Chelation controlled reduction of N-protected β-amino ketones toward the synthesis of HPA-12 and analogues

Article abstract of DOI:10.1016/j.tetasy.2015.04.016

Diastereoselective reduction of N-protected β-amino ketones does not proceed effectively under the conditions used for chelation controlled reductions of N-alkyl β-amino ketones. A thorough analysis of various conditions required for the stereoselective r

Full text of DOI:10.1016/j.tetasy.2015.04.016

Tetrahedron: Asymmetry 26 (2015) 623–631
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chelation controlled reduction of N-protected b-amino ketones
toward the synthesis of HPA-12 and analogues
⇑
Shibin Chacko, Mrinal Kalita, Ramesh Ramapanicker
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Diastereoselective reduction of N-protected b-amino ketones does not proceed effectively under the
conditions used for chelation controlled reductions of N-alkyl b-amino ketones. A thorough analysis of
Received 24 March 2015
Accepted 30 April 2015
Available online 19 May 2015
various conditions required for the stereoselective reduction of
c-aryl-c-oxo-b-amino alcohols is
reported. The products of the syn-selective reduction are used for the preparation of a ceramide traffick-
ing inhibitor HPA-12 and analogues.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
do not undergo chelation controlled reduction under conditions
which can be employed for the reduction of N-alkyl b-amino
Amino alcohols and amino diols are structural units of various
bioactive molecules, natural products, chiral ligands, and chiral
auxiliaries.1 Various methods are available for the synthesis of
amino alcohols, which include organocatalysis, Mannich type reac-
tions, rearrangement of isoxazolidines, Corey–Link reactions, and
crystallization induced asymmetric transformations.2 1,3-Amino
alcohols are most commonly synthesized by the reduction of
b-amino ketones. Various reagents are available for the chelation
controlled reduction of such compounds, which include
LiAlH4/TiCl4, DIBAL-H/ZnCl2,3 and NaBH4/AcOH.4 It has been shown
that SmI2 can be used for the directed reduction of b-amino
ketones to syn- or anti-1,3-amino alcohol derivatives.5 N-Sulfinyl
b-amino ketones can be selectively reduced to either syn- or anti-
1,3-amino alcohols using Li(t-BuO)3AlH and LiEt3BH, respectively.6
ketones. Herein we report the results of our studies on the
diastereoselective reduction of N-Boc derivatives of -aryl- -oxo-
b-amino alcohols. The diamino diol derivatives synthesized are
used for the synthesis of a ceramide trafficking inhibitor HPA-12
and its analogues.
c
c
The transport of ceramide, a component of sphingomyelin, from
endoplasmic reticulum to the Golgi apparatus is mediated by a
68 kDa cytosolic protein CERT. The effective transport of ceramide
leading to the synthesis of sphingolipids is vital, since misregula-
tion of this process could lead to a variety of diseases. As one of
the mediators for sphingolipid homeostasis, CERT possibly has a
role in many of the resulting disease states.9 (1R,3R)-N-(3-
Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecamide (HPA-12)
was found to be an inhibitor of CERT dependent ceramide traffick-
ing and is the first specific inhibitor of sphingomyelin biosynthesis
in mammalian cells. However, in a recent report on the synthesis of
HPA-12 by Berkeš et al., the potent molecule was shown to have a
(1R,3S)-configuration, which is contrary to the initial reports.10 The
revised structure was confirmed using X-ray crystallographic anal-
ysis by Kobayashi et al.11 Thus the revised structure of HPA-12 has
a syn-orientation of the amino and hydroxyl groups and hence
methodologies for its synthesis should rely on syn-stereoselective
reduction of the corresponding oxo-amino compounds. Recent
reports on the synthesis of the (1R,3S) derivative of HPA-12 include
a tandem approach using (S)-Wynberg lactone by Snowden et al.,12
Ru-catalyzed asymmetric rearrangement of isoxazolidines
reported by Kang et al.,13 and the synthesis of HPA-12 and its ana-
logues from serinol by Arenz et al.14 Very recently, Delgado et al.
L
-Selectrides can also be used for the stereoselective reduction of
various b-amino ketones to the corresponding 1,3-amino alcohols.7
The chelation controlled stereoselective reduction of N-alkyl b-
amino ketones using catalytic amounts of metal salts and equiva-
lent amounts of NaBH4 is a reliable route for the synthesis of
syn-c
-amino alcohols.8 The reduction proceeds through a tight
transition state, where the metal atoms are coordinated to the car-
bonyl oxygen and the amino group. The ability of the amino group
to coordinate tightly with the metal ions is critical to the selectivity
achieved in such reductions. b-Amino ketones are not necessarily
obtained as the N-alkyl or free amino derivatives in a synthesis
and are quite often protected as a carbamate or an amide. Such
compounds with reduced nucleophilicity on the nitrogen atom
reported a straightforward synthesis of HPA-12 from
D-aspartic
⇑
Corresponding author.
E-mail address: rameshr@iitk.ac.in (R. Ramapanicker).
acid,15 while Genisson et al. have used crystallization induced
http://dx.doi.org/10.1016/j.tetasy.2015.04.016
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

624
S. Chacko et al. / Tetrahedron: Asymmetry 26 (2015) 623–631
asymmetric transformation technology for the multi-gram scale
synthesis of HPA 12 and its isomers.16
synthesized three analogous derivatives 3h–j from L-threonine
using the same method (Scheme 2).
With access to the required b-amino ketones as the N-Boc
derivatives in hand, we looked at available procedures for the stere-
oselective reduction of such compounds. Various conditions are
available in the literature to achieve either syn- or anti-selective
reduction of b-amino ketones. However, all of the reported proce-
dures are only effective with N-alkyl derivatives, which would allow
chelation of the amino group to a metal ion effectively. Berkeš et al.
2. Results and discussion
We have reported an effective synthesis of enantiopure
-oxo- -amino acids starting from serine and aromatic
dithianes.17 One of the key intermediates of the synthesis is
-aryl- -oxo-b-amino alcohols 1, which upon reduction provide
c-aryl-
c
a
c
c
have reported the diastereoselective reduction of c-oxo-c-aryl-a-
1-aryl-3-amino-1,4-diols. A syn-selective reduction of 1 would
provide intermediates 2, which could be used for the synthesis of
HPA-12 and its analogues (Scheme 1).
amino acids, which are structurally very similar to 1, using NaBH4
in the presence of MnCl2Á4H2O.8c We hoped that compound 1,
would undergo selective syn-reduction under such conditions that
would provide the amino diols 2 required for the preparation of
HPA-12 and related compounds. The reduction of 1a using NaBH4
(2 equiv) in the presence of a catalytic amount of MnCl2Á4H2O
(20 mol %), at room temperature, as reported, did not generate any
diastereoselectivity. As explained by Berkeš et al., the key criterion
for achieving a syn-selective reduction under such conditions is
the preferential reduction of the chelated amino ketone to the
reduction of non-complexed amino ketone by NaBH4. It is not
surprising that the N-benzyl derivatives of the amino ketones
used by Berkeš et al., coordinated better with Mn2+ and provided a
tighter transition state required for the chelation controlled
reduction than the Boc protected amino group in 1a. We assumed
that using stoichiometric or more amounts of the metal salt and
the addition of NaBH4 only after complexation of 1a with the
Mn2+ could increase the selectivity. However the selectivity was
only 11:9 in favor of the syn-isomer 2a when the reaction was
carried out at 30 °C (2 equiv MnCl2Á4H2O and 2 equiv of NaBH4,
added after 20 min). Decreasing the temperature to À5 °C had a
positive impact on selectivity for the formation of 2a. We
achieved a selectivity of 16:4; carrying out the reaction at À50 °C
or À80 °C and in the presence of 2 equiv of MnCl2Á4H2O, did not
improve the selectivity. It was obvious from our observations that
an improved selectivity could only be achieved at lower
temperatures and in the presence of excess amount of the metal
salt (Table 1).
O
NHBoc
OH
OH
NHBoc
OH
diastere selective
reduction
1
2
X
X
O
CH3
OH HN
8
OH
HPA-12 and analogues
X
Scheme 1. Strategy for the synthesis of HPA-12 and its analogues.
To begin with, we synthesized
starting from an iodide derivative of
c
-aryl-
L
c-oxo-b-amino alcohols
-serine and aromatic dithi-
anes in excellent overall yields, following a strategy that we had
developed (Scheme 2).17 The iodide derivative was coupled with
aryl dithianes using n-BuLi (THF, À20 °C) and the resulting dithiane
derivatives 3 were treated with trifluoroacetic acid (7% in CH3OH)
to give the amino alcohol derivatives 4. Hydrolysis of the dithiane
group in 4 (I2, NaHCO3) yielded the required c-aryl-c-oxo-b-amino
alcohols 1. We have already shown that these transformations pro-
ceed without a loss of enantiopurity and that the amino alcohols 1
retain the configuration of the serine derivative used.17 We also
It is also known in the literature that various other metal salts
such as Zn2+ coordinates with b-amino ketones to give syn-selec-
tive reductions. Since the results obtained using MnCl2ÁH2O were
not satisfactory, we decided to carry out a thorough analysis of
the reduction of 1a to 2a in the presence of various Lewis acids.
R
R
O
O
S
S
S
I
X
Y
N
X
Y
N
S
Boc
Table 1
Boc
3
Diastereoselective reduction of 1a with MnCl2Á4H2O and NaBH4
nBuLi, -20 ºC, THF
OH
NHBoc
OH
7% TFA
CH3OH
2a
syn-
O
NHBoc
OH
MnCl2·4H2O
+
R
HO
R
HO
NaBH4, CH3OH
1a
O
OH
NHBoc
OH
S
S
I2, NaHCO3
X
X
BocHN
BocHN
CH3CN-H2O
Y
1
4
2a
anti-
Y
Entry
Equiv of MnCl2Á4H2O
0
0.20
1
2
2
2
2
Temperature (°C)
syn/antia Yieldb (%)
3a
3b
4a
4b
1a
1b
R = H, X = H, Y = H:
(85%),
(83%),
(93%),
(94%),
(84%)
(85%)
R = H, X = H, Y = CH3:
R = H, X = H, Y = CH(CH3)2:
R = H, X = H, Y = OCH3:
R = H, X = OCH3, Y = OCH3:
R = H, X = H, Y = F:
1
2
3
4
5
7
8
30
30
30
30
0
50:50
50:50
50:50
55:45
60:40
80:20
80:20
97
96
98
94
96
95
94
3c (85%), 4c (89%), 1c (79%)
3d
3e
4d
4e
1d
1e
(85%),
(87%),
(89%),
(94%),
(80%)
(84%)
3f (80%), 4f (93%), 1f (88%)
3g
3h
4g
4h
1g
1h
R = H, X = Cl, Y = H:
R = CH3, X= H, Y = H:
R = CH3, X= H, Y = OCH3:
(86%),
(76%),
(89%),
(85%),
(84%)
(94%)
À50
3i ( 81%), 4i (89% ), 1i (95%)
À80
3j
4j
1j
(96%)
R = CH3, X= OCH3, Y = OCH3: (80%),
(86%),
As determined from 1H NMR spectra.
Isolated yields of the mixture of diastereomers.
a
b
Scheme 2. Synthesis of c-aryl-c-oxo-b-amino alcohols 1.

S. Chacko et al. / Tetrahedron: Asymmetry 26 (2015) 623–631
625
-
Table 2
H
BH4
O
HO
Diastereoselective reduction of 1a with various Lewis acids
Ce3+
OH
NHBoc
OH
Ar
N
Boc
syn-2a
O
NHBoc
OH
Figure 1. Proposed transition state for the chelation controlled reduction of 1a.
Lewis acid (1 equiv)
NaBH4, 0 ºC, CH3OH
+
1a
OH
NHBoc
OH
ketones 1b–j under the same conditions (1 equiv CeCl3, 2 equiv
NaBH4, 30 °C, CH3OH). The diastereoselectivity was high and the
syn-isomers were formed preferentially (Table 3). The best selectiv-
ity was achieved for the reduction of 1e to 2e, which proceeded with
100% selectivity while the anti-diastereomer was not detected
(entry 5). Both isomers, when formed could be isolated and charac-
terized. All of the major isomers had similar 1H NMR patterns and
their syn-structure was confirmed unambiguously by the single
crystal X-ray structure analysis of a hydrochloride salt of the amine
derived from 2f, formed by the deprotection of the N-Boc using HCl
in ethyl acetate (Fig. 2).18 The amino ketones 1h and 1i (entries 8 and
anti-2a
Entry
Lewis acid
syn/antia
Yieldb (%)
1
2
3
4
5
6
7
8
None
50:50
97
96
60
—
MnCl2Á4H2O
BF3ÁEt2O
ZnCl2
CuI
CeCl3
60:40
60:40c
No reaction
No reaction
85:15
—
98
97
—
CeCl3Á7H2O
75:25
Metal triflatesd
No reactione
9), derived from
L-threonine underwent more selective reduction
a
b
c
As determined from 1H NMR spectra.
Isolated yields of the mixture of diastereomers.
CH2Cl2 is the solvent used.
than 1a and 1d (their analogues were derived from
L
-serine, entries
1 and 4). The diastereoselectivity in the reduction of 1j (entry 10)
was very high, although it was not 100% as with 1e (entry 5). The
high diastereoselective reduction of derivatives formed from
d
Triflates used are Sm(OTf)3, Bi(OTf)3, Fe(OTf)3, Sc(OTf)3, Sn(OTf)3, Yb(OTf)3,
Ag(OTf)3, In(OTf)3, La(OTf)3, Zn(OTf)3, Cu(OTf)2.
e
Cyclic ketal 5 was formed as the product.
Table 3
The results of our attempts on the stereoselective reduction of 1a
with different Lewis acids (1 equiv) and NaBH4 (2 equiv) are given
in Table 2. The best results were obtained with CeCl3 and the syn-
selectivity achieved in this case was better than those achieved
using MnCl2Á4H2O and BF3ÁEt2O (carried out in CH2Cl2). It was
interesting to note that the reduction did not happen in the pres-
ence of ZnCl2 and CuI. It was found that in the presence of ZnCl2
and CuI, even a non-selective reduction of 1a could not be achieved
with excess of NaBH4 (4 equiv). Use of a number of metal triflates
for these reduction reactions led to the formation of a cyclic ketal 5,
which did not undergo reduction. The formation of 5 from 1a was
observed upon the addition of metal triflates even in the absence of
NaBH4 (Scheme 3).
syn-Selective reduction of 1–2
O
NHBoc
OH
OH
NHBoc
OH
X
CeCl3
X
Y
NaBH4, CH3OH
R
R
1
2
Y
Entry
1(X, Y, R)
Yield of 2a (%)
syn/anti ratio for 2
Crudeb
Isolated
1
2
3
4
5
6
7
8
9
10
1a (X = H, Y = H, R = H)
92
95
94
93
91
90
93
94
94
92
85:15
85:15
85:15
80:20
>99:1
85:15
80:20
90:10
95:05
95:05
87:13
86:14
87:13
84:16
100:0
85:15
82:18
87:13
92:08
95:05
1b (X = H, Y = CH3, R = H)
1c (X = H, Y = (CH3)2CH, R = H)
1d (X = H, Y = OCH3, R = H)
1e (X = OCH3, Y = OCH3, R = H)
1f (X = H, Y = F, R = H)
1g (X = Cl, Y = H, R = H)
O
NHBoc
OH
O
1h (X = H, Y = H, R = CH3)
1i (X = H, Y = OCH3 R = CH3)
1j (X = OCH3, Y = OCH3 R = CH3)
NHBoc
metal triflates
CH3OH
OMe
a
1
5
Combined yield for both the diastereomers.
As determined from 1H NMR spectra.
b
Scheme 3. Formation of cyclic ketal 5 from 1a in the presence of metal triflates.
Having established that CeCl3 was the best Lewis acid to cat-
alyze the syn-selective reduction of 1a, we attempted to increase
the selectivity by varying the temperature and equivalents of
CeCl3 used. However, we did not find any noticeable increment
in selectivity for the reduction of 1a at lower temperatures and
on using up to 2 equiv of CeCl3. It is to be assumed that 1 equiv
of CeCl3 at 30 °C quantitatively forms a chelate with 1a and the
reduction proceeds with a preference for the formation of the
syn-isomer through a transition state similar to the one proposed
by Berkeš et al. (Fig. 1).8c The preference for the major isomer
results from the preferred orientation of the hydroxymethyl
group to an equatorial position. The structure of the major
diastereomer was confirmed to be that of 2a by matching NMR
spectra of the diastereomers with those reported.
Having found suitable conditions for the diastereoselective
reduction of 3-(tert-butyloxycarbonylamino)-4-hydroxy-1-phenyl
butan-1-one 1a to (1S,3R)-3-(tert-butyloxycarbonylamino)-1-
phenylbutane-1,4-diol 2a, we reduced the remaining b-amino
Figure 2. ORTEP diagram of the hydrochloride salt derived from 2f (displacement
ellipsoids are shown at 50% probability level), confirming the syn-orientation of amino
and hydroxyl groups for the major diastereomer formed by the reduction of 1f.13

626
S. Chacko et al. / Tetrahedron: Asymmetry 26 (2015) 623–631
OH
NHBoc
OH
3. Conclusion
Y
X
We have developed a very effective method for the diastereose-
lective reduction of N-Boc derivatives -aryl- -oxo-b-amino
2
c
c
alcohols to give the corresponding syn-3-amino-1-arylbutane-1,4-
diols using CeCl3 and NaBH4 (Luche reagent) in CH3OH. The reported
methods for the chelation controlled reduction of such compounds
do not work with the N-protected derivatives. The use of 1 equiv
of CeCl3 allowed for chelation controlled reduction even when the
amino group is rendered electron deficient through Boc protection;
the diastereoselectivity achieved was generally high and almost
complete in at least one of the examples studied. Together with a
2. CH3(CH2)10COCl
NaHCO3, THF, 0 ºC
1. HCl (10%),
EtOAc, 0 ºC
O
OH HN
9
Y
OH
6
X
methodology we have developed for the synthesis of c-aryl-c-oxo-
6a
6b
X = H, Y = H:
(70%)
(66%)
b-amino alcohols, we were able to obtain the CERT dependent cera-
mide trafficking inhibitor HPA-12 and a number of its analogues in
good yields using very simple synthetic transformations.
X = CH3, Y = H:
X = CH(CH3)2, Y = H:
X = F, Y = H:
6c (64%)
6f
6g
(70%)
(59%)
X = H, Y = Cl:
4. Experimental
Scheme 4. Synthesis of HPA-12 6a and its analogues from 2.
4.1. General information
L
-threonine could be attributed to the increased preference of the
hydroxyethyl group (compared to the hydroxymethyl group of
those derived from -serine) to be at the equatorial position in the
All chemicals were purchased from commercial sources and
were used without further purification. 1H and 13C NMR spectra
were recorded either on a 400 MHz (100 MHz for 13C) or on a
500 MHz (125 MHz for 13C) JEOL-Lambda NMR spectrometer at
25 °C. The 19F NMR spectra were recorded on a 470 MHz machine
at 25 °C. The 1H NMR signals are referenced to TMS (d = 0.00 ppm)
and the 13C NMR peaks are referenced to residual CHCl3 signal
(d = 77.0 ppm). Chemical shifts are reported in parts per million
and coupling constants in Hz. The multiplicities are assigned as s
(singlet), d (doublet), t (triplet), br s (broad singlet), dd (double
doublet) and m (multiplet). High-resolution mass spectra were
obtained using a Waters Q/Tof Premier Micromass HAB213 spec-
trometer with an ESI source. IR spectra were recorded on Bruker
Vector 22 FTIR instrument, optical rotations were recorded at
L
transition state shown in Figure 1.
The structures of 2a and 2b were confirmed by comparing the
specific rotations and 13C NMR with reported compounds.19
The amino diol 2a was converted into HPA-12 6a in two steps.
The N-Boc groups were removed by treating 2a with HCl (10%) in
ethyl acetate and the crude hydrochloride salt was acylated using
lauryl chloride (NaHCO3, THF, 0 °C) to give 6a in 70% overall yield
(Scheme 4) and the structure was confirmed by comparing the
spectroscopic data with those reported in the literature.10,12 This
provides an easy and effective route for the synthesis of HPA-12
starting from benzaldehyde and L-serine. The other amino alcohols
2b–g were also treated similarly to give analogues of 6a
(Scheme 4). However, amino diols 2d and 2e yielded a complex
reaction mixture when treated with HCl to remove the Boc group.
It is interesting to note that both these substrates decomposed in
commercial CDCl3 upon standing overnight. The electron rich aro-
matic rings in the above compounds could lead to the elimination
of the hydroxyl group even in the presence of mild acids, making
the selective deprotection of the Boc group difficult. Our efforts
to use different acids at varying strengths to deprotect the Boc
group in 2d and 2e selectively were unsuccessful. As an effort to
understand this unexpected reactivity, we treated 2e with 2%
TFA in methanol. Even under such mild acidic conditions, 2e
underwent SN1 reactions to give the solvolysis product 7 and an
intramolecular substitution product 8 as mixtures of diastere-
omers (Scheme 5).
25 °C on
a Rudolph Research Analytical Autopol—IV digital
polarimeter and melting points were recorded on a DBK automatic
programmable digital instrument. Column chromatography was
done using 100–200 mesh silica gel and appropriate mixtures of
petroleum ether and ethyl acetate were used as eluent.
4.2. Synthesis of
c-aryl-c-oxo-b-amino alcohols
The -aryl-c-oxo-b-amino alcohols were prepared according to
c
the previously reported methodology,12 where the characteriza-
tion data for the b-amino ketones 1–g along with those for the
intermediates 3a–g and 4a–g are available.
4.2.1. (4R,5R)-3-(tert-Butyloxycarbonyl)-2,2,5-trimethyl-4-((2-
phenyl-1,3-dithian-2-yl)methyl)oxazolidine 3h
Column chromatography (95:5 petroleum ether/EtOAc); clear
oil (0.955 g, 76%); [
a]
25 = +4.2 (c 0.700, CHCl3); IR (thin film):
D
2977, 2932, 1697, 1384, 1084 cmÀ1
;
1H NMR (CDCl3, 500 MHz):
OH
OH
mixture of rotamers: d = 7.95–7.94 (m, 2H), 7.39–7.36 (m, 2H),
7.26–7.24 (m, 1H), 4.00–3.82 (m, 1H), 3.41–3.25 (m, 1H), 2.72–
2.57 (m, 4H), 2.49–2.16 (m, 2H), 1.92–1.89 (m, 2H), 1.50, 1.37 (s,
15H), 0.98–0.91 (m, 3H) ppm; 13C NMR (CDCl3, 125 MHz):
d = 151.7, 151.6, 141.4, 141.3, 129.0, 128.9, 127.3, 93.6, 92.8, 80.5,
80.1, 60.1, 59.9, 57.9, 57.5, 49.5, 48.6, 29.0, 28.8, 28.5, 28.4, 28.2,
27.6, 27.5, 27.3, 24.9, 21.6 ppm; HRMS (ES): m/z calcd for
H3CO
NHBoc
H3CO
2e
TFA (2%), CH3OH
22H33NO3S2 [M+Na+]: 446.1800, found: 446.1809.
OH
C
O
OCH3
NHBoc
H3CO
H3CO
NHBoc
+
4.2.2. (4R,5R)-3-(tert-Butyloxycarbonyl)-2,2,5-trimethyl-4-((2-
(4-methoxyphenyl)-1,3-dithian-2-yl)methyl)oxazolidine 3i
Column chromatography (93:7 petroleum ether/EtOAc); clear
H3CO
H3CO
8
7
oil (1.100 g, 81%); [
a]
D
25 = À12.9 (c 0.610, CHCl3); IR (thin film):
Scheme 5. Acid sensitivity of the electron rich amino diol 2e.

S. Chacko et al. / Tetrahedron: Asymmetry 26 (2015) 623–631
627
2977, 2931, 1697, 1504, 1385, 1251, 1167, 1085 cmÀ1
;
1H NMR
4.2.7. (3R,4R)-3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-
phenylpentan-1-one 1h
(CDCl3, 500 MHz): mixture of rotamers: d = 7.85–7.79 (m, 2H),
6.90–6.87 (m, 2H), 4.40–4.38 (m, 1H), 3.80 (s, 3H), 3.59–3.42
(m, 1H), 2.75–2.62 (m, 4H), 2.35–2.26 (m, 2H), 1.94–1.89
(m, 2H), 1.44, 1.37 (s, 15H), 1.01 (d, J = 6.65 Hz, 3H) ppm; 13C
NMR (CDCl3, 125 MHz): d = 158.7, 15.5, 133.2, 130.4, 130.2,
129.9, 114.0, 79.3, 57.1, 55.4, 55.3, 52.7, 46.7, 31.0, 29.7, 29.4,
28.8, 28.4, 28.3, 27.7, 27.5, 25.0, 21.7, 19.9 ppm; HRMS (ES): m/z
calcd for C23H35NO4S2 [M+Na+]: 476.1905, found: 476.1905.
Column chromatography (65:35 petroleum ether/EtOAc); solid
(0.550 g, 94%); mp: 64–66 °C; [
a
]
D = À2.2 (c 0.900, CHCl3); IR
(KBr): 3380, 2975, 2931, 1686, 1502, 1366, 1169 cmÀ1
;
1H NMR
(CDCl3, 500 MHz): compound is in equilibrium with the cyclic
hemiketal: d = 7.96–7.95 (m, 2H), 7.56–7.42 (m, 3H), 5.24 (bm,
1H), 3.98–3.93 (m, 1H), 3.36–3.30 (m, 3H), 1.39 (s, 9H), 1.20 (d,
J = 6.75 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): d = 199.5,
156.4, 136.8, 133.5, 128.7, 128.3, 79.7, 68.6, 52.9, 40.9, 28.3,
20.5 ppm; HRMS (ES): m/z calcd for
C
16H23NO4 [M+Na+]:
4.2.3. (4R,5R)-3-(tert-Butyloxycarbonyl)-2,2,5-trimethyl-4-((2-
(3,4-dimethoxyphenyl)-1,3-dithian-2-yl)methyl)oxazolidine 3j
Column chromatography (90:10 petroleum ether/EtOAc); solid
316.1525, found: 316.1521.
4.2.8. (3R,4R)-3-(tert-Butyloxycarbonylamino)-4-hydroxy-1-(4-
methoxyphenyl)pentan-1-one 1i
(1.159 g, 80%); [
a]
25 = À8.1 (c 0.610, CHCl3); IR (KBr): 2976, 2932,
D
1696, 1508, 1385, 1256, 1137 cmÀ1
;
1H NMR (CDCl3, 500 MHz):
Column chromatography (60:40 petroleum ether/EtOAc); clear
mixture of rotamers: d = 7.56–7.42 (m, 2H), 6.85–6.84 (m, 1H),
3.97–3.91 (m, 1H), 3.88, 3.87 (s, 6H), 3.46–3.35 (m, 1H), 2.72–
2.47 (m, 4H), 2.25–2.16 (m, 2H), 1.91–1.88 (m, 2H), 1.53–1.39 (s,
15H), 1.02–0.96 (m, 3H) ppm; 13C NMR (CDCl3, 125 MHz):
d = 151.6, 149.0, 148.1, 133.6, 121.7, 121.5, 112.1, 112.0, 111.2,
111.0, 93.6, 92.8, 80.4, 80.1, 60.2, 59.9, 57.8, 57.3, 56.0, 55.9, 49.5,
48.5, 29.8, 28.8, 28.5, 28.2, 27.7, 27.5, 27.3, 25.0, 21.8 ppm; HRMS
oil (0.613 g, 95%); [
a]
25 = À6.4 (c 0.466, CHCl3); IR (thin film):
D
3481, 3391, 3366, 2978, 2935, 1705, 1611, 1524, 1168 cmÀ1
;
1H
NMR (CDCl3, 500 MHz): compound is in equilibrium with the cyclic
hemiketal: d = 7.97–7.92 (m, 2H), 7.54–7.53 (m, 0.5H), 6.93–6.87
(m, 2H), 6.38–6.37 (m, 0.2H), 6.01–5.99 (m, 0.2H), 3.97–3.90 (m,
1.5H), 3.86 (s, 3H), 3.81–3.80 (m, 1H), 3.31–3.27 (m, 1.5H), 2.34–
2.33 (m, 0.7H), 1.44, 1.40 (s, 9H), 1.24–1.20 (m, 3H) ppm; 13C
NMR (CDCl3, 125 MHz): d = 198.2, 197.0, 164.2, 163.9, 158.6,
156.4, 152.3, 151.2, 130.8, 124.8, 114.1, 114.0, 113.9, 107.5,
104.2, 79.8, 68.6, 67.4, 55.6, 55.3, 53.1, 52.4, 40.7, 39.6, 28.4,
(ES): m/z calcd for
C
24H37NO5S2 [M+Na+]: 506.2011, found:
506.2014.
4.2.4. (2R,3R)-3-(tert-Butyloxycarbonylamino)-4-(2-phenyl-1,3-
dithian-2-yl)butan-2-ol 4h
28.3, 20.6, 20.5 ppm; HRMS (ES): m/z calcd for
C17H25NO5
[M+Na+]: 346.1630, found: 346.1630.
Column chromatography (70:30 petroleum ether/EtOAc); clear
oil (0.651 g, 85%); [
a]
25 = +7.0 (c 0.283, CHCl3); IR (thin film):
D
4.2.9. (3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimeth
oxyphenyl)-4-hydroxypentan-1-one 1j
3414, 2929, 2973, 1691, 1507, 1365, 1170 cmÀ1
;
1H NMR (CDCl3,
500 MHz): d = 7.90 (d, J = 7.30 Hz, 2H), 7.37 (t, J = 7.35 Hz, 2H,),
7.26–7.23 (m, 1H), 4.38 (bm, 1H), 3.56–3.45 (m, 2H), 2.71–2.67
(m, 4H), 2.37–2.28 (m, 2H), 1.95–1.90 (m, 2H), 1.37 (s, 9H), 1.01
(d, J = 6.10 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): d = 155.9,
141.5, 128.8, 128.6, 127.2, 79.4, 70.2, 57.5, 52.7, 46.7, 28.4, 27.7,
27.6, 24.9, 19.8 ppm; HRMS (ES): m/z calcd for C19H29NO3S2
[M+Na+]: 406.1487, found: 406.1487.
Column chromatography (60:40 petroleum ether/EtOAc); clear
oil (0.677 g, 96%); [
a]
25 = +1.9 (c 1.050, CHCl3); IR (thin film):
D
3376, 2974, 2930, 1690, 1515, 1272, 1166 cmÀ1
;
1H NMR (CDCl3,
500 MHz): compound is in equilibrium with the cyclic hemiketal:
d = 7.64–7.62 (m, 1H), 7.51 (m, 1H), 6.86 (d, J = 6.30 Hz, 1H), 5.23
(bm, 1H), 3.94–3.93 (m, 1H), 3.91, 3.90 (s, 6H), 3.45 (m, 1H),
3.31–3.21 (m, 2H), 1.38 (s, 9H), 1.19 (d, J = 6.10 Hz, 3H) ppm; 13C
NMR (CDCl3, 125 MHz): d = 198.1, 156.4, 153.7, 149.1, 129.9,
123.5, 110.2, 110.1, 79.7, 68.4, 56.1, 56.0, 53.2, 40.6, 28.4,
4.2.5. (2R,3R)-3-(tert-Butyloxycarbonylamino)-4-(2-(4-methoxy-
phenyl)-1,3-dithian-2-yl)butan-2-ol 4i
20.5 ppm; HRMS (ES): m/z calcd for
C
18H27NO6 [M+Na+]:
Column chromatography (65:35 petroleum ether/EtOAc); clear
376.1736, found: 376.1731.
oil (0.735 g, 89%); [
a]
25 = +12.5 (c 0.400, CHCl3); IR (thin film):
D
3384, 2971, 2922, 1691, 1504, 1249 cmÀ1
;
1H NMR (CDCl3,
4.3. Diastereoselective reduction of b-amino ketones, 1a–j
500 MHz): d = 7.79 (d, J = 8.55 Hz, 2H), 6.88 (d, J = 8.55 Hz, 2H),
4.40 (bm, 1H), 3.80 (s, 3H), 3.58–3.54 (m, 1H), 3.46–3.41 (m, 1H),
2.75–2.66 (m, 4H), 2.39–2.25 (m, 2H), 1.93–1.90 (m, 2H), 1.36
(s, 9H), 1.00 (d, J = 6.45 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz):
d = 158.5, 155.9, 133.2, 129.9, 114.0, 79.3, 70.3, 51.1, 55.3, 52.7,
46.7, 28.4, 27.7, 27.5, 25.0, 19.8 ppm; HRMS (ES): m/z calcd for
To a solution of the b-amino ketone (2 mmol) in methanol
(5 mL) at rt (30 °C), CeCl3 (0.492 g, 2 mmol) was added and stirred
for 5 min. To the solution NaBH4 (0.150 g, 4 mmol) was added in
portions using a solid addition funnel. After the complete disap-
pearance of the starting material (cc 20 min), the reaction was
quenched with saturated NaHCO3 (10 mL), extracted with dichlor-
omethane (2 Â 30 mL) and dried over anhydrous Na2SO4, and con-
centrated under vacuum. The diastereomeric ratio was determined
from the 1H NMR spectra of the crude mixture and the desired
amino diols 2a–j were purified by column chromatography.
C
20H31NO4S2 [M+Na+]: 436.1592, found: 436.1596.
4.2.6. (2R,3R)-3-(tert-Butyloxycarbonylamino)-4-(2-(3,4-dimeth
oxyphenyl)-1,3-dithian-2-yl)butan-2-ol 4j
Column chromatography (65:35 petroleum ether/EtOAc); clear
oil (0.761 g, 86%); [
a]
25 = +7.1 (c 0.700, CHCl3); IR (thin film):
D
3383, 2932, 2972, 2834, 1693, 1509, 1257, 1168 cmÀ1
;
1H NMR
4.3.1. (1S,3R)-3-(tert-Butyloxycarbonylamino)-1-phenylbutane-
1,4-diol 2a
(CDCl3, 500 MHz): d = 7.46–7.44 (m, 2H), 6.85–6.83 (m, 1H), 4.39
(bm, 1H), 3.88, 3.87 (2s, 6H), 3.59–3.54 (m, 1H), 3.48–3.45 (m,
1H), 2.76–2.67 (m, 4H), 2.33–2.24 (m, 2H), 1.94–1.89 (m, 2H),
1.35 (s, 9H), 1.01 (d, J = 6.30 Hz, 3H) ppm; 13C NMR (CDCl3,
125 MHz): d = 155.9, 148.9, 148.0, 133.7, 121.1, 111.9, 110.9,
79.3, 70.3, 57.5, 56.0, 55.8, 52.6, 46.8, 28.3, 27.8, 27.6, 25.0,
Column chromatography (petroleum ether/EtOAc, 70:30);
white solid (0.449 g, 80%); mp 112–114 °C; [
CHCl3); lit.19a
D = +33.8 (c 0.8, CHCl3); IR (KBr): 3354, 3030,
2976, 1684, 1169 cmÀ1 1H NMR (CDCl3, 500 MHz): d = 7.29–7.20
a]
25 = +32.5 (c 0.191,
D
[a]
;
(m, 5H), 5.27 (bm, 1H), 4.73–4.71 (m, 1H), 3.91 (bm, 1H), 3.56–
3.55 (d, J = 3.7 Hz, 2H), 1.96–1.82 (m, 2H), 1.40 (s, 9H) ppm; 13C
NMR (CDCl3, 125 MHz): d = 156.4, 144.4, 128.5, 127.6, 125.8,
19.8 ppm; HRMS (ES): m/z calcd for
C
21H33NO5S2 [M+Na+]:
466.1698, found: 466.1693.

628
S. Chacko et al. / Tetrahedron: Asymmetry 26 (2015) 623–631
79.8, 71.3, 65.1, 50.4, 41.2, 28.4 ppm; lit.;19a HRMS (ESI): m/z calcd
(m, 3H), 1.92 (m, 2H), 1.43 (br s, 9H) ppm; 13C NMR (CD3OD,
125 MHz): d = 159.1, 156.6, 136.4, 127.2, 113.4, 78.7, 70.9, 63.8,
54.3, 49.7, 40.2, 27.5 ppm; HRMS (ESI): m/z calcd for C16H25NO5
[M+Na+]: 334.1630, found: 334.1628.
for C15H23NO4 [M+Na+]: 304.1525; found 304.1520.
4.3.2. (1R,3R)-3-(tert-Butyloxycarbonylamino)-1-phenylbutane-
1,4-diol anti-2a
Column chromatography (75:25 petroleum ether/EtOAc); clear
4.3.8. (1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-methoxy
phenyl)butane-1,4-diol anti-2d
oil (0.067 g, 12%); [
a]
25 = À6.4 (c 0.333, CHCl3); lit.19a
[a]
D = À7.5
D
(c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz): d = 7.36–7.22 (m, 5H),
4.75 (m, 1H), 3.96–3.94 (m, 1H), 3.74–3.62 (m, 2H), 1.87–1.75
(m, 2H), 1.45 (s, 9H) ppm; 13C NMR (CDCl3, 100 MHz): d = 157.3,
144.0, 128.4, 127.4, 125.6, 80.3, 70.5, 65.5, 49.8, 42.3, 28.4 ppm
lit.19a,b
Column chromatography (40:60 petroleum ether/EtOAc); clear
oil (0.093 g, 15%); [a]
25 = +25.0 (c 0.950, CHCl3); 1H NMR (CD3OD,
D
400 MHz): d = 7.13–7.11 (m, 2H), 6.73–6.70 (m, 2H), 4.54–4.46
(m, 1H), 3.61 (s, 3H), 3.06–3.01 (m, 3H), 1.86–1.51 (m, 2H), 1.29
(s, 9H) ppm; 13C NMR (CD3OD, 100 MHz): d = 157.4, 155.6, 135.5,
125.1, 111.7, 77.2, 68.5, 62.7, 52.7, 48.2, 39.1, 25.8 ppm.
4.3.3. (1S,3R)-3-(tert-Butyloxycarbonylamino)-1-p-tolylbutane-
1,4-diol 2b
4.3.9. (1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimeth
oxyphenyl)butane-1,4-diol 2e
Column chromatography (petroleum ether/EtOAc, 70:30);
white solid (0.483 g, 82%); mp 92–94 °C; [
a]
25 = +21.2 (c 0.103,
Column chromatography (petroleum ether/EtOAc, 55:45);
D
CHCl3); IR (KBr): 3353, 2925, 1685, 1169, 1046 cmÀ1
;
1H NMR
colorless oil (0.629 g, 91%); [
a]
25 = +4.2 (c 0.70, CHCl3); IR (thin
D
(CDCl3, 500 MHz): d = 7.22–7.20 (m, 2H), 7.13–7.12 (m, 2H), 5.25
(bm, 1H), 4.77–4.75 (m, 1H), 3.73 (m, 1H), 3.63 (d, J = 3.9 Hz, 2H),
2.31 (s, 3H), 2.00–1.86 (m, 2H), 1.43 (s, 9H) ppm. 13C NMR
(CDCl3, 125 MHz): d = 156.4, 141.3, 137.4, 129.3, 125.7, 79.8,
71.5, 65.6, 50.8, 41.1, 28.4, 21.1 ppm; HRMS (ESI): m/z calcd for
film): 3367, 2925, 1684, 1596, 1515, 1260, 1163, 1027 cmÀ1 1H
;
NMR (CD3OD, 500 MHz): d = 7.95–7.90 (m, 1H), 6.95–6.88
(m, 2H), 4.68–4.64 (m, 1H), 3.84 (s, 6H), 3.46–3.37 (m, 3H), 1.94–
1.91 (m, 2H), 1.42 (br s, 9H) ppm; 13C NMR (CD3OD, 125 MHz):
d = 156.6, 148.9, 148.3, 137.4, 118.4, 111.4, 109.8, 78.6, 71.1, 63.9,
55.2, 55.0, 48.0, 40.3, 27.2 ppm; HRMS (ESI): m/z calcd for
C
16H25NO4 [M+Na+]: 318.1681, found: 318.1683.
C
17H27NO6 [M+Na+]: 369.1736, found: 369.1733.
4.3.4. (1R,3R)-3-(tert-Butyloxycarbonylamino)-1-p-tolylbutane-
1,4-diol anti-2b
4.3.10. (1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dimeth-
oxyphenyl)butane-1,4-diol anti-2e
Column chromatography (40:60 petroleum ether/EtOAc); clear
oil (This isomer was prepared by a non-selective reduction of 1e,
Column chromatography (75:25 petroleum ether/EtOAc); clear
oil (0.076 g, 13%); [
a]
25 = +3.4 (c 0.910, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d = 7.24–7.22 (m, 2H), 7.13–7.11 (m, 2H), 5.13 (bm,
1H), 4.71–4.68 (m, 1H), 3.96–3.60 (m, 3H), 2.31 (s, 3H), 1.81–
1.77 (m, 2H), 1.44 (s, 9H) ppm; 13C NMR (CDCl3, 100 MHz):
d = 157.3, 141.1, 137.0, 129.1, 125.5, 80.2, 70.4, 65.5, 49.9, 42.1,
28.4, 21.1 ppm.
for characterization).
[
a
]
25 = À2.5 (c 0.400, CHCl3); 1H NMR
D
(CD3OD, 400 MHz): d = 6.85–6.75 (m, 3H), 4.55–4.46 (m, 1H),
3.69, 3.66 (s, 6H), 3.04–2.97 (m, 3H), 1.78–1.55 (m, 2H), 1.30
(s, 9H) ppm; 13C NMR (CD3OD, 100 MHz): d = 155.5, 147.4, 146.6,
136.5, 116.4, 109.8, 107.8, 77.2, 68.7, 62.7, 53.6, 53.4, 48.2, 39.1,
25.8 ppm.
4.3.5. (1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-isopropyl-
phenyl)butane-1,4-diol 2c
Column chromatography (petroleum ether/EtOAc, 70:30);
4.3.11. (1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-fluorophe-
nyl)butane-1,4-diol 2f
white solid (0.529 g, 82%); mp 79–80 °C; [
a]
25 = À17.9 (c 0.111,
D
CHCl3); IR (KBr): 3352, 2961, 1686, 1170, 1052 cmÀ1
;
1H NMR
Column chromatography (petroleum ether/EtOAc, 70:30); pale
(CDCl3, 500 MHz): d = 7.25–7.23 (d, J = 7.95 Hz, 2H), 7.18–7.17
(d, J = 7.95 Hz, 2H), 5.29 (bm, 1H), 4.78–4.75 (m, 1H), 3.74 (m,
1H), 3.62 (d, J = 3.4 Hz, 2H), 2.90–2.84 (s, 1H), 2.03–1.86 (m, 2H),
1.42 (s, 9H), 1.22 (d, J = 6.75 Hz, 6H) ppm; 13C NMR (CDCl3,
125 MHz): d = 156.4, 148.4, 141.7, 126.8, 125.7, 79.7, 71.4, 65.5,
50.8, 41.0, 33.8, 28.4, 24.0 ppm; HRMS (ESI): m/z calcd for
yellow oil (0.460 g, 77%); [
a]
25 = À14.2 (c 0.266, CHCl3); IR (thin
D
film): 3346, 2978, 2930, 1685, 1510, 1169 cmÀ1
;
1H NMR (CDCl3,
500 MHz): d = 7.26–7.24 (m, 2H), 6.98–6.95 (m, 2H) 5.28 (bm,
1H), 4.74 (bm, 1H), 3.94 (m, 1H), 3.67–3.59 (m, 2H), 1.99–1.90
(m, 2H), 1.39 (s, 9H) ppm; 13C NMR (CDCl3, 125 MHz): d = 163.0,
161.0, 156.2, 139.9, 127.4, 115.2, 79.9, 70.8, 65.1, 50.4, 41.4,
28.2 ppm; 19F NMR (CDCl3, 470 MHz): À114.7 ppm; HRMS (ESI):
m/z calcd for C15H22FNO4 [M+Na+]: 322.1431, found: 322.1433.
C
18H29NO4 [M+Na+]: 346.1994, found: 346.1995.
4.3.6. (1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-isopropyl-
phenyl)butane-1,4-diol anti-2c
4.3.12. (1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-fluorophe-
nyl)butane-1,4-diol anti-2f
Column chromatography (75:25 petroleum ether/EtOAc); clear
oil (0.077 g, 12%); [
a
]
D
25 = +1.3 (c 0.716, CHCl3); 1H NMR (CDCl3,
Column chromatography (50:50 petroleum ether/EtOAc); clear
400 MHz): d = 7.26–7.24 (m, 2H), 7.17–7.15 (m, 2H), 5.17 (bm,
1H), 4.71–4.68 (m, 1H), 4.00–3.96 (m, 1H), 3.69–3.58 (m, 2H),
2.92–2.81 (s, 1H), 1.84–1.76 (m, 2H), 1.43 (s, 9H), 1.21 (d,
J = 7.12 Hz, 6H) ppm; 13C NMR (CDCl3, 100 MHz): d = 157.3,
141.1, 137.0, 129.1, 125.5, 80.2, 70.4, 65.5, 49.9, 42.1, 33.8, 28.4,
21.1 ppm.
oil (0.080 g, 13%); [a]
25 = +4.1 (c 1.216, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d = 7.31–7.27 (m, 2H), 6.99–6.95 (m, 2H), 5.17 (m,
1H), 4.68 (m, 1H), 3.91 (m, 1H), 3.69–3.57 (m, 2H), 1.81–1.72 (m,
2H), 1.42 (s, 9H) ppm; 13C NMR (CDCl3, 100 MHz): d = 163.2,
160.8, 157.4, 139.9, 127.2, 115.2, 80.3, 69.8, 65.3, 49.7, 42.4,
28.4 ppm; 19F NMR (CDCl3, 470 MHz): À115.4 ppm.
4.3.7. (1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(4-methoxy-
phenyl)butane-1,4-diol 2d
4.3.13. (1S,3R)-3-(tert-Butyloxycarbonylamino)-1-(3-chlorophe-
nyl)butane-1,4-diol 2g
Column chromatography (petroleum ether/EtOAc, 60:40);
Column chromatography (petroleum ether/EtOAc, 70:30); pale
colorless oil (0.485 g, 78%); [
film): 3359, 2975, 2931, 1685, 1611, 1513, 1247, 1172,
1033 cmÀ1 1H NMR (CD3OD, 500 MHz): d = 7.86 (m, 1H), 7.28
(m, 2H), 6.85 (m, 2H), 4.64 (m, 1H), 3.74 (s, 3H), 3.46–3.28
a]
D
25 = +12.0 (c 0.083, CHCl3); IR (thin
yellow oil (0.435 g, 76%); [
a]
D
25 = À43.8 (c 0.086, CHCl3); IR (thin
film): = 3348, 2977, 1685, 1169, 1048 cmÀ1
;
1H NMR (CDCl3,
;
500 MHz): d = 7.29–7.14 (m, 4H), 5.34 (bm, 1H), 4.71–4.70 (m,
1H), 3.89 (m, 1H), 3.59 (m, 2H), 1.90–1.80 (m, 2H), 1.38 (s, 9H)

S. Chacko et al. / Tetrahedron: Asymmetry 26 (2015) 623–631
629
ppm; 13C NMR (CDCl3, 125 MHz): d = 156.4, 146.5, 134.3, 129.8,
3385, 2972, 2927, 1686, 1516, 1263, 1162, 1029 cmÀ1
;
1H NMR
127.5, 125.8, 123.9, 80.0, 70.6, 64.8, 50.1, 41.1, 28.4 ppm; HRMS
(ESI): m/z calcd for
316.1316.
(CDCl3, 500 MHz): d = 6.87–6.77 (m, 3H), 5.15 (m, 1H), 4.74–4.71
(m, 1H), 3.84, 3.82 (s, 6H), 3.55 (m, 2H), 2.04–1.87 (m, 2H), 1.42
(s, 9H), 1.14 (d, J = 5.7 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz):
d = 156.5, 149.0, 148.4, 137.1, 118.0, 111.1, 109.1, 79.6, 71.2, 69.4,
55.9, 55.9, 53.5, 42.3, 28.4, 20.2 ppm; HRMS (ES): m/z calcd for
C
15H22ClNO4 [M+H+]: 316.1316, found:
4.3.14. (1R,3R)-3-(tert-Butyloxycarbonylamino)-1-(3-chloroph-
enyl)butane-1,4-diol anti-2g
C
18H29NO6 [M+Na+]: 378.1893, found: 378.1891.
Column chromatography (70:30 petroleum ether/EtOAc); clear
oil (0.109 g, 17%); [
a
]
25 = +2.0 (c 0.500, CHCl3); 1H NMR (CDCl3,
4.3.20. (1R,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dime-
thoxyphenyl)pentane-1,4-diol 2j-anti
D
400 MHz): d = 7.35–7.34 (m, 1H), 7.23–7.17 (m, 3H), 5.18 (bm,
1H), 4.69–4.66 (m, 1H), 3.96–3.90 (m, 1H), 3.72–3.68 (m, 1H),
3.62–3.58 (m, 1H), 1.84–1.68 (m, 2H), 1.43 (s, 9H) ppm; 13C NMR
(CDCl3, 100 MHz): d = 157.5, 146.3, 134.3, 129.7, 127.3, 125.9,
123.7, 80.4, 69.8, 65.3, 49.5, 42.4, 28.4 ppm.
Column chromatography (55:45 petroleum ether/EtOAc); clear
oil (0.026 g, 4%); [
a
]
25 = À5.5 (c 0.716, CHCl3); 1H NMR (CDCl3,
D
500 MHz): d = 6.93–6.78 (m, 3H), 5.07 (m, 1H), 4.65 (m, 1H), 4.21
(m, 1H), 3.87, 3.84 (s, 6H), 3.78–3.74 (m, 1H), 1.88–1.73 (m, 2H),
1.45 (s, 9H), 1.23–1.21 (m, 3H) ppm; 13C NMR (CDCl3, 125 MHz):
d = 157.8, 149.0, 148.1, 137.0, 117.7, 111.0, 108.9, 80.2, 70.1, 69.5,
56.0, 55.9, 52.9, 43.8, 28.4, 20.7 ppm.
4.3.15. (1S,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-phenylpen
tane-1,4-diol 2h
Column chromatography (70:30 petroleum ether/EtOAc); clear
oil (0.482 g, 82%); [
a]
25 = À19.4 (c 1.233, CHCl3); IR (thin film):
4.3.21. (3R)-3-(tert-Butyloxycarbonylamino)-5-methoxy-5-phe-
nyltetrahydrofuran 5
D
3405, 2975, 1686, 1506, 1169 cmÀ1
;
1H NMR (CDCl3, 500 MHz):
d = 7.30–7.23 (m, 5H), 5.20 (m, 1H), 4.74–4.73 (m, 1H), 3.95–3.85
(m, 2H), 3.56–3.50 (m, 1H), 2.04–2.00 (m, 1H), 1.90–1.84 (m, 1H),
1.42 (s, 9H), 1.12 (d, J = 6.1 Hz, 3H) ppm; 13C NMR (CDCl3,
125 MHz): d = 156.5, 144.4, 128.5, 127.5, 125.8, 79.6, 71.2, 69.2,
53.4, 42.2, 28.4, 20.1 ppm; HRMS (ES): m/z calcd for C16H25NO4
[M+Na+]: 318.1681, found: 318.1683.
To a solution of the b-amino ketone 1a (1 mmol) in methanol
(5 mL) at rt (30 °C), triflates (10 mol %) was added and stirred well
for 5 min. To this solution, NaBH4 (0.150 g, 4 mmol) was added in
portions using a solid addition funnel. After the complete disap-
pearance of starting material, reaction was quenched with satu-
rated NaHCO3 (10 mL) and extracted with dichloromethane
(2 Â 30 mL). Organic layer dried over anhydrous Na2SO4 and con-
centrated under vacuum and crude diastereomers were purified
through column chromatography. Diastereomer 1 Column chro-
matography (95:5 petroleum ether/EtOAc); clear oil (0.131 g,
45%); IR (thin film): 3345, 3061, 2977, 1715, 1511, 1170,
1042 cmÀ1; 1H NMR (CDCl3, 500 MHz): d = 7.45–7.25 (m, 5H),
5.60–5.58 (bm, 1H), 4.48–4.42 (m, 2H), 3.88–3.87 (m, 1H), 3.04
(s, 3H), 2.24–2.22 (m, 1H), 2.10–2.06 (m, 1H), 1.46 (s, 9H) ppm;
13C NMR (CDCl3, 125 MHz): d = 155.4, 139.4, 128.3, 128.2, 126.2,
109.4, 79.5, 75.8, 50.4, 49.4, 47.2, 28.5 ppm; HRMS (ES): m/z calcd
for C16H23NO4 [M+Na+]: 316.1500, found: 316.1508
4.3.16. (1R,3R,4R)-3-(tert-Butylcarbonylamino)-1-phenylpentane-
1, 4-diol anti-2h
Column chromatography (70:30 petroleum ether/EtOAc); clear
oil (0.072 g, 12%); [a]
25 = +5.6 (c 1.066, CHCl3); 1H NMR (CDCl3,
D
500 MHz): d = 7.34–7.20 (m, 5H), 5.13 (bm, 1H), 4.68–4.66 (m,
1H), 4.36 (m, 1H), 3.81–3.72 (m, 1H), 1.87–1.71 (m, 2H), 1.44 (s,
9H), 1.19 (d, J = 6.7 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz):
d = 157.9, 144.3, 128.4, 127.2, 125.6, 80.1, 70.3, 69.4, 53.0, 43.7,
28.4, 20.6 ppm.
4.3.17. (1S,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(4-meth
oxyphenyl)pentane-1,4-diol 2i
Diastereomer 2; Column chromatography (95:5 petroleum
ether/EtOAc); clear oil (0.161 g, 55%); IR (thin film): 3345, 3061,
Column chromatography (60:40 petroleum ether/EtOAc); clear
2977, 1715, 1511, 1170, 1042 cmÀ1 1H NMR (CDCl3, 500 MHz):
;
oil (0.568 g, 87%); [
a]
25 = À21.0 (c 0.616, CHCl3); IR (thin film):
d = 7.48–7.25 (m, 5H), 4.62–4.60 (bm, 1H), 4.51–4.44 (m, 1H),
4.23–4.20 (m, 1H), 3.91–3.89 (m, 1H), 2.98 (s, 3H), 2.75–2.71 (m,
1H), 1.79–1.75 (m, 1H), 1.40 (s, 9H) ppm; 13C NMR (CDCl3,
125 MHz): d = 155.3, 140.2, 128.4, 128.1, 126.1, 108.8, 79.7, 73.3,
51.4, 49.6, 48.0, 28.4 ppm; HRMS (ES): m/z calcd for C16H23NO4
[M+Na+]: 316.1500, found: 316.1508.
D
3396, 2930, 2975, 1682, 1513, 1249, 1173, 1036 cmÀ1
;
1H NMR
(CDCl3, 500 MHz): d = 7.28–7.23 (m, 2H), 6.85 (d, J = 8.85 Hz, 2H),
5.06 (m, 1H), 4.66–4.64 (m, 1H), 4.11–4.01 (m, 1H), 3.85–3.83
(m, 1H), 3.77 (s, 3H), 1.86–1.73 (m, 2H), 1.45 (s, 9H), 1.21 (d,
J = 6.4 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): d = 159.1, 156.5,
136.5, 127.1, 113.9, 79.5, 70.9, 69.4, 55.3, 53.5, 42.2, 28.4,
20.2 ppm; HRMS (ES): m/z calcd for
C
17H27NO5 [M+Na+]:
4.4. Synthesis of HPA-12 and its analogues 6
348.1787, found: 348.1794.
N-Boc protected amino diol 2 (1 mmol) was dissolved in metha-
nol (1 mL) and cooled to 0 °C. Ethyl acetate saturated with HCl
(3 mL) was added with stirring and the reaction mixture was
allowed to attain rt. Upon the complete disappearance of 2 on
TLC, the solvents were removed under reduced pressure and the
residue was dissolved in anhydrous THF (5 mL). This solution
was cooled to 0 °C, after which solid NaHCO3 (1 g) was added
and the mixture was vigorously stirred. Lauroyl chloride
(0.231 mL, 0.219 g, 1 mmol, 1 equiv) was added to this mixture
dropwise and stirring was continued at 0 °C for 1 h and then at rt
for 2 h. The reaction mixture was diluted with dichloromethane
(20 mL) and filtered, the residue was washed with dichloro-
methane (20 mL) and the filtrate and washings were combined.
The crude solution of the 5 in dichloromethane was washed with
water (20 mL), dried over anhydrous Na2SO4, concentrated under
reduced pressure, and purified by column chromatography.
4.3.18. (1R,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(4-meth
oxyphenyl)pentane-1,4-diol anti-2i
Column chromatography (60:40 petroleum ether/EtOAc); clear
oil (0.042 g, 7%); [
a
]
25 = À4.2 (c 0.466, CHCl3); 1H NMR (CDCl3,
D
500 MHz): d = 7.23 (d, J = 8.55 Hz, 2H), 6.83 (d, J = 8.55 Hz, 2H),
5.16 (bm, 1H), 4.74–4.71 (m, 1H), 3.85–3.84 (m, 1H), 3.76 (s, 3H),
3.54–3.36 (m, 1H), 2.03–1.86 (m, 2H), 1.42 (s, 9H), 1.13 (d,
J = 6.1 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): d = 158.8, 157.8,
136.4, 126.8, 113.8, 80.1, 69.9, 69.6, 55.3, 53.2, 43.7, 28.4,
20.7 ppm.
4.3.19. (1S,3R,4R)-3-(tert-Butyloxycarbonylamino)-1-(3,4-dime-
thoxyphenyl)pentane-1,4-diol 2j
Column chromatography (55:45 petroleum ether/EtOAc); clear
oil (0.627 g, 88%); [
a
]
D
25 = À14.6 (c 0.883, CHCl3); IR (thin film):

630
S. Chacko et al. / Tetrahedron: Asymmetry 26 (2015) 623–631
4.4.1. N-((2R,4S)-1,4-Dihydroxy-4-phenylbutan-2-yl)dodecan
amide 6a
(t, J = 7.05 Hz, 3H) ppm; 13C NMR (CDCl3, 125 MHz): d = 174.5,
146.6, 134.4, 129.8, 127.6, 125.8, 123.8, 71.1, 65.1, 50.0, 41.0,
36.8, 31.9, 29.77, 29.72, 29.61, 29.44, 29.43, 29.4, 25.78, 22.7,
14.2 ppm; HRMS (ESI): m/z calcd for
398.2464, found: 398.2462.
Column chromatography (petroleum ether/EtOAc, 50:50); white
solid (0.254 g, 70%); mp 86–88 °C; lit.;12 mp 90–91 °C; lit.10 mp
C
22H36ClNO3 [M+H+]:
81–82 °C; [
a
]
25 = À30.7 (c 0.533, CHCl3); lit.12
[
a
]
D = À34.8 (c 1.0,
D
CHCl3); lit.10
[
a]
D = À34.7 (c 0.36, CHCl3) IR (KBr): 3293, 2920,
1642, 1551, 1053 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d = 7.30–7.22
4.5. Acid sensitivity of the electron rich amino diol 2e
(m, 5H), 6.52 (b, 1H), 4.75 (m, 1H), 4.01 (m, 1H), 3.64–3.58 (m,
2H), 2.12–2.09 (t, J = 7.7 Hz, 2H), 2.01–1.85 (m, 2H), 1.56–1.54 (m,
2H), 1.24 (m, 16H), 0.86 (t, J = 6.7 Hz, 3H) ppm; 13C NMR (CDCl3,
125 MHz): d = 174.4, 144.4, 128.6, 127.6, 125.6, 71.7, 65.4, 50.3,
40.8, 36.8, 32.0, 29.73, 27.71, 29.6, 29.4, 29.3, 25.8, 22.7, 14.2 ppm;
Amino diol 2e (0.341 g, 1 mmol) was dissolved in a solution of
TFA (2%) in CH3OH (8 mL) at 0 °C and stirred until 2e disappeared
in TLC (2 h). The reaction mixture was then neutralized with
NaHCO3 (1 g), filtered, and the filtrate was removed under vacuum
and the products were isolated by column chromatography. The
solvolysis product 7 and the intramolecular SN1 product 8 were
isolated in equimolar amounts, as mixtures of diastereomers.
lit.10 13C NMR); lit.12 13C NMR); HRMS (ESI): m/z calcd for
( (
C22H37NO3 [M+Na+]: 386.2671, found: 386.2679.
4.4.2. N-((2R,4S)-1,4-Dihydroxy-4-p-tolylbutan-2-yl)dodecan
amide 6b
4.5.1. 2-(tert-Butyloxycarbonylamino)-4-(3,4-dimethoxyphenyl)-
4-methoxybutan-1-ol 7
Column chromatography (petroleum ether/EtOAc, 50:50);
white solid (0.248 g, 66%); mp 103–104 °C; [
a]
D
25 = À12.0 (c 0.250,
Column chromatography (60:40 petroleum ether/EtOAc); clear
oil (0.177 g, 50%); IR (thin film): 3364, 2926, 2854, 1692, 1515,
CHCl3); IR (KBr): 3297, 2919, 1643, 1549, 1057 cmÀ1
;
1H NMR
(CDCl3, 500 MHz): d = 7.20–7.19 (d, J = 7.95 Hz, 2H), 7.12–7.11 (d,
J = 7.6 Hz, 2H), 6.46 (b, 1H), 4.74 (m, 1H), 4.01 (m, 1H), 3.62 (m,
2H), 2.31 (s, 3H), 2.13 (t, J = 7.65 Hz, 2H), 2.00–1.88 (m, 2H), 1.56
(m, 2H), 1.26–1.24 (m, 16H), 0.87 (t, J = 6.75 Hz, 3H) ppm; 13C
NMR (CDCl3, 125 MHz): d = 174.4, 141.3, 137.4, 129.3, 125.5,
71.8, 65.7, 50.6, 40.73, 36.8, 32.0, 29.7, 29.6, 29.46, 29.43, 29.39,
25.8, 22.7, 21.1, 14.1 ppm; HRMS (ESI): m/z calcd for C23H39NO3
[M+Na+]: 400.2828, found: 400.2828.
1261, 1169, 1027 cmÀ1 1H NMR (CDCl3, 500 MHz): mixture of
;
diastereomers: d = 6.81–6.77 (m, 3H), 5.19–5.15 (m, 1H), 4.16–
4.14 (m, 1H), 3.85, 3.84 (s, 6H), 3.69–3.56 (m, 3H), 3.17–3.15
(s, 3H), 1.95–1.75 (m, 2H), 1.42 (s, 9H) ppm; 13C NMR (CDCl3,
125 MHz): d = 156.2, 149.3, 148.6, 134.2, 133.9, 118.9, 111.0,
109.2, 109.0, 81.1, 79.5, 65.5, 56.5, 56.3, 55.9, 51.1, 50.7, 40.0,
28.4 ppm; HRMS (ES): m/z calcd for
C
18H29NO6 [M+Na+]:
378.1893, found: 378.1897.
4.4.3. N-((2R,4S)-1,4-Dihydroxy-4-(4-isopropylphenyl)butan-2-
yl)dodecanamide 6c
4.5.2. 5-(3,4-Dimethoxyphenyl)tetrahydrofuran-3-(tert-butyl-
oxy carbonylamine) 8
Column chromatography (petroleum ether/EtOAc, 50:50);
Column chromatography (petroleum ether/EtOAc 85:15); clear
oil (0.161 g, 50%); IR (thin film): 3355, 2973, 2928, 1709, 1516,
white solid (0.259 g, 64%); mp 96–98 °C; [
a]
25 = À10.0 (c 0.300,
D
CHCl3); IR (KBr): 3298, 2920, 1643, 1549, 1056 cmÀ1
;
1H NMR
1162 cmÀ1 1H NMR (CDCl3, 400 MHz): mixture of diastereomers:
;
(CDCl3, 500 MHz): d = 7.25–7.23 (d, J = 8.00 Hz, 2H), 7.19–7.17 (d,
J = 7.80 Hz, 2H), 6.46 (b, 1H), 4.76 (m, 1H), 4.04 (m, 1H), 3.66–
3.60 (m, 2H), 2.87 (s, 1H), 2.14 (t, J = 7.45 Hz, 2H), 2.03–1.88 (m,
2H), 1.58 (m, 2H), 1.27–1.21 (m, 22H), 0.86 (t, J = 6.30 Hz, 3H)
ppm; 13C NMR (CDCl3, 125 MHz): d = 174.2, 148.5, 141.6, 126.7,
125.6, 71.98, 65.9, 56.7, 40.5, 36.9, 33.8, 31.9, 29.76, 29.7, 29.61,
29.45, 29.43, 25.8, 24.0, 22.7, 14.1 ppm; HRMS (ESI): m/z calcd
for C25H43NO3 [M+Na+]: 428.3141, found: 428.3149.
d = 6.88–6.78 (m, 3H), 4.96–4.71 (m, 1H), 4.34–4.22 (m, 1H),
4.00–3.96 (m, 0.5H), 3.86–3.81 (m, 6H), 3.70–3.69 (m, 0.5H),
2.69–2.62 (m, 0.5H), 2.18–2.04 (m, 0.5H), 1.76–1.64 (m, 1H),
1.43–1.40 (s, 9H) ppm; 13C NMR (CDCl3, 100 MHz): d = 155.4,
149.1, 148.5, 134.5, 117.9, 111.1, 108.8, 80.0, 79.4, 74.0, 56.0,
55.9, 52.0, 51.8, 41.8, 41.6, 28.4 ppm; HRMS (ES): m/z calcd for
C
17H25NO5 [M+Na+]: 346.1630, found: 346.1631.
Acknowledgements
4.4.4. N-((2R,4S)-4-(4-Fluorophenyl)-1,4-dihydroxybutan-2-yl)
dodecanamide 6f
The authors thank the Department of Science and Technology,
Ministry of Science and Technology for financial support (grant
number: SR/FT/CS-12/2011). S.C. thanks the Council of Scientific
and Industrial Research for a Senior Research Fellowship and
Column chromatography (petroleum ether/EtOAc, 60:40);
white solid (0.267 g, 70%); mp 78–79 °C; [
a]
25 = À21.0 (c 0.666,
D
CHCl3); IR (KBr): 3290, 2920, 1642, 1552, 1056 cmÀ1
;
1H NMR
(CDCl3, 500 MHz): d = 7.30–7.27 (m, 2H), 7.01–6.98 (m, 2H),
6.38–6.37 (b, 1H), 4.78–4.76 (m, 1H), 4.03 (m, 1H), 3.68–3.62 (m,
2H), 2.15 (t, J = 7.9 Hz, 2H), 2.02–1.85 (m, 2H), 1.59–1.55 (m, 2H),
1.24 (m, 16H), 0.86 (t, J = 7.05 Hz, 3H) ppm; 13C NMR (CDCl3,
125 MHz): d = 173.5, 162.3, 160.3, 139.2, 126.4, 114.6, 114.4,
70.4, 64.6, 49.4, 40.2, 36.0, 31.1, 28.9, 28.8, 28.7, 28.5, 28.5, 28.4,
24.9, 21.8, 13.3 ppm; 19F NMR (CDCl3, 470 MHz): À114.6 ppm;
HRMS (ESI): m/z calcd for C22H36FNO3 [M+H+]: 382.2750, found:
382.2757.
M.K. thanks UGC, New Delhi, India for
Fellowship.
a Junior Research
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