Asymmetric tosylation of racemic 2-hydroxyalkanamides with chiral copper catalyst

Article abstract of DOI:10.1016/j.tetlet.2007.10.128

Kinetic resolution of 2-hydroxyalkanamides was performed by tosylation in the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst. This method was successfully applied to a variety of 2-hydroxyalkanamides in high enantioselectivity with up to 9

Full text of DOI:10.1016/j.tetlet.2007.10.128

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Tetrahedron Letters 48 (2007) 9080–9084
Asymmetric tosylation of racemic 2-hydroxyalkanamides
with chiral copper catalyst
Osamu Onomura,* Masaru Mitsuda, My Thi Thuy Nguyen and Yosuke Demizu
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 4 October 2007; revised 22 October 2007; accepted 26 October 2007
Available online 30 October 2007
Dedicated to the memory of Professor Yoshihiro Matsumura
Abstract—Kinetic resolution of 2-hydroxyalkanamides was performed by tosylation in the presence of copper(II) triflate and (R,R)-
Ph-BOX as a catalyst. This method was successfully applied to a variety of 2-hydroxyalkanamides in high enantioselectivity with up
to 92% ee, and then tosylated product was easily transformed into optically active a-amino acid derivatives.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Optically active 2-hydroxyalkanoic acid derivatives are
important precursors for biologically active com-
pounds.1 In particular, optically active 2-sulfonyloxy-
alkanoic acid derivatives are important precursors of
a-amino acids.2 A multitude of enzymatic kinetic resolu-
tion methods have been developed for preparation of
optically pure 2-hydroxyalkanoic acid derivatives.3 To
the best of our knowledge, for non-enzymatic methods
Ph-BOX5 by benzoylation to obtain optically active
alcohols with excellent enantioselectivity.6 In this Letter,
we apply our methodology to kinetic resolution of
2-hydroxyalkanamides 1 to afford optically active
2-tosyloxyalkanamides 3 with high yields and enantio-
selectivities, which is based on molecular recognition
by Cu(II)–(R,R)-Ph-BOX complex to form the activated
intermediates 2 followed by tosylation (Eq. 1).7
L*
O
O
OH R3
OTs R3
N
Cu2+
Cu2+
H
p-TsCl
N
N
O
N
R2
R2
R1
R1
ð1Þ
N
R2
L*
K2CO3
R1
Ph
Ph
O
O
R3
-HCl
O
-Cu2+
L*
L* (R,R)-Ph-BOX
1
2
3
only one has been reported by Reiser and co-workers
in 2005.4 We recently reported an efficient method for
kinetic resolution of 1,2-diols and vic-amino alcohols
with copper(II) ion associated with chiral ligand (R,R)-
We began on investigation by trying the tosylation of
methyl DL-mandelate (4) as a model compound to
see whether it was recognized by chiral copper(II)
complex. The result showed that in the absence of
copper(II) triflate and (R,R)-Ph-BOX the reaction of 4
with TsCl afforded 5 in 37% yield (Eq. 2). However, in
the presence of copper(II) triflate and (R,R)-Ph-
BOX, any reaction did not proceed. In contrast,
DL-mandelanilide (1a) was tosylated more efficiently in
the presence of Cu(II)–(R,R)-Ph-BOX than in the
Keywords: Asymmetric sulfonylation; 2-Hydroxyalkanamide; 2-Tosyl-
oxyalkanamide, Copper complex.
*
Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819
2476; e-mail: onomura@nagasaki-u.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.128

O. Onomura et al. / Tetrahedron Letters 48 (2007) 9080–9084
9081
absence of it (Eq. 3). These results suggest that
1a might be recognized with Cu(II)–(R,R)-Ph-BOX
complex in the same way as kinetic resolution of 1,2-
diols.
of (S)-3a and ee was low compared to that of K2CO3
(entry 10). The result of using 0.05 equiv of Cu(OTf)2
and (R,R)-Ph-BOX was slightly inferior to that of using
0.1 equiv of chiral Cu(II) catalyst (entry 11).
p
-TsCl (0.5 equiv)
OH
OTs
K2CO3 (1.0 equiv)
OMe
OMe
Ph
Ph
MeCN
rt, 12 h
O
O
ð2Þ
4
5
in the absence of Cu(OTf)2 (0.1 equiv),
and ( )-Ph-BOX (0.1 equiv)
37% yield
0% yield
R,R
in the presence of Cu(OTf)2 (0.1 equiv),
and (
R,R)-Ph-BOX (0.1 equiv)
p
-TsCl (0.5 equiv)
OH
OTs
H
N
H
N
K2CO3 (1.0 equiv)
Ph
Ph
Ph
Ph
MeCN
rt, 12 h
O
O
ð3Þ
1a
in the absence of Cu(OTf)2 (0.1 equiv),
and ( )-Ph-BOX (0.1 equiv)
in the presence of Cu(OTf)2 (0.1 equiv),
and ( )-Ph-BOX (0.1 equiv)
3a
28% yield
42% yield, 80% ee
R,R
R,R
OH
OTs
O
OH
p
-TsCl (0.5 equiv)
H
H
N
H
N
N
+
Cu(OTf)2 (0.1 equiv)
Ph
Ph
Ph
Ph
Ph
Ph
ð4Þ
(R,R)-Ph-BOX (0.1 equiv)
O
DL-1a
O
(R)-1a
base (1.0 equiv)
solvent, rt, 12 h
(
S
)-3a
Next, we investigated the effect of solvents and bases so
as to optimize reaction conditions for kinetic resolution
of DL-1a by tosylation (Eq. 4).8 The results are summa-
rized in Table 1, which shows a dependence of the yield
and % ee of the product 3a on the used base and solvent.
Use of MeCN as a solvent and K2CO3 as a base gave
tosylated product (S)-3a9 in 42% yield and with a high
enantioselectivity (80% ee) and selectivity s11 value of
17 (entry 1). Other solvents except for CH2Cl2 (entry
6) were less effective (entries 2–5). Although, Na2CO3,
NaHCO3 and Li2CO3 gave comparable s value to
K2CO3, the yield of (S)-3a was low (entries 7–9). In
the case of diisopropylethylamine (DIPEA), the yield
Utilizing the conditions optimized in Table 1, we
screened the effect of amide substituents (Eq. 5).
The results are shown in Table 2. The s value of
compound 1b substituted with chloro atom at the
para position was slightly lower than that of 1c with
methyl group (entries 1 and 2). Whereas aliphatic
amide 1d was ineffective (entry 3), N,N-dialkylated
mandelamide 1e was asymmetrically tosylated to
afford (S)-3e with moderate enantioselectivity (68%
ee) (entry 4). This result indicates that N–H group
is not essential. Unsubstituted mandelamide (1f) gave
high s value of 29 with somewhat low conversion
(entry 5).
OH R3
OTs R3
N
OH R3
N
p
-TsCl (0.5 equiv)
N
Ph
R2
Ph
R2
Ph
R2
Cu(OTf)2 (0.1 equiv),
+
ð5Þ
(R,R)-Ph-BOX (0.1 equiv)
O
O
O
K2CO3 (1.0 equiv)
MeCN, rt, 12 h
DL-1b-f
(S)-3b-f
(R)-1b-f

9082
O. Onomura et al. / Tetrahedron Letters 48 (2007) 9080–9084
Table 1. Kinetic resolution of DL-mandelanilide (DL-1a)a
Entry
Solvent
Base
Product (S)-3a
Recovered (R)-1a
Yield (%)
eeb (%)
Selectivity s
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
MeCN
Et2O
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Na2CO3
NaHCO3
DIPEA
K2CO3
42
44
28
15
45
46
13
33
15
23
47
80
46
59
22
49
78
90
79
86
51
72
52
56
62
80
53
54
60
48
80
45
47
64
25
17
5
34
55
18
61
8
17
3
5
2
4
14
23
16
14
4
Toluene
AcOEt
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
10
11c
20
64
12
a
DL-1a (0.5 mmol), Cu(OTf)2 (0.05 mmol), (R,R)-Ph-BOX (0.05 mmol), p-TsCl (0.25 mmol), base (0.5 mmol) in a solvent (2.0 mL) at rt for 12 h.
b Determined by HPLC.
c
DL-1a (0.5 mmol), Cu(OTf)2 (0.025 mmol), (R,R)-Ph-BOX (0.025 mmol), p-TsCl (0.25 mmol), K2CO3 (0.5 mmol) in MeCN (2.0 mL) at rt for 12 h.
Table 2. Kinetic resolution of DL-mandelamide derivatives (DL-1b–f)a
Entry
R2
R3
Product (S)-3b–f
Yield (%)
eeb (%)
Recovered (R)-1b–f
Yield (%)
eeb (%)
Selectivity s
1
2
3
4
5
1b
1c
1d
1e
1f
p-ClPh
p-MePh
Cyclohexyl
H
H
H
3b
3c
3d
3e
3f
44
29
30
50
28
71
80
30
68
90
48
65
52
50
61
79
69
18
73
43
14
18
2
11
29
–(CH2)5–
H
H
a 1b–f (0.5 mmol), Cu(OTf)2 (0.05 mmol), (R,R)-Ph-BOX (0.05 mmol), p-TsCl (0.25 mmol), K2CO3 (0.5 mmol) in MeCN (2.0 mL) at rt for 12 h.
b Determined by HPLC.
Table 3. Kinetic resolution of DL-1an–aza
Entry
R1
R3
Product (S)-3an–az
Yield (%)
eeb (%)
3an 90
Recovered (R)-1an–az
Selectivity s
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1an
1ao
1ap
1aq
1ar
1as
1at
Me
Et
n-Pr
n-Bu
H
H
H
H
H
H
H
H
H
H
H
H
26
44
42
30
45
38
30
40
30
30
42
30
6
70
44
48
59
45
56
60
57
66
50
42
64
86
24
61
56
84
52
57
62
69
36
82
82
67
1
24
20
22
16
15
26
17
22
11
61
61
18
1
3ao
3ap
3aq
3ar
3as
3at
83
85
72
80
87
80
83
78
92
92
80
8
Allyl
PhCH2CH2
C6H11CH2
i-Pr
1au
1av
1aw
1ax
1ay
1az
3au
3av
3aw
3ax
3ay
3az
t-Bu
Cyclobutyl
Cyclopentyl
Cyclohexyl
–CMe2–CH2–
a 1an–az (0.5 mmol), Cu(OTf)2 (0.05 mmol), (R,R)-Ph-BOX (0.05 mmol), p-TsCl (0.25 mmol), K2CO3 (0.5 mmol) in MeCN (2.0 mL) at rt for 12 h.
b Determined by HPLC.
Table 3 summarizes kinetic resolution of various 2-
hydroxyalkanamides 1an–az by tosylation under the
optimized reaction condition (Eq. 6).12 Straight chained
2-hydroxyalkanamides 1an–at were asymmetrically
tosylated to afford corresponding optically active
(S)-3an–at in moderate yield and high enantioselectivity
(entries 1–7). Compound 1au substituted with i-Pr group
was kinetically resolved with high s value of 22 (entry 8),
while compound 1av substituted with t-Bu group fell
short in terms of yield and enantioselectivity (entry 9).
Both cyclobutylated compound 1aw and cyclopentyl-
ated 1ax were asymmetrically tosylated to afford (S)-
3aw and (S)-3ax with the highest s value of 61 (entries
10 and 11), while cyclohexylated 1ay gave lower s value
of 18 (entry 12). Tosylation of lactam 1az did not almost
proceed to afford 3az (entry 13). This result might
support an intermediary formation of N,O-chelated
intermediate 2 in Eq. 1.

O. Onomura et al. / Tetrahedron Letters 48 (2007) 9080–9084
9083
OH R3
N
OTs R3
N
OH R3
N
p
-TsCl (0.5 equiv)
Cu(OTf)2 (0.1 equiv),
R1
Ph
R1
Ph
R1
Ph
+
ð6Þ
(R,R)-Ph-BOX (0.1 equiv)
O
O
O
K2CO3 (1.0 equiv)
MeCN, rt, 12 h
DL-1an-az
(
S
)-3an-az
(R)-1an-az
11, 1679–1682; (c) Lin, W.-Q.; He, Z.; Jing, Y.; Cui, X.;
Liu, H.; Mi, A.-Q. Tetrahedron: Asymmetry 2001, 12,
1583–1587.
Tosyloxyl group is a good leaving group, thus (S)-3a
undergoes SN2 reaction with primary amine to form
N-alkylated a-amino acid (R)-6 with a slight degree of
racemization in high yield,15 while N,N-dialkylated
derivative (R)-7 was obtained using secondary amine
without any loss of optical purity (Eq. 7).
3. Recent literatures for kinetic resolution of 2-hydroxy-
alkanoic acid derivatives by enzymatic methods: (a)
Campbell, R. F.; Fitzpatrick, K.; Inghardt, T.; Karlsson,
O.; Nilsson, K.; Reilly, J. E.; Yet, L. Tetrahedron Lett.
2003, 44, 5477–5481; (b) Ito, T.; Matsushita, Y.; Abe, Y.;
Han, S.; Wada, S.; Hayase, S.; Kawatsura, M.; Takai, S.;
Morimoto, M.; Hirose, Y. Chem. Eur. J. 2006, 12, 9228–
9237.
4. Kinetic resolution of ethyl DL-mandelate by benzoylation
catalyzed with Cu(II)-aza(bisoxazoline) catalyst: Gissibl,
A.; Finn, M. G.; Reiser, O. Org. Lett. 2005, 7, 2325–2328.
5. A recent review of chiral bis(oxazoline) ligands: Desimoni,
G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106,
3561–3651.
Bn
Bn-NH2 (1.0 equiv)
OTs
NH
H
N
H
N
Et3N (1.2 equiv)
Ph
Ph
Ph
Ph
THF
60 ºC, 24 h
O
O
(
S
)-3a
(
R
)-6
80% ee
95% yield, 76% ee
Bn
Ph
Me
6. Cu(II)–Ph-BOX catalyzed mono-benzoylation of 1,2-
diols: (a) Matsumura, Y.; Maki, T.; Murakami, S.;
Onomura, O. J. Am. Chem. Soc. 2003, 125, 2052–2053;
Cu(II) catalyzed mono-benzoylation of 1,2-diols reported
by other groups: (b) Mazet, C.; Ko¨hler, V.; Pfaltz, A.
Angew. Chem., Int. Ed. 2005, 44, 4888–4891; (c) Nakam-
ura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Org. Lett.
2006, 8, 6139–6142; (d) Arai, T.; Mizukami, T.; Yanagis-
awa, A. Org. Lett. 2007, 9, 1145–1147; Cu(II)–Ph-BOX
catalyzed carbamoylation of 1,2-diols: (e) Matsumoto, K.;
Mitsuda, M.; Ushijima, N.; Demizu, Y.; Onomura, O.;
Matsumura, Y. Tetrahedron Lett. 2006, 47, 8453–8456;
Cu(II)–Ph-BOX catalyzed mono-oxidation of 1,2-diols: (f)
Onomura, O.; Arimoto, H.; Matsumura, Y.; Demizu, Y.
Tetrahedron Lett. 2007, 48, 8668–8672; Cu(II)–Ph-BOX
catalyzed benzoylation of vic-aminoalcohols: (g) Mitsuda,
M.; Tanaka, T.; Tanaka, T.; Demizu, Y.; Onomura, O.;
Matsumura, Y. Tetrahedron Lett. 2006, 47, 8073–8077;
Review: (h) Matsumura, Y.; Onomura, O.; Demizu, Y.
Yuki Gosei Kagaku Kyokaishi 2007, 65, 216–225.
Bn-NH-Me (1.0 equiv)
Et3N (1.2 equiv)
N
H
N
(
S
)-3a
Ph
THF
60 ºC, 24 h
80% ee
O
(
R
)-7
94% yield, 80% ee
ð7Þ
In conclusion, we have demonstrated a new non-enzy-
matic method for kinetic resolution of 2-hydroxyalkan-
amides16 and converted the chiral tosylated products to
optically active a-amino acid derivatives. The mechanis-
tic study of this tosylation and its further synthetic
application are underway.
Acknowledgements
7. Asymmetric monosulfonylation of meso-1,2-diols cata-
lyzed with Cu(II)–Ph-BOX: Demizu, Y.; Matsumoto, K.;
Onomura, O.; Matsumura, Y. Tetrahedron Lett. 2007, 48,
7605–7609.
O.O. and Y.D. are very grateful for a Grant-in-Aid for
Scientific Research (C) (19550109) from Japan Society
for the Promotion of Science and a Grant-in-Aid for
Young Scientists (B) (19790017) from the Ministry of
Education, Science, Sports and Culture, Japan,
respectively.
8. A typical procedure for kinetic resolution: Under an
aerobic atmosphere, a solution of Cu(OTf)2 (18.1 mg, 0.05
mmol) and (R,R)-Ph-BOX (16.7 mg, 0.05 mmol) in MeCN
(2 mL) was stirred for 10 min. Into the solution were
added 1a (113.5 mg, 0.5 mmol), potassium carbonate
(69.1 mg, 0.5 mmol) and p-TsCl (47.7 mg, 0.25 mmol).
After stirring for 12 h at rt, the solution was poured in
water and extracted with AcOEt (20 mL · 3). The com-
bined organic layer was dried over MgSO4 and the solvent
was removed under reduced pressure. The residue was
purified by silica gel column chromatography (n-hexane/
AcOEt = 3:1) to afford (S)-3a (42% yield, 80% ee) as a
References and notes
1. (a) Bigi, F.; Bocelli, G.; Maggi, R.; Sartori, G. J. J. Org.
Chem. 1999, 64, 5004–5009; (b) Groger, H. Adv. Synth.
Catal. 2001, 343, 547–558; (c) Tao, J.; McGee, K. In
Asymmetric Catalysis on Industrial Scale: Challenges,
Approaches and Solutions; Blaser, H. U., Schmidt, E.,
Eds.; John Wiley and Sons Ltd: Weinheim, 2004; pp 323–
334; (d) Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2005, 127, 1080–1081.
26
1
white solid. Mp 140–141 ꢁC. ½aꢀD +8.9 (c 1.0, CHCl3). H
NMR (300 MHz, CDCl3) d 8.06 (s, 1 H), 7.71 (d,
J = 8.1 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.35–7.22 (m,
9H), 7.17 (t, J = 7.5 Hz, 1H), 5.85 (s, 1H), 2.38 (s, 3H).
HR-FAB: [M+H]+ calcd for C21H20NO4S, 381.1113;
found, 382.1111. The optical purity of 3a was determined
by chiral HPLC: Daicel Chiralcel OD-H column (4.6 mm
2. (a) Szymanski, W.; Ostaszewski, R. Tetrahedron: Asym-
metry 2006, 17, 2667–2671; (b) Blaser, H.-U.; Burkhardt,
S.; Kirner, H. J.; Mo¨ssner, T.; Studer, M. Synthesis 2003,

9084
O. Onomura et al. / Tetrahedron Letters 48 (2007) 9080–9084
/, 250 mm), n-hexane/isopropanol = 10:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 17.3 min
((R)-3a), 18.7 min ((S)-3a).
tions of (S)-3ao–at,av–az shown in Eq. 6 and Table 3 were
deduced on the basis of those of (S)-3a,an,au.
13. Maran, F. J. Am. Chem. Soc. 1993, 115, 6557–
6563.
9. The absolute stereoconfiguration of recovered (R)-1a
was determined by comparing with specific rotation
14. Girreser, U.; Noe, C. R. Synthesis 1995, 1223–
1224.
27
of authentic sample. Compound (R)-1a: ½aꢀD ꢁ25.1 (c
25
2.36, acetone). [lit.10 (R)-1a (71% ee); ½aꢀD ꢁ22.3 (c 2.36,
15. Absolute stereoconfiguration of (R)-6 was determined by
comparison with specific rotation of (R)-6 derived from
acetone)].
29
10. Weng, S.-S.; Shen, M.-W.; Kao, J.-Q.; Munot, Y. S.;
Chen, C.-T. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3522–
3527.
D-phenylglycine. Compound (R)-6: ½aꢀD ꢁ15.9 (c 1.0
CHCl3). [(R)-6 (92% ee) derived from D-phenylglycine;
29
½aꢀD ꢁ18.3 (c 1.0, CHCl3)].
11. Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry;
Eliel, E. L., Ed.; Wiley & Sons: New York, 1988; Vol. 18,
pp 249–330.
16. Somewhat scaled up kinetic resolution of 1ao (2.0 mmol),
which was carried out by using Cu(OTf)2 (0.20 mmol),
(R,R)-Ph-BOX (0.20 mmol), p-TsCl (1.0 mmol), and
K2CO3 (2.0 mmol) in MeCN (5.0 mL) at rt for 8 h,
afforded (S)-3ao (47% yield, 91% ee) and (R)-1ao (51%
yield, 89% ee) with high s value of 65.
12. Absolute stereoconfigurations of recovered (R)-1an13 and
(R)-1au14 were determined by comparing with specific
rotation of authentic samples. Absolute stereoconfigura-