Chemoenzymatic dynamic kinetic resolution of primary amines catalyzed by CAL-B at 38-40°c

Article abstract of DOI:10.1021/jo201256w

The (R)-selective chemoenzymatic dynamic kinetic resolution of primary amines was performed at 38-40 °C in MTBE, in good to high yields and with high enantiomeric excesses. These reactions associating CAL-B to octanethiol as radical racemizing agent were carried out in the presence of methyl β-methoxy propanoate as acyl donor, under photochemical irradiation at 350 nm in glassware.

Full text of DOI:10.1021/jo201256w

NOTE
pubs.acs.org/joc
Chemoenzymatic Dynamic Kinetic Resolution of Primary Amines
Catalyzed by CAL-B at 38À40 °C
Florent Poulhꢀes,† Nicolas Vanthuyne,‡ Michꢀele P. Bertrand,*,† Stꢁephane Gastaldi,*,† and Gꢁerard Gil*,‡
†Equipe Chimie Molꢁeculaire Organique, LCP UMR 6264, Boite 562, and ‡Equipe Stꢁerꢁeochimie Dynamique et Chiralitꢁe, ISM2, UMR
6263, Universitꢁe Aix-Marseille, Facultꢁe des Sciences St Jꢁer^ome, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20,
France
S Supporting Information
b
ABSTRACT: The (R)-selective chemoenzymatic dynamic kinetic resolution of
primary amines was performed at 38À40 °C in MTBE, in good to high yields and
with high enantiomeric excesses. These reactions associating CAL-B to octa-
nethiol as radical racemizing agent were carried out in the presence of methyl β-
methoxy propanoate as acyl donor, under photochemical irradiation at 350 nm in
glassware.
he advantages of dynamic kinetic resolution (DKR) over a
simple kinetic resolution (KR) are well-known and have
T
been exemplified in numerous reviews.1 Over the past few years,
we have devoted research work to the performance of metal-free
chemoenzymatic DKR of primary amines. Contrary to most
other groups involved in this field, we have discarded homo-
geneous and heterogeneous metal catalysts as racemizing
agents.2 We opted for a radical racemization procedure mediated
by the intermediacy of sulfanyl radicals. After having optimized
both the racemization procedure3 and the enzymatic resolution
conditions,4 we were able to propose the first DKR methodology
that could be adapted to the synthesis of either (R)- or (S)-
amides by changing the nature of the enzyme, i.e., moving from a
lipase to a protease.5
Most racemization procedures associated with enzymatic reso-
lutions are carried out at temperatures higher than 70 °C.2,6 Owing
to the lack of thermostability of lipases, most investigations are
limited to the thermally stable supported lipase B of Candida
antartica (CAL-B), i.e., Novozym 435. It has been pointed out that
two routes could be envisaged to circumvent this problem in DKR
processes. One could either carry out racemization at a lower
temperature or increase the thermostability of the enzyme.
B€ackvall and co-workers, who used ruthenium-based catalysts to
racemize amines at 90 °C, selected the second route and opted for
increasing the thermal stability of the enzyme through its im-
mobilization in silica-based mesocellular foam.7 We rather selected
the alternative pathway, that is, the decrease of the temperature of
racemization,3c which we successfully realized for the DKR of
amines mediated with proteases.5c The performance of racemiza-
tion at low temperature was made possible by initiating the
formation of sulfanyl radical at 38À40 °C upon irradiation at
350 nm in glassware. Blank experiments having demonstrated that
CAL-B was not denaturated in the presence of the thiol and the
acyl donor under these conditions, we had to adapt the CAL-B-
catalyzed KR at 40 °C to make it kinetically compatible with the
new racemization conditions.
Figure 1. Amine structures.
Amine 1a (Figure 1) was used as model substrate in these
optimization experiments.
The selection of the acyl donor was restricted to three
candidates (Figure 2):
•
Ethyl laurate (2a), which gave the best results in KR
catalyzed by CAL-B at 80 °C and was taken as reference.
• Methyl β-methoxypropionate (2b), which has scarcely been
used as acyl donor. It reacts 11 times faster than ethyl butyrate
and 18 times slower than ethyl R-methoxyacetate in the BCL-
catalyzed acylation of 1-phenethanamine.8 Even though the
use of ethyl R-methoxyacetate is widespread because it leads to
very fast kinetic resolutions, this donor proved to be incompa-
tible with the racemization conditions.9
Received: June 23, 2011
Published: July 27, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201256w J. Org. Chem. 2011, 76, 7281–7286
|

The Journal of Organic Chemistry
NOTE
Table 1. KR of Amines (()-1aÀn
Figure 2. Acyl donors.
aminea
time, h
C, %b
amine ee, %c
amide ee, %d
E
• The trifluoroethyl ester of racemic N-octanoyl alanine (2c),
because it led to very good results in KR achieved at 30 °C
with proteases.4c,5c Moreover, it had never been tested with
any lipase.
Test reactions were carried out by monitoring the enantio-
meric excess of the amine during the KR performed at 38À40 °C
in toluene. The amine reached an ee of >99% in 4 h, when using
1.5 equiv of 2c. After the same time of reaction, the amine ee was
70% when using 2b, whereas it was only 20% with 2a.
However, 2c had to be discarded for two reasons. It led to a
significant amount of noncatalyzed acylation (10% in 24 h),10
and in addition, the racemization reaction was inhibited by the
release of trifluoroethanol in the reaction medium. Thus, further
experiments were conducted with 2b. A significant practical
advantage is that, compared to 2a, 2b is volatile and can easily
be removed from the reaction medium.
1a
1b
1c
1d
1e
2.5
6
50
40
44
47
45
>98
67
>99
>99
>99
>99
>99
>200
>200
>200
>200
>200
6
77
2.5
3
88
81
20
5
>99
92
1f
48
50
49
>99
>99
85
>200
>200
30
1g
1h
1
>99
83
6
18
3
>99
74
1i
1j
50
38
75
95
15
70
3
60
24
24
6
>99
71
1k
1l
42
45
>98
53
>200
5
A rapid screening of solvents led us to select MTBE (methyl
tert-butyl ether) rather than toluene or even THF. In this solvent,
a 50% conversion, together with a 95% amine ee, was reached in
45
24
20
20
>99
79
1m
1n
45
42
95
90
ꢁ
2 h in the presence of 4 Å molecular sieves. In the absence of the
71
>99
>200
dehydrating agent, the conversion was only 20%, and the amine
ee was 45% within the same time of reaction. The molecular sieve
is likely to trap both traces of water and methanol released from
the acyl donor.11
a Standard protocol: amine (0.25 mmol, 0.1 M solution), 2b (0.75
ꢁ
mmol, 1.5 equiv), MTBE (2.5 mL), 4 Å molecular sieve (250 mg),
CAL-B (50 mg), temperature 38À40 °C. b Enantioselectivity factors
were calculated according to E = ln[(1 À C)(1 À ee)]/ ln[(1 À C)-
(1 + ee)].12 c Determined by GC after derivatization. d Determined
by HPLC.
The results of the acylation of amines 1aÀn (Figure 1) are
reported in Table 1.
The enantioselectivity factors are high in most cases. They are
at least similar or even superior to those observed for the KR
performed at 80 °C with 2a as acyl donor.4a The amines can
roughly be separated into three classes: those for which E values
are excellent, i.e. E >200, those which give mean E values (1j, 1h,
and 1m), and those for which E values are very low (1i, 1l). The
latter are amines with little stereodifferentiation between the two
alkyl substituents.
For the radical racemization to be efficient, the time of reaction
must not exceed 3À5 h. Thus another important parameter to
take into account is the rate of KR, which must be as close as
possible to that of racemization. Time of KR ranges between 2.5
and 24 h. Substrates for which KR is particularly slow (1j, 1k, 1m,
1n) will be good probes to evaluate the efficiency of the DKR
process.
similar or superior. In the cases of amines 1h and 1l, method B
made it possible to reach enantiomeric excesses higher than with
the KR alone.
Amine 1n gave the slowest KR of the series. Method B enabled
81% yield and 99% ee for the corresponding (R)-amide. This
result can be compared to the result obtained by Gotor,13 who
used Shvo’s catalyst as racemizing agent and R-methoxyacetate as
acyl donor at 100 °C (50% yield and 97% ee).
The benefit of carrying out the DKR experiments at 38À40 °C
instead of 80 °C is well demonstrated by the cases of amines 1c
and 1j. Amine 1c, which was degraded under racemization
conditions at 80 °C, led to amide 3c in 82% yield and an ee
>99% under these new conditions. The DKR of amine 1j could
not be achieved at 80 °C because lactamization proceeded faster
than the enzymatic resolution. 5-Methylpyrrolidin-2-one was
formed in 67% yield with no ee. This means that performing
DKR at a lower temperature opens access to the formation of
optically pure amides from substrates that are unstable or
undergo competitive reactions at 80 °C.
The DKR experiments are reported in Table 2. Most reactions
were carried out by running a DKR period over 3.75 h (AIBN,
overall 20 mol % was added portion-wise each 45 min) followed
by an additional KR period of 4 h (after stopping the racemiza-
tion process by switching off the UV lamps of the Rayonet
apparatus).
In some cases (very slow KR), it was found even more
advantageous to perform a preliminary KR period, before starting
the DKR and the subsequent KR. A few data, which allowed us to
evaluate the significant gain in the overall yield by applying this
procedure are given in Table 2 (1a, 1b, 1h, 1k, 1l, 1m, 1n). It is
worth noting that in all cases where comparative data were
available, isolated yields were superior to those obtained in the
DKR performed at 80 °C,5a and the enantiomeric excesses were
In conclusion, performing the radical racemization at
38À40 °C under photochemical initiation enabled us to carry
out CAL-B-catalyzed DKR of a wide series of non benzylic
amines, bearing different functional groups. Under standard
experimental conditions, optimized for amine 1a, high yields
and excellent enantiomeric excesses were reached in most cases.
This procedure might open the route to the use of other lipases in
further work.
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dx.doi.org/10.1021/jo201256w |J. Org. Chem. 2011, 76, 7281–7286

The Journal of Organic Chemistry
NOTE
Table 2. DKR of Amines (()-1aÀn
for an unretained peak determined by injection of tritertiobutyl-
benzene), the enantioselectivity factor R = k2/k1, and the resolution Rs
are given to characterize the chiral separations. The enantiomeric
excesses of the primary amines were determined, after derivatization
in trifluoroacetamide with 1.5 equiv of N-methyl-bis-trifluoroacetamide,
by gas chromatography (GC) analysis on a chromatograph fitted with a
Lipodex D column or a Crompack column with flame ionization
detector (FID), using the derivatized racemic compounds as reference
(see Supporting Information). Octanethiol, ethyl laurate (2a), methyl
3-methoxypropanoate (2b), and amines (1a, 1b, 1d, 1e, 1h, 1i and 1m)
are commercially available; they were used without further purification.
Compounds 1c,4a,14 1f,3a 1g,3c 1j,15 1n,16 and 2c5c were prepared ac-
cording to literature procedures.
Synthesis of Amine 1k.
amine
procedurea,b
amide isolated yield, % (ee, %)c
1a
DKR + KR
81 (>99)
89 (>99)
61 (>99)
74 (>99)
82 (98)
84 (>99)
75 (>99)
81 (>99)
72 (>99)
57 (85)
62 (90)
84 (70)
85 (95)
58 (98)d
66 (98)
55 (56)
71 (75)
68 (74)
71 (75)
37 (>99)
81 (>99)
KR + DKR + KR
DKR + KR
2-(2-Azidopropyl)-2-methyl-1,3-dioxolane (A)17. To a solu-
tion of 3-penten-2-one (1.68 g, 20 mmol) in dichloromethane (50 mL)
were added sodium azide (1.56 g, 23 mmol) and trimethylsilyl chloride
(3.04 mL, 23 mmol). This mixture was stirred for 15 min at rt, and then
ethylene glycol (1.338 mL, 23 mmol) was added. The solution was
refluxed for 8 h, cooled to rt, and diluted with water. The aqueous
solution was extracted twice with dichloromethane and dried under
MgSO4. After concentration, the crude material was subjected to flash
column chromatography on silica gel (0/100 to 50/50 Et2O/pentane)
to give A (1.21 g, 14 mmol, 71%). 1H NMR (400 MHz, CDCl3): 3.96
(m, 4H), 3.63 (m, 1H), 1.94 (dd, J = 14.7, 7.8, 1H), 1.77 (dd, J = 14.7,
4.5, 1H), 1.36 (s, 3H), 1.29 (d, J = 6.6, 3H). 13C NMR (75 MHz,
CDCl3): 108.6 (C), 64.6 (CH2), 64.5 (CH2), 53.9 (CH), 44.6 (CH2),
24.2 (CH3), 20.9 (CH3). HRMS ([M + H]+, ESI): m/z calcd for
C7H14N3O2 172.1081, found 172.1082.
1b
KR + DKR + KR
DKR + KR
1c
1d
1e
1f
DKR + KR
DKR + KR
DKR + KR
1g
1h
DKR + KR
DKR + KR
KR + DKR + KR
DKR + KR
1i
1j
1k
DKR + KR
DKR + KR
KR + DKR + KR
DKR + KR
1l
1-(2-Methyl-1,3-dioxolan-2-yl)propan-2-amine (1k). A solution
of A (1.05 g, 6.14 mmol) and Pd/C (5 wt %) (50 mg) in a mixture of Et2O/
MeOH (20 mL/0.5 mL) was stirred overnight under H2 (1 atm). After
filtration and concentration, the crude product was distilled with a Kugelrohr
apparatus (150 °C/20 mbar) leading to 1k (750 mg, 5.16 mmol, 84%). 1H
NMR (400 MHz, CDCl3): 3.89 (m, 4H), 3.13 (m, 1H), 2.00 (broad s, 2H),
1.70À1.57 (m, 2H), 1.27 (s, 3H), 1.02 (d, J = 6.4, 3H). 13C NMR (75 MHz,
CDCl3): 109.9 (C), 64.5 (CH2), 64.1 (CH2), 47.6 (CH2), 43.2 (CH), 24.6
(CH3), 24.1 (CH3). HRMS ([M + H]+, ESI): m/z calcd for C7H16NO2
146.1176, found 146.1170.
KR + DKR + KR
DKR + KR
1m
1n
KR + DKR + KR
DKR + KR
KR + DKR + KR
a Standard protocol for direct DKR: amine (1 mmol, 0.1 M solution),
2b (1.5 mmol, 1.5 equiv), MTBE (10 mL), 4 Å molecular sieve (1 g),
CAL-B (200 mg), n-OctSH (1.2 mmol, 208 μL), AIBN (1 g, 0.76 mmol
added portion-wise 5 times, i.e., 20 mg each 45 min), temperature 38À40 °C.
b See Experimental Section. c Determined by HPLC. d Determined by GC.
ꢁ
Synthesis of Amine 1l.
’ EXPERIMENTAL SECTION
General. The 1H and 13C NMR spectra were recorded at 400 and 75
MHz, respectively. Chemical shifts (δ) are reported in ppm, and
coupling constants (J) are given in Hz. Enantiomeric excesses (ee's)
of amides were determined by analytical chiral HPLC. The solvents for
chiral chromatography (n-hexane, i-PrOH, EtOH) were HPLC grade.
They were degassed and filtered on a 0.45 μm membrane before use.
The chiral HPLC analyses were performed with UV detection on
Chiralcel OD-H or OD-3 (250 Â 4.6 mm, cellulose tris(3,5-
dimethylphenylcarbamate)), Chiralpak AD (250 Â 4.6 mm, amylose
tris(3,5-dimethylphenylcarbamate)) and Chiralpak AS-3 (amylose tris-
[(S)-R-phenethyl]carbamate) from Chiral Technologies Europe
(Illkirch, France), Lux-Cellulose-2 (cellulose tris(3-chloro-4-methyl-
phenylcarbamate)), Lux-Cellulose-4 (cellulose tris(4-chloro-3-methyl-
phenylcarbamate)) from Phenomenex, and TCI chiral BP-S from Tokyo
Chemical Industry. The retention times tR are given in minutes for each
enantiomer, the retention factor k = (tR À t0)/t0 (t0 is the retention time
7-Azido-1,4-dioxaspiro[4.4]nonane (B). To a solution of
2-cyclopenten-1-one (1.64 g, 20 mmol) in dichloromethane (50 mL)
were added sodium azide (1.56 g, 23 mmol) and trimethylsilyl chloride
(3.04 mL, 23 mmol). This mixture was stirred for 15 min at rt, and then
ethylene glycol (1.338 mL, 23 mmol) was added. The solution was
refluxed for 8 h, cooled to rt, and diluted with water. The aqueous
solution was extracted twice with dichloromethane and dried under
MgSO4. After concentration, the crude material was subjected to flash
column chromatography on silica gel (0/100 to 50/50 Et2O/pentane)
to give B (1.645 g, 11.6 mmol, 58%). 1H NMR (400 MHz, CDCl3): 3.98
(broad quint, J = 7.0, 1H), 3.94À3.87 (m, 4H), 2.16 (dd, J = 14.2, 7.3,
1H), 2.07À1.97 (m, 2H), 1.90 (dd, J = 14.2, 5.7, 1H), 1.85À1.76 (m,
2H). 13C NMR (75 MHz, CDCl3): 116.05 (C), 64.4 (CH2), 64.1
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The Journal of Organic Chemistry
NOTE
(CH2), 59.8 (CH), 42.0 (CH2), 34.5 (CH2), 30.0 (CH2). HRMS ([M +
Li]+, ESI): m/z calcd for C7H11N3O2Li 176.1006, found 176.1008.
1,4-Dioxaspiro[4.4]nonan-7-amine (1l). A solution of B (569
mg, 3.37 mmol) and Pd/C (5 wt %) (50 mg) in a mixture of Et2O/
MeOH (20 mL/1 mL) was stirred overnight under H2 (1 atm). After
filtration and concentration, the crude product was distilled with a
Kugelrohr apparatus (150 °C/50 mbar) leading to 1l (400 mg, 2.79
mmol, 83%). 1H NMR (400 MHz, CDCl3): 3.84 (m, 4H), 3.34 (quint,
J = 6.7, 1H), 2.06 (dd, J = 13.6, 7.2, 1H), 2.02 (broad s, 2H), 1.99À1.90
(m, 2H), 1.78À1.70 (m, 1H), 1.54 (dd, J = 13.6, 6.8, 1H), 1.43À1.34 (m,
1H). 13C NMR (75 MHz, CDCl3): 116.8 (C), 64.1 (CH2), 64.0 (CH2),
50.7 (CH), 45.7 (CH2), 35.0 (CH2), 34.0 (CH2). HRMS ([M + H]+,
ESI): m/z calcd for C7H14NO2: 144.1019, found 144.1021.
General Procedure for the Kinetic Resolution of Amines.
In a glass tube (diameter 1.8 cm), the amine (0.5 mmol) was added to a
solution of methyl 3-methoxypropanoate (2b) (0.75 mmol), molecular
sieves 4 Å (0.5 g), and CAL-B (100 mg) in MTBE (5 mL). The resulting
mixture was stirred at rt, and the reaction was monitored by chiral GC
and/or chiral HPLC.
General Procedure for the Dynamic Kinetic Resolution of
Amines. Method A (DKR + KR Sequence). To a solution of methyl
3-methoxypropanoate (2b) (1.5 mmol) in MTBE (10 mL) were added
amine (1aÀn) (1 mmol), CAL-B (200 mg), octanethiol (1.2 mmol),
and molecular sieves 4 Å (1 g). The mixture was irradiated at 38À40 °C
in a glass tube (diameter 1.8 cm) in a Rayonet apparatus (RPR-200, 16
UV lamps Sylvania Blacklight 351 F15W/T5/BL350) for 3.75 h, and
AIBN (75 mg, 0.55 mmol) was added portion-wise every 45 min (5 Â 15
mg). After the irradiation was switched off, the resulting mixture was
stirred at 38 °C for 5 h. The enzyme was filtered out from the solution
and washed with dichloromethane (5 mL). The combined organic
phases were then evaporated, and the crude material was purified by
flash chromatography on silica gel (dichloromethane/methanol; gradi-
ent from 0 to 5%) to give pure amide.
Method B (KR + DKR + KR Sequence). In a glass tube (diameter
1.8 cm), the amine (1 mmol) was added to a solution of methyl
3-methoxypropanoate (2b) (1.5 mmol), molecular sieves 4 Å (1 g),
and CAL-B (200 mg) in MTBE (10 mL). The resulting mixture was
stirred at rt for 2.5 to 20 h depending on the substrate (see Table 1).
Then octanethiol (1.2 mmol) was added. The mixture was irradiated at
38À40 °C in a Rayonet apparatus (RPR-200, 16 UV lamps Sylvania
Blacklight 351 F15W/T5/BL350) for 3.75 h, and AIBN (75 mg, 0.55
mmol) was added portion-wise every 45 min (5 Â 15 mg). After the
irradiation was switched off, the resulting mixture was stirred at 38 °C for
5 h. The enzyme was filtered out from the solution and washed with
dichloromethane (5 mL). The combined organic phases were then
evaporated, and the crude material was purified by flash chromatography
on silica gel (dichloromethane/methanol; gradient from 0 to 5%) to give
pure amide.
1H NMR (400 MHz, CDCl3): 5.97 (broad s, 1H), 4.00 (pseudo sept, J =
6.6, 1H), 3.62 (t, J = 5.7, 2H), 3.35 (s, 3H), 2.41 (t, J = 5.7, 2H), 1.84 (br
s, 1H), 1.51À1.35 (m, 6H), 1.19 (s, 3H), 1.18 (s, 3H), 1.12 (d, J = 6.6,
3H). 13C NMR (75 MHz, CDCl3): 170.8 (CO), 70.6 (C), 68.8 (CH2),
58.6 (CH3), 44.7 (CH), 43.3 (CH2), 37.2 (CH2), 37.1 (CH2), 29.4
(CH3), 28.9 (CH3), 21.0 (CH3), 20.5 (CH2). HPLC conditions:
Chiralcel OD-3, n-hexane/i-PrOH 95:5, flow rate = 1 mL/min, UV
220 nm, tR (R) = 15.05 min, tR (S) = 16.83 min, k (R) = 4.02, k (S) =
4.61, R = 1.42. ee >99%. [R]25D = +6.2 (c 5.6, MeOH). HRMS ([M +
H]+, ESI): m/z calcd for C12H26NO3 232.1907, found 232.1909.
3-Methoxy-N-(1-phenylpropan-2-yl)propanamide (3c).
Amide 3c was prepared in 82% yield from amine 1c according to the
general procedures for dynamic kinetic resolutions. 1H NMR (400 MHz,
CDCl3): 7.33À7.30 (m, 2H), 7.26À7.20 (m, 3H), 6.07 (broad s, 1H),
4.29 (m, 1H), 3.59 (m, 2H), 3.33 (s, 3H), 2.80 (AB part of an ABX
spectrum, 2H, JAB= 13.5, Δν= 23.7), 2.42 (AB part of an ABX2 spectrum,
2H), 1.14 (d, J = 6.6, 3H). 13C NMR (75 MHz, CDCl3): 170.7 (CO),
138.1 (C), 129.5 (CH), 128.3 (CH), 126.4 (CH), 68.7 (CH2), 58.6
(CH3), 45.9 (CH), 42.4 (CH2), 37.0 (CH2), 20.0 (CH3). HPLC
conditions: Chiralcel OD-H, n-hexane/i-PrOH 95:5, flow rate =
1 mL/min, UV 220 nm, tR (R) = 16.15 min, tR (S) = 19 min, k (R) =
4.4, k (S) = 5.3, R = 1.20, Rs = 2.3. ee 98%. [R]25 = +15.4 (c 1.5,
D
CHCl3). HRMS ([M + H]+, ESI): m/z calcd for C13H20NO2 222.1489,
found 222.1485.
3-Methoxy-N-(octan-2-yl)propanamide (3d). Amide 3d was
prepared in 84% yield from amine 1d according to the general
procedures for dynamic kinetic resolutions. 1H NMR (400 MHz,
CDCl3): 6.00 (broad s, 1H), 3.94 (m, 1H), 3.60 (t, J = 5.8, 2H), 3.34
(s, 3H), 2.41 (t, J = 5.8, 2H), 1.39 (m, 2H), 1.24 (m, 8H), 1.09 (d, J = 6.6,
3H), 0.85 (t, J = 7.1, 3H). 13C NMR (75 MHz, CDCl3): 170.4 (CO),
68.8 (CH2), 58.5 (CH3), 45.0 (CH), 37.1 (CH2), 36.8 (CH2), 31.7
(CH2), 29.1 (CH2), 25.8 (CH2), 22.4 (CH2), 20.7 (CH3), 13.8 (CH3).
HPLC conditions: Chiralpak AS-3, n-hexane/ethanol 95:5, flow rate =
1 mL/min, UV 220 nm, tR (S) = 14 min, tR (R) = 15.6 min, k (S) = 3.7, k
(R) = 4.2, R = 1.13, Rs = 1.5. ee >99%. [R]25D = +1.1 (c 1.4, CHCl3).
HRMS ([M + H]+, ESI): m/z calcd for C12H26NO2 216.1958, found
216.1961.
3-Methoxy-N-(6-methylheptan-2-yl)propanamide (3e).
Amide 3e was prepared in 75% yield from amine 1e according to the
general procedures for dynamic kinetic resolutions. 1H NMR (400 MHz,
CDCl3): 5.87 (broad s, 1H), 3.89 (m, 1H), 3.56 (t, J = 5.8, 2H), 3.30 (s,
3H), 2.35 (t, J = 5.8, 2H), 1.45 (nonet, J = 6.7, 1H), 1.31 (m, 2H), 1.23
(m, 2H), 1.10 (m, 2H), 1.05 (d, J = 6.6, 3H), 0.79 (d, J = 6.6, 6H). 13C
NMR (75 MHz, CDCl3): 170.5 (CO), 68.8 (CH2), 58.5 (CH3), 44.9
(CH), 38.7 (CH2), 37.1 (CH2), 37.0 (CH2), 27.8 (CH), 23.6 (CH2),
22.5 (2 x CH3), 20.8 (CH3). HPLC conditions: Chiralpak AS-3, n-
hexane/i-PrOH 95:5, flow rate = 1 mL/min, UV 220 nm, tR (S) = 12.8
min, tR (R) = 14.5 min, k (S) = 3.28, k (R) = 3.85, R = 1.17, Rs = 1.73. ee
>99%. [R]25D = +1.2 (c 1.4, CHCl3). HRMS ([M + H]+, ESI): m/z calcd
for C12H26NO2 216.1958, found 216.1959.
3-Methoxy-N-(7-methyloct-6-en-2-yl)propanamide (3f).
Amide 3f was prepared in 81% yield from amine 1f according to the
general procedures for dynamic kinetic resolutions. 1H NMR (400 MHz,
CDCl3): 6.00 (broad d, J = 5.9, 1H), 5.09 (broad t, J = 7.2, 1H), 3.97
(pseudo sept, J = 6.7, 1H), 3.62 (t, J = 5.8, 2H), 3.37 (s, 3H), 2.43 (t, J =
5.8, 2H), 1.99 (broad q, J = 7.3, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.44 (q,
J = 7.0, 2H), 1.12 (d, J = 6.7, 3H). 13C NMR (75 MHz, CDCl3): 170.3
(CO), 131.2 (C=), 123.4 (HC=), 68.4 (CH2), 58.1 (CH3), 44.4 (CH),
36.6 (CH2), 36.3 (CH2), 25.2 (CH3), 24.2 (CH2), 20.4 (CH3), 17.1
(CH3). HPLC conditions: Chiralcel OD-H, n-hexane/i-PrOH 95:5,
flow rate = 1 mL/min, UV 220 nm, tR (R) = 27.3 min, tR (S) = 29 min, k
(R) = 8.1, k (S) = 8.7, R = 1.07, Rs = 1.9. ee >99%. [R]25D = +7.5 (c 1.3,
CHCl3). HRMS ([M + H]+, ESI): m/z calcd for C12H24NO2 214.1802,
found 214.1803.
3-Methoxy-N-(4-phenylbutan-2-yl)propanamide (3a).
Amide 3a was prepared in 81% yield from amine 1a according to the
general procedures for dynamic kinetic resolutions. 1H NMR (400 MHz,
CDCl3): 7.30 (m, 2H), 7.20 (m, 3H), 5.98 (broad d, J = 6.6, 1H), 4.08
(pseudo sept, J = 6.7, 1H), 3.65 (t, J = 5.8, 2H), 3.40 (s, 3H), 2.66 (m,
2H), 2.44 (t, J = 5.8, 2H), 1.77 (pseudo q, J = 7.8, 2H), 1.08 (d, J = 6.6,
3H). 13C NMR (100 MHz, CDCl3): 170.8 (CO), 144.9 (C), 128.4
(CH), 128.3 (CH), 125.9 (CH), 68.9 (CH2), 58.7 (CH3), 44.9 (CH),
38.7 (CH2), 37.2 (CH2), 32.4 (CH2), 21.0 (CH3). HPLC conditions:
Chiralcel OD-H, n-hexane/ethanol 95:5, flow rate = 1 mL/min, UV
254 nm, tR (S) = 19 min, tR (R) = 23.5 min, k (S) = 5.13, k (R) = 6.60, R =
1.28, Rs = 3. ee > 99%. [R]25D = +20.8 (c 1.0, CHCl3). HRMS ([M +
H]+, ESI): m/z calcd for C14H22NO2 236.1645, found 236.1648.
N-(6-Hydroxy-6-methylheptan-2-yl)-3-methoxypropana-
mide (3b). Amide 3b was prepared in 61% yield from amine 1b
according to the general procedures for dynamic kinetic resolutions.
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NOTE
3-Methoxy-N-(4-(octylthio)butan-2-yl)propanamide (3g).
Amide 3g was prepared in 72% yield from amine 3g according to the
general procedures for dynamic kinetic resolutions. 1H NMR (400 MHz,
CDCl3): 6.11 (broad s, 1H), 4.08 (pseudo sept, J = 6.7, 1H), 3.63 (t, J =
5.6, 2H), 3.37 (s, 3H), 2.53À2.48 (m, 4H), 2.47À2.43 (m, 2H),
1.77À64 (m, 2H), 1.56 (quint, J = 7.7, 2H), 1.36 (pseudo quint, J =
6.6, 2H), 1.24 (m, 8H), 1.06 (d, J = 6.7, 3H), 0.88 (t, J = 7.0, 3H). 13C
NMR (75 MHz, CDCl3): 170.8 (CO), 68.7 (CH2), 58.6 (CH3), 44.6
(CH), 37.1 (CH2), 36.9 (CH2), 32.2 (CH2), 31.7 (CH2), 29.5 (CH2),
29.1 (CH2), 29.1 (CH2), 28.8 (CH2), 28.5 (CH2), 22.6 (CH2), 20.8
(CH3), 14.0 (CH3). HPLC conditions: Chiralpak AD, n-hexane/i-
PrOH (95/5), 1 mL/min. Detectors: UV (220 nm). tR (S) = 10.2
min, tR (R) = 11.35 min, k (S) = 2.4, k (R) = 2.8, R = 1.16, Rs = 2.9. ee
>99%. [R]25D = +13.5 (c 1.5, CHCl3). HRMS ([M + H]+, ESI): m/z
calcd for C16H34NO2S 304.2305, found 304.2302. The assignment of
the absolute configuration is based on the selectivity of the lipase.
N-(5-(Diethylamino)pentan-2-yl)-3-methoxypropana-
mide (3h). Amide 3h was prepared in 57% yield from amine 1h
according to the general procedures for dynamic kinetic resolutions. 1H
NMR (400 MHz, CDCl3): 6.28 (broad d, J = 7.3, 1H), 3.99 (pseudo
sept, J = 6.6, 1H), 3.63 (m, 2H), 3.35 (s, 3H), 2.66 (q, J = 7.2, 4H), 2.56
(m, 2H), 2.42 (t, J = 5.9, 2H), 1.63À1.54 (m, 2H), 1.50À1.44 (m, 2H),
1.13 (d, J = 6.6, 3H), 1.10 (t, J = 7.2, 6H). 13C NMR (75 MHz, CDCl3):
170.6 (CO), 68.7 (CH2), 58.5 (CH3), 52.4 (CH2), 46.5 (2 x CH2), 44.6
(CH), 37.0 (CH2), 34.5 (CH2), 22.8 (CH2), 20.8 (CH3), 10.9 (2 x
CH3). HPLC conditions: TCI chiral BP-S, n-hexane/ethanol (90/10),
1 mL/min. Detectors: DAD. tR (R) = 6.75 min, tR (S) = 8.33 min, k (R) =
1.25, k (S) = 1.78, R = 1.42, Rs = 2.53. ee 90%. [R]25D = +37.8 (c 1.2,
CHCl3). HRMS ([M + H]+, ESI): m/z calcd for C13H29N2O2 245.2224,
found 245.2216. The assignment of the absolute configuration is based
on the selectivity of the lipase.
21.8 (CH3). GC analysis for the racemic mixture: Lipodex D column,
injector 250 °C, program: 20 min/120 °C then 3 °C/min from 120 to
180 °C and 20 min/180 °C. Detector: FID. tR (R) = 42.37 min, tR (S) =
42.98 min, k (R) = 15.94, k (S) = 16.19, R = 0.99, Rs = 2.92. ee 98%.
[R]25D = À2.4 (c 1.2, CHCl3). HRMS ([M + H]+, ESI): m/z calcd for
C11H22NO4 232.1543, found 232.1540. The assignment of the absolute
configuration is based on the selectivity of the lipase.
N-(1,4-Dioxaspiro(4,4)nonan-7-yl)-3-methoxypropana-
mide (3l). Amide 3l was prepared in 55% yield from amine 1l according
to the general procedures for dynamic kinetic resolutions. 1H NMR (400
MHz, CDCl3): 6.53 (broad s, 1H), 4.43À4.35 (m, 1H), 3.91 (m, 4H),
3.62 (t, J = 5.8, 2H), 3.36 (s, 3H), 2.41 (t, J = 5.8, 2H), 2.18À2.08 (m,
2H), 1.97À1.80 (m, 2H), 1.69À1.56 (m, 2H). 13C NMR (75 MHz,
CDCl3): 170.5 (CO), 116.5 (C), 68.5 (CH2), 64.2 (CH2), 63.9 (CH2),
58.5 (CH3), 47.9 (CH), 42.2 (CH2), 36.7 (CH2), 34.2 (CH2), 30.9
(CH2). HPLC conditions: Lux-Cellulose-4, n-hexane/i-PrOH 70:30,
flow rate = 1 mL/min, UV 220 nm, tR (R) = 11.27 min, tR (S) = 20.59
min, k (R) = 2.76, k (S) = 5.86, R = 1.83, Rs = 10.5. ee 75%. [R]25
=
D
À7.6 (c 1.4, CHCl3). HRMS ([M + H]+, ESI): m/z calcd for
C11H20NO4 230.1387, found 230.1388. The assignment of the absolute
configuration is based on the selectivity of the lipase.
N-(1,2,3,4-Tetrahydronaphthalen-3-yl)-3-methoxypropa-
namide (3m). Amide 3m was prepared in 68% yield from amine 1m
according to the general procedures for dynamic kinetic resolutions. 1H
NMR (400 MHz, CDCl3): 7.13À7.05 (m, 4H), 6.30 (broad s, 1H), 4.31
(m, 1H), 3.61 (t, J = 5.7, 2H), 3.28 (s, 3H), 3.11 (dd, J = 16.2, 5.0, 1H),
2.95À2.81 (m, 2H), 2.65 (dd, J = 16.2, 7.7, 1H), 2.44 (t, J = 5.7, 2H),
2.08À2.01 (m, 1H), 1.84À1.75 (m, 1H). 13C NMR (75 MHz, CDCl3):
170.9 (CO), 135.5 (C), 134.3 (C), 129.4 (HC=), 128.8 (HC=), 126.0
(HC=), 125.8 (HC=), 68.8 (CH2), 58.6 (CH3), 45.0 (CH), 37.0 (CH2),
35.6 (CH2), 28.7 (CH2), 27.3 (CH2). HPLC conditions: Lux-Cellulose-
4, n-hexane/i-PrOH 80:20, flow rate = 1 mL/min, UV 220 nm, tR (R) =
9.23 min, tR (S) = 16.49 min, k (R) = 7.6, k (S) = 7.8, R = 0.5, Rs = 2.58.
ee 75%. [R]25D = +13.7 (c 1.6, CHCl3). HRMS ([M + H]+, ESI): m/z
calcd for C14H20NO2 234.1489, found 234.1485.
3-Methoxy-N-(1-(naphthalen-8-yl)propan-2-yl)propana-
mide (3n). Amide 3n was prepared in 37% yield from amine 1n
according to the general procedures for dynamic kinetic resolutions. 1H
NMR (400 MHz, CDCl3): 8.31 (d, J = 8.5, 1H), 7.84 (d, J = 8.0, 1H),
7.74 (d, J = 8.2, 1H), 7.56 (m, 1H), 7.47 (m, 1H), 7.39 (t, J = 7.0, 1H),
7.30 (d, J = 6.7, 1H), 6.16 (broad d, J = 6.5, 1H), 4.40 (sept, J = 6.5, 1H),
3.62À3.52 (m, 2H), 3.51 (dd, J = 13.6, 5.5, 1H), 3.30 (s, 3H), 2.96 (dd,
J = 13.6, 8.3, 1H), 2.43À2.39 (m, 2H), 1.13 (d, J = 6.5, 3H). 13C NMR
(75 MHz, CDCl3): 171.0 (CO), 134.7 (C=), 133.9 (C=), 132.4 (C=),
128.6 (HC=), 127.6 (HC=), 127.3 (HC=), 126.2 (HC=), 125.7 (HC=),
125.2 (HC=), 124.4 (HC=), 68.7 (CH2), 58.6 (CH3), 45.9 (CH), 40.0
(CH2), 37.0 (CH2), 20.0 (CH3). HPLC conditions: Chiralcel OD-H, n-
hexane/i-PrOH 95:5, flow rate = 1 mL/min, UV 220 nm, tR (S) = 19.96
min, tR (R) = 24.1 min, k (S) = 5.53, k (R) = 6.7, R = 1.2, Rs = 4.9. ee
>99%. [R]25D = À17.3 (c 1.2, CHCl3). HRMS ([M + H]+, ESI): m/z
calcd for C17H22NO2 272.1645, found 272.1643.
N-sec-Butyl-3-methoxypropanamide (3i). Amide 3i was pre-
pared in 84% yield from amine 1i according to the general procedures for
dynamic kinetic resolutions. 1H NMR (400 MHz, CDCl3): 5.96 (s, 1H),
3.91 (m, 1H), 3.63 (t, J = 5.8, 2H), 3.37 (s, 3H), 2.43 (t, J = 5.8, 2H),
1.42À1.47 (m, 2H), 1.11 (d, J = 6.6, 3H), 0.90 (t, J = 7.3, 3H). 13C NMR
(75 MHz, CDCl3): 170.7 (CO), 68.8 (CH2), 58.6 (CH3), 46.3 (CH),
37.1 (CH2), 29.5 (CH2), 20.3 (CH3), 10.2 (CH3). HPLC conditions:
Lux-Cellulose-2, n-hexane/ethanol 95:5, flow rate = 1 mL/min, UV
220 nm, tR (R) = 19.91 min, tR (S) = 20.53 min, k (R) = 5.64, k (S) =
5.84, R = 1.08, Rs = 2.6. ee 70%. [R]25D = À8.6 (c 1.3, CHCl3). HRMS
([M + H]+, ESI): m/z calcd for C8H18NO2 160.1332, found 160.1331.
tert-Butyl 5-(3-Methoxypropanamido)hexanoate (3j).
Amide 3j was prepared in 85% yield from amine 1j according to the
general procedures for dynamic kinetic resolutions. 1H NMR (400 MHz,
CDCl3): 6.03 (broad d, J = 8.1, 1H), 4.08À3.95 (m, 1H), 3.64 (t, J = 5.8,
2H), 3.38 (s, 3H), 2.42 (t, J = 5.8, 2H), 2.29 (m, 2H), 1.81À1.67 (m,
4H), 1.46 (s, 9H), 1.16 (d, J = 6.6, 3H). 13C NMR (75 MHz, CDCl3):
172.7 (CO), 170.6 (CO), 80.1 (C), 68.6 (CH2), 58.4 (CH3), 44.5 (CH),
36.9 (CH2), 36.8 (CH2), 32.1 (CH2), 31.4 (CH2), 27.8 (3xCH3), 20.7
(CH3). HPLC conditions: TCI chiral BP-S, n-hexane/i-PrOH 80:20,
flow rate = 1 mL/min, DAD and polarimeter, tR (S) = 4.77 min, tR (R) =
7.40 min, k (S) = 0.59, k (R) = 1.47, R = 2.5, Rs = 5.01. ee 95%. [R]25
=
D
’ ASSOCIATED CONTENT
+7.0 (c 1.2, CHCl3). HRMS ([M + H]+, ESI): m/z calcd for C13H26NO4
260.1856, found 260.1857. The assignment of the absolute configura-
tion is based on the selectivity of the lipase.
S
Supporting Information. Amine analysis procedures and
b
NMR spectra for compounds 1c, 1f, 1g, 1j, 1k, 1l, 1n, A, B, 2c,
and 3aÀ3n. This material is available free of charge via the
Internet at http://pubs.acs.org.
3-Methoxy-N-(1-(2-methyl-1,3-dioxolan-2-yl)propan-
2-yl)propanamide (3k). Amide 3k was prepared in 66% yield from
amine 1k according to the general procedures for dynamic kinetic
resolutions. 1H NMR (400 MHz, CDCl3): 6.48 (broad s, 1H), 4.08 (m,
1H), 3.97À3.88 (m, 4H), 3.62 (m, 2H), 3.35 (s, 3H), 2.40 (t, J = 5.8,
2H), 1.80 (m, 2H), 1.30 (s, 3H), 1.18 (d, J = 6.5, 3H). 13C NMR (75
MHz, CDCl3): 170.5 (CO), 109.2 (C), 68.6 (CH2), 64.6 (CH2), 64.1
(CH2), 58.6 (CH3), 44.5 (CH2), 42.3 (CH), 37.2 (CH2), 23.8 (CH3),
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: michele.bertrand@univ-cezanne.fr; stephane.gastaldi@
univ-cezanne.fr; gerard.gil@univ-cezanne.fr.
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NOTE
’ ACKNOWLEDGMENT
(12) E-values were calculated according to Chen, C.-S.; Fujimoto,
Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294.
(13) Rodríguez-Mata, M.; Gotor-Fernꢁandez, V.; Gonzꢁalez-Sabin, J.;
Rebolledo, F.; Gotor, V. Org. Biomol. Chem. 2011, 9, 2274.
(14) Gonzalez-Sabin, J.; Gotor, V.; Rebolledo, F. Tetrahedron:
Asymmetry 2002, 13, 1315.
A gift of Novozym 435 from Novozymes (Denmark) is grate-
fully acknowledged. This work was supported by the Agence
Nationale de la Recherche (ANR 06-Blan-0137).
(15) Kokotos, G.; Six, D. A.; Loukas, V.; Smith, T.; Constantinou-
Kokotou, V.; Hadjipavlou-Litina, D.; Kotsovolou, S.; Chiou, A.; Beltzner,
C. C.; Dennis, E. A. J. Med. Chem. 2004, 47, 3615–3628.
(16) Foye, W. O.; Tovivich, S. J. Pharm. Sci. 1979, 68, 591.
(17) Gil, G. Tetrahedron Lett. 1984, 25, 3805.
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(9) We suspect it to compete with the amine in the crucial step of
hydrogen atom abstraction, which slows down the rate of racemization.
(10) This could become significant owing to the length of some
DKR reactions.
(11) Similar observations have been recently reported; see: van Pelt,
S.; Teeuwen, R. L. M.; Janssen, M. H. A.; Sheldon, R. A.; Dunn, P. J.;
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