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LETTERS
SYNLETT
metathesis. The primary disadvantage of the metathesis reaction is the
intolerance of available catalysts to substrates containing nitrogen.
More generally, RACS offers an opportunity for application of libraries
of all kinds generated in solution. To date, the majority of synthetic
effort in combinatorial chemistry has focused on solid phase
20
21,22
23
synthesis, tagging methods,
and subtraction methods. Much
work remains to be done, however, to exploit the potential of RACS for
exploiting libraries with the high effective sizes needed to permit
combinatorial chemistry to become a "lead discovery" technology rather
than a "lead enhancement" technology.
Experimental part
Metathesis. Reagents were degassed by freezing and thawing under
vacuum. In a typical metathesis reaction, a solution of alkene (1.5
mmol) in CH Cl (2 mL) was degassed and added to 1 (25 mg, catalyst
2
2
mw 822.97, ca. 2 mol%) by cannula transfer. The mixture was stirred at
45-50 °C under Ar for 6 h. The mixture was filtered (silica gel, 2 g) to
remove catalyst. An aliquot (0.2 mL) was then removed, dissolved in
+
CH Cl (1 mL) and resolved by GC-MS (Finnigan GCQ, EI -mode,
2
2
10°C/min, 50-250°C). For product analysis, biphenyl was used as an
internal standard. This in turn permitted the use of the external standards
for 2, 3, and 6 to determine the amount of each of these in the product
mixture. As crude metathesis product mixtures were examined, and no
significant amounts of side products were observed, 5 could be
calculated as the difference between the amount of 2 added initially and
the amount of 2 plus 6 (taken twice) in the product mixture. Amounts
for 4 were obtained by difference given amounts of starting material, 3,
and 5. Except where noted by * in Table 1, peaks for 4 were seen by GC-
MS, and displayed response factors between 0.5 and 2. To prepare
libraries,
a solution of alkenes (0.38 mmol each, 17 alkenes
incorporated, for a total of 6.46 mM alkene) in CH Cl (5 mL) was
2
2
degassed and then added to 1 (100 mg, 2 mol %). After 6 h at 45-50°C,
the mixture was analyzed by GC-MS as above.
17
Sharpless dihydroxylation. The reagent was prepared by dissolving
K Fe(CN) (1.25 g), K CO (0.5 g), (DHQD) PHAL (6 mg),
3
6
2
3
2
(DHQ) PHAL (6 mg) and K OsO (OH) (2 mg) in H O (6 mL) and
2
2
2
4
2
t
BuOH (6 mL) at RT. The crude alkene library (1 mL, ca. 1.25 mmol
alkene) and methanesulfonamide (119 mg) were added. The mixture
was stirred (12 h, RT) and treated with sodium sulfite (1.6 g). The diols
were extracted (EtOAc, 3x30 mL) and dried (Na SO ), the solvent
2
4
evaporated, the mixture analyzed by GC-MS as above.
(9) Kelly, M. A.; Liang, H.; Sytwu, I.; Vlattas, I.; Lyons, N. L.;
Bowen, B. R.; Wennogle, L. P. Biochemistry 1996, 35, 11747-
11755.
References and Notes
(1) Nawrocki, J. P.; Wigger, M.; Watson, C. H.; Hayes, T. W.; Senko,
M. W.; Benner, S. A.; Eyler, J. R. Rapid Comm. Mass Spect. 1996,
10, 1860-1864.
(10) Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769-774.
(11) Van Duin, M.; Kiebom, A. P. G.; Van Bekkum, H. Tetrahedron
1985, 41, 3411-3421.
(2) Huc, I.; Lehn, J. M. Proc. Nat. Acad. Sci. 1997, 94, 2106-2110.
(3) Wigger, M., Nawrocki, J. P.; Watson, C. H.; Eyler, J. R.;Benner, S.
(12) Henderson, W. G.; How, M. J.; Kennedy, G. R.; Mooney, E. F.
A.; Rapid Comm. Mass Spect. 1997, submitted.
Carbohydrate Res. 1973, 28, 1-12.
(4) Jencks, W. P. Adv. Enzymol. 1975, 43, 219-410.
(13) Boger, D. L.; Chai, W. Y.; Ozer, R. S.; Andersson, C. M. Bioorg.
Med. 1997, 7, 463-468.
(5) Moradian. A.; Benner, S. A. J. Am. Chem. Soc. 1992, 114, 6980-
6987.
(14) Crowe, W. E.; Golberg, D. R. J. Am. Chem. Soc. 1995, 117, 5152-
5163.
(6) Everse, J.; Kaplan, N. O. Adv. Enzymol. 1973, 37, 61-134.
(15) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
(7) Nambiar, K. P.; Stauffer, D. M.; Kolodziej, P. A.; Benner, S. A. J.
Am. Chem. Soc. 1983, 105, 5886-5890.
446-452.
(8) Winger, B. E.; Campana, J. E. Rapid Comm. Mass Spect. 1996,
10, 1811-1813.
(16) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 9606-9614.