 (m, 2H), 2.61-2.77
(m, 2H), 3.80 (s, 3H), 4.63-4.67 (dd, J = 7.0 Hz, J = 10.2 Hz,
1H), 6.79-6.83 (m, 1H), 6.90-6.92 (t, 1H), 7.15-7.31 (m, 7H);
89% ee, OD-H column (90/10 hexane/2-propanol), 1.0 mL/min,
major enantiomer tR = 14.9 min, minor enantiomer tR = 18.8
min.
4.7. (S)-1-(2-Methoxyphenyl)-3-phenylpropan-1-ol (38):34
flash column, 8/1 petroleum ether/ethyl acetate; colorless oil,
20
1
yield 68% (82.2 mg); [R]D = -7 ° (c = 0.84, CH3OH); H
NMR (400 MHz) δ 2.07-2.16 (m, 2H), 2.64-2.72 (m, 1H),
2.79-2.87 (m, 1H), 3.84 (s, 3H), 4.86-4.89 (dd, J = 5.2 Hz, J =
8.0 Hz, 1H), 6.87-6.89 (d, J = 8.0 Hz, 1H), 6.93-6.97 (t, J =
7.4 Hz, 3H), 7.15-7.31 (m, 7H); 77% ee, OD-H column (90/10
hexane/2-propanol), 1 mL/min, major enantiomer tR = 10.1
min, minor enantiomer tR = 14.0 min.
4.2. (S)-1,3-Diphenylpropan-1-ol (33):14a,28 flash column, 8/1
petroleum ether/ethyl acetate; white solid, yield 62% (65.7 mg);
enantioselectivity enriched to >99% with recrystallization from
hexane; mp 45 °C; [R]D20 =-17° (c=3, CH3OH, >99% ee) (lit.29
[R]D20 =-14.5 (c=1, CH3OH, >90% ee)); 1H NMR (400 MHz)
δ 1.76 (s, 1H), 2.02-2.15 (m, 2H), 2.67-2.76 (m, 2H), 4.68-4.71
(dd, J = 5.4 Hz, J = 8.0 Hz, 1H), 7.16-7.36 (m, 10H); 13C NMR
(100 MHz) δ 17.8, 29.6, 56.4, 98.6, 124.8, 125.5, 126.1, 127.1,
129.7, 130.9, 131.6, 133.0, 153.2; 96% ee, OD-H column (95/5
hexane/2-propanol), 1.0 mL/min, major enantiomer tR = 16.9 min,
minor enantiomer tR = 20.1 min.
4.8. (S)-3-Phenyl-1-p-tolylpropan-1-ol (39):31b,35 flash col-
umn, 8/1 petroleum ether/ethyl acetate; white solid, yield 63%
20
1
(71.0 mg); mp 42 °C; [R]
= -16° (c = 2.2, CH3OH); H
D
NMR (400 MHz) δ 1.91 (s, 1H, OH), 1.96-2.13 (m, 2H), 2.33 (s,
3H), 2.63-2.73 (m, 2H), 4.60-4.63 (dd, J = 5.6 Hz, J = 7.6 Hz,
1H), 7.13-7.28 (m, 9H); 90% ee, OD-H column (90/10 hexane/
2-propanol), 1.0 mL/min, major enantiomer tR = 10.6 min,
minor enantiomer tR = 13.4 min.
4.9. (S)-1-(2-Chlorophenyl)-3-phenylpropan-1-ol (40): flash
column, 8/1 petroleum ether/ethyl acetate; colorless oil, yield
60% (73.7 mg); [R]D20 = -7° (c = 0.5, CH3OH); 1H NMR (400
MHz) δ 1.94-2.12 (m, 3H), 2.62-2.77 (m, 2H), 4.62-4.66 (dd,
J = 5.4 Hz, J = 7.8 Hz, 1H), 6.78-6.79 (d, J = 3.2 Hz, 1H),
6.89-6.91 (m, 1H), 7.01-7.11 (d, J = 4.8 Hz, 3H), 7.17-7.33
(m, 9H); 13C NMR (100 MHz) δ 31.8, 40.3, 73.1, 123.9, 125.9,
126.0, 127.6, 128.3, 128.4, 129.7, 134.3, 141.3, 146.6; HRMS m/z
calcd for (C15H15ClO þ NH4)þ 264.1150, found 264.1155; 82%
ee, OD-H column (90/10 hexane/2-propanol), 1.0 mL/min,
major enantiomer tR = 10.3 min, minor enantiomer tR = 13.3 min.
4.10. (S)-3-Phenyl-1-(3-(trifluoromethyl)phenyl)propan-1-ol
(41):36 flash column, 8/1 petroleum ether/ethyl acetate; color-
less oil, yield 80% (111.8 mg); [R]D20 = -10 ° (c = 0.8, CH3OH);
1H NMR (400 MHz) δ 1.99-2.14 (m, 3H), 2.65-2.76 (m, 2H),
4.70-4.75 (dd, J = 6.6 Hz, J = 10.6 Hz, 1H), 7.16-7.31 (m,
5H), 7.41-7.60 (m, 4H); 92% ee, OD-H column (90/10 hexane/
2-propanol), 1.0 mL/min, major enantiomer tR = 9.2 min, minor
enantiomer tR = 12.4 min.
4.11. (S)-3-Phenyl-1-(4-(trifluoromethyl)phenyl)propan-1-ol
(42):37 flash column, 8/1 petroleum ether/ethyl acetate; colorless
oil, yield 75% (105.0 mg); [R]D20 = -18 ° (c = 0.5, CH3OH); 1H
NMR (400 MHz) δ 1.98-2.12 (m, 3H), 2.67-2.74 (m, 2H),
4.71-4.74 (dd, J = 5.0 Hz, J = 7.8 Hz, 1H), 6.78-6.79 (d, J =
3.2 Hz, 1H), 7.17-7.30 (m, 5H), 7.43-7.45 (d, J = 8.0 Hz, 2H),
7.58-7.60 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (100 MHz) δ
31.8, 40.5, 73.1, 125.4, 126.0, 126.1, 128.4, 128.5, 141.2, 148.5;
88% ee, OD-H column (90/10 hexane/2-propanol), 1.0 mL/min,
major enantiomertR =9.9min, minor enantiomertR = 11.6 min.
4.12. (S)-3-Phenyl-1-(thiophen-2-yl)propan-1-ol (43):31a,38
flash column, 8/1 petroleum ether/ethyl acetate; pale yellow
oil, yield 52% (56.5 mg); [R]D20 = -9° (c = 2, CH3CH2OH); 1H
NMR (400 MHz) δ 2.02 (s, 1H, OH), 2.09-2.26 (m, 2H),
2.67-2.81 (m, 2H), 4.90-4.94 (t, J = 6.8 Hz, 1H), 6.95-6.97
(m, 2H), 7.17-7.32 (m, 6H); 88% ee, OD-H column (90/10
4.3. (S)-1-(Naphthalen-1-yl)-3-phenylpropan-1-ol (34):30 flash
column, 8/1 petroleum ether/ethyl acetate; pale yellow oil, yield
86% (112.7 mg); [R]D20 = -78° (c = 1.5, CH3OH); 1H NMR
(400 MHz) δ 2.20 (s, 1H), 2.22-2.27 (m, 2H), 2.79-2.92 (m,
2H), 5.45-5.48 (dd, J = 4.6 Hz, J = 7.8 Hz, 1H), 7.18-7.31 (m,
5H), 7.43-7.49 (m, 3H), 7.66-7.68 (d, J = 6.8 Hz, 1H), 7.76-
7.78 (d, J = 8.4 Hz, 1H), 7.85-7.92 (m, 2H); 93% ee, OD-H
column (90/10 hexane/2-propanol), 1.0 mL/min, major enan-
tiomer tR = 12.4 min, minor enantiomer tR = 21.3 min.
4.4. (S)-1-(Naphthalen-2-yl)-3-phenylpropan-1-ol (35):30b,31
flash column, 8/1 petroleum ether/ethyl acetate; white solid,
20
yield 88% (115.2 mg); mp 65 °C; [R]
= -10° (c = 2,
D
1
CH3CH2OH); H NMR (400 MHz) δ 2.00 (s, 1H, OH),
2.08-2.24 (m, 2H), 2.65-2.80 (m, 2H), 4.83-4.86 (dd, J =
5.8 Hz, J = 7.4 Hz, 1H), 7.16-7.30 (m, 5H), 7.44-7.49 (m, 3H),
7.77-7.84 (m, 4H); 90% ee, OD-H column (90/10 hexane/2-
propanol), 1.0 mL/min, major enantiomer tR = 15.6 min, minor
enantiomer tR = 19.6 min.
4.5. (S)-1-(4-Methoxyphenyl)-3-phenylpropan-1-ol (36):31b,32
flash column, 8/1 petroleum ether/ethyl acetate; white needles,
yield 63% (76.2 mg); mp 70 °C; [R] D20 = -26° (c = 1, CH3OH);
1H NMR (400 MHz) δ 1.89 (s, 1H), 1.94-2.03 (m, 1H), 2.07-
2.15 (m, 1H), 2.58-2.74 (m, 2H), 3.80 (s, 3H), 4.60-4.63 (dd,
J = 4.6 Hz, J = 7.8 Hz, 1H), 6.86-6.88 (d, J = 4.6 Hz, 2H),
7.17-7.19 (m, 3H), 7.24-7.28 (m, 4H); 88% ee, OD-H column
(90/10 hexane/2-propanol), 1.0 mL/min, major enantiomer tR =
13.5 min, minor enantiomer tR = 15.1 min.
4.6. (S)-1-(3-Methoxyphenyl)-3-phenylpropan-1-ol (37):33
flash column, 8/1 petroleum ether/ethyl acetate; colorless oil,
yield 65% (78.5 mg); [R]D20 = -9 ° (c = 0.4, CH3OH); 1H NMR
(29) (a) Node, M.; Nishide, K.; Shigeta, Y.; Obata, K.; Shiraki, H;
ꢀ
Kunishige, H. Tetrahedron 1997, 53, 12883. (b) Skarzewski, J.; Siedlecka,
ꢀ
ꢀ
R.; Wojaczynska, E.; Zielinska-Bzajet, M. Tetrahedron: Asymmetry 2002, 13,
2105.
(30) (a) Ross, D. R.; Waight, E. S. J. Am. Chem. Soc. 1965, 6710.
(b) Basaif, S. A.; Albar, H. A.; Khalaf, A. A. Int. J. Chem. 1995, 6, 55.
(31) (a) Cho, C. S. J. Mol. Catal. A: Chem. 2007, 267, 49. (b) Cho, C. S.;
Kim, B. T.; Kim, H. S.; Kim, T. J.; Shim, S. C. Organometallics 2003, 22,
3608.
(32) (a) Salokhe, P. R.; Rashinkar, G. S.; Salunkhe, R. S. Indian J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 2010, 49B, 199. (b) Hixson, S. S.;
Garrett, D. W. J. Am. Chem. Soc. 1974, 96, 4872.
(34) Hase, T. Acta Chem. Scand. 1968, 22, 2845.
(35) (a) Pines, H.; Shabtai J. Org. Chem. 1961, 26, 4220. (b) Martinez, R.;
Ramon, D. J.; Yus, M. Tetrahedron 2006, 62, 8982.
(36) Kuck, D.; Gruetzmacher, H. F. Org. Mass Spectrom. 1978, 13, 81.
(37) (a) Bushby, R. J.; Ferber, G. J. J. Chem. Soc., Perkin Trans. 2 1976,
1683. (b) Spogliarich, R.; Farnetti, E.; Graziani, M. Tetrahedron 1991, 47,
1965. (c) Kwon, M. S.; Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.;
Park, J. Angew. Chem., Int. Ed. 2005, 44, 6913.
(33) Sattlegger, M.; Buschmann, H.; Koegel, B. Y. Preparation of 3-amino-
2-benzyl-1-phenylpropanes as drugs, WO Patent 2001005743, 2001.
(38) Cervena, I.; Hradil, F.; Protiva, M. Collect. Czech. Chem. Commun.
1972, 37, 3124.
6876 J. Org. Chem. Vol. 75, No. 20, 2010

Liu et al.
JOCArticle
hexane/2-propanol), 1.0 mL/min, major enantiomer tR = 10.8
min, minor enantiomer tR = 14.2 min.
3H), 4.59-4.62 (dd, J = 4.6 Hz, J = 8.6 Hz, 1H), 6.83-6.91 (m,
2H), 7.13-7.20 (m, 2H), 7.24-7.27 (m, 1H), 7.30-7.35 (m, 4H);
82% ee, OD-H column (80/20 hexane/2-propanol), 1.0 mL/min,
major enantiomer tR = 8.4 min, minor enantiomer tR = 23.1 min.
4.19. (S)-1,3-Bis(naphthalen-1-yl)propan-1-ol (50):43 flash
column, 6/1 petroleum ether/ethyl acetate; colorless needles,
4.13. (S,E)-1,5-Diphenylpent-1-en-3-ol (44):39 flash column,
8/1 petroleum ether/ethyl acetate; colorless oil, yield 70% (83.1
mg); [R]D þ20° (c = 0.6, CH3CH2OH); 1 H NMR (400 MHz) δ
20
1.58-1.64 (s, 1H, OH), 1.91-2.01 (m, 2H), 2.71-2.80 (m, 2H),
4.27-4.32 (t, J = 6.4 Hz, J = 13.2 Hz, 1H), 6.21-6.27 (dd, J =
6.4 Hz, J = 15.6 Hz, 1H), 6.56-6.59 (d, 1H), 7.17-7.38 (m,
10H); 79% ee, OD-H column (90/10 hexane/2-propanol), 1.0
mL/min, minor enantiomer tR = 17.0 min, major enantiomer
tR = 19.8 min.
20
yield 80% (124.7 mg); mp 101 °C; [R]D = -141° (c = 2,
CHCl3); 1H NMR (400 MHz) δ 2.03 (s, 1H, OH), 2.32-2.41 (m,
2H), 3.22-3.41 (m, 2H), 5.52-5.55 (dd, J = 4.0 Hz, J = 8.0 Hz,
1H), 7.34-7.48 (m, 7H), 7.68-7.85 (m, 6H), 7.98-8.00 (m, 1H);
13C NMR (100 MHz) δ 29.5, 39.0, 70.6, 122.7, 122.9, 123.8,
125.4, 125.7, 125.9, 126.1, 126.7, 128.0, 128.7, 128.8, 130.2,
131.9, 133.8, 137.9, 140.2; 83% ee, OD-H column (90/10 hex-
ane/2-propanol), 1.0 mL/min, major enantiomer tR = 18.7 min,
minor enantiomer tR = 31.8 min.
4.14. (S)-1-Cyclohexyl-3-phenylpropan-1-ol (45):14,22b flash
column, 8/1 petroleum ether/ethyl acetate; colorless needles,
20
yield 43% (46.8 mg); mp 61-63 °C; [R]D = -16° (c = 0.6,
CH3CH2OH) (lit.28b,40 [R]D20 = þ28.7° (c = 0.91, CHCl3) for R
enantiomer); 1H NMR (400 MHz) δ 0.99-1.18 (m, 3H), 1.20-
1.42 (m, 4H), 1.64-1.78 (m, 7H), 2.61-2.68 (m, 1H), 2.80-2.87
(m, 1H), 3.36-3.41 (m, 1H), 7.16-7.30 (m, 5H); 13C NMR (100
MHz) δ 26.1, 26.3, 26.5, 27.7, 29.1, 29.6, 32.3, 35.9, 43.8, 75.6,
125.7, 128.3, 128.4, 142.3; 96% ee, OD-H column (90/10 hexane/
2-propanol), 1.0 mL/min, major enantiomer tR = 5.4 min, minor
enantiomer tR = 7.9 min.
4.20. (S)-1-Cyclohexyl-3-(naphthalen-1-yl)propan-1-ol (51):
flash column, 6/1 petroleum ether/ethyl acetate; colorless oil,
yield 40% (53.6 mg); [R]D20 = -21° (c = 0.3, CHCl3); 1H NMR
(400 MHz) δ 0.96-1.27 (m, 5H), 1.33-1.41 (m, 1H), 1.51 (s, 1H,
OH), 1.64-1.95 (m, 7H), 3.04-3.11 (m, 1H), 3.30-3.37 (m, 1H),
3.46-3.50 (dd, J = 5.4 Hz, J = 9.0 Hz, 1H), 7.34-7.53 (m, 4H),
7.70-7.72 (d, J = 7.6 Hz, 1H), 7.84-7.86 (d, J = 7.6 Hz, 1H),
8.06-8.08 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz) δ 26.1,
26.2, 26.5, 27.8, 29.2, 29.5, 35.3, 43.8, 76.0, 123.8, 125.3, 125.4,
125.5, 125.7, 125.8, 126.5, 128þ.7, 131.8, 133.9, 138.6; HRMS m/z
calcd for (C19H24O þ NH4) 286.2165, found 286.2161; 91%
ee, OD-H column (90/10 hexane/2-propanol), 1.0 mL/min,
major enantiomer tR = 11.1 min, minor enantiomer tR = 12.5 min.
4.21. (S)-3-(Naphthalen-1-yl)-1-phenylpropan-1-ol (52):31,35b
flash column, 6/1 petroleum ether/ethyl acetate; colorless oil,
yield 56% (73.3 mg); [R]D20 = -26° (c = 0.5, CHCl3); 1H NMR
(400 MHz) δ 1.94 (s, 1H, OH), 2.123-2.28 (m, 2H), 3.06-3.28
(m, 2H), 4.78-4.81 (dd, J = 5.0 Hz, J = 7.4 Hz, 1H), 7.24-7.50
(m, 9H), 7.69-7.71 (d, J = 8.0 Hz, 1H), 7.83-7.85 (m, 1H),
7.96-7.98 (t, 1H); 81% ee, OD-H column (90/10 hexane/2-
propanol), 1.0 mL/min, major enantiomer tR = 16.4 min, minor
enantiomer tR = 19.0 min.
4.15. (R)-1-Phenylhexan-3-ol (46):41 flash column, 8/1 petro-
leum ether/ethyl acetate; colorless oil, yield 46% (40.8 mg);
[R]D20 = -15° (c = 1.0, CH3CH2OH) (lit.41a [R]D24 = þ12.8° (c
= 1.0, EtOH) for S enantiomer); 1H NMR (400 MHz) δ
0.90-0.95 (t, J = 8.8 Hz, 3H), 1.25-1.48 (m, 5H), 1.61-1.83
(m, 2H), 2.63-2.83 (m, 2H), 3.61-3.67 (m, 1H), 7.16-7.30 (m,
3H); 90% ee, OD-H column (95/5 hexane/2-propanol), 1.0 mL/
min, major enantiomer tR = 8.4 min, minor enantiomer tR
11.3 min.
=
4.16. (S)-3-(2-Methoxyphenyl)-1-(naphthalen-1-yl)propan-1-
ol (47): flash column, 8/1 petroleum ether/ethyl acetate; colorless
oil, yield 77% (112.2 mg); [R]D20 = -67° (c = 0.9, CHCl3); 1H
NMR (400 MHz) δ 2.09-2.26 (m, 2H), 2.56 (br s, 1H, OH),
2.82-2.99 (m, 2H), 3.82 (s, 3H), 5.36-5.39 (dd, J = 3.2 Hz, J =
9.2 Hz, 1H), 6.88-6.95 (m, 2H), 7.19-7.24 (m, 2H), 7.41-7.48
(m, 3H), 7.67-7.85 (m, 4H); 13C NMR (100 MHz) δ 26.9, 38.6,
55.3, 70.1, 110.3, 120.7, 122.5, 123.1, 125.3, 125.4, 125.7, 127.3,
127.7, 128.8, 129.9, 130.2, 133.8, 140.3, 157.4; HRMS m/z calcd
for (C20H20O2 þ NH4)þ 310.1802, found 310.1803; 85% ee,
OD-H column (90/10 hexane/2-propanol), 1.0 mL/min, major
enantiomer tR = 15.0 min, minor enantiomer tR = 35.7 min.
4.17. (S)-1-Cyclohexyl-3-(2-methoxyphenyl)propan-1-ol (48):
flash column, 8/1 petroleum ether/ethyl acetate; white solid,
yield 43%; mp 51 °C; [R]D20 = -20° (c = 0.4, CHCl3); 1 H NMR
(400 MHz) δ 0.96-1.36 (m, 6H), 1.62-1.79 (m, 7H), 1.95 (s, 1H,
OH), 2.68-2.75 (m, 2H), 3.27-3.32 (m, J = 4.2 Hz, J = 8.8 Hz,
1H), 3.82 (s, 3H), 6.84-6.91 (m, 2H), 7.14-7.25 (m, 2H); 13C
NMR (100 MHz) δ 24.3, 26.3, 26.5, 26.7, 27.9, 29.2, 34.5, 43.5,
55.3, 75.1, 110.3, 120.6, 127, 130.0, 130.5, 157.3; HRMS m/z
calcd for (C16H 24O2 þ NH4)þ 266.2115, found 266.2120; 84%
ee, OD-H column (80/20 hexane/2-propanol), 1.0 mL/min,
major enantiomer tR = 5.3 min, minor enantiomer tR = 20.0 min.
4.18. (S)-3-(2-Methoxyphenyl)-1-phenylpropan-1-ol (49):42
flash column, 8/1 petroleum ether/ethyl acetate; colorless oil,
yield 53% (53.0 mg); [R]D20 = -15 ° (c = 0.4, CHCl3); 1H NMR
(400 MHz) δ 1.95-2.08 (m, 2H), 2.72-2.77 (m, 2H), 3.76 (s,
4.22. (S)-1-(Naphthalen-1-yl)-3-(thiophen-2-yl)propan-1-ol (53):
flash column, 6/1 petroleum ether/ethyl acetate; pale yellow oil,
20
1
yield 78% (104.2 mg); [R]D = -105° (c = 0.35, CHCl3); H
NMR (400 MHz) δ 2.04 (s, 1H, OH), 2.19-2.33 (m, 2H), 3.04-
3.08 (t, J = 7.8 Hz 2H), 5.46-5.50 (dd, J = 4.8 Hz, J = 7.8 Hz,
1H), 6.83-6.94 (m, 2H), 7.12-7.14 (m, 1H), 7.44-7.49 (m, 3H),
7.64-7.97 (m, 4H); 13C NMR (100 MHz) δ 26.5, 39.8, 70.0, 122.8,
123.0, 123.1, 124.5, 125.4, 125.5, 126.0, 126.7, 128.0, 128.8, 130.2,
133.8, 140.0, 144.5; HRMS m/z calcd for (C17H16OS þ NH4)þ
286.1260, found 286.1259; 97% ee, OD-H column (90/10 hexane/2-
propanol), 1.0 mL/min, major enantiomer tR = 13.7 min, minor
enantiomer tR = 26.8 min.
4.23. (S)-1-Cyclohexyl-3-(thiophen-2-yl)propan-1-ol (54): flash
column, 6/1 petroleum ether/ethyl acetate; colorless needles, yield
42% (47.0 mg); mp 38 °C; [R]D20 = -7° (c = 0.7, CHCl3); 1
H
NMR (400 MHz) δ 0.96-1.36 (m, 6H), 1.53 (s, 1H, OH), 1.64-
1.90 (m, 7H), 2.85-3.05 (m, 2H), 3.38-3.41 (m, 1H), 6.80-6.81
(d, J = 3.2 Hz, 1H), 6.90-6.92 (t, 1H), 7.10-7.11 (d, J = 4.8 Hz,
1H);13CNMR(100 MHz) δ26.1, 26.2, 26.4, 27.8, 29.1, 36.0, 43.7,
75.2, 122.9, 124.1, 126.6, 145.2; HRMS m/ z calcd for (C13H20-
OS þ H)þ 225.1308, found 225.1311; 93% ee, OD-H column (95/
5 hexane/2-propanol), 1.0 mL/min, major enantiomer tR = 7.5
min, minor enantiomer tR = 8.0 min.
(39) (a) Ogata, A.; Nemoto, M.; Kobayashi, K.; Tsubouchi, A.; Takeda,
T. J. Org. Chem. 2007, 72, 3816. (b) Rao, W.; Tay, A.; Hui, L.; Goh, P. J.;
Choy, J.; Mun, L.; Ke, J. K.; Chan, P.; Wai, H. Tetrahedron Lett. 2008, 49,
122.
(40) (a) Node, M; Nishide, K.; Shlgeta, Y; Obata, K.; Shiraki, H.;
Kunishige, H. Tetrahedron 1997, 53, 1288.
4.24. (S)-1-Phenyl-3-(thiophen-2-yl)propan-1-ol (55):42 flash
column, 6/1 petroleum ether/ethyl acetate; colorless oil, yield
51% (55.5 mg); [R]D20 = -21° (c = 0.6, CHCl3); 1H NMR (400
MHz) δ 2.02-2.18 (m, 3H), 2.87-2.93 (m, 2H), 4.67-4.70 (dd,
(41) (a) Aquino, M.; Cardani, S.; Fronza, G.; Fuganti, C.; P, R.; Tagliani,
A. Tetrahedron 1991, 47, 7887. (b) Node, M.; Nishide, K.; Shigeta, Y.;
Shiraki, H.; Obata, K. J. Am. Chem. Soc. 2000, 122, 1927.
(42) Cheung, H. W.; Lee, T. Y.; Lui, H. Y.; Yeung, C. H.; Lau, C. P. Adv.
Synth. Catal. 2008, 350, 2975.
(43) (a) Itoh, K.; Ikeda, T.; Tazuke, S.; Shibata, T. J. Phys. Chem. 1992,
96, 5759. (b) Todesco, R.; Gelan, J.; Martens, H.; Put, J.; De Schryver, F. C.
Tetrahedron 1983, 39, 1407.
J. Org. Chem. Vol. 75, No. 20, 2010 6877

Liu et al.
JOCArticle
J = 5.4 Hz, J = 7.8 Hz, 1H), 6.78-6.79 (d, J = 3.2 Hz, 1H),
6.89-6.91 (m, 1H), 7.01-7.11 (d, J = 4.8 Hz, 3H), 7.25-7.36
(m, 5H); 13C NMR (100 MHz) δ 26.1, 40.6, 73.4, 123.0, 124.2,
125.8, 126.7, 127.6, 128.5, 144.3, 144.5; HRMS m/ z calcd for
(C13H14OS þ NH4) þ 236.1104, found 236.1109; 93% ee, OD-H
column (95/5 hexane/2-propanol), 1.0 mL/min, minor enantio-
mer t R = 16.5 min, major enantiomer tR = 17.8 min.
53% (59.1 mg); [R]D20 = -5° (c = 0.4, CH3OH); 1H NMR (400
MHz) δ 2.07 (s, 1H, OH), 2.13-2.31 (m, 2H), 2.90-3.02 (m,
2H), 4.94-4.98 (t, J = 6.8 Hz, 1H), 6.81-6.81 (t, 1H),
6.91-6.98 (m, 3H), 7.11-7.13 (t, 1H), 7.24-7.26 (m, 1H); 13
C
NMR (100 MHz) δ 25.7, 40.5, 68.8, 122.8, 123.6, 124.1, 124.4,
126.3, 126.4, 143.8, 147.9; HRMS m/ z calcd for (C11H12OS2 þ
Na)þ 247.0222, found 247.0225; 90% ee, OB-H column (98/2
hexane/2-propanol), 1.0 mL/min, major enantiomer tR = 61.7
min, minor enantiomer tR = 67.1 min.
4.25. (S)-1-(Naphthalen-2-yl)-3-(thiophen-2-yl)propan-1-ol (56):
flash column, 6/1 petroleum ether/ethyl acetate; colorless prisms,
yield 81% (108.2 mg); mp 56 °C; [R]D20 = -9° (c = 0.35, CH3-
1
OH); H NMR (400 MHz) δ 2.04 (s, 1H, OH), 2.11-2.30 (m,
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Nos. 20672051, 21072087)
and grants from the Key National S&T Program “Major New
Drug Development” of the Ministry of Science and Techno-
logy (2009ZX09503-017) for their financial support.
2H), 2.90-2.97 (m, 2H), 4.86-4.89 (dd, J = 5.6 Hz, J = 7.6 Hz,
1H), 6.80-6.81 (m, 1H), 6.91-6.93 (q, J = 3.2 Hz, J = 4.8 Hz,
1H), 7.11-7.13 (q, J = 5.6 Hz, 1H), 7.44-7.50 (m, 3H), 7.77-
7.84 (m, 4H); 13C NMR (100 MHz) δ 26.1, 40.5, 73.5, 123.1,
123.9, 124.3, 124.46, 125.8, 126.2, 126.7, 127.9, 128.4, 133.0,
133.2, 141.6,144.5; HRMS m/z calcd for (C17H 16OS þ Na)þ
291.0814, found 291.0813; 93% ee, OJ-H column (90/10 hexane/
2-propanol), 1.0 mL/min, major enantiomer tR = 43.7 min,
minor enantiomer tR = 50.5 min.
Supporting Information Available: Text, figures, and tables
giving characterization and spectral data of the compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
4.26. (S)-1,3-Bis(thiophen-2-yl)propan-1-ol (57): flash col-
umn, 6/1 petroleum ether/ethyl acetate; pale yellow oil, yield
6878 J. Org. Chem. Vol. 75, No. 20, 2010