Divergent enantioselective pathways in the catalytic asymmetric addition of diethylzinc to aldehydes in the presence and absence of titanium tetraisopropoxide

Article abstract of DOI:10.1016/j.tetasy.2008.10.033

The stereochemical outcome of the asymmetric addition of diethylzinc to aldehydes catalyzed by (R,R)-hydrobenzoin can be influenced by the absence or presence of Ti(O-iPr)₄. The enantiomeric ratios obtained in the absence of Ti(O-iPr)₄

Full text of DOI:10.1016/j.tetasy.2008.10.033

Tetrahedron: Asymmetry 19 (2008) 2563–2567
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Divergent enantioselective pathways in the catalytic asymmetric
addition of diethylzinc to aldehydes in the presence and absence
of titanium tetraisopropoxide
*
Melissa A. Dean, Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 August 2008
Accepted 21 October 2008
The stereochemical outcome of the asymmetric addition of diethylzinc to aldehydes catalyzed by (R,R)-
hydrobenzoin can be influenced by the absence or presence of Ti(O-iPr)4. The enantiomeric ratios
obtained in the absence of Ti(O-iPr)4 favor the (S)-enantiomer, whereas the ratios obtained from the
use of Ti(O-iPr)4 favor the formation of the (R)-enantiomer. The formation of the opposite enantiomers
is attributed to the different transition states mediated by either zinc or titanium.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
been attributed to structural changes of the catalyst systems that
have been used.8 However, to our knowledge a reaction mediator,
The catalytic asymmetric addition of diorganozinc reagents to
carbonyl compounds, which was first reported by Oguni et al. in
1984, has experienced tremendous growth.1 The process has been
well studied and reviewed by Pu2 and Walsh.3 A common additive
that is employed to help facilitate the asymmetric addition of
diorganozinc reagents to carbonyl substrates, is titanium tetra-
isopropoxide [Ti(O-iPr)4]. This reagent has become nearly ubiqui-
tous in its application in this process, as it has been demonstrated
to be a powerful promoter of the addition process.3–6 In this regard,
Walsh et al. demonstrated that there is a reaction between the
such as Ti(O-iPr)4, has only been employed with the discrete
purpose of achieving practical divergent enantioselective reactions
with diethylzinc.7,9
Lake and Moberg9 conducted a study in which they employed a
tridentate catalyst derived from L-valine in conjunction with vary-
ing amounts of Ti(O-iPr)4 in the asymmetric addition of diethylzinc
to aromatic aldehydes. The enantioselectivities that were obtained
using this catalyst system, ranged from 63:37 favoring the (R)-
enantiomer to 14:86 favoring the (S)-enantiomer with increasing
amounts of Ti(O-iPr)4. Zhang10 and Seebach11 have independently
observed that the use of sub-stoichiometric amounts of Ti(O-iPr)4
with varying chiral catalysts in the asymmetric addition of
Ti(O-iPr)4 and diethylzinc to give
a reactive intermediate
EtTi(O-iPr)3 that is the likely alkylating agent.3
An interesting aspect of the use of Ti(O-iPr)4 in the diorganozinc
addition reaction is the impact on the stereochemical outcome of
the enantioselective addition. It has been reported that varying
the stoichiometric amount of Ti(O-iPr)4 from zero equivalents to
multiple equivalents can cause significant changes in the observed
ratio of enantiomers from the addition reaction. The change in the
enantiomeric ratio of the addition product by the addition of Ti(O-
iPr)4 and Et2Zn to aldehydes was previously observed by Wan, Lu
et al. using a tridentate ephedrine-based ligand (Scheme 1).7 The
reversal of enantioselectivity was significant but not practical in
its scope. It was suggested that the reversal was the result of the
differences in the ‘coordination forms’, wherein zinc is the central
coordinating atom in one case and titanium in the other.7a There
have been reports on the successful and practical reversal of the
enantioselectivity of the catalytic asymmetric addition, which have
O
OH
2
4
ligand or
R
H
R
Et2Zn, toluene
Et
H
3
1
Me
Wan, Lu et al.
Ph
er = 58:42 (R:S), 16%ee
w/Ti(O-iPr)4
Ph
N
er = 11:89 (R:S), 78%ee w/o
Ti(O-iPr)4
OH Me NHTs
2
4
Bn
N
Lake and Moberg
er = 14:86 (R:S), 72%ee
w/Ti(O-iPr)4
NHTf
NHTf
er = 63:37 (R:S), 26%ee w/o
Ti(O-iPr)4
* Corresponding author. Fax: +1 309 438 5538.
E-mail address: hitchcock@ilstu.edu (S. R. Hitchcock).
Scheme 1. Enantioselective addition of diethylzinc to aldehydes.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.033

2564
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 2563–2567
Table 1
diorganozinc reagents to carbonyl compounds afforded decreased
enantioselectivities.
Catalytic asymmetric synthesis with (R,R)-hydrobenzoin 5
A central theme in these literature examples is that it is difficult
to predict if changing the amount of the Ti(O-iPr)4 will cause a sig-
nificant reversal of enantioselectivity, or if the enantioselectivity
will simply be compromised. We became interested in determin-
ing if there might be an optimal ligand system that would be useful
in terms of achieving high enantioselectivity for one enantiomer in
the absence of Ti(O-iPr)4 and high selectivity for the opposite
enantiomer in the presence of Ti(OiPr)4. Numerous research groups
have pursued and, in some cases, have achieved excellent enantio-
selectivities for the Ti(O-iPr)4 mediated addition of diorganozinc
reagents to carbonyl compounds.1,2 However, there are few exam-
ples of exploiting the presence and absence of Ti(O-iPr)4 as a means
of obtaining either enantiomer of the addition product.7a,b The
optimal ligand for such an application would allow for the oppos-
ing ‘coordination forms’ and was proposed by Mao et al. to be
‘symmetrical’ from the standpoint of the interaction of the metal
center. This appeared to be a feature that previous studies either
did not pursue or did not optimize. One ligand system that was
explored early in the development of the catalytic asymmetric
addition of diethylzinc to aldehydes was 1,2-diphenyl-1,2-ethane-
diol 5 (hydrobenzoin).12 Salvadori et al. employed this ligand sys-
tem in the enantioselective addition of diethylzinc to a variety of
aromatic aldehydes and generated enantiomeric ratios that were
as high as 89:11.12 The use of Ti(O-iPr)4 with binaphthol-based
systems and bis(sulfonamides) has been well documented.2,3 In
contrast, to the best of our knowledge, there are no reports describ-
ing the use of Ti(O-iPr)4 with enantiomerically enriched hydro-
benzoin. Herein, we report our efforts to evaluate hydrobenzoin
in the catalytic asymmetric addition of diethylzinc to aldehydes
in the absence and the presence of Ti(O-iPr)4. We also report on
the divergent pathways that occur for these two systems and con-
trast them with previous observations of the reversal of enantio-
selectivity of the diethylzinc reactions with carbonyl compounds
involving Ti(O-iPr)4. The reversal of enantioselectivities observed
herein represents some of the best changes in magnitude reported
in the literature to date.
HO
Ph
OH
Ph
OH
H
O
5
(x equiv.)
H
Et
Et2Zn, toluene
Ti(O-iPr)4
6
3a
Entry
Cat. 5 (equiv)
Ti(O-iPr)4
(equiv)
Yielda
er [R:S, (|RꢀS|)]b
Config.c
1
2
3
4
5
6
7
8
9
0.10
0.20
0.30
0.40
0.50
0.10
0.20
0.30
0.40
0.50
0
0
0
0
0
1
1
1
1
1
74d
95
93
11.5:88.5 (77)
8.0:92.0 (84)
7.5:92.5 (85)
8.5:91.5 (83)
13.5:86.5 (73)
79.1:20.9 (58)
81.5:18.5 (63)
82.0:18.0 (64)
86.5:13.5 (73)
82.0:18.0 (64)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
93
70d
85
84
87
83
10
70d
a
Isolated yield after flash chromatography.
b
c
Enantiomeric ratios were determined by CSP HPLC with a Chiralcel OD column.
The absolute configuration of the product was determined by correlation of
HPLC data with literature values for HPLC and specific rotations.8a,14
d
There was a significant amount of remaining aldehyde and the corresponding
reduction product.13
Table 2
Variation of Ti(O-iPr)4 in the asymmetric catalysis with (R,R)-hydrobenzoin
5 (0.3 equiv.)
6
3a
2 equiv. Et2Zn, toluene
Ti(O- Pr)4 (x equiv.)
i
Entry
Ti(O-iPr)4
Yielda
er [R:S, (|RꢀS|)]b
Config.c
1
2
3
4
5
0.30
0.50
0.70
1.00
1.25
92
78.5:21.5 (57)
86.0:14.0 (72)
85.0:15.0 (70)
82.0:18.0 (64)
78.0:22.0 (56)
(R)
(R)
(R)
(R)
(R)
70d
70d
87
70d
2. Results and discussion
a
Isolated yield after flash chromatography.
Enantiomeric ratios were determined by CSP HPLC with a Chiralcel OD column.
The absolute configuration of the product was determined by correlation of
b
c
We began this study by first examining the impact of the num-
ber of equivalents of the (R,R)-hydrobenzoin ligand 5 on the asym-
metric addition of diethylzinc to 2-naphthaldehyde in the absence
or presence of Ti(O-iPr)4 (Table 1). All reactions were run for 18 h
at ambient temperature. Attempts to run the reactions at lower
temperatures (0 °C, ꢀ10 °C, and ꢀ78 °C) gave incomplete reactions
and lower enantioselectivities. It was determined that the enantio-
meric ratios underwent a slight improvement as the amount of 5
was increased (entries 1–4) but decreased at a point of 0.5 equiv
(entry 5). Mechanistically, this might suggest that that an excess
of 5 may lead to multiple reactive intermediates that are structur-
ally dissimilar and have different capacities for enantioselection.
The results collected suggest that the use of 0.3 equiv of 5 would
be ideal for further experimentation. It is worth noting that the
use of 0.4 equiv gave comparable or better enantioselectivities
(entries 4 and 9); however, the amount of catalytic ligand was con-
sidered to be too excessive for practical consideration.
Furthermore, there was a change in the absolute configuration
of the product of the asymmetric addition in the presence of
Ti(O-iPr)4 from the (R)-configuration to the (S)-configuration
(entries 1–5 vs entries 6–10). We became interested in determin-
ing if varying the relative amount of the Ti(O-iPr)4 relative to the
(R,R)-hydrobenzoin in the asymmetric addition would have a
similar effect as observed in other research programs7,9 (Table 2).
HPLC data with literature values for HPLC and specific rotations.
d
There was
a significant amount of the direct reduction product, 2-
naphthylmethanol.13
With the exception of one instance (entry 2), the enantioselectivi-
ties were fairly consistent and ranged between 78:22 and 87:13
favoring the (R)-enantiomer. However, some of the addition reac-
tions were compromised in terms of the isolated yield due to the
presence of unreacted aldehyde and 2-naphthylmethyl alcohol,
the product of reduction by diethylzinc.13 The use of 25% excess
of Ti(O-iPr)4 caused the enantiomeric ratio to decrease. As was
postulated for the results in Table 1, we propose that an excess
of the reagent, Ti(O-iPr)4 in this case, was responsible for the
evolution of multiple catalytic species that afford different enantio-
selectivities. Ultimately, the combination that was determined to
be optimal in terms of the enantiomeric ratio and isolated yield
involved the use of 0.30 equiv of 5 and 1.0 equiv of the Ti(O-iPr)4.
The use of an alternate titanium alkoxide was also considered as
a means of improving the enantioselectivity of the process.
Recently, Tanski and co-workers disclosed that the identity of the
alkoxy group of the titanium mediator could have an influence
over the course of the asymmetric addition of diethylzinc to

M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 2563–2567
2565
Table 3
by-products and was not pursued further. Interestingly, there
was no reversal of the enantiomeric ratio as compared to the
example of hydrobenzoin without a titanium mediator. The use of
Ti(O-t-Bu)4 was not pursued as an earlier study suggested that this
compound had provided limited success. Thus, it was determined
that Ti(O-iPr)4 was the best stoichiometric reagent for the
transformation.
Catalysis with different titanium reagents
5 (0.3 equiv.)
6
3a
2 equiv. Et2Zn, toluene
TiX4
Entry
TiX4, X=
Yielda
er, [R:S, (|RꢀS|)]b
Config.c
The last variable that was explored was the use of the sol-
vent. Using the optimized conditions of 0.3 equiv of the catalyst
and one equivalent of Ti(O-iPr)4, the use of dichloromethane
and diethyl ether was explored. It was determined that the
use of dichloromethane led to the formation of the product
1-(2-naphthyl)-1-propanol in an enantiomeric ratio of 83.5 (R)
to 16.5 (S) versus that of the reaction conducted in toluene,
which afforded a diastereomeric ratio of 82.0 (R) to 18.0 (S).
The use of diethyl ether gave a slight improvement in the
enantiomeric ratio of 85.0 (R):15.0 (S). Based on this informa-
tion, we conducted a series of reactions with different aromatic
aldehydes (Table 4).
In general, the aldehyde substrates underwent a smooth trans-
formation to form either enantiomer depending on the conditions
that were applied. This suggested that the difference in the free
energies of zinc-mediated pathway and the titanium-mediated
pathway was not as good as in related literature examples (cf.
Mao et al.7 and Lake and Moberg9). In contrast, the use of trans-
cinnamaldehyde gave inferior results, presumably due to the
1
2
3
4
–OCH3
–O-n-Bu
–O-i-Pr
–Cl
61
92
87
37
52.0:48.0 (4)
69.0:31.0 (38)
82.0:18.0 (64)
47.0:53.0 (6)
(R)
(R)
(R)
(S)
a
Isolated yield after flash chromatography.
Enantiomeric ratios were determined by CSP HPLC with a Chiralcel OD column.
The absolute configuration of the product was determined by correlation of
b
c
HPLC data with literature values for HPLC and specific rotations.
aldehydes.15 Although Tanski et al. employed enantiomerically
enriched titanium tetra-2-butoxide as the mediator, we only
sought to make simple adjustments in the nature of the alkoxy
group (Table 3).
We were disappointed to learn that the use of either titanium
tetra-methoxide [Ti(OMe)4] or titanium tetra-n-butoxide [Ti(O-n-
Bu)4] led to significantly lower enantioselectivities. This may have
been a result of a faster background reaction with the smaller
alkoxides. As expected, the more Lewis acidic titanium tetrachlo-
ride generated the desired product as well as numerous
Table 4
Optimized conditions diethylzinc addition catalyzed by hydrobenzoin
5
(0.3 equiv.)
3a-e
1a-e
Ti(O-iPr)4 (1 equiv.)
2 equiv. Et2Zn, Et2O
Yielda
Entry
RCHO
Ti(O-iPr)4 (equiv)
er [R:S, (|RꢀS|)]b
½
a 2D4
CHCl3
ꢁ
in
Config.c
1
2
3
4
5
6
7
8
9
2-C10H7–
2-C10H7–
1-C10H7–
1-C10H7–
4-MeOC6H5–
4-MeOC6H5–
C6H5CH@CH–
C6H5CH@CH–
C6H5–
1
0
1
0
1
0
1
0
1
0
87
93
71
81
64
65
66
71
85
89
82.0:18.0 (64)
7.5:92.5 (85)
83.7:16.3 (68)
11.0:89.0 (78)
71.9:28.1 (44)
17.4:82.6 (65)
61.6:38.4 (23)
22.7:77.3 (55)
80.9:19.1 (62)
7.3:92.7 (85)
+22.4 (c 1.11)
ꢀ32.3 (c 1.11)
+34.9 (c 0.54)
ꢀ41.7 (c 0.57)
+21.6 (c 0.40)
ꢀ23.4 (c 0.30)
+0.90 (c 0.44)
ꢀ5.25 (c 0.45)
+29.6 (c 0.31)
ꢀ36.1 (c 0.30)
(R)-3a
(S)-3a
(R)-3b
(S)-3b
(R)-3c
(S)-3c
(R)-3d
(S)-3d
(R)-3e
(S)-3e
10
C6H5–
a
Isolated yield after flash chromatography.
Enantiomeric ratios were determined by CSP HPLC with a Chiralcel OD column.
The absolute configuration of the product was determined by correlation of HPLC data with literature values for HPLC and specific rotations.
b
c
Et
Et
Ph
H
H
H
H
Zn
Ph
H
Et2Zn
RCHO
H
O
H
HO
Et
Zn
O
O
O
O
Ar
Zn
Et
Ar
Ph
Ph
Et
O-iPr
O-iPr
Ph
H
Ar
H
Ph
H
Ar
H
Ti
H
Ti
Et Ti(O- iPr)3
O
O
HO
Et
O
O-iPr
O
O
-O-iPr
Et
Ph
Ti
Ph
RCHO
iPr-O
O-iPr
O-iPr
Figure 1. Proposed mechanism for enantiodivergent pathways.

2566
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 2563–2567
Ligand 7 or 8
6
3a
Et2Zn, toluene
Ti(O-iPr)4
NMe2
Me
HO
Ph
OH
HO
1-Nap
Diminished
enantioselectivity
Reversal of
enantioselectivity
8
1-Nap
7
er = 14.5:85.5 (R:S) w/o Ti(O-iPr)4
er = 82.0:18.0 (R:S) w/Ti(O-iPr)4
er = 85.0:14.0 (R:S) w/o Ti(O-iPr)4
er = 58.0:42.0 (R:S) w/Ti(O-iPr)4
Scheme 2. Ligand comparison.
stereoelectronic differences as compared to the aromatic
aldehydes employed. Aliphatic aldehydes also proved to be
problematic due to poor enantioselectivities and so were not
pursued in this work.
diol that would be able to afford very high enantioselectivities
for either enantiomer when employed in the catalytic asymmetric
addition of diorganozinc reagents with carbonyl compounds with
and without Ti(O-iPr)4.
The results listed in Table 4 strongly suggest that the develop-
ment of enantiodivergent pathways in the asymmetric addition
of diethylzinc to aldehydes via the use of Ti(O-iPr)4 might be
optimal under the constraints of employing an ideal C2-symmetric
vicinal diol. This argument was developed based on the literature
precedent that other ligand families that were not C2-symmetric
did not offer practical reversal of enantioselectivities.
4. Experimental
4.1. General remarks
All reactions were run under a nitrogen atmosphere. Anhydrous
toluene was purchased and stored under a nitrogen atmosphere.
Diethylzinc was purchased as a 1 M solution in hexanes. All 1H
NMR spectra were recorded at 25 °C in CDCl3 operating at
400 MHz. Chemical shifts are reported in parts per million (d scale),
and coupling constants (J values) are listed in Hertz (Hz). Optical
activities were measured using at 589 nm using a Jasco digital
polarimeter purchased with NSF grant #CHE 644950.
Based on the literature precedents established Noyori et al.16
and Walsh et al.,3 a tentative mechanism has been proposed for
these enantiodivergent pathways (Fig. 1). There are other mecha-
nistic pathways that may be viable but these pathways most likely
involve similar features, that is, the opposing coordinating forms as
proposed by Mao et al..7 More data should be collected before a
more defined mechanism can be proposed as the results that have
been obtained only suggest that C2-symmetry is superior to C1-
systems and does not suggest any particular intermediates.
In order to further support this mechanistic proposal, two
ligands, a C1 b-amino alcohol 7 (N-methylephedrine) and a C2-sym-
metric diol 8 (1,2-bis(1-naphthyl)ethane-1,2-diol), were employed
in the asymmetric addition of diethylzinc with and without
Ti(O-iPr)4 (Scheme 2). Ligand 7 afforded only a decrease in the
enantioselection of the addition process. In contrast, the C2-sym-
metric ligand 8 gave the opposite enantiomers in good to moderate
enantioselectivity in the absence or presence of Ti(O-iPr)4.
Although this evidence is limited in its scope, it still supports the
use of C2-symmetric vicinal diols in order to achieve practical
levels of the reversal of enantioselectivity. A reaction mechanism
detailing the key difference between the zinc-mediated and
titanium-mediated pathways remains to be developed. It is postu-
lated that whatever the key intermediates of the two pathways,
C2-symmetrical vicinal diols would allow them to have nearly
opposite enantiofacial discrimination with aromatic aldehydes.
4.2. General procedure for the catalytic asymmetric addition of
diethylzinc to aldehydes
In a flame-dried, nitrogen-purged round-bottomed flask were
placed (R,R)-hydrobenzoin (0.10 g, 0.48 mmol, 0.3 equiv) and
anhydrous ether (5 mL, ꢂ0.3 M based on aldehyde). To this mix-
ture, which was maintained at ambient temperature, was added
diethylzinc (3.2 mL, 3.2 mmol, 2 equiv). This mixture was stirred
for 15 min before the addition of the aldehyde (0.25 g, 1.6 mmol,
1 equiv). The reaction mixture was stirred overnight and then
quenched by the slow addition of 1 M HCl, and extracted with
EtOAc. The organic layer was dried over MgSO4 and the solvent
removed under reduced pressure to afford the crude products
3a–e.
4.3. General procedure for the catalytic asymmetric addition of
diethylzinc to aldehydes in the presence of Ti(O-iPr)4
In a flame-dried, nitrogen-purged round-bottomed flask were
placed (R,R)-hydrobenzoin (0.10 g, 0.48 mmol, 0.3 equiv) and
anhydrous diethyl ether (5 mL, ꢂ0.3 M based on aldehyde). To
this mixture, which was maintained at ambient temperature,
was added titanium tetraisopropoxide (0.48 mL, 1.6 mmol,
1 equiv). This mixture was stirred for 25 min before the addition
of the diethylzinc (3.2 mL, 3.2 mmol, 2 equiv). After 15 min, the
aldehyde (0.25 g, 1.6 mmol, 1 equiv) was added and the reaction
mixture was stirred overnight, and was quenched by the slow
addition of 1 M HCl and extracted with EtOAc. The organic layer
was dried over MgSO4 and the solvent removed under reduced
pressure to afford the crude products 3a–e. In all cases, the
enantiomeric ratio was determined by chiral stationary phase
HPLC.
3. Conclusion
(R,R)-Hydrobenzoin has been employed as a ligand for the
catalytic asymmetric addition of diethylzinc to aromatic and alde-
hydes in the absence or presence of Ti(O-iPr)4. The enantioselectiv-
ities of the process involving no Ti(O-iPr)4 were as high as 7.5:92.5,
favoring the (S)-enantiomer (Table 4, entry 2). The enantioselectiv-
ities of the process where Ti(O-iPr)4 was used were as high as
83.7:16.3 favoring the (R)-enantiomer. A reversal in enantioselec-
tivity was not observed when using N-methylephedrine, only
diminished levels of selectivity. The results of this study suggest
that it may be possible to design an optimal C2-symmetric vicinal

M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 2563–2567
2567
4.4. 1-(20-Naphthyl)-1-propanol 3a16
Acknowlegment
Purified by flash chromatography (95:5, hexanes/EtOAc). 0.95
The authors acknowledge support for this work by the National
Science Foundation (NSF CHE #644950).
(t, J = 7.4 Hz, 3H), 1.80–1.95 (m, 2H), 4.78 (t, J = 6.3 Hz, 1H), 7.45–
7.49 (m, 4H), 7.78–7.85 (m, 3H). (S)-3a: ½a D24
¼ ꢀ32:3 (c 1.11,
ꢁ
CHCl3); (R)-3a: ½a D24
¼ þ22:4 (c 1.11, CHCl3). CSP HPLC: OD, 98:2
ꢁ
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(hex/IPA); tR (R)-enantiomer (min) = 29.8. tR (S)-enantiomer
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4380; (b) Kang, S.-W.; Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2003, 5, 4517–
4519; (c) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233–6236; (d) Zhang,
F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 585–
589.
Purified by flash chromatography (95:5, hexanes/EtOAc). 1.04
(t, J = 7.4 Hz, 3H), 1.91 (d, J = 3.6 Hz, 1H), 1.94–2.07 (m, 2H), 5.42
(dt, J = 4.3, 3.6 Hz, 1H), 7.46–7.54 (m, 3H), 7.64 (d, J = 6.8 Hz, 1H),
7.78 (d, J = 8.4 Hz, 1H), 7.86–7.88 (m, 1H), 8.12 (d, J = 7.6 Hz, 1H).
(S)-3b: ½a 2D4
ꢁ
¼ ꢀ41:7 (c 0.57, CHCl3); (R)-3b: ½a D24
¼ þ34:9 (c 0.54,
ꢁ
CHCl3). CSP HPLC: OD, 90:10 (hex:IPA); tR (R)-enantiomer
(min) = 12.1. tR (S)-enantiomer (min) = 7.08.
6. (a) Kozakiewicz, A.; Ullrich, M.; Welniak, M.; Wojtczak, A. J. Mol. Catal. A 2008,
286, 106–113; (b) Jeon, S.-J.; Li, H.; García, C.; Larochelle, L. K.; Walsh, P. J. J. Org.
Chem. 2005, 70, 448–455; (c) Wu, K.-H.; Gau, H.-M. Organometallics 2004, 23,
580–588; (d) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802–1803; (e)
Prieto, O.; Ramón, D. J.; Yus, M. Tetrahedron: Asymmetry 2000, 11, 1629–1644;
(f) Prichett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J. Am. Chem. Soc.
1998, 120, 6423–6424.
7. (a) Mao, J.; Wan, B.; Zhang, Z.; Wang, R.; Wu, F.; Lu, S. J. Mol. Catal. A 2005, 225,
33–37; (b) Mao, J.; Wan, B.; Wang, R.; Wu, F.; Lu, S. J. Mol. Catal. A 2005, 232, 9–
12.
4.6. 1-(4-Methoxyphenyl)-1-propanol 3c17
Purified by flash chromatography (80:20, hexanes/EtOAc). 0.90
(t, J = 7.4 Hz, 3H), 1.67–1.88 (m, 2H), 3.81 (s, 3H), 4.56 (m, 1H),
6.88 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H). (S)-3c: ½a D24
¼
ꢁ
ꢀ23:4 (c 0.30, CHCl3); (R)-3a: ½a D24
¼ þ21:6 (c 0.40, CHCl3). CSP
ꢁ
HPLC: OD, 98:2 (hex:IPA); tR (R)-enantiomer (min) = 16.6. tR (S)-
8. (a) Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew. Chem., Int. Ed.
2007, 46, 9002–9005; (b) Huang, H.; Zheng, Z.; Chen, H.; Bai, C.; Wang, J.
Tetrahedron: Asymmetry 2003, 14, 1285–1289; (c) Huang, H.; Chen, H.; Hu, X.;
Bai, C.; Zheng, Z. Tetrahedron: Asymmetry 2003, 14, 297–304; (d) Cobb, A. J. A.;
Marson, C. M. Tetrahedron: Asymmetry 2001, 12, 1547–1550; (e) Goldfuss, B.;
Steigelmann, M.; Rominger, F. Eur. J. Org. Chem. 2000, 9, 1785–1792; (f) Sibi, M.
P.; Chen, J.-X.; Cook, G. R. Tetrahedron Lett. 1999, 40, 3301–3304; (g) Kimura, K.;
Sugiyama, E.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1992, 33, 3147–3150.
9. Lake, F.; Moberg, C. Tetrahedron: Asymmetry 2001, 12, 755–760.
10. Zhang, X.; Guo, C. Tetrahedron Lett. 1995, 36, 4947–4950.
11. Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 99–101.
12. Rosini, C.; Franzini, L.; Pini, D.; Salvadori, P. Tetrahedron: Asymmetry 1990, 1,
587–588.
13. The presence of the alcohol suggests the slow reduction of aldehyde by an
ethylzincate intermediate wherein the b-hydrogen of the ethyl was reactive.
See: (a) Sung, D. W. L.; Hodge, P.; Stratford, P. W. J. Chem. Soc., Perkin Trans. 1
1999, 1463–1472; (b) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem.
Soc. 1989, 111, 4028–4036; (c) Itsuno, S.; Fréchet, J. M. J. J. Org. Chem. 1987, 52,
4140–4142.
enantiomer (min) = 18.5.
4.7. 1-Phenyl-1-penten-3-ol 3d17
Purified by flash chromatography (95:5, hexanes/EtOAc). 0.98
(t, J = 7.4 Hz, 3H), 1.61–1.73 (m, 2H), 4.22 (dt, J = 12.4, 7.0 Hz,
1H), 6.22 (dd, J = 16.0, 7.0 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 7.24–
7.40 (m, 5H). (S)-3d:
½
a 2D4
ꢁ
¼ ꢀ5:25 (c 0.45, CHCl3); (R)-3d:
½
a 2D4
ꢁ
¼ þ0:9 (c 0.44, CHCl3). CSP HPLC: OD, 98:2 (hex/IPA); tR (R)-
enantiomer (min) = 21.1. tR (S)-enantiomer (min) = 39.2.
4.8. 1-Phenyl-1-propanol 3e17
Purified by flash chromatography (80:20 hexanes/EtOAc). 0.92
14. Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2965–2968.
15. MacMillan, S. N.; Ludford, K. T.; Tanski, J. M. Tetrahedron: Asymmetry 2008, 19,
543–548.
16. Ko, D.-H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4, 3759–3762.
17. Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew. Chem., Int. Ed.
2007, 46, 9002–9005.
(t, J = 7.4 Hz, 3H), 1.70–1.88 (m, 2H), 4.60 (t, J = 6.6 Hz, 1H), 7.26–
7.29 (m, 2H), 7.34–7.36 (m, 3H). (S)-3e: ½a D24
¼ ꢀ36:1 (c 0.30,
ꢁ
CHCl3); (R)-3e: ½a D24
¼ þ29:6 (c 0.31, CHCl3). CSP HPLC: OD, 98:2
ꢁ
(hex/IPA); tR (R)-enantiomer (min) = 11.5. tR (S)-enantiomer
(min) = 15.0.