Co(iii)(salen)-catalyzed phenolic kinetic resolution of two stereocentered benzyloxy and azido epoxides: Its application in the synthesis of ICI-118,551, an anti-hypertensive agent

Article abstract of DOI:10.1039/c3ob42501k

The salen Co(iii)-catalyzed phenolic kinetic resolution of racemic anti- or syn-azido and benzyloxy epoxides provides a practical route to a range of enantioenriched anti- or syn-1-aryloxy-3-azido or benzyloxy-2-alcohols in excellent yields and ees. The synthetic potential of this protocol is illustrated with an enantioselective synthesis of ICI-118,551, a β-blocker, in a highly optically pure form (99% ee). the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob42501k

Organic &
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Co(III)(salen)-catalyzed phenolic kinetic resolution
of two stereocentered benzyloxy and azido
epoxides: its application in the synthesis of
ICI-118,551, an anti-hypertensive agent†
Cite this: Org. Biomol. Chem., 2014,
12, 2349
Received 13th December 2013,
Accepted 14th February 2014
DOI: 10.1039/c3ob42501k
Pratibha U. Karabal, Dayanand A. Kamble and Arumugam Sudalai*
www.rsc.org/obc
The salen Co(III)-catalyzed phenolic kinetic resolution of racemic
anti- or syn-azido and benzyloxy epoxides provides a practical
route to a range of enantioenriched anti- or syn-1-aryloxy-3-azido
or benzyloxy-2-alcohols in excellent yields and ees. The synthetic
potential of this protocol is illustrated with an enantioselective
synthesis of ICI-118,551, a β-blocker, in a highly optically pure
form (99% ee).
Introduction
Fig. 1 Structures of anti- and syn-1-aryloxy-3-azido or benzyloxy-2
alcohols (1 & 2), Co(III)-salen complex (3) and ICI-118,551 (4).
Enantiomerically pure anti- or syn-1-aryloxy-3-azido or benzyl-
oxy-2-alcohols (1 and 2) are valuable ‘building blocks’ for
asymmetric synthesis of bioactive pharmaceuticals.1 These
structural units are present in numerous bioactive compounds
such as erythritol,2 an antidiabetic C4 polyol, β-adrenolytic
drugs,3 and the broussonetine family of naturally occurring
iminosugars,4 which show potent glucosidase inhibitory activi-
ties with enormous therapeutic potential as anti-tumor and
anti-HIV agents. In addition, these aryloxy azido or benzyloxy
alcohols (1a–o and 2a–c) are the direct precursors of amino
alcohols and simple aziridines,5 which are versatile intermedi-
ates in the synthesis of bioactive molecules6 (Fig. 1).
Jacobsen’s hydrolytic and phenolic kinetic resolutions
(HKR & PKR) of terminal epoxides with one stereocenter cata-
lyzed by Co(III)-salen complex 3 employ water and phenol as
nucleophiles, respectively.7 While HKR of epoxides has been
comprehensively studied in recent years to understand its
mechanistic and synthetic aspects that include a recent study8
relating to HKR of functionalized epoxides with two stereo-
centres, its phenolic version (PKR) has been less explored.7b In
the present work, we have extended the scope of the applicable
substrates to cover multi-functionalized epoxides with two
Scheme 1 PKR of anti-azido- and benzyloxy epoxides.
stereocenters and employing functionalized phenols (6a–u) as
the nucleophiles. The aim of such an investigation was to
obtain enantioenriched 1-aryloxy-3-azido or benzyloxy-2-alco-
hols (1 and 2) by a direct method from the respective racemic
materials, thus complementing the other tedious routes.9 In
this note, we wish to report a flexible, novel method that
employs PKR of racemic azido and benzyloxy epoxides 5 and 7
to generate azido- and benzyloxy alcohols 1 and 2 respectively,
with two stereocenters of high optical purities in a single step
(Schemes 1 and 2).
Chemical Engineering and Process Development Division, National Chemical
Results and discussion
Laboratory, Dr Homi Bhabha Road, Pune 411008, India.
E-mail: a.sudalai@ncl.res.in; Fax: +91-02025902676
We envisioned that the extension of PKR to the two stereoc-
entered racemic epoxides would enable us to obtain both the
†Electronic supplementary information (ESI) available: Experimental details and
spectral data of all the new compounds. See DOI: 10.1039/c3ob42501k
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PKR displayed strong epoxide concentration dependence,
requiring at least 2.2 equivalents of epoxides to realize excel-
lent enantioselectivity (Scheme 1).
A variety of phenolic substrates were then screened for the
PKR process that led to the isolated yields of 1a–u, with com-
plete regiocontrol (Table 1). In the case of azido epoxides, a
wide range of substituted phenols bearing both electron-
donating and electron-withdrawing groups reacted efficiently,
delivering the corresponding benzyloxy alcohols (1a–o) in good
to excellent yields and enantioselectivity (entries a–o), whereas
benzyloxy epoxides underwent the reaction only with electron-
deficient phenols (entries p–u). Additionally, ortho substituted
phenol displayed poor reactivity (entry d), while 1-naphthol
failed to undergo reaction.
Similarly, the racemic syn-azido- and benzyloxy epoxides
(7a–d), prepared readily from the corresponding cinnamyl
alcohols,8 were subjected to PKR under identical reaction con-
ditions that produced the corresponding enantiopure syn- pro-
ducts 2a–d in high isolated yields and ees (Table 2).
Scheme 2 PKR of syn-azido- and benzyloxy epoxides.
enantiomers of anti- or syn- aryloxy alcohols depending upon
the chiral ligand chosen. Thus, the racemic anti- and syn-
azido- and benzyloxy epoxides (5 and 7), the substrates for
PKR, were efficiently prepared in a highly diastereoselective
manner from the corresponding (Z)- and (E)-allylic alcohols,
respectively, by following a reported procedure.8 In this strat-
egy, the relative stereochemistry between the benzyloxy or
azido and epoxide groups is established prior to the PKR step
itself and in this way a simple asymmetric reaction can be
used to obtain the key enantiomerically pure 1-aryloxy-3-azido-
or benzyloxy-2-alcohols (1 and 2).
Interestingly, only electron-deficient phenols reacted
efficiently with the epoxides. Overall, phenols with a wide
range of electronic properties participated in the ring-opening
reaction with good yields and ees. The relative and absolute
stereochemistry of the products 1 and 2 was confirmed by the
asymmetric synthesis of ICI-118,551 from 1o (Scheme 2).
Finally, an application of this methodology is demonstrated
by the short synthesis of ICI-118,551 (4),10 the most potent and
selective β2 AR antagonist, used in the treatment of a wide
range of diseases including heart failure,11 ischemic heart
disease12 and hypertension.13 Its reported synthesis employs
Sharpless asymmetric epoxidation as the key reaction.10 Our
synthesis commences from optically pure azido alcohol 1o
(entry o, Table 1). The acid-catalyzed silyl deprotection of 1o
followed by the resulting diol protection with 2,2-dimethoxy-
propane produced acetonide 9 in 89% yield over two steps.
The catalytic hydrogenation of azide 9 gave crude amine,
which was smoothly N-alkylated14 with 2-bromopropane under
basic conditions to give the N-isopropyl derivative 10. The
acid-catalyzed acetonide deprotection gave diol 11 in 65%
yields. Selective monotosylation of diol 11 gave the crude tosy-
late, which on reduction with LiAlH4 afforded 4 in 21% overall
yield and 99% ee (Scheme 3).
Thus, when PKR of racemic anti-azido epoxide 5a was per-
formed with (R,R)-Co(III)-salen complex 3 (0.044 equiv.) and
phenol (1 equiv.) in tert-butyl methyl ether (TBME), the corres-
ponding anti-1-aryloxy-3-azido-2-alcohol 1a was isolated in
65% yield and 92% ee (entry a, Table 1). The PKR can be con-
ducted at low temperatures (−20 °C), although yields obtained
were found to be low. Further, the stereoselectivities in the
Table 1 PKR of anti-azido- and benzyloxy epoxidesa
anti-Azido- and benzyloxy alcohols
(1a–u)
Entry
Phenols (R) (6a–u)
X
Yieldb (%)
eec (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
4-CH3
3-CH3
2-CH3
4-tert-Bu
3-OMe
4-CN
4-F
4-Br
N3
N3
N3
N3
N3
N3
N3
N3
N3
N3
N3
N3
N3
N3
N3
OBn
OBn
OBn
OBn
OBn
OBn
65
72
70
35
76
60
87
72
86
90
89
88
81
92
75
87
89
98
75
81
78
92
99
95
94
99
93
98
68
97
97
95
98
94
96
99
98
97
86
99
97
97
4-Cl
3,5-Cl2
4-COCH3
4-CO2Me
4-NO2
7-Me-4-indanol
4-CN
Table 2 PKR of syn-azido- and benzyloxy epoxidesa
syn-Azido- and benzyloxy alcohols
(2a–d)
4-NO2
4-COCH3
4-CHO
4-CO2Me
2,3,5-Cl3
s
t
u
Entry
Phenols (R) (6l–n)
X
Yieldb (%)
eec (%)
a
b
c
4-COCH3
4-CO2Me
4-NO2
N3
N3
N3
OBn
88
96
90
89
93
93
94
98
a Racemic azido or benzyloxy epoxide 5 (5 mmol), (R,R)-Co(III)-salen
complex 3 (86 mg, 0.1 mmol), TBME, 3 Å MS, phenol (6) (2.25 mmol).
b Isolated yield after column chromatographic purification with respect
to nucleophiles. c ee determined by chiral HPLC analysis (see the
Experimental section for details).
d
4-COCH3
a For reaction conditions, see footnotes under Table 1.
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time: tmajor = 14.36 and tminor = 19.88 min; HRMS (ESI) m/z
Calcd C16H27N3O3NaSi [M + Na]+, 360.1714; found, 360.1713.
(2S,3S)-1-(p-Tolyloxy)-3-azido-4-(tert-butyldimethylsiloxy)-
butan-2-ol (1b)
Yield: 72%; gum; [α]D25 +28 (c 1, CHCl3); IR (CHCl3, cm−1): 777,
838, 1047, 1109, 1172, 1258, 1289, 1462, 1490, 1586, 1603,
2098, 2857, 2284, 2929, 2953, 3451; 1H NMR (200 MHz, CDCl3)
δ 0.12 (s, 6H), 0.92 (s, 9H), 2.29 (s, 3H), 2.67 (d, J = 4.9 Hz, 1H)
3.55–3.60 (m, 1H), 3.86–4.08 (m, 5H), 6.8 (d, J = 8.5 Hz, 2H),
7.05–7.09 (d, J = 8.4 Hz, 2H); 13C NMR (50 MHz, CDCl3): −5.5,
18.2, 20.5, 25.8, 63.5, 63.8, 69.2, 69.6, 114.4, 130.0, 130.5,
156.2; optical purity: 99% ee determined by HPLC analysis
(chiral OJ-H column, n-hexane–2-propanol (95 : 5), 0.5 mL
Scheme 3 Asymmetric synthesis of ICI-118,551 (4).
Conclusion
min−1, 210 nm); retention time: tminor = 23.71 and tmajor
=
25.23 min; HRMS (ESI) m/z Calcd C17H29N3O3NaSi [M + Na]+,
In conclusion, the (salen) Co(III)-catalysed PKR of racemic
azido- and benzyloxy epoxides provides a highly practical route
to enantiopure anti- or syn-azido- and benzyloxy alcohols 1 and
2 in a single step. The reaction is convenient to carry out
under mild conditions displaying a wide range of substrate
scope. This methodology has been successfully demonstrated
in the enantioselective synthesis of ICI-118,551, an anti-hyper-
tensive agent. We believe that this PKR strategy will find appli-
cations in the field of asymmetric synthesis of bioactive
molecules owing to the flexible nature of the synthesis of
racemic azido and benzyloxy epoxides and the readily accessi-
ble catalyst in both enantiomeric forms.
374.1870; found, 374.1874.
(2S,3S)-1-(m-Tolyloxy)-3-azido-4-(tert-butyl-dimethyl siloxy)-
butan-2-ol (1c)
Yield: 70%; gum; [α]D25 +16 (c 1.0, CHCl3); IR (CHCl3, cm−1):
774, 838, 1109, 1172, 1258, 1289, 1462, 1500, 1603, 2098, 2857,
1
2884, 2929, 2953, 3451; H NMR (200 MHz, CDCl3) δ 0.12 (s,
6H), 0.93 (s, 9H), 2.33 (s, 3H), 2.65–2.68 (d, J = 4.84 Hz, 1H),
3.56–3.62 (m, 1H), 3.67–4.15 (m, 5H), 6.69–6.80 (m, 3H),
7.12–7.20 (t, 1H); 13C NMR (50 MHz, CDCl3): −5.52, 18.25,
21.53, 25.85, 63.55, 63.80, 69.02, 69.63, 111.56, 115.43, 122.25,
129.30, 139.51, 158.30; optical purity: 95% ee determined by
HPLC analysis (chiral OJ-H column, n-hexane–2-propanol
(95 : 5), 0.5 mL min−1, 210 nm); retention time: tminor = 22.71
and tmajor = 28.23 min; HRMS (ESI) m/z Calcd C17H29N3O3NaSi
[M + Na]+, 374.1870; found, 374.1868.
Experimental section
General procedure for the phenolic kinetic resolutions of anti-
and syn-aryloxy azido- and benzyloxy alcohols (see Schemes 1
and 2)
(2S,3S)-1-(o-Tolyloxy)-3-azido-4-(tert-butyl-dimethyl siloxy)-
butan-2-ol (1d)
To a stirred solution of (R,R)-(salen) Co[OC(CF3)3](H2O) (3)
(86 mg, 0.1 mmol), molecular sieve (100 mg, 3 Å) and racemic
anti- or syn-azido or benzyloxy epoxide (5 or 7) (5 mmol), in
tert-butyl methyl ether (0.15 mL), phenol (2.25 mmol) (6) was
added at 25 °C. The reaction was stirred for 6–15 h till all the
phenol gets converted (as monitored by TLC). The solvent was
removed under reduced pressure. The crude product was puri-
fied by column chromatography over silica gel (eluting with
pet. ether–EtOAc) to give optically pure anti- or syn-1-aryloxy-3-
azido or benzyloxy-2-alcohols in a pure form. The enantio-
meric purity was determined by chiral HPLC analysis.
Yield: 35%; gum; [α]D25 +15 (c 1.0, CHCl3); IR (CHCl3, cm−1):
774, 838, 1109, 1172, 1258, 1289, 1462, 1500, 1603, 2098, 2857,
1
2884, 2929, 2953, 3451; H NMR (200 MHz, CDCl3) δ 0.12 (s,
6H), 0.93 (s, 9H), 2.24 (s, 3H), 2.63–2.65 (d, J = 5.36 Hz, 1H),
3.57–3.65 (m, 1H), 3.88–4.15 (m, 5H), 6.81–6.91 (m, 2H),
7.11–7.15 (m, 2H); 13C NMR (50 MHz, CDCl3): −5.50, 16.38,
18.27, 25.85, 29.75, 63.65, 63.90, 69.07, 69.83, 111.33, 121.19,
126.61, 126.98, 130.87, 156.30 optical purity: 94% ee deter-
mined by HPLC analysis (chiral OJ-H column, n-hexane–2-pro-
panol (95 : 5), 0.5 mL min−1, 210 nm); retention time: tminor
=
20.71 and tmajor
= 24.23 min; HRMS (ESI) m/z Calcd
(2S,3S)-3-Azido-4-(tert-butyldimethylsiloxy)-1-phenoxybutan-
2-ol (1a)
C17H29N3O3NaSi [M + Na]+, 374.1870; found, 374.1865.
(2S,3S)-1-(4-tert-Butylphenoxy)-3-azido-4-(tert-butyldimethyl-
siloxy)butan-2-ol (1e)
Yield: 65%; gum; [α]D25 +16 (c 1, CHCl3); IR (CHCl3, cm−1): 690,
752, 837, 1042, 1108, 1243, 1497, 1599, 2099, 2857, 2929, 2953,
3460; H NMR (200 MHz, CDCl3) δ 0.12 (s, 6H), 0.93 (s, 9H), Yield: 76%; gum; [α]2D5 +12 (c 1, CHCl3); IR (CHCl3, cm−1): 777,
1
1
2.7 (d, J = 5.0 Hz, 1H), 3.88–4.17 (m, 5H), 6.89–7.00 (m, 3H), 836, 1113, 1243, 1513, 2095, 2858, 2929, 2956, 3460; H NMR
7.29–7.33 (m, 2H); 13C NMR (50 MHz, CDCl3): −5.5, 18.2, 25.8, (200 MHz, CDCl3) δ 0.12 (s, 6H), 0.92 (s, 9H), 1.30 (s, 9H), 2.64
63.4, 63.7, 69.0, 69.6, 114.5, 121.4, 129.5, 158.2; optical purity: (d, J = 5.2 Hz, 1H), 3.53–3.62 (m, 1H), 3.87–4.13 (m, 5H),
92% ee determined by HPLC analysis (chiral OD-H column, 6.82–6.86 (m, 2H), 7.27–7.31 (m, 2H); 13C NMR (50 MHz,
n-hexane–2-propanol (95 : 5), 0.5 mL min−1, 254 nm); retention CDCl3): −5.4, 18.2, 25.8, 31.6, 34.1, 63.5, 63.8, 69.1, 69.6, 114.1,
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126.3, 144.1, 156.0; optical purity: 99% ee determined by CDCl3): −5.5, 18.2, 25.8, 63.2, 63.7, 69.4, 69.6, 113.6, 116.3,
HPLC analysis (chiral OJ-H column, n-hexane–2-propanol 132.4, 157.3; optical purity: 97% ee determined by HPLC analy-
(95 : 5), 0.5 mL min−1, 210 nm); retention time: tmajor = 21.61 sis (OD-H column, n-hexane–2-propanol (10 : 90), 0.5 mL
and tminor = 29.29 min; HRMS (ESI) m/z Calcd C20H35N3O3SiNa min−1, 254 nm); retention time: tmajor = 10.99 and tminor
=
[M + Na]+, 416.2340; found, 416.2346.
12.08 min. HRMS (ESI) m/z Calcd for C16H26BrN3O3NaSi
[M + Na]+, 438.0819; found, 438.0821.
(2S,3S)-1-(3-Methoxyphenoxy)-3-azido-4-(tert-butyldimethyl-
siloxy)butan-2-ol (1f)
(2S,3S)-1-(4-Chlorophenoxy)-3-azido-4-(tert-butyldimethyl-
siloxy)butan-2-ol (1j)
Yield: 60%; gum; [α]D25 +18 (c 1, CHCl3); IR (CHCl3, cm−1): 771,
839, 1112, 1170, 1254, 1283, 1436, 1511, 1606, 1716, 2099, Yield: 90%; gum; [α]2D5 −6.5 (c 1, CHCl3); IR (CHCl3, cm−1):
2857, 2930, 3471; 1H NMR (200 MHz, CDCl3) δ 0.12 (s, 6H), 778, 837, 1095, 1243, 1492, 2100, 2858, 2929, 2953, 3446; 1H
0.93 (s, 9H), 2.7 (d, J = 3.1 Hz, 1H), 3.56–3.59 (m, 1H), 3.78 (s, NMR (200 MHz, CDCl3) δ 0.12 (s, 6H), 0.93 (s, 9H), 2.66 (d, J =
3H), 3.90–3.93 (m, 1H), 4.03 (br s, 1H), 4.02–4.12 (m, 3H), 4.6 Hz, 1H), 3.57–3.62 (m, 1H), 3.91–4.12 (m, 5H), 6.85 (d, J =
6.46–6.53 (m, 3H), 7.19 (t, 1H); 13C NMR (50 MHz, CDCl3): 8.9 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H); 13C NMR (50 MHz,
−5.4, 18.3, 25.8, 55.2, 63.5, 63.8, 69.2, 69.7, 101.2, 106.7, 107.1, CDCl3): −5.5, 18.2, 25.8, 63.3, 63.7, 69.5, 69.6, 115.8, 126.4,
130.0, 159.5, 160.9; optical purity: 93% ee determined by 129.4, 156.9; optical purity: 97% ee determined by HPLC analy-
HPLC analysis (chiral OJ-H column, n-hexane–2-propanol sis (OD-H column, n-hexane–2-propanol (10 : 90), 0.5 mL
(95 : 5), 0.5 mL min−1, 210 nm); retention time: tmajor = 14.45 min−1, 254 nm); retention time: tmajor = 12.33 and tminor
and tminor = 20.25 min; HRMS (ESI) m/z Calcd C17H29N3O4NaSi 13.14 min. HRMS (ESI) m/z Calcd for C16H26ClN3O3NaSi
[M + Na]+, 390.1820; found 390.1815. [M + Na]+, 394.1324; found, 394.1320.
=
4-(2S,3S)-[3-Azido-4-(tert-butyldimethylsiloxy)-2-hydroxybutoxy]- (2S,3S)-1-(3,5-Dichlorophenoxy)-3-azido-4-tert-butyl-dimethylsiloxy)-
benzonitrile (1g) butan-2-ol (1k)
Yield: 87%; gum; [α]2D5 +70 (c 1, CHCl3); IR (CHCl3, cm−1): 778, Yield: 89%; gum; [α]2D5 +12 (c 1.0, CHCl3); IR (CHCl3, cm−1):
836, 1031, 1111, 1172, 1257, 1463, 1471, 1509, 1609, 2099, 771, 839, 1112, 1170, 1254, 1283, 1436, 1511, 1606, 1716, 2099,
2226, 2857, 2929, 2953, 2445; 1H NMR (200 MHz, CDCl3) 2857, 2930, 3471; 1H NMR (200 MHz, CDCl3) δ 0.12 (s, 6H),
δ 0.13 (s, 6H), 0.93 (s, 9H), 2.71 (d, J = 4.9 Hz, 1H), 3.54–3.62 0.93 (s, 9H), 2.73–2.76 (d, J = 5.56 Hz, 1H), 3.58–3.67 (m, 1H),
(m, 1H), 3.94–4.23 (m, 5H), 6.9 (d, J = 9.1 Hz, 2H), 7.6 (d, J = 3.88–4.21 (m, 5H), 6.86–6.91 (d, J = 8.82 Hz, 1H), 7.17–7.22
8.7 Hz, 2H); 13C NMR (50 MHz, CDCl3): −5.5, 18.1, 25.7, 63.1, (dd, J = 2.53, 8.80 Hz, 1H), 7.37–7.38 (d, J = 2.53, 1H); 13C NMR
63.6, 69.5, 69.6, 104.7, 115.3, 133.9, 161.6; optical purity: 98% (50 MHz, CDCl3): −5.48, 18.27, 25.87, 63.40, 63.83, 69.44,
ee determined by HPLC analysis (chiral OD-H column, 70.82, 114.65, 124.07, 126.76, 127.72 130.12, 152.72; optical
n-hexane–2-propanol (80 : 20), 0.5 mL min−1, 210 nm); retention purity: 95% ee determined by HPLC analysis (OD-H column,
time: tmajor = 10.35 and tminor = 11.80 min; HRMS (ESI) m/z n-hexane–2-propanol (90 : 10), 0.5 mL min−1, 254 nm); reten-
Calcd C17H26N4O3NaSi [M + Na]+, 385.1666; found 385.1656.
tion time: tminor = 10.20 and tmajor = 11.50 min. HRMS (ESI)
m/z Calcd for C16H25Cl2N3O3NaSi [M + Na]+, 428.0934; found,
428.0936.
(2S,3S)-1-(4-Fluorophenoxy)-3-azido-4-(tert-butyldimethyl-
siloxy)butan-2-ol (1h)
(2S,3S)-1-(4-(3-Azido-4-(tert-butyldimethylsiloxy)-2-hydroxybutoxy)-
phenyl)-ethanone (1l)
Yield: 72%; gum; [α]D25 +26 (c 1, CHCl3); IR (CHCl3, cm−1): 778,
836, 1098, 1220, 1252, 1507, 2100, 2858, 2930, 2953, 3440; H
1
NMR (200 MHz, CDCl3) δ 0.12 (s, 6H), 0.93 (s, 9H), 2.68 (d, J = Yield: 88%; gum; [α]2D5 +6 (c 1, CHCl3); IR (CHCl3, cm−1): 777,
5.0 Hz, 1H), 3.53–3.62 (m, 1H), 3.88–4.14 (m, 5H), 6.82–6.89 836, 1033, 1114, 1173, 1256, 1307, 1600, 2098, 2857, 2929,
1
(m, 2H), 6.94–7.03 (m, 2H); 13C NMR (50 MHz, CDCl3): −5.5, 2953, 3440; H NMR (200 MHz, CDCl3) δ 0.13 (s, 6H), 0.93 (s,
18.2, 25.8, 63.3, 63.7, 69.6, 69.8, 115.5, 115.7, 116.2, 154.3, 9H), 2.56 (s, 3H), 2.74 (d, J = 4.9 Hz, 1H), 3.55–3.67 (m, 1H),
154.4, 155.2, 155.9; optical purity: 68% ee determined by 3.89–4.25 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.9 Hz,
HPLC analysis (chiral OD-H column, n-hexane–2-propanol 2H); 13C NMR (50 MHz, CDCl3): −5.5, 18.1, 25.7, 26.2, 63.4,
(95 : 5), 0.5 mL min−1, 210 nm); retention time: tmajor = 15.53 63.6, 69.4, 114.2, 130.6, 162.2, 196.6; optical purity: 98% ee
and tminor
= 17.74 min; HRMS (ESI) m/z Calcd for determined by HPLC analysis (Chiral OD-H column, n-hexane–
C16H26FN3O3NaSi [M + Na]+, 378.1620; found, 378.1624.
2-propanol (70 : 30), 0.5 mL min−1, 254 nm); retention time:
tmajor = 10.15 and tminor = 11.35 min; HRMS (ESI) m/z Calcd for
C18H29N3O4NaSi [M + Na]+, 402.1820; found, 402.1823.
(2S,3S)-1-(4-Bromophenoxy)-3-azido-4-(tert-butyldimethyl-
siloxy)butan-2-ol (1i)
(2S,3S)-(Methyl-4-(3-azido-4-(tert-butyldimethylsiloxy)-
2-hydroxybutoxy)benzoate (1m)
3461; H NMR (200 MHz, CDCl3) δ 0.12 (s, 6H), 0.93 (s, 9H), Yield: 81%; gum; [α]2D5 +14 (c 1, CHCl3); IR (CHCl3, cm−1): 771,
2.68 (d, J = 4.7 Hz, 1H), 3.53–3.61 (m, 1H), 3.87–4.12 (m, 5H), 839, 1112, 1170, 1254, 1283, 1436, 1511, 1606, 1716, 2099,
6.78–6.82 (m, 2H), 7.36–7.41 (m, 2H); 13C NMR (50 MHz, 2857, 2930, 3471; 1H NMR (200 MHz, CDCl3) δ 0.13 (s, 6H),
Yield: 86%; gum; [α]D25 +20 (c 1, CHCl3); IR (CHCl3, cm−1): 778,
837, 1003, 1072, 1103, 1242, 1488, 2099, 2857, 2929, 2953,
1
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0.93 (s, 9H), 2.73 (d, J = 5.1 Hz, 1H), 3.55–3.64 (m, 1H), 3.89 (s, (2R,3S)-4-(tert-Butyldimethylsiloxy)-1-(4-nitrophenoxy)-
3H), 3.94–4.23 (m, 5H), 6.94 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 3-(benzyloxy)butan-2-ol (1q)
9.0 Hz, 2H); 13C NMR (50 MHz, CDCl3): −5.5, 18.2, 25.7, 51.8,
Yield: 89%; colorless liquid; [α]2D5 −16.52 (c 1, CHCl3); IR (neat,
63.2, 63.7, 69.3, 69.6, 114.1, 123.1, 131.6, 162.0, 166.6; optical
cm−1): 752, 778, 1111, 1263, 1340, 1517, 1593, 2856, 2928,
purity: 94% ee determined by HPLC analysis (OD-H column,
n-hexane–2-propanol (30 : 70), 0.5 mL min−1, 254 nm); reten-
tion time: tminor = 12.56 and tmajor = 13.31 min; HRMS (ESI)
m/z Calcd for C18H29N3O5NaSi [M + Na]+, 418.1769; found,
418.1765.
1
3472; H NMR (200 MHz, CDCl3): δ 0.10 (s, 6H), 0.92 (s, 9H),
2.97 (br s, 1H), 3.58–3.67 (m, 1H), 3.87–3.90 (m, 2H), 4.10–4.21
(m, 3H), 4.51–4.73 (dd, J = 11.6 and 11.8 Hz, 2H), 6.89–6.97 (m,
2H), 7.24–7.32 (m, 5H), 8.14–8.22 (m, 2H); 13C NMR (50 MHz,
CDCl3): δ −5.4, 18.2, 25.8, 63.0, 69.8, 71.0, 72.6, 78.1, 114.4,
125.7, 127.9, 128.4, 137.7, 141.6, 163.7; optical purity: 97% ee
determined by HPLC analysis (Chiral OJ-H column, n-hexane–
2-propanol (80 : 20), 0.5 mL min−1, 210 nm); retention time:
(2S,3S)-1-(4-Nitrophenoxy)-3-azido-4-(tert-butyldimethylsiloxy)-
butan-2-ol (1n)
Yield: 92%; gum; [α]2D5 +18 (c 1, CHCl3); IR (CHCl3, cm−1): 779, tmajor = 12.53 and tminor = 15.12 min; HRMS (ESI) m/z Calcd for
840, 862, 1111, 1260, 1298, 1343, 1498, 1514, 1593, 1608, 2100, C23H33NO6NaSi [M + Na]+, 470.1969; found, 470.1975.
2857, 2929, 2954, 3461; 1H NMR (200 MHz, CDCl3) δ 0.13 (s,
1-(4-((2R,3S)-4-(tert-Butyl dimethylsiloxy)-3-(benzyloxy)-
2-hydroxybutoxy)phenyl)ethanone (1r)
6H), 0.93 (s, 9H), 2.74 (d, J = 4.8 Hz, 1H), 3.59–3.65 (m, 1H),
3.91–4.28 (m, 5H), 7.1 (d, J = 9.3 Hz, 2H), 8.22 (d, J = 9.3 Hz,
2H); 13C NMR (50 MHz, CDCl3): −5.6, 18.1, 25.7, 63.0, 63.5,
69.6, 70.0, 114.5, 125.8, 141.8, 163.2; optical purity: 96% ee
determined by HPLC analysis (OJ-H column, n-hexane–2-pro-
Yield: 98%, white solid; mp: 91–92 °C; [α]2D5 −19.89 (c 1.0,
CHCl3); IR (CHCl3, cm−1): 699.28, 775.75, 957.19, 1093.07,
1258.78, 1359.27, 1470.93, 1575.75, 1600.40, 1671.94, 2856.59,
2928.76, 3473.28; 1H NMR (200 MHz, CDCl3) δ 0.09 (s, 6H),
0.92 (s, 9H), 2.56 (s, 3H), 2.90 (br s 1H), 3.61–3.69 (m, 1H),
3.87–3.90 (dd, J = 3.01, 5.44 Hz, 2H), 4.09–4.19 (m, 3H),
4.53–4.74 (dd, J = 11.62 Hz, 2H), 6.85–6.95 (m, 2H), 7.27 (s,
5H), 7.89–7.95 (m, 2H); 13C NMR (50 MHz, CDCl3): −5.43,
18.29, 25.91, 26.29, 63.25, 69.19, 71.02, 72.79, 78.40, 114.25,
127.88, 127.99, 128.43, 130.56, 137.96, 162.62, 196.44; optical
purity: 86% ee determined by HPLC analysis (OJ-H column,
n-hexane–2-propanol (80 : 20), 0.5 mL min−1, 254 nm); retention
time: tminor = 14.38 and tmajor = 15.07 min. HRMS (ESI) m/z
Calcd for C25H36O5NaSi [M + Na]+, 467.2224; found, 467.2220.
panol 40 : 60), 0.5 mL min−1, 254 nm); retention time: tmajor
=
10.51 and tminor = 13.84 min; HRMS (ESI) m/z Calcd for
C16H26N4O5NaSi [M + Na]+, 405.1565; found, 405.1558.
(2S,3S)-3-Azido-4-((tert-butyldimethylsilyl)oxy)-1-[(7-methyl-2,3-
dihydro-1H-inden-4-yl)oxy]butan-2-ol (1o)
Yield: 75%; gum; [α]D25 −6.7 (c 1, CHCl3); IR (CHCl3, cm−1):
1
770, 1170, 1112, 1253, 1284, 1510, 1605, 1715, 2104, 3550; H
NMR (200 MHz, CDCl3) δ 0.12 (s, 6H), 0.93 (s, 9H), 2.08 (app.
quintet, J = 7.4 Hz, 2H), 2.20 (s, 3H), 2.66 (d, J = 5.4 Hz, 1H),
2.86 (q, J = 7.7 Hz, 4H), 3.54–3.63 (m, 1H), 3.80–4.11 (m, 5H),
6.59 (d, J = 8.2 Hz, 1H), 6.9 (d, J = 7.9 Hz, 1H); 13C NMR
(50 MHz, CDCl3): −5.5, 18.2, 18.4, 24.4, 25.8, 29.7, 31.8, 63.7,
63.8, 69.1, 69.6, 109.6, 126.6, 127.9, 131.4, 144.9, 152.7; optical
purity: 99% ee determined by HPLC analysis (Chiral OD-H
column, n-hexane–2-propanol (95 : 5), 0.5 mL min−1, 254 nm);
retention time: tmajor = 9.94 and tminor = 11.41 min; HRMS
(ESI) m/z Calcd for C20H33N3O3NaSi [M + Na]+, 414.2183;
found, 414.2188.
(2R,3S)-4-(4-(tert-Butyldimethylsiloxy)-3-(benzyloxy)-
2-hydroxybutoxy)benzaldehyde (1s)
Yield: 75%; gum; [α]D25 +14.02 (c 1, CHCl3); IR (neat, cm−1):
755, 834, 1097, 1256, 1462, 1509, 1600, 1693, 2928, 3454; 1H
NMR (200 MHz, CDCl3): δ 0.09 (s, 6H), 0.92 (s, 9H), 2.95 (br s,
1H), 3.63–3.69 (m, 1H) 3.87–3.91 (m, 2H), 4.11–4.21 (m, 3H),
4.62 (dd, J = 11.6 and 11.8 Hz, 2H), 6.96–7.00 (m, 2H),
7.24–7.35 (m, 5H), 7.80–7.85 (m, 2H), 9.88 (s, 1H); 13C NMR
(50 MHz, CDCl3): δ −5.4, 18.2, 25.9, 63.2, 69.3, 71.0, 72.7, 78.3,
114.8, 128, 128.4, 130.1, 131.9, 137.9, 163.7, 190.4; optical
purity: 99% ee determined by HPLC analysis (OJ-H column,
n-hexane–2-propanol (80 : 20), 0.5 mL min−1, 254 nm); retention
time: tminor = 14.38 and tmajor = 15.07 min; HRMS (ESI) m/z
Calcd for C24H34O5NaSi [M + Na]+, 453.2068; found, 453.2062.
(2R,3S)-4-(4-(tert-Butyldimethylsiloxy)-3-(benzyloxy)-
2-hydroxybutoxy)benzo-nitrile (1p)
Yield: 87%; colorless solid, mp: 62–63 °C; [α]2D5 −7.74 (c 1,
CHCl3); IR (CHCl3, cm−1): 778, 835, 1096, 1172, 1258, 1302,
1
1454, 1508, 1605, 2224, 2856, 2883, 2929, 2953, 3474; H NMR
(200 MHz, CDCl3) δ 0.09 (s, 6H), 0.91 (s, 9H), 2.90–2.92
(m, 1H), 3.64 (q, J = 5.4 Hz, 1H), 3.86–3.89 (m, 2H), 4.10–4.18
(m, 3H), 4.51–4.73 (dd, J = 11.5 and 11.7 Hz, 2H), 6.90–6.96 (m,
2H), 7.27 (m, 5H), 7.53–7.61 (m, 2H); 13C NMR (50 Hz, CDCl3):
(2R,3S)-Methyl 4-(4-(tert-butyldimethylsiloxy)-3-(benzyloxy)-
2-hydroxybutoxy)-benzoate (1t)
−5.5, 18.1, 25.7, 62.9, 69.3, 70.6, 72.5, 78.2, 104.0, 115.1, 118.8, Yield: 81%, colorless liquid; [α]2D5 −20.04 (c 1, CHCl3); IR
127.7, 127.8, 128.2, 133.7, 137.7, 161.9; optical purity: 98% ee (CHCl3, cm−1): 771, 837, 1169, 1255, 1435, 1511, 1605, 1718,
1
determined by HPLC analysis (Chiral OD-H column, n-hexane– 2928, 3478; H NMR (200 MHz, CDCl3) δ 0.09 (s, 6H), 0.91 (s,
2-propanol (80 : 20), 0.5 mL min−1, 210 nm); retention time: 9H), 2.94 (br s, 1H), 3.63–3.68 (m, 1H), 3.81–3.96 (m, 5H),
tmajor = 10.15 and tminor = 11.35 min; HRMS (ESI) m/z Calcd for 4.07–4.17 (m, 3H), 4.53–4.74 (dd, J = 11.6 and 11.8 Hz, 2H),
C24H33NO4NaSi [M + Na]+, 450.2071; found, 450.2070.
6.85–6.92 (m, 2H), 7.27 (m, 5H), 7.93–8.00 (m, 2H); 13C NMR
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(50 MHz, CDCl3): −5.4, 18.2, 25.8, 51.7, 63.2, 69.0, 70.8, 72.7, (1R,2S)-3-(4-Nitrophenoxy)-1-azido-1-phenylpropan-2-ol (2c)
78.4, 114.1, 122.7, 127.8, 127.9, 128.3, 131.5, 137.9, 162.4,
Yield: 90%; gum; [α]D25 +21.56 (c 1, CHCl3); IR (CHCl3, cm−1):
166.6; optical purity: 97% ee determined by HPLC analysis
702, 752, 845, 1111, 1167, 1260, 1342, 1510, 1592, 2105, 3481;
(OJ-H column, n-hexane–2-propanol (80 : 20), 0.5 mL min−1
,
1H NMR (200 MHz, CDCl3) δ 2.64 (d, J = 4.2 Hz, 1H), 3.83–3.87
(dd, J = 4.8 and 9.8 Hz, 1H), 4.00–4.17 (m, 2H), 4.80 (d, J = 7.3
Hz, 1H), 6.88–6.92 (m, 2H), 7.32–7.40 (m, 5H), 8.16–8.21 (m,
2H); 13C NMR (50 MHz, CDCl3): 67.8, 68.8, 73.1, 114.4, 125.8,
127.4, 129.1, 135.8, 141.8, 163.1; optical purity: 94% ee deter-
254 nm); retention time: tminor = 14.38 and tmajor = 15.07 min.
HRMS (ESI) m/z Calcd for C25H36O6NaSi [M + Na]+, 483.2173;
found, 483.2169.
(2R,3S)-1-(2,4,5-Trichlorophenoxy)-4-(tert-butyldimethylsiloxy)- mined by HPLC analysis (chiral OJ-H column, n-hexane–2-pro-
3-(benzyloxy)butan-2-ol (1u)
Yield: 78%; gum; [α]2D5 +5.9 (c 1.0, CHCl3); IR (neat, cm−1): 701,
panol (70 : 30), 0.5 mL min−1, 254 nm); retention time: minor
= 13.27 and tmajor = 14.03 min; HRMS (ESI) m/z Calcd for
C15H14N4O4Na [M + Na]+, 337.0907; found, 337.0898.
1
763, 1050, 1261, 1454, 1492, 2104, 2935, 3034, 3416; H-NMR
(200 MHz, CDCl3): δ 0.09 (s, 6H), 0.92 (s, 9H), 2.88–2.95 (m,
1H), 3.64–3.71 (m, 1H) 3.84–3.91 (m, 2H), 4.06–4.13 (m, 3H),
4.52–4.75 (dd, J = 11.76, 2H), 6.93 (s, 1H), 7.28–7.30 (m, 5H),
7.43 (s, 1H); 13C-NMR (50 MHz, CDCl3): δ −5.39, 18.32, 25.95,
63.43, 70.63, 70.90, 72.92, 78.24, 115.05, 122.11, 124.40,
127.92, 127.99, 128.11, 128.47, 130.82, 131.27, 137.99, 153.36;
optical purity: 97% ee determined by HPLC analysis (OJ-H
(2R,3R)-1-[4-(3-(Benzyloxy)-2-hydroxy-3-phenylpropoxy)phenyl]-
ethanone (2d)
Yield: 89%; gum; [α]D25 +21.56 (c 1, CHCl3); IR (neat, cm−1):
701, 755, 1065, 1255, 1358, 1454, 1599, 1673, 3453; 1H NMR
(200 MHz, CDCl3): δ 2.54 (s, 3H), 3.04 (br s, 1H), 3.74–3.80 (m,
1H), 3.97–4.16 (m, 2H), 4.30–4.56 (dd, J = 11.2 and 11.3 Hz,
2H), 4.61 (d, J = 6.8 Hz, 1H), 6.79–6.86 (m, 2H), 7.30–7.42 (m,
10H), 7.86 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 26.2, 68.0,
70.8, 73.9, 81.4, 114.1, 127.4, 127.8, 127.9, 128.4, 128.5, 128.7,
130.4, 137.5, 137.8, 162.4, 196.2; optical purity: 98% ee deter-
mined by HPLC analysis (chiral OJ-H column, n-hexane–2-pro-
panol (70 : 30), 0.5 mL min−1, 254 nm); retention time: minor
= 10.72 and tmajor = 11.28 min; HRMS (ESI) m/z Calcd for
C24H24O4Na [M + Na]+, 399.1567; found, 399.1567.
column, n-hexane–2-propanol (90 : 10), 0.5 mL min−1
,
254 nm); retention time: tminor = 14.38 and tmajor = 15.07 min;
HRMS (ESI) m/z Calcd for C23H31Cl3O4NaSi [M + Na]+,
527.0949; found, 527.0953.
(2S,3R)-1-(4-(3-Azido-2-hydroxy-3-phenylpropoxy)phenyl)-
ethanone (2a)
Yield: 88%; gum; [α]D25 +16 (c 1, CHCl3); IR (CHCl3, cm−1): 775,
1
845, 1110, 1173, 1254, 1359, 1599, 1671, 2104, 3426; H NMR
(200 MHz, CDCl3) δ 2.54 (s, 3H), 2.65–2.67 (d, J = 4.6 Hz, 1H),
3.77–3.84 (dd, J = 4.8 and 9.7 Hz, 1H), 3.96–4.15 (m, 2H), 4.81
(d, J = 7.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.32–7.41 (m, 5H),
7.89 (d, J = 8.6 Hz, 2H); 13C NMR (50 MHz, CDCl3): 26.1, 67.7,
68.3, 73.1, 114.0, 127.4, 128.7, 128.8, 130.4, 136.0, 162.0, 196.6;
optical purity: 93% ee determined by HPLC analysis (chiral
Acknowledgements
PUK and DAK thank CSIR New Delhi for senior research
fellowships and DST, New Delhi (sanction no. SR/S1/OC-67/
2010) for financial support. The authors are also thankful to
Dr V. V. Ranade, Chair, Chemical Engineering and Process
Development Division for his encouragement and support and
Dr R. Gonnade, CMC Division for providing us with XRD data.
OJ-H column, n-hexane–2-propanol (70 : 30), 0.5 mL min−1
,
214 nm); retention time: tminor = 11.21 and tmajor = 11.64 min;
HRMS (ESI) m/z Calcd for C17H17N3O3Na [M + Na]+, 334.1162;
found, 334.1169.
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