Chemoenzymatic method for the preparation of γ-amino alcohols from phenylfuran-based aldehydes; lipase-catalyzed kinetic resolution of β-hydroxy nitriles

Article abstract of DOI:10.1016/j.tetasy.2010.04.025

The chemoenzymatic preparation of novel enantiopure phenylfuran-based γ-amino alcohols with N-Boc-protection starting from the corresponding aldehydes is described. Enantiopurity (ee 98-99%) is introduced using Thermomyces lanuginosus lipase as the IMMTLL

Full text of DOI:10.1016/j.tetasy.2010.04.025

Tetrahedron: Asymmetry 21 (2010) 739–745
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic method for the preparation of -amino alcohols
c
from phenylfuran-based aldehydes; lipase-catalyzed kinetic resolution of
b-hydroxy nitriles
*
Mihaela C. Turcu, Päivi Perkiö, Liisa T. Kanerva
Department of Pharmacology, Drug Development and Therapeutics/Laboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku,
Lemminkäisenkatu 5 C, FIN-20520 Turku, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemoenzymatic preparation of novel enantiopure phenylfuran-based c-amino alcohols with N-Boc-
Received 29 March 2010
Accepted 19 April 2010
Available online 18 May 2010
protection starting from the corresponding aldehydes is described. Enantiopurity (ee 98–99%) is intro-
duced using Thermomyces lanuginosus lipase as the IMMTLL-T1-1500 preparation with b-hydroxy nitriles
in an acylation/alcoholysis sequence in tert-butylmethyl ether.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
der mild conditions and usually by small number of reaction steps.
Potential enzymatic methods to the enantiomers of 3-amino-1-aryl-
Amino alcohol moieties with a certain stereochemistry infer
interesting biological activities to organic molecules. Many natu-
rally occurring molecules, synthetic pharmaceutically active inter-
mediates, and chiral ligands and auxiliaries are amino alcohols.
Compounds containing vicinal b-amino alcohol (1,2-amino alco-
hol) moieties have been thoroughly studied, and synthetic ap-
proaches to access such molecules by chemical and biocatalytic
propan-1-ols exploit asymmetric synthesis by the reduction of
ketone precursors (Scheme 1, routes A and B) and the kinetic
resolution of racemic alcohol precursors (routes C and D). The
biocatalytic reduction of b-keto nitriles,12,13 the lipase-catalyzed
acylation of b-hydroxy nitriles,14–18 and the lipase-catalyzed
hydrolysis19 and alcoholysis18 of their racemic esters have been
reported. On the other hand, the enzymatic reduction of 3-amino-
1-arylpropan-1-one has not been described evidently due to
potential imine formation between the functional groups. 1-Aryl-
3-aminopropan-1-ols are not ideal substrates for lipase-catalyzed
enantioselective acylation in spite of the fact that some lipases
(e.g., Burkholderia cepacia lipase) are known to acylate the alcohol
ways are abundant.1 Compounds containing
c-amino alcohol
(1,3-amino alcohol) moieties, 3-amino-1-arylpropan-1-ols in par-
ticular, are widely used for the treatment of psychiatric and meta-
bolic disorders and an access to such molecules is described. Such
compounds include fluoxetine (Prozac™, a selective serotonin
reuptake inhibitor),2,3 atomoxetine (Strattera™, a norepinephrine
reuptake inhibitor),4 and duloxetine (Cymbalta™, a serotonin–nor-
epinephrine reuptake inhibitor).5 Because the enantiomers of
pharmaceutically active compounds often display different physio-
logical properties and may have their own effects on drug–ligand
interactions and metabolic behavior, the preparation of enantio-
pure molecules is of great importance. Reported chemocatalyzed
synthesis strategies include the asymmetric hydrogenation of pro-
chiral amino ketones6,7 and the preparation of chiral 3-hydroxy-
propanenitriles (b-hydroxy nitriles)8–11as methods to introduce
enantiopurity in the1,3-amino alcohol moiety.
function of an amino alcohol in
a highly chemoselective
manner.20–22 This is due to the chemical and/or enzyme-aided
O?N acyl migration, leading to the mixture of mono- and diacylated
products when the two functionalities are separated by 2–4 carbon
atoms.
Our aim herein has been to study the chemoenzymatic synthe-
sis of new enantiopure phenyl-furan-based 1,3-amino alcohols in
N-Boc-protected forms 4a–e starting from the corresponding com-
mercial aldehydes 1a–e (Scheme 2). High stability and enantiose-
lectivity in addition to good availability have made lipases as the
most commonly used biocatalysts in organic chemistry, producing
both enantiomers (one as an alcohol and the other as an ester) in
the highly enantioselective acylation of an initially racemic alcohol
(or amine) or in the deacylation of the corresponding racemic ester.
Herein, the enantioseparation step was chosen to be the lipase-cat-
alyzed acylation of phenylfuran-based nitriles 2a–e, allowing the
separation of the unreacted (S)-2a–e from the resolved mixture.
The lipase-catalyzed deacylation of the esters (R)-3a–e thereafter
Today, enzymes as green chemistry catalysts often replace chem-
ocatalysts as enantiopurity-producing steps in chemoenzymatic
synthesis. This is due to the enantio- and chemoselectivity of en-
zymes, allowing the preparation of highly enantiopure products un-
* Corresponding author. Tel.: +358 2 3336773; fax: +358 2 3337955.
E-mail address: lkanerva@utu.fi (L.T. Kanerva).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.025

740
M. C. Turcu et al. / Tetrahedron: Asymmetry 21 (2010) 739–745
OH
N
Ar
D. Kinetic
resolution
C. Kinetic
resolution
OH
OH
OH
Ar
O
A. Reduction
N
and/or
Ar
NH2
Ar
NH2
H2N
Ar
B. Reduction
O
Ar
NH2
Scheme 1. Potential biocatalytic methods to introduce enantiopurity in 3-amino-1-arylpropan-1-ols.
1) Me3SiCH2CN/
RCOOR1
AcOLi(10 %), DMF
2) H+
Ar
Ar
Ar
Ar
H
CN
R1OH
CN +
OCOR
(R)-3a-e
Lipase
R2OH
+
NC
Lipase
OH
OH
(S)-2a-e
O
1a-e
rac-2a-e
Ar
NaBH4/
CoCl2 6H2O
BOC2O
CN
.
O
O
O
Ar -
:
OH
(R)-2a-e
Cl
Cl
a
b
c
Cl
NaBH4/
.
CoCl2 6H2O
BOC2O
O
O
Boc HN
Ar
OH
Ar
NH Boc
Br
O2N
OH
(R)-4a-e
e
d
(S)-4a-e
Scheme 2. Chemoenzymatic route to enantiopure N-Boc-protected c-amino alcohols.
allows the preparation of the corresponding (R)-alcohols. In the
subsequent reduction step N-Boc-protected (R)- and (S)-4a–e are
obtained.
sisting of an acylation/alcoholysis sequence for the production of
both (R)- and (S)-2a–e as novel phenylfuran-based b-hydroxy ni-
triles (Scheme 2). This enzymatic sequence achieves the highest
possible enantiopurities for both alcohol enantiomers with the
minimal number of reaction steps even in the cases when the
enantioselectivity for the kinetic resolution is not high enough to
allow the enantioseparation at the theoretical 50% conversion.24
To start the work, rac-2a was chosen as a model substrate. Unlike
the case with previous sulfur heterocycles,18 the lipase PS-D-cata-
lyzed acylation of rac-2a (0.05 M) with vinyl acetate (0.1 M) in tert-
butylmethyl ether (TBME) was barely enantioselective (Table 1,
entry 1). Thus, lipase screening with potential lipases from B. cepa-
cia, Pseudomonas fluorescens, Thermomyces lanuginosus, and Can-
dida antarctica in various immobilized forms started the studies.
Lipases from T. lanuginosus (lipozyme TL IM and lipase IMMTLL-
T1-1500) gave the most promising enantioselectivities (entries 7
and 8). Because the acylation with lipozyme TL IM (on granulated
silica material) practically stopped at 16% conversion (entry 7), the
work continued with lipase IMMTLL-T1-1500 (on dry polypropyl-
2. Results and discussion
2.1. Preparation of racemates
Sulfur heterocyclic b-hydroxy nitriles have previously been pre-
pared from sulfur-containing aldehydes and (trimethylsilyl)aceto-
nitrile in the presence of lithium acetate as a Lewis base using a
known method.18,23 The same method was successfully exploited
to obtain racemic b-hydroxy nitriles 2a–e from commercial phen-
ylfuran-based aldehydes 1a–e with isolated yields within the
range 78–83% (Scheme 2). The reaction between rac-2a–e and ace-
tic anhydride in the presence of catalytic amounts of DMAP (1%)/Py
produced the corresponding racemic acetate esters rac-3a–e. Race-
mic mixtures were needed for kinetic resolution studies and also to
provide the analytical methods.
ene beads with size <1500 lm, entry 8). The same enantiomer of
2.2. Lipase-catalyzed acylation
rac-2a reacted faster with all the lipases tested. In accordance with
the enantiopreference of lipase PS-D with previous sulfur hetero-
cycles,18 the (R)-enantiomer reacts faster also with the present
substrates.
In continuation of our work with heterocyclic aromatic b-hy-
droxy nitriles,18 we planned to use a lipase-catalyzed reaction con-

M. C. Turcu et al. / Tetrahedron: Asymmetry 21 (2010) 739–745
741
Table 1
Table 2
Lipase screening (50 mg mLꢀ1) for the acylation of rac-2a (0.05 M) with vinyl acetate
Acylation of rac-2a–e (0.1 M) with vinyl acetate (0.2 M) in the presence of lipase
(0.1 M) in TBME
IMMTLL-T1-1500 (50 mg mLꢀ1) in TBME
Entry Enzyme
preparation
Time
(h)
ee(S)-2a
(%)
ee(R)-3a
(%)
Conversion
(%)
E
Entry rac- Time
ee(R)-3a–e
(%)
Conversion
(%)
E
Conversiona
(%)
2
(h)
1
2
3
4
Lipase PS-D
Lipase PS-C II
Lipase AK
Lipase IMMAPF-
T2-150
0.25
0.25
3
10
11
50
22
47
43
93
97
18
20
35
19
3
3
50
60
1
1
3
5
1
2
3
4
5
a
b
c
0.5
97
98
98
95
95
19
17
26
25
40
79
120
3
5
51–53
50–52
0.25
0.25
0.25
2
115 11 50–52
96 51–52
46 12 53–55
3
d
7
eb
5
6
7
8
CAL-A
3
3
51
14
14
87
41
93
99
93
55
13
13
48
5
30
1
2
a
Theoretical conversion calculated from E-producing ee(S)-2a–eover the range
CAL-B
Lipozyme TL IMa 0.5
ꢁ200
(95–99)%.
b
TBME/acetone (9/1) as a solvent.
Lipase IMMTLL-
T1-1500
3
79
3
9
Lipase IMMTLL-
T2-150
3
16
99
14
50
5
a consequence, for instance enhanced
p–p–interactions may im-
prove substrate binding at the active site. Indeed, the electron-
withdrawing halogen atoms at ortho- and para-positions (entries
2–4) are favorable compared to the electron-donating meta-chlo-
rine (entry 1). However, the lowest reactivity and enantioselectiv-
ity were recorded for the acylation of rac-2e with the strongly
electron-withdrawing para-nitro group (Table 2, entry 5). This re-
sult can be explained by the use of acetone as a co-solvent (1 part)
to make the compound soluble in TBME. As a conclusion, the con-
ditions optimized for the acylation of rac-2a are suitable for the ki-
netic resolution of all the substrates rac-2a–e. In order to plan the
second alcoholysis step of the acylation/alcoholysis sequence
(Scheme 2), the theoretical conversions (50–55%) to reach ee(S)-2a–e
95–99% for the unreacted substrates were calculated based on the
observed E values and are given in Table 2 (column at the right).
a
Acylation stopped at 16% conversion after 1 h.
In order to make kinetic resolution attractive in a preparative
sense, the concentrations of rac-2a and vinyl acetate were doubled
for further optimization. Thus, the acylation of rac-2a (0.1 M) with
vinyl acetate (0.2 M) and lipase IMMTLL-T1-1500 (50 mg mLꢀ1
)
was tested in three commonly used solvents, namely in TBME,
diisopropyl ether (DIPE), and toluene. When the acylation was per-
formed in DIPE (E = 64 2) and in toluene (E = 47 2) the enanti-
oselectivity was low compared to the reaction in TBME
(E = 79 3). For the reaction in toluene, the conversion rate was
also considerably reduced (33% conversion in 3 h) compared to
the reactions in TBME and DIPE with 50–51% conversions in 3 h.
When the acylation was performed in neat isopropyl acetate (a sol-
vent and an acyl donor) the reaction was extremely slow (1% con-
version in 1 day). In terms of enantioselectivity, the acylation with
vinyl acetate was favorable compared to that with isopropenyl ace-
tate (E = 67 1), another commonly used irreversible acyl donor in
TBME. For economic reasons, the lipase IMMTLL-T1-1500 content
50 mg mLꢀ1 was finally chosen for the acylation of rac-2a (0.1 M)
with vinyl acetate (0.2 M) in TBME after it was shown that the fur-
ther increase of the catalyst content had just a negligible effect on
conversion with time (Fig. 1).
2.3. Lipase-catalyzed alcoholysis
Naturally, the same enantiopreference is observed in the acyla-
tion and deacylation (alcoholysis, hydrolysis, and so on) directions
with a certain lipase. Alcoholysis was preferred in the present work
due to the low solubility of compounds 2 and 3 in aqueous envi-
ronments. Lipase IMMTLL-T1-1500-mediated alcoholysis was
investigated primarily aiming to deacylate the (R)-esters 3a–e ob-
tained through the preparative-scale kinetic resolution of rac-2a–e.
In addition, we wanted to know how enantioselectively the alco-
holysis proceeds. Alcohols are known to be competitive inhibitors
of lipases,25,26 and accordingly low alcohol contents were favored.
Each of the esters rac-3a–e (0.1 M) was subjected to alcoholysis
(Scheme 3) with butan-1-ol (0.3 M) in TBME in the presence of li-
pase IMMTLL-T1-1500 (50 mg mLꢀ1), and the results are shown in
Table 3. Reactions proceeded slowly although in highly enantiose-
lective fashion compared to the corresponding acylation reactions
(Table 2). Both the unreacted (S)-3a–d and the produced (R)-2a–d
were furnished in enantiopure forms at close to 50% conversion
(entries 1–4) while the alcoholysis of rac-3e was slow and the
enantioselectivity was low (entry 5) the presence of acetone being
again an evident reason. The reactivity with 3a in 3 h was im-
proved from 26% conversion with 50 mg mLꢀ1 of lipase IMMTLL-
T1-1500 to 46% conversion with 100 mg mLꢀ1 of the enzyme. On
the other hand, 0.2 M (conversion 29% in 3 h) and 0.3 M (conver-
sion 26% in 3 h) butan-1-ol concentrations gave practically the
same reactivity in the presence of lipase IMMTLL-T1-1500
(50 mg mLꢀ1) while higher alcohol contents caused dramatic rate
retardations. Accordingly, the highly enantioselective alcoholysis
with butan-1-ol proved to be an excellent second step in the
two-step acylation/deacylation protocol, improving the enantiopu-
rity of the reactive (R)-enantiomer at the same time. In spite of
excellent enantioselectivity, alcoholysis is not the choice for kinetic
resolution due to the fact that the unreacted ester enantiomers
then cannot be transformed into the corresponding alcohol enanti-
omers by lipase catalysis under mild conditions.
Finally, the acylation of all the substrates rac-2a–e was per-
formed under the above optimized conditions. The results in Ta-
ble 2 indicate clear effects of the substrate structure on both
reactivity and enantioselectivity. Electron-withdrawing substitu-
ents lead to reduced electron density at the aromatic system. As
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
Time/h
Figure 1. Progression curves for the acylation of rac-2a in TBME with different
amounts of lipase IMMTLL-T1-1500 (
25 mg mLꢀ1
,
50 mg mLꢀ1
,
75 mg mLꢀ1).

742
M. C. Turcu et al. / Tetrahedron: Asymmetry 21 (2010) 739–745
Ar
Ar
Ar
BuOH
CN
OCOMe
rac-3a-e
NC
MeCO2Bu
CN
+
+
Lipase IMMTLL-T1-1500
OCOMe
OH
(S)-3a-e
(R)-2a-e
Scheme 3. Kinetic resolution of rac-3a–e with butan-1-ol.
Table 5
Prepared enantiopure
Table 3
c-amino alcohols 4a–d
Alcoholysis of rac-3a–e (0.1 M) with butan-1-ol (0.3 M) and lipase IMMTLL-T1-1500
(50 mg mLꢀ1) in TBME
c
-Amino alcohol
ee (%)
Specific rotationa
Yieldb (%)
ee(R)-2a–e
(%)
ee(S)-3a–e
(%)
Conversion
(%)
E
(S)-4a
(S)-4b
(R)-4b
(S)-4c
(S)-4d
(R)-4d
99
98
99
99
95
94
+1.4c
+0.2
ꢀ0.2
+1.9
+1.2
ꢀ1.1
59
68
70
57
61
68
Entry rac-
Time
(h)
3
1
2
3
4
5
a
b
c
24
24
24
24
24
96
95
96
94
97
97
98
98
99
52
50
51
51
51
35
>200
162 16
>200
>200
d
ea
72 19
a
b
c
(c 2, CHCl3).
Isolated yields for the reduction step.
(c 1, CHCl3).
a
TBME/acetone (4/1) as a solvent.
2.4. Chemoenzymatic preparation of (R)- and (S)-4a–e
3. Conclusion
Finally the preparative-scale kinetic resolution of rac-2a–e was
performed under optimized conditions of the substrate (0.1 M), vi-
nyl acetate (0.2 M), and lipase IMMTLL-T1-1500 (50 mg mLꢀ1) in
TBME, affording unreacted (S)-2a–e enantiopure at 83–97% iso-
lated yields when the reactions were stopped at 51–53% conver-
sions. After purification by column chromatography, the isolated
(R)-3a–e ester products were subjected to alcoholysis with bu-
tan-1-ol (0.2 M) in TBME in the presence of lipase IMMTLL-T1-
1500 (50 mg mLꢀ1), affording (R)-2a–e at 71–92% isolated yields
also enantiopure. For the kinetic resolution of rac-2e and for the
deprotection of (R)-3e acetone served as a co-solvent due to solu-
bility problems. The outcome of the enzymatic preparative work is
given in Table 4.
Four new enantiopure phenylfuran-based 1,3-amino alcohols in
N-Boc-protected forms 4a–d were prepared chemoenzymatically
starting from the corresponding commercial aldehydes 1a–d. The
lipase IMMTLL-T1-1500 (lipase from T. lanuginosus)-catalyzed
reaction, consisting of an acylation/alcoholysis sequence, was
successfully applied as an enantiopurity-producing step through
kinetic resolution of b-hydroxy nitrile precursors. The products
(R)- and (S)-2a–e were obtained at excellent enantiopurity
(>98%) and in high isolated yields. Further transformation of the
b-hydroxy nitriles into the corresponding N-Boc-protected c-ami-
no alcohols was achieved by reduction with NaBH4 in the presence
of CoCl2ꢂ6H2O.
Table 4
4. Experimental part
Enantiopure 2a–e prepared by lipase IMMTLL-T1-1500-catalyzed kinetic resolution:
the R-enantiomers obtained through acylation/alcoholysis sequence and the S-
enantiomers through acylation
4.1. Materials and methods
(R)-2
(S)-2
All solvents were of the highest analytical grade and were dried
by standard methods when necessary. Aldehydes 1a–e, trimethyl-
silyl acetonitrile, lithium acetate, and vinyl acetate were purchased
from Sigma–Aldrich. Vinyl butanoate was the product of Fluka and
isopropenyl acetate of Merck. Lipase PS from B. cepacia on
diatomaceous earth (lipase PS-D) and on ceramic particles (lipase
PS-C II) and lipase AK powder from P. fluorescens were purchased
from Amano Pharmaceuticals. C. antarctica lipase A (CAL-A) was
the product of Roche. CAL-A and lipase AK were immobilized on
Celite in the presence of sucrose as described before.29 C. antarctica
lipase B (CAL-B, Novozym 435) and Lipozyme TL IM were obtained
from Novozymes. Lipase preparations IMMAPF-T2-150 from P. flu-
orescens and IMMTLL-T1-1500 and IMMTLL-T2-150 from T. lanugi-
nosus were acquired from ChiralVision. The 1H and 13C NMR spectra
were recorded at 25 °C on a Brucker Avance 500 spectrometer
equipped with a BBO-5 mm-Zgrad probe operating at 500.13 and
125.77 MHz, respectively, with tetramethylsilane (TMS) as an
internal standard. HRMS were recorded with a ZabSpec-oaTof
instrument. Analytical thin layer chromatography (TLC) was carried
out on Merck Kieselgel 60F254 sheets. Preparative chromatographic
separations were performed using column chromatography on
ee
(%)
Yielda
(%)
Specific
ee
(%)
Yieldc
(%)
Specific
rotationb
rotationb
a
b
c
d
e
99
99
99
99
99
71
92
88
89
74
+46.7
+44.7
+45.5
+39.4
+55.4
98
99
99
99
97
83
97
91
89
95
ꢀ46.3
ꢀ43.8
ꢀ48.2
ꢀ36.2
ꢀ56.6
a
b
c
Overall yields from the enzymatic acylation/deacylation sequence.
(c 1, CHCl3).
Isolated yields based on the conversion of enzymatic acylation.
With the enantiomers of b-hydroxy nitriles at hands, the reduc-
tion of the nitrile group finished the chemoenzymatic synthesis
(Scheme 2). Sodium borohydride as a mild and easy-to-handle re-
agent was used in the presence of CoCl2ꢂ6H2O for the reductions.
CoCl2ꢂ6H2O was present because transition metal salts have been
reported to allow the fine-tuning of the reactivity of the metal hy-
dride.27 The reduction of (R)- and/or (S)-2a–d was achieved with
57–70% isolated yields without any significant depletion of the ori-
ginal enantiopurity (Table 5). The primary amine products ob-
tained by reduction were trapped with di-tert-butyl dicarbonate
(Boc2O) in situ in order to prevent the dimerization of the amine
produced with an imine intermediate.28 Reduction of rac-2e was
not completed because the nitro group was primarily reduced by
NaBH4 as reported also in the literature.28
Merck Kieselgel 60 (0.063–0.200 lm). Optical rotations were
measured with a Perkin–Elmer 341 Polarimeter using the sodium
D line, and the ½a D25
ꢃ
values are given in units of 10ꢀ1 deg cm2 gꢀ1
.
Melting points were measured with a Gallenkamp apparatus and

M. C. Turcu et al. / Tetrahedron: Asymmetry 21 (2010) 739–745
743
are uncorrected. The determination of E was based on the equation
E = ln[(1 ꢀ c)(1 ꢀ eeS)]/ln[(1 ꢀ c)(1 + eeS)] using linear regression {E
as the slope of the line ln[(1 ꢀ c)(1 ꢀ eeS)] versus ln[(1 ꢀ c)(1
+ eeS)]}.30 For enzymatic acylation conversion was obtained using
equation c = eeS/(eeS + eeP). For enzymatic alcoholysis conversion
was obtained using benzil for (R)-3a, acetophenone for (R)-3b,
and 1,4-dimethoxybenzene for (R)-3c–e as external standards.
The enzymatic reactions were performed at room temperature
(23–24 °C) unless otherwise stated.
J = 0.5 Hz, 1H, C(3)-H), 6.60 (d, J = 3.5 Hz, 1H, C(4)-H), 7.35 (dt,
J = 8.5 Hz, J = 2.5 Hz, 1H, (C(30)-H, C(50)-H), 7.57 (dt, J = 8.5 Hz,
J = 2.5 Hz, 1H, C(20)-H, C(60)-H); 13C NMR (CDCl3, 126 MHz), d
(ppm): 25.03 (C(2)-CH(OH)CH2CN), 63.96 (C(2)-CH(OH)CH2CN),
106.16 (C(3)), 109.74 (C(4)), 116.71 (CN), 125.15 (C(20), C(60)),
128.63 (C(10)), 129.01 (C(30)), C(50)), 133.63 (C(40)), 152.48 (C(5)),
153.42 (C(2)).
4.2.4. 3-[5-(4-Bromophenyl)furan-2-yl]-3-hydroxypropane-
nitrile rac-2d
4.2. Preparation of rac-2a–e
Light yellow solid (mp 111–112 °C) in 78% yield. HRMS M+
found (M+ calculated for C13H10BrNO2): 290.98860 (290.98949);
MS: m/z (relative intensity) = 291 (18), 251 (100), 172 (9), 144
(7), 115 (17); 1H NMR (CDCl3, 500 MHz), d (ppm): 2.67 (d,
J = 5.5 Hz, 1H, OH), 2.96 (dd, J = 6.0 Hz, J = 2.5 Hz, 2H, C(2)-
CH(OH)CH2CN), 5.09 (q, J = 5.5 Hz, 1H, C(2)-CH(OH)CH2CN), 6.48
(d, J = 3.5 Hz, 1H, C(3)-H), 6.61 (d, J = 3.5 Hz, 1H, C(4)-H), 7.51 (s,
4H, C(20)-H, C(30)-H, C(50)-H, C(60)-H); 13C NMR (CDCl3, 126 MHz),
d (ppm): 25.03 (C(2)-CH(OH)CH2CN), 63.95 (C(2)-CH(OH)CH2CN),
106.27 (C(3)), 109.77 (C(4)), 116.73 (CN), 121.74 (C(40)), 125.39
(C(20), C(60)), 129.06 (C(10)), 131.93 (C(30), C(50)), 152.56 (C(5)),
153.41 (C(2)).
4.2.1. 3-[5-(3-Chlorophenyl)furan-2-yl]-3-hydroxypropane-
nitrile rac-2a
Racemates 2a–e were all prepared according to the known
method.18,23 (Trimethylsilyl)acetonitrile (1.53 g, 13.51 mmol,
1.85 mL) was added to the combined solution of lithium acetate
(10% molar) in DMF (17 mL) and 5-(3-chlorophenyl)furan-2-carb-
aldehyde (2.00 g, 9.68 mmol) in DMF (40 mL) at 0 °C. The mixture
was allowed to warm slowly to room temperature, and thereafter
the stirring was continued for 3 h. The reaction was quenched with
HCl (1 M, 8 mL) and MeOH (40 mL). Distilled water (200 mL) was
added and the mixture was extracted with diethyl ether
(3 ꢄ 120 mL). The organic layer was washed with brine, dried over
MgSO4, and evaporated. The crude product was purified by passing
through a silica gel column with ethyl acetate/hexane (3/7) as an
eluent to obtain rac-2a as light yellow solid (1.98 g, 7.99 mmol,
mp 76–78 °C) in 83% yield. HRMS M+ found (M+ calculated for
C13H10ClNO2): 247.03900 (247.04001); MS: m/z (relative inten-
sity) = 115(15), 149 (8), 207(100), 247(18); 1H NMR (CDCl3,
500 MHz), d (ppm): 2.71 (d, J = 5.0 Hz, 1H, OH), 2.92–3.01 (dd,
J = 6.0 Hz, J = 2.0 Hz, 2H, C(2)-CH(OH)CH2CN), 5.10 (q, J = 6.0 Hz,
1H, C(2)-CH(OH)CH2CN), 6.49 (dd, J = 3.5 Hz, J = 0.5 Hz, 1H, C(3)-
H), 6.64 (d, J = 3.5 Hz, 1H, C(4)-H), 7.23–7.25 (m, 1H, C(40)-H),
7.31 (t, J = 8.0 Hz, 1H, C(50)-H), 7.52 (dt, J = 8.0 Hz, J = 1.5 Hz, 1H,
C(60)-H), 7.62 (t, J = 2.0 Hz, 1H, C(20)-H); 13C NMR (CDCl3,
4.2.5. 3-Hydroxy-3-[5-(4-nitrophenyl)furan-2-yl]-propane-
nitrile rac-2e
Orange solid (mp 111–112 °C) in 81% yield. HRMS M+ found (M+
calculated for C13H10N2O4): 258.06500 (258.06500); MS: m/z (rela-
tive intensity) = 258 (15), 240 (7), 218 (100), 178 (32), 115 (13); 1H
NMR (CDCl3, 500 MHz), d (ppm): 2.67 (s, 1H, OH); 3.00 (t, J = 6.5 Hz,
2H, C(2)-CH(OH)CH2CN), 5.16 (t, J = 6.0 Hz, 1H, C(2)-CH(OH)
CH2CN), 6.58 (dd, J = 3.5 Hz, J = 0.5 Hz, C(3)-H), 6.85 (d, J = 3.5 Hz,
1H, C(4)-H), 7.78 (dt, J = 9.0 Hz, J = 2.5 Hz, 2H, C(20)-H, C(60)-H),
8.25 (dt, J = 9.0 Hz, J = 2.5 Hz, 2H, C(30)-H, C(50)-H); 13C NMR (CDCl3,
126 MHz),
d (ppm): 25.11 (C(2)-CH(OH)CH2CN), 63.95 (C(2)-
CH(OH)CH2CN), 109.63 (C(4)), 110.26 (C(3)), 116.50 (CN), 124.15
(C(30), C(50)), 124.39 (C(20), C(60)), 135.72 (C(10)), 146.76 (C(40)),
152.10 (C(5)), 154.47 (C(2)).
126 MHz),
d (ppm) 25.05 (C(2)-CH(OH)CH2CN), 63.96 (C(2)-
CH(OH)CH2CN), 106.80 (C(3)), 109.74 (C(4)), 116.72 (CN), 121.97
(C(60), 123.89 (C(20)), 127.81 (C(40)), 130.09 (C(50)), 131.79 (C(10)),
134.82 (C(30)), 152.81 (C(5)), 152.95 (C(2)).
4.3. Lipase-catalyzed acylation of rac-2a–e
In a typical small-scale experiment, one of the lipases (typically
50 mg mLꢀ1) was added to the solution of one of the substrates rac-
2a–e (0.05 or 0.1 M) and an acyl donor (2 equiv) in an organic sol-
vent. The reaction mixture was shaken at room temperature. The
4.2.2. 3-[5-(2-Chlorophenyl)furan-2-yl]-3-hydroxypropane-
nitrile rac-2b
Yellow solid (mp 60–61 °C) in 81% yield. HRMS M+ found (M+
calculated for C13H10ClNO2): 247.03990 (247.04001); MS: m/z (rel-
ative intensity) = 247 (20), 207 (100), 149 (7), 115 (15), 84 (18), 49
(20); 1H NMR (CDCl3, 500 MHz), d (ppm): 2.74 (d, J = 5.0 Hz, 1H,
OH), 2.96 (dd, J = 6.2 Hz, J = 2.2 Hz, 2H, C(2)-CH(OH)CH2CN), 5.11
(q, J = 5.5 Hz, 1H, C(2)-CH(OH)CH2CN), 6.52 (dd, J = 3.5 Hz,
J = 0.5 Hz, 1H, C(3)-H), 7.07 (d, J = 3.5 Hz, 1H, C(4)-H), 7.22 (td,
J = 7.5 Hz, J = 1.5 Hz, 1H, C(40)-H), 7.32 (td, J = 7.5 Hz, J = 1.5 Hz,
1H, C(50)-H), 7.43 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, C(30)-H), 7.81 (dd,
J = 8.0 Hz, J = 1.5 Hz, 1H, C(60)-H); 13C NMR (CDCl3, 126 MHz), d
(ppm): 25.05 (C(2)-CH(OH)CH2CN), 63.95 (C(2)-CH(OH)CH2CN),
109.54 (C(3)), 115.59 (C(4)), 116.79 (CN), 126.96 (C(50)), 128.00
(C(60)), 128.59 (C(30)), 130.36 (C(40)), 130.79 (C(20), C(10)), 150.67
(C(5)), 152.29 (C(2)).
progress of the reaction was followed by taking samples (10 lL)
at intervals. After derivatization the samples were analyzed by
HP 1090 Liquid Chromatograph equipped with Daicel Chiralcel
(0.46 ꢄ 25 cm) OD-H column. Derivatization with butanoic anhy-
dride for rac-2c–d and with propanoic anhydride for rac-2e in
the presence of catalytic amounts of DMAP (1%)/Py was needed
to achieve base-line separation of both the substrate and product
enantiomers.
4.4. Preparative-scale kinetic resolution of rac-2a–e
4.4.1. Kinetic resolution of rac-2a
The general procedure is described for rac-2a as a model com-
pound. Lipase IMMTLL-T1-1500 (2.02 g) was added to the solution
of rac-2a (1.00 g, 4.04 mmol) and vinyl acetate (0.69 g, 8.08 mmol,
0.74 mL) in TBME (40 mL), and the mixture was shaken at room
temperature. The reaction was stopped by filtering off the enzyme
after 4 h at 52% conversion. The enzyme was washed twice with
TBME (2 ꢄ 10 mL). After evaporation of the solvent, the unreacted
(S)-2a and the produced (R)-3a were separated on silica gel by
elution with ethyl acetate/hexane (1/4). Compound (S)-2a was ob-
tained as a light yellow solid in 83% yield {mp 90–91 °C, ee = 98%),
4.2.3. 3-[5-(4-Chlorophenyl)furan-2-yl]-3-hydroxypropane-
nitrile rac-2c
Light yellow solid (mp 96–97 °C) in 79% yield. HRMS M+ found
(M+ calculated for C13H10ClNO2): 247.04080 (247.04001); MS: m/z
(relative intensity) = 247 (18), 207 (100), 149 (8), 115 (12), 84 (26),
49 (29); 1H NMR (CDCl3, 500 MHz), d (ppm): 2.59 (d, J = 5.0 Hz, 1H,
OH), 2.96 (dd, J = 6.0 Hz, J = 2.5 Hz, 2H, C(2)-CH(OH)CH2CN), 5.10
(q, J = 5.5 Hz, 1H, C(2)-CH(OH)CH2CN), 6.48 (dd, J = 3.5 Hz,

744
M. C. Turcu et al. / Tetrahedron: Asymmetry 21 (2010) 739–745
½
a 2D5
ꢃ
¼ ꢀ46:3 (c 1, CHCl3)}. Compound (R)-3a was obtained as a
6.09 (t, J = 6.5 Hz, 1H, CH(OCOCH3)CH2CN), 6.56 (d, J = 3.5 Hz, 1H,
yellow oil in 82% yield {ee = 89%, ½a D25
ꢃ
¼ þ181:6 (c 1, CHCl3)}.
C(3)-H), 6.63 (d, J = 3.5 Hz, 1H, C(4)-H), 7.52 (s, 4H, C(20)-H, C(30)-
H, C(50)-H, C(60)-H); 13C NMR (CDCl3, 500 MHz), d (ppm): 20.85
(OCOCH3), 22.15 (CH(OCOCH3)CH2CN), 63.70 (CH(OCOCH3)
CH2CN), 106.30 (C(3)), 112.28 (C(4)), 115.72 (CN), 121.94 (C(40)),
125.53 (C(20), C(60)), 128.93 (C(10)), 131.94 (C(30), C(50)), 148.62
(C(5)), 153.85 (C(2)), 169.60 (OCOCH3).
HRMS M+ found (M+ calculated for C15H12ClNO3): 289.05057
(289.05060); MS: m/z (relative intensity) = 289 (26), 230 (25),
207 (100), 149 (9), 43 (24); 1H NMR (CDCl3, 500 MHz), d (ppm):
2.15 (s, 3H, OCOCH3), 3.08 (dd, J = 7.5 Hz, J = 6.5 Hz, 2H,
CH(OCOCH3)CH2CN), 6.09 (t, J = 6.5 Hz, 1H, CH(OCOCH3)CH2CN),
6.57 (d, J = 3.5 Hz, 1H, C(3)-H), 6.65 (d, J = 3.5 Hz, 1H, C(4)-H),
7.25–7.27 (ddd, J = 8.0 Hz, J = 2.0 Hz, J = 1.0 Hz, 1H, C(40)-H), 7.32
(t, J = 8.0 Hz, 1H, C(50)-H), 7.54 (dt, J = 7.5 Hz, J = 1.5 Hz, 1 H,
4.4.5. Kinetic resolution of rac-2e
The reaction for rac-2e was stopped after 7 h, at 51% conversion,
C(60)-H), 7.64 (t, J = 2.0 Hz,
1
H, C(20)-H); 13C NMR (CDCl3,
yielding (S)-2e as an orange solid in 95% yield {mp 112–113 °C,
500 MHz), d (ppm): 20.84 (OCOCH3), 22.15 (CH(OCOCH3)CH2CN),
63.72 (CH(OCOCH3)CH2CN), 106.83 (C(3)), 112.27 (C(4)), 115.69
(CN), 122.12 (C(60)), 124.02 (C(20)), 127.98 (C(40)), 130.09 (C(50)),
131.65 (C(10)), 134.82 (C(30)), 148.84 (C(5)), 153.40 (C(2)), 169.59
(OCOCH3).
ee = 97%, ½a 2D5
¼ ꢀ56:6 (c 1, CHCl3)}. Compound (R)-3e was ob-
ꢃ
tained as an orange solid in 89% yield {mp 106–107 °C, ee = 93%,
½
a 2D5
ꢃ
¼ þ221:9 (c 1, CHCl3)}. HRMS M+ found (M+ calculated for
C15H12N2O5): 300.07570 (300.07462); MS: m/z (relative inten-
sity) = 300 (23), 241 (20), 218 (100), 195 (9), 172 (11), 139 (4),
115 (8), 43 (31); 1H NMR (CDCl3, 500 MHz), d (ppm): 2.17 (s, 3H,
OCOCH3), 3.10 (d, J = 6.0 Hz, 2H, CH(OCOCH3)CH2CN), 6.12 (t,
J = 6.0 Hz, 1H, CH(OCOCH3)CH2CN), 6.65 (d, J = 3.5 Hz, 1H, C(3)-
H), 6.86 (d, J = 3.5 Hz, 1H, C(4)-H), 7.80 (dt, J = 9.0 Hz, J = 2.0 Hz,
2H, C(20)-H, C(60)-H), 8.26 (dt, J = 9.0 Hz, J = 2.0 Hz, 2H, C(30)-H,
C(50)-H); 13C NMR (CDCl3, 500 MHz), d (ppm): 20.81 (OCOCH3),
22.22 (CH(OCOCH3)CH2CN), 63.61 (CH(OCOCH3)CH2CN), 109.55
(C(4)), 112.62 (C(3)), 115.52 (CN), 124.34 (C(30), C(50)), 124.39
(C(20), C(60)), 135.56 (C(10)), 146.92 (C(40)), 150.48 (C(5)), 152.52
(C(2)), 169.52 (OCOCH3).
4.4.2. Kinetic resolution of rac-2b
The reaction for rac-2b was stopped after 4 h at 53% conversion,
yielding (S)-2b as an orange solid in 97% yield {mp 43 °C, ee = 99%,
½
a 2D5
ꢃ
¼ ꢀ43:8 (c 1, CHCl3)}. Compound (R)-3b was obtained as a
yellow solid in 97% yield {mp 41 °C, ee = 88%, ½a D25
¼ þ171:0 (c 1,
ꢃ
CHCl3)}. HRMS M+ found (M+ calculated for C15H12ClNO3):
289.05060 (289.05057); MS: m/z (relative intensity) = 289 (27),
230 (25), 207 (100), 149 (11), 43 (26); 1H NMR (CDCl3, 500 MHz),
d (ppm): 2.15 (s, 3H, OCOCH3), 3.09 (dd, J = 6.5 Hz, J = 6.0 Hz, 2H,
CH(OCOCH3)CH2CN), 6.12 (t, J = 6.5 Hz, 1H, CH(OCOCH3)CH2CN),
6.61 (d, J = 3.5 Hz, 1H, C(3)-H), 7.08 (d, J = 3.5 Hz, 1H, C(4)-H),
7.23 (ddd, J = 9.0 Hz, J = 7.5 Hz, J = 1.5 Hz, 1H, C(40)-H), 7.33 (td,
J = 8.0 Hz, J = 1.0 Hz, 1H, C(50)-H), 7.44 (dd, J = 8.0 Hz, J = 1.5 Hz, 1
H, C(30)-H), 7.83 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H, C(60)-H); 13C NMR
4.5. Lipase-catalyzed deprotection of (R)-3a–e
General procedure is described for (R)-3a as a model compound.
Lipase IMMTLL-T1-1500 (0.34 g) and butan-1-ol (0.13 mL) were
added to the solution of (R)-3a (0.20 g, 0.69 mmol, ee 89%) in TBME
(6.90 mL), and the mixture was shaken at room temperature for
48 h to reach 91% conversion. The reaction was stopped by filtering
off the enzyme. The produced (R)-2a was purified in 84% yield as a
(CDCl3, 500 MHz),
d (ppm): 20.84 (OCOCH3), 22.17 (CH(O-
COCH3)CH2CN), 63.68 (CH(OCOCH3)CH2CN), 111.60 (C(3)), 111.99
(C(4)), 115.74 (CN), 126.99 (C(40)), 128.15 (C(60)), 128.48 (C(20)),
128.75 (C(50)), 130.49 (C(10)), 130.81 (C(30)), 148.35 (C(5)), 151.14
(C(2)), 169.61 (OCOCH3).
light yellow solid {mp 90–91.5 °C, ee = 99%, ½a D25
¼ þ46:7 (c 1,
ꢃ
CHCl3)} by silica gel column chromatography with ethyl acetate/
hexane (3/7) as an eluent.
4.4.3. Kinetic resolution of rac-2c
The reaction for rac-2c was stopped after 2.5 h at 53% conver-
Compound (R)-2b was obtained as an orange solid in 95% yield
sion, yielding (S)-2c as a yellow solid in 91% yield {mp 93–94 °C,
{mp 46–47 °C, ee = 99%, ½a D25
¼ þ44:7 (c 1, CHCl3)}.
ꢃ
ee = 99%, ½a 2D5
ꢃ
¼ ꢀ48:2 (c 1, CHCl3)}. Compound (R)-3c was ob-
Compound (R)-2c was obtained as a light yellow solid in 92%
tained as a light yellow solid in 91% yield {mp 108–109 °C,
yield {mp 95–96 °C, ee = 99%, ½a D25
¼ þ45:5 (c 1, CHCl3)}.
ꢃ
ee = 93%, ½a 2D5
ꢃ
¼ þ198:8 (c 1, CHCl3)}. HRMS M+ found (M+ calcu-
Compound (R)-2d was obtained as a yellow solid in 90% yield
lated for C15H12ClNO3): 289.05090 (289.05057); MS: m/z (relative
intensity) = 289 (30), 230 (28), 207 (100), 149 (12), 43 (21); 1H
NMR (CDCl3, 500 MHz), d (ppm): 2.15 (s, 3H, OCOCH3), 3.08 (dd,
J = 6.5 Hz, J = 3.5 Hz, 2H, CH(OCOCH3)CH2CN), 6.09 (t, J = 6.5 Hz,
1H, CH(OCOCH3)CH2CN), 6.56 (d, J = 3.5 Hz, 1H, C(3)-H), 6.61 (d,
J = 3.5 Hz, 1H, C(4)-H), 7.36 (dt, J = 8.5 Hz, J = 2.5 Hz, 2H, C(30)-H,
C(50)-H), 7.59 (td, J = 8.5 Hz, J = 2.5 Hz, 2H, C(20)-H, C(60)-H); 13C
NMR (CDCl3, 500 MHz), d (ppm): 20.85 (OCOCH3), 22.16 (CH(O-
COCH3)CH2CN), 63.71 (CH(OCOCH3)CH2CN), 106.19 (C(4)), 112.27
(C(3)), 115.72 (CN), 125.29 (C(20), C(60)), 128.53 (C(10)), 129.02
(C(30), C(50)), 133.80 (C(40)), 148.58 (C(5)), 153.85 (C(2)), 169.60
(OCOCH3).
{mp 109–110 °C, ee = 99%, ½a D25
¼ þ39:4 (c 1, CHCl3)}.
ꢃ
Compound (R)-2e was obtained as an orange solid in 82% yield
{mp 115–116 °C, ee = 99%, ½a D25
¼ þ55:4 (c 1, CHCl3)}.
ꢃ
4.6. Preparation of the enantiomers of 4a–d
After derivatization with butanoic anhydride for 4a–b and 4d
and with acetic anhydride for 4c the values of ee were determined
with HP 1090 Liquid Chromatograph equipped with a Daicel Chi-
ralcel (0.46 ꢄ 25 cm) OD-H column using hexane/isopropyl alcohol
as an eluent.
The preparation of (S)-4a is used to illustrate the general proce-
.
dure. Boc2O (0.88 g, 4.03 mmol) and CoCl2 6H2O (0.48 g,
4.4.4. Kinetic resolution of rac-2d
2.02 mmol) were introduced into a round-bottomed flask in meth-
anol (75 mL) under argon atmosphere, at 0 °C, and (S)-2a (0.50 g,
2.02 mmol) was added. NaBH4 (0.53 g, 14.01 mmol) was added
with caution in small portions. The mixture was stirred at room
temperature for 2 h before methanol was removed under reduced
pressure. The residue was dissolved in ethyl acetate (100 mL) and
the solution was saturated with NaHCO3 (50 mL). The mixture was
filtered and the organic layer was separated and washed once with
ethyl acetate (100 mL). The combined organic layers were washed
with brine (100 mL) and dried over anhydrous Na2SO4 before the
The reaction for rac-2d was stopped after 2 h at 52% conversion,
yielding (S)-2d as a yellow solid in 89% yield {mp 109–110 °C,
ee = 99%, ½a 2D5
¼ ꢀ36:2 (c 1, CHCl3)}. Compound (R)-3d was ob-
ꢃ
tained as a light yellow solid in 96% yield {mp 128–129 °C,
ee = 82%, ½a 2D5
ꢃ
¼ þ167:4 (c 1, CHCl3)}. HRMS M+ found (M+ calcu-
lated for C15H12BrNO3): 334.99790 (334.99800); MS: m/z (relative
intensity) = 333 (34), 274 (24), 251 (100), 195 (12), 172 (10), 114
(10), 43 (50); 1H NMR (CDCl3, 500 MHz), d (ppm): 2.15 (s, 3H,
OCOCH3), 3.08 (dd, J = 6.0 Hz, J = 4.0 Hz, 2H, CH(OCOCH3)CH2CN),

M. C. Turcu et al. / Tetrahedron: Asymmetry 21 (2010) 739–745
745
solvent was evaporated. The crude product was purified by column
chromatography with ethyl acetate/hexane (3/7) as an eluent to
yield (S)-4a as a yellow solid {0.47 g, 1.33 mmol, yield 59%, mp
Compound (S)-4d was obtained as a yellow oil in 68% yield
{ee = 95%, ½a 2D5
ꢃ
¼ þ1:2 (c 2, CHCl3)}. HRMS M+ found (M+ calculated
for C18H22BrNO4): 395.07350 (395.07322); MS: m/z (relative inten-
sity) = 395 (10), 339 (33), 323 (12), 304 (14), 294 (26), 265 (46), 251
(100), 193 (14), 116 (26); 1H NMR (CDCl3, 500 MHz), d (ppm): 1.45
(s, 9H, C(CH3)3), 2.01 (q, J = 6.5 Hz, 2H, CH(OH)CH2CH2NH), 3.20–
3.26 (m, 1H, CH(OH)CH2CH2NH), 3.51–3.56 (m, 1H, CH(OH)
CH2CH2NH), 4.80 (t, J = 6.5 Hz, 1H, C(2)CH(OH)), 4.87 (b, 1H, NH),
6.34 (dd, J = 3.5 Hz, J = 0.5 Hz, 1H, C(3)-H), 6.58 (d, J = 3.5 Hz, 1H,
C(4)-H), 7.46–7.52 (m, 4H, C(20)-H, C(30)-H, C(50)-H, C(60)-H); 13C
NMR (CDCl3, 126 MHz), d(ppm): 28.39 (C(CH3)3), 36.14
(CH(OH)CH2CH2NH), 36.97 (CH(OH)CH2CH2NH), 65.15 (C(2)CH
(OH)), 79.84 (C(CH3)), 106.20 (C(3)), 108.09 (C(4)), 121.00 (C(40)),
125.21 (C(20), C(60)), 129.68 (C(10)), 131.75 (C(30), C(50)), 152.25
(C(5)), 156.37 (C(2)), 157.06 (NHCOOC(CH3)3).
79–80 °C, ee = 99%, ½a D25
ꢃ
¼ þ1:4 (c 1, CHCl3)}. HRMS M+ found
(M+ calculated for C18H22ClNO4): 351.12320 (351.12373); MS: m/
z (relative intensity) = 351 (4), 295 (29), 277 (22), 260 (16), 250
(20), 234 (28), 221 (48), 207 (100), 191 (7), 116 (15); 1H NMR
(CDCl3, 500 MHz),
d (ppm): 1.45 (s, 9H, C(CH3)3), 2.02 (q,
J = 6.0 Hz, 2H, CH(OH)CH2CH2NH), 3.20–3.26 (m, 1H, CH(OH)
CH2CH2NH), 3.52–3.56 (m, 1H, CH(OH)CH2CH2NH), 3.62 (s, 1H,
OH), 4.81 (t, J = 7.0 Hz, 1H, C(2)CH(OH)), 4.88 (b, 1H, NH), 6.35 (d,
J = 3.5 Hz, 1H, C(3)-H), 6.60 (d, J = 3.5 Hz, 1H, C(4)-H), 7.20 (dd,
J = 8.0 Hz, J = 1.0 Hz, 1H, C(40)-H), 7.28 (t, J = 8.0 Hz, 1H, C(50)-H),
7.50 (dt, J = 7.5 Hz, J = 1.5 Hz, 1H, C(60)-H), 7.63 (t, J = 2.0 Hz, 1H,
C(20)-H); 13C NMR (CDCl3, 126 MHz), d (ppm): 28.39 (C(CH3)3),
36.17 (CH(OH)CH2CH2NH), 36.95 (CH(OH)CH2CH2NH), 65.15
(C(2)CH(OH)), 79.85 (C(CH3)), 106.74 (C(4)), 108.06 (C(3)), 121.74
(C(60)), 123.67 (C(20)), 127.16 (C(40)), 129.91 (C(50)), 132.42
(C(10)), 134.67 (C(30)), 151.79 (C(5)), 156.63 (C(2)), 157.11 (NHC
OOC(CH3)3).
Compound (R)-4d was prepared as a light brown solid in 61%
yield {mp 76–77 °C, ee = 94%, ½a D25
¼ ꢀ1:1 (c 2, CHCl3)}.
ꢃ
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Compound (S)-4b was obtained as a yellow oil in 68% yield
{ee = 98%, ½a 2D5
ꢃ
¼ þ0:2 (c 2, CHCl3)}. HRMS M+ found (M+ calculated
for C18H22ClNO4): 351.12360 (351.12373); MS: m/z (relative inten-
sity) = 351 (4), 295 (23), 277 (16), 250 (18), 56 (221), 207 (100), 191
(11), 115 (18); 1H NMR (CDCl3, 500 MHz), d (ppm): 1.44 (s, 9H,
C(CH3)3), 2.03 (q, J = 6.0 Hz, 2H, CH(OH)CH2CH2NH), 3.22–3.27 (m,
1H, CH(OH)CH2CH2NH), 3.51–3.55 (m, 1H, CH(OH)CH2CH2NH),
4.83 (t, J = 7.0 Hz, 1H, C(2)CH(OH)), 4.89 (b, 1H, NH), 6.39 (d,
J = 3.5 Hz, 1H, C(3)-H), 7.05 (d, J = 3.5 Hz, 1H, C(4)-H), 7.17 (td,
J = 8.0 Hz, J = 1.5 Hz, 1H, C(40)-H), 7.29 (td, J = 8.0 Hz, J = 1.0 Hz,
1H, C(50)-H), 7.41 (dd, J = 8.0 Hz, J = 1.0 Hz, 1H, C(30)-H), 7.33 (dd,
J = 8.0 Hz, J = 1.5 Hz, 1H, C(60)-H); 13C NMR (CDCl3, 126 MHz), d
(ppm): 28.39 (C(CH3)3), 36.12 (CH(OH)CH2CH2NH), 36.99 (CH(OH)
CH2CH2NH), 65.24 (C(2)CH(OH)), 79.79 (C(CH3)), 107.95 (C(3)),
111.64 (C(4)), 126.79 (C(50)), 127.84 (C(40)), 127.95 (C(60)), 129.11
(C(10)), 130.01 (C(30)), 130.67 (C(20)), 149.46 (C(5)), 156.03 (C(2)),
157.03 (NHCOOC(CH3)3).
Compound (R)-4b was obtained as a light yellow oil in 70% yield
{ee = 99%, ½a 2D5
¼ ꢀ0:2 (c 2, CHCl3)}.
ꢃ
Compound (S)-4c was obtained as a light yellow solid in 57%
yield {mp 89.5–90.5 °C, ee = 99%, ½a D25
¼ þ1:9 (c 2, CHCl3)}. HRMS
ꢃ
M+ found (M+ calculated for C18H22ClNO4): 351.12510 (351.
12373); MS: m/z (relative intensity) = 351 (10), 295 (32), 277 (9),
250 (20), 221 (45), 191 (6), 116 (15); 1H NMR (CDCl3, 500 MHz), d
(ppm): 1.45 (s, 9H, C(CH3)3), 2.01 (q, J = 6.5 Hz, 2H, CH(OH)
CH2CH2NH), 3.20–3.26 (m, 1H, CH(OH)CH2CH2NH), 3.51–3.57 (m,
1H, CH(OH)CH2CH2NH), 4.80 (t, J = 6.5 Hz, 1H, C(2)CH(OH)), 4.88
(b, 1H, NH), 6.33 (dd, J = 3.5 Hz, J = 0.5 Hz, 1H, C(3)-H), 6.56 (d,
J = 3.5 Hz, 1H, C(4)-H), 7.32 (dt, J = 8.5 Hz, J = 2.0 Hz, 2H, C(20)-H,
C(60)-H), 7.56 (dt, J = 8.5 Hz, J = 2.0 Hz, 1H, C(30)-H, C(50)-H); 13C
NMR (CDCl3, 126 MHz), d(ppm): 28.39 (C(CH3)3), 36.12 (CH(OH)
CH2CH2NH), 36.98 (CH(OH)CH2CH2NH), 65.15 (C(2)CH(OH)),
79.82 (C(CH3)), 106.08 (C(3)), 108.04 (C(4)), 124.93 (C(20), C(60)),
128.83(C(30), C(50)), 129.27 (C(10)), 132.90 (C(40)), 152.24 (C(5)),
156.31 (C(2)), 157.06 (NHCOOC(CH3)3).
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