N-Glyoxyl Prolyl and Pipecolyl Amides and Thioesters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3555
solvent was purified on silica gel, eluting with 20% ethyl
acetate in hexane, to obtain 1.60 g of 3-(2-naphthyl)propan-
1-ol as a clear oil. H NMR (CDCl3, 300 MHz): δ 1.98 (m, 2H);
2.87 (t, 2H, J ) 7.38 Hz); 3.70 (t, 3H, J ) 6.42 Hz); 7.23-7.45
(m, 3H); 7.62 (m, 1H); 7.76 (m, 3H).
4.75 (m, 1H); 7.17-7.25 (m, 1H); 7.47-7.49 (m, 1H); 8.42-
8.44 (m, 2H).
1
3-(o-Ch lor op h en yl)-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-
d ioxop en tyl)-2-p yr r olid in e-ca r both ioa te (25). 1H NMR
(CDCl3, 300 MHz): δ 0.87 (t, 3H, J ) 7.42 Hz); 1.23 (s, 3H);
1.27 (s, 3H); 1.59-2.27 (m, 7H); 2.80 (t, 2H, J ) 7.53 Hz); 2.96
(t, 2H, J ) 7.1 Hz); 3.12-3.23 (m, 1H); 3.55 (t, 2H, J ) 5.13
Hz); 4.69-4.72 (m, 1H); 7.12-7.34 (m, 4H). MS: M+ ) 410.
3-(o-F lu or op h en yl)-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-
d ioxop en tyl)-2-p yr r olid in e-ca r both ioa te (26). 1H NMR
(CDCl3, 300 MHz): δ 0.87 (t, 3H, J ) 7.5 Hz); 1.223(s, 3H);
1.26 (s, 3H); 1.70-2.09 (m, 7H); 2.19-2.23 (m, 1H); 2.71 (t,
2H, J ) 7.4 Hz); 2.93 (t, 2H, J ) 7.12 Hz); 3.55 (t, 2H, J )
6.74 Hz); 4.70 (dd, 1H, J ) 8.54, 3.03 Hz); 6.99-7.07 (m, 2H);
7.14-7.19 (m, 1H); 7.20-7.26 (m, 1H).
3-(m -Ch lor op h en yl)-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-
d ioxop en tyl)-2-p yr r olid in e-ca r both ioa te (27). 1H NMR
(CDCl3, 300 MHz): δ 0.87 (t, 3H, J ) 7.4 Hz); 1.23 (s, 3H);
1.26 (s, 3H); 1.66-2.09 (m, 7H); 2.16-2.26 (m, 1H); 2.66 (t,
2H, J ) 7.45); 2.87-2.94 (m, 2H); 3.53-3.57 (m, 2H); 4.69 (dd,
1H, J ) 8.44, 2.97 Hz); 7.04 (d, 1H, J ) 7.00 Hz); 7.15-7.27
(m, 3H).
Gen er a l P r oced u r e for Syn th esis of Th iols fr om Alco-
h ols, Exem p lified by 3,3-Dip h en yl-1-p r op ylth iol. A solu-
tion of 3,3-diphenyl-1-propanol (35.1 g, 165 mmol) and carbon
tetrabromide (60.3 g, 182 mmol) in methylene chloride (500
mL) was cooled to 0 °C, and triphenylphosphine (47.7 g, 129
mmol) was added. The resulting mixture was stirred for 24 h
and then concentrated in vacuo. The crude material was
passed through a flash column, eluting with 10% methylene
chloride in hexane, to yield 39.9 g (88%) of 3,3-diphenyl-1-
bromopropane as a clear oil. 1H NMR (300 MHz, CDCl3): δ
2.03-2.55 (m, 4H); 4.13 (m, 1H); 7.17-7.28 (m, 10H).
A solution of 3,3-diphenyl-1-bromopropane (35.0 g, 127
mmol) in 95% ethanol (25 mL) was added to a refluxing
solution of thiourea (10.6 g, 140 mmol) in 125 mL of 95%
ethanol. After the resulting mixture was refluxed for 24 h, 76.3
mL of 10% (w/v) NaOH solution was added, and refluxing
continued for 2 h. After it was cooled to room temperature,
the reaction mixture was diluted with water and extracted
with 3 × 400 mL of ethyl acetate. The combined organic layers
were dried over MgSO4 and concentrated. The crude yellow
oil was purified on a silica gel column (5% ethyl acetate/
3-(m -F lu or op h en yl)-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-
d ioxop en tyl)-2-p yr r olid in e-ca r both ioa te (28). 1H NMR
(CDCl3, 300 MHz): δ 0.87 (t, 3H, J ) 7.5 Hz); 1.23(s, 3H); 1.26
(s, 3H); 1.73-2.09 (m, 7H); 2.19-2.23 (m, 1H); 2.68 (t, 2H, J
) 7.4 Hz); 2.91 (t, 2H, J ) 7.24 Hz); 3.55 (t, 2H, J ) 6.9 Hz);
4.70 (d, 1H, J ) 8.54 Hz); 6.85-6.95 (m, 3H); 7.22-7.27 (m,
1H).
1
hexane) to obtain 21.8 g (75%) of the thiol as an oil. H NMR
(300 MHz, CDCl3): δ 2.03-2.55 (m, 4H); 4.13 (m, 1H); 7.17-
7.28 (m, 10H).
Gen er a l P r oced u r e for Cou p lin g of Th iols w ith Ca r -
boxylic Acid s, Exem p lified for 3,3-Dip h en yl-1-p r op yl
(2S)-1-(3,3-Dim eth yl-1,2-d ioxop en tyl)-2-p yr r olid in e-ca r -
both ioa te (33). A solution of (2S)-1-(1,2-dioxo-3,3-dimethyl-
pentyl)-2-pyrrolidinecarboxylic acid (2.99 g, 12.4 mmol) and
dicyclohexylcarbodiimide (3.84 g, 18.6 mmol) in methylene
chloride (150 mL) was treated with 3,3-diphenyl-1-propylthiol
(3.40 g, 14.8 mmol) and dimethylamino pyridine (0.450 g, 3.72
mmol). After it was stirred at room temperature for 24 h, the
reaction mixture was filtered through Celite, concentrated,
redissolved in ether, filtered once more through Celite, and
concentrated in vacuo to a pale yellow oil. This was purified
on a flash column to obtain 4.19 g (75%) of the product, as a
pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ 0.86 (t, 3H, J )
6.6 Hz); 1.22 (s, 3H); 1.27 (s, 3H); 1.60-2.20 (m, 6H); 2.31 (q,
2H, J ) 7.4 Hz); 2.77-2.85 (m, 2H); 3.52 (t, 2H, J ) 7.3 Hz);
4.00 (t, 1H, J ) 7.7 Hz); 4.66 (dd, 1H, J ) 8.5, 2.8 Hz); 7.14-
7.29 (m, 10H). TLC: Rf ) 0.65 (25% EtOAc/hexane).
2-P h en eth yl (2S)-1-(3,3-Dim eth yl-1,2-d ioxop en tyl)-2-
3-(p-Ch lor op h en yl)-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-
d ioxop en tyl)-2-p yr r olid in e-ca r both ioa te (29). 1H NMR
(CDCl3, 300 MHz): δ 0.87 (t, 3H, J ) 7.50 Hz); 1.23 (s, 3H);
1.26 (s, 3H); 1.60-2.30 (m, 8H); 2.63-2.68 (m, 2H); 2.86-2.96
(m, 2H); 3.52-3.57 (m, 2H); 4.67-4.71 (m, 1H); 7.09 (d, 2H, J
) 8.3 Hz); 7.24 (d, 2H, J ) 9.1 Hz).
3-[4-(Tr iflu or om et h yl)p h en yl]p r op yl (2S)-1-(3,3-Di-
m eth yl-1,2-d ioxop en tyl)-2-p yr r olid in e-ca r both ioa te (30).
1H NMR (CDCl3, 300 MHz): δ 0.82-0.90 (m, 3H); 1.23 (s, 3H);
1.26 (s, 3H); 1.67-1.81 (m, 3H); 1.87-2.01 (m, 4H); 2.21-2.34
(m, 1H); 2.74 (t, 2H, J ) 7.4 Hz); 2.91 (t, 2H, J ) 6.01 Hz);
3.52-3.57 (m, 2H); 4.68-4.72 (m, 1H); 7.26 (d, 2H, J ) 10.31
Hz); 7.53 (d, 2H, J ) 7.96 Hz).
3-(p a r a -Met h oxyp h en yl)p r op yl (2S)-1-(3,3-Dim et h yl-
1,2-dioxopen tyl)-2-pyr r olidin e-car both ioate (31). 1H NMR
(CDCl3, 300 MHz): δ 0.9 (t, 3H, J ) 7.1 Hz); 1.26 (s, 3H); 1.29
(s, 3H); 1.65-2.25 (m, 8H); 2.65 (m, 2H); 2.89-2.96 (m, 2H);
3.55-3.73 (m, 2H); 3.80 (s, 3H); 4.70-4.81 (m, 1H); 6.83 (d,
2H, J ) 8.0 Hz); 7.09 (d, 2H, J ) 8.0 Hz).
3-(2-Na p h th yl)p r op yl (2S)-1-(3,3-Dim eth yl-1,2-d ioxo-
p en tyl)-2-p yr r olid in e-ca r both ioa te (32). 1H NMR (CDCl3,
300 MHz): δ 0.85-0.95 (t, 3H, J ) 7.1 Hz); 1.21 (s, 3H); 1.24
(s, 3H); 1.70-1.85 (m, 3H); 1.91-2.23 (m, 4H); 2.23-2.40 (m,
1H); 2.80 (t, 2H, J ) 7.4 Hz); 2.94 (t, 2H, J ) 6.03 Hz); 3.50-
3.61 (m, 2H); 4.71-4.74 (m, 1H); 7.30-7.39 (m, 1H); 7.40-
7.49 (m, 2H); 7.65 (s, 1H); 7.80-7.91 (m, 3H). Mass spectrum:
M+ ) 426.
4-P h en yl-1-bu tyl (2S)-1-(3,3-Dim eth yl-1,2-dioxop en tyl)-
2-p yr r olid in eca r b ot h ioa t e (34). 1H NMR (CDCl3, 300
MHz): δ 0.86 (t, 3H, J ) 7.5 Hz); 1.21 (s, 3H); 1.24 (s, 3H);
1.52-1.80 (m, 6H); 1.82-2.01 (m, 2H); 2.10-2.30 (m, 2H); 2.60
(t, 2H, J ) 7.2 Hz); 2.92 (m, 2H); 3.52 (t, 2H, J ) 6.3 Hz); 4.67
(m, 1H); 7.13-7.28 (m, 5H).
2-P h en eth yl (2S)-1-(3,3-Dim eth yl-1,2-d ioxop en tyl)-2-
p ip er id in eca r both ioa te (35). 1H NMR (CDCl3, 300 MHz):
δ 0.94 (t, 3H, J ) 7.5 Hz); 1.27 (s, 3H); 1.30 (s, 3H); 1.34-1.88
(m, 7H); 2.45 (m, 1H); 2.90 (t, 2H, J ) 7.7 Hz); 3.26 (t, 2H, J
) 7.7 Hz); 3.27 (m, 1H); 3.38 (m, 1H); 5.34 (m, 1H); 7.24-7.36
(m, 5H).
3-P h en yl-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-d ioxop en -
tyl)-2-p ip er id in eca r both ioa te (36). 1H NMR (CDCl3, 400
MHz): δ 0.91 (t, 3H, J ) 7.48 Hz); 1.24 (s, 3H); 1.28 (s, 3H);
1.43-1.92 (m, 10H); 2.69 (t, 2H, J ) 7.52 Hz); 2.93 (t, 2H, J )
6.84 Hz); 3.22 (m, 1H); 3.38 (m, 1H); 5.29 (m, 1H); 7.16-7.30
(m, 5H).
1
p yr r olid in eca r both ioa te (20). H NMR (CDCl3, 300 MHz):
δ 0.85 (t, 3H, J ) 7.5 Hz); 1.29 (s, 3H); 1.31 (s, 3H); 1.70-2.32
(m, 6H); 2.92 (t, 2H, J ) 7.4 Hz); 3.22 (t, 2H, J ) 7.4 Hz); 3.58
(m, 2H); 4.72 (m, 1H); 7.23-7.34 (m, 5H).
2-P h en eth yl (2S)-1-(3-Cyclop en tyl-1,2-d ioxop en tyl)-2-
1
p yr r olid in eca r both ioa te (21). H NMR (CDCl3, 300 MHz):
δ 1.57-1.61 (m, 6H); 1.75-2.03 (m, 6H); 2.10-2.30 (m, 2H);
2.82-2.88 (m, 2H); 3.08-3.15 (m, 2H); 3.58-3.74 (m, 3H);
4.80-4.82 (m, 1H); 7.19-7.28 (m, 5H).
3-P h en yl-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-d ioxop en -
1
tyl)-2-p yr r olid in eca r both ioa te (22). H NMR (CDCl3, 300
MHz): δ 0.86 (t, 3H, J ) 7.2 Hz); 1.22 (s, 3H); 1.25 (s, 3H);
1.55-1.80 (m, 4H); 1.87 (tt, 2H, J ) 6.9, 6.9 Hz); 2.05-2.28
(m, 2H); 2.65 (t, 2H, J ) 6.9 Hz); 2.90 (t, 2H, J ) 6.9 Hz); 3.50
(m, 2H); 4.68 (m, 1H); 7.13-7.29 (m, 5H).
3-P h en yl-1-p r op yl (2S)-1-(3-Cycloh exyl-1,2-d ioxop en -
1
tyl)-2-p yr r olid in eca r both ioa te (23). H NMR (CDCl3, 300
MHz): δ 1.10-1.35 (m, 6H); 1.50-2.30 (m, 10H); 2.60-2.70
(t, 2H, J ) 7.3 Hz); 2.82-2.94 (m, 2H); 3.08-3.15 (m, 1H);
3.63-3.73 (dd, 2H, J ) 12.8, 7.0 Hz); 4.71 (m, 1H); 7.13-7.28
(m, 5H).
3-(3-P yr id yl)-1-p r op yl (2S)-1-(3,3-Dim eth yl-1,2-d ioxo-
p en tyl)-2-p yr r olid in eca r bo-th ioa te (24). 1H NMR (CDCl3,
300 MHz): δ 0.78-0.88 (m, 3H); 1.15-1.25 (m, 6H); 1.70-
1.75 (m, 3H); 1.88-1.93 (m, 2H); 1.98-2.25 (m, 3H); 2.65-
2.70 (m, 2H); 2.89-2.92 (m, 2H); 3.51-3.67 (m, 2H); 4.66-