Chiral scandium-catalysed enantioselective ring-opening of meso-epoxides with N-heterocycle, alcohol and thiol derivatives in water

Article abstract of DOI:10.1002/adsc.200600290

In the presence of catalytic amounts of Sc(OSO₃C ₁₂H₂₅)₃ and a chiral bipyridine ligand, asymmetric ring-opening of meso-epoxides with aromatic N-heterocycles, an alcohol and thiols proceeded smoothly to afford

Full text of DOI:10.1002/adsc.200600290

COMMUNICATIONS
DOI: 10.1002/adsc.200600290
Chiral Scandium-Catalysed Enantioselective Ring-Opening
of meso-Epoxides with N-Heterocycle, Alcohol and Thiol
Derivatives in Water
Marine Boudou,a Chikako Ogawa,a and Shu¯ Kobayashia,*
a
Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO (Japan) and Science
Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-03-5684-0634; e-mail: skobayas@mol.f.u-tokyo.ac.jp
Received: June 18, 2006; Accepted: September 6, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: In the presence of catalytic amounts of
Sc(OSO3C12H25)3 and a chiral bipyridine ligand,
asymmetric ring-opening of meso-epoxides with ar-
omatic N-heterocycles, an alcohol and thiols pro-
ceeded smoothly to afford the corresponding prod-
ucts in moderate to good yields (34–85%) with high
to excellent enantioselectivities (74–96% ee). Water
was used as the sole and essential solvent in these
important enantioselective transformations.
Nitrogen-containing heterocycles and their deriva-
tives have found broad applications in synthetic and
biological chemistry.[5] Moreover, the indole frame-
work is widely represented in natural substances and
medicinal compounds.[6] Therefore, generation of
chiral N-heteroaromatic derivatives in optically active
form, in particular those incorporating indolic archi-
tectures, is a challenging and important facet of this
research area.[7] To date, several catalytic, regioselec-
tive ring-opening of racemic epoxides[8] or chiral aro-
matic epoxides[9] with indole derivatives have been
described. However, the catalytic enantioselective de-
symmetrisation of epoxides has received much less at-
tention in the literature, and only one protocol for
highly selective addition of indole derivatives to
meso-stilbene oxide in tert-butyl methyl ether has
Keywords: epoxides; Lewis acids; scandium; surfac-
tant; water chemistry
Water has emerged as a versatile solvent for organic been reported.[10] Furthermore, to the best of our
chemistry in recent years.[1] In addition to its low cost, knowledge, only one report of racemic ring-opening
water is environmentally benign and frequently pro- of epoxides with nucleophiles in pure water has ap-
motes unique reactivity and selectivity in chemical peared[11] before our recent report.[3]
transformations. Indeed, the hydrophobic effect and
Our preliminary experiment was performed using
solvation are expected to control reaction courses in cis-stilbene oxide 1a and indole as model reagents
water.
Catalytic, enantioselective ring opening of meso-ep-
(Scheme 1). We were pleased to see that, after only
oxides is an efficient method to convert readily avail-
able bulk chemicals into chiral 1,2-difunctionalised
fine chemicals in enantiomerically enriched form.[2]
Recently, we have developed catalytic asymmetric
ring-opening reactions of meso-epoxides with aromat-
ic amines using a chiral scandium complex in water.[3]
This is a successful example of chiral Lewis acid catal-
ysis based on Lewis acid-surfactant combined cata-
lysts (LASCs)[4] using water as the sole solvent. We
have further investigated this unique and important
catalysis and, in this paper, we describe catalytic
asymmetric desymmetrisation of meso-epoxides with
aromatic N-heterocycles, an alcohol and thiols using a
chiral scandium catalyst in water.
Scheme 1. Desymmetrisation of cis-stilbene oxide with ben-
zotriazole.
Adv. Synth. Catal. 2006, 348, 2585 – 2589
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2585

Marine Boudou et al.
COMMUNICATIONS
five hours, the reaction had proceeded smoothly to moderate to good yields with high enantioselectivities
give the desired alcohol in 50% yield with excellent (entries 6–8).
À
enantioselectivity in the presence of catalytic amounts
Benzotriazole bears a relatively acidic N H proton
of Sc(OSO3C12H25)3 [Sc(DS)3] and bypiridine ligand (pKa =8.2) and exists in solution in two tautomeric
(S,S)-3[12] (Table 1, entry 1). Running the reaction at a forms (1H- and 2H-forms).[13] Extending our method-
higher concentration increased the yield dramatically ology to this heterocycle was highly interesting as
while maintaining a high level of selectivity (entry 2). such a moiety is present in numerous biologically
It should be noted that the same reaction using active substances. For instance, the non-natural nu-
Sc(OTf)3 instead of Sc(DS)3 in dichloromethane pro- cleoside DRBTwas recognised as possessing a potent
G
ceeded sluggishly under the conditions. On the other inhibitory effect on the hepatitis C virus,[14] whereas a
hand, neither increasing the amount of nucleophile benzotriazole-containing phosphate was described as
(entry 3) nor lengthening the reaction time (entry 4) an inhibitor of PTP1B and therefore could be a
resulted in further improvement of the yield or selec- potent treatment for type 2 diabetes and obesity.[15]
tivity. Thus, the desymmetrisation of cis-stilbene oxide Potential applications might include preparation of
1a with indole was carried out with 5 mol% of novel non-natural nucleosides (NNNs), a class of
Sc(DS)3 and 6 mol% of 3 in water as the sole solvent, compounds with a broad range of important biologi-
affording the desired alcohol 4a in 85% yield with cal applications.[16] This fused aromatic heterocyclic
93% ee.
substrate was found to undergo a smooth reaction
It is noteworthy that this reaction could be per- with indole, although a longer reaction time was re-
formed under air without epimerisation of the alcohol quired, generating 5a in excellent regioselectivity (5a/
4a or loss of reactivity (Table 2, entry 1). As the next 5b=13.2/1, total yield of 65%) with 74% ee.
step, other indole derivatives were examined under
The present catalytic asymmetric desymmetrisation
the optimised conditions. The electron-rich 5-methoxy- of meso-epoxides was also applied to optically active
indole allowed the maintenance of the very high diol and sulfide derivatives. In the presence of
enantioselectivity and yield (entry 2) although a slight Sc(DS)3 (10 mol%) and chiral bipyridine ligand (S,S)-
decrease in the yield and the enantioselectivity was 3 (12 mol%), cis-stilbene oxide 1a reacted with para-
observed for the 5-methylindole derivative 4c bromobenzyl alcohol in water to afford the corre-
(entry 3). The sterically hindered 2-methylindole sponding protected diol 6 in good enantioselectivity
gave, as expected, lower yield, although the enantio- and moderate yield (Scheme 2). To the best of our
selectivity of 4d was satisfactory (entry 4). Use of the knowledge, no enantioselective addition of alcohols in
more electron-deficient 5-bromoindole gave the cor- pure water was previously described.[17]
responding alcohol 4e in moderate yield but with high
In addition, thiophenol and its derivatives were suc-
enantioselectivity (entry 5). The meso-epoxide cis- cessfully used as nucleophiles in this asymmetric de-
4,4’-dimethylstilbene oxide 1b and cis-4,4’-dibromo- symmetrisation (Table 3), and the corresponding sul-
stilbene oxide 1c reacted with indole and 4c to afford fides 7a–e were obtained in moderate to good yields
the desired products 4f, 4g and 4h, respectively, in with high enantioselectivities. While thiol derivatives
Table 1. Optimisation of the reaction conditions.
Entry
2 (equivs.)
Concentration[a]
Time
Yield[b] [%]
ee[c] [%]
1
2
3
4
1.1
1.1
1.5
1.1
0.5M
1M
1M
5 h
6 h
6 h
24 h
50
85
81
82
96
93
88
92
1M
[a]
With respect to the epoxide.
Isolated yield after chromatographic purification.
Determined by HPLC analysis on chiral stationary phase.
[b]
[c]
2586
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2585 – 2589

Enantioselective Ring-Opening of meso-Epoxides
COMMUNICATIONS
Table 2. Asymmetric ring opening of meso-epoxides with indole derivatives.
[a]
[b]
[c]
Isolated yield after chromatographic purification.
Determined by HPLC analysis on chiral stationary phase.
The reaction was conducted under air.
Adv. Synth. Catal. 2006, 348, 2585 – 2589
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2587

Marine Boudou et al.
COMMUNICATIONS
indole derivative (0.33 mmol) were successively added. Vig-
orous stirring was continued for 4 to 6 h at room tempera-
ture, and the reaction mixture was diluted with CH2Cl2 or
AcOEt (20 mL). After phase separation, the aqueous layer
was extracted with CH2Cl2 or AcOEt (3”20 mL). The com-
bined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. The resulting crude
mixture was purified by chromatography on silica gel.
Further details of the experimental procedures are de-
scribed in the Supporting Information, which also contains
characterisation data for the compounds made.
Scheme 2. Desymmetrisation of cis-stilbene oxide with 4-
bromobenzyl alcohol.
Acknowledgements
have been employed in the catalytic ring-opening of
meso-epoxides in organic solvents,[18] the present
enantioselective addition is the first example in water,
and it is noteworthy that high levels of enantioselec-
tivities have been attained in pure water.
This work was partially supported by a Grant-in-Aid for Sci-
entific Research from the Japan Society of the Promotion for
Science (JSPS).
In summary, we have developed a chiral scandium-
catalysed highly selective asymmetric ring-opening of
meso-epoxides in the presence of different substituted
indoles. The corresponding indolyl derivatives were
isolated in moderate to good yields with high to excel-
lent enantioselectivities. In addition, the first enantio-
selective addition of alcohol and thiol derivatives to
meso-epoxide in water has been realised.
References
[1] Recent reviews on organic reactions in water: a) C.-J.
Li, L. Chen, Chem. Soc. Rev. 2006, 35, 68; b) C.-J. Li,
Chem. Rev. 2005, 105, 3095; c) U. M. Lindstroem,
Chem. Rev. 2002, 102, 2751; d) D. Sinou, Adv. Synth.
Catal. 2002, 344, 237; e) K. Manabe, S. Kobayashi,
Chem. Eur. J. 2002, 8, 4094.
[2] a) M. C. Willis, J. Chem. Soc., Perkin Trans. 1 1999,
1765; b) D. M. Hodgson, A. R. Gibbs, G. P. Lee, Tetra-
hedron 1996, 52, 14361; c) E. N. Jacobsen, M. H. Wu,
in: Comprehensive Asymmetric Catalysis, Vol. 3, (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer-
Verlag, Berlin, 1999, p. 1309.
[3] S. Azoulay, K. Manabe, S. Kobayashi, Org. Lett. 2005,
7, 4593.
[4] K. Manabe, Y. Mori, T. Wakabayashi, W. Nagayama, S.
Kobayashi, J. Am. Chem. Soc. 2000, 122, 7202; see also:
S. Kobayashi, Y. Mori, S. Nagayama, K. Manabe,
Green Chem. 1999, 175.
Experimental Section
General Procedure for the Catalytic Asymmetric
Ring-Opening of meso-Epoxides with Indole
Derivatives
To Sc(DS)3 (12.6 mg, 0.15 mmol) and ligand (S,S)-3 (5.9 mg,
0.18 mmol) under argon was added deionised water
(300 mL, 1M concentration with respect to the epoxide).
The reaction mixture was stirred for 1 hour at room temper-
ature (r.t.), and then an epoxide 1a, 1b (0.30 mmol) and an
[5] A. R. Katritzky, A. F. Pozharskii, Handbook ofHetero-
cyclic Chemistry, 2nd edn., Pergamon, Oxford, 2002.
Table 3. Desymmetrisation of meso-oxide with thiophenol derivatives.
Entry
R1
R2
Concentration[a]
Product
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
Ph
H
H
H
t-Bu
OMe
OMe
0.1M
1M
0.1M
0.1M
0.1M
0.1M
7a
7b
7b
7c
7d
7e
73
44
76
69
66
70
89
92
85
92
87
93
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
Ph
4-Br-C6H4
[a]
With respect to the epoxide.
Isolated yield after chromatographic purification.
Determined by HPLC analysis on chiral stationary phase.
[b]
[c]
2588
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2585 – 2589

Enantioselective Ring-Opening of meso-Epoxides
COMMUNICATIONS
[6] J. F. Austin, D. W. C. MacMillan, J. Am. Chem. Soc.
2002, 124, 1172.
[13] H. Wamhoff, in: Comprehensive Heterocyclic Chemis-
try, Vol. 5, (Eds.: A. R. Katritzky, C. W. Rees, K. T.
Potts), Pergamon Press, Oxford, 1984, p. 669.
[14] P. Borowski, J. Deinert, S. Schalinski, M. Bretner, K.
Ginalski, T. Kulikowski, D. Shugar, Eur. J. Biochem.
2003, 270, 1645.
[15] C. K. Lau, C. I. Bayly, J. Y. Gauthier, C. S. Li, M. Ther-
ien, E. Asante-Appiah, W. Cromlish, Y. Boie, F. For-
ghani, S. Desmarais, Q. Wang, K. Skorey, D. Waddle-
ton, P. Payette, C. Ramachandran, B. P. Kennedy, G.
Scapin, Bioorg. Med. Chem. Lett. 2004, 1043.
[16] a) M. G. M. Purwanto, K. Weisz, Curr. Org. Chem.
2003, 7, 427; b) E. DeClerq, J. Med. Chem. 1995, 38,
2491; c) U. Englisch, D. H. Gauss, Angew. Chem. 1991,
30, 613; Angew. Chem. Int. Ed. 1991, 103, 629.
[17] Catalytic desymmetrisation of meso-epoxides with alco-
hols in dichloromethane: C. Schneider, A. R. Sree-
kanth, E. Mai, Angew. Chem. 2004, 116, 5809; Angew.
Chem. Int. Ed. 2004, 43, 5691.
[18] a) J. Wu, X.-L. Hou, L.-X. Dai, L.-J. Xia, M.-H. Tang,
Tetrahedron: Asymmetry 1998, 9, 3431; b) M. H. Wu,
E. N. Jacobsen, J. Org. Chem. 1998, 63, 5252; c) T. Iida,
N. Yamamoto, H. Sasai, M. Shibasaki, J. Am. Chem.
Soc. 1997, 119, 4783.
[7] a) A. F. Pozharskii, A. T. Soldatenkov, A. R. Katritzky,
Heterocycles in Life and Society, Wiley, New York,
1997; b) M. Shipman, Contemp. Org. Synth. 1995, 2, 1.
[8] a) M. L. Kantam, K. Aziz, P. R. Likhar, Cat. Lett. 2004,
117; b) J. S. Yadav, B. V. S. Reddy, S. Abraham, G.
Sabita, Synlett 2002, 1550; c) H. Kotsuki, K. Hayashida,
T. Shimanouchi, H. Nishizawa, J. Org. Chem. 1996, 61,
984.
[9] a) M. Bandini, M. Fagioli, A. Melloni, A. Umani-
Ronchi, Adv. Synth. Catal. 2004, 346, 573; b) M. Bandi-
ni, P. G. Cozzi, P. Melchiorre, A. Umani-Ronchi, J. Org.
Chem. 2002, 67, 5386.
[10] M. Bandini, P. G. Cozzi, P. Melchiorre, A. Umani-
Ronchi, Angew. Chem. 2004, 116, 86; Angew. Chem.
Int. Ed. 2004, 43, 84.
[11] R.-H. Fan, X.-L. Hou, J. Org. Chem. 2003, 68, 726.
[12] a) C. Bolm, M. Zehnder, D. Bur, Angew. Chem. 1990,
102, 205; Angew. Chem. Int. Ed. 1990, 29, 191; b) C.
Bolm, M. Ewald, M. Felder, G. Schlingloff, Chem. Ber.
1992, 125, 1169; c) S. Ishikawa, T. Hamada, K. Manabe,
S. Kobayashi, J. Am. Chem. Soc. 2004, 126, 12236.
Adv. Synth. Catal. 2006, 348, 2585 – 2589
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2589