Diastereoselective synthesis of N,N-dibenzyl-protected aminoalkyl hydroxyethylamines: Key building blocks for hydroxyethylamine-based BACE1 inhibitor

Article abstract of DOI:10.1080/00397911.2011.572217

(Chemical Equation Presented) L-Amino acids were reduced with NaBH ₄ followed by reacting with benzyl bromide to give N,N-dibenzyl-protected aminoalkyl ethanol 3, which in turn underwent a Swern oxidation, a Johnson-Corey-Chaykovsky reaction, and a nucleophilic reaction to afford N,N-dibenzyl-protected aminoalkyl hydroxyethylamine 6 with a diastereomer ratio 2.5-2.9:1 of (2R, 3S)-6:(2S, 3S)-6. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.572217

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Diastereoselective Synthesis of
N,N-Dibenzyl-Protected Aminoalkyl
Hydroxyethylamines: Key Building Blocks
for Hydroxyethylamine-Based BACE1
Inhibitor
Jie Wu a b , Shanyun Gao a , Guochao Liao a , Hansen Lin b & Aihua
Nie a
a Department of Medicinal Chemistry, Institute of Pharmacology and
Toxicology, Academy of Military Medical Science, Beijing, China
b Department of Medicinal Chemistry, Pharmaceutical College,
Guangdong Pharmaceutical University, Guangdong, China
Published online: 29 May 2012.
To cite this article: Jie Wu , Shanyun Gao , Guochao Liao , Hansen Lin & Aihua Nie (2012):
Diastereoselective Synthesis of N,N-Dibenzyl-Protected Aminoalkyl Hydroxyethylamines: Key Building
Blocks for Hydroxyethylamine-Based BACE1 Inhibitor, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:19, 2907-2916
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Synthetic Communications1, 42: 2907–2916, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.572217
DIASTEREOSELECTIVE SYNTHESIS OF
N,N-DIBENZYL-PROTECTED AMINOALKYL
HYDROXYETHYLAMINES: KEY BUILDING BLOCKS FOR
HYDROXYETHYLAMINE-BASED BACE1 INHIBITOR
Jie Wu,1,2 Shanyun Gao,1 Guochao Liao,1 Hansen Lin,2 and
Aihua Nie1
1Department of Medicinal Chemistry, Institute of Pharmacology and
Toxicology, Academy of Military Medical Science, Beijing, China
2Department of Medicinal Chemistry, Pharmaceutical College, Guangdong
Pharmaceutical University, Guangdong, China
GRAPHICAL ABSTRACT
Abstract L-Amino acids were reduced with NaBH4 followed by reacting with benzyl bromide
to give N,N-dibenzyl-protected aminoalkyl ethanol 3, which in turn underwent a Swern oxi-
dation, a Johnson–Corey–Chaykovsky reaction, and a nucleophilic reaction to afford N,N-
dibenzyl-protected aminoalkyl hydroxyethylamine 6 with a diastereomer ratio 2.5ꢀ2.9:1 of
(2R, 3S)-6:(2S, 3S)-6.
Keywords Aminoalkyl hydroxyethylamine; BACE1 inhibitor; diastereoselective synthesis
INTRODUCTION
Alzheimer’s disease (AD) is a devastating neurodegenerative disease for which
no specific treatment is currently available. According to the amyloid hypothesis,
BACE1 (b-site APP cleaving enzyme, b-secretase) has been regarded as a potential
druggable target for therapeutic intervention in AD.[1] Inhibition of BACE1 activity
is expected to reduce concentration of Ab and stop amyloid plaque formation.
Therefore, the development of BACE1 inhibitors is considered a valuable strategy
for discovering AD drugs.[2] So far many BAEC1 inhibitors have been designed and
synthesized. Among them, hydroxyethylamine-based compounds are the most
inhibitory potency against BACE1 (Scheme 1).[3] A structural characteristic of
the hydroxyethylamine-based BACE1 inhibitors is that hydroxyl substituted chiral
Received August 11, 2010.
Address correspondence to Aihua Nie, Department of Medicinal Chemistry, Institute of
Pharmacology and Toxicology, Academy of Military Medical Science, Beijing 100850, China. E-mail:
aihuanie@yahoo.com
2907

2908
J. WU ET AL.
Scheme 1. General structure of hydroxyethylamine-based BACE1 inhibitors and its retrosynthetic
strategy.
center (C2) should be R configuration and another (C3) S configuration. To dis-
cover new hydroxyethylamine-based BACE1 inhibitors, we need to synthesize some
N,N-dibenzyl-protected aminoalkyl hydroxyethylamine dipeptide isosteres as the
intermediates for preparing these inhibitors (Scheme 1). In this article we report
the synthesis of these hydroxyethylamine derivatives.
RESULTS AND DISCUSSION
According to the structural characteristic of hydroxyethylamine-based BACE1
inhibitors, it is a critical step to construct the correct configuration (2R,3S) of the
two chiral centers. The C3 chiral center can be produced by using L-amino acids
as starting materials. The other chiral center (C2) comes from the reaction of ami-
noalkyl epoxides with substituted-amine as shown in Scheme 1. The preparation
of these aminoalkyl epoxides is described in Scheme 2. Reetz et al. reported a method
of synthesizing 3, in which amino acids react with benzyl bromide (BnBr) first and
then to reduce N,N-dibenzyl-protected amino acids to amino alcohols by using
Scheme 2. Synthesis of N,N-dibenzyl-protected aminoalkyl epoxides (2S,3S)-5a and 5b and (2R,3S)-5a0
and 5b0.

AMINOALKYL HYDROXYETHYLAMINES
2909
LiAlH4.[4] To avoid this pyrophoric reagent (LiAlH4), N,N-dibenzyl-protected
aminoalkyl ethanols 3 are prepared from the corresponding amino acids following
the procedure reported by Abiko and Masammune.[5] L-leucine (1a) or L-phenylala-
nine (1b) was reacted with sodium borohydride (NaBH4) catalyzed by iodine in tetra-
hydrofuran (THF) to produce aminoalkyl ethanol 2a or 2b, and then 2a or 2b
reacted with benzyl bromide (BnBr) in a solvent mixture of methanol–water
(v=v ¼ 2.4:1) to afford N,N-dibenzyl-protected aminoalkyl ethanol 3a or 3b
(Scheme 2). The aminoalkyl ethanol 3a or 3b was converted quantitatively to ami-
noalkyl aldehyde 4a or 4b by a Swern oxidation. Beaulieu and Wernic[6] reported
a methodology of aldehyde 4 diastereoselectively transformed to epoxide 5, in which
aldehyde is reacted with bromochloromethane and lithium metal at ꢁ75 ꢂC in anhy-
drous tetrahydrofuran (THF) under an argon atmosphere to give (2S,3S)- and
(2R,3S)-epoxide in good yield as an 89:11 mixture of diastereomers. A drawback
of this procedure is that the reaction temperature must be carefully controlled below
ꢁ55 ꢂC. Ng et al.[7] also reported the preparation of epoxide 5 by using a Johnson–
Corey–Chaykovsky reaction. Under an atmosphere of nitrogen a mixture of NaH
and dimethylsulfoxide (DMSO) is heated at 75–80 ꢂC for 45 min, and then at room
temperature THF is added. The mixture cooled to ꢁ10 ꢂC. Trimethylsulfonium iod-
ide and aldehyde 4 are added successively and stirred for about 0.5 h at ꢁ10 ꢂC. After
stirring at room temperature for another hour, epoxide 5 is obtained in a yield of
75% with the diastereomers ratio 6:1 of (2S,3S):(2R,3S). Following the procedure
reported by Reetz et al.,[8] epoxide 5 was synthesized in this study, but we found that
the reaction mixture did not need to be cooled to ꢁ10 ꢂC. In our study the transform-
ation of aldehyde 4 to epoxide 5 via Johnson–Corey–Chaykovsky reaction was con-
trolled at room temperature. Thus, this conversion was diastereoselective, and the
diastereomeric ratio of the crude mixture was determined by integration of charac-
teristic 1H NMR signals of C-2 for the major and minor isomers.[6,7] Epoxide 5 was
provided as about a 2.7:1 mixture of (2S,3S)-5 and (2R,3S)-5 diastereomers.
Although the diastereomers ratio in our experiment was less than that of Reetz’s,
the procedure was convenient. Further, to ascertain the absolute stereochemistry
of the adducts, epoxide 5 were converted into the corresponding N,N-dibenzyl-
protected aminoalkyl hydroxyethylamine 6 (Table 1) by reacting with different R0
NH2 in alcohol under an atmosphere of nitrogen at reflux for 20 h, because deriva-
tive 6 (table 1) would be an appropriate substrate for the NMR studies considering
the relative instability of the epoxides 5 on silica gel. The reaction was completely
regioselective with the attack of the nucleophile on the less substituted oxirane car-
bon. Thus, (2S,3S)-5 and (2R,3S)-5 were converted to (2R,3S)-6 and (2S,3S)-6
respectively. The diastereomers of (2R,3S)-6 and (2S,3S)-6 were separated by
silica-gel flash chromatography with dichloromethane–methanol (20:1) as eluent.
Because (2S,3S)-5 is the major isomer of the epoxide diastereomers, (2R,3S)-6 is
accordingly the major isomer of the minoalkyl hydroxyethylamine diastereomers.
An analytical sample of the desired major diastereomeric product (2R,3S)-6 and
minor diastereomeric product (2S,3S)-6 were obtained by purifying the crude pro-
duct by silica-gel chromatography [dichloromethane–methanol (20:1)], which were
characterized by 1H NMR analysis with characteristic proton NMR signals of
C-2. As an example, the 1H NMR spectrum of major isomer 6f revealed the charac-
teristic H-2 at d 3.91–3.93 as multiplet (2R configuration); the same proton in

2910
J. WU ET AL.
Table 1. Reaction of epoxides (2S,3S)-5a and 5b and (2R,3S)-5a0 and 5b0 with NH2R0 to afford
hydroxyethylamine derivatives (2S,3S)-6a–h and (2R,3S)-6a0–h0
R
R0
Compound 6x (6x0)a
Yieldb of 6x (6x0) (%)
Ratio of 6x/6x0
(CH3)2CH2-
(CH3)2CH2-
(CH3)2CH2-
(CH3)2CH2-
C6H5CH2-
C6H5CH2-
C6H5CH2-
C6H5CH2-
c-C3H5-
6a (6a0)
6b (6b0)
6c (6c0)
6d (6d0)
6e (6e0)
6f (6f0)
6g (6g0)
6h (6h0)
41.5 (16.9)
56.9 (21.9)
31.0 (10.8)
31.8 (12.0)
38.0 (15.2)
30.0 (10.4)
29.4 (12.6)
40.8 (14.5)
2.46: 1
2.60: 1
2.87: 1
2.65: 1
2.50: 1
2.88: 1
2.33: 1
2.81: 1
(CH3)2CHCH2-
m-CF3C6H5CH2-
m-OCH3C6H5CH2-
c-C3H5-
(CH3)2CHCH2-
m-CF3C6H5CH2-
m-OCH3C6H5CH2-
a6x ¼ (2R,3S)-6a–h, 6x0 ¼ (2S,3S)-6a0–h0.
bAfter separation.
the minor isomer 6f0 resonated at d 4.29–4.32 as multiplet (2S configuration) based
on literature evidence.[6,7] Similarly, all the derived (2R,3S)-6 obtained from
epoxide (2S,3S)-5 exhibited smaller chemical shift constants for the characteristic
H-2. It could be concluded that the C-2 stereocenter in (2S,3S)-5 is ‘S’. To ensure
that the BACE1 inhibitors prepared by this method were of high enantiomeric
purity, we developed high-performance liquid chromatographic (HPLC) methods
to analyze the enantiomeric excess of various key intermediates. Enantiomers of
intermediate were analyzed using a CHIRALPAK AD-H column. In all cases, the
intermediates from the synthesis described were determined to be of high optical
purity (>99.5% de).
The ratio of (2R,3S)-6 to (2S,3S)-6 was determined by the yield of those two
isomers (Table 1).
EXPERIMENTAL
All unspecified reagents were from commercial resources and were used with-
out further purification. Melting points were determined with an electrothermal
melting-point apparatus and were uncorrected. The 1H NMR spectra were recorded
on JNM-ECA-400 superconduction spectrometer at 400 MHz in CDCl3 or d6-
DMSO containing TMS as an internal reference. 13C NMR spectra were recorded
on a JNM-ECA-400 superconduction spectrometer at 100 MHz in CDCl3 containing
TMS as an internal reference. Infrared (IR) spectra were recored on a Nicolet 6700
(American) spectrophotomer. Chemical shifts are given in parts per million (ppm, d
scale), with coupling constants (J) in hertz (Hz). Optical rotation values were mea-
sured on a polAAr3005 polarimeter. Crude products were purified by column chro-
matography on silica gel of 300–400 mesh. Optical purity was analyzed using a
Waters 2487 HPLC instrument equipped with a CHIRALPAK AD-H column.

AMINOALKYL HYDROXYETHYLAMINES
2911
Compounds 2a, 2b, 3a, and 3b
For the synthesis of compounds 2a, 2b, 3a, and 3c, refer to the literature.[9]
(S)-2-Amino-4-methylpentan-1-ol (2a). Colorless oil; yield 86.0%;
29:4
½aꢃD ¼ þ26:4 (c ¼ 0.80, MeOH); 1H NMR (DMSO-d6, 400 MHz): d 0.82–0.86
(m, 6 H, 2 CH3), 1.41–1.46 (m, 2 H, CH2), 1.64–1.67 (m, 1 H, CH), 3.34 (s, 2 H,
NH2), 3.51–3.55 (m, 1 H, CH), 4.74–4.76 (m, 2 H, CH2), 4.89 (s, 1 H, OH).
(S)-2-Amino-3-phenylpropan-1-ol (2b). White powder; yield 66.7%; mp:
29:4
82–84 ꢂC; ½aꢃD ¼ ꢁ18:1 (c ¼ 1.05, MeOH); 1H NMR (DMSO-d6, 400 MHz): d
1.41 (s, 2 H, NH2), 2.49–2.51 (m, 2 H, CH2), 2.91–2.92 (m, 1 H, CH), 3.18–3.32
(m, 2 H, CH2), 4.57 (s, 1 H, OH).
(S)-2-(Dibenzylamino)-4-methylpentan-1-ol (3a). Colorless oil; yield
29:4
1
88.0%; ½aꢃD ¼ þ9:7 (c ¼ 1.08, MeOH); H NMR (CDCl3, 400 MHz): d 0.86–0.92
(dd, J ¼ 5.6 Hz, 6.4 Hz, 6 H, 2 CH3), 1.13–1.18 (m, 1 H, CH), 1.48–1.52 (m, 2 H,
CH2), 2.81–2.89 (m, 1 H, CH), 3.34–3.37 (m, 4 H, 2 CH2), 3.80 (d, J ¼ 13.6 Hz,
2 H, CH2), 7.20–7.35 (m, 10 H, ArH).
(S)-2-(Dibenzylamino)-3-phenylpropan-1-ol (3b). White powder; yield
29:4
89.6%; mp: 68–69 ꢂC; ½aꢃD ¼ þ8:0 (c ¼ 1, MeOH); 1H NMR (DMSO-d6,
400 MHz): d 2.71–2.90 (m, 3 H, CH2 and CH), 3.65–3.72 (m, 6 H, 3 CH2), 4.41 (s,
1H, OH), 7.10–7.25 (m, 15 H, ArH).
Compounds 4a and 4b
Compounds 4a and 4b were synthesized according to the method reported by
Huang et al.[10]
(S)-2-(Dibenzylamino)-4-methylpentanal (4a). Yellow oil; yield 99.0%;
29:4
½aꢃD ¼ þ5:6 (c ¼ 0.996, MeOH); 1H NMR (DMSO-d6, 400 MHz): d 0.77 (d,
J ¼ 6.8 Hz, 6 H, 2 CH3), 1.88–1.92 (m, 1 H, CH), 2.22–2.45 (m, 2 H, CH2),
3.17–3.19 (m, 1 H, CH), 3.61 (s, 4 H, 2 CH2), 7.25–7.35 (m, 10 H, ArH), 9.70 (s,
1 H, CHO).
(S)-2-(Dibenzylamino)-3-phenylpropanal (4b). Yellow oil; yield 100%;
29:4
1
½aꢃD ¼ þ2:3 (c ¼ 1.1, MeOH); H NMR (DMSO-d6, 400 MHz): d 2.96–3.00 (m, 1
H, 1=2 CH2), 3.04–3.06 (m, 1 H, 1=2 CH2), 3.45–3.48 (m, 1 H, CH), 3.74 (s, 4 H,
2 CH2), 7.20–7.30 (m, 15 H, ArH), 9.70 (s, 1 H, CHO).
Synthesis of Compounds (2R,3S)-5a and 5b and (2S,3S)-5a’ and 5b’
NaH 60% (1.28 g, 0.032 mol) was added to 40 mL dry DMSO under nitrogen,
and the temperature was kept between 25 ꢂC and 30 ꢂC. (CH3)3SOI was added por-
tionwise over 40 min, and then the suspension was stirred for 20 min followed by
dropwise addition of the compound 4 (0.02 mol) dissolved in 20 mL dry DMSO.
The reaction mixture was stirred for 3 h at the temperature. The resulting mixture
was partitioned between EtOAc=H2O (1:1, v=v). The organic layer was washed with
saturated NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The

2912
J. WU ET AL.
crude product triturated with petroleum ether to give compound 5 as a pale yellow
oil, which was used in the next step without further purification.
Compounds (2R,3S)-6a–h and (2S,3S)-6a’–h’
Compound 5 (0.0046 mol) and various amines (0.1 mol) were dissolved in
anhydrous ethanol, and the mixture was refluxed for 20 h under nitrogen. Solvent
was removed by evaporation in vacuo. The crude product was purified using
silica-gel chromatography, with dichloromethane=methanol (100:1) as eluent, to
get compound 6.[11] The chemically and optically pure compound 6 was analyzed
using Waters 2487 HPLC. HPLC analysis: CHIRALPAK AD-H column, 230 nm,
90% hexane=isopropanol, flow rate: 1 mL=min, UV detector.
(2R,3S)-1-(Cyclopropylamino)-3-(dibenzylamino)-5-methylhexan-2-
ol [(2R,3S)-6a]
25
Colorless oil; yield 41.5%; ½aꢃD ¼ ꢁ31 (c ¼ 0.53, MeOH); chemical purity:
93.3%; optical purity (de): 99.5%; retention time: 8.24 min; 1H NMR (CDCl3,
400 MHz): d 0.29–0.31 (m, 2 H, CH2), 0.38–0.40 (m, 2 H, CH2), 0.93–0.95 (m, 6
H, 2 CH3), 1.24–1.27 (m, 2 H, CH2), 1.66–1.71 (m, 1 H, CH), 2.05–2.06 (m, 1 H,
CH), 2.53–2.56 (m, 2 H, CH2), 2.72–2.75 (m, 1 H, CH), 3.42 (d, J ¼ 13.6 Hz, 2 H,
CH2), 3.59–3.62 (m, 1 H, CH), 3.88 (d, J ¼ 13.2 Hz, 2 H, CH2), 7.26–7.34 (m, 10
H, ArH). 13C NMR (CDCl3, 100 MHz): d 140.33, 129.02, 128.18, 126.87, 68.51,
57.21, 54.63, 53.13, 35.56, 30.36, 24.98, 23.36, 22.52, 6.79, 5.93. IR (KBr): v 3432,
3085, 3027, 2952, 2856, 1602, 1494, 1453, 1380, 1367, 1069, 746, 730, 698 cmꢁ1
.
(2S,3S)-1-(Cyclopropylamino)-3-(dibenzylamino)-5-methylhexan-2-ol
25
[(2S,3S)-6a’]. Colorless oil; yield 16.9%; ½aꢃD ¼ ꢁ6 (c ¼ 0.50, MeOH); chemical
purity: 93.8%; optical purity (de): 99.5%; retention time: 5.423 min;1H NMR
(CDCl3, 400 MHz): d 0.31–0.33 (m, 2 H, CH2), 0.41–0.45 (m, 2 H, CH2), 0.69 (d,
J ¼ 6.4 Hz, 3 H, CH3), 0.90 (d, J ¼ 6.4 Hz, 3 H, CH3), 1.25–1.28 (m, 2 H, CH2),
1.85–1.89 (m, 1 H, CH), 2.10–2.11 (m, 1 H, CH), 2.60–2.80 (m, 3 H, CH2 and
CH), 3.60–3.70 (dd, J ¼ 13.76 Hz, 13.76 Hz, 4 H, 2 CH2), 3.85–3.87 (m, 1 H, CH),
7.26–7.32 (m, 10 H, ArH). 13C NMR (CDCl3, 100 MHz): d 139.41, 129.08, 128.39,
127.13, 70.35, 58.71, 53.98, 52.86, 35.37, 30.26, 26.16, 23.45, 22.88, 6.20, 5.93. IR
(KBr): v 3440, 3085, 3027, 2953, 2865, 1601, 1494, 1455, 1384, 1374, 1072, 748,
733, 699 cmꢁ1
.
(2R,3S)-3-(Dibenzylamino)-1-(isobutylamino)-5-methylhexan-2-ol [(2R,
25
3S)-6b]. Colorless oil; yield 56.9%; ½aꢃD ¼ ꢁ5 (c ¼ 0.50, MeOH); chemical purity:
91.9%; optical purity (de): 99.5%; retention time: 5.965 min; 1H NMR (CDCl3,
400 MHz): d 0.67 (d, J ¼ 6.4 Hz, 3 H, CH3), 0.89–0.93 (m, 9 H, 3 CH3), 1.24–1.26
(m, 2 H, CH2), 1.63–1.65 (m, 1 H, CH), 1.88–1.92 (m, 1 H, CH), 2.40–2.50 (m, 4
H, 2 CH2), 2.76–2.78 (m, 1 H, CH), 3.55–3.70 (dd, J ¼ 13.6 Hz,13.6 Hz, 4 H, 2
CH2), 3.94–3.96 (m, 1 H, CH), 7.25–7.40 (m, 10 H, ArH). 13C NMR (CDCl3,
100 MHz): d 139.94, 129.62, 128.78, 128.12, 68.60, 62.12, 57.37, 54.49, 52.93,
32.60, 28.37, 24.34, 22.36, 21.61, 20.57. IR (KBr): v 3316, 3084, 3026, 2954, 2926,
2869, 1598, 1494, 1453, 1385, 1365, 1118, 1073, 1028, 743, 698 cmꢁ1
.

AMINOALKYL HYDROXYETHYLAMINES
2913
(2S,3S)-3-(Dibenzylamino)-1-(isobutylamino)-5-methylhexan-2-ol [(2S,
25
3S)-6b’]. Colorless oil; yield 21.9%; ½aꢃD ¼ ꢁ18 (c ¼ 0.22, MeOH); chemical purity:
90.5%; optical purity (de): 99.5%; retention time: 5.184 min; 1H NMR (CDCl3,
400 MHz): d 0.70 (d, J ¼ 6.4 Hz, 3 H, CH3), 0.89–0.95 (m, 9 H, 3 CH3), 1.26–1.28
(m, 2 H, CH2), 1.63–1.66 (m, 1H, CH), 1.86–1.90 (m, 1 H, CH), 2.50–2.60 (m, 4
H, 2 CH2), 2.91–2.94 (m, 1 H, CH), 3.60 (dd, J ¼ 13.6 Hz, 13.6 Hz, 4 H, 2 CH2),
4.10–4.13 (m, 1 H, CH), 7.22–7.32 (m, 10 H, ArH). 13C NMR (CDCl3, 100 MHz):
d 140.14, 129.06, 128.20, 126.91, 67.14, 57.63, 56.08, 54.41, 53.19, 35.87, 26.81,
25.23, 23.36, 22.56, 20.35. IR (KBr): v 3452, 3058, 3021, 2953, 2927, 2867, 1600,
1561, 1491, 1454, 1383, 1374, 1109, 1063, 1022, 746, 698 cmꢁ1
.
(2R,3S)-1-(3-(Trifluoromethyl)benzylamino)-3-(dibenzylamino)-5-methyl-
25
hexan-2-ol [(2R,3S)-6c]. Colorless oil; yield 31.0%; ½aꢃD ¼ ꢁ27 (c ¼ 0.53, MeOH);
1
chemical purity: 96.6%; optical purity (de): 99.5%; retention time: 8.244 min; H
NMR (CDCl3, 400 MHz): d 0.75 (d, J ¼ 6.4 Hz, 3 H, CH3), 0.90 (d, J ¼ 6.8 Hz,
3 H, CH3), 1.25–1.27 (m, 2 H, CH2), 1.84–1.89 (m, 1 H, CH), 2.55–2.60 (m, 2 H,
CH2), 2.71–2.74 (m, 1 H, CH), 3.60–3.62 (m, 4 H, 2 CH2), 3.80–3.91 (m, 3 H,
CH2 and CH), 7.20–7.55 (m, 14 H, ArH). 13C NMR (CDCl3, 100 MHz): d 140.60,
140.12, 131.48, 128.96, 128.87, 128.49, 128.20, 126.94, 124.78, 123.96, 69.15, 57.24,
54.63, 52.97, 52.33, 35.60, 25.20, 23.17, 22.75. IR (KBr): v 3337, 3085, 3029, 2954,
2930, 2866, 1603, 1494, 1453, 1384, 1366, 1328, 1166, 1126, 1073, 909, 799, 747,
699 cmꢁ1
.
(2S,3S)-1-(3-(Trifluoromethyl)benzylamino)-3-(dibenzylamino)-5-methyl-
25
hexan-2-ol [(2S,3S)-6c’]. Colorless oil; yield 10.8%; ½aꢃD ¼ ꢁ9 (c ¼ 0.65, MeOH);
1
chemical purity: 91.3%; optical purity (de): 99.5%; retention time: 4.517 min; H
NMR (CDCl3, 400 MHz): d 0.82 (d, 3 H, J ¼ 6.2 Hz, CH3), 0.92 (d, J ¼ 6.4 Hz, 3
H, CH3), 1.37–1.39 (m, 2 H, CH2), 1.75–1.85 (m, 1 H, CH), 2.46–2.48 (m, 1 H,
CH), 2.60–2.75 (d, J ¼ 6.4 Hz, 2 H, CH2), 3.74–3.75 (m, 4 H, 2 CH2), 3.85–3.88
(m, 2 H, CH2), 3.97–4.01 (m, 1 H, CH), 7.25–7.55 (m, 14 H, ArH). 13C NMR
(CDCl3, 100 MHz): d 141.03, 139.23, 131.45, 129.01, 128.80, 128.63, 128.36,
127.13, 124.82, 123.67, 70.53, 58.13, 54.47, 53.92, 52.30, 35.35, 26.15, 23.35, 22.78.
IR (KBr): v 3326, 3086, 3028, 2955, 2928, 2867, 1602, 1494, 1453, 1384, 1365,
1328, 1164, 1125, 1073, 908, 798, 748, 700 cmꢁ1
.
(2R,3S)-1-(3-Methoxybenzylamino)-3-(dibenzylamino)-5-methylhexan-
25
2-ol [(2R,3S)-6d]. Colorless oil; Yield 31.8%; ½aꢃD ¼ ꢁ26 (c ¼ 0.52, MeOH);
Chemical purity: 93.8%; Optical purity (de): 99.5%; Retention time: 13.553 min;
1H NMR (CDCl3, 400 MHz): d 0.69 (d, J ¼ 6.4 Hz, 3 H, CH3), 0.89 (d, J ¼ 6.8 Hz,
3 H, CH3), 1.24–1.26 (m, 2 H, CH2), 1.85–1.88 (m, 1 H, CH), 2.53–2.57 (m, 2 H,
CH2), 2.72–2.75 (m, 1 H, CH), 3.58–3.76 (m, 6 H, 3 CH2), 3.80 (s, 3 H, CH3),
3.89–3.91 (m, 1 H, CH), 6.81–6.93 (m, 3 H, ArH), 7.22–7.34 (m, 11 H, ArH). 13C
NMR (CDCl3, 100 MHz): d 159.70, 141.57, 140.25, 129.42, 128.98, 128.16, 126.87,
120.36, 113.54, 112.51, 68.67, 57.24, 55.17, 54.59, 53.41, 52.34, 35.58, 25.04, 23.32,
22.60. IR (KBr): v 3295, 3083, 3054, 3027, 2952, 2865, 2834, 1601, 1586, 1492,
1454, 1379, 1362, 1263, 1155, 1048, 1027, 782, 746, 698 cmꢁ1
.
(2S,3S)-1-(3-Methoxybenzylamino)-3-(dibenzylamino)-5-methylhexan-
25
2-ol [(2 S,3S)-6d’]. Colorless oil; yield 12.0%; ½aꢃD ¼ ꢁ10 (c ¼ 0.07, MeOH);

2914
J. WU ET AL.
1
chemical purity: 91.1%; optical purity (de): 99.5%; retention time: 5.344 min; H
NMR (CDCl3, 400 MHz): d 0.78 (d, J ¼ 6.4 Hz, 3 H, CH3), 0.89 (d, J ¼ 6.4 Hz, 3
H, CH3), 1.35–1.36 (m, 2 H, CH2), 1.86–1.89 (m, 1 H,CH), 2.61–2.63 (m, 2 H,
CH2), 2.81–2.83 (m, 1 H, CH), 3.50–3.90 (m, 9 H, CH3 and 3 CH2), 4.19–4.20 (m,
1 H, CH), 6.80–6.90 (m, 3 H, ArH), 7.20–7.35 (m, 11 H, ArH). 13C NMR (CDCl3,
100 MHz): d 159.66, 141.53, 139.41, 129.36, 129.04, 128.37, 126.45, 120.49, 113.73,
112.98, 70.17, 58.41, 55.18, 54.44, 53.47, 52.38, 34.89, 26.01, 23.82, 22.73. IR
(KBr): v 3304, 3058, 3025, 2951, 2864, 2834, 1601, 1585, 1489, 1465, 1454, 1384,
1362, 1263, 1153, 1046, 1028, 785, 747, 698 cmꢁ1
.
(2R,3S)-1-(Cyclopropylamino)-3-(dibenzylamino)-4-phenylbutan-2-ol [(2R,
25
3S)-6e]. Colorless oil; yield 38.0%; ½aꢃD ¼ ꢁ7 (c ¼ 0.96, MeOH); chemical purity:
91.4%; optical purity (de): 99.5%; retention time: 8.595 min; 1H NMR (CDCl3,
400 MHz): d 0.24–0.26 (m, 2 H, CH2), 0.40–0.45 (m, 2 H, CH2), 2.05–2.06 (m, 1
H, CH), 2.60–2.70 (m, 1 H, CH2), 2.82–3.06 (m, 4 H, 2 CH2), 3.59–3.72 (m, 4 H,
2 CH2), 3.85–3.90 (m, 1 H, CH), 7.17–7.26 (m, 15 H, ArH). 13C NMR (CDCl3,
100 MHz): d 141.44, 139.91, 129.57, 128.81, 128.18, 128.14, 126.81, 125.72, 69.14,
61.99, 54.54, 52.80, 32.58, 30.28, 6.81, 5.93. IR (KBr): v 3314, 3084, 3061, 3025,
2928, 2849, 2801, 1602, 1582, 1494, 1453, 1372, 1104, 1072, 1027, 743, 698 cmꢁ1
.
(2S,3S)-1-(Cyclopropylamino)-3-(dibenzylamino)-4-phenylbutan-2-ol
25
[(2S,3S)-6e’]. Colorless oil; yield 15.2%; ½aꢃD ¼ ꢁ3 (c ¼ 0.40, MeOH); chemical
purity: 90.3%; optical purity (de): 99.5%; retention time: 5.651 min; 1H NMR
(CDCl3, 400 MHz): d 0.41–060 (m, 4 H, 2 CH2), 2.10 (m, 1 H, CH), 2.75–3.10 (m,
5 H, CH and 2 CH2), 3.40–3.71 (m, 4 H, 2 CH2), 4.01–4.03 (m, 1 H, CH),
7.20–7.35 (m, 15 H, ArH). 13C NMR (CDCl3, 100 MHz): d 140.50, 140.04, 129.59,
128.69, 128.10, 127.87, 127.06, 125.76, 71.32, 61.80, 54.87, 52.06, 32.93, 31.72,
6.60, 6.14. IR (KBr): v 3312, 3085, 3061, 3025, 2925, 2853, 2804, 1602, 1557, 1494,
1454, 1364, 1125, 1072, 1027, 745, 698 cmꢁ1
.
(2R,3S)-3-(Dibenzylamino)-1-(isobutylamino)-4-phenylbutan-2-ol [(2R,
25
3S)-6f]. Colorless oil; yield 30.0%; ½aꢃD ¼ ꢁ13:1 (c ¼ 0.50, MeOH); chemical purity:
90.2%; optical purity (de): 99.5%; retention time: 5.417 min; 1H NMR (CDCl3,
400 MHz): d 0.86–0.89 (m, 6 H, 2 CH3), 1.69–1.71 (m, 1 H, CH), 2.35–2.50 (m, 3
H, CH and CH2), 2.75–3.08 (m, 4 H, 2 CH2), 3.58–3.70 (m, 4 H, 2 CH2), 3.91–3.93
(m, 1 H, CH), 7.15–7.31 (m, 15 H, ArH). 13C NMR (CDCl3, 100 MHz): d 141.63,
140.08, 129.77, 128.98, 128.36, 128.32, 126.98, 125.89, 69.30, 62.17, 54.71, 53.01,
32.78, 30.45, 20.6. IR (KBr): v 3312, 3084, 3061, 3026, 2929, 2835, 2801, 1602,
1582, 1494, 1453, 1384, 1374, 1245, 1121, 1073, 1028, 973, 825, 743, 698 cmꢁ1
.
(2S,3S)-3-(Dibenzylamino)-1-(isobutylamino)-4-phenylbutan-2-ol [(2S,
25
3S)-6f’]. Colorless oil; yield 10.4%; ½aꢃD ¼ ꢁ5:8 (c ¼ 0.50, MeOH); chemical purity:
90.0%; optical purity (de): 99.5%; retention time: 4.358 min; 1H NMR (CDCl3,
400 MHz): d 0.75–0.90 (m, 6 H, 2 CH3), 1.50 (m, 1 H, CH), 2.30–3.10 (m, 7 H, 3
CH2 and CH), 3.61–3.68 (m, 4 H, 2 CH2), 4.29–4.32 (m, 1 H, CH), 7.16–7.31 (m,
15 H, ArH). 13C NMR (CDCl3, 100 MHz): d 142.05, 141.20, 129.99, 129.30,
128.51, 128.48, 127.08, 126.21, 71.09, 62.54, 54.99, 53.85, 33.45, 29.85, 20.6. IR
(KBr): v 3299, 3085, 3061, 3026, 2928, 2835, 2801, 1601, 1582, 1494, 1453, 1381,
1369, 1244, 1121, 1072, 1027, 973, 827, 743, 699 cmꢁ1
.

AMINOALKYL HYDROXYETHYLAMINES
2915
(2R,3S)-3-(Dibenzylamino)-4-phenyl-1-(3-(trifluoromethyl)benzylamino)-
25
butan-2-ol [(2R,3S)-6g]. Colorless oil; yield 29.4%; ½aꢃD ¼ ꢁ10 (c ¼ 0.97, MeOH);
1
chemical purity: 89.4%; optical purity (de): 99.5%; retention time: 17.669 min; H
NMR (CDCl3, 400 MHz): d 2.60–2.63 (m, 1 H, CH), 2.75–3.10 (m, 4 H, 2 CH2),
3.67–3.78 (m, 4 H, 2 CH2), 3.82–3.85 (m, 1 H, CH), 7.15–7.56 (m, 19 H, ArH).
13C NMR (CDCl3, 100 MHz): d 141.34, 140.08, 138.99, 131.29, 129.16, 129.02,
128.56, 128.45, 128.39, 127.19, 126.16, 124.69, 123.57, 69.87, 61.35, 54.10, 53.26,
52.31, 31.75. IR (KBr): v 3299, 3062, 3027, 2924, 2839.99, 2801, 1601, 1582, 1494,
1453, 1328, 1164, 1124, 1072, 909, 798, 748, 699 cmꢁ1
.
(2S,3S)-3-(Dibenzylamino)-4-phenyl-1-(3-(trifluoromethyl)benzylamino)-
25
butan-2-ol ((2S,3S)-6g’). Colorless oil; yield 12.6%; ½aꢃD ¼ þ8:2 (c ¼ 1, MeOH);
1
Chemical purity: 92.2%; Optical purity (de): 99.5%; Retention time: 3.517 min; H
NMR (CDCl3, 400 MHz): d 2.32–2.35 (m, 1 H, CH), 2.55–2.73 (m, 2 H, CH2),
3.00–3.15 (m, 2 H, CH2), 3.42 (d, J ¼ 6.8 Hz, 2 H, CH2), 3.55–3.70 (m, 4 H,
2CH2), 3.95–3.99 (m, 1 H, CH), 7.20–7.50 (m, 19 H, ArH). 13C NMR (CDCl3,
100 MHz): d 141.39, 140.10, 138.99, 131.31, 129.15, 129.05, 128.58, 128.47, 128.39,
127.21, 126.18, 124.69, 123.60, 71.25, 61.36, 54.12, 53.26, 52.34, 31.79. IR (KBr): v
3291, 3062, 3027, 2925, 2843, 2797, 1601, 1582, 1494, 1453, 1328, 1164, 1125,
1073, 907, 798, 748, 699 cmꢁ1
.
(2R,3S)-3-(Dibenzylamino)-1-(3-methoxybenzylamino)-4-phenylbutan-
25
2-ol [(2R,3S)-6h]. Colorless oil; yield 40.8%; ½aꢃD ¼ ꢁ11:2 (c ¼ 0.55, MeOH);
1
chemical purity: 89.5%; optical purity (de): 99.5%; retention time: 13.425 min; H
NMR (CDCl3, 400 MHz): d 2.50–2.53 (m, 1 H, CH), 2.79–3.09 (m, 4 H, 2 CH2),
3.57–3.70 (m, 6 H, 3 CH2), 3.80 (s, 3 H, CH3), 3.89–3.90 (m, 1 H, CH), 6.82–6.86
(m, 3 H, ArH), 7.12–7.31 (m, 16 H, ArH). 13C NMR (CDCl3, 100 MHz): d
159.65, 140.76, 140.03, 139.22, 129.27, 129.02, 128.48, 128.39, 128.18, 127.15,
126.10, 113.46, 112.75, 69.52, 61.50, 55.17, 53.53, 53.01, 52.42, 31.52. IR (KBr): v
3289, 3058, 3021, 2925, 2830, 1598, 1586, 1495, 1453, 1258, 1040, 1026, 781, 748,
698 cmꢁ1
.
(2S,3S)-3-(Dibenzylamino)-1-(3-methoxybenzylamino)-4-phenylbutan-
25
2-ol ((2S,3S)-6h’). Colorless oil; yield 14.5%; ½aꢃD ¼ þ3 (c ¼ 0.49, MeOH); chemi-
1
cal purity: 94.4%; optical purity (de): 99.5%; retention time: 4.921 min; H NMR
(CDCl3, 400 MHz): d 2.22–2.27 (m, 1 H, CH), 2.60–2.96 (m, 4 H, 2 CH2),
3.56–3.67 (m, 6 H, 3 CH2), 3.72 (s, 3 H, CH3), 3.95–3.97 (m, 1 H, CH), 6.65–6.75
(m, 3 H, ArH), 7.02–7.20 (m, 16 H, ArH). 13C NMR (CDCl3, 100 MHz): d
159.61, 140.18, 139.94, 139.19, 129.25, 129.01, 128.47, 128.38, 128.16, 127.14,
120.48, 113.43, 112.68, 70.92, 61.78, 55.15, 53.57, 53.02, 52.43, 31.53. IR (KBr): v
3299, 3060, 3026, 2924, 2834, 1601, 1585, 1493, 1454, 1264, 1154, 1043, 1028, 784,
747, 698 cmꢁ1
.
ACKNOWLEDGMENTS
This work is supported by National Natural Science Foundation of China
(General Program) (Grant No. 81172924) and Beijing Municipal Natural Science
Foundation of China (General Program) (Grant No. 7112106).

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J. WU ET AL.
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