CAL-B catalyzed synthesis of chiral polyamides

Article abstract of DOI:10.1016/j.tetasy.2012.05.021

CAL-B (Novozym 435) plays a dual role in our approach to chiral polyamides. It is used to introduce the appropriate chirality in the synthesis of monomers (amino-esters and diamines) from racemic 12-methyldodecalactone and then to catalyze their polycondensation. The AB and AABB enzymatic polymerizations have been carried out under reduced pressure; they give rise to optically active polymers in good yield, with a good degree of polymerization, and a narrow polydispersity index. This approach demonstrates that the presence of a methyl group at the stereogenic center at the α-position relative to the nitrogen atom does not slow down the polymerization as compared with the polycondensation of a related achiral monomer.

Full text of DOI:10.1016/j.tetasy.2012.05.021

Tetrahedron: Asymmetry 23 (2012) 867–875
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
CAL-B catalyzed synthesis of chiral polyamides
Florent Poulhès a,b, Dominique Mouysset a,b, Gérard Gil c,d, , Michèle P. Bertrand a,b, , Stéphane Gastaldi a,b,
⇑
⇑
⇑
a Aix-Marseille Univ, Institut de Chimie Radicalaire UMR 7273, Equipe CMO, 13397 Cedex 20, Marseille, France
b CNRS, Institut de Chimie Radicalaire UMR 7273, Equipe CMO, 13397 Cedex 20, Marseille, France
c Aix-Marseille Univ, ISM2 UMR 7313, Equipe Chirosciences, 13397 Cedex 20, Marseille, France
d CNRS, ISM2 UMR 7313, Equipe Chirosciences, 13397 Cedex 20, Marseille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2012
Accepted 22 May 2012
CAL-B (Novozym 435) plays a dual role in our approach to chiral polyamides. It is used to introduce
the appropriate chirality in the synthesis of monomers (amino-esters and diamines) from racemic
12-methyldodecalactone and then to catalyze their polycondensation. The AB and AABB enzymatic poly-
merizations have been carried out under reduced pressure; they give rise to optically active polymers in
good yield, with a good degree of polymerization, and a narrow polydispersity index. This approach dem-
onstrates that the presence of a methyl group at the stereogenic center at the a-position relative to the
nitrogen atom does not slow down the polymerization as compared with the polycondensation of a
related achiral monomer.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The main limitation is the necessity to select precursors from
the chiral pool to synthesize optically active monomers, and
Polyamides are widely recognized for their excellent thermal,
mechanical and chemical properties.1 These interesting character-
istics, which can be assigned to the polar amide bond, can be cou-
pled with chiroptical effects resulting from the introduction of
stereocenters all along the polymeric backbone. The combination
of these two kinds of useful properties is very promising for the
development of new materials equipped with unique features.2–7
Indeed, some optically active polyamides can be used as materials
for chiral separation membranes or as chiral stationary phases for
high performance liquid chromatography, due to their chiral recog-
nition abilities.8,9 They may also be useful as chiral media for
asymmetric synthesis, chiral liquid crystals in ferroelectric and
non-linear optical devices.10–12
being able to transmit their chiroptical properties to the poly-
meric chains. Moreover the monomer structure has to be suit-
able for the solubility and physical property requirements of
the targeted polyamide. Classical experimental conditions used
in polyamide syntheses are rather harsh (temperatures ranging
from 200 to 300 °C, high pressure, etc)21–23 and restrict the use
of sophisticated monomers. All of these factors prompt the
development of alternative strategies for the design of optically
active monomers, starting from inexpensive and racemic materi-
als, coupled with a non-racemizing polymerization procedure
able to lead to chiral polymers with the intrinsic physical fea-
tures of polyamides.
Following this guideline, enzymes can play a crucial role. In the
last few years, we have been involved in the improvement of for-
mation of the amide bond catalyzed by lipases and proteases (from
While a large amount of research dealing with the properties of
conventional nylons has been performed,13,14 little has been
reported on with regard to optically active non-polypeptidic polya-
amines bearing a stereocenter at the
a-position relative to the
mides, in particular those bearing a stereocenter at the
a
-position
nitrogen atom).24–26 The ultimate goal was to make it compatible
with the thiyl radical-promoted racemization of aliphatic amines
in dynamic kinetic resolution processes.27–31 Our aim was to
approach the enzyme-catalyzed synthesis of chiral polyamides,
by applying the successful strategy developed by Meijer and
coworkers for the synthesis of chiral polyesters starting from race-
mic monomers.32–34 To reach this goal, we have recently developed
an efficient enzymatic polymerization using lipase B of Candida
Antarctica (CAL-B).35 These polymerization experiments were
achieved on achiral monomers. It was therefore necessary to check
the kinetic compatibility of the enzymatic procedure with an
relative to the nitrogen atom. Chiral moieties are usually either in-
cluded in the main chain,15,16 or as pendant groups with the aim of
improving the hydrolytic degradation of the materials.17–19 For
example, carbohydrates are frequently employed as they provide
varied functionalities, degradability, and chirality to the mono-
meric precursors.17,20
⇑
Corresponding authors.
E-mail addresses: gerard.gil@univ-amu.fr (G. Gil), michele.bertrand@univ-amu.fr
a-substituted optically active monomer.
(M.P. Bertrand), stephane.gastaldi@univ-amu.fr (S. Gastaldi).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.021

868
F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
Herein we report our results on the lipase-mediated synthesis
polymerization. A retrosynthetic route of monomers (R,R)-1 and
(R)-2 is shown in Scheme 1.
of stereo-regular AB and AABB type polyamides based on an opti-
cally active amino-ester or a diamine as monomers. Both mono-
mers were synthesized from racemic 12-methyldodecalactone
(12-Me-DDL). The supported CAL-B [Novozym 435 (N435)] was
first used to introduce chirality into the structure of the monomers
via a kinetic resolution of the starting materials, and then to incor-
porate this chirality all along the polyamide chain via enzymatic
polymerization.
In order to prepare diamine 1, the synthesis of the correspond-
ing diazido precursor could be envisaged as the result of a double
Williamson etherification involving diethylene glycol and (R)-9 as
substrates. The latter could be derived from diol (S)-5, which pre-
sents the opposite configuration at the stereogenic center. This
configuration is essential in order to obtain the required (R)-stereo-
chemistry through the azidation step.37 Compound 5 was prepared
from the reduction of the optically active lactone (S)-4.
A similar pathway was followed for the synthesis of monomer
2, involving the key-intermediate (S)-11 obtained from the ring-
opening of (S)-4. In this retrosynthetic strategy, the key-factor for
the successful synthesis of these two monomers is the preparation
of lactone (S)-4 with a high enantiomeric excess.
2. Results and discussion
2.1. Monomers synthesis
In order to investigate both AB and AABB type polymerizations,
optically active diamine (R,R)-1, aminoester (R)-2 and diester 3
(Fig. 1) were synthesized.
To reach this goal, we chose to apply the strategy developed by
Meijer et al. for the enantioselective ring-opening polymerization
(ROP) of
x
-methylated lactones, as shown in Scheme 2.32
O
O
O
O
NH2
O
(S)
(R)
O
O
O
N435
(R)
NH2
+
O
(R,R)-1
toluene
70 °C
(R)
n
50 %
50 %
NH2
CO2Et
4
(S)-4
(R)
(R)-2
Scheme 2. Enzyme-mediated kinetic resolution polymerization of racemic methyl-
dodecalactone.
O
OEt
O
EtO
O
O
These authors have shown that the enantioselectivity of the
3
O
enzymatic process depended on the ring-size of the
x-methylated
lactones. This feature, assigned to the conformation of the ester
bond of the lactone, has been used by the same group to synthesize
enantiopure polyesters with excellent enantiomeric excess. When
applied to 12-Me-DDL, this straightforward kinetic resolution
polymerization allowed the isolation of the corresponding (R)-
polyester with excellent enantiomeric excess (>99%), and the
non-reactive enantiomer (S)-4 in 50% yield with optimal ee (>99%).
The synthesis of diamine 1 could be achieved from lactone (S)-4
(Scheme 3). The reduction of the lactone using lithium aluminium
hydride afforded the linear diol (S)-5. Selective protection of the
primary hydroxyl function with a trityl group was successfully
completed. The functionalization of the remaining alcohol was
achieved through a mesylation/azidation sequence. These last
two steps proceeded in good yield, and with inversion of configu-
ration at the stereogenic center.
Figure 1. Structure of monomers (R,R)-1, (R)-2 and 3.
Both monomers 1 and 2 have stereocenters at the
a-position
relative to the amine function, and include long lipophilic chains
to ensure good thermal properties in the resulting polymers and
make their purification easier using a precipitation work-up. The
configuration of the stereogenic centers has to be (R) to be fully
consistent with the well-known selectivity of CAL-B in organic
media36 which should provide the targeted polymers with high
yields. In the case of diamine 1, a diethylene glycol moiety was in-
serted into the backbone of the molecule in order to optimize its
solubility all along the polymerization process, and that of the
resulting polyamides. This strategy has been used with success in
our previous work,35 for the coupling of diester 3, with an oxygen-
ated diamine in an AABB polymerization.
After removal of the protecting group and bromination of the
alcohol, the key intermediate (R)-9 was used in a double William-
son reaction, in the presence of a phase-transfer catalyst.38 This
procedure gave (R,R)-10, with a modest yield (19%). The final step
Regarding the synthesis of these monomers, the main con-
straint resides in full control of the configuration of their stereo-
genic centers, to reach optimal conversions during the enzymatic
O
NH2
N3
OH
10
NH2
NH2
O
O
Br
OH
O
11
1
(R,R)-
(R)-9
(S)-5
O
(
)
S
CO2Et
OH
CO2Et
N3
CO2Et
(S)-4
(R)-2
(R)-12
(S)-11
Scheme 1. Retrosynthetic analysis of monomers (R,R)-1 and (R)-2.

F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
869
O
O
TrCl/DMAP
OH
OH
CH2Cl2
LiAlH4
98%
OTr
OH
(S)
86%
(S)-6
(S)-5
(S)-4
1. MsCl/Et3N
2. NaN3/DMF
91%
Amberlyst 15
MeOH
N3
N3
N3
PPh3/CBr4
OTr
OH
Br
80%
94%
(R)-7
(R)-9
(R)-8
diethyleneglycol
KOH 45%
Pd/ C 10%
H2
R
O
MeNBu3HSO4
(R,R)-10 R = N3,
(R,R)-1 R = NH2
O
O
88%
R
19%
Scheme 3. Synthesis of (R,R)-1.
consisted of the reduction of the two azido functions, to give dia-
mine (R,R)-1 in 9.7% overall yield over 8 steps from lactone (S)-4.
The synthesis of aminoester (R)-2 was performed from the same
precursor, starting from lactone (S)-4 via ring-opening in the pres-
ence of NaOEt (Scheme 4).
This reaction allowed the preparation of hydroxy-ester 11,
which was then transformed into azide 12, using the mesylation/
azidation sequence. Again, inversion of the configuration of the ste-
reogenic center was achieved during the introduction of the azido
group. The last step led to the targeted monomer, with the appro-
priate configuration for a lipase-promoted polymerization, in 37%
overall yield over 4 steps.
tography (SEC) after isolation and drying of the product. The main
results are shown in Table 1.
In the case of the AABB polymerization involving monomers 1
and 3 (Table 1, entry a), SEC analyses highlighted a very good value
of the average degree of polymerization, close to sixteen units,
which falls in the same range as the best results published in the
field of lipase-assisted synthesis of polyamides.35,42 The excellent
value of the average degree of polymerization, due to the good
yields in the isolated polymers, tends to prove that the presence
of the methyl group at the a-position relative to the nitrogen atom
did not hamper the progression of the reaction. The low value of
the polydispersity index is in good agreement with the reported
data.35 These data confirmed the asset of the enzyme-mediated
synthesis of polyamides. The specific rotation of polymer P(1)
was found to be +11.7, thus confirming the chiral nature of the
macromolecule. The low magnitude of this value could be easily
explained by the symmetry in the structure of the monomers.
Moreover, the flexibility endowed by the insertion of an oxyethyl-
ene moiety inside the polymeric backbone increases the number of
available conformations for the polymer in solution.2
In the case of monomer 2 (entry c), SEC data were much more
disappointing (Scheme 6). The reaction failed to reach a DPn higher
than four units, which corresponds to an average molecular mass
close to 700 daltons. Low yields and the recovery of a significant
amount of the starting material isolated at the end of the reaction
were observed.
2.2. Enzymatic polymerization
Monomers (R,R)-1 and (R)-2 were used in an enzymatic poly-
merization procedure. The experimental conditions were trans-
posed from our previous work,35 which involved diphenyl ether
as the solvent. It has been previously demonstrated that this sol-
vent, when used in small quantities, allowed to perform enzymatic
polymerization in ‘pseudo-bulk’ conditions without any drawbacks
due to viscosity and limited-diffusion of the reactive species.39,40
Moreover, its high boiling point allowed the enzymatic reaction
to be performed at 80 °C under a reduced pressure of 3 mbars, with
continuous removal of the ethanol formed during the polymeriza-
tion, in order to drive the reaction forward.
The AB and AABB polymerizations were then investigated, fol-
lowing this experimental procedure. In the case of the AABB reac-
tion (Scheme 5), a 1:1 ratio of diamine 1 and diester 3 was used, as
previous work had clearly demonstrated that this stoichiometry
was well suited to the enzymatic polymerization.41
In both cases, the resulting oligomeric products were isolated
by precipitation. The average molecular masses in number (Mn)
and in weight (Mw) were determined by Size-Exclusion Chroma-
It is worth noting, however, that in both cases, the polyamide
synthesis did not proceed without a catalyst (Table 1, entries b
and d), thus ruling out the possibility of a non-catalyzed reaction
at this temperature.42
The efficiency of the polymerization involving monomers 1 and
3 proved that the poor Mw and Mn values obtained with amino-es-
ter 2 probably did not result from the presence of the stereogenic
center close to the reactive amine function. Since deactivation of
O
EtONa
58%
OH
CO2Et
1. MsCl/Et3N
2. NaN3/DMF
O
( )
S
4
(S)-
(S)-11
73%, 2 steps
Pd/ C 10%
NH2
CO2Et
N3
CO2Et
H2
(R)
88%
(R)-2
(R)-12
Scheme 4. Synthesis of (R)-2.

870
F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
EtO2C
Ph2O
O
O
NH2
O
O
H2N
11O
O
10
9O
O
CO2Et
9
+
NH2
O
O
+
O
CO2Et
O
NH2
EtO2C
11
3
10
10
10
(R,R)-1
3
13
N435
80 °C, 3 mbars
Ph2O
N435
O
240 h
80 °C, 3 mbars
240 h
O
O
O
8
10
+2n EtOH
O
O
O
NH
O
O
O
O
HN
O
8
N
H
10
+ 2n EtOH
10
11
NH
O
O
O
P(1)
O
8
9
P(3)
Scheme 7. Novozym 435-catalyzed synthesis of model polymer P(3).
Scheme 5. Novozym 435-catalyzed polymerization of monomers (R,R)-1 and 3.
Table 1
Characterization of the optically active polyamides synthesized.
Table 2
Evolution of the conversion (%) of diamine (R,R)-1 and 13 during the polymerization
Entry
Monomer
Yield
Mn
Mw
PDI
DPn
a
1 + 3
1 + 3
2
87%
ndb
64%
ndb
14718
1781
689
19280
3757
1316
—
1.31
2.11
1.91
—
15.7
1.9
3.3
—
Diamine
After 1 ha
After 45 ha
After 240 ha
DPn
ba
c
13
1
57
48
77
75
94
93
16.7
15.7
da
2
—
c
a
Conversion is based on the total conversion of amino groups.
a
b
c
Blank experiments without N435.
Not determined.
The conversion value is lower than the limit of detection by NMR.
that involving (R-R)-1 during the first few hours of the reaction.
After one hour of polymerization 57% of non-chiral diamine 13
was inserted inside the polymeric backbone versus only 48% for
the chiral substrate. However, this slight imbalance is no longer
observed after 45 h of reaction. At this stage, the conversion of 1
caught up the level of that of 13 with values close to 75% for both
monomers. At the end of the reaction, the conversion levels were
similar, which shows that the difference in propagation rate ob-
served at the very beginning has no influence on the progression
of the polymerization reaction, and as a result, on the average de-
gree of polymerization of the isolated product.
NH2
CO2Et
(R)-2
Ph2O
80 °C, 3 mbars
240 h
N435
+ n EtOH
O
N
H
P(2)
n
2.3. Polymer characterization
Scheme 6. Novozym 435-catalyzed polymerization of monomer (R)-2.
Isolated polymer P(1) was then fully characterized and its 1H
NMR spectrum is shown in Fig. 2. It is important to note that this
spectrum was recorded in CDCl3, thus confirming the good solubil-
ity of the polymer obtained in this common organic solvent despite
its high methylene content, the high crystallinity, and the low sol-
ubility often associated with polyamide backbones.45
In this spectrum, the characteristic signals of the ethyl carbox-
ylate terminations are indicated (CH2C(O)OCH2CH3). The charac-
teristic signals of the amine terminations (CH2NH2), expected at
2.95 ppm, are hardly visible. The signals corresponding to the
CH2O groups are lettered d, d’, and c; those of the methylene pro-
the catalyst could not be suspected at this temperature,43 and as
water-content was limited by using a drastic drying procedure,44
the poor solubility of the monomer in diphenyl oxide, which is
responsible for the early precipitation of oligomeric chains of low
molecular masses, is the most likely explanation for these results
(Table 1, entry c). It therefore impedes the propagation of the poly-
merization. This provides additional evidence for the advantage of
inserting a diethylene glycol moiety into the backbone of mono-
mers 1 and 3, in order to overcome the solubility problem, and
to optimize the polymerization procedure.
tons at the
a
-position to the amide nitrogen atom are lettered b;
In order to fully evaluate the influence of the stereogenic center
on the smooth progress of the reaction, the evolution of the con-
version of diamine 1 during the reaction was monitored. This en-
abled us to draw a parallel with the conversion of diamine 13 in
its copolymerization with diester 3 in the presence of Novozym
435 (Scheme 7).
the signals of the methylene protons at the
a-position relative to
the amide carbonyl group are lettered e; the other methylene
group signals are indicated by letters f, g, and h; the amide group
protons give rise to the broad singlets lettered a.
The FTIR spectrum (Fig. 3) shows the characteristic absorption
of C@O stretching (amides band I) at 1639 cmꢀ1. The low fre-
quency is in agreement with a hydrogen bonding association of
the amido groups. The amide band II (N–H bending vibration) ab-
sorbs at 1553 cmꢀ1, whereas the N–H stretching vibrations absorb
at 3292 cmꢀ1. The rather sharp characteristic anti-symmetric and
symmetric elongations of methylene groups at 2933 and
2849 cmꢀ1 also argue in favor of a spatial proximity between the
alkyl chains due to van der Waals interactions.46 This phenomenon
has already been observed in non-chiral polyamide samples. It is a
consequence of the introduction of long methylene chains into the
backbone of monomers.
This polymerization, already described,35 has the advantage of
proceeding under the same experimental conditions, that is, in di-
phenyl oxide under reduced pressure. Moreover, diamine 13 pre-
sents a backbone rather similar to that of diamine 1, with long
alkyl chains on both sides of a central diethylene glycol moiety.
The evolution of the conversion of these diamines is shown in Ta-
ble 2. The conversions were assessed by 1H NMR spectroscopy.33
These results demonstrate that the presence of the stereogenic
center
a to the amino group generally did not notably influence the
rate of the reaction during the polymerization. The progression of
the polymerization involving the non-chiral diamine is faster than

F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
871
f
i
d
c
H
N
b
h
e
f
g
6
O
d'
O
O
O
O
NH
a
O
O
O
6
7
7
f+i
f+i
P(1)
n
h
d d'
c
e
g
CH2C(O)OCH2CH3
b
CH2C(O)OCH2CH3
CH2NH2
a
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Chemical Shift (ppm)
Figure 2. 1H NMR spectrum of polymer P(1).
Figure 3. FTIR spectrum of polymer P(1).
Figure 4. TGA of polymer P(1).
2.4. Bulk properties
A sharp melting endotherm at 95.4 °C was observed in the DSC
analysis of P(1), thus confirming the crystalline character of this
polyamide (Fig. 5).
This supports the idea of supramolecular organization between
polymeric chains, probably enhanced by the strong hydrogen
bonding interactions already highlighted by FTIR.
In the WAXD spectrum of P(1) (Fig. 6), a rather large peak was
observed, spread between the scattering angles of 18° and 25°. This
could be assigned to the superimposed peaks of close values of
scattering angles.49 According to the literature, some crystalline
polyetheramides exhibit a similar behavior. It is difficult to con-
clude whether the second peak (between 36° and 38°) indicates
the presence of two superimposed crystal-like phases, due to the
Polymer P(1) was subjected to a thermogravimetric analysis in
order to evaluate its resistance to heat. The results are shown in
Fig. 4.
This analysis clearly shows that the degradation of P(1) takes
place in one straight stage spread between 310 and 520 °C. In this
temperature range, the sample loses more than 50% of its weight.
This simple behavior fits well with the good mass properties high-
lighted in Table 1, as a low value for the polydispersity index is
often correlated with a good thermal resistance. The reported
thermal behavior of polymer P(3) is in agreement with the known
data corresponding to poly(ether)amides.47,48

872
F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
recorded at 400 or 300 MHz and 100 or 75 MHz, respectively.
Chemical shifts (d) are reported in ppm and coupling constants
(J) are given in Hz. Ethyl 11-{2-[2-(10-ethoxycarbonyl-decyloxy)-
ethoxy]-ethoxy}-undecanoate 3 and 11-{2-[2-(11-amino-undecyl-
oxy)-ethoxy]-ethoxy}-undecylamine 13 were prepared according
to literature procedures.35
4.2. Gel permeation chromatography analyses
The analyses and the monitoring of polymerization reactions
were achieved by gel permeation chromatography (GPC) using
Macherey-Nagel Nucleogel GPC 500, 100, and 50 (10 lm porosity;
300 ꢁ 7.7 mm) analytical columns fitted in series after a GPC
(50 ꢁ 7.7 mm) pre-column. The system was piloted by Azur (Jas-
coÓ) software, and equipped with Waters 600 pump, a Varian oven
(model 510), and a Waters differential diffractometer (model 410).
Analyses used a 0.1 M solution of LiBr in N,N-dimethylacetamide
(ACROS, HPLC grade, degassed and filtered on a Millipore mem-
brane before use) as the solvent at 80 °C (0.6 mL/min rate of flow).
Sample concentrations of 1–3 mg/mL and injection volumes of
Figure 5. DSC data of polymer P(1).
200 lL were used. Toluene (500 lL/100 mL) was introduced in
the mobile phase as an elution marker. System calibration data
and relative molar mass calculations were acquired and processed
using PSS WinGPC (Polymer laboratories) software. Narrow distri-
bution polyethylene glycol standards (Varian) with Mn values of
106, 194, 430, 615, 1010, 1970, 3390, 7980, 12140, and 21030 Da
were used to establish the calibration curves. Weight-average
molecular weight (Mw), number-average molecular weight (Mn),
and polydispersity index (PDI= Mw/Mn) were calculated from the
chromatograms.
FTIR data were recorded with a Vertex 70 Bruker spectrometer.
Attenuated Total Reflectance (ATR) analyses were performed with
a cell centered on a germanium crystal. The acquisition of data was
processed with EZ OMNIC 7.2a software. DSC analyses were ef-
fected with a Q200 DSC TA Instrument, the calorimeter under
nitrogen (30 mL/min) connected to a cryostat from the same man-
ufacturer. DSC scans were run at temperatures ranging from ꢀ150
to 150 °C with a heating rate of 5 °C/min. A controlled cooling rate
of ꢀ10 °C was applied between heating runs. TGA analyses were
recorded with TGA Q500 TA Instruments apparatus, under an air
flux (60 mL/min). The measurements were carried out with a rate
of 10 °C/min. WAXD spectrum was registered on powders with a
Figure 6. Wide angle X-ray diffraction analysis of polymer P(1).
lack of references for WAXD patterns for this type of structure,
especially when dealing with optically active macromolecules.
3. Conclusion
Herein, we have reported the lipase-catalyzed synthesis of non-
peptidic optically active polyamides. These polymers were pre-
pared from chiral monomers with stereocenters that have the
appropriate configuration to be fully compatible with the enzy-
matic procedure. The synthesis of the optically active monomers
from racemic 12-methyldodecalactone is based on a lipase-medi-
ated kinetic resolution polymerization, which enables the enantio-
selective formation of the targeted precursors. The AABB
enzymatic polymerization was carried out under reduced pressure,
and gave rise to an optically active polymer, obtained in a good
yield, with a high degree of polymerization, and a narrow polydis-
persity index. This polyamide exhibits interesting physical proper-
ties. This work is an additional proof of the versatility of lipases as
highly enantioselective catalysts that can be used to control both
the stereospecific synthesis of chiral monomers from achiral start-
ing materials, and to polymerize them in an efficient manner.
Siemens D5000 XRD diffractometer using Cu (40 Kv 40 mA) K
a
as source of radiations (k = 1.54 Å) and a scintillator (hꢀ2h). WAXD
were obtained by setting a step size of 0.04 with a scattering angle
2h ranging between 10° and 45 °.
4.2.1. (S)-Tridecane-1,12-diol 5
To a 0 °C solution of (S)-12-methyldodecalactone32 4 (1 g,
4.7 mmol) in Et2O (25 mL) was added LiAlH4 (182 mg, 4.8 mmol).
The reaction mixture was allowed to warm slowly to room temper-
ature and stirred overnight at rt. Next, Na2SO4ꢂ10 H2O (1.5 g,
4.8 mmol) was added and the resulting suspension was stirred
for 5 h at rt. After drying over MgSO4 and concentration, the crude
material was subjected to column chromatography on silica gel
(pentane/AcOEt 90/10 to 70/30) to give 5 (999 mg, 4.61 mmol,
98%). 1H NMR (400 MHz, CDCl3): 3.80 (sext, J = 6.0, 1H), 3.63 (t,
J = 6.6, 2H), 1.60–1.50 (m, 6H), 1.48–1.24 (m, 16H), 1.21 (d,
J = 6.0, 3H). 13C NMR (100 MHz, CDCl3): 68.1 (CH), 63.0 (CH2),
39.3 (CH2), 32.8 (CH2), 29.6 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5
(CH2 ꢁ 2), 25.7 (CH2), 25.7 (CH2), 23.4 (CH3). IR (ATR, cmꢀ1):
4. Experimental
4.1. General
3342, 2925, 2848, 1469, 1461, 1124, 1056, 657. ½a D25
¼ þ4:5 (c
ꢃ
1.5, CHCl3). HRMS ([M+H]+, ESI): m/z calcd for C13H29O2:
All reactions were carried out under an argon atmosphere. Sol-
vents were degassed before use. The 1H and 13C NMR spectra were
217.2162. Found: 217.2157.

F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
873
4.2.2. (S)-13-(Trityloxy)tridecan-2-ol 6
4.2.5. (R)-12-Azido-1-bromotridecane 9
A solution of diol 5 (664 mg, 3 mmol), triphenylmethane chlo-
ride (1.112 g, 3.98 mmol), and DMAP (50 mg, 0.4 mmol) in pyridine
(6 mL) was stirred for 60 h at rt. After the addition of water
To a 0 °C solution of tetrabromomethane (3.592 g, 10.8 mmol)
in dry THF (15 mL) was added triphenylphosphine (2.471 g,
9.4 mmol). After complete consumption of triphenylphosphine,
alcohol 8 (1.137 g, 4.7 mmol) in dry THF (5 mL) was added at
0 °C. Next, the solution was stirred for 96 h at 30 °C. After concen-
tration, the crude material was subjected to column chromatogra-
phy on silica gel (pentane/AcOEt 100/0 to 90/10) to give 9 (1.35 g,
4.4 mmol, 94%). 1H NMR (400 MHz, CDCl3): 3.42 (m, 1H), 3.41 (t,
J = 6.8, 2H), 1.86 (quint, J = 6.8, 2H), 1.52–1.26 (m, 18H), 1.24 (d,
J = 6.5, 3H). 13C NMR (75 MHz, CDCl3): 58.2 (CH), 36.3 (CH2), 34.2
(CH2), 33.0 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.5 (CH2),
28.9 (CH2), 28.3 (CH2), 29.3 (CH2), 26.2 (CH2), 19.6 (CH3).
(300 ll), the solution was concentrated. The crude material was di-
luted with water and extracted with dichloromethane (3 ꢁ 20 mL).
The organic phase was then washed with 1 M aqueous HCl, water
and brine, and dried over MgSO4. After filtration and concentration,
the crude material was subjected to column chromatography on
silica gel (pentane/AcOEt 100/0 to 92/8) to give 6 (1.183 g,
2.58 mmol, 86%). 1H NMR (400 MHz, CDCl3): 7.48 (m, 6H), 7.38–
7.22 (m, 9H), 3.81 (sext, J = 6.1, 1H), 3.08 (t, J = 6.5, 2H), 1.65 (quint,
J = 6.5, 2H), 1.53–1.24 (m, 19H), 1.21 (d, J = 6.1, 3H). 13C NMR
(100 MHz, CDCl3): 144.6 (C), 128.7 (CH), 127.7 (CH), 126.8 (CH),
86.3 (C), 68.2 (CH), 63.7 (CH2), 39.4 (CH2), 30.1 (CH2), 29.7 (CH2),
29.6 (CH2), 29.6 (CH2 ꢁ 3), 29.5 (CH2), 26.3 (CH2), 25.8 (CH2),
23.5 (CH3). IR (ATR, cmꢀ1): 3396, 3089, 3062, 3053, 2927, 2854,
4.2.6. (R)-1-(2-(2-((R)-12-Azidotridecyloxy)ethoxy)ethoxy)-12-
azidotridecane 10
A solution of 9 (1.35 g, 5.2 mmol), diethylene glycol (230 ll,
1598, 1489, 1448, 1089, 1074, 1066, 1027, 761, 702, 634.
2.36 mmol), and NBu4HSO4 (160 mg, 0.5 mmol) was stirred vigor-
ously, after which KOH 45% (1.3 mL) was added dropwise. The
resulting solution was stirred for 48 h (TLC monitoring) at 70 °C.
After dilution with CH2Cl2 (10 mL) and water (10 mL), the aqueous
phase was extracted with CH2Cl2 (3 ꢁ 10 mL). The combined or-
ganic fractions were washed with brine and dried over MgSO4.
After concentration, the crude material was subjected to column
chromatography on silica gel (pentane/AcOEt 100/0 to 95/5) to
give 10 (247 mg, 0.44 mmol, 19%). 1H NMR (400 MHz, CDCl3):
3.68–3.56 (m, 8H), 3.47 (t, J = 6.8, 4H), 3.42 (sext, J = 6.4, 2H),
1.60 (quint, J = 7.1, 4H),1.52–1.28 (m, 36H), 1.24 (d, J = 6.4, 6H).
13C NMR (75 MHz, CDCl3): 70.6 (CH2), 70.7 (CH2), 70.1 (CH2),
58.0 (CH), 36.2 (CH2), 29.7 (CH2), 29.6 (CH2), 29.6 (CH2), 29.6
(CH2), 29.5 (CH2), 29.5 (CH2), 29.5 (CH2), 29.4 (CH2), 26.1 (CH2),
25
½
a
ꢃ
¼ þ10:4 (c 0.3, CHCl3). HRMS ([M+Na]+, ESI): m/z calcd for
365
C32H42O2Na: 481.3077. Found: 481.3075.
4.2.3. (R)-(12-Azidotridecyloxy)triphenylmethane 7
To a solution of alcohol 6 (3.15 g, 6.86 mmol) and triethylamine
(1.17 g, 11.52 mmol) in dichloromethane (30 mL) was added at
0 °C methanesulfonyl chloride (1.10 g, 9.6 mmol). The reaction
mixture was allowed to warm slowly to room temperature. After
30 min (TLC monitoring), the reaction mixture was diluted with
water, washed with 1 M aqueous HCl and brine, and dried over
MgSO4. After filtration and concentration, the corresponding mes-
ylate was obtained (1.05 g, 3.12 mmol, 81%) and used without fur-
ther purification. 1H NMR (400 MHz, CDCl3): 7.44 (m, 6H), 7.32–
7.19 (m, 9H), 4.78 (sext, J = 6.3, 1H), 3.03 (t, J = 6.6, 2H), 2.98 (s,
3H), 1.65–1.56 (m, 2H), 1.41 (d, J = 6.3, 3H), 1.40–1.21 (m, 18H).
A solution of the freshly prepared mesylate and sodium azide
(1.79 g, 27.44 mmol) in DMF (40 mL) was stirred overnight at
60 °C. The reaction mixture was diluted with water (400 mL) and
extracted with AcOEt (3 ꢁ 50 mL). The organic phase was then
washed with water and brine, and dried over MgSO4. After filtra-
tion and concentration, the crude material was subjected to col-
umn chromatography on silica gel (pentane/AcOEt 100/0 to 95/5)
to give 7 (2.94 g, 6.23 mmol, 91%). 1H NMR (400 MHz, CDCl3):
7.44 (m, 6H), 7.32–7.19 (m, 9H), 3.41 (sext, J = 6.3, 1H), 3.04 (t,
J = 6.6, 2H), 1.61 (quint, J = 7.2, 2H), 1.52–1.21 (m, 21H). 13C NMR
(100 MHz, CDCl3): 144.6 (C), 128.8 (CH), 127.7 (CH), 126.8 (CH),
86.3 (C), 63.7 (CH2), 58.1 (CH), 36.2 (CH2), 30.1 (CH2), 29.6
(CH2 ꢁ 2), 29.6 (CH2), 29.5 (CH2 ꢁ 2), 29.4 (CH2), 26.3 (CH2), 26.1
(CH2), 19.5 (CH3). IR (ATR, cmꢀ1): 3089, 3062, 3053, 2929, 2856,
19.5 (CH3). IR (ATR, cmꢀ1): 2927, 2854, 2102, 1465, 1122, 1066.
25
365
½
a
C
ꢃ
¼ ꢀ45:3 (c 0.4, CHCl3). HRMS ([M+NH4]+, ESI): m/z calcd for
30H64N7O3: 570.5065. Found: 570.5069.
4.2.7. (R)-13-(2-(2-((R)-12-
Aminotridecyloxy)ethoxy)ethoxy)tridecan-2-amine 1
A solution of 10 (245 mg, 0.44 mmol), and Pd/C (10%) (50 mg) in
EtOH (30 mL) was stirred overnight at rt under H2 (8 bars). After
filtration and concentration, 1 was obtained (194 mg, 0.39 mmol,
88%) and used without further purification. 1H NMR (400 MHz,
CDCl3): 3.66–3.57 (m, 8H), 3.45 (t, J = 6.8, 4H), 2.87 (m, 2H), 1.57
(m, 8H), 1.34–1.24 (m, 36H), 1.06 (d, J = 6.3, 6H). 13C NMR
(75 MHz, CDCl3): 71.6 (CH2), 70.7 (CH2), 70.1 (CH2), 47.0 (CH),
40.2 (CH2), 29.7 (CH2), 29.6 (2 ꢁ CH2), 29.6 (3 ꢁ CH2), 29.5 (CH2),
26.4 (CH2), 26.1 (CH2), 23.9 (CH3). IR (ATR, cmꢀ1): 3326, 2919,
25
365
2850, 1591, 1469, 1143.
½
a
ꢃ
¼ ꢀ1:3 (c 1.0, CHCl3). HRMS
2100, 1600, 1490, 1448, 1089, 1072, 1058, 744, 703, 632.
([M+H]+, ESI): m/z calcd for C30H65N2O3: 501.4990. Found:
25
365
½
aꢃ
¼ ꢀ41:3 (c 1.0, CHCl3). HRMS ([M+Na]+, ESI): m/z calcd for
501.4977.
C32H41N3ONa: 506.3142. Found: 506.3137.
4.2.8. (S)-Ethyl 12-hydroxytridecanoate 11
4.2.4. (R)-12-Azidotridecan-1-ol 8
A solution of (S)-12-methyldodecalactone (100 mg, 0.47 mmol)
and EtONa (11 mg, 0.47 mmol) in ethanol (5 mL) was stirred for 6 h
at reflux (TLC monitoring). After concentration, the crude mixture
was diluted with AcOEt (15 mL) and washed successively with
water (5 mL), 0.1 M HCl solution (5 mL) and brine (5 mL). After
drying over MgSO4 and concentration, 11 was obtained (71 mg,
0.27 mmol, 58%) and was used without further purification. 1H
NMR (400 MHz, CDCl3): 4.05 (q, J = 7.3, 2H), 3.70 (sext, J = 6.0,
1H), 2.21 (t, J = 7.5, 2H), 1.56–1.12 (m, 22H), 1.11 (d, J = 6.0, 3H).
13C NMR (100 MHz, CDCl3): 173.9 (CO), 68.1 (CH), 60.1 (CH2),
39.3 (CH2), 34.4 (CH2), 29.6 (CH2 ꢁ 2), 29.5 (CH2), 29.4 (CH2),
29.2 (CH2), 29.1 (CH2), 25.7 (CH2), 25.0 (CH3), 23.4 (CH2), 14.2
(CH3). IR (ATR, cmꢀ1): 3504, 2929, 2856, 1737, 1467, 1375, 1247,
A solution of 7 (700 mg, 1.48 mmol) and Amberlyst 15 (600 mg)
in methanol (20 ml) was stirred overnight at 45 °C. After filtration
and concentration, the crude material was subjected to column
chromatography on silica gel (pentane/AcOEt 100/0 to 90/10) to
give 8 (286 mg, 1.18 mmol, 80%). 1H NMR (400 MHz, CDCl3): 3.64
(t, J = 6.6, 2H), 3.41 (sext, J = 6.4, 1H), 1.57 (quint, J = 6.6, 2H),
1.51–1.26 (m, 19H), 1.24 (d, J = 6.4, 3H). 13C NMR (100 MHz,
CDCl3): 63.0 (CH2), 58.0 (CH), 36.2 (CH2), 32.8 (CH2), 29.6 (CH2),
29.5 (CH2), 29.5 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 26.1
(CH2), 25.7 (CH2), 19.4 (CH3). IR (ATR, cmꢀ1): 3375, 2929, 2854,
25
365
2102, 1467, 1062. ½
aꢃ
¼ ꢀ63:6 (c 1.2, CHCl3). HRMS ([M+NH4]+,
ESI): m/z calcd for C13H31N4O: 259.2492. Found: 259.2491.

874
F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
25
Na
1188, 1130, 1041. ½
aꢃ
¼ þ2:2 (c 1.3, CHCl3). HRMS ([M+Na]+, ESI):
0.88 (t, J = 7.3, COOCH2CH3, terminations).13C NMR (100 MHz,
CDCl3): 171.9 (CONH), 71.6 (CH2), 70.7 (CH2), 70.6 (CH2), 70.1
(CH2), 44.2 (CH2), 39.0 (CH2), 36.1 (CH2), 31 (CH2), 29.7 (CH2),
29.6 (CH2), 29.5 (CH2), 26.9 (CH2), 26.1 (CH2), 20.2 (CH3). IR (FTIR,
m/z calcd for C15H30O3Na: 281.2087. Found: 281.2084.
4.2.9. (R)-Ethyl 12-azidotridecanoate 12
To a solution of alcohol 11 (1 g, 3.87 mmol) and triethylamine
(587 mg, 5.80 mmol) in dichloromethane (40 mL) was added at
0 °C methanesulfonyl chloride (554 mg, 4.84 mmol). The reaction
mixture was then allowed to warm slowly to room temperature.
After 3 h, triethylamine (587 mg, 5.80 mmol) and methanesulfonyl
chloride (554 mg, 4.84 mmol) were added again. After 6 h, the
reaction mixture was diluted with water, washed with 1 M aque-
ous HCl and brine, and dried over MgSO4. After filtration and con-
centration, the corresponding mesylate was obtained (1.05 g,
3.12 mmol, 81%) and used without further purification. 1H NMR
(400 MHz, CDCl3): 4.71 (sext, J = 6.3, 1H), 4.05 (q, J = 7.3, 2H),
2.93 (s, 3H), 2.21 (t, J = 7.5, 2H), 1.69–1.52 (m, 4H), 1.34–1.16 (m,
20H). A solution of the freshly prepared mesylate and sodium azide
(1.26 g, 19.35 mmol) in DMF (30 mL) was stirred overnight at
60 °C. The reaction mixture was diluted with water (400 mL) and
extracted with AcOEt (3 ꢁ 50 mL). The organic phase was then
washed with water and brine, and dried over MgSO4. After filtra-
tion and concentration, the crude material was subjected to col-
umn chromatography on silica gel (pentane/AcOEt 100/0 to 95/5)
to give 12 (807 mg, 2.85 mmol, 91%). 1H NMR (400 MHz, CDCl3):
4.05 (q, J = 7.3, 2H), 3.34 (sext, J = 6.8, 1H), 2.21 (t, J = 7.5, 2H),
1.56–1.16 (m, 24H). 13C NMR (100 MHz, CDCl3): 173.9 (CO), 60.1
(CH2), 58.0 (CH), 36.5 (CH2), 36.1 (CH2), 34.4 (CH2), 31.4 (CH2),
29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 29.1 (CH2), 26.1 (CH2), 25.0
cmꢀ1): 3292, 3233, 2849, 1639, 1553, 1468, 1119, 956, 719.
25
365
½
aꢃ
¼ þ11:7 (c 0.8, CHCl3). No amine terminations were detected.
Acknowledgments
The authors thank: Dr Emmanuel Beaudoin and Dr Tran Phan
for DSC measurements, Dr Jean-Valère Naubron for FTIR spectra,
Dr Alain Garnier for WAXD analysis, and Dr Emilie Bloch for TGA
measurements. A gift of Novozym 435 from Novozymes (Denmark)
is gratefully acknowledged.
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A solution of 12 (800 mg, 2.82 mmol), Pd/C (10%) (50 mg) in
EtOH (60 mL) was stirred overnight at rt under H2 (8 bars). After
filtration and concentration, 2 was obtained (639 mg, 2.49 mmol,
88%) and used without further purification.1H NMR (300 MHz,
CDCl3): 4.05 (q, J = 7.3, 2H), 2.80 (m, 1H), 2.21 (t, J = 7.3, 2H), 1.54
(quint, J = 7.0, 2H), 1.56 (m, 2H), 1.6–1.2 (m, 19H), 0.98 (d, J = 6.3,
3H). 13C NMR (75 MHz, CDCl3): 173.1 (CO), 60.1 (CH2), 46.9 (CH),
40.9 (CH2), 34.4 (CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4
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25
Na
1375, 1186. ½
a
ꢃ
¼ ꢀ0:6 (c 1.4, CHCl3). HRMS ([M+H]+, ESI): m/z
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(132 mg, 0.25 mmol) in Ph2O (515 mg) was stirred 15 min at rt,
after which Novozym 435 (50 mg) was added. After filtration and
concentration, 2 was obtained (639 mg, 2.49 mmol, 88%) and used
without further purification. The mixture was then heated at 80 °C
under 3 mbars for 240 h. After completion, the mixture was cooled
to 60 °C and 10 mL of chloroform was added. The hot solution was
filtered to remove the enzyme, the latter was washed with hot
chloroform and the solution was concentrated up to 2 mL. The pre-
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then washed with the same solvent. The polymer was recovered
after drying at 40 °C under vacuum for 48 h (233 mg). 1H NMR
(400 MHz, CDCl3): 5.3 (br s, NH), 4.13 (q, J = 7.3, OCH2CH3 termina-
tions), 3.96 (pseudo quint, J = 6.5, CH2CH(NH)CH3), 3.67–3.56 (m,
OCH2CH2OCH2CH2O), 3.45 (t, J = 6.8, CH2OCH2CH2OCH2CH2OCH2),
2.28 (t, J = 7.5, CH2COOEt, terminations), 2.12 (t, J = 7.3, CH2CONH),
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(m,
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1.39
(m,
CH2CH2NHCO), 1.27 (br s (CH2)8), 1.11 (d, J = 4.5, CH2CH(NH)CH3),

F. Poulhès et al. / Tetrahedron: Asymmetry 23 (2012) 867–875
875
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