Asymmetric addition of diethylzinc to aldehydes catalyzed by β-amino alcohols derived from limonene oxide

Article abstract of DOI:10.1016/S0957-4166(02)00342-7

A series of β-amino alcohols, conveniently prepared from limonene oxide, were evaluated as catalysts for the enantioselective addition of dialkylzinc to benzaldehyde. These limonene-based amino alcohols are of particular interest because they are easily synthesized in both enantiomeric forms. Ethylation of benzaldehyde using diethylzinc and catalyzed by limonene derived amino alcohols proceeded with enantioselection of up to 87% ee. This is an unusually high level of induction for amino alcohols possessing a trans relationship between the amino and alcohol functionalities. Both enantiomers of 1-phenyl-1-propanol can be synthesized with equal control since both enantiomers of the chiral catalyst are readily available. When (1S,2S,4R)-limonene amino alcohols are used as chiral catalysts, (R)-1-phenyl-1-propanol is obtained as the major product. A plausible mechanism is proposed to explain the facial selectivity determining the asymmetric induction observed in these reactions.

Full text of DOI:10.1016/S0957-4166(02)00342-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1477–1483
Asymmetric addition of diethylzinc to aldehydes catalyzed by
b-amino alcohols derived from limonene oxide†
Derek Steiner,a Steven G. Sethofer,a Christian T. Goralskib and Bakthan Singarama,*
aDepartment of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
bCustom and Fine Chemicals, Pharmaceutical Services, The Dow Chemical Company, 1710 Building, Midland, MI 48674, USA
Received 29 April 2002; accepted 21 May 2002
Abstract—A series of b-amino alcohols, conveniently prepared from limonene oxide, were evaluated as catalysts for the
enantioselective addition of dialkylzinc to benzaldehyde. These limonene-based amino alcohols are of particular interest because
they are easily synthesized in both enantiomeric forms. Ethylation of benzaldehyde using diethylzinc and catalyzed by limonene
derived amino alcohols proceeded with enantioselection of up to 87% ee. This is an unusually high level of induction for amino
alcohols possessing a trans relationship between the amino and alcohol functionalities. Both enantiomers of 1-phenyl-1-propanol
can be synthesized with equal control since both enantiomers of the chiral catalyst are readily available. When (1S,2S,4R)-
limonene amino alcohols are used as chiral catalysts, (R)-1-phenyl-1-propanol is obtained as the major product. A plausible
mechanism is proposed to explain the facial selectivity determining the asymmetric induction observed in these reactions. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently, we reported the use of catalytic nopinone-
derived amino alcohols in additions of diethylzinc to
aromatic aldehydes, producing (R)-1-aryl-1-propanols
in 52–80% ee.13 In continuation of our work in this
area, a new class of b-amino alcohols derived from
limonene have been synthesized.14 Herein we report the
results of our study on the effectiveness of limonene-
derived amino alcohols as chiral auxiliaries in diethyl-
zinc additions. We also report the diastereoselective
synthesis of structurally interesting, novel b-amino
alcohols.
The enantioselective additions of organometallic
reagents to aldehydes is recognized as one of the most
effective methods for generating optically active sec-
ondary alcohols.1–4 Oguni and Omi first reported the
ability of amino acid-derived b-amino alcohols to cata-
lyze the enantioselective addition of diethylzinc to benz-
aldehyde, yielding up to 48.8% ee of (R)-1-phenyl-1-
propanol.5 In 1986, Noyori and co-workers used (−)-3-
exo-(dimethylamino)isoborneol (DIAB) as the first
highly enantioselective catalyst for diethylzinc addition
to aldehydes, producing (S)-1-phenyl-1-propanol in
98% ee.6 In 1987, Soai introduced a series of pyrro-
lidinylmethanols derived from (S)-proline that could
produce both (R)- and (S)-enantiomers of 1-phenyl-1-
propanol in high enantiomeric excess.7 Since these ini-
tial efforts, an expansive body of work attaining high
levels of enantioselectivity has been described in the
literature.4 In addition, mechanisms have been pro-
posed to explain the facial selectivity observed in the
catalytic asymmetric addition of diethylzinc to carbonyl
compounds using enantiomerically pure b-amino alco-
hols.8–12
2. Results and discussion
2.1. Synthesis of limonene oxide-derived amino alcohols
Chiral, non-racemic b-amino alcohols derived from
limonene oxide are easily synthesized and can be iso-
lated with high diastereomeric purity in excellent yields.
The limonene-derived b-amino alcohols used in our
study are synthesized through epoxide ring opening of
commercially available (R)-(+)- or (S)-(−)-limonene
oxide with readily available amines.14
Usually, epoxidation of enantiomerically pure limonene
results in a 1:1 mixture of cis- and trans-limonene
oxides (1,2 or 3,4). The cis and trans mixture of
limonene oxide diastereomers is not easily separable15
* Corresponding author. Tel.: 831-459-3479; fax: 831-459-2935;
e-mail: singaram@chemistry.ucsc.edu
This paper is cordially dedicated to Professor Herbert C. Brown on
†
the occasion of his 90th birthday.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00342-7

1478
D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 1477–1483
and consequently, the commercially available 1:1 mix-
ture of limonene oxide has not previously been used in
the synthesis of chiral auxiliaries.16
equatorial propenyl group at the C(4)-position provide
a sizable energy barrier and prevent the conformational
flip from occurring. Consequently, kinetic resolution of
limonene oxide occurs by the trans-limonene oxide
reacting with the amine, whereas the unreacted cis-
limonene oxide is recovered by simple distillative
workup.
We recently reported a convenient method for resolu-
tion of limonene oxide diastereomers that involves
selective epoxide ring opening by amines.14 The differ-
ence in reactivity of cis- and trans-limonene oxides
towards amines can be attributed to the unique confor-
mation of limonene oxide. Conformational differences
in the cis- and trans-limonene oxide result in kinetic
resolution of the isomers, and allow a simple method by
which to generate b-amino alcohols with high
diastereoselectivity. There are two possible modes for
nucleophilic attack of an amine on the epoxide ring of
cis- and trans-limonene oxide. However, as shown in
Scheme 1, only one of the possible diastereomers of
limonene amino alcohol is obtained by nucleophilic
attack of an amine on trans-limonene oxide. The SN2
attack of a nucleophile on a cyclohexene oxide takes
place by axial approach of the nucleophile on the
epoxide moiety. The nucleophile is thus limited to
attack on the trans-limonene oxide from the axial direc-
tion retaining the chair conformation in the transition
state, leading to a regio- and stereospecific ring open-
ing. In contrast, the cis-isomer must undergo ring flip
to the unfavored boat transition state to allow for a
traditional SN2 backside attack to occur. The bicyclic
nature of the epoxide ring in limonene oxide and the
It should be pointed out that these ring-opening reac-
tions do not occur under normal uncatalyzed reaction
conditions. Heating neat mixtures of limonene oxide
and amines typically results in only 11% conversion
after 7 days at 110°C. Water was subsequently found to
be an excellent catalyst for this reaction. The addition
of water facilitates the conversion of trans-limonene
oxide to limonene amino alcohol, such that the reac-
tions occur in essentially quantitative yield. All reac-
tions are easily followed using gas chromatography by
monitoring the consumption of trans-limonene oxide.
Typical reaction times are 24 h. The amino alcohol
products are easily separated from the unreacted cis-
limonene oxide by simple distillation. The crude
limonene amino alcohols thus obtained were purified
further by formation and crystallization of the corre-
sponding oxalate salts in methanol. The oxalate salts
were converted back to the amine with potassium
hydroxide and purified further by distillation or
recrystallization.
Scheme 1. Synthesis of limonene b-amino alcohols 5a–j and 6a–j.

D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 1477–1483
1479
This reaction sequence provides limonene-based b-
amino alcohols with high diastereomeric purity and
also opens up an opportunity to use a wide range of
amines resulting in a diverse library of useful b-amino
alcohols. Using this reaction we have synthesized a
collection of both enantiomers of b-amino alcohols
derived from (+)- and (−)-limonene oxide. From (+)-
limonene oxide, the (1S,2S,4R) stereoisomers 5a–j are
synthesized and (−) limonene oxide provided the
(1R,2R,4S) stereoisomers 6a–j (Scheme 1).
limonene amino alcohols (6b and 5i, respectively) were
tested at 10–20 mol% catalyst loadings. The results,
summarized in Table 1, show no dramatic effect on
changing the amount of catalyst. Consequently, for the
rest of our study, we employed 10 mol% of amino
alcohol catalyst.
Following our initial study, all of the available
limonene amino alcohols were screened to evaluate
their ability to catalyze the asymmetric addition of
diethylzinc to benzaldehyde. We also evaluated the
limonene amino alcohols (5a–j and 6a–j) derived from
(+)- and (−)-limonene oxide respectively, to determine
their facial selectivity in the asymmetric synthesis of
1-phenyl-1-propanol.
2.2. Evaluation of limonene-based amino alcohols in
diethylzinc addition to benzaldehyde
With the b-amino alcohols 5a–j and 6a–j in hand, their
efficiency in the addition of diethylzinc to benzaldehyde
was evaluated. Four amino alcohols were originally
examined: 2-(4-morpholinyl)-, 2-(1-pyrrolidinyl)-, 2-(1-
piperidinyl), and 2-(benzylmethylamino)-(1S,2S,4R)-
limonene amino alcohols. The initial work was done
with 10 mol% of amino alcohol as a catalyst, and the
enantiomeric excess observed was promising (in the
range 78–85%).14 We then wanted to investigate
whether increasing the loading of the catalyst would
influence the magnitude of the asymmetric induction in
this reaction. The catalytic effectiveness of (1R,2R,4S)-
The highest enantioselectivity was obtained from the
piperidine derived amino alcohols 5a and 6a with an
induction of 87% ee (entry 1, Tables 2 and 3). The
(1S,2S,4R)-limonene amino alcohols always delivered
the ethyl group in such a way to form the (R)-1-phenyl-
1-propanol as the major enantiomer. As expected, the
(1R,2R,4S)-limonene amino alcohol-catalyzed reactions
produced the (S)-1-phenyl-1-propanol, thus making it
possible to synthesize both enantiomers of 1-phenyl-1-
propanol.
(1-pyrrolidinyl)-
and
(1S,2S,4R)-dimethylamino
Table 1. Effects of change in the percentage of catalyst used
Catalyst
Amine
Mol%
Yield (%)a
Ee (%)b
1
2
3
4
6b
6b
5i
Pyrrolidine
Pyrrolidine
Dimethylamine
Dimethylamine
10
20
10
20
90
88
94
76
70(S)
62(S)
67(R)
64(R)
5i
a Isolated yield after distillation.
b Determined by chiral GC (Supelco b-Dex 120 30m) 125°C isothermal, 1-phenyl-1-propanol: tR(R)=18.41 min, tR(S)=19.00 min.
Table 2. Results for reactions catalyzed with (1R,2R,4S)-limonene amino alcohols 6
Catalyst
Amine
Mol%
Yield (%)a
Ee (%)b
1
2
3
4
5
6
6a
6b
6c
6d
6f
Piperidine
Pyrrolidine
Homopiperidine
Tetrahydroisoquinoline
Morpholine
10
10
10
10
10
10
88
90
84
70
98
94
87(S)
70(S)
80(S)
77(S)
80(S)
83(S)
6g
4-Benzylpiperidine
a Isolated yield after distillation.
b Determined by chiral GC (Supelco b-Dex 120 30m) 125°C isothermal, 1-phenyl-1-propanol: tR(R)=18.41 min, tR(S)=19.00 min.
Table 3. Results for reactions catalyzed with (1S,2S,4R)-limonene amino alcohols 5
Catalyst
Amine
Mol%
Yield (%)a
Ee (%)b
1
2
3
4
5
5a
5d
5e
5i
Piperidine
10
10
10
10
10
89
80
83
85
79
87(R)
78(R)
79(R)
67(R)
48(R)
Tetrahydroisoquinoline
4-Methylpiperizine
Dimethylamine
n-Butylamine
5j
a Isolated yield after distillation.
b Determined by chiral GC (Supelco b-Dex 120 30m) 125°C isothermal, 1-phenyl-1-propanol: tR(R)=18.41 min, tR(S)=19.00 min.

1480
D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 1477–1483
The results summarized in Table 3 suggest that the
steric requirement of the amine moiety plays an impor-
tant role in the asymmetric induction observed.
Whereas, the n-butylamine-derived amino alcohol 5j
showed poor asymmetric induction (entry 5, Table 3),
increasing the steric requirements by use of a tertiary
amine group, such as the dimethylamine-derived amino
alcohol 5i, increases the asymmetric induction signifi-
cantly. Similarly, the sterically more demanding tetra-
hydoisoquinoline-derived amino alcohol 5d, afforded
the product with 78% ee (entry 2, Table 3). The highest
asymmetric induction was obtained using the pipe-
ridine-derived amino alcohol 5a, which suggests that
the piperidine moiety is more sterically demanding than
the other amino groups. Similar trends are observed in
the results summarized in Table 2.
bulky amino group with respect to the isopropenyl
group (Scheme 2).17 Consequently, limonene amino
alcohols containing large amino groups are expected to
be in a conformation where the amine and hydroxy
groups are in a trans-diequatorial orientation (Scheme
2).
1
The H NMR data of limonene amino alcohols derived
from piperidine (5a) and ammonia (7) are compared in
Table 4 to show the spectral differences between trans
diaxial and trans diequatorial amino alcohol conforma-
tions. Amino alcohol 7 was chosen because the amine
group by itself does not have an A-value high enough
to induce ring flip. The 1H NMR spectrum of 5a clearly
displays two different signals for protons b and b%
(Scheme 2) which is characteristic of the axially ori-
ented isopropenyl group.18 In compound 7, the hydro-
gens b and b% of the isopropenyl group are identical,
2.3. Effect of conformation on facial selectivity
1
indicative of equatorial orientation. H NOESY analy-
1
Comparison of the H NMR spectra of the limonene
sis of the piperidinyl limonene amino alcohol 5a shows
vinylic proton Hb% with a NOE crosspeak between axial
protons Ha and Hf which is consistent with the isopro-
amino alcohols derived from ammonia and piperidine
clearly indicated the differences in the steric require-
ments of the two amino groups and the conformational
preferences of these amino alcohols. The limonene
oxide-derived amino alcohol chiral auxiliaries are
unique because of the trans geometry of the amine and
hydroxyl moieties. Most of the amino alcohols used as
catalytic ligands in asymmetric diethylzinc addition
reactions have the amine and hydroxyl groups in a cis
relationship to each other. In spite of the trans-diaxial
orientation of the amine and hydroxy groups, the
limonene-derived amino alcohols are efficient chiral
sources for these addition reactions of diethylzinc. This
intriguing result can be explained using conformational
analysis: with amino alcohols containing sterically
demanding amino groups, such as piperidine, a confor-
mational change occurs due to the large A-value of the
Table 4. 1H NMR comparison of piperidinyl 5a and pri-
mary amino 7, limonene amino alcohols
H1a
Piperidinyl
Amino
a
b,b%
c
3.68(t)
4.88(s),4.80(s)
ꢀ2.63(m)
1.14(s)
2.86(t)
4.74(s)
ꢀ2.25(m)
1.21(s)
d
e
1.69(s)
1.72(s)
a Selected H1 NMR shifts for (1S,2S,4R)-1-methyl-4-(1-methyl-
ethenyl)-2-(1-piperidinyl)cyclohexanol and (1S,2S,4R)-2-amino-1-
methyl-4-(1-methylethenyl)cyclohexanol. All shifts determined in
CDCl3 at 25°C.
Scheme 2. Proposed conformations of (1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(1-piperidinyl)cyclohexanol and (1S,2S,4R)-2-
amino-1-methyl-4-(1-methylethenyl)cyclohexanol.

D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 1477–1483
1481
penyl group in the axial position. The single signals for
paper demonstrate that (1S,2S,4R)-limonene amino
alcohols 5 and (1R,2R,4S)-limonene amino alcohols 6
are efficient catalysts in the addition of diethylzinc to
benzaldehyde. These ligands are easily prepared
through simple kinetic resolution of the commercially
available 1:1 diastereomeric mixture of limonene
oxides. Both enantiomers of limonene amino alcohols
are readily synthesized, providing an easy access to
either (R)- or (S)-enantiomer of 1-phenyl-1-propanol.
The limonene-derived amino alcohols reported herein
are effective catalysts for the addition of diethylzinc to
benzaldehyde. A plausible model has been proposed to
explain the facial selectivity observed in this reaction.
We are actively screening the utility of these limonene-
derived amino alcohols in other types of asymmetric
catalytic reactions.
protons d and e as well as 13C NMR data (see Section
4) show that compounds 5a and
diastereomers.
7 are single
The conformation of limonene-based amino alcohols
led us to propose a working transition state model for
diethylzinc addition reactions catalyzed by these new
chiral auxiliaries. Noyori has done extensive mechanis-
tic work on the transition state model for the amino
alcohol-catalyzed asymmetric diethylzinc addition reac-
tion.8–12 Based on the Noyori system of a six-membered
cyclic transition state, we propose a transition state
model for our limonene amino alcohol-catalyzed asym-
metric diethylzinc ethylation reaction. This model rea-
sonably predicts the facial selectivity observed in our
system (Scheme 3).
As shown in Scheme 3, the facial selectivity observed in
the present work is controlled by the amine moiety and
the C(1)-methyl group. The b-hydroxyl group initially
reacts with diethylzinc liberating ethane, the resulting
zinc ion then coordinates with the amine lone pair to
form a diequatorially oriented five-membered hetero-
cyclic ring. Both the isopropenyl- and amino-groups
hinder coordination of the aldehyde to the top face of
the catalyst. The axial C(1)-methyl group of 5a directs
the re-face approach of benzaldehyde from below,
while the oxygen of the aldehyde is coordinated to the
zinc with the lone pairs anti to the phenyl group, to
minimize the steric repulsion from the C(1)-methyl
group. An ethyl group then adds to the activated
aldehyde from the diethylzinc that is coordinated to a
lone pair of the oxygen atom. The transition model
proposed in Scheme 3 illustrates how (1S,2S,4R)-amino
alcohols 5a–j direct attack to the re-face leading to the
(R)-1-phenyl-1-propanol and how (1R,2R,4S)-amino
alcohols 6a–j can direct attack to the si-face leading to
the (S)-1-phenyl-1-propanol.
4. Experimental
4.1. General
Reactions were carried out in oven-dried glassware
under an inert atmosphere. cis/trans-(+)-Limonene
oxide, benzaldehyde and the diethylzinc reagents used
were supplied by the Aldrich Chemical Company and
1
used as received. H NMR spectra were recorded on a
Bruker at 250 MHz and 13C at 62.9 MHz. Optical
rotations were recorded on a Jasco DIP-371 polarime-
ter, with samples dissolved in either cyclohexane or
methanol. Analysis of enantioselectivity was accom-
plished using an HP 5890 gas chromatograph with a
flame-ionization detector equipped with a Supelco b-
cyclodextrin 120 chiral GC column (30 m×0.25 mm).
Samples of known stereochemistry were used to associ-
ate the major isomer formed by (+)-limonene b-amino
alcohols with (R)-1-phenyl-1-propanol, thus permitting
the monitoring of the aromatic alcohol products. GC
conditions for 1-phenyl-1-propanol: 125°C isothermal;
tR, (R)-alcohol: 18.41 min, tR, (S)-alcohol: 19.01 min.
3. Conclusion
4.2. Representative procedure for synthesis of b-amino
alcohols from limonene oxide
Several new b-amino alcohols derived from limonene
oxide were screened as catalysts in the asymmetric
synthesis of 1-phenyl-1-propanol using diethylzinc addi-
tion to benzaldehyde. The results presented in this
4.2.1.
(1S,2S,4R)-1-Methyl-4-(1-methylethenyl)-2-(1-
piperidinyl)cyclohexanol. cis/trans-(+)-Limonene oxide
mixture (60 mmol, 9.13 g, 4.9 mL) was combined with
Scheme 3. Facial selectivity of diethylzinc addition with 2-piperidine limonene amino alcohols.

1482
D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 1477–1483
deionized water (18 mL) and piperidine (300 mmol,
5.36 g, 6.23 mL.) The reaction flask was fitted with a
reflux condenser and maintained at 100°C for 24 h. The
majority of trans-(+)-limonene oxide had reacted
according to GC analysis, so the reaction was cooled
and fitted with a distillation head. The excess piperidine
and cis-limonene oxide were distilled at reduced pres-
sure (2.5 torr) resulting in 13.85g of oil. The oil was
dissolved in methanol (15 mL). To this solution, a
solution of oxalic acid (5.50 g, 61 mmol) in methanol
(50 mL) was slowly added. A heavy slurry of white
crystals quickly formed. The slurry was cooled to 0°C
and stirred for 0.5 h. The solid was isolated by filtra-
tion, washed with cold methanol (15 mL), air dried,
and vacuum dried at 40°C to give oxalate salt as a
white, crystalline solid (7.48 g), mp 217–218°C. A sam-
ple of the oxalate salt (4.59 g) was converted to the free
base with potassium hydroxide to give 5a (1S,2S,4R)-1-
methyl - 4 - (1 - methylethylenyl) - 2 - (1 - piperidinyl)cyclo-
hexanol as a colorless oil (3.32 g). A sample of this
material (3.11 g) was distilled at reduced pressure to
give pure piperidinyl amino alcohol (2.86 g); bp 133–
135°C (3.5 torr) [h]2D3=+13.5 (c, 4.0, methanol). IR
(neat): 3479.4, 2933 cm−1; 1H NMR (250 MHz,
DMSO): l=1.11 (s, 3H), 1.35 (m, 2H), 1.45 (m, 5H),
1.52 (m, 2H), 1.61 (m, 1H), 1.69 (m, 4H), 1.72 (m, 1H),
2.30 (m, 2H), 2.38 (m, 2H), 2.65 (m, 2H), 3.80 (s, 1H),
4.74 (s, 1H), 4.80 (s, 1H). 13C NMR (62.5 MHz,
CDCl3) l=22.03, 22.44, 24.39, 24.68, 25.01, 26.91,
35.84, 39.14, 53.07, 67.62, 72.40, 99.33, 110.89, 145.67.
4.2.5.
(1S,2S,4R)-1-Methyl-4-(1-methylethenyl)-2-(4-
methyl-1-piperazinyl)cyclohexanol, 5e. Bp 143–147°C
(2.6 torr), [h]2D3=+27.1 (c, 4.0, methanol), IR 3480,
2964, 27.91, 1640, 1454, 1372, 1285, 1173, 1160, 1145,
1136, 1116, 1098, 1013, 948, 888, 794 cm−1, H NMR
1
(300 MHz, DMSO): l=1.11 (s, 3H), 1.66 (s, 3H), 2.12
(s, 3H), 2.20–2.70 (mult, 10H), 3.87 (s, 1H, OH), 4.73
(s, 1H), 4.78 (s, 1H). 13C NMR (75 MHz, DMSO)
l=21.29, 24.90, 25.14, 25.25, 38.66, 45.72, 51.22, 55.54,
66.64, 71.43, 109.45, 147.80.
4.2.6.
(1S,2S,4R)-1-Methyl-4-(1-methylethenyl)-2-(4-
morpholinyl)cyclohexanol, 5f. Mp 43–44°C, [h]2D3=+37.5
(c, 4.0, methanol), IR (neat): 3474.3, 2949.6–2851.4,
1639.4, 1449.7, 1118.2, 882.4 cm−1, 1H NMR (250
MHz, DMSO): l 1.13 (s, 3H), 1.48–1.46 (m, 2H), 1.60
(m, 1H), 1.70 (s, 3H), 1.84 (m, 1H), 2.29 (m, 2H), 2.49
(m, 2H), 2.64 (m, 2H), 3.52 (m, 2H), 3.60 (m, 2H), 3.94
(s, 1H), 4.75 (s, 1H), 4.80 (s, 1H). 13C NMR (62.5
MHz, DMSO) l=21.41, 24.86, 24.92, 25.33, 36.34,
39.45, 52.13, 66.89, 67.18, 71.62, 109.64, 147.72.
4.2.7. (1R,2R,4S)-2-(4-Benzyl-1-piperidinyl)-1-methyl-4-
(1-methylethenyl)cyclohexanol, 6g. Mp 78–81°C, [h]2D3=
−14.45 (c, 4.0, methanol), IR 3480.8, 3081.9–2721.5,
16.37.4, 1445.0, 1134.9, 1102.4, 890.6, 747.5, 702.2
cm−1, H NMR (250 MHz, DMSO): l=1.09 (s, 3H),
1
1.37–3.34 (m, 23H), 3.82 (s, 1H), 4.51 (s, 1H), 4.73 (s,
1H), 4.77 (s, 1H), 6.87–7.52 (m, 5H). 13C NMR (62.5
MHz, DMSO) l=21.79, 25.17, 25.32, 25.35, 32.95,
33.30, 36.72, 37.98, 42.92, 49.36, 55.24, 67.49, 71.85,
109.94, 125.98, 128.39, 129.25, 140.79, 148.03.
4.2.2.
(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-(1-
pyrrolidinyl)cyclohexanol, 6b. Bp 128–131°C (3.0 torr),
[h]2D3=−34.9 (c, 4.0, methanol), IR (neat): 3460.5,
2873.4, 2795.2, 1640.9, 1455, 1368.8, 1123.8, 1089.5
4.2.8.
(1S,2S,4R)-2-(Dimethylamino)-1-methyl-4-(1-
methylethenyl)cyclohexanol, 5i. See citations in Ref. 15.
1
cm−1, H NMR (250 MHz, DMSO): l=1.25 (s, 3H),
1.37–1.68 (m, 9H), 1.68 (s, 3H), 1.90 (m, 1H), 2.25 (m,
1H), 2.54 (m, 2H), 2.68 (m, 2H), 3.94 (m, 1H), 4.79 (s,
2H). 13C NMR (62.5 MHz, DMSO) l=21.59, 23.50,
24.01, 25.73, 26.98, 29.29, 36.14, 52.80, 66.47, 71.88,
109.56, 148.86.
4.2.9.
(1S,2S,4R)-2-(1-Butylamino)-1-methyl-4-(1-
methylethenyl)cyclohexanol, 5j. This sample was a mix-
ture of three diastereomers, with the illustrated
diastereomer being the predominant one. The ratio of
diastereomers was 77:3:19 by capillary GC, and 75:4:20
by integration of the singlet methyl signals of the
methyl group on the cyclohexane ring in the 300 MHz
1H NMR (DMSO): l=1.09, 1.00, 0.97.
4.2.3.
(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-(1-
hexamethyleneiminyl)cyclohexanol, 6c. Mp 45–47°C,
[h]2D3=+2.4 (c, 4.0, methanol IR (neat): 3481.4, 2982–
2844, 1660.7, 1441.8, 1376.4, 1121.9, 885.3 cm−1, 1H
NMR (300 MHz, DMSO): l=1.11 (s, 3H), 1.70 (s,
3H), 1.30–1.90 (mult, 14H), 2.25–2.40 (mult, 1H), 2.40–
2.50 (mult, 1H), 2.50–2.65 (mult, 2H), 2.70–2.90 (mult,
2H), 3.83 (s, 1H, OH), 4.78 (s, 1H), 4.84 (s, 1H). 13C
NMR (75 MHz, DMSO): l=21.70, 23.58, 24.92, 26.05,
26.47, 29.56, 36.53, 39.10, 53.35, 67.91, 71.84, 109.91,
147.00.
4.3. Representative procedure for the enantioselective
alkylation of benzaldehyde with diethylzinc
4.3.1. 1-Phenyl-1-propanol. To the catalyst (1 mmol)
was slowly added diethylzinc (11 mL of 1 M solution in
hexanes, 11 mmol). The resulting solution was stirred at
room temperature for 20 min and cooled to 0°C. Ben-
zaldehyde (10 mmol, 1.06 g, 1.1 mL) was added drop-
wise over 2 min causing the solution to acquire a pale
yellow color. The reaction was maintained at 0°C for 24
h, during which time the yellow color faded. The metal-
lic reagent was quenched by addition of 45 mL satu-
rated NH4Cl solution and then washed with water
(1×25 mL) and brine (1×25 mL). The aqueous phase
was extracted with CH2Cl2 (3×20 mL) and the com-
bined organic fractions were dried over MgSO4 and
then concentrated under reduced pressure. GC condi-
tions (Supelco b-cyclodextrin 120) for 1-phenyl-1-
4.2.4.
(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-[2-
(1,2,3,4-tetrahydroisoquinolinyl)]cyclohexanol, 6d. Mp
86–88°C, [h]2D3=−5.2 (c, 4.0, methanol), H NMR (250
1
MHz, DMSO): l=1.16 (s, 3H), 1.52 (m, 3H)1.76–1.91
(m, 6H), 2.32b (s, 1H), 2.49–2.8 (m, 4H), 3.01 (m, 1H),
3.67–3.95 (q, 2H), 4.02 (s, 1H), 4.80 (s, 1H), 4.84 (s,
1H). 13C NMR (62.5 MHz, DMSO) l=21.95, 24.82,
25.37, 25.60, 29.93, 36.83, 48.61, 55.15, 66.71, 72.16,
110.19, 125.54, 125.98, 126.64, 128.68, 135.00, 136.46.

D. Steiner et al. / Tetrahedron: Asymmetry 13 (2002) 1477–1483
1483
propanol: 125°C isothermal; tR, (R) alcohol: 18.41 min,
tR, (S) alcohol: 19.01 min. 1H NMR (250 MHz,
CDCl3): l=0.92 (t, J=6.9, 3H), 1.81 (m, 2H), 1.97 (bs,
OH), 4.6 (t, J=6.9, 3H), 7.3–7.5 (Ar, 5H).
5. (a) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823–
2824; (b) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura,
A. Chem. Lett. 1983, 841–842.
6. Noyori, R.; Kitamura, M.; Suga, S.; Kawai, K. J. Am.
Chem. Soc. 1986, 108, 6071–6072.
7. Soai, K.; Ookawa, A.; Tatsuya, K.; Ogawa, K. J. Am.
Chem. Soc. 1987, 109, 7111–7115.
8. Noyori, R.; Kitamura, M.; Okada, S.; Suga, S. J. Am.
Chem. Soc. 1989, 111, 4028–4036.
9. Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem.
1991, 56, 4264–4268.
10. Noyori, R.; Yamakawa, M. J. Am. Chem. Soc. 1995, 117,
6327–6335.
11. Noyori, R.; Kitamura, M.; Oka, H.; Suga, S. J. Am.
Chem. Soc. 1998, 120, 9800–9809.
12. Noyori, R.; Kitamura, M.; Oka, H. Tetrahedron 1999, 55,
3605–3614.
13. Goralski, C. T.; Chrisman, W.; Hasha, D. L.; Nicholson,
L. W.; Rudolf, P. R.; Zakett, D.; Singaram, B. Tetra-
hedron: Asymmetry 1997, 8, 3863–3871.
14. (a) Chrisman, W.; Camara, J. N.; Marcellini, K.; Sin-
garam, B.; Goralski, C. T.; Hasha, D. L.; Rudolf, P. R.;
Nicholson, L. W.; Borodychuk, K. Tetrahedron Lett.
2001, 42, 5805–5807; (b) Singaram, B.; Chrisman, W.;
Goralski, C. T. World Patent Application WO 02/22550
A2, 2002; (c) Goralski, C. T.; Singaram, B.; Chrisman,
W. US Patent 6 362 373 B1, 2002.
4.3.2. Recovery of catalyst. In order to demonstrate the
recovery of the catalyst in this procedure, ligand 5a was
extracted from the crude product. This residue was
dissolved in 45 mL EtOAc, and combined with 9 mL of
1 M HCl at 0°C with stirring. 3 M HCl was added
dropwise until the solution was slightly acidic to litmus.
The organic phase was washed with 0.5 M HCL (2×25
mL) and the combined aqueous fractions were then
washed with CH2Cl2 (2×25 mL). While stirring at 0°C
with CH2Cl2 (45 mL) the catalyst hydrochloride salt
was treated with 3 M aqueous NaOH until basic to
litmus (approx. 3 mL). The aqueous layer was washed
with CH2Cl2 (2×25 mL) and the solvent was evaporated
from the combined organic fractions. The resulting
crude oil was distilled at 200 millitorr and b-amino
alcohol 5a (FW=223, 0.21 g, 0.94 mmol) was recovered
in 91% of the 1 mmol theoretical yield.
Acknowledgements
15. (a) Kuczynski, H.; Piatkowski, K. Rocziniki Chem. 1959,
33, 299; (b) Newhall, W. F. J. Org. Chem. 1959, 24, 1673;
(c) Chadbudzinski, Z. Acad. Polon. Sci. Ser. Sci. Chim.
1962, 10, 157.
The authors would like to thank the Dow Chemical
Company for financial and research support.
16. (a) Comins, D. L.; Guerra-Weltzien, L.; Salvador, J. M.
Synlett 1994, 972; (b) Comins, D. L.; Guerra-Weltzien, L.
Tetrahedron Lett. 1996, 37, 3807–3810; (c) Ho, T.-L.; Lee,
K.-Y. Tetrahedron Lett. 1995, 36, 947–948.
17. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp. 695–783.
18. Crews, P.; Rodriguez, J.; Jaspars, M. Organic Structure
Analysis; Oxford University Press: New York, 1998; pp.
68–95.
References
1. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994; pp. 255–297.
2. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49–69.
3. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
4. Pu, L.; Hong-Bin, Y. Chem. Rev. 2001, 101, 757–824.