Stereoselective synthesis of vic-halohydrins via l-tert-leucine-catalyzed syn-selective aldol reaction

Article abstract of DOI:10.1055/s-0031-1290316

L-tert-Leucine was found to be an effective organocatalyst for the asymmetric aldol reaction of chloroacetone. The stereoselective synthesis of vic-halohydrins was accomplished with excellent regioselectivity (>99%) to generate α-chloro-β-hydroxy ketones

Full text of DOI:10.1055/s-0031-1290316

LETTER
453
Stereoselective Synthesis of vic-Halohydrins via L-tert-Leucine-Catalyzed
syn-Selective Aldol Reaction
Stereoselective
Sy
t
nthesis
s
of vic-Ha
l
ohydrins shi Umehara, Takuya Kanemitsu, Kazuhiro Nagata, Takashi Itoh*
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax +81(3)37845982; E-mail: itoh-t@pharm.showa-u.ac.jp
Received 9 November 2011
diastereo-, and enantioselectivity.9b Although Gong and
co-worker have reported that primary amine catalyzed di-
rect asymmetric aldol reactions of chloroacetone primari-
ly provide syn products, the syn diastereoselectivity was
Abstract: L-tert-Leucine was found to be an effective organocata-
lyst for the asymmetric aldol reaction of chloroacetone. The stereo-
selective synthesis of vic-halohydrins was accomplished with
excellent regioselectivity (>99%) to generate a-chloro-b-hydroxy
ketones with high syn selectivity (syn/anti = 16:1) and enantioselec- very low.9e Despite recent advances in the area of catalytic
asymmetric aldol reactions,10 high regioselective, syn-dia-
tivity (up to 95% ee).
stereoselective, and enantioselective synthesis of a-chlo-
ro-b-hydroxy ketones remains challenging. In this paper,
we report the highly syn-selective direct asymmetric aldol
reaction of chloroacetone catalyzed by L-tert-leucine to
afford syn-vic-harohydrins.
Key words: aldol reaction, amino acids, asymmetric synthesis,
chloroacetone, organocatalysis
Optically active vic-halohydrins are versatile building
blocks and key intermediates for the synthesis of biologi-
cally active compounds and natural products such as b-
agonists,1 substituted pyrrolidines,2 a polychlorosulfolip-
id,3 and insect sex pheromones.4 Thus, the development of
effective synthetic methods for the production of these
compounds has attracted much attention. The most com-
mon procedure for the preparation of optically active vic-
halohydrins is the ring opening of enantiomerically pure
epoxides,5 but this approach results in a mixture of regio-
isomers. On the other hand, asymmetric reductions of
prochiral a-halo ketones by chiral oxazaborolidine cata-
lysts with borane1b,c,2,6 and asymmetric hydrogenation us-
ing chiral Ru1a,7 or Rh7c,8 catalysts have shown excellent
enantioselectivity to afford a variety of vic-halohydrins.
Moreover, organocatalyzed direct asymmetric aldol reac-
tion of chloroacetone with aldehydes has been reported by
several groups.9 We have been interested in an alternate
approach, which provides a-chloro-b-hydroxy ketones,
for obtaining vic-chlorohydrins. The development of an
organocatalyst for the asymmetric aldol reaction of chlo-
roacetone with aldehydes is a formidable task, since the
reaction can lead to the formation of regio- and diastereo-
meric isomers and their enantiomers (Scheme 1). Nájera
and co-workers reported an L-proline-derivative-cata-
lyzed direct asymmetric aldol reaction of chloroacetone,
which afforded anti-vic-chlorohydrins in high regio-,
Initially, a test reaction was carried out using L-proline as
a catalyst (20 mol%). The reaction of chloroacetone (1a)
with 4-nitrobenzaldehyde (2a) at room temperature gave
the anti-selective product 4a in low yield with low regio-
selectivity (Scheme 2). This anti selectivity was in agree-
ment with literature data.9b Next, we examined the utility
of a series of primary amino acids as catalysts for syn-se-
lective aldol reaction of chloroacetone (1a). Natural pri-
mary amino acids and commercially available unnatural
amino acids were used as catalysts in the reaction of chlo-
roacetone (1a) with 4-nitrobenzaldehyde (2a) at room
temperature (Table 1).
L-tert-Leucine exhibited much higher efficiency than the
other primary amino acids, providing syn-aldol product 3a
in high yield (89%) with excellent regioselectivity
(>99:1), and high diastereo- (syn/anti = 7:1), and enantio-
selectivity (83% ee, Table 1, entry 1). Although L-alanine,
L-valine, L-leucine, L-threonine, and L-phenylglycine ex-
hibited excellent regioselectivity, only low reaction yields
were obtained (Table 1, entries 2–4, 9, and 11). L-Isoleu-
cine, L-phenylalanine, L-tryptophan, and L-methionine
gave the syn product 3a in moderate yields and diastereo-
selectivities (Table 1, entries 5, 7, 8, and 10). L-Tyrosine
and L-penicillamine showed no catalytic activity in this
reaction (Table 1, entries 6 and 12). All the primary amino
O
OH
O
OH
O
OH
O
O
organocatalyst
+
+
+
R
R
R
H
R
Cl
Cl
Cl
3
Cl
1a
4
5
2
syn
anti
linear
Scheme 1 Organocatalyzed asymmetric aldol reaction of chloroacetone (1a)
SYNLETT 2012, 23, 453–457
x
x.
x
x.
2
0
1
2
Advanced online publication: 19.01.2012
DOI: 10.1055/s-0031-1290316; Art ID: U64911ST
© Georg Thieme Verlag Stuttgart · New York

454
A. Umehara et al.
LETTER
O
OH
O
OH
O
OH
O
L-proline
O
(20 mol%)
+
+
+
PNP
PNP
PNP
neat, r.t.
H
PNP
Cl
3a
8%
Cl
4a
24%
Cl
Cl
1a
5a
2a
8%
PNP = p-nitrophenyl
Scheme 2 L-Proline-catalyzed asymmetric aldol reaction of chloroacetone (1a)
acids, except L-tyrosine and L-penicillamine, afforded ticular, 2-nitrobenzaldehyde afforded the syn product 3c
perfect regioselectivity and the desired aldol product 3a with excellent yield (99%) and enantioselectivity (95%
with syn selectivity; of these amino acids, L-tert-leucine ee, Table 2, entry 3). The reaction of 2-bromobenzalde-
was the most effective catalyst in the aldol reaction with hyde resulted in the syn product 3f with high diastereo-
chloroacetone (1a).11 We previously reported that L-tert- selectivity (syn/anti = 10:1) (Table 2, entry 6). 2-
leucine exhibits high catalytic activity compared to other Trifluoromethylbenzaldehyde gave the product 3g with
amino acids due to the stability of an enamine derived high diastereoselectivity (syn/anti = 7:1) and excellent
from L-tert-leucine in the presence of aromatic alde- enantioselectivity (94% ee, Table 2, entry 7). On the other
hydes.12
hand, benzaldehyde and 1-naphthaldehyde were less reac-
tive and gave 3h and 3i in low yield, but the enantioselec-
tivities remained high (Table 2, entries 8 and 9).
Next, to investigate the generality of this reaction, a vari-
ety of aromatic aldehydes 2a–i were used as substrates for
the L-tert-leucine-catalyzed aldol reaction (Table 2).11 In We then examined L-tert-leucine-catalyzed asymmetric
all cases, syn-vic-chlorohydrins 3a–i were obtained with aldol reactions of 4-nitrobenzaldehyde (2a) with a-het-
excellent regioselectivity. When aldehydes with an elec- eroatom-substituted ketones, 2-butanone, or 4-hydroxy-2-
tron-withdrawing substituent were employed, the reaction butanone (Table 3).11 Although hydroxyacetone smoothly
proceeded smoothly to afford desired syn adducts 3a–g underwent the reaction to give syn adduct 3j with excel-
with high stereoselectivities (Table 2, entries 1–7). In par- lent regioselectivity, the enantioselectivity was low
Table 1 L-Amino Acid Catalyzed Asymmetric Aldol Reaction of Chloroacetone (1a)
O
OH
O
OH
O
catalyst
(20 mol%)
O
OH
O
+
+
+
PNP
PNP
PNP
neat
r.t., 7 d
H
PNP
Cl
Cl
4a
Cl
Cl
3a
1a
2a
5a
PNP = p-nitrophenyl
Entrya
Catalyst
Yield (%)b
(3a + 4a)/5ac
>99:1
>99:1
>99:1
>99:1
>99:1
n.d.e
3a/4ac
7:1
ee of 3a (%)d
1
2
L-tert-leucine
L-alanine
89
7
83
6:1
70
3
L-valine
14
30
71
trace
66
64
6
5:1
80
4
L-leucine
7:1
73
5
L-isoleucine
L-tyrosine
2:1
38
6
n.d.e
4:1
n.d.e
69
7
L-phenylalanine
L-tryptophan
L-threonine
L-methionine
L-phenylglycine
L-penicillamine
>99:1
>99:1
>99:1
>99:1
>99:1
n.d.e
8
2:1
68
9
5:1
n.d.e
72
10
11
12
66
13
trace
4:1
3:1
18
n.d.e
n.d.e
a The reaction was performed with 4-nitrobenzaldehyde (2a, 1 equiv), chloroacetonene (1a, 10 equiv), and L-amino acid (0.2 equiv) at r.t. for
7 d.
b The combined isolated yield of the diastereomers.
c Determined by 1H NMR.
d Determined by HPLC.
e Not determined.
Synlett 2012, 23, 453–457
© Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of vic-Halohydrins
455
Table 2 L-tert-Leucine-Catalyzed Asymmetric Aldol Reaction of Chloroacetone (1a)
OH
H2N
O
O
OH
O
O
OH
O
OH
O
(20 mol%)
+
+
+
Ar
Ar
Ar
H
Ar
neat
r.t., 7 d
Cl
Cl
Cl
3a–i
Cl
4a–i
1a
2a–i
5a–i
Entrya
Ar
Product (syn)
Yield (%)b
(3 + 4)/5c
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
94:6
3/4c
7:1
6:1
8:1
5:1
7:1
10:1
7:1
5:1
16:1
ee of 3 (%)d
1
2
3
4
5
6
7
8
9
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-NCC6H4
4-O2CMeC6H4
2-BrC6H4
2-F3CC6H4
Ph
3a
3b
3c
3d
3e
3f
89
87
99
81
72
84
80
33
29
83
87
95
80
83
89
94
87
90
3g
3h
3i
1-naphthyl
>99:1
a The reaction was performed with arylaldehyde 2 (1 equiv), chloroacetonene (1a, 10 equiv), and L-tert-leucine (0.2 equiv) at r.t. for 7 d.
b The combined isolated yield of the diastereomers.
c Determined by 1H NMR.
d Determined by HPLC.
Table 3 L-tert-Leucine-Catalyzed Asymmetric Aldol Reaction of a-Substituted Acetone 1a–h
OH
H2N
O
O
OH
PNP
O
OH
O
OH
PNP
O
O
(20 mol%)
+
+
+
PNP
H
PNP
neat
r.t., 7 d
R
R
R
3
R
4
1a–h
2a
5
Entrya
R
Product (syn)
Yield (%)b
(3+4)/5c
>99:1
>99:1
19:1
4:1
3/4c
7:1
2:1
2:1
3:1
4:1
n.d.f
2:1
1:1
ee of 3 (%)d
1
2
3
4e
5
6
7
8
Cl
3a
3j
89
83
OH
OMe
F
85
46
3k
3l
74
60
23
85
SMe
Br
3m
3n
3o
3p
88
14:1
n.d.f
5:1
64
trace
83
n.d.f
68
Me
CH2OH
68
2:6
n.d.f
a Unless otherwise stated, the reaction was performed with 4-nitrobenzaldehyde (2a, 1 equiv), a-substituted acetone 1 (10 equiv), and L-tert-
leucine (0.2 equiv) at r.t. for 7 d.
b The combined isolated yield of the diastereomers.
c Determined by 1H NMR.
d Determined by HPLC.
e The reaction was performed in the presence of 0.35 equiv of L-tert-leucine.
f Not determined.
© Thieme Stuttgart · New York
Synlett 2012, 23, 453–457

456
A. Umehara et al.
LETTER
O
O
O
O
a) proline catalyst
N
N
O
OH
Cl
H
H
H
<
R
O
O
Cl
Cl
4
anti
R
H
R
O
O
Z-enamine
R
E-enamine
R
+
H
R
O
O
Cl
O
O
H
H
N
O
OH
N
1a
2
Cl
H
H
<
R
O
O
Cl
Cl
b) primary amino acid
catalyst
R
H
R
H
3
syn
E-enamine
Z-enamine
Scheme 3 A proposed mechanism for the organocatalyzed asymmetric aldol reaction of chloroacetone (1a)
(Table 3, entry 2). Methoxyacetone and methylthioace- In summary, we have developed a protocol for the highly
tone gave syn adducts 3k and 3m, respectively, as a major stereoselective organocatalyzed synthesis of vic-halohy-
product with good regioselectivities, but the stereoselec- drins. Using L-tert-leucine as the catalyst, the aldol reac-
tivities were moderate (Table 3, entries 3 and 5). The use tions of chloroacetone with aromatic aldehydes were
of fluoroacetone resulted in high enantioselectivity, but accomplished with excellent regioselectivity (>99%) to
the chemical yield was low (Table 3, entry 4). In the case generate the corresponding a-chloro-b-hydroxy ketones
of bromoacetone, only trace amounts of the desired prod- with high syn selectivity (up to syn/anti = 16:1) and high
uct 3n were obtained (Table 3, entry 6). Furthermore, the enantioselectivity (up to 95% ee). Thus, L-tert-leucine-
reactions of 2-butanone and 4-hydroxy-2-butanone, catalyzed reactions hold promise for the synthesis of opti-
which lack a functional group at the a-position, afforded cally active vic-chlorohydrins. Further applications of this
syn adducts 3o and 3p with low and no diastereoselectiv- approach to total synthesis are currently under investiga-
ity, respectively (Table 3, entries 7 and 8).
tion in our laboratory.
In previous reports, direct asymmetric aldol reaction of a-
hydroxy ketones catalyzed by a secondary amine such as
L-proline or its derivatives provided anti-selective aldol
adducts,13 whereas the reaction catalyzed by a chiral pri-
mary amine provided syn-selective aldol adducts.9e,14 Ac-
cording to the model proposed by Barbas,14a in the case of
a secondary amine, E-enamine intermediates predominate
because of steric repulsion. As a result, secondary amine
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported in part by a Grant for the High-Tech
Research Center Project from the Ministry of Education, Culture,
catalyzed aldol reactions of a-hydroxy ketone 1b afford Sports, Science and Technology of Japan.
anti-aldol adducts 4. In contrast, Z-emanine intermediates
predominate in the case of a primary amine because of sta-
References and Notes
bilization of the intermediate due to the formation of an
(1) (a) Lu, C.; Luo, Z.; Huang, L.; Li, X. Tetrahedron:
intramolecular hydrogen bond. Therefore, primary amine
catalyzed reactions afford syn-aldol adducts 3. For the re-
action of chloroacetone (1a), we propose a mechanism
similar to the case of a-hydroxy ketone (Scheme 3).15 Ac-
cording to the results in Table 2, a hydrogen bond can be
formed in an enamine generated from a primary amine
and chloroacetone (1a). The asymmetric aldol reaction
provides syn adducts 3 with high syn diastereoselectivities
in the presence of appropriate chiral primary amine cata-
lysts. In addition, the results in Table 3 suggest that in-
tramolecular hydrogen bonding is necessary for the
reaction to proceed in high regio- and stereoselectivity,
and only chloro and methylthio groups at the a-position
can effectively bond with the neighboring hydrogen.
Thus, sufficient electronegativity and an appropriate
atomic radius might be prerequisite for the formation of
the intramolecular hydrogen bonds necessary to afford
syn selectivity.
Asymmetry 2011, 22, 722. (b) Bloom, J. D.; Dutia, M. D.;
Johnson, B. D.; Wissner, A.; Burns, M. G.; Largus, E. E.;
Dolan, J. A.; Claus, T. H. J. Med. Chem. 1992, 35, 3081.
(c) Corey, E. J.; Link, J. O. J. Org. Chem. 1991, 56, 442.
(2) (a) Chung, J. Y. L.; Cvetovich, R.; Amato, J.; McWilliams,
J. C.; Reamer, R.; DiMichele, L. J. Org. Chem. 2005, 70,
3592. (b) Draper, J.; Britton, R. Org. Lett. 2010, 12, 4034.
(3) Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.; Tanaka, T.
Org. Lett. 2011, 13, 908.
(4) Kang, B.; Britton, R. Org. Lett. 2007, 9, 5083.
(5) (a) Stewart, C. A.; VanderWerf, C. A. J. Am. Chem. Soc.
1954, 76, 1259. (b) Owen, L. N.; Saharia, G. S. J. Chem.
Soc. 1953, 2582. (c) Ranu, B. C.; Banerjee, S. J. Org. Chem.
2005, 70, 4517. (d) Yadav, J. S.; Reddy, B. V. S.; Baishya,
G.; Harshavardhan, S. J.; Chary, C. J.; Gupta, M. K.
Tetrahedron Lett. 2005, 46, 3569. (e) Nishitani, K.;
Shinyama, K.; Yamakawa, K. Heterocycles 2007, 74, 191.
(f) Neimi, H.; Moradian, M. Polyhedron 2008, 27, 3639.
(g) Pajkert, R.; Kolomeitsev, A. A.; Milewska, M.;
Synlett 2012, 23, 453–457
© Thieme Stuttgart · New York

LETTER
Röschenthaler, G.-V.; Koroniak, H. Tetrahedron Lett. 2008,
Stereoselective Synthesis of vic-Halohydrins
457
analysis of the residue. Then, the residue was purified by
column chromatography on silica gel in gradient elution
with hexane–EtOAc to give a 7:1 inseparable mixture of the
desired products 3a and 4a (108 mg, 89%).
49, 6046.
(6) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986.
(7) (a) Ohkuma, T.; Tsutsumi, K.; Utsumi, N.; Arai, N.; Noyori,
R.; Murata, K. Org. Lett. 2007, 9, 255. (b) Bayston, D. J.;
Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry
1998, 9, 2015. (c) Cross, D. J.; Kenny, J. A.; Houson, I.;
Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron:
Asymmetry 2001, 12, 1801. (d) Morris, D. J.; Hayes, A. M.;
Wills, M. J. Org. Chem. 2006, 71, 7035.
(8) (a) Hamada, T.; Torii, T.; Izawa, K.; Ikariya, T. Tetrahedron
2004, 60, 7411. (b) Hamada, T.; Torii, T.; Izawa, K.;
Noyori, R.; Ikariya, T. Org. Lett. 2002, 4, 4373.
Analytical Data for Compound 3a
1H NMR (400 MHz, CDCl3): d = 8.24–8.20 (m, 2 H), 7.61–
7.58 (m, 2 H), 5.47 (t, J = 3.6 Hz, 1 H), 4.46 (d, J = 3.2 Hz,
1 H), 3.43 (d, J = 4.0 Hz, 1 H), 2.40 (s, 3 H). 13C NMR (100
MHz, CDCl3): d = 203.4, 147.6, 146.2, 127.3, 123.5, 72.0,
67.3, 28.3. HPLC: 83% ee [Daicel CHRALCEL OJ-H,
hexane–iPrOH (9:1), flow rate 1.0 mL/min, l = 254 nm]:
tR(major) = 34.7 min; tR(minor) = 39.1 min.
(12) Kanemitsu, T.; Umehara, A.; Miyazaki, M.; Nagata, K.;
Itoh, T. Eur. J. Org. Chem. 2011, 993.
(c) Matharu, D. S.; Morris, D. J.; Kawamoto, A. M.;
Clarkson, G. J.; Wills, M. Org. Lett. 2005, 7, 5489.
(9) (a) He, L.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Tetrahedron 2006, 62, 346. (b) Guillena, G.;
Hita, M. C.; Nájera, C. Tetrahedron: Asymmetry 2007, 18,
1272. (c) Sato, K.; Kuriyama, M.; Shimazawa, R.;
Morimoto, T.; Kakiuchi, K.; Shirai, R. Tetrahedron Lett.
2008, 49, 2402. (d) Russo, A.; Botta, G.; Lattanzi, A.
Tetrahedron 2007, 63, 11886. (e) Xu, X.-Y.; Wang, Y.-Z.;
Gong, L.-Z. Org. Lett. 2007, 9, 4247.
(10) (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem. Int. Ed.
2000, 39, 1352. (b) Vogl, H. G. E. M.; Shibasaki, M. Chem.
Eur. J. 1998, 4, 1137. (c) Nelson, S. G. Tetrahedron:
Asymmetry 1998, 9, 357. (d) Guillena, G.; Nájera, C.;
Ramón, D. J. Tetrahedron: Asymmetry 2007, 18, 2249.
(e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471.
(11) Optimized Procedure for the Synthesis of 3a
To a mixture of chloroacetone (1a, 400 mL, 5 mmol) and L-
tert-leucine (13 mg, 0.1 mmol), 4-nitrobenzaldehyde (2a, 76
mg, 0.5 mmol) was added, and the mixture was stirred at r.t.
The reaction was monitored by TLC analysis. After 7 d, H2O
was added and extracted with CH2Cl2 (3×), dried over
MgSO4, and concentrated in vacuo. To determine the
regioselectivity and the diastereomeric ratio, the remaining
residue was analyzed by 1H NMR. Moreover, the ee value of
the product 3a was determined by chiral-phase HPLC
(13) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. III. J. Am.
Chem. Soc. 2001, 123, 5260. (c) Córdova, A.; Notza, W.;
Barbas, C. F. III. Chem. Commun. 2002, 3024.
(d) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron:
Asymmetry 2006, 17, 1027. (e) Guillena, G. M. C.; Nájera,
C.; Viózquez, S. F. Tetrahedron: Asymmetry 2007, 18, 2300.
(14) (a) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C.
F.. III. J. Am. Chem. Soc. 2007, 129, 288. (b) Ramasastry,
S. S. V.; Albertshofer, K.; Utsumi, N.; Tanaka, F.; Barbas,
C. F. III. Angew. Chem. Int. Ed. 2007, 46, 5572. (c) Wu, X.;
Jiang, Z.; Shen, H. M.; Lu, Y. Adv. Synth. Catal. 2007, 349,
812. (d) Utsumi, N.; Imai, M.; Tanaka, F.; Ramasastry, S. S.
V.; Barbas, C. F. III. Org. Lett. 2007, 9, 3445. (e) Da C, S.;
Che, L. P.; Guo, Q. P.; Wu, F. C.; Ma, X.; Jia, Y. N. J. Org.
Chem. 2009, 74, 2541. (f) Larionova, N. A.; Kucherenko,
A. S.; Siyutkin, D. E.; Zlotin, S. G. Tetrahedron 2011, 67,
1948. (g) Wu, X.; Ma, Z.; Ye, Z.; Qian, S.; Zhao, G. Adv.
Synth. Catal. 2009, 351, 158. (h) Li, J.; Luo, S.; Cheng, J. P.
J. Org. Chem. 2009, 74, 1747.
(15) (a) Banerjee, R.; Desiraju, G. R.; Mondal, R.; Howard, J. A.
K. Chem. Eur. J. 2004, 10, 3373. (b) In this paper (ref. 15a),
Howard and co-workers claimed that chlorine in organic
compound is able to work as an intramolecular hydrogen
bond acceptor. Their results support the proposed
mechanism of our reaction system.
© Thieme Stuttgart · New York
Synlett 2012, 23, 453–457

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.