Use of diamines containing the α-phenylethyl group as chiral ligands in the asymmetric hydrosilylation of prochiral ketones

Article abstract of DOI:10.1016/j.tet.2003.12.039

Chiral diamines 1-7 were used in the enantioselective hydrosilylation of prochiral aromatic and aliphatic ketones. Some of these ligands combine chiral backbones and chiral N,N′-α-phenylethyl substituents that give rise to synergistic effects between these two groups and lead to catalysts that exhibit high enantioselectivity.

Full text of DOI:10.1016/j.tet.2003.12.039

Tetrahedron 60 (2004) 1781–1789
Use of diamines containing the a-phenylethyl group as chiral
ligands in the asymmetric hydrosilylation of prochiral ketones
c
Virginia M. Mastranzo,a,b Leticia Quintero,b Cecilia Anaya de Parrodi,a Eusebio Juaristi and
,
,
*
*
Patrick J. Walshd
,
*
a
´
´
´
´
Centro de Investigaciones Quımico Biologicas, Universidad de las Americas-Puebla, Santa Catarina Martir, Cholula, 72820 Puebla, Mexico
´
b
´
´
Centro de Investigacion de la Facultad de Ciencias Quımicas, Universidad Autonoma de Puebla, Puebla 72570, Mexico
´
c
´ ´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
Mexico, D.F. 07000, Mexico
dDepartment of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Received 18 November 2003; revised 15 December 2003; accepted 15 December 2003
Abstract—Chiral diamines 1–7 were used in the enantioselective hydrosilylation of prochiral aromatic and aliphatic ketones. Some of these
ligands combine chiral backbones and chiral N,N0-a-phenylethyl substituents that give rise to synergistic effects between these two groups
and lead to catalysts that exhibit high enantioselectivity.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
ketones has been reported by Lipschutz with excellent
results.5b,c
The catalytic reduction of prochiral ketones to secondary
alcohols with high enantioselectivity is an important goal in
synthetic organic chemistry. Among the most efficient
catalysts for this transformation are the ruthenium-BINAP
hydrogenation catalysts developed by Noyori1 and the chiral
oxazaborolidine complexes of Itsuno,2a Corey,2b and
others.2c A practical alternative to these methodologies is
the asymmetric hydrosilylation of ketones, which affords
secondary alcohols upon work-up. Several catalysts pro-
mote this reaction in an enantioselective fashion.3 In some
cases, polymethylhydrosiloxane (PMHS) has been used as
the hydrosilylating reagent.4 PMHS is a coproduct of the
silicone industry that is inexpensive and can be easily
handled in air. PMHS has been used with chiral ansa-
titanocene catalysts in the reduction of ketones with high
enantioselectivity by the Buchwald group.5a Additionally,
the use of copper hydride in the hydrosilylation of aryl
Recent work in the enantioselective hydrosilylation of ketones
byMimounandco-workers6 hasdemonstratedthatanefficient
and enantioselective catalyst can be prepared from zinc
precursors such as diethylzinc and zinc carboxylates in
combination with homochiral diamine ligands and PMHS
Eq. (1). The active species in the reduction is proposed to be
L*ZnH2, where L* is the chiral bidentate ligand. From a
structure-enantioselectivitystudy,itwasfoundthattheligands
with the stilbene diamine backbone afforded better enantios-
electivity than ligands derived from trans-1,2-diaminocyclo-
hexane. They also observed that the catalyst generated from
N,N0-ethylene bis(1-phenylethylamine) 1 (Chart 1), gave high
enantioselectivities. Their results demonstrated that ligands
with chiral backbones and achiral N,N0-dialkyl groups gave
similar results to ligands with achiral backbones and chiral
N,N0-dialkyl groups.6
ð1Þ
Keywords: Asymmetric reactions; Enantioselective hydrosilylation; Chiral ligands; Chiral auxiliaries; a-Phenylethylamine; Enantioselective reduction.
*
Corresponding authors. Tel.: þ2-2292067; fax: þ2-2292419 (CAdP); e-mail addresses: anaya@mail.pue.udlap.mx; juaristi@chem.cinvestav.mx;
pwalsh@sas.upenn.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.039

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V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
Chart 1.
Inspiredbytheseresults, we thought it wouldbeinformativeto
explore the structure-enantioselectivity relationship of ligands
bearing both chiral backbones and chiral N,N0-dialkyl groups
in the asymmetric hydrosilylation of ketones. We have,
therefore, synthesized a series of such diamines and found that
there is indeed a strong synergistic effect between these
moieties in the catalytic asymmetric reduction of ketones.
Higher homolog 29b was prepared according to our
procedure.10 The synthesis of diamine 3 was prepared
from succinic acid as shown in Scheme 1.11
trans-Cyclohexane-1,2-diamines 4a and 4b, as well as
unsaturated analogs 5a and 5b and trans-cyclopentane
1,2-diamines 6a and 6b were prepared from the appropriate
epoxide precursors, via chiral aziridine intermediates A,
as outlined in Scheme 2.12b The major products were 4a,
5a and 6a, and the diastereomeric ratios were 2:1 in all
cases.
Chiral diamines 1–7 (Chart 1) were selected with two
considerations in mind: (1) The presence of C2-symmetry
was expected to confer a high degree of enantiotopic
differentiation.7 (2) Incorporation of the a-phenylethylamino
group was deemed attractive as chiral moieties, because they
have proven quite effective in asymmetric synthesis.8
The separation of the diastereomeric pairs 4a/4b, 5a/5b, and
6a/6b was accomplished by flash chromatography [hexane–
EtOAc (12:1)]. The assignment of configuration of
cyclopentane diamines 6a (all S configurations) and 6b
[(S,R,R,S) isomer] was achieved by chemical correlation of
6a with the known10 trans-diamide (S,S)-8 (Scheme 3).
Likewise, the configuration of cyclohexene diamines 5a and
5b was possible via chemical correlation with 4a and 4b,
respectively, by simple hydrogenation of the double bond
(Scheme 4).
2. Results and discussion
2.1. Synthesis of chiral diamines 1–7
Convenient procedures for the preparation of N,N0-ethylene
bis(1-phenylethylamine) 1 are available in the literature.9
Scheme 1. Reagents and conditions: (a) (S)-CH3CH(Ph)NH2/Et2O/rt/12 h. (b) (S)-CH3CH(Ph)NH2DCC/DMAP/CH2Cl2/rt/16 h. (c) LiAlH4/THF/reflux/48 h.

V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
1783
Scheme 2. Reagents and conditions: (a) (S)-a-Phenylethylamine/LiClO4/CH3CN/reflux/18 h. (b) CH3SO2Cl/Et3N/CH2Cl2/rt/24 h. (c) (S)-a-
Phenylethylamine/LiClO4/CH3CN/reflux/50 h. (d) Flash chromatography [hexane–EtOAc (12:1)].
Scheme 3.
Finally, the preparation of (R,R,R,R)-N,N0-di(a-phenyl-
ethyl)-1,2-diphenyl-1,2-ethylenediamine 714a was accom-
plished following the procedure described in the literature,
which involves the stereoselective addition of phenylmag-
nesium bromide to the chiral bis-imine,14b,c derived from
glyoxal and 2 equiv. of (R)-a-phenylethylamine.
Examination of Table 1 indicates that highest enantioselec-
tion is achieved with chiral ligands 4a, 5a and 6a where the
a-phenylethylamino chiral groups are bonded to a fairly
rigid cycloalkane (or cycloalkene in the case of 5a)
framework. As can be appreciated in entries 4, 5, 7, 8, and
11 in Table 1, the use of ligands 4a, 5a and 6a (all
S-configuration) afforded consistently high enantioselectiv-
ities (80–84%). In contrast, ligands 4b, 5b and 6b [(S,R,R,S)
configuration] led to reduced carbinol products of low
enantiopurity (10–29%). These results demonstrate that the
stereogenic centers of phenylethyl groups are important in
the enantioselectivity determining step.15
Whereas ethylene diamine derivative 1 induces high
enantioselectivity in the reduction process (79% ee, entry
1 in Table 1), higher homologs 2 and 3 proved to be
inefficient ligands (5% ee and 17% ee, respectively). It has
been known since early studies by Knowles and co-
workers16 that chiral ligands with stereogenic centers
directly attached to the metal center can exhibit excellent
enantioselectivities. We believe that a key factor in the
control of enantioselectivity in the asymmetric hydrosilyla-
tion of ketones is the stereochemistry of coordination of the
amino groups to the zinc center. Upon coordination nitrogen
inversion ceases and the bound nitrogens become stereo-
genic centers. It is possible that the ligand 1 binds to the
metal with high diastereoselectivity and that the chiral
phenylethyl groups and stereogenic nitrogens contribute
constructively to the enantioselectivity of the catalyst. In
contrast, ligands 2 and 3, with longer, more flexible
Scheme 4.
3. Enantioselective reduction of aromatic and aliphatic
prochiral ketones
According to the general procedures described for the
enantioselective reduction of prochiral ketones,6 acetophe-
none was treated with 5 mol% of diethylzinc (1.0 M in
hexanes), and 5 mol% of the chiral ligand in toluene solvent
at ambient temperature in the presence of 2 equiv. of PMHS
for 24 h (method A) or 1.5 equiv. of (EtO)3SiH for 18 h
(method B). The results are collected in Table 1.

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V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
Table 1. Enantioselective reduction of acetophenone in the presence of diethylzinc and a chiral ligand
Entry
Chiral ligand
Reducing silylating agenta
Reaction time (h)
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8
1
2
3
PMHS
PMHS
PMHS
(EtO)3SiH
PMHS
PMHS
(EtO)3SiH
PMHS
(EtO)3SiH
PMHS
PMHS
24
24
24
18
24
24
18
24
18
24
24
24
24
100
85
20
100
90
40
99
90
100
40
95
50
18
79 (R)c
5 (R)
17 (R)
80 (R)
83 (R)
18 (S)
84 (R)
82 (R)
29 (R)
10 (R)
83 (R)
21 (S)
2 (R)
4a
4a
4b
5a
5a
5b
5b
6a
6b
7
9
10
11
12
13
PMHS
PMHS
a
Experiments were carried out using 1.0 equiv. of acetophenone and 2.0 equiv. of PMHS or 1.5 equiv. of (EtO)3SiH.
The enantiomeric excess was determined by HPLC with a Chiralcel OD column.
Mimoun et al.6 reported 75% ee in this reaction using 2 mol% zinc-ligand catalyst, in the presence of 1.1 equiv. of PMHS.
b
c
backbones, may permit formation of diastereomeric cata-
lysts (Chart 2) that are less enantioselective. The magnitude
of the difference in enantioselectivity between the match
and mismatched diastereoisomers is surprisingly large,
being 101% (4a/4b), 92% (5a/5b), and 104% (6a/6b). We
believe these results indicate that the enantioselectivities of
the catalysts are highly sensitive to their chiral environ-
ments. It is also noteworthy that the mismatched ligands
resulted in much slower catalysts. Although catalysts
derived from 4a, 5a and 6a proceeds to at least 90% yield
in 24 h, those using catalysts prepared from 4b, 5b and 6b
did not exceed 50% in this time. It is also clear that the
difference in enantioselectivities between the catalysts
derived from (S,S,S,S)- and (R,S,S,R)-configured ligands
arises from a mismatched combination between the
stereogenic nitrogens and the phenylethyl groups. Amino
groups that become stereochemically fixed on coordination
have been shown to have a powerful impact on enantio-
selectivity in zinc(diamine)-based catalysts.17
ligand (R,R)-N,N0-bis(1-naphthylenemethyl)-trans-1,2-
cyclohexanediamine gave 70% enantioselectivity with
acetophenone under the same conditions. These res0ults
suggest that the synergistic effects of the chiral N,N -a-
phenylethyl groups with the diamine backbone in 4a can
raise the level of enantioselectivity of the catalyst over that
of a similar catalysts bearing only achiral N,N0-dialkyl
groups. The poor stereoinduction achieved with ligand 7 (all
R-configured) show again that a proper combination of
stereogenic center on the a-phenylethylamino groups and
the ligand’s backbone is essential for good enantiofacial
differentiation in this system.
Since there is not a significant difference in the enantio-
selectivity of acetophenone reduction with diamines 4a, 5a
and 6a (Table 1), and 4a can be prepared more
economically, the use of diamine 4a in the enantioselective
reduction of other prochiral ketones with PMHS in the
presence of ZnEt2 has been explored (Table 2). Prochiral
ketones were treated with 2 mol% diethylzinc (1.0 M in
toluene), and 2 mol% of the chiral ligand in toluene solvent
at ambient temperature and in the presence of 2 equiv. of
PMHS for 24 h (method C). From Table 2, it can be seen
that with aryl alkyl ketones better enantioselectivities were
obtained with longer alkyl groups, that is, n-Pr.Et.Me
(Table 2 entries 1 and 2, Table 1 entry 5). The enantio-
selectivity with b-acetonaphthone gave similar results to
It is also informative to compare the enantioselectivities of
our matched and mismatched ligands with a ligand0that has
chirality in the diamine backbone and achiral N,N -dialkyl
groups. In the reduction of acetophenone with matched
catalyst derived from 4a and mismatched catalyst derived
from 4b the enantioselectivities and configurations were
83% (R) and 18% (S), respectively. The previously reported
Chart 2.

V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
1785
Table 2. Enantioselective reduction of prochiral ketones by PMHS in the
presence of ZnEt2 (2 mmol%) and diamine 4a (2 mmol%)a
cannot readily differentiate between them. On the other
hand, the unsaturated substrate give very good enantio-
selectivity (84%) indicating the importance of the double
bond in this asymmetric reduction.
Entry
Ketones
Yield (%)
ee (%)
In conclusion, chiral diamines 1–7 were used in the
enantioselective hydrosilylation of prochiral acetophenone.
Diamines 4a, 5a, and 6a combine chiral backbones and
chiral N,N0-a-phenylethyl substituents that give rise to
synergistic effect between these two groups and lead to
catalysts that exhibit high enantioselectivities. The enan-
tioselectivities of prochiral aromatic ketones in the presence
of 4a were found to range from poor with dialkyl ketones to
very good with acetophenone derivatives and a,b-unsatu-
rated ketones.
1
75
84 (R)b
2
3
4
5
80
72
95
87
89 (R)b
84 (R)b
19 (S)c
11 (R)c
4. Experimental
4.1. General
Melting points were determined on a Fischer Jones
1
apparatus and are uncorrected. H NMR (200 MHz) and
13C NMR (50 MHz) spectra were measured on a Varian
Mercury spectrometer, with tetramethylsilane (TMS) as an
internal standard. Chemical shifts are given as d values
(ppm) and coupling constants J are given in Hz. Optical
rotations [a]D were measured at ambient temperature in
0.1 dm cells, using a Perkin–Elmer 241 spectrophotometer.
IR-FT spectra were recorded on a BioRad instrument. Mass
spectra were recorded on a Saturn Varian GC-mass
spectrometer. Microanalyses were performed by Galbraith
Laboratories, Inc., Knoxville, TN. All reagents were
purchased from Aldrich Chemical Co.
6
7
80
81
68 (R)b
84 (R)c
8
9
95
82 (R)c
4.1.1. N,N0-Bis[(S)-a-phenylethyl]propane-1,3-diamine,
2. In a dry two-necked flask fitted with an addition funnel,
condenser, and magnetic stirrer was placed (S)-a-phenyl-
ethylamine (3.3 mL, 26 mmol) under a nitrogen atmos-
phere. The reaction flask was heated to 100 8C with stirring
followed by slow addition of 2.0 g (13.0 mmol) of freshly
prepared 1-mesylate-3-chloro-propane (prepared from 3-
chloro-propanol) over 2 h. Stirring of the mixture was
continued for 16 h at 100 8C, followed by cooling to 60 8C,
and addition of 2 mL of saturated aqueous KOH. The
resulting mixture was allowed to cool to ambient tempera-
ture and extracted with three 20 mL portions of CH2Cl2. The
combined organic layers were washed with brine and dried
over anh. Na2SO4, and concentrated in a rotary evaporator.
The excess (S)-a-phenylethylamine was removed by
vacuum distillation (40 8C/5 mm Hg) affording the desired
product as a colorless liquid 1.3 g (50% yield). [a]D¼264.6
(c¼1.1, CHCl3); [a]D¼266.3 (c¼0.55, CHCl3).9b 1H NMR
(CDCl3) d: 1.3 (m, 2H), 1.4 (d, 6H, J¼7 Hz), 2.1 (m, 2H),
3.7 (q, 1H, J¼7 Hz), 7.2–7.3 (m, 10H). 13C NMR (CDCl3)
d: 24.3, 30.3, 46.4, 58.4, 126.5, 126.7, 128.3, 145.7.
67
70
15 (R)b
84 (R)b
10
a
Experiments were carried out using 1.0 equiv. of prochiral ketone and
2.0 equiv. of PMHS.
The enantiomeric excess were determined by HPLC after purification on
silica gel (hexane–ethyl acetate, 10:1).
The enantiomeric excess were determined by GC on a b-Dex column.
b
c
acetophenone (entry 3). However, the enantioselective
reduction of trifluoroacetophenone proceeded with low
selectivity due to the electronic effect of the trifluoromethyl
group (entry 4). Additionally, the reduction of prochiral
ketones with substituents on the aromatic ring was
performed. Enantioselectivity was significantly diminished
when p-MeO and p-NO2 group were present (entries 5 and
6). Nevertheless, p-Cl or m-CF3-acetophenones were very
good substrates, exhibiting (82–84% ee, entries 7 and 8). To
examine the effect of substrate unsaturation on the catalyst
enantioselectivity, we examined the use of 4-phenyl-2-
butanone and trans-4-phenyl-3-buten-2-one (entries 9 and
10). The saturated derivative gave low enantioselectivity
(15%). This is not surprising, given that the lone pair
environments of the substrate are so similar and the catalyst
4.1.2. N,N0-Bis[(S)-a-phenylethyl]butane-1,4-diamine,
3.11 Succinic anhydride 0.7 g (7.0 mmol) was dissolved in
10 mL of diethyl ether at rt and a solution of (S)-a-
phenylethylamine (0.90 mL, 7.0 mmol) in 2 mL of diethyl
ether was added dropwise over 10 min with stirring. The
mixture was stirred overnight at rt. The product was purified

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V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
by column chromatography [hexane–EtOAc (1:1)] and
isolated as a white solid (1.4 g, 95% yield), mp¼102–
103 8C, [a]D¼286.6 (c¼1.0, CH3OH). 1H NMR (CD3OD)
d: 1.4 (d, 3H, J¼6.6 Hz), 2.4 (m, 2H), 2.6 (m, 2H), 5.1 (q,
1H, J¼6.6 Hz), 6.4 (m, 1H), 7.3 (m, 5H), 10.5 (b, 1H). 13C
NMR (CD3OD) d: 21.8, 29.7, 30.7, 49.2, 126.1, 127.4,
126.7, 142.8, 171.5, 176.6.11a
After purification, the aziridine was used to obtain the 1,2-
diamines, which were separated by flash chromatography
[hexanes–ethyl acetate (12:1)].
1,2-Diamine 5a dihydrochloride. White crystals, mp 177–
178 8C. Anal. calcd C22H28N2·2HCl·H2O: C 64.22%, H
7.84%; found C 64.55%, H 7.65%.
To a stirred solution of N-(S)-a-phenylethylsuccinamidic
acid (0.44 mg, 2.1 mmol) in anhydrous CH2Cl2 (20 mL)
under nitrogen at 0 8C was added 4-dimethylaminopyridine
(10.3 g, 2.1 mmol), and 1,3-dicyclohexylcarbodiimide
(10.4 g, 2.1 mmol). Then, (S)-a-phenylethylamine
(0.27 mL, 2.1 mmol) was added. The reaction mixture was
stirred at rt over 16 h, and filtered to remove the white
precipitate. The filtrate was extracted with water and
CH2Cl2 (3£10 mL). The organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pressure.
The residue was purified by column chromatography
[hexane–EtOAc (4:1)]. (1S,10S)-N,N0-Bis-(a-phenylethyl)-
1,4-succinil-diamide was obtained as a colorless solid
(0.58 g, 80% yield), mp 206–207 8C, [a]D¼66.9 (c¼1.0,
Free 1,2-diamine (1S,2S,10S,100S)-5a. The main product is
1
the all-S yielding 55%, [a]D¼þ36.2 (c¼1.0, CHCl3). H
NMR (CDCl3) d: 1.3 (d, 6H, J¼6 Hz), 1.7–1.8 (m, 4H), 2.2
(d, 2H), 2.6 (t, 2H), 3.8 (q, 2H, J¼6 Hz), 5.4 (s, 2H), 7.1–7.3
(m, 10H). 13C NMR (CDCl3) d: 24.3, 32.5, 55.3, 56.5,
125.1, 126.7, 126.8, 128.4, 147.2.
1,2-Diamine 5b dihydrochloride. White crystals, mp
240 8C. MS (m/z): 42, 79, 82, 105 (base peak), 120, 134,
161, 187, 201, 217, 266, 305, 321, 322 (Mþ).
Free 1,2-diamine (1R,2R,10S,100S)-5b. 18% yield,
1
[a]D¼275.0 (c¼1.0, CHCl3). H NMR (CDCl3) d: 1.3 (d,
6H, J¼6 Hz), 1.6–1.8 (m 4H), 1.9 (s, 1H), 2.2–2.5 (m, 3H),
3.9 (q, 2H, J¼6 Hz), 5.5 (s, 2H), 7.2–7.4 (m, 10H). 13C
NMR (CDCl3) d: 25.6, 31.7, 53.9, 54.6, 124.8, 126.5, 126.6,
128.3, 145.7. HRMS (FABþ) calcd for C22H28N2 (MþþH)
321.2331; found 321.2332.
1
CH3OH). H NMR (CD3OD) d: 1.4 (d, 6H, J¼7.0 Hz), 2.5
(m, 4H), 4.8 (q, 2H, J¼7.0 Hz), 7.2–7.3 (m, 10H). 13C
NMR (CD3OD) d: 21.4, 31.0, 48.9, 125.9, 126.8, 128.3,
144.0, 172.4. MS (m/z): 42, 77, 195, 120 (base peak), 160,
188, 204, 221, 281, 303, 324.11a
4.1.4. (1S,2S,10S,100S)- and (1R,2R,10S,100S)-N,N0-Di(a-
phenylethyl)cyclopentane-1,2-diamines, 6a and 6b. Fol-
lowing the general procedure, the diastereomeric mixture of
b-aminoalcohols was prepared from cyclopentene oxide,
affording a yellow liquid (98% yield). Immediately, the
mixture was used to prepare the N-[(S)-a-phenylethyl]-
cyclopenteneaziridine. The crude product was purified by
flash chromatography [hexanes–ethyl acetate (30:1)] to
provide the aziridine (1.5 g, 80.0% yield) as a yellow liquid,
A solution of (1S,10S)-N,N0-bis-(a-phenylethyl)-1,4-succi-
nildiamide (0.23 g, 0.70 mmol) in THF (2 mL) was added
slowly to a vigorously stirred suspension of LiAlH4 (0.13 g,
3.5 mmol) in THF (10 mL). The resulting mixture was
refluxed over 48 h, and quenched by careful addition of an
aqueous 10% NaOH solution (10 mL). The mixture was
stirred vigorously for 30 min and filtered. The filtrate was
concentrated, dissolved in CH2Cl2 (20 mL), dried over
anhydrous Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography
[hexanes–EtOAc (1:1)]. N,N0-Bis[(S)-a-phenylethyl]bu-
tane-1,4-diamine, 3, was obtained as a colorless liquid
(0.19 g, 90% yield), [a]D¼267.5 (c¼1.0, CHCl3), (R,R),
[a]Dlit.¼þ60 (c¼1.1, CHCl3). 1H NMR (CDCl3) d: 1.2 (s, 2H),
1.6 (d, 6H, J¼6.6 Hz), 1.7 (m, 2H), 2.4 (m, 4H), 3.7 (q, 2H,
J¼6.6 Hz), 4.5 (b, 2H), 7.2–7.3 (m, 10H). 13C NMR (CDCl3)
d: 23.2, 27.0, 46.9, 58.2, 126.7, 127.3, 128.6, 143.8.11b
1
[a]D¼210.5 (c¼1.0, CHCl3). H NMR (CDCl3) d: 1.3 (d,
3H, J¼7 Hz), 1.2–1.4 (m, 4H), 1.7–2.1 (m, 4H), 2.5 (q, 1H,
J¼7 Hz), 7.1–7.4 (m, 5H). 13C NMR (CDCl3) d: 21.3, 23.5,
27.4, 27.8, 44.5, 45.2, 66.8, 126.4, 126.0, 128.0, 145.8. MS
(m/z): 42, 53, 55, 68, 83, 91, 105 (base peak), 119, 130, 143,
144, 158, 172, 187 (Mþ). HRMS (FABþ) calcd for
C13H17N1 (MþþH) 188.1439; found 188.1442.
The aziridine was then used to obtain the 1,2-diamines,
which were separated by flash chromatography [hexanes–
ethyl acetate (12:1)].
4.1.3. (1S,2S,10S,100S)- and (1R,2R,10S,100S)-N,N0-Di(a-
phenylethyl)-4-cyclohexene-1,2-diamines, 5a and 5b.
Diamines 5a and 5b were prepared following the general
procedure. The diastereomeric mixture of b-aminoalcohols
were prepared from 1,4-cyclohexadiene monoxide (98%
yield).12a The crude mixture was used immediately for the
synthesis of 4-cyclohexen-1-aziridine following the litera-
ture procedure.10 The product was obtained as a colorless
liquid, 80% yield, after purification by flash chromatog-
raphy [hexanes–ethyl acetate (30:1)], [a]D¼290.0 (c¼1.0,
CHCl3). 1H NMR (CDCl3) d: 1.4 (d, 3H, J¼7 Hz), 1.6–1.8
(m, 2H), 2.2–2.4 (m, 4H), 2.6 (q, 1H, J¼7 Hz), 5.5 (s, 2H),
7.2–7.5 (m, 5H). 13C NMR (CDCl3) d: 22.2, 23.2, 23.6,
35.1, 36.4, 68.4, 121.3, 121.7, 125.1, 125.2, 126.6, 143.6.
MS (m/z): 39, 41, 55, 67, 77, 79, 95, 96, 105, 120, 136, 154,
184, 198, 200 (MþþH). HRMS (FABþ) calcd for
C14H17N1 (MþþH) 200.1439 found 200.1446.
Free 1,2-diamine (1S,2S,10S,100S)-6a. The main product is
1
the all-S yielding 55%, [a]D¼þ63.1 (c¼1.0, CHCl3). H
NMR d: 1.1 (m, 2H), 1.3 (d, 6H, J¼6 Hz), 1.5 (m, 2H), 1.7
(m, 2H), 2.0 (broad, 2H), 2.7 (t, 2H), 3.8 (q, 2H, J¼6 Hz),
7.2–7.4 (m, 10H). 13C NMR (CDCl3) d: 21.1, 24.1, 31.5,
57.0, 63.6, 126.6, 126.7, 128.2, 146.4. IR (cm21) 3100,
2954–2862, 1450.
1,2-Diamine 6a dihydrochloride. White crystals, mp 230–
232 8C. MS (m/z): 308, 208, 189, 160, 120, 105 (base peak),
79, 56. Anal. calcd C21H28N2·2HCl·H2O: C 63.14%, H
8.07%; found C 62.92%, H 8.19%.
Free 1,2-diamine (1R,2R,10S,100S)-6b. 22% yield,
1
[a]D¼283.4 (c¼1.0, CHCl3). H NMR d: 1.1 (m, 2H),

V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
1787
1.3 (d, 6H, J¼6 Hz), 1.5 (m 2H), 1.9 (m, 4H), 2.4 (t, 2H), 3.7
4.2. Enantioselective reduction of prochiral ketones.
General procedure
(q, 2H, J¼6 Hz), 7.2–7.4 (m, 10H). 13C NMR (CDCl3) d:
21.0, 25.5, 30.3, 56.1, 62.2, 126.4, 126.5, 128.1, 146.1. MS
(m/z): 27, 41, 43, 55, 77, 91, 105, 120, 136, 154, 160, 187,
188, 203, 224, 231, 252, 267, 289, 309 (Mþþ1). HRMS
(FABþ) calcd for C21H28N2 (MþþH) 309.2331; found
309.2332.
Method A. In a Schlenk flask ZnEt2 (0.08 mL, 1 M in
hexanes, 0.082 mmol) and chiral ligand (0.082 mmol) were
dissolved in 1 mL of toluene and stirred under nitrogen
atmosphere for 10 min. Then 1.66 mmol of the correspond-
ing ketone was added, and PMHS (0.13 g, 2 mmol) was
added slowly to the mixture. The reaction was kept at rt for
24 h. The reaction mixture was poured on KOH 15%
aqueous solution (5 mL) and extracted with CH2Cl2
(3 mL£3). The organic layer was washed with water
(3 mL), dried over MgSO4 and concentrated in vacuo. The
organic layer was washed with water (3 mL), dried over
MgSO4 and concentrated in vacuo. The product was purified
by column chromatography on silica gel, with hexanes–
EtOAc, 10:1, as eluent.
1,2-Diamine 6b dihydrochloride. White crystals, mp 240–
243 8C.
4.1.5. (1R,2R,10R,100R)-N,N0-Di(a-phenylethyl)-1,2-
diphenyl-1,2-ethylenediamine, 7. The N,N0-bis-[(R)-1-
phenylethyl]-ethanediimine was prepared from 40%
aqueous glyoxal and (R)-a-phenylethylamine (2 equiv.)
following the reported procedure.14b
1H NMR d: 1.5 (d, 6H, J¼6.5 Hz), 4.4 (q, 2H, J¼6.5 Hz),
7.3 (m, 10H), 8.0 (s, 2H). 13C NMR d: 23.9, 69.6, 126.6,
127.2, 128.5, 160.6.13c
Method B. In a Schlenk flask ZnEt2 (0.08 mL, 1 M in
toluene, 0.082 mmol) and chiral ligand (0.082 mmol) were
dissolved in 1 mL of toluene and stirred under nitrogen
atmosphere for 10 min. Then 1.66 mmol of the corresponding
ketone was added, and (EtO)3SiH (2 mmol) was added slowly
to the mixture. The reaction was kept at rt for 18 h. The
reaction mixture was poured on KOH 15% aqueous solution
(5 mL) and extracted with CH2Cl2 (3 mL£3). The organic
layer was washed with water (3 mL), dried over MgSO4 and
concentrated in vacuo.). The organic layer was washed with
water (3 mL), dried over MgSO4 and concentrated in vacuo.
The product was purified by column chromatography on silica
gel, with hexanes–EtOAc, 10:1, as eluent.
To a stirred solution of N,N0-bis-[(R)-1-phenylethyl]-
ethanediimine (170 mg, 0.64 mmol) in Et2O (3 mL) at
270 8C under a nitrogen atmosphere was added PhMgBr
(2.57 mL of a 2 M solution in THF) over 10 min. A white
precipitate formed immediately, and the mixture was then
allowed to warm to rt over a period of 5 h. The mixture was
then cooled to 0 8C, quenched by the addition of a saturated
aqueous solution of NH4Cl, and the organic product
extracted with ethyl acetate (3£20 mL). The combined
organic layers were dried over Na2SO4, filtered, the solvent
removed under reduced pressure, and the residue was
purified by column chromatography [hexanes–EtOAc
(10:1)] to yield a yellowish oil 76 mg, 45% yield,
[a]D¼þ190.0 (c¼1.0, CHCl3), 93% ee, [a]D¼þ205.0
(c¼0.7, CHCl3).14a 1H NMR d: 1.2 (d, 6H, J¼6.6 Hz), 2.4
(broad, 2H), 3.4 (s, 2H), 3.5 (q, 2H, J¼6.6 Hz), 6.9–7.4 (m,
20H). 13C NMR d: 25.2, 54.9, 65.7, 126.8, 127.7, 127.8,
128.20, 128.2, 141.5, 141.5.14a
Method C. In a Schlenk flask ZnEt2 (0.03 mL, 1 M in
toluene, 0.033 mmol) and chiral diamine 4a (0.033 mmol)
were dissolved in 1 mL of toluene and stirred under nitrogen
atmosphere for 10 min. Then 1.66 mmol of the correspond-
ing ketone was added, and PMHS (0.13 g, 2 mmol) was
added slowly to the mixture. The reaction was kept at rt for
24 h. The reaction mixture was poured on KOH 15%
aqueous solution (5 mL). The organic layer was washed
with water (3 mL), dried over MgSO4 and concentrated in
vacuo. The product was purified by column chromatography
on silica gel, with hexanes–EtOAc, 10:1, as eluent.
4.1.6. (1S,2S)-N,N0-Cyclopentane-1,2-dibenzyldicarba-
mate, (S,S)-8. The hydrogenation flask was rinsed with
methanol and 30 mol% palladium hydroxide was added
followed by 5a (100 mg, 0.3 mmol) in methanol (15 mL).
The reaction vessel was purged three times with nitrogen,
three times with hydrogen, pressurized with 800 psi of
hydrogen, and heated with stirring to 60 8C for 48 h. After
completion of the reduction the catalyst was filtered over
celite and the solvent was removed in vacuo.
4.3. Conditions for the analysis and assignment of
configuration of the chiral secondary alcohol products
from the enantioselective reductions
Chiral capillary GC: Supelco b-Dex 120 column
30 m£0.25 mm (i.d.), 0.25 mm film. Carrier gas He.
Detector FID, 270 8C. Injector 250 8C.
The reaction mixture was dissolved in THF (2 mL). NaH
(14.4 mg, 0.6 mmol) and benzyl chloroformate (0.086 mL,
0.6 mmol) were added and the mixture was refluxed for 3 h.
The resulting solution was extracted with CH2Cl2
(3£20 mL), dried, and evaporated under reduced pressure.
The product was purified by flash chromatography
[EtOAc–hexanes (1:10)] to afford an oil (35 mg, 32%
yield), [a]D¼þ8.1 (c¼1.75, CHCl3), ee¼69%. [mp¼147–
149 8C, [a]D¼þ10.2 (c¼0.47, CHCl3), ee¼87%]. 1H NMR
(CDCl3) d: 1.4 (m, 2H), 1.7 (m, 2H), 2.2 (m, 2H), 3.7 (m,
2H), 4.9 (m, 2H, NH), 5.1 (m, 4H), 7.3 (s, 10H). 13C NMR
(CDCl3) d: 19.1, 28.6, 54.4, 66.3, 126.3, 127.7, 128.4, 136.1,
156.3.13
Chiral HPLC: Chiralcel OB or Chiralcel OD column,
254 nm UV detector.
Specific optical rotations of the secondary alcohols were
measured and compared with those reported on the literature
to assign configuration.18
The racemic alcohol products were obtained by addition of
NaBH4 to the ketones in MeOH. The retention times of the
racemic products under the given conditions are listed
below.

1788
V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
4.3.1. 1-Phenyl-1-ethanol. tR¼19.90 min, tS¼24.80 min
(HPLC OD column, hexanes–i-PrOH 95:5, 0.5 mL/min).
(R)-1-Phenyl-1-ethanol: [a]lDit.¼þ33.0 (c¼1, CHCH3).18a
References and notes
1. Ohkuma, T.; Noyori, R. Hydrogenation of carbonyl com-
pounds. Comprehensive asymmetric catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer, 1999; Vol. 1, p 199
and Refs. 8, 9, 18, 19 and 20 therein.
4.3.2. 1-Phenyl-1-propanol. tR¼21.47 min, tS¼29.27 min
(HPLC OD column, hexanes–i-PrOH 95:5, 0.5 mL/min).
[a]D¼þ34 (c¼1, CHCl3). (R)-1-Phenyl-1-propanol:
[a]lDit.¼þ48 (c¼1, CHCl3).18a
2. (a) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.
J. Chem. Soc., Perkin Trans. 1 1985, 2039. (b) Corey, E. J.;
Bakshi, R. K.; Shibata, S.; Chen, S. P.; Singh, V. K. J. Am.
Chem. Soc. 1987, 109, 7925. (c) Itsuno, S. In Hydroboration of
carbonyl groups. Comprehensive asymmetric catalysis; Jacob-
sen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 1, p 267.
4.3.3. 1-Phenyl-1-butanol. tR¼18.01 min, tS¼20.72 min
(HPLC OD column, hexanes–i-PrOH 97:3, 0.5 mL/min).
[a]D¼þ34 (c¼1, CHCl3). (S)-1-Phenyl-1-butanol:
[a]lDit.¼248 (c¼1, CHCl3).18b
3. (a) For a review, see: Nishiyama, H. In Hydrosilylation of
CvO and CvN. Comprehensive asymmetric catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. 1, p 289. (b) Fu, G.; Tao, B. Angew. Chem.,
Int. Ed. 2002, 41, 3892. and references cited therein. (c)
Carpentier, J.-F.; Bette, V. Curr. Org. Chem. 2002, 6, 913. and
references cited therein.
4.3.4. 1-(b-Naphtyl)-ethanol. tR¼36.84 min, tS¼40.10 min
(HPLC OB column, hexanes–i-PrOH 98:2, 0.5 mL/min).
[a]D¼þ29 (c¼1, CHCl3). (S)-1-(b-Naphtyl)-ethanol:
[a]lDit.¼231 (c¼1, CHCl3).18c
4.3.5. 2,2,2-Trifluoro-1-phenyl-ethanol. tS¼14.44 min,
tR¼15.85 min (GC 115 8C, 2.8 mL/min). [a]D¼þ6
(c¼0.5, CHCl3). (S)-2,2,2-Trifluoro-1-phenyl-ethanol:
[a]lDit.¼þ30.4 (c¼1.56, CHCl3).18d
4. For a review, see: Lawrence, N. J.; Drew, M. D.; Bushell, S. M.
J. Chem. Soc., Perkin Trans. 1 1999, 3381.
´
5. (a) Carter, M. B.; Schiott, B.; Gutierrez, A.; Buchwald, S. L.
J. Am. Chem. Soc. 1994, 116, 11667. (b) Lipshutz, B. H.;
Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem. Soc. 2003,
125, 8799. (c) Lipshutz, B. H.; Caires, C. C.; Kuipers, P.;
Chrisman, W. Org. Lett. 2003, 5, 3085.
4.3.6.
1-(p-Methoxyphenyl)-ethanol.
tR¼61.75 min,
tS¼65.6 min (GC 120 8C, 1.0 mL/min). [a]D¼þ5 (c¼0.7,
CHCl3). (S)-1-(p-Methoxyphenyl)-ethanol: [a]lDit.¼240.6
(c¼1.12, CHCl3).18c
6. Mimoun, H.; de Saint Laumer, J. Y.; Giannini, L.; Scopelliti,
R.; Floriani, C. J. Am. Chem. Soc. 1999, 121, 6158.
4.3.7.
1-(p-Nitrophenyl)-ethanol.
tR¼32.21 min,
7. (a) Whitesell, J. K. Chem. Rev. 1989, 89, 1581. (b) Juaristi, E.
Introduction to stereochemistry and conformational analysis.
Wiley: New York, 1991; p 208. (c) Togni, A.; Venanzi, L. M.
Angew. Chem., Int. Ed. 1994, 33, 497. (d) Bennani, Y. L.;
Hanessian, S. Chem. Rev. 1997, 97, 3161.
tS¼34.11 min (HPLC OB column, hexanes–i-PrOH 95:5,
0.5 mL/min). [a]D¼þ18 (c¼1, CHCl3). (S)-1-(p-Nitrophe-
nyl)-ethanol: [a]lDit.¼230.5 (c¼1, CHCl3).18e
4.3.8.
1-(p-Chlorophenyl)-propanol.
tR¼18.38 min,
8. (a) Jaen, J. Encyclopedia of reagents for organic synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 5, p 3427.
´
(b) Juaristi, E.; Escalante, J.; Leon-Romo, J. L.; Reyes, A.
tS¼19.76 min (GC 136 8C, 2.6 mL/min). [a]D¼þ23
(c¼1.6,
C6H6).
(S)-1-(p-Chlorophenyl)-propanol:
[a]lDit.¼þ28.59 (c¼5.1, C6H6).18f
´
Tetrahedron: Asymmetry 1998, 9, 715. (c) Juaristi, E.; Leon-
Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry 1999, 10,
2441.
4.3.9. 1-(m-Trifluoromethylphenyl)-ethanol. tR¼13.56
min, tS¼14.64 min (GC 115 8C, 1.6 mL/min). [a]D¼þ14
(c¼0.9, MeOH). (S)-1-(m-Trifluoromethylphenyl)-ethanol:
[a]lDit.¼217.1 (c¼2.92, MeOH).18g
9. (a) Horner, L.; Dickerhof, L. Liebigs Ann. Chem. 1984, 124.
(b) Hulst, R.; de Vries, K.; Feringa, B. L. Tetrahedron:
Asymmetry 1995, 5, 699.
10. Anaya de Parrodi, C.; Moreno, G. E.; Quintero, L.; Juaristi, E.
Tetrahedron: Asymmetry 1998, 9, 2093.
4.3.10.
trans-4-Phenyl-3-buten-2-ol.
tR¼27.66 min,
tS¼46.17 min (HPLC OD column, hexanes–i-PrOH 95:5,
0.5 mL/min). [a]D¼þ27 (c¼0.5, CHCl3). (S)-trans-4-
Phenyl-3-buten-2-ol: [a]lDit.¼232.16 (c¼5, CHCl3).18h
11. (a) Potapov, V. M.; Koval’, G. N.; Solov’eva, L. D. J. Org.
Chem. USSR 1985, 21, 705. (b) Kobayashi, Y.; Hayashi, N.;
Kishi, Y. Org. Lett. 2002, 4, 411.
´
12. (a) Anaya de Parrodi, C.; Juaristi, E.; Quintero-Cortes, L. An.
4.3.11. 4-Phenyl 2-butanol. tR¼19.17 min, tS¼28.07 min
(HPLC OD column, hexanes–i-PrOH 95:5, 0.5 mL/min).
[a]lDit.¼22.0 (c¼0.5, CHCl3). (S)-4-Phenyl-2-butanol:
[a]lDit.¼þ15.8 (c¼1.00, CHCl3).18i
Quim., Int. Ed. 1996, 92, 400. (b) Anaya de Parrodi, C.;
Vazquez, V.; Quintero, L.; Juaristi, E. Synth. Commun. 2001,
31, 3295.
13. Luna, A.; Alfonso, I.; Gotor, V. Org. Lett. 2002, 4, 3627.
14. (a) Bambridge, K.; Begley, M. J.; Simpkins, N. S. Tetrahedron
Lett. 1994, 35, 3391. (b) Dieck, H.; Dietrich, J. Chem. Ber.
1984, 117, 694. (c) Alvaro, G.; Grepioni, F.; Savoia, D. J. Org.
Chem. 1997, 62, 4180.
Acknowledgements
15. Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. 1985, 24, 1.
We thank CONACyT for financial support (Project No.
39500-E and Grant No. 144937), P. J. W. thanks NIH
(National Institute of General Medical Sciences) for
additional support.
16. Knowles, W. S. Acc. Chem. Res. 1983, 16, 106.
17. Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll, P. J.; Walsh,
P. J. J. Am. Chem. Soc. 2002, 124, 6929.
18. (a) Sato, S.; Watanabe, H.; Asami, M. Tetrahedron:

V. M. Mastranzo et al. / Tetrahedron 60 (2004) 1781–1789
1789
Asymmetry 2000, 11, 4329. (b) Salvi, N. A.; Chattopadhyay, S.
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Org. Lett. 2002, 4, 4139. (e) Mathre, D. J.; Thompson, A. S.;
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