A structural examination of the impact of oxygenated side chains in Ephedra compounds in the catalytic asymmetric addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2009.08.028

An investigation of the impact of oxygenated side chains in Ephedra compounds on the catalytic asymmetric addition of diethylzinc to aldehydes has been conducted. (1R,2S)-Ephedrine and (1S,2S)-pseudoephedrine were alkylated with either alkyl halides or β-

Full text of DOI:10.1016/j.tetasy.2009.08.028

Tetrahedron: Asymmetry 20 (2009) 2351–2356
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Tetrahedron: Asymmetry
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A structural examination of the impact of oxygenated side chains in Ephedra
compounds in the catalytic asymmetric addition of diethylzinc to aldehydes
*
Melissa A. Dean, Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An investigation of the impact of oxygenated side chains in Ephedra compounds on the catalytic asym-
metric addition of diethylzinc to aldehydes has been conducted. (1R,2S)-Ephedrine and (1S,2S)-pseudo-
ephedrine were alkylated with either alkyl halides or b-alkoxyalkyl halides to afford a series of ligands
9a–h and 10a–h. These compounds were employed in the enantioselective addition of diethylzinc to a
variety of aldehydes. It was determined that the presence of oxygen could have a negative effect in terms
of obtaining high levels of enantiomeric discrimination, but the effect is diminished with higher levels of
substitution near the oxygen.
Received 6 August 2009
Accepted 27 August 2009
Available online 14 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
ciated with the use of these compounds is based on the fact that
varying the substituents appended to the nitrogen of the Ephedra
The synthesis and application of chiral auxiliaries and chiral
catalysts for conducting asymmetric synthesis remains as a source
of continued interest for the synthetic community.1 There are a
number of such ligands that have been designed and successfully
employed in asymmetric reactions that involve additional coordi-
nation as a means of enhancing the observed stereoselection.
Meyers’ oxazoline,2 Whitesell’s amide,3 and Enders’ hydrazone4
are examples of chiral auxiliaries that possess an ether component
capable of contributing to a more well-defined region where the
process of asymmetric induction may take place (Fig. 1). In each
of these examples, the stereoelectronic properties of the chiral aux-
iliaries contribute to high levels of diastereoselectivity in a variety
of reactions such as the aldol reaction, alkylation, and conjugate
addition.5 Ultimately, the presence of the coordinating ether group
has a positive impact on the overall success of these reactions. We
became interested in determining if the same type of coordination
might be exploited in the design of ligands for the asymmetric
addition of diethylzinc to aldehydes. The chiral auxiliaries that em-
ploy this mode of coordination often involve the use of lithium
bases (e.g., n-BuLi, LDA, and LiHMDS). Lithium is considered to be
a hard Lewis acid and a very effective coordinating metal, whereas
zinc is considered to be ‘borderline’ hard Lewis acid. Nonetheless,
we wanted to explore the concept of using ether linkages in chiral,
non-racemic ligands as a means of controlling the stereochemical
outcome of the zinc-mediated asymmetric addition reaction. In
this regard, b-amino alcohols have enjoyed much success in diorg-
anozinc alkylation reactions, and ligands derived from Ephedra
alkaloids have been part of this success.6 Much of the success asso-
template has a measurable impact on the level of stereoselectivity
observed in the addition reaction.7 Thus, we began an investigation
directed at examining the impact of having ether N-b-alkoxyalkyl
side chains and their N-alkyl analog derivatives appended to the
Ephedra template.
2. Results and discussion
We began our investigation by alkylating (1R,2S)-ephedrine 7 or
(1S,2S)-pseudoephedrine 8 with a variety of alkyl halides and b-al-
koxylalkyl halides in the presence of potassium carbonate (Scheme
1). This process afforded ephedrine derivatives 9a–h and pseudoe-
phedrine derivatives 10a–h in good chemical yields after flash
chromatography (Table 1). With these ligands in hand, the asym-
metric 1,2-addition of diethylzinc to benzaldehyde was conducted
as a test reaction. The results of these test reactions using ligands
9a–h and 10a–h are reported in Table 2. The (1R,2S)-ephedrine-de-
rived ligands 9a–h afforded the (R)-configuration in the product
1-phenyl-1-propanol, whereas the (1S,2S)-pseudoephedrine-based
ligands 10a–h provided the corresponding (S)-configuration. In
using ligand 9e (Table 2, entry 10), it was determined that lowering
the temperature of the reaction led to slightly lower enantiomeric
excess. In addition, it was determined that the use of 20 mol %
(0.2 equiv) of the ligand 9e (Table 2, entry 11) afforded the same
level of enantioselection as when the catalyst was used in
10 mol %.
There was a clear difference in the level of enantioselection
depending on the nitrogen substituent that was present. In the
case of ligands 9a and 10a, the enantioselectivity was measured
to be 73% and 80%, respectively. The oxygenated versions of these
* Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538.
E-mail address: hitchcock@ilstu.edu (S.R. Hitchcock).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.028

2352
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 20 (2009) 2351–2356
CH3
O
CH3O
OCH3
OCH3
N
base
CH2OCH3
N
base
O
N
O
N
M
M
O
O
O
Ph
Ph
R
CH3
R
1
2
3
4
Meyers' oxazoline2
Whitesell's amide3
CH3
O
H
H
N
CH3
O
N
M
N
base
N
R
R
R'
R'
5
6
Enders' hydrazones4
Figure 1. Chiral auxiliaries with proposed modes of coordination.
OH
R2
OH
R2
CH3
N
NHCH3
CH3
R3CH2X, K2CO3, DMF
X = Br or I
R1
R1
R3
CH3
7: R1 = -Ph; R2 = -H (1R,2S)-ephedrine
8: R1 = -H; R2 = -Ph (1S,2S)-pseudoephedrine
9a-h: R1 = -Ph; R2 = -H
10a-h: R1 = -H; R2 = -Ph
a: R3 = -CH2CH2CH2CH3
b: R3 = -CH2CH2OCH3
c: R3 = -CH2CH(CH3)2
d: R3 = -CH2CH(CH2CH3)2
e: R3 = -CH2CH(OCH3)2
f: R3 = -CH2CH(OCH2CH3)2
H
H
O
O
g: R3 =
h: R3 =
Scheme 1. Synthesis of N-alkyl and N-b-alkoxyalkyl Ephedra ligands 9a–h and 10a–h.
Table 1
ligands 9b and 10b gave substantially lower enantiomeric ratios,
that is, 30% and 32%ee, respectively. It is proposed that the ethereal
linkages may contribute an alternate transition state that compro-
mises the overall selectivity of the asymmetric addition process
(Fig. 2).8 This would ultimately suggest that either the oxygen of
the five-membered ring zinc chelate is more Lewis basic than the
ethereal oxygen of the side chain or the formation of the four-
membered ring zincate is more favored than the formation of the
seven-membered ring chelate.
When the nitrogen substituent was changed to the 2-ethylbutyl
side chain in the ephedrine and pseudoephedrine derivatives 9d
and 10d, the enantiomeric ratio of the product was determined
to be 73% and 57%ee, respectively. Interestingly, the oxygenated
versions of 9d and 10d, namely, the 2,2-dimethoxyethyl-substi-
tuted derivatives 9e and 10e gave enantiomeric excesses that were
comparable. The same observation was made in the case of the al-
kyl derivatives 9g and 10g and their oxygenated derivatives 9h and
Chemical yields for N-alkyl and N-alkoxyalkyl Ephedra ligands 9a–h and 10a–h
Entry
Ligand
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
9a
9b
9c
9d
9e
9f
9g
9h
10a
10b
10c
10d
10e
10f
10g
10h
73
75
77
67
52
81
53
60
75
73
89
72
78
78
52
72

M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 20 (2009) 2351–2356
2353
Table 2
Finally, the Ephedra ligands 9f and 10f which contained a 2,2-
diethoxyethyl nitrogen substituent performed poorly and this is
believed to be due not to the contribution of the putative minor
pathway described in Figure 3, but to steric forces associated with
a longer side chain contributing to poor facial selectivity with the
aldehyde substrate.
Ephedra ligand 9h was used to catalyze the asymmetric addition
of diethylzinc to a series of aldehydes (Table 3) and this process
afforded a range of enantiomeric ratios from 81.5:18.5 (63%ee) to
95:5 (90%ee). The lowest enantiomeric excess was generated from
the substrate trans-cinnamaldehyde and the highest was the o-
chlorobenzaldehyde. It is presumed that the stereoelectronic dif-
ferences between these substrates are responsible for the differ-
ences in the observed selectivities.
Catalytic asymmetric addition of diethylzinc to benzaldehydea
OH
R2
CH3
N
R3
R1
O
HO
R
Et
H
CH3
10-20 mol%
Et2Zn, hexanes, toluene
R
H
9a-h:
R1 = -Ph; R2 = -H
10a-h: R1 = -H; R2 = -Ph
11
12
Entry
Ligand
Temp. (°C)
Equiv (%)
er, R:S, (|R ꢀ S|)b
Config.c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
9a
10a
9b
10b
9c
10c
9d
10d
9e
9e
9e
10e
9f
25
25
25
25
25
25
25
25
25
0
25
25
25
25
25
25
25
25
10
10
10
10
10
10
10
10
10
10
20
10
10
10
10
10
10
10
86.5:13.5 (73)
10:90 (80)
66:34 (32)
35:65 (30)
76:24 (52)
16.5:83.5 (67)
86.5:13.5 (73)
21.5:78.5 (57)
90:10 (80)
87:13 (74)
90:10 (80)
21.5:78.5 (57)
66.5:33.5 (33)
30.5:69.5 (39)
90:10 (80)
13:87 (74)
91:9 (82)
R
S
R
S
R
S
R
S
R
R
R
S
R
S
R
S
R
S
3. Conclusion
We have developed (1R,2S)-ephedrine and (1S,2S)-pseudoe-
phedrine-derived chiral ligands that have a variety of N-b-alkyox-
yalkyl and N-alkyl side chains. It was determined that when the
ephedrine-derived ligands 9a–h were used in an asymmetric 1,2-
addition of diethylzinc to benzaldehyde the (R)-configuration of
the product was obtained, whereas when the pseudoephedrine-de-
rived ligands 10a–h were used in the same process the (S)-config-
uration of the product was afforded. The application of the
methoxyethyl side chain of 9b in the addition reaction afforded
lower enantioselectivities and the application of the acetal bearing
side chains of 9e and 9h yielded enantioselectivities comparable to
their non-oxygenated side chain analogs.
10f
9g
10g
9h
10h
10:90 (80)
a
All reactions went to completion as determined by 1H NMR spectroscopy and
CSP HPLC.
b
The enantiomeric ratios were determined by HPLC using a Chiralcel-OD column,
2% IPA in hexanes. Flow rate: 1 mL/min, UV detector (254 nm). tR = 11.8 (R) and 14.8
(S) min.
4. Experimentals
c
The configuration was determined by comparison of literature values (see Ref. 7).
4.1. General information
Toluene was purchased as an anhydrous reagent and was used
without further purification. All reactions were run under a nitro-
gen atmosphere. 1H and 13C spectra were measured with a
400 MHz NMR spectrometer using CDCl3 at room temperature.
10h. The argument made for these results is that the steric volume
of the oxygenated nitrogen substituents diminished their ability to
effectively coordinate with the diethylzinc (Fig. 3).
Proposed dominant pathway for 9b
Proposed contributing pathway for 9b
CH3
CH3
Et
CH3
Et
CH3
H
H
H
H
O
O
OH
H
N
OH
Ph
N
Zn
Et
Ph
Zn
Et
Ph
Zn
Et
Ph
O
H
CH3
O
CH3
Ph
O
O
Et
(R)-12
(S)-12
Zn
H
Et
Ph
Et
H
Figure 2. Proposed transition states for enantioselection with the Ephedra ligand 9b in combination with diethylzinc and benzaldehyde.
Proposed dominant pathway for 9e and 9h
Proposed minor pathway for 9e and 9h
CH3
OR
CH3
OR
H
Et
H
Et
H
OR
H
N
OR
Zn
OH
H
OH
Ph
N
H
H
Zn
Ph
Et
Et
Zn
Et
O
Ph
Ph
H
CH3
Et
Ph
O
CH3
O
O
Et
Zn
(R)-12
(S)-12
Et
H
Ph
H
Figure 3. Proposed transition states for enantioselection with the Ephedra ligands 9e and 9h in combination with diethylzinc and benzaldehyde.

2354
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 20 (2009) 2351–2356
Table 3
127.3, 127.8, 142.0. HRMS Calcd for C14H24NO: 222.1858. Found:
222.1857.
Catalytic asymmetric addition of diethylzinc to aldehydesa
OH
CH3
N
O
4.2.3. (1R,2S)-2-((2-Methoxyethyl)(methyl)amino)-1-
phenylpropan-1-ol (9b)
O
Ph
Using (1R,2S)-ephedrine and 1-bromo-2-methoxyethane as
substrates. The title compound was purified by flash column chro-
matography (hexanes/EtOAc, 1:1, 2.5% triethylamine). Colorless oil
O
H
H
Et
HO
R
CH3
10 mol%
(2.02 g, 75%). ½a D25
ꢂ
¼ ꢀ196 (c 0.71, CHCl3). IR (neat): 3422, 1602,
Et2Zn, hexanes, toluene
H
R
H
1450, 1119, 756, 701 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.86 (d,
Entrya
RCHO, R– =
Yield (%)
er, R:S, (|R ꢀ S|)b
Config.c
J = 7.0 Hz, 3H), 2.30 (s, 3H), 2.67- 2.81 (m, 2H), 2.84–2.90 (m,
2H), 3.38 (s, 3H), 4.84 (d, J = 3.9 Hz, 1H), 7.12–7.33 (m, 5H). 13C
NMR (CDCl3) d (ppm): 9.0, 39.5, 53.2, 58.2, 63.4, 70.7, 73.3, 125.6,
126.2, 127.3, 142.3. HRMS Calcd for C13H22NO2: 224.1651. Found:
224.1644.
1
2
3
4
5
–C6H5
84
96
97
82
89
91:9 (82)
91:9 (82)
R
R
R
R
R
–2-C10H7 (–2-naphthyl)
–1-C10H7 (–1-naphthyl)
–trans-CH@CHC6H5
o-C6H4Cl
88.5:11.5 (77)
81.5:18.5 (63)
95:5 (90)
a
All reactions went to completion as determined by 1H NMR spectroscopy and
4.2.4. (1S,2S)-2-((2-Methoxyethyl)(methyl)amino)-1-
phenylpropan-1-ol (10b)
CSP HPLC.
b
The enantiomeric ratio values were determined by CSP HPLC using a Chiralcel-
OD column.
Using (1S,2S)-pseudoephedrine and 1-bromo-2-methoxyethane
as substrates. The title compound was purified by flash column
chromatography (EtOAc, 2.5% triethylamine). Clear liquid (1.97 g,
c
The configuration was determined by comparison of literature values (see Ref. 7).
Chemical shifts are reported in parts per million (d scale), and cou-
pling constants (J values) are listed out in hertz (Hz). Tetramethyl-
silane (TMS) was used as the internal standard (d = 0 ppm).
73%). ½a 2D5
ꢂ
¼ ꢀ553 (c 0.107, CHCl3). IR (neat): 3376, 1604, 1452,
1120, 752, 701 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.74 (d, J = 6.6 Hz,
3H), 2.35 (s, 3H), 2.53 (dt, J = 13.3, 5.1 Hz, 1H), 2.66 (dq, J = 9.6,
6.6 Hz, 1H), 2.78–2.84 (m, 1H), 3.40 (s, 3H), 3.49–3.56 (m, 2H),
4.21 (d, J = 9.6 Hz, 1H), 7.27–7.37 (m, 5H). 13C NMR (CDCl3) d
(ppm): 6.9, 36.5, 51.4, 57.9, 65.0, 70.2, 74.1, 126.6, 126.8, 127.3,
141.6. HRMS Calcd for C13H22NO2: 224.1651. Found: 224.1656.
Infrared spectra are reported in reciprocal centimeters (cmꢀ1
)
and are measured as a neat liquid. Observed rotations were mea-
sured using a Jasco P-2000 polarimeter. Measurements of the ob-
served rotation were made at 589 nm.
4.2. Preparation of (1R,2S)-ephedrine and (1S,2S)-
pseudoephedrine derivatives 9a–h and 10a–h
4.2.5. (1R,2S)-2-(Isobutyl(methyl)amino)-1-phenylpropan-1-ol
(9c)
Using (1R,2S)-ephedrine and 1-bromo-2-methylpropane as sub-
strates. The title compound was purified by flash column chroma-
tography (hexanes/EtOAc, 9:1, 2.5% triethylamine). Colorless oil
In a 100 mL round-bottomed flask were placed (1R,2S)-ephed-
rine (2.00 g, 12.1 mmol), 2-bromomethyl-1,3-dioxalane (1.95 mL,
12.7 mmol), and potassium carbonate (3.34 g, 24.2 mmol) with
dmf (12 mL). The solution was heated to reflux and was stirred
overnight. The solution was then cooled to room temperature
and quenched with 1 M HCl (75 mL). The organic layer was then
diluted and extracted with ethyl ether (2 ꢁ 75 mL). The organic
layer was washed with brine (50 mL), dried (MgSO4), and the sol-
vent was removed by rotary evaporation to afford the desired
material.
(1.03 g, 77%). ½a D25
ꢂ
¼ ꢀ165 (c 0.83, CHCl3). IR (neat): 3424, 2955,
1047, 758, 700 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.84–0.89 (m,
9H), 1.76 (n, J = 7.4 Hz,1H), 2.17 (s, 3H), 2.21–2.51 (m, 2H), 2.75–
2.78 (m, 1H), 4.79 (d, J = 4.7 Hz, 1H), 7.23–7.33 (m, 5H). 13C NMR
(CDCl3) d (ppm): 9.8, 20.4, 20.6, 26.3, 38.4, 63.6, 64.2, 73.1, 126.0,
126.6, 127.7, 142.5. HRMS Calcd for C14H24NO: 252.1858. Found:
252.1860.
4.2.6. (1S,2S)-2-(Isobutyl(methyl)amino)-1-phenylpropan-1-ol
(10c)
4.2.1. (1R,2S)-2-Butyl(methyl)amino)-1-phenylpropan-1-ol (9a)
Using (1R,2S)-ephedrine and 1-bromobutane as substrates. The
title compound was purified by flash column chromatography
(EtOAc) and 2.5% triethylamine. Colorless oil (0.97 g, 73%).
Using (1S,2S)-pseudoephedrine and 1-bromo-2-methylpropane
as substrates. The title compound was purified by flash column
chromatography (hexanes/EtOAc, 9:1, 2.5% triethylamine). Clear li-
½
a 2D5
ꢂ
¼ ꢀ184 (c 0.71, CHCl3). IR (neat): 3350, 2958, 1040, 755,
quid (1.19 g, 89%). ½a D25
ꢂ
¼ ꢀ136 (c 0.61, CHCl3). IR (neat): 3356,
700 cmꢀ1 1H NMR (CDCl3) d (ppm): 0.85 (d, J = 6.6 Hz, 3H), 0.91
.
2957, 1039, 754, 700 cmꢀ1 1H NMR (CDCl3) d (ppm): 0.73 (d,
.
(t, J = 7.0 Hz, 3H), 1.24–1.33 (m, 2H), 1.42–1.50 (m, 2H), 2.24 (s,
3H), 2.39–2.52 (m, 4H), 2.77–2.81 (m, 1H), 3.89 (br s, 1H), 4.80
(d, J = 4.3, 1H), 7.22–7.32 (m, 5H). 13C NMR (CDCl3) d (ppm): 9.7,
13.9, 20.3, 29.4, 38.6, 54.4, 63.4, 72.7, 125.9, 126.5, 127.7, 142.5.
HRMS Calcd for C14H24NO: 222.1858. Found: 222.1853.
J = 6.7 Hz, 3H), 0.96 (app. t, J = 6.2 Hz, 6H), 1.77–1.87 (m, 1H),
2.17 (dd, J = 12.1, 6.6 Hz, 1H), 2.24 (s, 3H), 2.28 (dd, J = 12.5,
8.2 Hz, 1H), 2.55–2.63 (m, 1H), 4.23 (d, J = 9.8 Hz, 1H), 7.24–7.37
(m, 5H). 13C NMR (CDCl3) d (ppm): 6.9, 20.4, 20.5, 25.9, 35.8,
61.6, 65.9, 74.6, 127.1, 127.4, 127.9, 142.0. HRMS Calcd for
C14H24NO: 252.1858. Found: 252.1849.
4.2.2. (1S,2S)-2-Butyl(methyl)amino)-1-phenylpropan-1-ol
(10a)
4.2.7. (1R,2S)-2-((2-Ethylbutyl)(methyl)amino)-1-phenylpropan-
1-ol (9d)
Using (1S,2S)-pseudoephedrine and 1-bromobutane as sub-
strates. The title compound was purified by flash column chroma-
tography (hexanes/EtOAc, 9:1, 2.5% triethylamine). Colorless oil
Using (1R,2S)-ephedrine and 1-bromo-2-ethylbutane as sub-
strates. The title compound was purified by flash column chroma-
tography (hexanes/EtOAc, 95:5, 2.5% triethylamine). Clear liquid
(1.01 g, 75%). ½a D25
¼ ꢀ84 (c 0.85, CHCl3). IR (neat): 3348, 2956,
ꢂ
1041, 755, 700. 1H NMR (CDCl3) d (ppm): 0.37 (d, J = 6.6 Hz, 3H),
0.97 (t, J = 7.1 Hz, 3H), 1.35–1.44 (m, 2H), 1.51–1.60 (m, 2H), 2.56
(s, 3H), 2.32–2.40 (m, 2H), 2.51–2.59 (m, 2H), 2.61–2.69 (m, 1H),
4.23 (d, J = 9.8, 1H), 5.24 (br s, 1H), 7.26–7.39 (m, 5H). 13C NMR
(CDCl3) d (ppm): 6.9, 13.8, 20.1, 30.1, 35.5, 53.0, 65.3, 74.4, 127.0,
(1.01 g, 67%). ½a D25
¼ ꢀ225 (c 0.61, CHCl3). IR (neat): 3424, 1039,
ꢂ
758, 700 cmꢀ1 1H NMR (CDCl3) d (ppm): 0.82–0.90 (m, 9H),
.
1.22–1.49 (m, 5H), 2.16 (s, 3H), 2.30 (dd, J = 6.6, 4.6 Hz, 1H), 2.75
(dd, J = 6.6, 5.1 Hz, 1H), 3.67 (br s, 1H), 4.77 (d, J = 4.7 Hz, 1H),
7.23–7.33 (m, 5H). 13C NMR (CDCl3) d (ppm): 9.8, 10.4, 10.8, 23.4,

M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 20 (2009) 2351–2356
2355
23.7, 38.4, 38.6, 59.5, 64.4, 73.2, 126.1, 126.7, 127.8, 142.5. HRMS
Calcd for C16H28NO: 250.2147. Found: 250.2163.
less oil (2.64 g, 78%). ½a D25
ꢂ
¼ ꢀ138 (c 0.65, CHCl3). IR (neat): 3408,
1604, 1452, 1129, 755, 701 cmꢀ1 1H NMR (CDCl3) d (ppm): 0.73
.
(d, J = 6.6 Hz, 3H), 1.24–1.28 (m, 6H), 2.39 (s, 3H), 2.48 (dd,
J = 13.3, 4.7 Hz, 1H), 2.64–2.68 (m, 1H), 2.73 (dd, J = 13.3, 6.Hz,
1H), 3.55–3.63 (m, 2H), 3.69–3.79 (m, 2H), 4.22 (d, J = 9.8 Hz,
1H), 4.63–4.67 (m, 1H), 7.28–7.37 (m, 5H). 13C NMR (CDCl3) d
(ppm): 7.1, 14.6, 31.2, 37.5, 54.6, 61.3, 61.6, 65.6, 74.2, 100.7,
126.6, 126.8, 127.4, 141.4. HRMS Calcd for C16H28NO3: 282.2069.
Found: 282.2078.
4.2.8. (1S,2S)-2-((2-Ethylbutyl)(methyl)amino)-1-phenylpropan-
1-ol (10d)
Using (1S,2S)-pseudoephedrine and 1-bromo-2-ethylbutane as
substrates. The title compound was purified by flash column chro-
matography (hexanes/EtOAc, 9.5:0.05, 2.5% triethylamine). Color-
less oil (1.08 g, 72%). ½a D25
ꢂ
¼ ꢀ166 (c 0.55, CHCl3). IR (neat): 3360,
1605, 1454, 754, 700 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.74 (d,
J = 6.6 Hz, 3H), 0.87–0.95 (m, 6H), 1.33–1.53 (m, 5H), 2.23 (s, 3H),
2.24 (dd, J = 12.5, 6.64 Hz, 1H), 2.37 (dd, J = 11.1, 7.0 Hz, 1H),
2.56–2.63 (m, 1H), 4.23 (d, J = 9.77 Hz, 1H), 5.20 (br s, 1H), 7.25–
7.38 (m, 5H). 13C NMR (CDCl3) d (ppm): 7.1, 10.6, 23.6, 35.6, 38.3,
57.8, 65.9, 74.8, 127.3, 127.5, 128.1, 142.2. HRMS Calcd for
C16H28NO: 250.2147. Found: 250.2183.
4.2.13. (1R,2S)-2-((Cyclopentylmethyl)(methyl)amino)-1-
phenylpropan-1-ol (9g)
Using (1R,2S)-ephedrine and iodomethylcyclopentane as sub-
strates. The title compound was purified by flash column chroma-
tography (hexanes/EtOAc, 7:3, 2.5% triethylamine). Clear liquid
(0.59 g, 53%). ½a D25
ꢂ
¼ ꢀ211 (c 0.65, CHCl3). IR (neat): 3418, 2949,
1041, 759, 700 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.86 (d, J = 7.0,
4.2.9. (1R,2S)-2-((2,2-Dimethoxyethyl)(methyl)amino)-1-
phenylpropan-1-ol (9e)
3H), 1.11–1.18 (m, 2H), 1.50–1.61 (m, 4H), 1.68–1.74 (m, 2H),
1.97–2.09 (m,1H), 2.18 (s, 3H), 2.32 (dd, J = 12.5, 7.4 Hz, 1H), 2.39
(dd, J = 12.5, 7.8 Hz, 1H), 2.76 (m, 1H), 4.04 (br s, 1H), 4.74 (d,
J = 4.7 Hz, 1H), 7.19- 7.35 (m, 5H). 13C NMR (CDCl3) d (ppm): 9.6,
24.9, 30.7, 37.9, 38.4, 60.8, 63.7, 72.8, 125.9, 126.4, 127.6, 142.5.
HRMS Calcd for C16H26NO: 248.2014. Found: 248.2011.
Using (1R,2S)-ephedrine and 2-bromo-1,1-dimethoxyethane as
substrates. The title compound was purified by flash column chro-
matography (hexanes/EtOAc, 1:1, 2.5% triethylamine). Clear liquid
(1.60 g, 52%). ½a D25
ꢂ
¼ ꢀ337 (c 0.40, CHCl3). IR (neat): 3431, 1637,
1451, 1126, 750, 702 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.87 (d,
J = 7.0 Hz, 3H), 2.30 (s, 3H), 2.63 (dd, J = 14.2, 5.2 Hz, 1H), 2.73
(dd, J = 14.2, 5.6 Hz, 1H), 2.82–2.88 (m, 1H), 3.37 (appt. d,
J = 8.2 Hz, 6H), 3.81 (br s, 1H), 4.44 (t, J = 5.5 Hz, 1H), 4.81 (d,
J = 3.9 Hz, 1H), 7.20–7.37 (m, 5H). 13C NMR (CDCl3) d (ppm): 9.4,
40.7, 53.6, 53.9, 56.3, 64.2, 74.1, 103.5, 126.0, 126.7, 127.8, 142.3.
HRMS Calcd for C14H24NO3: 254.1756. Found: 254.1756.
4.2.14. (1S,2S)-2-((Cyclopentylmethyl)(methyl)amino)-1-
phenylpropan-1-ol (10g)
Using (1S,2S)-pseudoephedrine and iodomethylcyclopentane as
substrates. The title compound was purified by flash column chro-
matography (hexanes/EtOAc, 7:3, 2.5% triethylamine). Colorless oil
(0.582 g, 52%). ½a D25
ꢂ
¼ ꢀ173 (c 0.52, CHCl3). IR (neat): 3346, 2949,
1038, 754, 700 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.73 (d, J = 6.6 Hz,
4.2.10. (1S,2S)-2-((2,2-Dimethoxyethyl)(methyl)amino)-1-
phenylpropan-1-ol (10e)
3H), 1.20–1.26 (m, 2H), 1.54–1.64 (m, 4H), 1.78–1.85 (m, 2H),
2.06–2.17 (m, 1H), 2.56 (s, 3H), 2.32 (dd, J = 12.1, 7.0 Hz, 1H), 2.41
(dd, J = 11.7, 8.2 Hz, 1H), 2.58–2.65 (m, 1H), 4.22 (d, J = 9.8 Hz, 1H),
5.24 (br s, 1H), 7.24–7.37 (m, 5H). 13C NMR (CDCl3) d (ppm): 7.0,
25.1, 30.9, 36.0, 37.8, 59.4, 65.5, 74.6, 127.2, 127.5, 128.0, 142.2.
HRMS Calcd for C16H26NO: 248.2014. Found: 248.2024.
Using (1R,2S)-pseudoephedrine and 2-bromo-1,1-dimethoxy-
ethane as substrates. The title compound was purified by flash col-
umn chromatography (hexanes/EtOAc, 7:3, 2.5% triethylamine).
Colorless oil (2.39 g, 78%). ½a D25
ꢂ
¼ ꢀ45:6 (c 1.13, CHCl3). IR (neat):
3385, 1604, 1127, 755, 702 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.74
(d, J = 6.3 Hz, 3H), 2.38 (s, 3H), 2.50 (dd, J = 13.4, 3.9 Hz, 1H),
2.64–2.68 (m, 1H), 2.72 (dd, J = 13.4, 5.9 Hz, 1H), 3.42 (appt. d,
J = 5.9 Hz, 6H), 4.21 (d, J = 9.8 Hz, 1H), 4.54 (t, J = 4.7 Hz, 1H),
7.29–7.35 (m, 5H) 13C NMR (CDCl3) d (ppm): 7.0, 37.0, 52.7, 52.9,
53.8, 65.5, 74.1, 102.3, 126.6, 126.8, 127.3, 141.3. HRMS Calcd for
C14H24NO3: 254.1756. Found: 254.1750.
4.2.15. (1R,2S)-2-(((1,3-Dioxolan-2-yl)methyl)(methyl)amino)-
1-phenylpropan-1-ol (9h)
Using (1R,2S)-ephedrine and 2-(bromomethyl)-1,3-dioxolane as
substrates. The title compound was purified by flash column chro-
matography (hexanes/EtOAc, 5.5:4.5, 2.5% triethylamine). Clear li-
quid (1.82 g, 60%). ½a D25
ꢂ
¼ ꢀ126 (c 1.15, CHCl3). IR (neat): 3445,
3062, 1030, 751, 702 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.87 (d,
4.2.11. (1R,2S)-2-((2,2-Diethoxyethyl)(methyl)amino)-1-
phenylpropan-1-ol (9f)
J = 6.3 Hz, 3H), 2.38 (s, 3H), 2.71 (dd, J = 14.0, 4.3 Hz, 1H), 2.81
(dd, J = 14.0, 4.3 Hz, 1H), 2.85–2.91 (m, 1H), 3.72 (br s, 1H), 3.86–
3.88 (m, 2H), 3.98–4.01 (m, 2H), 4.86 (d, J = 3.9 Hz, 1H), 4.97 (t,
J = 4.4 Hz, 1H), 7.22–7.34 (m, 5H). 13C NMR (CDCl3) d (ppm): 8.9,
40.6, 56.4, 64.1, 64.3, 64.4, 73.5, 103.1, 125.6, 126.3, 127.4, 142.4.
HRMS Calcd for C14H24NO: 252.1600. Found: 252.1600.
Using (1R,2S)-ephedrine and 2-bromo-1,1-diethoxyethane as
substrates. The title compound was purified by flash column chro-
matography (hexanes/EtOAc, 7:3, 2.5% triethylamine). Colorless oil
(2.75 g, 81%). ½a D25
ꢂ
¼ ꢀ170 (c 0.81, CHCl3). IR (neat): 3441, 1602,
1451, 1127, 756, 701 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.85 (d,
J = 7.0 Hz, 3H), 1.24 (appt. q, J = 7.0 Hz, 6H), 2.32 (s, 3H), 2.62 (dd,
J = 14.1, 5.0 Hz, 1H), 2.77 (dd, J = 13.7, 5.5 Hz, 1H), 2.84–2.87 (m,
1H), 3.53–3.59 (m, 2H), 3.70–3.74 (m, 2H), 4.58 (t, J = 5.5 Hz, 1H),
4.83 (d, J = 3.9 Hz, 1H), 7.21–7.34 (m, 5H). 13C NMR (CDCl3) d
(ppm): 8.9, 14.9, 40.4, 56.8, 61.6, 62.0, 63.9, 73.9, 101.6, 125.7,
126.2, 127.3, 142.1. HRMS Calcd for C16H28NO3: 282.2069. Found:
282.2067.
4.2.16. (1S,2S)-2-(((1,3-Dioxolan-2-yl)methyl)(methyl)amino)-
1-phenylpropan-1-ol (10h)
Using (1S,2S)-pseudoephedrine and 2-(bromomethyl)-1,3-dio-
xolane as substrates. The title compound was purified by flash col-
umn chromatography (hexanes/EtOAc, 7:3, 2.5% triethylamine).
Colorless oil (2.20 g, 72%). ½a D25
ꢂ
¼ ꢀ51 (c 1.08, CHCl3). IR (neat):
3398, 3062, 1041, 758, 702 cmꢀ1
.
1H NMR (CDCl3) d (ppm): 0.72
(d, J = 6.6 Hz, 3H), 2.40 (s, 3H), 2.56 (dd, J = 13.7, 3.9 Hz, 1H), 2.66–
2.71 (m,1H), 2.76 (dd, J = 13.7, 4.7 Hz, 1H), 3.84–3.86 (m, 2H),
3.96–3.99 (m, 2H), 4.20 (d, J = 9.8 Hz, 1H), 4.87 (br s, 1H), 5.02 (t,
J = 4.3 Hz, 1H) 7.25–7.36 (m, 5H). 13C NMR (CDCl3) d (ppm): 7.3,
37.8, 54.9, 64.2, 64.5, 65.9, 74.4, 103.0, 126.9, 127.1, 127.6, 141.5.
HRMS Calcd for C14H22NO3: 252.1600. Found: 252.1591.
4.2.12. (1S,2S)-2-((2,2-Diethoxyethyl)(methyl)amino)-1-
phenylpropan-1-ol (10f)
Using (1S,2S)-pseudoephedrine and 2-bromo-1,1-diethoxyeth-
ane as substrates. The title compound was purified by flash column
chromatography (hexanes/EtOAc, 8:2, 2.5% triethylamine). Color-

2356
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 20 (2009) 2351–2356
4.3. General procedure for the addition of diethylzinc to
aldehydes
4.4.4. 1-(3-Chlorophenyl)propan-1-ol
Hexanes/IPA, 98:2; 1 mL/min. tr (R)-enantiomer (min) = 11.3, tr
(S)-enantiomer (min) = 14.8.
In a nitrogen purged, flame-dried 100 mL round-bottomed flask
was placed the chiral ligand 9a (0.075 g, 0.34 mmol) and anhy-
drous toluene (5 mL). The solution was cooled to 0 °C and diethyl-
zinc (10.2 mL, 1 M in hexane) was added with a syringe. After
stirring for 1 h, benzaldehyde (0.40 mL, 3.4 mmol) was added to
the reaction mixture. The solution was allowed to stir overnight
at ambient temperature and the reaction was quenched by the
addition of 1 M HCl (100 mL). The organic layer was extracted with
dichloromethane (2 ꢁ 40 mL). The combined organic layers were
washed with brine (50 mL), dried with MgSO4, and the solvent
was removed by rotary evaporation. If necessary, the crude prod-
uct was purified by flash column chromatography using appropri-
ate eluents (hexanes/EtOAc). The enantiomeric excess was
determined with CSP HPLC using a Chiracel OD column.
4.4.5. 1-(10-Naphthyl)propan-1-ol
Hexanes/IPA, 90:10; 1 mL/min. tr (S)-enantiomer (min) = 9.0, tr
(R)-enantiomer (min) = 19.7.
Acknowledgments
The authors acknowledge support for this work by the donors of
the Petroleum Research Fund as administered by the American
Chemical Society (PRF 48367-B1). The authors also thank the Na-
tional Science Foundation (NSF CHE-644950) for support of this
research.
References
4.4. Chiral HPLC analyses of 1-arylpopan-1-ols
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A Chiracel OD column was used in all cases, temp. = 25 °C, UV
detection, k = 254 nm. The solvent systems were HPLC grade hex-
anes and isopropanol (IPA).
4.4.1. 1-Phenylpropan-1-ol
Hexanes/IPA, 98:2; 1 mL/min. tr (R)-enantiomer (min) = 11.3, tr
(S)-enantiomer (min) = 15.0.
4.4.2. 1-(20-Naphthyl)propan-1-ol
Hexanes/IPA, 98:2; 1 mL/min. tr (S)-enantiomer (min) = 25.1, tr
(R)-enantiomer (min) = 27.9.
7. (a) Soai, K.; Yokoyama, S.; Ebihara, K.; Hayasaka, T. J. Chem. Soc., Chem. Commun.
1987, 1690; (b) Soai, K.; Hayase, T.; Takai, K.; Sugiyama, T. J. Org. Chem. 1994, 59,
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19, 19–26.
4.4.3. (E)-1-Pheny-1-penten-3-ol
Hexanes/IPA, 98:2; 1 mL/min. tr (S)-enantiomer (min) = 12.7, tr
(R)-enantiomer (min) = 25.4.
8. Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63, 8998–9006. and references cited
therein.