3-Pyrroline-1-carbonyl (Pyroc) group: A removable protecting group for the kinetic resolution of racemic carboxylic acids and alcohols through catalytic asymmetric acylation

Article abstract of DOI:10.1055/s-0029-1217321

The O-3-pyrroline-1-carbonyl (O-Pyroc) group and 3-pyrrolinamide are useful removable protecting groups for the kinetic resolution of racemic α-hydroxycarboxylic acids, β-hydroxycarboxylic acids, 1,2-dicarboxylic acids, and 1,2-diols using the L-histidine

Full text of DOI:10.1055/s-0029-1217321

CLUSTER
1647
3-Pyrroline-1-carbonyl (Pyroc) Group: A Removable Protecting Group
for the Kinetic Resolution of Racemic Carboxylic Acids and Alcohols through
Catalytic Asymmetric Acylation
3
-Pyrroline-1-carb
k
onyl (Pyroc)
iG
roupra Sakakura,a Shuhei Umemura,b Kazuaki Ishihara*b
a
EcoTopia Science Institute, Nagoya University, Chikusa, Nagoya 464-8603, Japan
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan
Fax +81(52)7893222; E-mail: ishihara@cc.nagoya-u.ac.jp
b
Received 3 February 2009
Brønsted acid
nucleophilic Lewis base
i-Pr
O2
Abstract: The O-3-pyrroline-1-carbonyl (O-Pyroc) group and 3-
pyrrolinamide are useful removable protecting groups for the kinet-
ic resolution of racemic a-hydroxycarboxylic acids, b-hydroxy-
carboxylic acids, 1,2-dicarboxylic acids, and 1,2-diols using the
L-histidine-derived bifunctional catalysts. The Pyroc group can be
easily introduced from Pyroc chloride. Selective deprotection of the
Pyroc group and 3-pyrrolinamide can be carried out via DDQ oxi-
dation followed by hydrolysis using sodium hydroxide, without
epimerization.
i-Pr
S
H
N
N
i-Pr
OSiR3
N
1a R3Si = t-BuPh2Si = TBDPS
1b R3Si = (TMS)3Si
Figure 1 L-Histidine-derived bifunctional catalysts 1
Key words: kinetic resolution, 3-pyrroline-1-carbonyl (Pyroc),
asymmetric acylation, protective and removable, L-histidine frame-
work
OTBDPS
(+)-3a
N
OTBDPS
O
O
O
CO2t-Bu
N
1. t-BuCOCl or DCC
+
2. 1 (5 mol%)
t-BuOH (0.6 equiv)
O
O
CO2H
The kinetic resolution of racemic compounds through cat-
alytic asymmetric acylation is a useful method for obtain-
ing optically active compounds.1 We recently reported the
kinetic resolution of racemic carboxylic acids 2 bearing a
pyrrolidine-1-carbonyl group as a Brønsted base site.2–5
Compounds 1 are bifunctional acylation catalysts that
contain an N-methylimidazole moiety as a nucleophilic
base and a sulfonamidyl proton as a Brønsted acid (Figure
1). They induce the high-level kinetic resolution of ( )-2
through hydrogen bonding between a sulfonamidyl pro-
ton of 1 and a carbonyl oxygen of 2 (Scheme 1). The
strong basicity of the pyrrolidine-1-carbonyl group is es-
( )-2a
OTBDPS
N
(–)-2a
O
CO2H
S = up to 56
N
OTBDPS
O
O
t-BuOH
O
H
N
O
O
N
H
+
S
N
X–
Ar
OTBDPS
sential for the effective induction of kinetic resolution. Scheme 1 Kinetic resolution of ( )-2a induced by 1 (previous
work2)
However, the pyrrolidine-1-carbonyl group in 3a is too
robust to be removed chemoselectively without epimer-
ization.6 Therefore, an alternative protecting group which
O
1.
is easily protective and removable is urgently required for
N
Cl
(1.0 equiv)
the practical use of the present kinetic resolution. We re-
port here the 3-pyrroline-1-carbonyl (Pyroc) group and 3-
pyrrolinamide as useful protecting groups for the kinetic
resolution of racemic a-hydroxycarboxylic acids, b-
hydroxycarboxylic acids, 1,2-dicarboxylic acids, and 1,2-
diols by 1a-induced asymmetric acylation.
OTBDPS
CO2Me
OTBDPS
CO2H
DMAP (10 mol%)
Et3N (2.0 equiv), 50 °C, 1 h
N
HO
O
O
2. KOH (2.5 equiv)
THF–MeOH–H2O
0 °C, 3 h to r.t., 1 h
4a
5a
77% yield
Scheme 2 Protection of a-hydroxycarboxylic acids by a Pyroc
Scheme 2 shows the preparation of O-Pyroc-protected
a-hydroxycarboxylic acid 5a. The a-hydroxy group of 4a
could be easily protected with Pyroc chloride7,8 (1.0
equiv) in the presence of 4-(N,N-dimethylamino)pyridine
group
(DMAP, 10 mol%) and triethylamine (2.0 equiv) under
solvent-free conditions. Subsequent selective hydrolysis
of methyl ester with KOH (2.5 equiv) in THF–MeOH–
H2O gave carboxylic acid 5a in 77% overall yield.
SYNLETT 2009, No. 10, pp 1647–1650
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217321; Art ID: Y00909ST
© Georg Thieme Verlag Stuttgart · New York
With O-Pyroc-protected a-hydroxycarboxylic acid ( )-5a
in hand, we examined the kinetic resolution of ( )-5a with

1648
A. Sakakura et al.
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N,N¢-dicyclohexylcarbodiimide (DCC) in the presence yield of 7a. The pyrrole-1-carbonyl group in 7a could be
of 1a (5 mol%) under the same conditions as reported rapidly and chemoselectively hydrolyzed under mild ba-
previously (Scheme 3). As a result, the reaction gave sic conditions [NaOH (1.5 equiv) in THF–MeOH–H2O
(+)-6a in 37% yield with 91% ee. The selective factor (2:2:1), 0 °C, 0.5 h] and gave a-hydroxycarboxylic ester
(S = kfast-reacting enantiomer/kslow-reacting enantiomer)9 was 35, which 8a in 93% yield.11 The enantiomeric excess of 8a (91%
is almost the same as that for the reaction of ( )-2a ee) was completely retained during the deprotection se-
(S = 37) under the same reaction conditions. This result quences.
suggested that the Pyroc group in 5a also acted as a Brøn-
To explore the generality and scope of the 1a-induced ki-
sted base to form a hydrogen bonding with the sulfon-
netic resolution of racemic carboxylic acids protected by
amidyl proton of 1a.
a Pyroc group, we examined asymmetric acylation and se-
lective removal of the Pyroc group (Table 1). The asym-
metric acylation of O-protected 3-phenyllactic acid 5b
1. DCC (1.2 equiv)
OTBDPS
collidine (1.0 equiv), CCl4, –20 °C, 1 h
and mandelic acid 5c also gave high S values (27 and 6.6,
entries 1 and 2). Deprotection of the Pyroc group in esters
(+)-6b and (+)-6c proceeded smoothly under the opti-
mized conditions described in Scheme 4, and gave a-hy-
droxyesters 8b and 8c in respective yields of 90% and
95%. The enantiomeric excesses of 8b and 8c were com-
pletely retained (86 and 56% ee).
N
2. 1a (5 mol%)
t-BuOH (0.6 equiv), CCl4, –20 °C, 3 h
O
O
CO2H
( )-5a
OTBDPS
OTBDPS
CO2t-Bu
N
N
+
O
O
CO2H
(–)-5a
52% ee
O
O
(+)-6a
37% conv., 91% ee
The present 1a-induced asymmetric acylation was also ef-
fectively applied to racemic 1,2-dicarboxylic mono-3¢-
pyrrolinamides. ( )-syn-6-(Pyroc)cyclohex-3-enecarbox-
ylic acid (9) was also a suitable substrate for 1a-induced
kinetic resolution (entry 3). As in the kinetic resolution of
pyrrolidine derivative of 9,2 the use of i-PrOH as a nucleo-
phile was essential for effective promotion of the reaction.
Subsequent selective hydrolysis of the 3-pyrrolinamide
group12 of ester 10 could be carried out using DDQ [1.5
equiv, dioxane, 85 °C, 2 h] followed by NaOH [1.0 equiv,
THF–i-PrOH–H2O (2:2:1), 0 °C, 3 h] to give carboxylic
acid 11 in 91% yield.
S = 35
Scheme 3 Kinetic resolution of ( )-5a induced by 1a
OTBDPS
DDQ (1.5 equiv)
N
(+)-6a
91% ee
dioxane, 85 °C, 2 h
O
O
CO2t-Bu
7a
98% yield
OTBDPS
CO2t-Bu
NaOH (1.5 equiv)
We previously described the kinetic resolution of racemic
secondary alcohols bearing a pyrrolidine-1-carbonyl
group as a Brønsted base site.5 Asymmetric acylation with
isobutyric anhydride induced by bifunctional catalysts 1
gave optically active isobutyrates with an S value of up to
132. We examined the 1a-induced kinetic resolution of ra-
cemic secondary alcohols and chemoselective deprotec-
tion. The asymmetric acylation of racemic 3-hydroxy-3-
phenylpropanoic 3¢-pyrrolinamide (12) with isobutyric
anhydride (0.5 equiv) in the presence of 1a (5 mol%) and
DIPEA (0.5 equiv) showed good selectivity (S = 25,
Scheme 5). This selectivity was almost the same as that of
the pyrrolidinamide derivative (S = 19).5 As in the case of
compounds 10, selective cleavage of 3-pyrrolinamide in
(R)-12 could be achieved using DDQ followed by NaOH
THF–MeOH–H2O (2:2:1)
0 °C, 0.5 h
HO
8a
93% yield, 91% ee
Scheme 4 Selective removal of the 3-pyrroline-1-carbonyl group in
(+)-6a
We next investigated selective removal of the Pyroc group
in (+)-6a (Scheme 4). Oxidation of Pyroc to pyrrole-1-
carbonyl was easily conducted using DDQ (1.5 equiv) in
dioxane at 85 °C and gave 7a in 98% yield.10 A relatively
high reaction temperature (85 °C) was essential for pro-
moting the reaction effectively. When the reaction was
conducted at 70 °C, the yield of 7a decreased to 50% (3
h), and a prolonged reaction time did not improve the
i-PrCO2
Ph
O
N
(R)-13
77% ee
1a (5 mol%)
(i-PrCO)2O (0.5 equiv)
OH
O
Ph
N
DIPEA (0.5 equiv)
CCl4, 0 °C, 3 h
OH
O
OH
O
1. DDQ (1.5 equiv)
dioxane, 85 °C, 1 h
( )-12
54% conv., S = 25
Ph
OH
Ph
N
2. NaOH (1.0 equiv)
THF–EtOH–H2O (1:1:1)
0 °C, 10 min
(S)-14
87% yield, 92% ee
(S)-12
92% ee
Scheme 5 Kinetic resolution of racemic b-hydroxycarboxylic 3-pyrrolinamide 12 and selective cleavage of 3-pyrrolinamide
Synlett 2009, No. 10, 1647–1650 © Thieme Stuttgart · New York

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3-Pyrroline-1-carbonyl (Pyroc) Group
1649
Table 1 1a-Induced Kinetic Resolution of Racemic Carboxylic Acids and Hydrolysis of Pyroc Groupa
Entry 1a-Induced kinetic resolution of racemic carboxylic acids
Hydrolysis of Pyroc group
( )-Carboxylic acid
Ester
Time
(h)b
Conv.
(%)c
ee (%)d of ester, Se
acid
Product
Yield (%),f
ee (%)d
Ph
Ph
Ph
N
N
1
2
6
44
52
86, 68
56, 61
27 (29)
90, 86
95, 56
HO
CO2t-Bu
O
O
O
CO2H
O
O
O
CO2t-Bu
8b
5b
6b
Ph
N
Ph
N
Ph
12
6.6 (8.9)
HO
CO2t-Bu
O
CO2H
O
CO2t-Bu
8c
5c
6c
O
N
N
3g
15
49
83, 79
25 (13h)
91, 83
OH
O
O
CO2i-Pr
CO2H
CO2i-Pr
11
10
9
a The acylation reaction of ( )-carboxylic acid (0.25 mmol) was conducted in CCl4 (1.5 mL) according to the reaction conditions shown in
Scheme 3.
b For step 2.
c Conversion (%) = 100 × (ee of acid)/(ee of ester + ee of acid).
d HPLC analysis.
e The S value was calculated by using the ee of esters and acids; S for the kinetic resolution of the corresponding pyrrolidine-1-carbonyl deriv-
ative is shown in parentheses. See ref. 9.
f Isolated yield.
g i-PrOH (0.6 equiv) was used at 0 °C.
h t-BuCOCl was used.
in THF–EtOH–H2O (1:1:1) to give b-hydroxycarboxylic group showed almost the same reactivity as the isobutyryl
acid 14 in 87% yield without epimerization.
group under basic hydrolysis conditions. After intensive
investigation of the chemoselective deprotection of
(1R,2S)-16, we found that acidic hydrolysis [4 M HCl in
EtOAc–EtOH–H2O (1:1:1), 40 °C, 6 h] selectively re-
moved the isobutyryl group and gave (1R,2S)-15 in 76%
yield without epimerization. For the practical use of chiral
15, a Pyroc group could be removed after some modifica-
tion of a 2-hydroxy group in 15.
The ( )-cis-1-(Pyroc-oxy)-2-cyclohexanol (15) was also a
suitable substrate for 1a-induced kinetic resolution
(S = 65, Scheme 6). We then examined the selective
deprotection of (1R,2S)-16. Although the corresponding
pyrrole derivative was obtained from (1R,2S)-16 in quan-
titative yield by DDQ oxidation, subsequent basic hydro-
lysis gave a complex mixture. The pyrrole-1-carbonyl
N
O
1. DDQ (1.5 equiv)
OH
dioxane, 85 °C, 2 h
O
1
1
2
2
2. NaOH (1.5 equiv)
THF–MeOH–H2O (2:2:1)
0 °C, 0.5 h
OCOi-Pr
OCOi-Pr
(1R,2S)-16
(1R,2S)-17
N
O
1a (5 mol%)
87% ee
(i-PrCO)2O (0.5 equiv)
O
N
O
DIPEA (0.5 equiv)
CCl4, 0 °C, 3 h
OH
N
O
4 M HCl
O
( )-15
1
2
53% conv., S = 65
EtOAc–EtOH–H2O (1:1:1)
40 °C, 6 h
O
OH
1
2
(1R,2S)-15
76% yield, 87% ee
OH
(1S,2R)-15
98% ee
Scheme 6 Kinetic resolution of racemic cyclohexane-1,2-diol derivative 14 and selective deprotection of 16
Synlett 2009, No. 10, 1647–1650 © Thieme Stuttgart · New York

1650
A. Sakakura et al.
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(4) For kinetic resolution of racemic carboxylic acids, see:
In conclusion, we reported a Pyroc group (for hydroxy
group) and 3-pyrrolinamide (for carboxy group) as re-
movable protecting groups that were suitable for the ki-
netic resolution induced by bifunctional catalysts 1. These
protecting groups played a key role in high-level asym-
metric induction through hydrogen bonding with a sul-
fonamidyl proton of 1. Furthermore, they could be
selectively removed via DDQ oxidation followed by hy-
drolysis using NaOH without any loss of stereochemical
integrity.
Shiina, I.; Nakata, K.; Onda, Y. Eur. J. Org. Chem. 2008,
5887.
(5) (a) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc.
2004, 126, 12212. (b) Ishihara, K.; Kosugi, Y.; Akakura, M.
Tetrahedron 2007, 63, 6191. (c) For an account article, see:
Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007, 686.
(6) Reduction with lithium aluminium hydride (4 equiv) gave
the corresponding 1,2-diol in high yield without epimeri-
zation.2
(7) Pyroc chloride was prepared as follows:
Diallylaminocarbonyl chloride was reacted in the presence
of Grubbs’ first-generation catalyst (0.5 mol%) under
heating conditions (CH2Cl2, reflux, 4 h). After the reaction
mixture was concentrated, the residue was purified by
column chromatography on SiO2 to give Pyroc chloride in
95% yield. (a) Ferguson, M. L.; O’Leary, D. J.; Grubbs,
R. H. Org. Synth. 2003, 80, 85. (b) Fu, G. C.; Nguyen, S. T.;
Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856.
(8) For the synthesis of Pyroc chloride by ring-closing
metathesis with the aid of microwave irradiation, see:
Vo Thanh, G.; Loupy, A. Tetrahedron Lett. 2003, 44, 9091.
(9) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(10) (a) Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.;
Harvey, J. N.; Hynd, G.; Ohara, D.; Picoul, W.; Robiette, R.;
Smith, C.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2006,
128, 2105. (b) Ohri, R. V.; Radosevich, A. T.; Hrovat, K. J.;
Musich, C.; Huang, D.; Holman, T. R.; Toste, F. D. Org.
Lett. 2005, 7, 2501.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This project was supported by JSPS.KAKENHI (Grant 20245022),
the Toray Science Foundation, METI (GSC Project), the G-COE in
Chemistry, Nagoya University and JSPS Research Fellowships for
Young Scientists (S.U.).
References and Notes
(1) For recent reviews, see: (a) Connon, S. J. Lett. Org. Chem.
2006, 3, 333. (b) Vedejs, E.; Jure, M. Angew. Chem. Int. Ed.
2005, 44, 3974. (c) Miller, S. J. Acc. Chem. Soc. 2004, 37,
601. (d) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(e) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem.
Rev. 2003, 103, 2985.
(2) Ishihara, K.; Kosugi, Y.; Umemura, S.; Sakakura, A. Org.
Lett. 2008, 10, 3191.
(3) For recent reports of asymmetric derivatization of racemic
alcohols, see: (a) Sánchez-Roselló, M.; Puchlopek, A. L. A.;
Morgan, A. J.; Miller, S. J. J. Org. Chem. 2008, 73, 1774.
(b) Lewis, C. A.; Chiu, A.; Kubryk, M.; Balsells, J.; Pollard,
D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen, K. B.;
Miller, S. J. J. Am. Chem. Soc. 2006, 128, 16454.
(11) Experimental Procedure for the Deprotection of Pyroc
Group in 6a
To a solution of 6a (0.1 mmol) in dioxane (1 mL) was added
DDQ (0.15 mmol), and the mixture was stirred at 85 °C for
2 h. After the reaction mixture was cooled to ambient
temperature, dioxane was removed under reduced pressure.
The residue was purified by column chromatography on
SiO2 to give 7a in 98% yield.
Compound 7a: 1H NMR (400 MHz, CDCl3): d = 1.05 (s, 9
H), 1.49 (s, 9 H), 4.02 (dd, J = 2.3, 11.0 Hz, 1 H), 4.21 (dd,
J = 4.1, 11.0 Hz, 1 H), 5.22 (dd, J = 2.3, 4.1 Hz, 1 H), 6.26
(dd, J = 1.8, 2.3 Hz, 2 H), 7.29 (dd, J = 1.8, 2.3 Hz, 2 H),
7.30–7.48 (m, 6 H), 7.60–7.74 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 19.2, 26.5, 28.0, 63.3, 76.0, 82.9, 112.6,
120.2, 127.8, 129.9, 132.7, 132.8, 135.4, 135.5, 149.9,
166.2.
(c) Lewis, C. A.; Miller, S. J. Angew. Chem. Int. Ed. 2006,
45, 5616. (d) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.;
Snapper, M. L. Nature (London) 2006, 443, 67. (e) Birman,
V. B.; Li, X. Org. Lett. 2006, 8, 1351. (f) Birman, V. B.;
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2006, 128, 6536. (g) Birman, V. B.; Guo, L. Org. Lett. 2006,
8, 4859. (h) Birman, V. B.; Jiang, H. Org. Lett. 2005, 7,
3445. (i) Lewis, C. A.; Sculimbrene, B. R.; Xu, Y.; Miller,
S. J. Org. Lett. 2005, 7, 3021. (j) Sculimbrene, B. R.; Xu,
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(k) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane,
C. J. J. Am. Chem. Soc. 2004, 126, 12226. (l) Fierman,
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S. J. F.; Anson, M. S. Synlett 2003, 679.
To a solution of 7a (0.085 mmol) in THF (0.17 mL) and
MeOH (0.17 mL) was added 1.5 M aq NaOH (0.085 mL,
0.13 mmol) at 0 °C, and the mixture was stirred at 0 °C for
0.5 h. The reaction mixture was quenched with 1 M aq HCl
and diluted with EtOAc. The organic layer was separated,
washed with brine, dried with Na2SO4, and concentrated.
The residue was purified by column chromatography on
SiO2 to give 8a in 93% yield.
Compound 8a: 1H NMR (400 MHz, CDCl3): d = 1.04 (s, 9
H), 1.51 (s, 9 H), 3.88 (dd, J = 2.8, 10.6 Hz, 1 H), 3.99 (dd,
J = 2.3, 10.6 Hz, 1 H), 4.10 (dd, J = 2.3, 2.8 Hz, 1 H), 7.31–
7.47 (m, 6 H), 7.61–7.74 (m, 4 H).
(12) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
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