A. Y. Shaw et al. / Tetrahedron Letters 53 (2012) 1313–1315
1315
O
O
O
N
O
N
N
N
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
OH
OH
OH
OH
MeO
HN
Br
3a (84%, 35%)a
3b (67%, 38%)
3c (63%, 41%)
3d (70%, 27%)
CH3
O
O
O
O
CH3
N
CH3
N
CH3
N
CH3 N
N
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
OH
OH
OH
OH
3e (76%, 23%)a
3f (56%, 23%)
3h (63%, 25%)
3g (66%, 26%)
CH3
Ph
Ph
Ph
Ph
O
O
O
O
N
N
N
N
HN
N
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
OH
OH
OH
OH
3i (70%, 38%)a
3j (41%, 38%)
3k (47%, 21%)
3l (61%, 29%)
Figure 2. Example analogs (x% = Passerini yield, x% = yield from 8 to 3).
reduced pressure, the residue was dissolved in EtOAc (20 mL), washed with
HCl (0.1 M, 3 Â 20 mL), satd NaHCO3 (3 Â 20 mL), and brine (30 mL). The
organic phase was collected, dried (MgSO4) and the solvent removed under
reduced pressure. The crude product was used in the following step without
further purification. The Weinreb amide (170 mg, 0.72 mmol, 1.0 equiv) was
large libraries of diverse analogs is now possible. Being amenable
to high-throughput synthesis, it is expected that this methodology
will be embraced by the lead generation community.
dissolved in dry THF (5 mL) and LiAlH4 (1.0 M in THF, 870 lL, 0.87 mmol,
Acknowledgments
1.2 equiv) was added dropwise at 0 °C over 20 min. The reaction was allowed
to warm to room temperature and stirred for 5 h. After completion, EtOAc
(20 mL) was added, followed by HCl (0.1 M, 20 mL). The resulting mixture was
extracted with EtOAc (20 mL Â 3), the organic layers collected, washed with
brine (50 mL), dried (MgSO4) and concentrated under reduced pressure.
Purification by column chromatography (ISCO™ purification system, EtOAc–
hexane, 30%) afforded the final product 6b as colorless oil (76 mg, 0.43 mmol,
61% over two steps).
We would like to thank the Office of the Director, NIH, and the
National Institute of Mental Health for funding (1RC2MH090878-
01). Particular thanks to N. Schechter PSM for copy editing.
References and notes
14. General procedure for the preparation of 3c: A mixture of (S)-tert-butyl (3-
methyl-1-oxobutan-2-yl)carbamate (0.403 g, 2.0 mmol, 1.0 equiv), butyric acid
(0.176 g, 2.0 mmol, 1.0 equiv) and tert-butyl (2-isocyanophenyl)carbamate 5
(0.437, 2.0 mmol, 1.0 equiv) in DCM (2 mL, 1.0 M) was stirred at rt overnight.
After removal of the solvent under reduced pressure, the residue was purified
by silica-gel column chromatography (EtOAc–hexane, 0–30%) using an ISCO™
purification system to afford (3S)-3-((tert-butoxycarbonyl)amino)-1-((2-((tert-
butoxycarbonyl)amino)phenyl)amino)-4-methyl-1-oxopentan-2-yl butyrate
(0.640 g, 1.260 mmol, 63% yield). Compound 8c (0.609 g, 1.2 mmol) in 10%
TFA/DCM (5 mL) was stirred at room temperature for 48 h. The reaction was
diluted in DCM (10 mL), washed with satd NaHCO3 (10 mL) and brine (10 mL).
The organic layers were collected, dried over MgSO4 and the solvent removed
under reduced pressure to give intermediate (3S)-3-amino-1-((2-
aminophenyl)amino)-4-methyl-1-oxopentan-2-yl butyrate 9c, which was
used in the following reaction without further purification. Compound 9c
was dissolved in TEA/MeOH (1:3, 10 mL) and the reaction stirred at rt for 3 h.
After completion, the mixture was diluted with ethyl acetate (30 mL) and
washed with HCl (0.1 M, 3 Â 10 mL). The organic layer was collected, dried
over MgSO4 and the solvent was evaporated under in vacuo to afford (3S)-N-
(2-aminophenyl)-3-butyramido-2-hydroxy-4-methylpentanamide 7c, which
was used in the following reaction without further purification. Compound
7c was dissolved in 10% TFA/DCE (3 mL), the resulting solution was placed in a
5 mL microwave tube and subjected to microwave irradiation in a Biotage
Initiator (10 min, 100 °C). The mixture was diluted in DCM (10 mL), washed
with satd NaHCO3 (10 mL) and the aqueous layer extracted with DCM
(3 Â 10 mL). The organic layers were collected, washed with further satd
NaHCO3 (10 mL), brine (20 mL), dried over MgSO4 and the solvent was
removed under reduced pressure to get the crude product 2c. The crude
product 3c were further purified by silica-gel column chromatography (EtOAc–
hexane, 0–80%) using a ISCO™ purification system to afford N-((2R)-1-(1H-
benzo[d]imidazol-2-yl)-1-hydroxy-3-methylbutan-2-yl)butyramide 3c (0.142
g, 0.492 mmol, 41% yield in three steps). LC–MS [M+1]+ 290.1; diastereomeric
ratio ꢀ1:1; 1H NMR (300 MHz, DMSO-d6, mixture of 2 diastereoisomers): d
0.58–0.71 (m, 3H), 0.84–0.88 (m, 2H), 0.90–0.93 (m, 3H), 1.05 (d, J = 6.0 Hz,
2H), 1.22–1.27 (m, 3H), 1.88–1.97 (m, 3H), 2.35 (m, 0.5 H), 2.51 (s, 0.5H), 3.98
(t, J = 9.0 Hz, 0.5H), 4.17 (t, J = 9.0 Hz, 0.5H), 4.97 (d, J = 9.0 Hz, 0.5 Hz), 5.35 (s,
0.5H), 7.33–7.35 (m, 2 H), 7.61–7.64 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) d
13.14, 13.28, 15.66, 18.92, 18.94, 19.38, 19.77, 27.68, 29.31, 29.66, 37.91, 38.02,
57.63, 58.79, 67.40, 113.91, 114.02, 115.19, 118.09, 125.22, 125.36, 131.95,
132.13, 155.28, 155.50, 163.03, 163.38, 175.24, 175.35 ppm.
1. (a) Dunn, B. M. In Structure and Function of the Aspartic Proteases: Genetics,
Structures and Mechanisms; Plenum Press: New York, 1991; Vol. 306, p 585.
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Biomedical Implications; Plenum Press: New York, 1995.
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p 669.
8. Nixey, T.; Hulme, C. Tetrahedron Lett. 2002, 43, 6833.
9. (a) Wells, J. I. In Pharmaceutical Preformulation; Ellis Horwood Ltd: London,
1998; p 25; (b) Clark, D. E. Drug Discov. Today 2003, 8, 927; (c) Upthagrove, A.
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Expert Opin. Drug Metab. Toxicol. 2006, 2, 139.
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4067; (b) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Mol. Div. 2003, 6, 227; (c) Faure,
S.; Hjelmgaard, T.; Roche, S. P.; Aitken, D. J. Org. Lett. 2009, 11, 1167; (d) Basso, A.;
Banfi, L.; Piaggio, P.; Riva, R.; Guanti, G. Tetrahedron Lett. 2003, 44, 2367.
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13. General procedure for the preparation of 6b: To a stirring solution of N-Boc-L-a-
alanine (200 mg, 1.05 mmol, 1.0 equiv) in DCM (5 mL), 1-ethyl-3
-[3-dimethylaminopropyl]carbodiimide hydrochloride (402 mg, 2.10 mmol,
2.0 equiv),
hydroxybenzotriazole
(170 mg,
1.26 mmol,
1.25 equiv),
4-dimethylaminopyridine (528
lL, 1.05 mmol, 1.0 equiv) and N,O-
dimethylhydroxylamine hydrochloride (123 mg, 1.26 mmol, 1.2 equiv) were
added and the reaction stirred for 18 h at rt. After removal of the solvent under