Asymmetric aminolytic kinetic resolution of racemic epoxides using recyclable chiral polymeric Co(III)-salen complexes: A protocol for total utilization of racemic epoxide in the synthesis of (R)-naftopidil and (S)-propranolol

Article abstract of DOI:10.1021/jo4012656

Chiral polymeric Co(III) salen complexes with chiral ((R)/(S)-BINOL, diethyl tartrate) and achiral (piperazine and trigol) linkers with varying stereogenic centers were synthesized for the first time and used as catalysts for aminolytic kinetic resolution (AKR) of a variety of terminal epoxides and glycidyl ethers to get enantio-pure epoxides (ee, 99%) and N-protected β-amino alcohols (ee, 99%) with quantitative yield in 16 h at RT under optimized reaction conditions. This protocol was also used for the synthesis of two enantiomerically pure drug molecules (R)-Naftopidil (α₁- blocker) and (S)-Propranolol (β-blocker) as a key step via AKR of single racemic naphthylglycidyl ether with Boc-protected isoproylamine with 100% epoxide utilization at 1 g level. The catalyst 1 was successfully recycled for a number of times.

Full text of DOI:10.1021/jo4012656

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Article
Asymmetric Aminolytic Kinetic Resolution of Racemic
Epoxides Using Recyclable Chiral Polymeric Co(III)-Salen
Complexes: A Protocol for Total Utilization of Racemic
Epoxide in the Synthesis of (R)-Naftopidil and (S)-Propranolol
Manish Kumar, Rukhsana I. Kureshy, Arpan K. Shah, Anjan
Das, Noor-ul H. Khan, Sayed H. R. Abdi, and Hari Chand Bajaj
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4012656 • Publication Date (Web): 30 Jul 2013
Downloaded from http://pubs.acs.org on July 31, 2013
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Asymmetric Aminolytic Kinetic Resolution of Racemic Epoxides Using
Recyclable Chiral Polymeric Co(III)-Salen Complexes: A Protocol for
Total Utilization of Racemic Epoxide in the Synthesis of (R)-Naftopidil and
(S)-Propranolol
Manish Kumar,a,b Rukhsana I. Kureshy,*a,b Arpan K. Shah,a,b Anjan Das,a,b Noor-ul H. Khan,a,b
Sayed H. R. Abdi,a,b Hari C. Bajaja,b
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aDiscipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute
(CSMCRI), Council of Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagar- 364 021, Gujarat,
India. Fax: +91-0278-2566970. E-mail: rukhsana93@yahoo.co.in
bAcademy of Scientific and Innovative Research, Central Salt and Marine Chemicals Research Institute
(CSMCRI), Council of Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagar- 364 021, Gujarat,
India.
____________________________________________________________________________________
ABSTRACT:
Chiral polymeric Co(III) salen complexes with chiral ((R)/(S)-BINOL, diethyl tartrate) and
achiral (piperazine and trigol) linkers with varying stereogenic centres were synthesised for
the first time and used as catalysts for aminolytic kinetic resolution (AKR) of a variety of
terminal epoxides and glycidyl ethers to get enantio-pure epoxides (ee, 99%) and N-
protected β-amino alcohols (ee, 99%) with quantitative yield in 16 h at RT under optimized
reaction conditions. This protocol is also used for the synthesis of two enantiomerically pure
drug molecules (R)-Naftopidil (α1-blocker) and (S)-Propranolol (β-blocker) as a key step via
AKR of single racemic naphthylglycidylether with Boc-protected isoproylamine with 100%
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epoxide utilization at 1 gram level. The catalyst 1 was successfully recycled for a number of
times.
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INTRODUCTION
Aminolytic kinetic resolution (AKR) of racemic epoxides is a simple, convenient and highly
efficient method to prepare highly valuable enantio-pure β-amino alcohols1 and
corresponding chiral epoxides2 in one go. Driven by the potential application of chiral β-
amino alcohols1 and epoxides,2 the last couple of decades have seen spurt of excellent reports
on use of chiral salen complexes of various metal ions for the synthesis of these molecules.2,3
Subsequently, Bartoli et al.4 effectively used chiral non-recyclable monomeric Cr(III) and
Co(III) salen complexes (2-5 mol%) for the AKR of aryloxy/trans epoxides with
aniline/carbamates. While recently, L. Vares et al.5 have made use of monomeric chiral
Co(III) salen complexes for the resolution of bis-epoxides through hydrolytic and aminolytic
kinetic resolution with water and N-protected amine derivatives as nucleophile giving
excellent results in term of yield and ee of the products. Consequently, we reported a couple
of modifications in the catalyst design6a-c and use of ionic liquids6d-e in order to improve the
efficiency of AKR reaction and to make the catalyst recyclable. In asymmetric catalysis often
an extra element of chirality and multiple catalytic sites embedded in the catalyst, play an
important role in enhancing the catalyst performance.7 However, in such cases multi-step
catalyst synthesis is detrimental for their practical application. Therefore, to keep catalyst
synthesis simple we visualized self-assembled polymer where chiral salen units are suitably
linked through chiral ((R)/(S)-BINOL, diethyltartrate as extra element of chirality) and non-
chiral (trigol and piperazine) groups. Such a self-assembled polymer can be easily
synthesised in two steps from substituted chloromethyl salicylaldehyde8 with readily
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available chiral cyclohexanediamine and then treated with suitable metal source cobalt
acetate to obtain the corresponding catalyst. To demonstrate their application in the AKR of
racemic epoxides, we chose N-protected amines as nucleophiles, as at the end of the reaction
the protecting group can easily be removed to get the desired amino alcohol in high
regioselectivity with practically no side-products. Among the catalysts 1-8 synthesized for the
AKR of racemic epoxides, the catalyst 1 with (S)-BINOL linker was found to be the best that
worked well with a catalyst loading of 1 mol% at which both N-protected amino alcohol and
epoxide were obtained in very high optical purity (ee, >99%). The catalyst 1 was recycled six
times without any loss of its performance. We further extended this protocol in the synthesis
of two important chiral drugs viz., (R)-Naftopidil9 and (S)-Propranolol10 at a gram scale from
single racemic epoxide in most atom economic way reported so far.
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RESULTS AND DISCUSSION
Chiral polymeric salen ligands 1’-8’ with chiral/achiral linker were synthesised in two
steps. In 1st step (R)/(S)-BINOL and diethyltartrate A’-C’ as chiral linker and piperazine,
trigol D’, E’ as achiral linker were reacted with 3-t-Bu-5-(chloromethyl)-2-
hydroxybenzaldehyde to get a dialdehydes A-E7a,11-13 which on condensation with
(1R,2R)/(1S,2S) cyclohexanediamine gave polymeric salen ligands 1’-8’. All the chiral
polymeric salen ligands were characterised by NMR, IR, MASS spectrometry, elemental
analysis, GPC and optical rotation (data are given in experimental section). GPC analysis of
representative polymeric ligand 1’ has shown an average molecular weight (Mn,13999) with
polymer distribution index (PDI) 1.08. Cobalt complexes of these ligands 1’-8’ were obtained
in quantitative yield by their reaction with Cobalt(II) acetate in Methanol:Toluene (1:1) first
under inert atmosphere followed by the addition of p-nitrobenzoic acid (PNBA) while
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exposing the reaction mixture to air for auto-oxidation to get active Co(III) catalysts
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(Scheme-1) (data for all the polymeric salen complexes is given in experimental section).
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Scheme 1. Synthetic steps for the preparation of chiral polymeric Co(III) salen complexes
The role of additives as counter ion/axial ligand and choice of solvent14 is crucial in Co(III)
catalysed AKR of racemic epoxides. Therefore, ligand 1’ was initially picked to optimize these
parameters in combination with Co(II) acetate to catalyse AKR of racemic 1,2-epoxy-3-
phenoxypropane 9a as a model substrate with tert-butylcarbamate 10a as nucleophile in DCM
at RT. The polymeric Co(III) salen complexes of this ligand (2.5 mol%) was prepared in situ by
its reaction with Co(II) acetate first in inert atmosphere and then in air in the presence of acetic
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Table 1. Optimization of reaction conditions for enantioselective AKR of 9a with 10a in
different solvents using the catalyst 1a
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Entry Catalyst
loading
Solvent
Additive
Time Unreacted
N-protected 1,2-amino
(h)
Epoxide
ee(%)b
alcohol
Conv.(%)c
ee(%)d
82
1
2
2.5
2.5
DCM
DCM
Acetic acid
Trichloro
acetic acid
PNBA
LPTS
25
25
76
65
68
75
74
3
4
2.5
2.5
2.5
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
ACN
14
48
30
12
14
16
20
25
24
24
26
16
99.4
-
99.3
-
99.2
-
5
PF6
75
72
81
6
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
99.2
99.4
99.3
76
99.5
99.4
99.5
86
99.7
99.6
99.8
75
7
1.5
1
8
9
0.5
1
10
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12
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14
15
45
65
58
1
THF
76
70
84
1
Toluene
DCE
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88
91
1
90
95
92
1
Chloroform PNBA
Propylene PNBA
carbonate
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90
90
1
40
90
68
93
a Reaction was conducted with epoxide 9a: BocNH2 10a :: 0.2 mmol: 0.1 mmol: in 0.5 mL solvent with 1.
b Determined by HPLC (chiral pack OD column)
c Based on HPLC (Chiral pack AD-H Column) using the calibration curve of racemic N-protected amino alcohol.
d Determined by HPLC (chiral pack AD-H column)
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acid, trichloroacetic acid, p-nitrobenzoic acid, lutidine 2,6-dimethyl pyridiniumtosylate (LPTS)
and ferrocenium hexafluorophosphate as counter ion/axial ligand and their AKR performance
is given in Table 1 as entries 1-5 respectively. Among these the Co(III) complex obtained with
PNBA hence forth designated as 1 was found to be the best to give the product R-amino
alcohol (11a) in excellent yield and ee (>99%) with concomitant recovery of S-enantioenriched
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epoxides (9a') (ee, >99%) in quantitative yield (entry 3). Although it is unclear at this point,
why PNBA as additive fared better with salen complex 1 for the AKR of 1,2 epoxy-3-
phenoxypropane 9a, a similar trend has been reported earlier by Bartoli et al.4b and us.6d The
effect of loading of the catalyst 1 (0.5-5 mol%) in the AKR of model reaction was then
evaluated in DCM at RT (Table 1, entries 6-9). The data revealed that 1 mol% of complex 1
(entry 8) matched the performance, albeit with marginally higher reaction time (16 h) of
initially used 2.5 mol% catalyst loading (entry 3, reaction time is 14 h). The nature of the
solvent is known to influence the reactivity and enantioselectivity of AKR of racemic epoxides
with amines. Therefore, 1 mol% of complex 1 (entry 8) at RT was used to screen various
solvents that include non-polar (toluene) and polar aprotic (CH3CN, CHCl3, DCM, DCE, THF,
propylene carbonate) solvent data is shown in Table 1 (entries 8,10-15). However, no other
solvent could match the performance of DCM.
The above optimized conditions with catalyst 1 (Table 1, entry 8) was then used to
evaluate other chiral polymeric salen complexes viz., 2-8 (1 mol%) for AKR reaction of 1,2
epoxy-3-phenoxypropane 9a as model substrate with tert. butyl carbamates 10a as nucleophile
(Table 2). Among these, the performance of BINOL based catalysts 1-4 (entries 1-4) were
better than the rest 6-8 (entry 6-8) both in terms of product yield and ees except in the case of 5
(entry 5), where the ligand was derived from racemic BINOL and (R,R)-1,2-
diaminocyclohexane gave significantly lower ee (36%) of epoxide as well as in amino alcohol
ee (63%). A possible explanation for this behaviour could be the distortions (random twists) in
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TABLE 2. Screening of chiral polymeric Co(III) salen complexes 1-8 for AKR of 9a with
10aa
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Entry 1
Entry 2
Entry 3
ee of
11a
ee of
11a
ee of
11a
Time
(h)
ee of
9a' (%)b
Conv.
(%)c
Time ee of 9a'
(h)
(%)d
Conv.
(%)c
Time
(h)
ee of 9a'
(%)b
Conv.
(%)c
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(%)d
(%)b
(%)d
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99
99
99
16
98
99
99
16
99
99
99
Entry 4
Entry 5
Entry 6
ee of
11a
(%)b
99
ee of
11a
(%)d
63
ee of
11a
(%)d
62
Time ee of 9a'
Conv.
(%)c
Time ee of 9a'
Conv.
(%)c
Time
(h)
ee of 9a'
Conv.
(%)c
(h)
(%)d
(h)
(%)b
(%)b
16
99
99
16
36
99
15
55
78
x = p-nitrobenzoicacid
Entry 8
Entry 7
ee of
11a
(%)d
51
ee of
11a
(%)d
65
Time ee of 9a'
(h)
(%)b
Conv.
(%)c
Time ee of 9a'
(h)
(%)b
Conv.
(%)c
16
48
91
18
54
85
a Reaction was conducted with epoxide 9a: BocNH2 10a: catalyst 1-8 :: 0.2 mmol: 0.1 mol:0.002 in 0.5 mL DCM
b Product configuration is (S) determined by HPLC.
c Based on HPLC (Chiral pack AD-H Column) using the calibration curve of racemic N-protected amino alcohol .
d Product configuration is (R) determined by HPLC.
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the structure of the polymeric salen ligand in the case of ligand 5’ prepared from racemic
BINOL where both (R) and (S)-BINOL motifs may possibly present randomly in a single
polymeric chain. This possibility does not exist in the case of catalysts 1-4 prepared with pure
(S) and (R)-BINOLs. In fact when we took physical 1:1 mixture of catalyst 1 and 3 and used
these for the AKR of the model reaction, we got the R-amino alcohol and S-enantiopure
epoxides in >99% ee. The configuration of the product amino alcohol is directly dependent
on the diamine collar of salen irrespective of the configuration of BINOL. That is, catalysts
derived from (1R,2R)-1,2-diaminocyclohexane yielded R form of amino alcohol in excess
leaving behind S form of the epoxides. Similarly catalysts originating from (1S,2S)-1,2-
diaminocyclohexane favours the formation of S form of amino alcohol and R form of the
epoxide in excess. It can also be concluded from these results that, though salen motif is
mainly responsible for the enantioselectivity, distance and/or orientation between the salen
motifs also play an important role as it is evident from the results obtained with other chiral
and non-chiral linkers of variable lengths, which were inferior (relatively lower product yield
and ee, entries 6-8) than BINOL based catalysts. To further strengthen this finding and to
understand the probable chirality element significantly contributing towards product
enantioselectivity we have recorded CD spectra of complexes 1-3 in DCM (Figure 1). The
complexes 1 and 2 having (S)- BINOL as linker with (1R,2R)/(1S,2S) cyclohexanediamine
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Catalyst-1
Catalyst-2
Catalyst-3
20
10
0
-10
-20
350 400 450 500 550 600 650 700 750 800 850
wavelength (nm)
Figure 1. CD Spectra of complexes 1-3 recorded in DCM.
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collar gave the d-d bands near 620 nm and d
π* bands at 430 nm of opposite cotton effect
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while the complex 3 derived from ((R)-BINOL with (1R,2R) cyclohexanediamine collar and
complex 1 derived from ((S-BINOL with (1R,2R) cyclohexanediamine) gave the similar trend
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in CD spectra for d-d and d
π* bands confirming that the configuration of the product is
controlled by the chirality of the diamine used and independent of the chiral linker (S)/(R)-
BINOL.
Having achieved very good results with the catalyst 1 under the optimised reaction
conditions, the scope of 1 (Table 1, entry 8) was further extended for AKR of variety of
aryloxy epoxides like 1,2-epoxy-3-phenoxy propane 9a, 4-tert-butyl phenyl glycidyl ether
9b, 4-chloro phenyl glycidyl ether 9c, glycidyl 2-methyl phenyl ether 9d with different
nucleophiles viz., tert-butyl carbamate 10a (BocNH2), urethane 10b and benzyl carbamate
10c. In general, substrates irrespective of electron donating or withdrawing group on phenyl
ring gave the products with excellent conversion (94-99 %) of N-protected amino alcohol
(Table 3, entries 1-12) with high enantioselectivity (97-99 %) in 16-20 h. Pleasantly
corresponding epoxides were also obtained in high quantitative yield and enantioselectivity
(Table 3, entries 1-12). The reactivity and selectivity of the catalyst 1 was further investigated
with other terminal epoxides viz., epichlorohydrin 9e, 1,2-epoxyhexane 9f, benzyl glycidyl
ether 9g and naphthylglycidylether 9h with BocNH2 10a as nucleophile where excellent
results in term of yield (99%) and enantioselectivity (ee, 99%) of both N-protected amino
alcohols and epoxides were achieved in 20 h (Table 4).
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Table 3. Enantioselective AKR of 9a-d with 10a-c in DCM using the polymeric catalyst 1a
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Entry
Epoxides
N-
Time
Unreacted N-protected 1,2-amino
(krel)e
protected (h)
amines
Epoxideb
alcohol
ee(%)
Conv.(%)c ee(%)d
1
2
16
99
99
99
99
99
99
99
99
99
99
99
99
99.5
99
99
99
99
96
94
98
98
99
99
97
99.8
99.0
99.9
99.9
98.5
99.4
99.7
98.3
97.4
98.8
99.9
99.8
4990
857
10a
10b
10c
10a
10b
10c
10a
10b
10c
10a
10b
10c
18
16
18
20
16
16
18
20
21
20
20
9a
3
9111
9111
543
4
5
9b
9c
6
1093
1978
426
7
8
9
266
10
11
12
695
9111
3580
9d
a Reaction was conducted with epoxides 9a-d : RNH2 10 a-c: 1 :: 0.2 mmol: 0.1:0.002 mmol. in 0.5 mL DCM.
b Product configuration is (S) determined by HPLC.
c
Based on HPLC (Chiral pack AD-H Column) using the calibration curve of racemic N-protected amino
alcohol.
d Product configuration is (R) determined by HPLC.
e krel = ln[1 - c(1 + ee)]/ln[1 - c(1 - ee)], where c is the conversion and ee is the enantiomeric excess of the
resulting product N-protected 1,2-amino alcohol
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Table 4. Enantioselective AKR of 9e-h with 10a in DCM using the polymeric catalyst 1a
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Entry
Epoxides
Time
(h)
Unreacted
Epoxideb
ee(%)
N-protected 1,2-amino
(krel)e
alcohols
Conv. (%)c
ee(%)d
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10131
9111
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9f
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98.5
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488
9g
99
99.9
9111
9h
a Reaction was conducted with epoxides 9e-h,: BocNH2 10a: 1 :: 0.2 mmol: 0.1:0.002 mmol in 0.5 mL DCM.
b Product configuration is (S) determined by HPLC and GC.
c Based on HPLC (Chiral pack AD-H Column) using the calibration curve of racemic N-protected amino alcohol.
d Product configuration is (R) determined by HPLC.
ekrel = ln[1 - c(1 + ee)]/ln[1 - c(1 - ee)], where c is the conversion and ee is the enantiomeric excess of the resulting
product N-protected 1,2-amino alcohol
In addition, the chiral polymeric catalyst 1 was precipitated out quantitatively from the
reaction mixture by the addition of hexane. The precipitated catalyst was washed with hexane
and directly used for next catalytic run without further purification. The products N-protected
amino alcohol 11a and chirally enriched epoxide 9a' were recovered from the organic layer
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by column chromatography. In this way the same catalyst was successfully reused six times
with complete retention of enantioselectivity (Figure 2). As there were no changes in the ee
of the product in the 6 recycled experiments conducted. This was further substantiated by the
microanalysis and FT-IR of the recovered catalyst which matched well with the fresh
catalyst. In order to ascertain the stability of the complex 1, kinetic experiments for the AKR
of epichlorohydrin 9e (20 mmol) as a representative substrate with tert-butyl carbamate
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conversion
ee
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Figure 2. Catalyst performance in enantioselective AKR of 9a with 10a in DCM
using recovered catalyst 1
(BocNH2) 10a (10 mmol) was performed with fresh and recovered catalyst which gave
quantitative yield with high optical purity (98-99%) of N-protected amino alcohol (Figure 3).
The kinetic data thus obtained clearly showed that the complex 1 is stable under the AKR
condition used in the present study. Encouraged by the overall results in term of yield and
enantioselectivity of N-protected amino alcohol and chiral epoxide obtained with the catalyst 1
we extended this protocol in the synthesis of chiral drugs viz., (R)-Naftopidil9 and (S)-
Propranolol,10 with 100% utilization of the racemic naphthylglycidylether15 (Scheme 2)
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10 12 14 16 18 20 22
Time(h)
Figure 3. Enantioselective AKR of 9e with 10a in DCM using catalyst 1
at different time intervals.
by the catalyst 2. The reported synthesis of (S)-Propranolol through AKR involved the use of
BocNH2 as nucleophile in 3 steps4b. However, we prepared Boc-protected isoproylamine16 and
used as nucleophile in the AKR of racemic naphthylglycidylether. Thus we got the Boc-
protected amino alcohol in 99% ee, which on deprotection directly gave (S)-Propranolol. The
remaining chirally pure (R)-epoxide on reaction with 1-(2-methoxyphenyl)piperazine gave (R)-
Naftopidil in DCM in one step. This process was also scaled up to one gram level with complete
retention of the results obtained at 1 mmol scale. This is to the best of our knowledge and a rare
example where both the products of AKR were utilized in making valuable products making the
entire process very high at atom economic way. (Details of the experimental procedure are given
in the experimental section).
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Scheme 2. Synthesis of (R)-Naftopidil and (S)-Propranolol
Conclusion
In conclusion we have designed efficient chiral Co(III) polymeric salen ligands with
chiral and achiral linkers for AKR of aryloxy and terminal epoxides with N-protected amine
derivatives. The catalyst 1 gave synthetically valuable enantio-pure epoxides (ee, 99%) and
N-protected 1,2-amino alcohol (ee, 99%) with quantitative yield in 16-20 h and the reaction
was scaled to one gram scale for the synthesis of chiral drugs viz., (R)-Naftopidil and (S)-
Propranolol, α1-adrenergic receptor antagonist or α-blocker and (β-blocker) respectively with
100% utilization of the racemic naphthylglycidylether in atom economic way. The catalyst
was recycled six times successfully.
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Synthesis of Polymeric Salen Ligands 1’-8’. Di-aldehydes A-E viz., (R)-5,5'-(1,1'-
binaphthyl-2,2'-diylbis(oxy))-bis(methylene)bis(3-tert-butyl-2-hydroxybenzaldehyde) A / (S)-
5,5'-(1,1'-binaphthyl-2,2'-diylbis(oxy))-bis(methylene)-bis(3-tert-butyl-2-
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hydroxybenzaldehyde)7a
B,
(2S,3S)-diethyl2,3-bis(3-tert-butyl-5-formyl-4-
hydroxybenzyloxy) succinate11 C, 5,5'-(piperazine-1,4-diylbis(methylene))bis(3-tert-butyl-2-
hydroxy benzaldehyde)12 D and 5,5'-(2,5,8,11-tetraoxadodecane-1,12-diyl) bis (3-tert-butyl-
2- hydroxybenzaldehyde)13 E (1 mmol) were dissolved in dry THF: EtOH mixture (2:1) at 65
oC to which (1R,2R)/(1S,2S)-diaminocyclohexane (0.14 g, 1.2 mmol) in EtOH were added
slowly under nitrogen atmosphere. The resulting solutions were stirred for 4 h under
refluxing condition (TLC checked) and the solvent was partially removed from the each
reaction mixture on a rotary evaporator that gave yellow precipitate. The solid obtained after
filtration were washed with hexane:DCM (50:1) to get the yellow colored desired polymeric
ligands 1’-8’ (Scheme 1).
Preparation of Polymeric Salen Catalysts 1-8. In 50 ml three neck RBF (equipped with a
magnetic bar) under nitrogen atmosphere, the polymeric salen ligands 1’-8’ (1 mmol) were
dissolved in deoxygenated toluene (10 ml). In another 25 ml vial Co(OAc)2.4H2O ( 0.37 g,
1.5 mmnol) was dissolved in methanol (10 ml) and deoxygenated by N2 for 10 min to ensure
complete deoxygenation. The solution of Co(OAc)2.4H2O in MeOH (purple) was transferred
under N2 via cannula to the solution of polymeric salen ligand (yellow), affording a dark red
precipitate. The mixture was stirred for 2 h at RT and then the solvent was removed under
vacuum, dissolved the residue in DCM (50 ml) and passed through celite-545 pad to remove
the excess of Co(OAc)2.4H2O. The filtrate was evaporated by vacuum afforded a dark red
powder. To get the desired active catalyst, Co(II) chiral polymeric salen complexes were
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dissolved in DCM (2 ml) under dry oxygen atmosphere and PNBA (1.2 mmol) was added to
them and the resulting solutions were stirred for 5 h to convert Co(II) chiral polymeric salen
complexes to Co(III) chiral polymeric salen complexes 1-8 (Scheme 1).
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Typical procedure for the AKR of racemic terminal epoxides. In a 5 ml RBF equipped with
a magnetic stirring bar, chiral Co(III) polymeric salen complexes 1-8 (0.002 mmol) were
dissolved in DCM and to these solutions appropriate carbamate 10a–c (0.1 mmol) was added.
The resulting mixture was stirred for 10 min, and then the desired epoxides 9a–h (0.2 mmol)
was added slowly. The reaction mixture was stirred until the HPLC/GC analysis showed
disappearance of the peak of the (R) enantiomer of the epoxide (for HPLC/GC profiles of the
products please see the supporting information). At the end of the reaction, the crude mixture
was repeatedly extracted with n-hexane/diethyl ether (90:10). The product, N-protected 1,2-
amino alcohols 11a–h, and the unreacted chiral epoxides 9a'–h' were recovered by flash
chromatography. The remaining mass was dried under vacuum and stored in a desiccator for
use in subsequent catalytic runs. The enantiomeric excess (ee) of the products 9a'–h' and
11a–h were determined by HPLC analysis using OD, AD-H, OJ, IC chiral columns with
iPrOH/n-hexane as eluent and GC analysis by chiral BTA column (see the Supporting
Information). HPLC traces of the products were compared with the corresponding racemic
samples prepared with racemic salen Co (III) complexes as catalyst.
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Polymeric salen ligand 1’: yield 0.56 g, 98%; yellow crystalline solid; m. p. 220 oC; []D
151.27 (c 0.25, CHCl3); 1H NMR (200 MHz, CDCl3)  = 1.22 (s, 18H), 1.61-1.65 (m, 3H),
1.76-1.88 (m, 5H), 4.71-4.91 (m, 6H), 6.24-6.51(m, 2H), 6.84-6.95 (m, 2H), 7.15-7.42 (m,
10H), 7.68-7.76 (m, 2H), 7.84-7.92 (m, 6H), 13.72 (bs, 2H); 13C NMR (50 MHz, CDCl3)  =
25.6, 26.1, 30.6, 33.3, 71.8, 73.9, 116.1, 117.9, 124.7, 125.2, 126.9, 127.6, 127.8, 129.2,
-
129.6, 130.5, 135.5, 138.31, 138.4, 138.5, 155.5, 166.5. IR (KBr) ν= 3431, 3055, 2930, 2860,
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1627, 1592, 1155, 1082, 869 cm-1; GPC: Average molecular weight (Mn) 13999, polymer
molecular weight distribution (PDI) 1.08; Anal. Calcd. for C51H56N2O4. C, 80.49; H, 7.42; N,
3.68; Found: C, 80.04; H, 7.16; N, 3.45; UV-Vis. (MeOH) max 330 nm.
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Polymeric salen ligand 2’: yield 0.21 g, 96%; yellow crystalline solid; m. p. 210 oC; []D
+165.25 (c 0.25, CHCl3); 1H NMR (200 MHz, CDCl3)  = 1.18 (s, 18H), 1.60-1.65 (m, 3H),
1.78-1.92 (m, 5H), 4.43-4.92 (m, 6H), 5.90-5.94 (m, 2H), 6.61-6.83 (m, 3H), 6.89-7.04 (m,
3H), 7.08-7.19 (m, 6H), 7.46-7.49 (m, 2H), 7.64-7.68 (m, 2H), 7.72-7.85 (m, 4H), 13.91 (bs,
2H); 13C NMR (50 MHz, CDCl3)  = 24.2, 24.9, 29.2, 34.5, 70.4, 72.5, 114.7, 116.5, 118.0,
121.0, 123.3, 123.8, 125.5, 126.4, 127.8, 128.2, 129.1, 129.2, 129.4, 129.5, 129.6, 134.0,
134.2, 154.1, 165.1; IR (KBr) ν = 3432, 3057, 2930, 2859, 1812, 1711, 1626, 1593, 1156,
1086, 869 cm-1; GPC: Average molecular weight (Mn) 13448, polymer molecular weight
distribution (PDI) 1.07; Anal. Calcd. for C51H56N2O4. C, 80.49; H, 7.42; N, 3.68; Found: C,
80.41; H, 7.26; N, 3.55; UV-Vis. (MeOH) max 330 nm.
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Polymeric salen ligand 3’: yield 0.20 g, 95%; yellow crystalline solid; m. p. 215 oC; []D
+136.54 (c 0.01, CHCl3); 1H NMR (200 MHz, CDCl3)  = 1.22 (s, 18H), 1.57-1.69 (m, 3H),
1.78-1.91 (m, 5H), 4.70-4.92 (m, 6H), 6.23-6.31 (m, 2H), 6.44-6.66 (m, 2H), 6.84-6.98 (m,
2H), 7.11-7.16 (m, 3H), 7.21-7.23 (m, 2H), 7.30-7.45 (m, 4H), 7.68-7.71 (m, 2H), 7.76-7.92
(m, 5H), 13.72 (bs, 2H); 13C NMR (50 MHz, CDCl3) = 23.8, 24.3, 28.6, 34.0, 35.97, 69.8,
72.0, 114.1, 115.9, 117.5, 120.6, 122.8, 123.3, 125.0, 125.6, 125.8, 126.1, 127.3, 127.8,
127.9, 128.7, 128.9, 128.9, 133.5, 133.6, 153.6, 164.7; IR (KBr) ν = 3430, 3055, 2931, 2860,
1811, 1736, 1627, 1592, 1155, 1082, 870 cm-1; GPC: Average molecular weight (Mn)
13435, polymer molecular weight distribution (PDI) 1.09; Anal. Calcd. for C51H56N2O4. C,
80.49; H, 7.42; N, 3.68; Found: C, 80.23; H, 7.32; N, 3.48; UV-Vis (MeOH) max 330 nm.
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Polymeric salen ligand 4’: yield 0.22 g, 96%; yellow crystalline solid; m. p. 218 oC; [α]D
+158.34 (c 0.125, CHCl3); 1H NMR (200 MHz, CDCl3)  = 1.22 (s, 18H), 1.56-1.69 (m, 3H),
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1.80-1.90 (m, 5H), 4.70-4.92 (m, 6H), 6.23-6.51(m, 2H), 6.61-6.95 (m, 3H), 7.21-7.26 (m,
3H), 7.30-7.46 (m, 5H), 7.68-7.70 (m, 2H), 7.77-8.03 (m, 6H), 13.75 (bs, 2H); 13C NMR (50
MHz, CDCl3)  = 23.8, 24.3, 28.6, 34.0, 69.8, 72.00, 114.1, 115.9, 117.5, 122.8, 123.3,
125.0, 125.6, 126.1, 127.9, 128.7, 129.1, 133.5, 133.7, 153.5, 164.63; IR (KBr) ν = 3432,
3056, 2931, 2860, 1808, 1722, 1626, 1591, 1326, 1156, 1086, 869, 696 cm-1; GPC: Average
molecular weight (Mn) 13658, polymer molecular weight distribution (PDI) 1.06; Anal.
Calcd. for C51H56N2O4. C, 80.49; H, 7.42; N, 3.68; Found: C, 80.09; H, 7.18; N, 3.35; UV-
Vis (MeOH) max 330 nm.
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Polymeric salen ligand 5’: yield 0.225 g, 98%; yellow crystalline solid; m. p. 225 oC; []D
-142.91(c 0.25, CHCl3); 1H NMR (200 MHz, CDCl3)  = 1.18 (s, 18H), 1.62-1.68 (m, 3H),
1.78-1.83 (m, 5H), 4.41-4.72 (m, 6H), 5.90-5.96 (m, 2H), 6.61-6.84 (m, 3H), 7.00-7.06 (m,
3H), 7.10-7.19 (m, 5H), 7.46-7.49 (m, 2H), 7.64-7.70 (m, 2H), 7.76-7.94 (m, 6H), 13.91 (bs,
2H); 13C NMR (50 MHz, CDCl3)  = 25.6, 26.3, 30.0, 35.9, 71.8, 73.9, 116.1, 117.9, 124.7,
125.2, 126.9, 127.6, 127.8, 129.2, 129.6, 129.9, 130.5, 135.5, 155.59, 165.5; IR (KBr) ν =
3431, 3055, 2931, 2860, 1736, 1627, 1592, 1505, 1155, 1082, 869, 744 cm-1; GPC: Average
molecular weight (Mn) 13208, polymer molecular weight distribution (PDI) 1.04, Anal.
Calcd. for C51H56N2O4. C, 80.49; H, 7.42; N, 3.68; Found: C, 80.38; H, 7.38; N, 3.55; UV-
Vis (MeOH) max 330 nm.
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Catalyst 1: yield 0.64 g, 99%; dark brown solid; m. p. 190 C; [α]D -921.54 (c 0.025,
CHCl3); IR (KBr) ν= 3431, 3057, 2937, 2861, 1695, 1621, 1592, 1523, 1015, 872, 721 cm-1;
Anal. Calcd. for C58H58CoN3O8. C, 70.79; H, 5.94; N, 4.27; Found: C, 70.70; H, 6.06; N,
4.17; UV-Vis (MeOH) max 330, 400 nm.
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Polymeric salen ligand 6’: yield 0.55 g, 95%; yellow crystalline solid; m. p. 110 oC; [α]D
1
+187.09 (c 0.01, CHCl3); H NMR (200 MHz, CDCl3)  = 0.97 (t, J=7 Hz, 6H), 1.34 (s,
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18H), 1.74-1.90 (m, 8H), 3.32-3.36 (m, 2H), 3.87-4.14 (m, 5H), 4.23-4.28 (m, 6H), 4.59-4.74
(m, 3H), 6.95 (s, 2H), 7.11 (s, 2H), 8.24 (s, 2H), 13.86 (bs, 2H); 13C NMR (50 MHz, CDCl3)
 = 13.9, 14.1, 24.2, 24.6, 29.3, 33.1, 33.6, 34.6, 54.6, 61.1, 72.3, 73.3, 76.4, 78.3, 118.1,
125.9, 130.1, 137.3, 160.4, 165.1, 169.2; IR (KBr) ν = 3437, 2932, 2862, 1755, 1629, 1158,
1100, 1027, 863, 704 cm-1; GPC: Average molecular weight (Mn) 3466, polymer molecular
weight distribution (PDI) 1.21; Anal. Calcd. for C39H56N2O8. C, 68.80; H, 8.29; N, 4.11;
Found: C, 68.76; H, 7.98; N, 4.05; UV-Vis. (MeOH) max 260, 330 nm.
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Catalyst 6: yield 0.65 g, 97%; dark brown solid; m. p. 130 C; [α]D -724.72 (c 0.025,
CHCl3); IR (KBr) ν = 3429, 3113, 2929, 2861, 1950, 1749, 1638, 1162, 1098, 1022, 875, 721
cm-1.; Anal. Calcd. for C47H60CoN3O12. C, 61.50; H, 6.59; N, 4.58; Found: C, 61.45; H, 6.34;
N, 4.48; UV-Vis (MeOH) max 400 nm.
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Polymeric salen ligand 7’: yield 0.58 g, 96%; yellow crystalline solid; m. p. 215 oC; [α]D
+93.35 (c 0.25, CHCl3); 1HNMR (200 MHz, CDCl3)  = 1.29 (s, 18H), 1.47-1.66 (m, 3H),
1.7-1.81 (m, 5H), 2.07(s, 2H), 2.29 (m, 8H), 2.79 (bs, 1H), 3.25-3.35 (m, 6H), 6.86 (m, 2H),
7.00-7.17 (m, 2H), 8.17 (s, 2H), 13.69 (bs, 2H); 13C NMR (50 MHz, CDCl3)  = 24.3, 29.4,
30.9, 34.7, 52.8, 62.5, 72.3, 118.2, 126.6, 130.3, 136.7, 151.7, 159.3, 165.4; IR (KBr) ν =
3421, 2934, 2863, 2807, 1629, 1159, 1095, 1013, 878 cm-1; GPC: Average molecular weight
(Mn) 4529, polymer molecular weight distribution (PDI) 1.42; Anal. Calcd. for C35H52N4O2.
C, 74.96; H, 9.35; N, 9.99; Found: C, 74.86; H, 9.08; N, 9.69; UV-Vis (MeOH) max 262, 330
nm.
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Catalyst 7: yield 0.70g, 98%; dark brown solid; m. p. 220 C; [α]D +245.75 (c 0.025,
CHCl3); IR (KBr) ν = 3425, 2925, 2856, 1629, 1524, 1162, 1096, 1025, 876, 724 cm-1; Anal.
Calcd. for C47H60CoN3O12. C, 61.50; H, 6.59; N, 4.58; Found: C = 61.35; H = 6.44; N, 4.48;
UV-Vis (MeOH) max 262, 400 nm.
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Polymeric salen ligand 8’: yield 0.54g, 96%; yellow crystalline solid; m. p. 100 oC; [α]D
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160.01 (c 0.25, CHCl3); 1H NMR (200 MHz, CDCl3)  = 1.38 (s, 18H), 1.69-1.75 (m, 3H),
1.85-2.06 (m, 5H), 3.30-3.32 (m, 3H), 3.56-3.63 (m, 14H), 4.38 (m, 5H), 6.98 (m, 2H), 7.20
(m, 2H), 8.26 (s, 2H), 13.55 (bs, 2H); 13C NMR (50 MHz, CDCl3)  = 23.7, 28.8, 32.5, 34.2,
68.5, 70.0, 71.8, 72.6, 117.6, 126.5, 129.0, 136.6, 159.4, 164.8; IR (KBr) ν = 3432, 2927,
2862, 1629, 1444, 1265, 1098, 1026, 870, 706 cm-1; GPC: Average molecular weight (Mn)
4543, polymer molecular weight distribution (PDI) 1.66; Anal. Calcd. for C37H56N2O6. C,
71.12; H, 9.03; N, 4.48; Found: C, 70.98; H, 9.08; N, 4.20; UV-Vis. (MeOH) max 260, 330
nm.
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Catalyst 8: yield 0.25 g, 95%; dark brown solid; m. p. 110 C; [α]D -638.69 (c 0.025,
CHCl3); IR (KBr) ν= 3432, 2925, 2856, 2364, 1722, 1638, 1526, 1262, 1094, 1026, 873, 790
cm-1; Anal. Calcd. for C44H58CoN3O10. C, 62.33; H, 6.89; N, 4.96; Found: C, 61.95; H, 6.84;
N, 4.78; UV-Vis (MeOH) max 262, 400 nm.
14: In a two neck 10 ml RBF, isopropyl amine (11 mmol, 0.94 ml) was added gradually to
the molten di-tert-butyl dicarbonate (Boc2O) (2.18 g, 10 mmol,) at room temperature. The
resulting solution was stirred for 45 minutes which result in the formation of precipitate. The
excess isopropyl amine was removed under vacuum until only product remained..
Characterization data of products
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14: yield 1.5 g, 95%; white crystalline solid; m. p. 68 C; 1H NMR (200 MHz, CDCl3)  =
1.11 (d, J=6 Hz, 6H), 1.44 (s, 9H), 3.70-3.79 (m, 1H), 4.35 (bs, 1H); 13C NMR (50 MHz,
CDCl3)  = 23.0, 28.4, 42.5, 78.9, 155.1; IR (KBr) ν = 3350, 2979, 2934, 1684, 1536, 1458,
1367, 1358, 1252, 1174, 1079 cm-1; ESI-MS m/z 160 [M+H]+; Anal. Calcd. for C8H17NO2 :
C, 60.35; H, 10.76; N, 8.80; found C, 60.33; H, 10.72; N, 8.71.
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15: yield 0.81 g, 90%; isolated by column chromatography (hexane/AcOEt 90/10) as a white
solid; m. p. 98 oC; [α]D27 +48.83 (c 0.1, CHCl3); The ee was determined by HPLC (Chiralpak
AD-H column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 12.63 min
(R, major) and 17.94 min (S, minor); 1H NMR (200 MHz, CDCl3)  = 1.10 (d, J=6 Hz, 6H),
1.44 (s, 9H), 3.64-3.89 (m, 3H), 4.00-4.49 (m, 4H), 6.82 (bs, 1H), 7.36-7.47 (m, 4H), 7.79
(bs, 1H), 8.22 (bs, 1H); 13C NMR (50 MHz, CDCl3)  = 23.0, 28.3, 42.4, 63.8, 69.2, 70.5,
79.0, 104.9, 120.8, 121.5, 125.3, 125.7, 126.4, 127.5, 134.4, 154.0; IR (KBr) ν = 3415, 2957,
2830, 1645, 1458, 1254, 1069 cm-1; ESI-MS m/z 360 [M+H]+; Anal. Calcd. for C21H29NO4 C,
70.17; H, 8.13; N, 3.90; found C, 70.11; H, 8.05; N, 3.82.
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(R)-Naftopidil 16: yield 0.87 g, 89%; isolated by column chromatography (hexane/AcOEt
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90/20) as a white solid; m. p. 128 C; [α]D -3.00 (c 1.50, MeOH); H NMR (200 MHz,
CDCl3)  = 2.51-2.55 (m, 4H), 2.69-2.74 (m, 2H), 2.90-3.02 (m, 4H), 3.67 (s, 3H), 3.96-4.20
(m, 3H), 6.63 (t, J=8 Hz, 2H), 6.75-6.85 (m, 3H), 7.15-7.34 (m, 5H), 7.61-7.65 (m, 1H), 8.14-
8.19 (m, 1H); 13C NMR(50 MHz, CDCl3) 50.7, 53.7, 55.4, 61.1, 65.8, 70.6, 105.0, 111.3,
118.3, 120.6, 120.8, 121.1, 122.0, 123.1, 125.3, 125.7, 125.9, 126.5, 127.6, 134.5, 141.1,
152.3, 154.5; ESI-MS m/z 393 [M+H]+; Anal. Calcd. For C24H28N2O3 C, 73.44; H, 7.19; N,
7.14; found: C, 73.40; H, 7.04; N, 7.10.
(S)-Propranolol 17: yield 0.61 g, 94%; isolated by column chromatography (hexane/AcOEt
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90/20) as a white solid; m. p. 72-73 C; [α]D -10.05 (c 0.5, EtOH); H NMR (200 MHz,
CDCl3)  = 0.90 (d, J= 6 Hz, 6H), 2.55-2.77 (m, 3H), 3.40 (bs, 1H), 3.89-4.19 (m, 3H), 6.54-
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6.64 (m, 1H), 7.11-7.27 (m, 5H), 7.60 (d, J= 4 Hz, 1H), 8.12 (m, 1H); C NMR(50 MHz,
CDCl3)  = 22.8, 49.0, 49.8, 68.4, 70.9, 104.9, 120.6, 121.9, 125.3, 125.6, 125.9, 126.5,
127.6, 134.5, 154.4; ESI-MS m/z 260 [M+H]+, 283[M+Na]+; Anal. Calcd. for C16H21NO2. C,
74.10; H, 8.16; N, 5.40; found C, 74.02; H, 8.12; N, 5.36.
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(R)-tert-butyl-2-hydroxy-3-phenoxypropylcarbamate (11a): The title compound was
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isolated by column chromatography (hexane/AcOEt 90/10) as a white solid; m. p. 82-85 C;
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[α]D +10.5 (c 2, CHCl3); The ee was determined by HPLC (Chiralpak AD-H column)
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mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 12.63 min (R, major) and
17.94 min (S, minor); 1H NMR (200 MHz, CDCl3): δ = 1.42 (s, 9H), 3.21 (bs, 1H), 3.25-3.35
(m, 1H), 3.42-3.55 (m, 1H), 3.91-4.03 (m, 2H), 4.08-4.19 (m, 1H), 5.02 (bs, 1H, NH), 6.90-
7.00 (m, 3H), 7.26-7.33 (m, 2H); ESI-MS m/z 268 [M+H]+.
(R)-ethyl-2-hydroxy-3-phenoxypropylcarbamate (12a): The title compound was isolated by
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column chromatography (hexane/AcOEt 90/10) as a colorless oil; [α]D +8.6 (c 1.04,
CHCl3); The ee was determined by HPLC (Chiralpak AD-H column) mobile phase, 90/10 n-
hexane/i-PrOH; flow rate 0.7 mL/min; tR = 21.12 min (R, major) and 32.02 min (S, minor);
1H NMR (200 MHz, CDCl3) δ = 1.25 (t, J = 7.2, 3H), 3.14 (bs, 1H), 3.30-3.39 (m, 1H), 3.47-
3.56 (m, 1H), 3.94 (dd, J = 6.4 Hz, 9.6 Hz, 1H), 3.98 (dd, J = 4.8 Hz, 9.6, 1H), 4.06-4.13 (m,
1H), 4.16 (q, J = 7.2 Hz, 2H), 5.15 (br. s, 1H), 6.87-7.02 (m, 3H), 7.26-7.34 (m, 2H); ESI-MS
m/z 240 [M+H]+.
(R)-benzyl-2-hydroxy-3-phenoxypropylcarbamate (13a): The title compound was isolated
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by column chromatography (hexane/AcOEt 90/10) as a white solid; m. p. 79-82 C; [α]D
+6.8° (c 1.04, CHCl3); The ee was determined by HPLC (Chiralpak AD-H column) mobile
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phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 34.44 min (R, major); H NMR
(200 MHz, CDCl3): δ = 2.94 (d, J =4.0 Hz, 1H), 3.34-3.45 (m, 1H), 3.51-3.59 (m, 1H), 3.90-
4.04 (m, 2H), 4.10-4.19 (m, 1H), 5.14 (s, 2H), 5.20 (bs, 1 H), 6.82-7.02 (m, 3H), 7.26-7.48 (m,
7H); ESI-MS m/z 302 [M+H]+.
(R)-tert-butyl-3-(4-tert-butylphenoxy)-2-hydroxypropylcarbamate (11b): The title
compound was isolated by column chromatography (hexane/AcOEt 90/10) as a white solid; m.
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p.115-120 oC ; [α]D27 +588.17 (c 0.012, CHCl3); The ee was determined by HPLC (Chiralpak
AD-H column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 15.28 min
(R, major) and 21.22 min (S, minor); 1H NMR (200 MHz, CDCl3)  1.33 (s, 9H), 1.44 (s, 9H),
2.78 (bs, 1H), 3.76-3.88 (bs, 2H), 3.90 (bs, 1H), 4.03-4.10 (m, 1H), 4.32-4.46 (bs, 2H), 6.84-
6.90 (dd, J = 4 Hz, 4.5, 2H), 7.30-7.34 (t, J = 7.5 Hz, 2H); ESI-MS m/z 324 [M+H]+.
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(R)-ethyl-3-(4-tert-butylphenoxy)-2-hydroxy propylcarbamate (12b): The title compound
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was isolated by column chromatography (hexane/AcOEt 90/10) as a colorless oil; [α]D
+24.96 (c 0.16, CHCl3); The ee was determined by HPLC (Chiralpak AD-H column) mobile
phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 17.78 min (R, major) and 20.19 min
(S, minor); 1H NMR (200 MHz, CDCl3) 1.26 (t, J=7.2 Hz, 3H), 1.44 (s, 9H), 3.40-3.45 (m,
1H), 3.49-3.64 (m, 1H), 3.96 (dd, 1H, J=6.4 Hz, 9.6 Hz, 4.08-4.12 (m,1H), 4.18 (q, J=7.2 Hz,
2H), 4.60-4.64 (m, 2H), 5.11 (s, 1H), 6.89 (d, J = 5.5 Hz, 2H), 7.34 (d, J = 10 Hz, 2H); ESI-
MS m/z 295 [M+1]+.
(R)-benzyl-3-(4-tert-butylphenoxy)-2-hydroxy propylcarbamate (13b): The title
compound was isolated by column chromatography (hexane/AcOEt 90/10) as a white solid;
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m. p. 110-115 C ; [α]D +245.91 (c 0.02, CHCl3); The ee was determined by HPLC
(Chiralpak AD-H column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR =
27.95 min (R, major) and 32.26 min (S, minor); 1H NMR (200 MHz, CDCl3)  = 1.46 (s, 9H),
3.01-3.08 (m, 1H), 3.20-3.26 (m, 1H), 3.42-3.45 (m, 2H), 3.62-3.63 (d, J = 5 Hz, 1H), 3.68-
3.69 (d, J = 3.5 Hz, 1H), 3.78-3.80 (t, J = 4.5 Hz, 1H), 5.08 (s, 2H), 7.32-7.65 (m, 9H); ESI-
MS m/z 357 [M+H]+.
(R)-tert-butyl-3-(4-chlorophenoxy)-2-hydroxy propylcarbamate (11c): The title
compound was isolated by column chromatography (hexane/AcOEt 90/10) as a white solid; m.
p. 92-95 oC ; [α]D27 +25.0 (c 0.16, CHCl3); The ee was determined by HPLC (Chiralpak AD-H
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column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 68.17 min (R,
major) and 73.69 min (S, minor); 1H NMR (200 MHz, CDCl3)  1.42 (s, 9H), 3.20=3.28 (m,
1H), 3.37 (bs, 1H), 3.66-3.98 (m, 2H), 4.07-4.08 (m, 2H), 4.85-5.02 (m, 1H), 6.90-7.12 (d, J =
6 Hz, 2H), 7.26-7.47 (d, J = 6, 2H ); ESI-MS m/z 302 [M+H]+.
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(R)-ethyl-3-(4-chlorophenoxy)-2-hydroxy propylcarbamate (12c): The title compound was
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isolated by column chromatography (hexane/AcOEt 90/10) as a colorless oil; [α]D +25.0 (c
0.16, CHCl3); The ee was determined by HPLC (Chiralpak AD-H column) mobile phase,
90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 75.00 min (R, major) and 82.49 min (S,
minor); 1H NMR (200 MHz, CDCl3)  = 1.24 (t, J = 7 Hz, 3H), 1.80 (bs, 1H), 3.77-3.99 (m,
3H), 4.09, (bs, 1H), 4.14 (q, J = 7 Hz, 2H), 4.68-4.69 (m, 2H), 6.85-7.22 (m, 4H); ESI-MS m/z
274 [M+H]+.
(R)-benzyl-3-(4-chlorophenoxy)-2-hydroxy propylcarbamate (13c): The title compound
was isolated by column chromatography (hexane/AcOEt 90/10) as a White solid; m. p. 86-90
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oC ; [α]D +16.5 (c 0.2, CHCl3); The ee was determined by HPLC (Chiralpak AD-H column)
mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 13.94 min (R, major) and
17.79 min (S, minor); 1H NMR (200 MHz, CDCl3 3.49 (bs, 1H), 3.70-3.75 (m, 1H), 3.82-3.87
(m, 1H), 4.03-4.08 (m, 2H), 4.15-4.17 (m, 1H), 4.70 (s, 1H), 5.10 (s, 2H), 6.82-6.90 (d, J = 8.5
Hz, 2H), 7.25-7.35 (m, 5H), 7.37 (d, J = 4 Hz, 2H ); ESI-MS m/z 336 [M+H]+.
(R)-tert-butyl-2-hydroxy-3-(O-tolyloxy)propylcarbamate (11d): The title compound was
isolated by column chromatography (hexane/AcOEt 90/10) as a white solid. m. p. 98-102 oC;
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[α]D +17.0 (c 2, CHCl3). The ee was determined by HPLC (Chiralpak AD-H column)
mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 38.20 min (R, major) and
45.81 min (S, minor); 1H NMR (200 MHz, CDCl3)  = 1.45 (s, 9H), 2.27 (s, 3H), 2.72 (bs,
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1H),3.72-3.90 (m, 2H), 4.05-4.10 (m, 2H), 4.14-4.17 (m, 1H), 6.82 (d, J= 8 Hz, 1H), 6.89 (t,
J = 7 Hz, 1H), 7.12-7.15 (m, 2H); ESI-MS m/z 282 [M+H]+.
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(R)-ethyl-2-hydroxy-3-(O-tolyloxy)propylcarbamate (12d): The title compound was
isolated by column chromatography (hexane/AcOEt 90/10) as a colorless oil; [α]D27 +19.24 (c
0.15, CHCl3); The ee was determined by HPLC (Chiralpak AD-H column) mobile phase,
90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 36.69 min (R, major); 1H NMR (200 MHz,
CDCl3) δ = 1.27 (t, J = 7 Hz, 3H), 2.24 (s, 3H), 2.70 (bs, 1H), 3.81-3.97 (m, 2H), 4.02-4.12(m,
2H), 4.16 (q, J = 7 Hz, 2H), 4.20-4.33 (m, 2H), 6.84 (d, J = 8 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H),
7.14-7.26 (m, 2H); ESI-MS m/z 254 [M+H]+.
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(R)-benzyl-2-hydroxy-3-(o-tolyloxy)propylcarbamate (13d): The title compound was
isolated by column chromatography (hexane/AcOEt 90/10) as a white solid; m. p. 98-105 oC ;
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[α]D +12.8 (c 0.25, CHCl3); The ee was determined by HPLC (Chiralpak AD-H column)
mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 22.91 min (R, major) and
25.13 min (S, minor); 1H NMR (200 MHz, CDCl3)  = 2.23 (s, 3H), 2.94 (bs, 1H), 3.75-3.86
(m, 2H), 3.90-4.13 (m, 2H), 4.21-4.33 (m, 2H), 5.09 (s, 2H), 6.84-6.87 (d, J = 8 Hz, 1H), 6.94
(bs, 1H), 7.10-7.18 (m, 2H), 7.21-7.36 (m, 5H); ESI-MS m/z 316 [M+H]+.
(R)-3-chloro-2-hydroxy-propyl)-carbamicacidtert-butylester (11e): The title compound
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was isolated by column chromatography (hexane/AcOEt 90/10) as a colorless oil; [α]D
+37.82 (c 0.25, CHCl3); The ee was determined by HPLC on the corresponding O-benzyl
derivative (Chiralpak AD-H column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7
mL/min; tR = 21.88 min (R, major) and 24.21 min (S, minor); 1H NMR (200 MHz, CDCl3)  =
2.98 (bs, 1H), 3.23-3.34 (m, 1H), 3.41-3.51 (m, 1H), 3.54-3.60 (m, 2H), 3.92-4.04 (m, 1H),
5.10 (s, 2H), 7.21-7.36 (m, 5H); ESI-MS m/z 244 [M+H]+.
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(R)-benzyl 2-hydroxyheptylcarbamate (11f): The title compound was isolated by column
chromatography (hexane/AcOEt 90/10) as a colorless oil; [α]D27 +48.32 (c 0.25, CHCl3); The
ee was determined by HPLC the corresponding O-benzyl derivative (Chiralpak AD-H
column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 18.58 min (R,
major); 1H NMR (200 MHz, CDCl3)  = 0.87 (t, J = 7.2 Hz, 3H), 1.26-1.41 (m, 4H), 1.43-
1.52 (m, 2H), 2.98 (bs, 1H), 3.23-3.34 (m, 1H), 3.41-3.51 (m, 1H), 3.92-4.04(m, 1H), 5.03
(bs, 1H); 5.10 (s, 2H), 7.21-7.36 (m, 5H); ESI-MS m/z 266 [M+H]+.
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(R)-tert-butyl-3-(benzyloxy)-2-hydroxypropylcarbamate (11g): The title compound was
isolated by column chromatography (hexane/AcOEt 90/10) as a White solid; m. p. 102-107
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oC; [α]D +116.6 (c 0.02, CHCl3); The ee was determined by HPLC (Chiralpak AD-H
column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR = 30.71 min (R,
major) and 35.63 min (S, minor); 1H NMR (500 MHz, CDCl3)  = 1.45 (s, 9H), 2.61 (bs, 1H),
2.98 (bs, 1H ), 3.49-3.50 (bs, 2H), 3.52 (bs, 1H), 3.62-3.65 (m, 1H), 3.88 (bs, 1H), 4.54, (s,
2H), 7.25-7.34 (m, 5H); ESI-MS m/z 282 [M+H]+.
(R)-2-hydroxy-3-(naphthalen-1-yloxy)-propyl-carbamic acid tert-butyl ester (11h): The
title compound was isolated by column chromatography (hexane/AcOEt 90/10) as a White
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solid; m. p. 102-107 C; [α]D +54.8 (c = 0.25, CHCl3); The ee was determined by HPLC
(Chiralpak AD-H column) mobile phase, 90/10 n-hexane/i-PrOH; flow rate 0.7 mL/min; tR =
22.91 min (R, major) and 25.13 min (S, minor); 1H NMR (CDCl3): δ = 1.46 (s, 9H), 3.36 (bs,
1H), 3.39-3.48 (m, 1H), 3.52-3.65 (m, 1H), 4.16 (d, J = 5.6 Hz, 2H), 4.20-4.31 (m, 1H), 5.08
(bs, 1H), 6.82-6.87 (m, 1H), 7.37-7.54 (m, 4H), 7.79-7.84 (m, 1H), 8.16-8.22 (m, 1H); ESI-MS
m/z 318 [M+H]+.
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(S)-Naphthylglycidylether(9h'): The title compound was isolated by column
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chromatography (hexane/AcOEt 90/20) as a yellow color viscous liquid; [α]D -34.2 (c 1.50,
9
MeOH); The ee was determined by HPLC (Chiralpak OD column) mobile phase, 80/20 n-
hexane/i-PrOH; flow rate 0.8 mL/min; tR = 10.11 min (R, minor) and 11.35 min (S, major); 1H
NMR (200 MHz, CDCl3)  = 2.75 (m, 1H), 2.86 (t, J=4 Hz, 1H), 2.72 (bs, 1H),3.38-3.43 (m,
1H), 3.99-4.07 (dd, J=12 Hz, J=10 Hz, 1H), 4.27-4.34 (dd, J=12 Hz, J=12 Hz, 1H), 6.71 (d,
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J= 6 Hz, 1H), 7.39-7.47 (m, 3H), 7.74-7.78 (m, 1H), 8.26-8.31 (m, 1H); C NMR(50 MHz,
CDCl3)  = 44.1, 49.8, 68.4, 104.5, 120.4, 121.6, 124.9, 125.1, 125.4, 126.1, 127.1, 134.1,
153.7; ESI-MS m/z 201 [M+H]+.
Acknowledgements
Authors are thankful to CSIR-SRF, DST and CSIR Network Project on Catalysis for
financial assistance. M. Kumar, A. K. Shah and Anjan Das are also thankful to AcSIR for
enrolment in Ph.D. and “Analytical Discipline and Centralized Instrumental Facilities”
for providing instrumentation facilities.
Supporting Information
1H, 13C NMR spectra, HPLC, GC and GPC profiles are given for new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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