Resolution of racemic 12-hydroxyl-1,15-pentadecanlactam using d-glucose derivative as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2008.01.007

Racemic 12-hydroxyl-1,15-pentadecanlactam 2 was resolved using glucose as a chiral auxiliary for the first time. Both the (R)- and (S)-isomers were obtained in high enantiomeric excesses (>99% by HPLC). The absolute configuration of (+)-2b and (-)-2a was determined by Horeau's method and a modified Mosher's method.

Full text of DOI:10.1016/j.tetasy.2008.01.007

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 379–383
Resolution of racemic 12-hydroxyl-1,15-pentadecanlactam using
D-glucose derivative as a chiral auxiliary
Chuan-Jin Hou, Xiao-Mei Liang, Jing-Ping Wu, Jia-Xing Huang,
Jian-Jun Zhang and Dao-Quan Wang*
Key Laboratory of Pesticide Chemistry and Application Technology, Department of Applied Chemistry,
China Agricultural University, Beijing 100094, PR China
Received 11 December 2007; accepted 5 January 2008
Abstract—Racemic 12-hydroxyl-1,15-pentadecanlactam 2 was resolved using glucose as a chiral auxiliary for the first time. Both the
(R)- and (S)-isomers were obtained in high enantiomeric excesses (>99% by HPLC). The absolute configuration of (+)-2b and (ꢀ)-2a
was determined by Horeau’s method and a modified Mosher’s method.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
had obtained enantiomerically pure alcohols using carbo-
hydrates as chiral auxiliaries.
Carbohydrates are readily available inexpensive natural
products with many functional groups and chiral carbons
in one molecule. A number of carbohydrate templates have
been used as chiral auxiliaries.1 The steric, stereoelectronic,
and coordinating properties of carbohydrate templates can
be used in various asymmetric reactions such as Diels–Al-
der reactions,2 [2 + 2] cycloadditions,3 1,3-dipolar cyclo-
additions,4 cyclopropanations5 and Michael additions.6
They have also proved to have the possibility of versatile
stereoselective applications in the synthesis of enantiomeri-
cally pure a-amino acid7 by Strecker8 and Ugi9 reactions.
Despite the intrinsic elegance of highly selective asymmet-
ric synthesis, the fact that both enantiomers are usually
desired for biological assays has sustained interest in
resolution methods. There have been a few reports of
carbohydrates as chiral auxiliaries in classic enantiomer
resolutions. For example, Ko¨ll’s10 D-Xylofuranosyl oxazo-
lidinone was described as an efficient chiral auxiliary for
the resolution of carboxylic and sulfonic acids. Banki11
showed that b-lactams may be resolved via Ferrier rear-
rangement with tri-O-acetyl-D-glucal. Itoh et al.12 had used
aD-glucose template to kinetically resolve auxiliary chiral
biaryl compounds. Moreover, Lubineau13 and Yoshida14
Macrocyclic lactams comprise a small family of com-
pounds that have shown a wide variety of biological activ-
ities.15 Among them, some macrocyclic lactam glycosides
showed good antibacterial activity.16 Stimulated by these
findings, we focus on the synthesis of compounds with
the structure of macrocyclic lactams and glycosides. Inter-
estingly, we find, in this course, that the D-glucose-derived
trichloroacetimidate 3 has the ability to function as a chiral
auxiliary since it may be easily removed after the separa-
tion of the anomers formed, leaving a new enantiomerically
pure substance, which provides a novel and convenient
method for the resolution of racemic macrocyclic lactams.
Herein, we would like to report the resolution of 12-hydro-
xyl-1,15-pentadecanlactam 2.
2. Results and discussion
The key step of this method is to attach the sugar to a
macrocyclic lactam molecule (aglycon). The well-known
Koenigs–Knorr method,17 introduced in 1901, is the oldest
and most classical method.18 However, inherent disadvan-
tages of the Koenigs–Knorr method (the use of heavy
metal salts, especially in large-scale reactions) could not
be overcome. Therefore, many attempts have been made
to search for new methods, which do not require the use
*
Corresponding author. Tel./fax: +86 10 6273 2219; e-mail: wangdq@
cau.edu.cn
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.007

380
C.-J. Hou et al. / Tetrahedron: Asymmetry 19 (2008) 379–383
of heavy metal salts.19 Among them, Schmidt’s trichloro-
acetimidate method20 has proved to be the most successful
method in the synthesis of O-glycosides. The glycosylation
reaction was smoothly promoted by a catalytic quantity of
yield (yield 88%) and high diastereoselectivity. Only the
b-isomer was obtained on the basis of the 1H NMR spectra
(J1,2 = 7.9 Hz). Glycoside 4 appeared as a mixture of
diastereomers (b,R/b,S). Indeed one of the isomers 4b
(Rf = 0.6, petroleum ether/ethyl acetate, 1:2) can be easily
obtained when recrystallized twice from EtOAc (yield
92%). Another isomer 4a (Rf = 0.5, petroleum ether/ethyl
acetate, 1:2) was then obtained by silica gel chromatogra-
phy (yield 72%). Removal of the benzoyl group of 4a and
4b with NH3 in MeOH and then hydrolysis31 under acid
condition gave enantiomerically pure (ꢀ)-2a and (+)-2b
(the total yield was 57% and 48%, respectively). The depro-
tection of the OBz group of 4a and 4b with NH3 was nec-
essary because the sugar template cannot be removed
directly.
BF3ꢁEt2O,21 TMSOTf22 and Cl3CCHO23 under mild condi-
tions. Other catalysts such as PPTS,24 ZnBr2
and
25
DDBOTf26 were also reported for the glycosylation. Re-
cently this has become the most widely used method due
to its good yield and high diastereoselectivity.
We choose 2,3,4,6-tetra-O-benzoyl-a-D-glucopyranosyl tri-
chloroacetimidate 327 as the donor. This benzoyl-protected
glucosyl imidate, which was readily prepared from the cor-
responding 1-OH sugar,28 was quite stable; no decomposi-
tion was detected under anhydrous conditions for several
months. 12-Hydroxyl-1,15-pentadecanlactam 2, which
was obtained by the reduction of 12-oxo-1,15-pentadecan-
lactam 129 with NaBH4 (Scheme 1), was selected as the
acceptor. To our surprise, we failed to obtain the coupling
product under normal Schmidt condition, probably due to
the lower reactivity of the hydroxyl group of 2. Fortu-
nately, when an ‘inverse Schmidt’s procedure’30 was
adopted, the glycosylation proceeded smoothly under a
mild condition. Thus the acceptor 2 and the catalyst
TMSOTf were first mixed in dry CH2Cl2, and then stirred
for 15 min (Scheme 2). Glycoside 4 was obtained in good
The absolute configuration of (ꢀ)-2a and (+)-2b was
detected by Horeau’s method32,33 (Scheme 3). Thus, the
secondary alcohol (+)-2b was reacted with an excess of
racemic 2-phenylbutyric acid anhydride 5 in pyridine. After
20 h at room temperature, the excess anhydride was hydro-
lyzed and the remaining 2-phenylbutyric acid 7 separated
from the Horeau ester 6. The optical rotation of acid 7
had a negative signal, indicating that (+)-2-phenylbutyric
acid had reacted preferentially. This is indicative of an
(S)-configuration of (+)-2b. So the absolute configuration
of (ꢀ)-2a was assigned as (R).
H
H
O
O
N
N
NaBH4
H
O
N
OH
O
Ph
Ph
OH
H
i) py
O
+
ii) NaHCO3
iii) HCl
O
O
1
2
(+)-2b
( )-5
Scheme 1.
H
N
O
O
Ph
OBz
OH
O
O
+
BzO
BzO
Ph
+
O
2
H
OBz
O
CCl3
NH
6
(-)-7
3
a
Scheme 3.
H
O
N
OBz
O
BzO
BzO
O
The absolute configuration of (ꢀ)-2a and (+)-2b can be
further confirmed by modified Mosher’s method.34
Thus compound 2b was treated with commercially avail-
able (S)-a-methoxy-a-(trifluoromethyl)-phenylacetic acid
(MTPA) and (R)-MTPA to afford the corresponding
MTPA esters 8 and 9 (Scheme 4).
OBz
b
4
H
O
H
N
O
N
OBz
H
O
OBz
H
O
O
BzO
BzO
BzO
BzO
O
OBz
OBz
4b
4a
c
c
H
H
N
O
N
H
H
N
O
15
12
O
O
N
OR
H
OH
H
H
H
i or ii
HO
HO
8 R=(
S
)-MTPA
)-MTPA
(+)-2b
(-)-2a
(+)-2b
9 R=(
R
Scheme 2. Reagents and conditions: (a) TMSOTf, CH2Cl2; (b) recrystal-
Scheme 4. Reagents and conditions: (i) (S)-MTPA, DCC, DMAP; (ii) (R)-
lization and chromatography; (c) (i) methanol/NH3(g); (ii) 1 M HCl.
MTPA, DCC, DMAP.

C.-J. Hou et al. / Tetrahedron: Asymmetry 19 (2008) 379–383
381
The 1H NMR signal of 8 at d 5.67 disappeared upon shak-
H
OMTPA
Δδ= +0.08
Hb
ing with D2O and two multiplets at d 3.23–3.33 and d 3.34–
3.43 simultaneously collapsed to two ‘ddd’s. Therefore, the
triplet at d 5.67 can be assigned to the proton at the nitro-
gen atom and two multiplets at d 3.23–3.33 and d 3.34–3.43
to the two protons at C15, respectively. Further consider-
ation indicated that the oxygen atom at C12 is more close
to C15–Ha and far away from C15–Hb, therefore the mul-
tiplet at d 3.23–3.33 could be assigned to C15–Hb and the
multiplet at d 3.34–3.43 to C15–Ha. The same result can
be obtained by homonuclear decoupling at d 5.67. The sep-
arate signals for the protons at C13 and C14 cannot be ob-
served due to the overlap of the signals. Analogously, in the
1H NMR spectrum of 9 the triplet at d 5.56 can be assigned
to the proton at the nitrogen atom, and two multiplets at d
3.14–3.25 and d 3.26–3.37 can be assigned to two protons
12
Ha
Δδ= +0.10
15
Δδ= +0.11
N
H
O
Figure 1. Dd values [Dd (in ppm) = dS ꢀ dR] obtained for (S)- and (R)-
MTPA ester of 2b.
1
at C15, respectively, in the same way. The H NMR data
of 8 and 9 are listed in Table 1.
1
From Table 1 we can see that H NMR signals of the (R)-
MTPA ester appeared upfield relative to those of the (S)-
MTPA ester and the absolute values of Dd (dS ꢀ dR) are
proportional to the distance from the MTPA moiety,
which indicated that the protons at the nitrogen atom
and C15 are on the right side of the MTPA plane
(Fig. 1), namely (+)-2b is the (S)-configuration. Of course
(ꢀ)-2a must be the (R)-configuration. Although we did
not obtain the Dd values for the protons at C13 and C14,
the results obtained are in accordance with that of the Hor-
eau’s method.
The enantiomer excess of 2a and 2b as their (R)-MTPA
esters as determined by HPLC was >99% (Fig. 2).
Thus, racemic 12-hydroxyl-1,15-pentadecanlactam 2 was
resolved using an inexpensive and easily accessible glucose
derivative as chiral auxiliary. More importantly, both of
the (R)- and (S)-isomers can be obtained in good yield
and high enantiomeric excess. The chiral template is a glu-
cose derivative which can easily be attached to the OH
group of macrocyclic lactam and removed after hydrolysis.
This new methodology might be very useful in the resolu-
tion of secondary alcohol compounds. Further study of
the scope and limitations of this method will reveal its full
potential.
Figure 2. Chromatographic separation of (R)-MTPA esters of 2a and 2b
(2 and 1). Column: KROMASIL 5 SIL 100R (250 ꢂ 4.6 mm 5 lm).
Mobile phase: 90:10 (hexane/isopropanol). A: (R)-MTPA esters of 2a and
2b. B: (R)-MTPA ester of 2b. C: (R)-MTPA ester of 2a.
as an internal standard. High resolution mass spectra were
obtained with Bruker Apex II. FT-ICR MS spectrometer.
High performance liquid chromatography (HPLC) was
performed on a JASCO 2000 HPLC system (JASCO Cor-
poration, Japan) equipped with PU-2089 plus quaternary
pump, UV-2075 plus ultraviolet (UV) detector, CD-2095
plus circular dichroism detector and 20 lL sample loop.
Elemental analysis was performed by the Institute of
Chemistry, Chinese Academy of Sciences. Commercially
available (+)- and (ꢀ)-MTPA (Matrix Scientific, No.
007167, 99%; No. 007168, 99%, respectively) were used
without purification. Other reagents and solvents were pur-
chased from common commercial sources and some were
purified with standard methods.
3. Experimental
Melting points were determined with a Yanagimoto
MFG.CO micro melting point apparatus and were uncor-
1
rected. H NMR and 13C NMR were recorded at Bruker
DPX300 NMR spectrometer. Chemical shifts were ex-
pressed in d value (ppm) using tetramethylsilane (TMS)
Table 1. 1H NMR data of (S)- and (R)-MTPA esters of 2b (in part)
8 (S)-MTPA
9 (R)-MTPA
Dd (dS ꢀ dR)
a
C15–Ha
C15–Hb
NH
3.39 (ddd, J = 4.4, 6.5, 14.0 Hz)
3.29 (ddd, J = 4.2, 8.1, 14.0 Hz)
5.67 (t, J = 5.7 Hz)
3.31 (ddd, J = 4.4, 6.7, 14.0 Hz)
3.19 (ddd, J = 4.1, 7.6, 14.0 Hz)
5.56 (t, J = 5.8 Hz)
0.08
0.10
0.11
a
a After homonuclear decoupling.

382
C.-J. Hou et al. / Tetrahedron: Asymmetry 19 (2008) 379–383
3.1. 12-Hydroxyl-1,15-pentadecanlactam 2
128.43, 128.76, 128.82, 129.30, 129.60, 129.64, 129.67,
129.73, 129.82, 133.09, 133.19, 133.32, 133.42, 164.95,
165.26, 165.78, 166.04, 173.00; HRMS: calcd for
C49H56NO11þ, 834.3848; found, 834.3838.
To a stirred solution of 12-oxo-1,15-pentadecanlactam (1)
(2.53 g, 0.01 mol) in methanol (20 mL) was added NaBH4
(0.38 g, 0.01 mol). The mixture was stirred for 1 h at room
temperature and then acidified with 1 N HCl. It was then
extracted with CH2Cl2, dried over anhydrous sodium sul-
fate, filtrated and evaporated to give 2.28 g white solid
(yield 89%). Mp 133–134 °C; 1H NMR (300 MHz, CDCl3)
d 1.31–1.71(m, 22H), 1.89 (s, 1H, OH), 2.18 (t, J = 6.4 Hz,
2H), 3.28–3.34 (m, 1H), 3.39–3.48 (m, 1H), 3.70–3.71 (m ,
1H), 5.83 (s, 1H, NH); 13C NMR d 22.47, 25.18, 25.54,
25.60, 26.14, 26.20, 26.90, 27.45, 27.83, 32.97, 36.24,
36.81, 38.89, 70.81, 173.29; Anal. Calcd for C15H29NO2:
C 70.54, H 11.45, N 5.48. Found: C 70.06, H 11.21, N 5.72.
3.3. (R)- and (S)-12-hydroxyl-1,15-pentadecanlactam [(+)-
2b and (ꢀ)-2a]
The macrocyclic lactam glucoside 4a (1.80 g, 2.16 mmol)
was dissolved in MeOH (20 mL) saturated with dry NH3
and stirred at room temperature for 72 h. The methanol
was removed in vacuo and washed with ethyl acetate and
acetone to give white solid ,which was dissolved in 1 N
HCl (30 mL). The above solution was stirred for 24 h at
60 °C. After cooling to room temperature the mixture
was extracted with CH2Cl2 and dried over anhydrous so-
3.2. 12-(20,30,40,60-Tetra-O-benzoyl-b-D-glucopyranosyl)-
1,15-pentadecanlactam (4)
dium sulfate, filtered and evaporated to give 0.39 g white
20
solid 2a (yield 71%). Mp 133–134 °C. ½aꢃD ¼ ꢀ10:5 (c
1
0.46, CHCl3). The H NMR was in accordance with 2.
To a stirred solution of 12-hyroxyl-1,15-pentadecanlactam
(2) (0.26 g, 0.001 mol) in dry CH2Cl2 (10 mL) at 0 °C was
added catalytic amount of TMSOTf. The mixture was stir-
The other isomer 2b was obtained with a similar procedure
20
(yield 76%). Mp 133–134 °C. ½aꢃD ¼ þ10:0 (c 0.46, CHCl3).
red for 15 min and trichloroacetimidate
3 (0.74 g,
1
The H NMR was in accordance with 2.
0.001 mol) was added dropwise within 30 min. The above
mixture was stirred for another 30 min and saturated aq
NaHCO3 solution was added. It was then extracted with
CH2Cl2, dried over anhydrous sodium sulfate, filtrated
and evaporated to give yellow oil, which was further puri-
fied by column chromatography (silica gel/petroleum ether
(v)/ethyl acetate (v) = 2:5) to give 0.73 g of a white solid
(mixture of 4a and 4b) (yield 88%).
3.4. Determination of absolute configuration of (+)-2b
3.4.1. Horeau’s method. A solution of (+)-2b (20 mg,
0.078 mmol) and racemic 2-phenylbutyric acid anhydride
(57.9 lL, 0.20 mmol) in dry pyridine (2 mL) was stirred
for 20 h at room temperature. Then 3 mL of 10% aq NaH-
CO3 was added and stirring was continued for additional
1 h. After adding 10 mL H2O, the reaction mixture was ex-
tracted with 5 ꢂ 8 mL of ether. The combined ether phase
was dried over Na2SO4, and the solvent was evaporated in
vacuo to give the diastereomeric mixture of ester of (+)-2b
with (+)- and (ꢀ)-2-phenylbutyric acid. The aq phase was
acidified with 10 mL of 2 M HCl and extracted with
4 ꢂ 8 mL benzene. The benzene phase was washed with
water to neutral, dried over Na2SO4 and the solvent was
evaporated. The remaining 2-phenylbutyric acid, dissolved
in a minimum amount of benzene, showed a specific optical
rotation (aD = ꢀ0.132) indicating an (S)-configuration for
(+)-2b.
Five grams of glucoside mixture of 4a and 4b was recrystal-
lized twice from ethyl acetate to give 2.3 g one isomer 4b
(yield 92%). The mother liquor was purified by column
chromatography (silica gel/petroleum ether (v)/ethyl ace-
tate (v) = 1:2) and then recrystallized from ethyl acetate
to give 1.8 g another isomer 4a (yield 72%) and a mixture
1
of 4a and 4b. Compound 4a: mp 188–190 °C; H NMR
(300 MHz, CDCl3) d 0.93–1.71 (m, 22H), 2.05–2.26 (m,
2H), 2.96–3.02 (m, 1H), 3.52–3.58 (m, 1H), 3.76–3.80 (m,
1H), 4.10–4.16 (m, 1H), 4.49 (dd, J = 5.4, 12.0 Hz, 1H),
4.66 (dd, J = 3.2, 12.0 Hz, 1H), 4.87 (d, J = 7.9 Hz, 1H),
5.49 (dd, J = 5.4, 9.8 Hz, 1H), 5.59–5.68 (m, 2H), 5.91 (t,
J = 9.7 Hz, 1H), 7.28–7.58 (m, 12H), 7.82–8.04 (m, 8H);
13C NMR d 21.28, 24.57, 25.37, 25.59, 25.79, 26.27,
26.63, 27.35, 27.70, 30.49, 31.79, 36.81, 38.38, 62.98,
69.93, 72.02, 72.05, 72.85, 79.45, 99.80, 128.23, 128.30,
128.36, 128.74, 128.79, 129.19, 129.55, 129.63, 129.69,
129.76, 133.12, 133.16, 133.22, 133.38, 165.10, 165.1þ9,
3.4.2. Modified Mosher’s method. To a stirred solution of
2b (0.0255 g, 0.10 mmol) and (S)-MTPA or (R)-MTPA
(0.0272 g, 0.12 mmol) in dry CH2Cl2 (10 mL) were added
DCC (0.0206 g, 0.10 mmol) and DMAP (a catalytic
amount). The above mixture was stirred for 24 h and the
precipitated urea was then filtered off. The filtrate was
washed twice with 0.5 N HCl and with saturated NaHCO3
solution, and then dried over Na2SO4. The solvent was re-
moved to give a white solid 8: 1H NMR (300 MHz, CDCl3)
d 1.07–1.73 (m, 22H), 2.16–2.20 (m, 2H), 3.23–3.33 (m,
1H), 3.34–3.43 (m, 1H), 3.54 (s, 1H), 5.07–5.15 (m, 1H),
5.67 (t, J = 5.7Hz, 1H), 7.37–7.44 (m, 3H), 7.51–7.54 (m,
165.74, 165.99, 173.10; HRMS: calcd for C49H56NO11
,
834.3848; found, 834.3841. Compound 4b: mp 222–
223 °C; 1H NMR (300 MHz, CDCl3) d 1.21–1.61 (m,
22H), 1.95–2.05 (m, 1H), 2.11–2.20 (m, 1H), 2.60–2.66(m,
1H), 3.16–3.22 (m, 1H), 3.62–3.65 (m, 1H), 4.13–4.19 (m,
1H), 4.49 (dd, J = 6.2, 12.0 Hz, 1H), 4.61(dd, J = 3.1,
12.0 Hz, 1H), 4.87 (d, J = 7.9Hz, 1H), 5.15–5.19 (m, 1H),
5.52 (dd, J = 7.9, 9.8 Hz, 1H), 5.61 (t, J = 9.8 Hz, 1H),
5.90 (t, J = 9.7 Hz, 1H), 7.28–7.57 (m, 12H), 7.82–8.03(m,
8H); 13C NMR d 22.39, 24.98, 25.10, 25.59, 26.15, 26.18,
26.97, 27.56, 27.84, 30.33, 33.64, 36.81, 38.27, 63.40,
69.98, 72.17, 72.90, 81.71, 101.67, 128.27, 128.31, 128.40,
1
2H). Compound 9: H NMR (300 MHz, CDCl3) d 1.07–
1.73 (m, 22H), 2.14–2.19 (m, 2H), 3.14–3.25 (m, 1H),
3.26–3.37 (m, 1H), 3.56 (s, 1H), 5.06–5.14 (m, 1H), 5.56
(t, J = 5.8 Hz), 7.36–7.44 (m, 3H), 7.52–7.55 (m, 2H).

C.-J. Hou et al. / Tetrahedron: Asymmetry 19 (2008) 379–383
383
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Acknowledgement
We acknowledge financial support of this investigation by
the National Basic Research Programme of China
(2003CB114407).
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