β-Amino alcohols derived from (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine as catalysts in the asymmetric addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2007.11.027

A family of N-alkylnorephedrine and N-alkylpseudonorephedrine derived ligands were prepared and applied in the asymmetric alkylation of benzaldehyde using diethylzinc. The absolute configuration of the addition product was directed primarily by the benzylic position of the Ephedra alkaloid, while the magnitude of the enantiomeric ratio was heavily influenced by the nitrogen substituent. However, sterically demanding substituents at the nitrogen position caused the enantioselectivity to be the same for the two diastereomeric systems. Among the ligands that were prepared, it was determined that the N-cyclooctylpseudonorephedrine derivative 7b yielded the highest enantiomeric ratios (87.5:12.5 to 91.0:9.0) when applied in the catalytic asymmetric addition of diethylzinc to aldehydes.

Full text of DOI:10.1016/j.tetasy.2007.11.027

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 19–26
b-Amino alcohols derived from (1R,2S)-norephedrine and
(1S,2S)-pseudonorephedrine as catalysts in the asymmetric
addition of diethylzinc to aldehydes
Raleigh W. Parrott, II and Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, United States
Received 28 August 2007; accepted 21 November 2007
Abstract—A family of N-alkylnorephedrine and N-alkylpseudonorephedrine derived ligands were prepared and applied in the asymmet-
ric alkylation of benzaldehyde using diethylzinc. The absolute configuration of the addition product was directed primarily by the benz-
ylic position of the Ephedra alkaloid, while the magnitude of the enantiomeric ratio was heavily influenced by the nitrogen substituent.
However, sterically demanding substituents at the nitrogen position caused the enantioselectivity to be the same for the two diastereo-
meric systems. Among the ligands that were prepared, it was determined that the N-cyclooctylpseudonorephedrine derivative 7b yielded
the highest enantiomeric ratios (87.5:12.5 to 91.0:9.0) when applied in the catalytic asymmetric addition of diethylzinc to aldehydes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
only modest degrees of success in terms of their ability to in-
duce asymmetry in this catalysis reaction (Fig. 1).7
The catalytic enantioselective addition of diorganozinc
reagents to carbonyl compounds has been examined using
many different types of b-aminoalcohols as asymmetric
templates.1–4 The b-aminoalcohols derived from the Ephe-
dra alkaloids have enjoyed a large degree of success with
their widespread use5 in this field. Among the Ephedra-de-
rived ligands that have been developed, the N,N-dialkylnor-
ephedrine derivatives have been demonstrated to be very
effective catalysts for the enantioselective addition of diorg-
anozinc reagents to aldehydes and ketones.5,6 In contrast,
mono-N-alkylated norephedrine derivatives have exhibited
In this context, Sardina et al. described a detailed study
that evaluated the impact of the substituents about the b-
aminoalcohol framework for a variety of N-fluorenylphen-
yl substrates.7b However, the work described by Sardina
et al. only has two examples that represented mono-N-
alkylated derivatives from the Ephedra family. We became
interested in examining further the scope and utility of
mono-N-alkylated Ephedra derivatives in the catalytic
enantioselective addition of diethylzinc to aldehydes. Here-
in we report on the synthesis and testing of a series of
Ph
H
CH3
OH
H
N
N
OH
H
N
OH
R2
N
H
N
Ph
Ph
R1
Ph
CH3
3
7c (Wu et al.)
CH3
7a (Unaleroglu et al.)
CH3
1
2a: R1 = Ph; R2 = H7b (Sardina et al.)
2b: R1 = H; R2 = Ph7b
Figure 1.
*
Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538; e-mail: hitchcock@ilstu.edu
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.027

20
R. W. Parrott, II, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 19–26
norephedrine and pseudonorephedrine-based derivatives in
their ability to serve as catalysts.
deprotonation by diethylzinc, yielding a catalytic site re-
mote from any asymmetry elements. All the remaining li-
gands, 6f, 6l, and 6u–w, shared the common aspect of a
nitrogen substituent that was sterically demanding (-an-
thryl, -o-phenylbenzyl, 2-indanyl, cyclooctyl, and -cyclo-
pentyl, respectively). Interestingly, when the nitrogen
substituent was cyclohexyl (catalyst 6t), the enantiomeric
ratio of the asymmetric addition was 84.5:15.5. Based on
the proposed literature mechanisms7b,11 of the ligand-cata-
lyzed addition of diorganozinc compounds to aldehydes, it
was proposed that the larger substituents on the nitrogen
caused the putative intermediate 16a responsible for the
catalysis process to be less stable (Fig. 2). This would give
2. Results and discussion
(1R,2S)-Norephedrine 4 and (1S,2S)-pseudonorephedrine
58 were reductively alkylated with a variety of aldehydes
and ketones to afford derivatives 6 and 7, respectively
(Scheme 1).9 The norephedrine and pseudonorephedrine
starting materials were also directly alkylated with triphen-
ylmethyl chloride to yield derivatives 8 and 9, respectively.
In addition, the Ephedra alkaloids 4 and 5 were reacted
with the N-nitroimine of D-camphor10 to generate imines
10 and 11. These products were reduced stereoselectively
with lithium aluminum hydride to afford camphor-based
b-aminoalcohols 12 and 13. The chemical yields for these
reactions are listed in Table 1.
Table 1. Norephedrine and pseudonorephedrine derivatives
Entry
Ligand
R3
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
6a
6b
6c
6d
6e
6f
-(CH2)7CH3
-CH2C(CH3)3
-CH2C6H5
-1-CH2C10H7(naphthyl)
-2-CH2C10H7(naphthyl)
-9-CH2C14H9(anthryl)
-o-CH2C6H4OH
-o-CH2C6H4OCH3
-m-CH2C6H4OCH3
-3,4-CH2C6H4(OCH3)2
-o-CH2C6H4C2H5
-o-CH2C6H4C6H5(biphenyl)
-p-CH2C6H4C6H5(biphenyl)
-2,4,6-CH2C6H2(CH3)3
-3,5-di-tert-butyl-2-methoxybenzyl
-2-OBn-3,5-di-tert-butylbenzyl
-3,5-CH2C6H3Br2
-CH(CH3)2
-CH(CH2CH3)2
-cyclohexyl
-2-indanyl
-C8H15(-cyclooctyl)
-C5H9(-cyclopentyl)
-o-CH2C6H4OCH3
-C8H15(-cyclooctyl)
-9-CH2C14H9(anthryl)
23
59
99
63
79
52
58
61
71
31
23
31
49
77
59
73
85
54
40
85
22
39
49
20
39
95
Once the ligands had been prepared, they were employed in
the asymmetric 1,2-addition of diethylzinc to benzalde-
hyde. The catalysts 6a–w, 7a–c, 8, 9, 12, and 13 were em-
ployed at a level of 10 mol % with 3 equiv of Et2Zn
relative to benzaldehyde. The use of 3 equiv of Et2Zn affor-
ded slightly improved yields and enantiomeric ratios over
the use of 2 equiv. (1R,2S)-Ephedrine 14 and (1S,2S)-
pseudoephedrine 15 were also employed as catalysts as
equivalents to N-methylnorephedrine and N-methyl-
pseudonorephedrine, respectively. The results of these
reactions are listed in Table 2. The (1R,2S)-norephedrine-
derived catalysts 6a–w primarily afforded the (R)-configu-
ration in the product 1-phenyl-1-propanol, whereas the
(1S,2S)-pseudonorephedrine-based catalysts 7a–c provided
the corresponding (S)-enantiomer. These observations
were in agreement with the observations of Sardina
et al.7b The norephedrine catalysts 6a–w afforded an aver-
age enantiomeric ratio of 80:20. The examples that gave
the lower enantiomeric ratios in this series included 6f,
6g, 6l, and 6u–w, with values ranging from 55:45 to
74:26. In the case of 6g, the presence of the phenolic posi-
tion most likely led to erosion of the enantioselectivity via
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
7a
7b
7c
a Isolated yields after either flash chromatography or recrystallization.
OH
OH
R3CHO, MgSO4, EtOH;
NaBH4
NH2
NHR3
R1
R1
R2
R2
CH3
CH3
4: R1 = Ph, R2 = H
6: R1 = Ph, R2 = H (Table 1)
5: R1 = H, R2 = Ph
7: R1 = H, R2 = Ph (Table 1)
1.
N NO2
Ph3CCl, TEA
CH2Cl2
H
N
H
OH
R2
CH3
CH3
OH
LiAlH4, THF
NHCPh3
OH
R1
N
H
R1
R1
CH3
R2
R2
8: R1 = Ph, R2 = H (99%)
9: R1 = H, R2 = Ph (77%)
10: R1 = Ph, R2 = H (ref. 10)
11: R1 = H, R2 = Ph (64%)
12: R1 = Ph, R2 = H (ref. 10)
13: R1 = H, R2 = Ph (79%)
Scheme 1. Norephedrine and pseudonorephedrine derivatives.

R. W. Parrott, II, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 19–26
Table 2. Catalytic asymmetric addition of diethylzinc to benzaldehydea
21
ion, the norephedrine and pseudonorephedrine camphor-
based derivatives 12 and 13 each gave the (R)-alcohol in
an enantiomeric ratio of 73.5:26.5. From these examples,
it would seem that the stereochemistry of the benzylic com-
ponent of the catalysts has a compromised role in directing
the asymmetric addition of the ethyl group to the benzalde-
hyde substrate when the nitrogen is sterically demanding.
This observation is limited in that it only reveals a small
part of a much larger question for which a complete mech-
anistic rationale has not been developed.
OH
H
O
Et2Zn, toluene
catalysts
Ph
Ph
H
Et
Entry
Ligand
erb
Config.c
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
84.5:15.5
85.0:15.0
84.5:15.5
75.0:25.0
85.0:15.0
67.5:32.5
54.0:46.0
83.0:17.0
80.0:20.0
82.5:17.5
82.5:17.5
74.0:26.0
82.0:18.0
80.0:20.0
90.0:10.0
89.5:10.5
80.5:19.5
87.0:13.0
85.0:15.0
84.5:15.5
64.5:35.5
55.0:45.0
65.5:34.5
56.0:44.0
90.0:10.0
74.0:26.0
60.0:40.0
94.0:6.0
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(S)
(S)
(R)
(R)
(R)
(S)
In the context of large nitrogen substituents, the N-trityl
catalysts 8 and 9 generated the (S)-configured product in
enantiomeric ratios of 60:40 and 94:6, respectively, when
applied in the diethylzinc addition reaction. The change
in the configuration of the product suggested a further
change in the reaction pathway leading to product forma-
tion. These catalytic processes did not go to completion
(32% completion for catalyst 8 and 76% completion for
catalyst 9), and generated significant amounts of benzyl
alcohol (>10%), the product of direct reduction by
diethylzinc.13 Based on these combined results, it was
determined that the N-trityl catalysts were not suitable
for use in the enantioselective addition of diethylzinc to
aldehydes.
6g
6h
6i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
7a
7b
7c
8
The derivative that gave the best enantioselectivity was the
N-cyclooctylpseudonorephedrine catalyst 7b. This ligand
was used to catalyze the asymmetric addition of diethylzinc
to a series of aldehydes and this process afforded a range of
enantiomeric ratios from 87.5:12.5 to 91.0:9.0 (Table 3). It
is proposed that 7b follows the mechanistic pathway as
depicted in Figure 2 and that the dominant pathway is
the closed ring system (16b?19b).
9
12
13
14
15
73.5:26.5
73.5:26.5
78.5:21.5
57.5:42.5
a All reactions, except entries 27 and 28, went to completion as determined
3. Conclusion
1
by NMR spectroscopy.
b The enantiomeric ratios [er (major:minor)] were determined via CSP
HPLC using a Chiralcel-OD column.
Norephedrine and pseudonorephedrine were employed as
templates for the preparation of a variety of N-substituted
Ephedra catalysts. It was determined that the norephe-
drine-based catalysts 6 afforded an average enantiomeric
ratio of 80:20 when employed in the diethylzinc addition
reaction with benzaldehyde. When the nitrogen substituent
was large in size (-methylanthryl, -o-phenylbenzyl, -bornyl)
the enantioselectivity was diminished. The pseudonorephe-
drine-based catalysts favored the formation of the (S)-alco-
hol product. Finally, sterically demanding substituents
caused both diastereomeric derivatives to afford the alco-
hol product with the same configuration.
c The configuration was determined by comparison with HPLC literature
values.12
rise to an alternate reaction pathway 20a?23a where the
asymmetric induction would be dependent on conforma-
tional factors associated with an open chain system. It
would be likely that the open chain pathway would not ex-
hibit the same level of stereoselectivity as the closed ring
pathway 16a?19a, and the prediction of the dominant ste-
reoisomer would also be compromised.
In contrast to the enantioselectivities obtained with nor-
ephedrine catalysts 6, the pseudonorephedrine-based cata-
lysts 7 and 15 primarily yielded the (S)-configuration in
the product. In addition, pseudonorephedrine-based cata-
lyzed reactions exhibited enantioselectivities that were
low when the nitrogen substituent was small and higher
when the substituent was larger. Interestingly, the use of
the pseudonorephedrine catalyst 7c (R3 = CH2-9-anthryl)
and the norephedrine catalyst 6f (R3 = CH2-9-anthryl)
each afforded the (R)-alcohol product in enantiomeric ra-
tios of 74:26 and 67.5:32.5, respectively. In the same fash-
4. Experimental
4.1. General remarks
Toluene was purchased as an anhydrous reagent and used
without further purification. All reactions were run under a
1
nitrogen atmosphere. Unless otherwise noted, all H and
13C NMR spectra were recorded in CDCl3 using an
NMR spectrometer operating at 400 MHz and 100 MHz,
respectively. Chemical shifts are reported in parts per

22
R. W. Parrott, II, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 19–26
Et
Ph
H
Ph
H
Et
Et
Zn
Et
Zn
Et
Zn
Et
O
O
Et
Zn
Et
O
O
Zn
R
H
R
H
Zn
R
Et
R
H
Zn
O
N
O
N
R
H
Et2Zn
PhCHO
N
Et
N
R1
R
1 R2
CH3
CH3
R2
CH3
R
1 R2
1 R2
CH3
16
17
18
19
Ph
Ph
H
O
H
Et2Zn
O
Et
Et2Zn
R1
Zn
OZnEt
R2
OZnEt
R2
Et
OZnEt
R2
OZnEt
Et2Zn
CH3
CH3
PhCHO
CH3
R1
CH3
R1
R1
NHR
R2
NHR
NHR
NHR
20
21
22
23
a) R1 = Ph; R2 = H (norephedrine based)
b) R2 = H; R2 = Ph (pseudonorephedrine based)
Figure 2. Proposed intermediates for the norephedrine-diethylzinc-based catalysis.
Table 3. Catalytic asymmetric addition of diethylzinc to benzaldehydea
13.9 mmol) was added and allowed to stir for 90 min. The
reaction solvent was removed under reduced pressure. The
product was extracted with ethyl acetate (50 mL ꢁ 3) and
sodium hydroxide (1 M, 50 mL), washed with brine
(50 mL), and dried with magnesium sulfate. The solvent
was removed under reduced pressure and the product
was recrystallized with ethyl ether and hexanes (1:2).
H
HO
Ph
N
OH
H
cat.
O
CH3
Ph
Ph
H
Et
Et2Zn, toluene
Entry
R
Yielda (%) erb
Config.c
4.2.1. (1R,2S)-2-(n-Octylamino)-1-phenylpropan-1-ol 6a.
Using octanal, the title compound was obtained as a white
1
2
3
4
5
-C6H5
52 90.0:10.0 (S)
25
-1-C10H9(-1-naphthyl) 40
-2-C10H9(-2-naphthyl) 78
-p-C6H4OCH3
91.0:9.0
91.0:9.0
(S)
(S)
solid (23%). ½aꢂD ¼ þ15:1 (c 0.12, CHCl3). Mp = 52–53 °C.
1H NMR (CDCl3): d 0.84 (d, J = 6.6 Hz, 3H), 0.88 (t,
J = 6.6 Hz, 3H), 1.29 (m, 4H), 1.52 (m, 4H), 2.72 (m,
4H), 2.95 (dq, J = 3.9, 6.6 Hz, 1H), 4.83 (d, J = 3.5 Hz,
1H), 7.24–7.26 (m, 3H), 7.33 (d, J = 4.3 Hz, 2H). 13C
NMR (CDCl3): d 14.1, 22.6, 27.3, 29.2, 29.4, 29.9, 30.0,
31.8, 47.1, 58.6, 72.7, 126.0, 127.0, 128.1, 141.3. IR
(CHCl3): 3438, 1132, 989, 741, 701 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C17H30NO, 264.2327; found, 264.2324.
40
73
89.5:10.5 (S)
87.5:12.5 (S)
-trans-CH@CHC6H5
a All yields are after flash chromatography.
b The enantiomeric ratios [er (major:minor)] were determined via CSP
HPLC using a Chiralcel-OD column.
c The configuration was determined by comparison with HPLC literature
values.12
million (d scale), and coupling constants (J values) are
listed in hertz (Hz). Tetramethylsilane (TMS) was used as
the internal standard (d = 0 ppm). Infrared spectra are
reported in reciprocal centimeters (cmꢀ1) and are measured
either as a Nujol mull, a neat liquid, or in CHCl3. Melting
points were recorded on a Mel-Temp apparatus and are
uncorrected. Optical activities were measured at 589 nm
using a digital polarimeter.
4.2.2. (1R,2S)-2-(2,2-Dimethylpropylamino)-1-phenyl-1-pro-
panol 6b. Using pivaldehyde, the title compound was ob-
tained as a white solid. Mp: 82–84 °C. [a]D = ꢀ12.0 (c 1.80,
CHCl3). Characterization data for this compound matched
exactly with the identical compound found in the
literature.14a
4.2.3. (1R,2S)-2-(Benzylamino)-1-phenyl-1-propanol 6c.
Using benzaldehyde, the title compound was obtained as
25
1
4.2. General procedure for the reductive alkylation of
(1R,2S)-norephedrine
a clear oil (99%). ½aꢂD ¼ ꢀ30:0 (c 0.86, CHCl3). H NMR
(CDCl3): d 0.86 (d, J = 6.6 Hz, 3H), 3.01 (dq, J = 3.9,
6.6 Hz, 1H), 3.89 (s, 2H), 4.80 (d, J = 3.2 Hz, 1H), 7.26–
7.35 (m, 10H). 13C NMR (CDCl3): d14.7, 51.4, 58.1,
73.9, 126.6, 127.4, 127.5, 128.4, 128.5, 128.9, 140.3, 142.2.
IR (neat): 3406, 1603, 1028, 910, 732, 700 cmꢀ1. ESI-
HRMS: (M+H+) calcd for C16H20NO, 242.1545; found,
242.1535.
To a flame-dried, nitrogen-purged flask were added
(1R,2S)-norephedrine (1.05 g,
6.96 mmol), ethanol
(10 mL), and a selected aldehyde (10.4 mmol). The mixture
was allowed to stir at room temperature for 18 h, and then
cooled to 0 °C. After cooling, sodium borohydride (0.53 g,

R. W. Parrott, II, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 19–26
23
4.2.4. (1R,2S)-2-(Naphthalen-10-ylmethylamino)-1-phenyl-
J = 8.2 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 7.20–7.29 (m,
7H). 13C NMR (CDCl3): d 14.5, 46.5, 55.0, 57.1, 72.9,
110.2, 120.3, 126.0, 126.8, 127.9, 128.3, 129.7, 141.6,
157.6. IR (Nujol mull): 3302, 1600, 1244, 1053, 1029, 756,
700 cmꢀ1. ESI-HRMS: (M+H+) calcd for C17H22NO2,
272.1651; found, 272.1644.
propan-1-ol 6d. Using 1-naphthaldehyde, the title com-
25
pound was obtained as a clear oil (63%). ½aꢂD ¼ ꢀ28:2 (c
1
0.59, CHCl3). H NMR (CDCl3): d 0.90 (d, J = 6.3 Hz,
3H), 3.12 (dq, J = 4.3, 6.6 Hz, 1H), 4.34 (AB spin system,
J = 12.5, 20.7 Hz, 2H), 4.88 (d, J = 3.9 Hz, 1H), 7.23–
7.27 (m, 2H), 7.33 (d, J = 4.3 Hz, 3H), 7.42–7.57 (m,
4H), 7.80 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H),
8.12 (d, J = 8.2 Hz, 1H). 13C NMR (CDCl3): d 14.6, 49.1,
58.4, 73.3, 123.4, 125.3, 125.6, 126.0, 126.2, 126.9, 127.9,
128.0, 128.7, 131.6, 133.8, 135.5, 141.3. IR (neat): 3402,
1219, 1112, 755, 701 cmꢀ1. ESI-HRMS: (M+H+) calcd
for C20H22NO, 292.1701; found, 292.1711.
4.2.9. (1R,2S)-2-(30-Methoxybenzylamino)-1-phenylpropan-
1-ol 6i. Using m-anisaldehyde, the title compound was
25
obtained as a clear oil (71%). ½aꢂD ¼ ꢀ11:9 (c 0.63, CHCl3).
1H NMR (CDCl3): d 0.85 (d, J = 6.6 Hz, 3H), 2.99 (dq,
J = 3.9, 6.3 Hz, 1H), 3.81 (s, 3H), 3.85 (s, 2H), 4.78 (d,
J = 3.9 Hz, 1H), 6.80–6.83 (m, 1H), 6.88–6.92 (m, 2H),
7.23–7.35 (m, 6H). 13C NMR (CDCl3): d 14.4, 50.9, 54.9,
57.5, 73.2, 112.3, 113.5, 120.1, 126.0, 126.8, 127.9, 129.3,
141.4, 141.6, 159.6. IR (neat): 3404, 1602, 1154, 1045,
780, 738, 701 cmꢀ1. ESI-HRMS: (M+H+) calcd for
C17H22NO2, 272.1651; found, 272.1659.
4.2.5. (1R,2S)-2-(Naphthalen-20-ylmethylamino)-1-phenyl-
propan-1-ol 6e. Using 2-naphthaldehyde, the title com-
25
pound was obtained as a white solid (79%). ½aꢂD ¼ ꢀ11:4
(c 0.64, CHCl3). Mp = 84–86 °C. 1H NMR (CDCl3): d
0.89 (d, J = 6.6 Hz, 3H), 3.04 (dq, J = 3.9, 6.3 Hz, 1H),
4.04 (s, 2H), 4.82 (d, J = 3.9 Hz, 1H), 7.24–7.32 (m, 3H),
7.45–7.49 (m, 2H), 7.75 (br s, 1H), 7.81–7.84 (m, 2H).
13C NMR (CDCl3): d 14.6, 51.2, 57.7, 73.2, 125.6, 126.1,
126.3, 126.4, 127.0, 127.6, 128.0, 128.2, 132.6, 133.3,
137.5, 141.3. IR (CHCl3): 3304, 1601, 1139, 1000, 902,
819, 748, 702 cmꢀ1. ESI-HRMS: (M+H+) calcd for
C20H22NO, 292.1701; found, 292.1695.
4.2.10. (1R,2S)-2-(30,40-Dimethoxybenzylamino)-1-phenyl-
propan-1-ol 6j. Using 3,4-dimethoxybenzaldehyde, the ti-
tle compound was obtained as a clear oil (47%).
25
1
½aꢂD ¼ ꢀ11:2 (c 0.60, CHCl3). H NMR (CDCl3): d 0.86
(d, J = 6.6 Hz, 3H), 3.00 (dq, J = 3.9, 6.6 Hz, 1H), 3.83
(s, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 4.79 (d, J = 3.9 Hz,
1H), 6.83–6.88 (m, 3H), 7.24–7.33 (m, 5H). 13C NMR
(CDCl3): d 14.2, 50.5, 55.4, 55.5, 57.3, 73.2, 110.8, 111.0,
119.8, 125.8, 126.6, 127.7, 132.4, 141.4, 147.7, 148.7. IR
(neat): 3388, 1592, 1139, 1029, 765, 702 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C18H24NO3, 302.1756; found, 302.1756.
4.2.6. (1R,2S)-2-(Anthracen-90-ylmethylamino)-1-phenylpro-
pan-1-ol 6f. Using 9-anthraldehyde, the title compound
25
was obtained as a yellow solid (52%). ½aꢂD ¼ ꢀ71:5 (c
0.55, CHCl3). Mp = 106–107 °C. 1H NMR (CDCl3): d
0.93 (d, J = 6.6 Hz, 3H), 3.26 (dq, J = 4.3, 6.3 Hz, 1H),
4.80 (AB spin system, J = 12.0, 13.7 Hz, 2H), 4.98 (d,
J = 4.3 Hz, 1H), 7.23–7.33 (m, 2H), 7.44–7.55 (m, 2H),
8.00 (d, J = 8.6 Hz, 2H), 8.28 (d, J = 9.0 Hz, 2H) 8.41 (s,
1H). 13C NMR (CDCl3; An extra aromatic signal is de-
tected and is attributed to asymmetry): d 14.9, 43.5, 59.3,
73.2, 123.7, 124.9, 126.1, 126.3, 127.0, 127.4, 128.1, 129.2,
130.2, 130.8, 131.5, 133.9, 141.2. IR (CHCl3): 3410, 1603,
1159, 1029, 841, 728, 703 cmꢀ1. ESI-HRMS: (M+H+)
calcd for C24H24NO, 342.1858; found, 342.1848.
4.2.11. (1R,2S)-2-(20-Ethylbenzylamino)-1-phenylpropan-1-
ol 6k. Using 2-ethylbenzaldehyde, the title compound
25
was obtained as a clear oil (23%). ½aꢂD ¼ ꢀ22:2 (c 0.43,
1
CHCl3). H NMR (CDCl3): d 0.87 (d, J = 6.6 Hz, 3H),
1.25 (t, J = 7.4 Hz, 3H), 2.71 (q, J = 7.4 Hz, 2H), 3.03
(dq, J = 3.9, 6.3 Hz, 1H), 3.88 (AB spin system, J = 12.5,
17.5 Hz, 2H), 4.81 (d, J = 3.9 Hz, 1H), 7.18–7.33 (m,
9H). 13C NMR (CDCl3): d 14.7, 15.5, 25.3, 48.9, 58.5,
73.0, 126.0, 126.1, 127.0, 127.5, 128.1, 128.7, 129.0, 137.2,
141.2, 142.4. IR (neat): 3404, 1604, 1199, 756, 705 cmꢀ1
.
ESI-HRMS: (M+H+) calcd for C18H24NO, 270.1858;
found, 270.1862.
4.2.7. 2-{[(1R,2S)-1-Hydroxyl-1-phenylpropan-2-ylamino]-
methyl}phenol 6g. Using salicylaldehyde, the title com-
25
pound was obtained as a clear oil (58%). ½aꢂD ¼ þ11:2 (c
4.2.12. (1R,2S)-2-(o-Biphenylmethylamino)-1-phenylpropan-
1-ol 6l. Using o-biphenylcarboxaldehyde, the title com-
1
0.57, CHCl3). H NMR (CDCl3): d 1.05 (d, J = 6.3 Hz,
25
3H), 3.02 (dq, J = 4.3, 6.6 Hz, 1H), 4.04 (AB spin system,
J = 14.1, 48.0 Hz, 2H), 4.87 (d, J = 3.9 Hz, 1H), 6.78 (t,
J = 7.4 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.99 (d,
J = 8.6 Hz, 1H), 7.17 (t, J = 6.6 Hz, 1H), 7.26–7.36 (m,
5H). 13C {1H} NMR (CDCl3): d 13.7, 49.8, 57.3, 75.1,
116.4, 119.0, 122.7, 126.1, 127.5, 128.1, 128.3, 128.6,
141.4, 158.0. IR (neat): 3420, 1590, 1103, 1035, 753,
702 cmꢀ1. ESI-HRMS: (M+H+) calcd for C16H20NO2,
258.1494; found, 258.1487.
pound was obtained as a clear oil (31%). ½aꢂD ¼ ꢀ12:7 (c
1
0.51, CHCl3). H NMR (CDCl3): d 0.65 (d, J = 6.6 Hz,
3H), 2.74 (dq, J = 3.9, 6.6 Hz, 1H), 3.83 (AB spin system,
J = 12.9, 18.4 Hz, 2H), 4.57 (d, J = 3.9 Hz, 1H), 7.19–
7.43 (m, 14H). 13C NMR (CDCl3): d 14.3, 49.0, 57.8,
72.9, 126.0, 126.8, 127.1, 127.5, 127.9, 128.2, 128.7, 129.3,
130.1, 137.2, 141.1, 141.2, 141.9. IR (neat): 3419, 1600,
1198, 1010, 753, 701 cmꢀ1. ESI-HRMS: (M+H+) calcd
for C22H24NO, 318.1858; found, 318.1854.
4.2.8. (1R,2S)-2-(20-Methoxybenzylamino)-1-phenylpropan-
4.2.13. (1R,2S)-2-(p-Biphenylmethylamino)-1-phenylpropan-
1-ol 6m. Using p-biphenylcarboxaldehyde, the title com-
1-ol 6h. Using o-anisaldehyde, the title compound was
25
25
obtained as a white solid (61%). ½aꢂD ¼ ꢀ17:6 (c 0.62,
pound was obtained as a white solid (49%). ½aꢂD ¼ ꢀ22:9
CHCl3). Mp = 90–92 °C. 1H NMR (CDCl3): d 0.81 (d,
J = 6.6 Hz, 3H), 2.88 (dq, J = 3.9, 6.6 Hz, 1H), 3.75 (s,
3H), 3.84 (s, 2H), 4.77 (d, J = 3.9 Hz, 1H), 6.83 (d,
(c 0.61, CHCl3). Mp = 84–86 °C. 1H NMR (CDCl3): d
0.88 (d, J = 6.6 Hz, 3H), 3.04 (dq, J = 3.9, 6.3 Hz, 1H),
3.93 (s, 2H), 4.83 (d, J = 3.5 Hz, 1H), 7.24–7.46 (m,

24
R. W. Parrott, II, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 19–26
10H), 7.57–7.61 (m, 4H). 13C NMR (CDCl3): d 14.7, 50.9,
57.8, 73.1, 126.1, 127.1, 127.3, 127.3, 128.1, 128.5, 128.8,
139.1, 140.2, 140.8, 141.2. IR (Nujol mull): 1601, 1120,
1072, 824, 754, 696 cmꢀ1. ESI-HRMS: (M+H+) calcd for
C22H24NO, 318.1858; found, 318.1861.
6H), 2.97 (m, 1H), 3.05 (dq, J = 3.6, 6.4 Hz, 1H), 4.70 (d,
J = 4.4 Hz, 1H), 7.23–7.35 (m, 5H). Characterization data
for this compound matched exactly with the identical com-
pound found in the literature.14b
4.2.19. (1R,2S)-2-(Pentan-30-ylamino)-1-phenylpropan-1-ol
4.2.14. (1R,2S)-1-Phenyl-2-(20,40,60-trimethylbenzylamino)-
6s. Using 3-pentanone, the title compound was synthe-
25
propan-1-ol 6n. Using mesitaldehyde, the title compound
sized as a pale yellow solid (40%). ½aꢂD ¼ ꢀ8:8 (c 0.61,
25
was obtained as a clear oil (77%). ½aꢂD ¼ ꢀ32:7 (c 0.61,
CHCl3). Mp = 54–56 °C. 1H NMR (CDCl3): d 0.77 (d,
J = 6.6 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H), 0.91 (t, 7.4 Hz,
3H), 1.42 (m, 4H), 2.52 (q, 5.86 Hz, 1H), 2.99 (dq,
J = 3.9, 6.6 Hz, 1H), 4.66 (d, J = 3.9 Hz, 1H), 7.22–7.32
(m, 5H). 13C NMR (CDCl3): d 9.6, 10.0, 15.1, 26.2, 26.7,
55.4, 57.00, 73.1, 126.00, 126.8, 127.7, 127.9, 141.5. IR
(CHCl3): 3402, 1604, 1121, 985, 745, 701 cmꢀ1. ESI-
HRMS: (M+H+) calcd for C14H24NO, 222.1858; found,
222.1868.
1
CHCl3). H NMR (CDCl3): d 0.86 (d, J = 6.6 Hz, 3H),
2.26 (s, 3H), 2.34 (s, 6H), 3.02 (dq, J = 3.9, 6.3 Hz, 1H),
3.82 (AB spin system, J = 11.7, 13.3 Hz, 2H), 4.80 (d,
J = 3.9 Hz, 1H), 6.85 (s, 2H), 7.22–7.31 (m, 5H). 13C
NMR (CDCl3): d 14.8, 19.4, 20.8, 45.5, 59.2, 73.0, 126.0,
127.0, 128.0, 129.0, 133.1, 136.7, 136.8, 141.2. IR (neat):
3417, 1613, 1217, 1109, 851, 758, 701 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C19H26NO, 284.2014; found, 284.2015.
4.2.15.
(1R,2S)-2-(30,50-Di-tert-butyl-20-methoxybenzyl-
4.2.20. (1R,2S)-2-Cyclohexylamino-1-phenyl-1-propanol 6t.
Using cyclohexanone, the title compound was obtained as
amino)-1-phenylpropan-1-ol 6o. Using 3,5-di-tert-butyl-2-
25
methoxybenzaldehyde, the title compound was obtained
a white solid (85%). ½aꢂD ¼ þ8:1 (c 0.60, CHCl3).
25
as a clear oil (59%). ½aꢂD ¼ þ1:7 (c 0.56, CHCl3). 1H
Mp = 89–91 °C. 1H NMR (CDCl3): d, 0.78 (d,
J = 6.8 Hz, 3H), 1.00–1.34 (m, 7H), 1.59–1.64 (m, 1H),
1.71–1.75 (m, 1H), 1.85–1.96 (m, 1H), 2.52–2.59 (m, 1H),
3.05–3.11 (m, 1H), 4.66 (d, J = 4.0 Hz, 1H), 7.21–7.34
(m, 5H). 13C NMR (CDCl3): d 12.7, 24.8, 24.9, 25.5,
31.8, 32.5, 54.3, 55.8, 72.4, 126.0, 127.0, 128.0, 140.9. IR
(Nujol mull): 3278, 1102, 738, 701 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C15H24NO, 234.1858; found, 234.1858.
NMR (CDCl3): d 0.84 (d, J = 6.3 Hz, 3H), 1.31 (s, 9H),
1.40 (s, 9H) 2.91 (dq, J = 3.9, 6.3 Hz, 1H), 3.77 (s, 3H),
3.94 (AB spin system, J = 13.3, 19.1 Hz, 2H), 4.82 (d,
J = 3.9 Hz, 1H), 7.20–7.31 (m, 7H). 13C NMR (CDCl3):
d 14.5, 31.1, 31.5, 34.5, 35.2, 47.0, 58.0, 61.7, 73.1, 123.3,
125.1, 126.1, 126.9, 128.0, 132.2, 141.4, 141.9, 145.8,
155.8. IR (neat): 3354, 1602, 1230, 1120, 881, 759,
701 cmꢀ1. ESI-HRMS: (M+H+) calcd for C25H38NO2,
384.2903; found, 384.2902.
4.2.21. (1R,2S)-2-(2,3-Dihydro-1H-inden-2-ylamino)-1-phe-
nylpropan-1-ol 6u. Using 2-indanone, the title compound
25
4.2.16.
(1R,2S)-2-(20-(Benzyloxy)-30,50-di-tert-butyl-20-
was obtained as a light brown solid (22%). ½aꢂD ¼ ꢀ22:2 (c
methoxybenzylamino)-1-phenylpropan-1-ol 6p. Using 2-
benzyloxy-3,5-di-tert-butylbezaldehyde, the title com-
0.18, CHCl3). Mp = 118–120 °C. 1H NMR (CDCl3): d 0.85
(d, J = 6.6 Hz, 3H), 2.76 (m, 2H), 3.10 (dq, J = 3.9, 6.2 Hz,
1H), 3.21 (m, 2H), 3.81 (pentet, J = 7.0 Hz, 1H), 4.75 (d,
J = 3.9 Hz, 1H), 7.15–7.34 (m, 9H). 13C NMR (CDCl3):
d 15.0, 40.4, 40.5, 56.5, 56.8, 73.4, 124.6, 124.7, 126.1,
126.4, 126.5, 127.0, 128.0, 141.3, 141.5. IR (CHCl3):
3278, 1604, 1145, 1026, 746, 701 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C18H22NO, 268.1701; found, 268.1705.
25
pound was obtained as a clear oil (73%). ½aꢂD ¼ ꢀ2:7 (c
1
0.61, CHCl3). H NMR (CDCl3): d 0.75 (d, J = 6.3 Hz,
3H), 1.33 (s, 9H), 1.44 (s, 9H), 2.82 (dq, J = 3.9, 6.6 Hz,
1H), 3.95 (AB spin system, J = 13.3, 32.4 Hz, 2H), 4.74
(d, J = 3.9 Hz, 1H), 4.97 (s, 2H), 7.20–7.48 (m, 12H). 13C
NMR (CDCl3): d 14.2, 31.2, 31.5, 34.5, 35.4, 47.0, 57.9,
73.2, 75.4, 123.5, 125.3, 126.0, 126.4, 126.9, 127.5, 127.9,
128.4, 132.5, 137.8, 141.4, 142.1, 146.1, 154.2. IR (neat):
3408, 1604, 1124, 1017, 734, 701 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C31H42NO2, 460.3216; found, 460.3209.
4.2.22.
(1R,2S)-2-(Cyclooctylamino)-1-phenylpropan-1-ol
6v. Using cyclooctanone, the title compound was ob-
25
tained as a white solid (39%). ½aꢂD ¼ þ27:7 (c 0.10,
1
CHCl3). Mp = 115–116 °C. H NMR (CDCl3): d 0.84 (d,
4.2.17. (1R,2S)-2-(3,5-Dibromobenzylamino)-1-phenylpro-
pan-1-ol 6q. Using 3,5-dibromobenzaldehyde, the title
J = 6.6 Hz, 3H), 1.49–1.87 (m, 14H), 2.89 (pentet,
J = 4.3 Hz, 1H), 3.09 (dq, J = 3.5, 6.3 Hz, 1H), 4.75 (s,
1H), 7.23–7.36 (m, 5H). 13C NMR (CDCl3): d 14.5, 23.7,
24.0, 25.6, 27.2, 27.3, 32.2, 32.5, 54.7, 55.5, 73.0, 126.1,
127.0, 128.0, 141.3. IR (CHCl3): 3428, 912, 741,
702 cmꢀ1. ESI-HRMS: (M+H+) calcd for C17H28NO,
262.2171; found, 262.2165.
25
compound was obtained as a clear oil (85%). ½aꢂD ¼ ꢀ5:4
1
(c 0.81, CHCl3). H NMR (CDCl3): d 0.89 (d, J = 6.6 Hz,
3H), 2.93 (dq, J = 3.9, 6.3 Hz, 1H), 3.79 (AB spin system,
J = 13.7, 19.1 Hz, 2H), 4.72 (d, J = 3.9 Hz, 1H), 7.24–7.39
(m, 7H), 7.56 (t, J = 2.0 Hz, 2H). 13C NMR (CDCl3): d
14.6, 50.0, 57.7, 73.8, 122.9, 126.0, 127.2, 128.1, 129.7,
132.6, 141.1, 144.2. IR (neat): 3404, 1586, 1198, 1101, 853,
4.2.23. (1R,2S)-2-(Cyclopentylamino)-1-phenylpropan-1-ol
6w. Using cyclopentanone, the title compound was ob-
741, 702 cmꢀ1
C16H18NOBr2, 397.9755; found, 397.9746.
.
EI-HRMS: (M+H+) calcd for
25
tained as a white solid (47%). ½aꢂD ¼ ꢀ2:8 (c 0.70, CHCl3).
Mp = 121–123 °C. 1H NMR (CDCl3):
d
0.81 (d,
4.2.18. (1R,2S)-2-Isopropylamino-1-phenyl-1-propanol 6r.
Using acetone, the title compound was obtained as a white
J = 6.6 Hz, 3H), 1.26–1.40 (m, 2H), 1.52–1.60 (m, 2H),
1.68–1.72 (m, 2H), 1.81–1.92 (m, 2H), 3.00 (dq, J = 4.3,
6.6 Hz, 1H), 3.24 (pentet, J = 7.0 Hz, 1H), 4.71 (d,
J = 3.9 Hz, 1H), 7.24–7.35 (m, 5H). 13C NMR (CDCl3):
25
1
solid. ½aꢂD ¼ ꢀ15:9 (c 0.69, CHCl3). Mp = 99–101 °C. H
NMR: d 0.80 (d, J = 6.8 Hz, 3H), 1.10 (t, J = 7.2 Hz,

R. W. Parrott, II, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 19–26
25
d 15.0, 23.6, 23.7, 33.3, 33.6, 56.6, 56.8, 73.4, 126.1, 126.8,
127.9, 141.6. IR (Nujol mull): 3280, 1604, 998, 745,
703 cmꢀ1. ESI-HRMS: (M+H+) calcd for C14H22NO,
220.1701; found, 220.1699.
J = 2.7 Hz, 1H), 2.95 (dq, J = 3.1, 6.6 Hz, 1H), 3.87 (s,
1H), 7.04–7.32 (m, 14H), 7.58 (d, J = 9.4 Hz, 6H). 13C
NMR (CDCl3): d 15.1, 53.9, 71.5, 74.4, 125.5, 126.5, 127.8,
127.9, 128.8, 142.1, 146.6. IR (neat): 3451, 1596, 1217, 992,
747, 704 cmꢀ1. ESI-HRMS: (M+H+) calcd for C28H28NO,
394.2171; found, 394.2175.
4.2.24.
(1S,2S)-2-(20-Methoxybenzylamino)-1-phenylpro-
pan-1-ol 7a. Using o-anisaldehyde, the title compound
25
was obtained as colorless prisms (20%), ½aꢂD ¼ þ87:1 (c
4.3.2. (1S,2S)-1-Phenyl-2-(tritylamino)propan-1-ol 9. Using
trityl chloride, the title compound was obtained as a white
solid after recrystallization from hexanes and ethyl acetate
1
0.64, CHCl3), mp = 70–72 °C. H NMR (CDCl3): d 0.96
(d, J = 6.3 Hz, 3H), 2.73 (pentet, J = 6.6 Hz, 1H), 3.77 (s,
3H), 3.69 (d, J = 12.9 Hz, 1H), 3.86 (d, J = 12.9 Hz, 1H),
4.18 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.90 (t,
J = 7.4 Hz, 1H), 7.17–7.35 (m, 7H). 13C NMR (CDCl3):
d 16.7, 47.1, 55.0, 59.2, 77.6, 110.1, 120.3, 126.8, 127.3,
128.1, 128.1, 128.3, 129.7, 142.5, 157.6. IR (CHCl3):
3313, 1602, 1243, 1048, 1029, 753, 702 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C17H22NO2, 272.1651; found, 272.1644.
25
1
(77%). ½aꢂD ¼ ꢀ0:2 (c 0.72, CHCl3), mp = 135–137 °C. H
NMR (CDCl3): d 0.25 (d, J = 6.3 Hz, 3H), 2.89 (dq,
J = 3.7, 6.3 Hz, 1H), 4.34 (d, J = 7.0 Hz, 1H), 7.16–7.32
(m, 14H), 7.55 (d, J = 7.8 Hz, 6H). 13C NMR (CDCl3): d
17.9, 54.5, 71.1, 78.7, 126.5, 127.3, 127.5, 127.9, 128.1,
128.9, 142.0, 146.6. IR (CHCl3): 3402, 1596, 1137, 1034,
735 cmꢀ1. ESI-HRMS: (M+H+) calcd for C28H28NO,
394.2171; found, 394.2175.
4.2.25.
(1S,2S)-2-(Cyclooctylamino)-1-phenyl-1-propanol
7b. Using cyclooctanone, the title compound was ob-
4.3.3. (1S,2S)-1-phenyl-2-(1,7,7-trimethylbicyclo[2.2.1]hep-
tan-2-ylideneamino)-1-propanol 11. Using (1S,2S)-pseudo-
25
tained as a clear oil (39%).½aꢂD ¼ þ84:8 (c 0.91, CHCl3).
1H NMR (CDCl3): d 0.94 (d, J = 6.3 Hz, 3H), 1.44–1.84
(m, 14H), 2.67 (pentet, J = 6.8 Hz, 1H), 2.73 (br s, 1H),
3.78–3.84 (m, 1H), 4.04 (d, J = 8.2 Hz, 1H), 7.23–7.36
(m, 5H). 13C NMR (CDCl3): d 12.7, 24.8, 24.9, 25.5,
31.8, 32.5, 54.3, 55.8, 72.4, 126.0, 127.0, 128.0, 140.9. IR
(Nujol mull): 3372, 1056, 734, 701 cmꢀ1. ESI-HRMS:
(M+H+) calcd for C17H28NO, 26.2171; found, 262.2167.
norephedrine and the literature experimental,10 the title
25
compound was obtained as a clear oil (64%). ½aꢂD
¼
1
þ90:3 (c 1.0, CHCl3). H NMR (CDCl3): d 0.72 (s, 3H),
0.89 (s, 3H), 0.96 (s, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.14–
1.21 (m, 1H), 1.55–1.65 (m, 2H), 1.70–1.84 (m, 2H), 2.16–
2.22 (m, 2H), 3.44 (pentet, J = 6.0 Hz, 1H), 3.52 (d,
J = 8.0 Hz, 1H), 4.61 (t, J = 8.1 Hz, 1H), 7.22–7.31 (m,
5H). 13C NMR (CDCl3): d 11.4, 17.8, 18.7, 19.2, 27.1,
32.1, 35.2, 43.4, 46.8, 53.5, 62.2, 77.8, 126.3, 126.9, 127.7,
142.9, 183.0. IR (Nujol mull): 3419, 1682, 1053, 737,
704 cmꢀ1. ESI-HRMS: (M+H+) calcd for C19H28NO,
286.2171; found, 286.2168.
4.2.26. (1S,2S)-2-(Anthracen-90-ylmethylamino)-1-phenyl-
propan-1-ol 7c. Using 9-anthraldehyde, the titled com-
pound was obtained as
a
yellow solid (95%),
25
½aꢂD ¼ þ133:9 (c 0.66, CHCl3), mp = 104–106 °C. 1H
NMR (CDCl3): d 1.21 (d, J = 6.6 Hz, 3H), 3.05 (dq,
J = 6.6, 8.2 Hz, 1H), 4.21 (d, J = 7.8 Hz, 1H), 4.60 (d,
J = 12.1 Hz, 1H), 4.87 (d, J = 11.7 Hz, 1H), 7.24–7.56
(m, 9H), 8.01 (d, J = 9.4 Hz, 2H), 8.30 (d, J = 9.8 Hz,
2H), 8.42 (s, 1H). 13C NMR (CDCl3): d 16.9, 43.3, 60.6,
77.6, 123.8, 124.9, 126.2, 126.9, 127.4, 127.6, 128.2, 129.1,
130.1, 130.9, 131.5, 142.1. IR (CHCl3): 3304, 1624, 1138,
1026, 732, 701 cmꢀ1. ESI-HRMS: (M+H+) calcd for
C24H24NO, 342.1858; found, 342.1866.
4.3.4. (1S,2S)-1-Phenyl-2-(1,7,7-trimethylbicyclo[2.2.1]hep-
tan-2-ylamino)-1-propanol 13. Using the literature experi-
mental10 for reduction, the title compound was obtained as
25
a white solid (79%). Mp = 63–65 °C. ½aꢂD ¼ þ144:4 (c 1.0,
1
CHCl3). H NMR (CDCl3): d 0.83 (s, 3H), 0.87 (s, 3H),
0.88 (s, 3H), 0.92 (d, J = 6.0 Hz, 3H), 0.95–0.97 (m, 1H),
1.19–1.31 (m, 2H), 1.64–1.74 (m, 2H), 1.89–1.96 (m, 1H),
2.04–2.09 (m, 1H), 2.58 (pentet, J = 6.4 Hz, 1H), 2.99
(dd, J = 2.4 Hz and J = 9.2 Hz, 1H), 4.07 (d, J = 9.0 Hz,
1H), 7.25–7.38 (m, 5H). 13C NMR (CDCl3): d 17.2, 22.6,
23.6, 25.1, 25.5, 27.2, 27.3, 27.4, 31.4, 34.0, 34.6, 54.9,
57.3, 72.0, 77.7, 126.9, 127.4, 128.1, 142.4. IR (Nujol mull):
3366, 1148, 1043, 735, 709 cmꢀ1. ESI-HRMS: (M+H+)
calcd for C19H30NO, 288.2327; found, 288.2329.
4.3. General procedure for N-alkylation of (1R,2S)-nor-
ephedrine or (1S,2S)-pseudonorephedrine via nucleophilic
substitution
To a flame-dried, nitrogen-purged flask were added
(1R,2S)-norephedrine (1.02 g, 6.76 mmol) and anhydrous
methylene chloride (22 mL). Triethylamine (1.4 mL,
10.1 mmol) was added via syringe and allowed to stir for
24 h at room temperature. The reaction was quenched via
saturated ammonium chloride solution (50 mL) and the
product was extracted with methylene chloride
(50 mL ꢁ 2), washed with brine, dried with magnesium
chloride, and gravity filtered. The solvent was removed un-
der reduced pressure.
5. General procedure for the asymmetric 1,2-addition with
diethylzinc and benzaldehyde
(1R,2S)-2-(Benzylamino)-1-phenyl-1-propanol 8 (0.085 g,
0.313 mmol) was added to a flame-dried round-bottomed
flask with toluene (4.1 mL) in an inert atmosphere. To
the flask was added a solution of diethylzinc in hexanes
(1 M, 9.4 mL) and the mixture was allowed to stir at room
temperature for 25 min. Benzaldehyde (0.32 mL,
3.13 mmol) was then added and allowed to stir at room
temperature for 24 h. The reaction was quenched with a
saturated solution of ammonium chloride (50 mL) and
4.3.1. (1R,2S)-1-Phenyl-2-(tritylamino)propan-1-ol 8. Using
trityl chloride, the title compound was obtained as a yellow
25
oil (99%). ½aꢂD ¼ þ74:5 (c 0.64, CHCl3). 1H NMR (CDCl3):
d 0.63 (d, J = 6.6 Hz, 3H), 2.21 (br s, 1H), 2.65 (br d,

26
R. W. Parrott, II, S. R. Hitchcock / Tetrahedron: Asymmetry 19 (2008) 19–26
5. Ephedra catalysts: (a) El-Shehawy, A. A. Tetrahedron 2007,
63, 5490–5500; (b) Wolf, C.; Hawes, P. A. J. Org. Chem.
2002, 67, 2727–2729; (c) Sato, I.; Saito, T.; Soai, K. Chem.
Commun. 2000, 2471–2472; (d) Kawanami, Y.; Mitsuie, T.;
Miki, M.; Sakamoto, T.; Nishitani, K. Tetrahedron 2000, 56,
175–178; (e) Bastin, S.; Delebecque, N.; Agbossou, F.;
extracted with ethyl acetate (50 mL ꢁ 2). The organic solu-
tion was washed with brine, dried over MgSO4, gravity fil-
tered, and concentrated under reduced pressure to afford
enantiomerically enriched 1-phenyl-1-propanol. The
enantioselectivity of this process was immediately deter-
mined via chiral stationary phase HPLC.
´
Brocard, J.; Pelinski, L. Tetrahedron: Asymmetry 1999, 10,
1647–1651; (f) Soai, K.; Hayase, T.; Takai, K.; Sugiyama, T.
J. Org. Chem. 1994, 59, 7908–7909; (g) Chaloner, P. A.;
Langadianou, E.; Perera, S. A. R. J. Chem. Soc., Perkin
Trans. 1991, 2731–2735; (h) Soai, K.; Yokoyama, S.; Haya-
saka, T. J. Org. Chem. 1991, 56, 4264–4268; (i) Chaloner, P.
A.; Langadianou, E. Tetrahedron Lett. 1990, 31, 5185–
5188.
Acknowledgments
We would like to thank Ryan Davis and Stephanie Kuschel
for their technical assistance. Financial support from the
Petroleum Research Fund (Grant 40777-B1) and the Na-
tional Science Foundation (Grant CHE 0644950) is grate-
fully acknowledged.
6. (a) Choudhury, A.; Moore, J. R.; Pierce, M. E.; Fortunak, J.
M.; Valvis, I.; Confalone, P. N. Org. Process Res. Dev. 2003,
7, 324–328; (b) Pierce, M. E.; Parsons, R. L., Jr.; Radesca, L.
A.; Lo, Y. S.; Silverman, S.; Moore, J. R.; Islam, Q.;
Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.;
Morgan, S. J.; Davis, W. P.; Confalone, P. N.; Chen, C.-y.;
Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.;
Thompson, A. S.; Corley, E. G.; Grabowski, E. J. J.; Reamer,
R.; Reider, P. J. J. Org. Chem. 1998, 63, 8536–8543.
7. (a) Unaleroglu, C.; Aydin, A. E.; Demir, A. S. Tetrahedron:
Asymmetry 2006, 17, 742–749; (b) Paleo, M. R.; Cabeza, I.;
Sardina, F. J. J. Org. Chem. 2000, 65, 2108–2113; (c) Yun, H.;
Wu, Y.; Wu, Y.; Ding, K.; Zhou, Y. Tetrahedron Lett. 2000,
41, 10263–10266.
8. Groeper, J. A.; Hitchcock, S. R. Tetrahedron: Asymmetry
2006, 17, 2884–2889.
9. Baxter, E. W.; Reitz, A. B. In Overman, L. E., Ed.;
Reductive aminations of carbonyl compounds with borohy-
dride and borane reducing agents Org. React. 2002, 59, 3–
714.
References
1. Reviews: (a) Pu, L. Tetrahedron 2003, 59, 9873–9886; (b)
Soai, K.; Shibata, T. Comprehensive Asymmetric Catalysis,
Supplement; Springer, 2004, pp 95–106; (c) Pu, L.; Yu, H.-B.
Chem. Rev. 2001, 101, 757–824; (d) Soai, K.; Niwa, S. Chem.
Rev. 1992, 92, 833–856.
2. b-Amino alcohol catalysts: (a) Dave, R.; Sasaki, N. A.
Tetrahedron: Asymmetry 2006, 17, 388–401; (b) Huang, J.;
Ianni, J. C.; Antoline, J. E.; Hsung, R. P.; Kozlowski, M. C.
Org. Lett. 2006, 8, 1565–1568; (c) Ionescu, R. D.; Blom, A.;
Frejd, T. Tetrahedron: Asymmetry 2003, 14, 2369–2380; (d)
Joshi, S. N.; Malhotra, S. V. Tetrahedron: Asymmetry 2003,
14, 1763–1766; (e) Nugent, W. A. Org. Lett. 2002, 4, 2133–
2136; (f) Dai, W.-M.; Zhu, H.-J.; Hao, X.-J. Tetrahedron:
Asymmetry 2000, 11, 2315–2337; (g) Corey, E. J.; Yuen, P.
W.; Hannon, F. J.; Wierda, D. A. J. Org. Chem. 1990, 55,
784–786.
10. Squire, M. D.; Burwell, A.; Ferrence, G. M.; Hitchcock, S. R.
Tetrahedron: Asymmetry 2002, 13, 1849–1854.
11. (a) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 9800–9809; (b) Goldfuss, B.; Houk, K.
N. J. Org. Chem. 1998, 63, 8998–9006; (c) Rousch, W. R.;
Hawkins, J. M.; Grubbs, R. H. Chemtracts: Org. Chem. 1988,
1, 21–25.
3. c-Amino alcohol catalysts: (a) Szakonyi, Z.; Balazs, A.;
Martinek, T. A.; Fueloep, F. Tetrahedron: Asymmetry 2006,
17, 199–204; (b) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A.
Tetrahedron: Asymmetry 1997, 8, 293–301.
´
´
12. (a) Gonzalez-Sabın, J.; Gotor, V.; Rebolledo, F. Tetrahedron:
Asymmetry 2006, 17, 449–454; (b) Bauer, T.; Gajewiak, J.
Tetrahedron: Asymmetry 2005, 16, 851–855.
4. d-Amino alcohol catalysts: (a) Zhong, J.; Wang, M.; Guo, H.;
Yin, M.; Bian, Q.-H.; Wang, M. Synlett 2006, 1667–1670; (b)
Scarpi, D.; Galbo, F. L.; Guarna, A. Tetrahedron: Asymme-
try 2006, 17, 1409–1414; (c) Tanyeli, C.; Suenbuel, M.
Tetrahedron: Asymmetry 2005, 16, 2039–2043; (d) Scarpi,
D.; Lo Galbo, F.; Occhiato, E. G.; Guarna, A. Tetrahedron:
Asymmetry 2004, 15, 1319–1324; (e) Nevalainen, M.; Neva-
lainen, V. Tetrahedron: Asymmetry 2001, 12, 1771–1777; (f)
Hanyu, N.; Aoki, T.; Mino, T.; Sakamoto, M.; Fujita, T.
Tetrahedron: Asymmetry 2000, 11, 2971–2979.
13. Hodge, P.; Sung, D. W. L.; Stratford, P. W. J. Chem. Soc.,
Perkin Trans. 1 1999, 2335–2342.
14. (a) Hitchcock, S. R.; Casper, D. M.; Nora, G. P.; Blackburn,
J. R.; Bentley, J. T.; Taylor, D. C. J. Heterocycl. Chem. 2002,
39, 823–828; (b) Hitchcock, S. R.; Casper, D. M.; Vaughn, J.
F.; Finefield, J. M.; Ferrence, G. M.; Esken, J. M. J. Org.
Chem. 2004, 69, 714–718.