Scheme 2
Table 2. Aryl Glycidyl Ether Intermediates 7 and Selected
Members of Libraries 9 and 10
a (R,R)-1b, F9-tBuOH, (CH2Cl2), 4 °C (6 h), 25 °C (2 h). bKOH,
c
ether, 3 h. Aliphatic amines: Yb(OTf)3, CH2Cl2, (polystyrene
methyl isocyanate, 2 h), 25 °C. Anilines: Cu(OTf)2, ether, 25 °C.
d(S,S)-1b, F9-tBuOH, CH2Cl2, 4 °C (3 h), 25 °C (3 h).
of catalysis. To effect complete conversion to 7, the crude
reaction mixtures were treated with powdered KOH after
catalyst removal by filtration. The aryl glycidyl ether
derivatives 7a′-e′,h′-l′ were thus generated in nearly
quantitative yield and high ee (Table 2).
a ee’s were determined by HPLC analysis on Chiralcel AD, OB, OJ,
and OD columns. b Yields were determined gravimetrically. c Purity was
assayed by HPLC analysis.
The set of ten aryl glycidyl ether derivatives 7 was
subjected to ring opening with a set of five different amines
to provide a parallel library of 50 different enantioenriched
aryloxy propanolamines 9 (Scheme 2). This class of com-
pounds, of which propanolol8 is an especially significant
example, has found widespread application in medicine.9
Reaction of 7 with aliphatic amines 8a′′-d′′ was effected
in the presence of 10 mol % of Yb(OTf)3 at room temperature
in dichloromethane.10 After GC analysis indicated complete
consumption of 7, ytterbium salts were removed by filtration
of the solutions through pads of silica gel, and excess amine
was removed by evaporation (or, in the case of nonvolatile
amines 8b′′ and 8d′′ by sequestration with resin-bound
methyl isocyanate11). Aniline 8e′′ was added cleanly to
glycidyl ethers 7 in the presence of 10 mol % of Cu(OTf)2
with complete regioselectivity for terminal attack.12 Deter-
mination of the enantiomeric excess of three library members
(Table 2, compounds 9a′c′′, 9a′d′′, and 9a′e′′) confirmed that
ring opening occurred without compromising the enantiopu-
rity of the starting epoxides. Experiments with primary
amines and anilines under similar conditions led to isolation
of ring-opened products of lower purity (<90%) as a result
of competing double alkylation pathways.
The preparation of 1,3-diaryloxy-2-propanol library 10
(Scheme 2) was explored by treating five of the aryl glycidyl
ether derivatives (7a′,b′,d′,h′,i′) with a set of ten phenols in
the presence of the resin-bound Co(salen) catalyst (S,S)-1b.
As anticipated, the use of the S,S enantiomer of the catalysts
the antipode to the one used to generate the starting aryl
glycidyl ether derivatives from epibromohydrinsled to a
further refinement of the optical purity of the bisphenol
adducts 10. Upon completion of the reaction, the catalyst
was removed by filtration and excess phenol separated by
solid-supported liquid extraction13 to provide products in
chemical purities exceeding 90%. As with libraries 4 and 9,
the identity of all compounds was verified by mass spec-
trometric analysis. Five representatives of the 50-member
library 10 were assayed for enantiopurity, and in all cases
(8) Crowther, A. F.; Smith, L. H. J. Med. Chem. 1968, 11, 1009.
(9) (a) Wright, J. L.; Gregory, T. J.; Heffner, T. G.; MacKenzie, R. G.;
Pugsley, T. A.; Meulen, S. V.; Wise, L. D. Bioorg. Med. Chem. Lett. 1997,
7, 1377. (b) Walsh, D. A. Chen, Y.-H.; Green, J. B.; Nolan, J. C.; Yanni,
J. M. J. Med. Chem. 1990, 33, 1823. (c) Baker, N. R.; Byrne, N. G.;
Economides, A. P.; Javed, T. Chem. Pharm. Bull. 1995, 43, 1045.
(10) Chini, M.; Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M.
Tetrahedron Lett. 1994, 35, 433.
(11) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882.
(12) Sekar, G.; Singh, V. K. J. Org. Chem. 1999, 64, 287.
(13) Johnson, C. R.; Zhang, P.; Fantauzi, M.; Hecker, M.; Yagar K. M.
Tetrahedron 1998, 54, 4097.
Org. Lett., Vol. 1, No. 8, 1999
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