5032 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15
Augeri et al.
1H), 3.68 (m, 1H), 4.38 (s, 1H), 5.05 (dd, J ) 11, 2.6, 1H); HPLC
(YMC S-5 C18 4.6 × 50 mm, 0-100% B, MeOH/H2O/H3PO4)
tR )2.48min;MS(FAB)m/z262[M+H]+.Anal.(C15H23N3O‚CF3-
CO2H‚0.4H2O) C, H, N.
13C NMR (125 MHz, MeOH-d4) 14.5, 19.5, 25.6, 25.7, 30.9, 31.9,
33.6, 39.6, 47.5, 51.2, 58.7, 68.2, 120.8, 168.5; MS m/z 264
[M + H]+. Anal. (C14H21N3O2‚1.20CF3CO2H) C, H, N.
General Method E. (S)-2-[1-(Hydroxymethyl)cyclobut-
1-yl]glycine-L-cis-4,5-methanoprolinenitrile TFA Salt
(16c). N-Boc-protected vinylcyclobutyl compound 15c (0.16 g,
0.46 mmol) was dissolved in 10 mL of a 1:1 mixture of
THF:H2O and treated with OsO4 (12 mg, 0.05 mmol) and
NaIO4 (0.59 g, 2.76 mmol, 6 equiv). After 2 h, the reaction
mixture was diluted with 50 mL of Et2O and 10 mL of water.
The layers were separated, and the organic layer was washed
with NaHCO3, dried (MgSO4), and concentrated to give a dark
oil. The oil was diluted with 10 mL of MeOH, and NaBH4
(0.08 g, 2.0 mmol) was added at 25 °C. After 30 min, the
mixture was diluted with Et2O and the reaction was quenched
with saturated NaHCO3. The layers were separated, and the
organic fraction was washed with 0.1 M HCl, saturated
NaHCO3, dried (MgSO4), and concentrated to give 90 mg of
the Boc-protected hydroxymethyl compound as a dark oil. The
crude intermediate (90 mg, 0.26 mmol) was dissolved in 3 mL
of CH2Cl2, cooled to 0 °C, and treated with 3 mL of freshly
distilled TFA. The deprotection was complete after 80 min and
the mixture was evaporated to dryness and then purified by
preparative HPLC (YMC S5 ODS 30 × 100 mm, 10 min
gradient 100% A to 100% B; solvent A ) 10% MeOH-
90%H2O-0.1% TFA; solvent B ) 90% MeOH-10% H2O-0.1%
TFA, to give, after lyophilization, 50 mg (60%) of title
compound 16c: 1H NMR (500 MHz, MeOH-d4) 0.95 (m, 1H),
1.06 (q, J ) 7.6, 1H), 1.30 (m, 2H), 1.54 (m, 1H), 1.75 (m, 1H),
1.90 (m, 1H), 2.00 (m, 3H), 2.20 (m, 1H), 2.35 (dd, J ) 13.8,
2.2, 1H), 2.50 (m, 1H), 2.63 (m, 1H), 3.85 (s+m, 3H), 4.63
(s, 1H), 5.22 (dd, J ) 10.7, 2.2, 1H); MS m/z 250 [M + H]+.
Anal. (C13H19N3O2‚CF3CO2H‚0.5H2O): C, H, N.
(S)-2-[1-(Hydroxymethyl)cyclohex-1-yl]glycine-L-cis-
4,5-methanoprolinenitrile TFA Salt (16e). This compound
was prepared using general method D: 1H NMR (500 MHz,
MeOH-d4) 0.92 (m, 1H), 1.10 (m, 1H), 1.26 (m, 1H), 1.35-1.76
(m, 10H), 1.95 (m, 1H), 2.01 (m, 1H), 2.36 (dd, J ) 13.8, 2.2,
1H), 2.64 (m, 1H), 3.78 (d, J ) 11.6, 1H), 3.90 (m, 1H), 4.48
(s, 1H), 5.22 (dd, J ) 11, 2.2, 1H); 13C NMR (125 MHz,
MeOH-d4) 14.2, 19.2, 22.1, 22.2, 26.6, 28.6, 31.1, 31.4, 39.3,
41.8, 47.1, 59.7, 64.7, 120.4, 167.9. Anal. (C15H23N3O2‚
CF3CO2H‚0.4H2O) C, H, N.
(2S)-2-[1-(1,2-Dihydroxyethyl)cyclopent-1-yl]glycine-
L-cis-4,5-methanoprolinenitrile (18d). Vinyl nitrile 15d
(70 mg, 0.19 mmol) was dissolved in 5 mL of a 3:2 mixture of
THF/t-BuOH, and N-methylmorpholine N-oxide (33 mg,
0.28 mmol) was added, followed by OsO4 (0.01 mmol, 2.5 wt
%/v in t-BuOH), and the reaction was stirred at room temper-
ature for 16 h. The reaction was then quenched with 1 mL of
10% Na2SO3, and the mixture was taken up in EtOAc (10 mL),
washed with brine, dried (Na2SO4), filtered, evaporated, and
purified by flash chromatography to give 41 mg of the desired
Boc-protected diol as a mixture of diastereomers, which was
immediately deprotected with TFA/CH2Cl2 using general
method A. Lyophilization of the product from water gave
27 mg (47%) of the desired diol 18d as a diastereomeric
mixture that was a white solid: 1H NMR (500 MHz,
DMSO-d6) 1.08 (m, 1H), 0.76 (m, 1H), 1.38-2.05 (m, 9H), 2.13
(dd, J ) 13.6, 1.6, 1H), 2.28 (d, J ) 3.1, 1H), 2.33 (m, 1H),
3.13 (m, 1H), 3.44 (m, 1H), 3.51-3.70 (m, 3H), 3.87 (m, 1H),
4.36 (dd, J ) 11.0, 8.8, 1H), 4.57 (m, 1H), 4.84 (s, 1H), 5.24
(dd, J ) 11.0, 2.7, 1H), 8.00 (br s, 2H); HRMS calcd for
C15H23N3O3 [M + H]+ 294.1818, found 294.1830.
(S)-2-(1,1-Dimethylprop-1-yl)glycine-L-cis-4,5-metha-
1
noprolinenitrile TFA salt (10a): H NMR (500 MHz, D2O)
0.69 (t, J ) 7.5, 3H), 0.82 (t, J ) 7.5, 3H), 0.88 (m, 1H), 1.07
(m, 1H), 1.20 (m, 1H), 1.44-1.64 (m, 2H), 1.70-1.82 (m, 2H),
1.88-1.96 (m, 2H), 2.29 (dd, J ) 13.8, 2.6, 1H), 2.56 (m, 1H),
3.76 (m, 1H), 4.37 (s, 1H), 5.08 (dd, J ) 10.5, 2.6, 1H), 5.13
(d, J ) 17.5, 1H), 5.33 (d, J ) 11, 1H), 5.66 (dd, J ) 17.5, 11,
1H); HPLC (YMC S-5 C18 4.6 × 50 mm, 0-100% B, MeOH/
H2O/H3PO4) tR ) 2.54 min; MS (FAB) m/z 262 [M + H]+. Anal.
(C13H21N3O·CF3CO2H·0.1H2O) C, H, N.
(S)-2-(1,1-Diethylprop-1-yl)glycine-L-cis-4,5-methano-
prolinenitrile TFA salt (10b): 1H NMR (500 MHz, D2O) 0.72
(t, J ) 7.5, 9H), 0.80 (m, 1H), 1.01 (m, 1H), 1.22-1.32 (m, 3H),
1.41-1.52 (m, 3H), 1.87 (m, 1H), 2.24 (dd, J ) 13.8, 2.6, 1H),
2.50 (m, 1H), 3.68 (m, 1H), 4.21 (s, 1H), 5.07 (dd, J ) 11, 2.6,
1H); HPLC (YMC S-5 C18 4.6 × 50 mm, 0-100% B, MeOH/
H2O/H3PO4) tR ) 2.60 min; MS (FAB) m/z 264 [M + H]+. Anal.
(C15H25N3O‚CF3CO2H‚0.1H2O) C, H, N.
(S)-2-(4-Ethyltetrahydropyran-4-yl)glycine-L-cis-4,5-
methanoprolinenitrile TFA salt (10g): 1H NMR (500 MHz,
D2O) 0.84 (t, J ) 7.5, 3H), 0.87 (m, 1H), 1.06 (m, 1H), 1.33
(dd, J ) 13.6, 2.2, 1H), 1.40-1.55 (m, 2H), 1.68 (dd, J ) 13.8,
2.2, 1H), 1.80-2.00 (m, 3H), 2.30 (dd, J ) 14, 2.6, 1H), 2.57
(m, 1H), 3.53-3.79 (m, 5H), 4.40 (s, 1H), 5.11 (dd, J ) 11, 2.6,
1H); HPLC (YMC S-5 C18 4.6 × 50 mm, 0-100% B, MeOH/
H2O/H3PO4) tR ) 1.60 min; MS (FAB) m/z 278 [M + H]+. Anal.
(C15H23N3O2‚CF3CO2H‚0.3H2O) C, H, N.
General Method D. Oxidative Cleavage of Vinyl Sub-
stituent by Ozonolysis. Protected vinyl nitriles 15 were
treated with ozone and subjected to a reductive quench with
NaBH4 to furnish the hydroxymethyl analogues directly, which
were then subsequently deprotected using TFA in CH2Cl2 at
0 °C to give target compounds 16.
(S)-2-[1-(Hydroxymethyl)cyclopent-1-yl]glycine-L-cis-
4,5-methanoprolinenitrile TFA Salt (16d). Vinyl nitrile
15d, prepared from 7d using general method A (1.28 g,
3.60 mmol), was dissolved in 56 mL of a 2:5 mixture of
CH2Cl2/MeOH, cooled to -78 °C, and treated with a stream
of ozone until the reaction solution took on a blue color, at
which time NaBH4 (566 mg, 15.0 mmol, 4.2 equiv) was added
and the reaction warmed to 0 °C. After 30 min, the reaction
was quenched with 2 mL of saturated NaHCO3 and then
warmed to room temperature. The reaction mixture was
evaporated to dryness and taken up in EtOAc. A small amount
of water was added to dissolve the inorganics, and the layers
were separated. The EtOAc layer was dried (Na2SO4), filtered,
and evaporated to an oil that was purified by flash column
chromatography with EtOAc to give 922 mg (71%) of N-Boc
hydroxymethyl compound: MS m/z 364 [M + H]+; 1H NMR
(500 MHz, CDCl3) 1.08 (td, J ) 6.3, 2.1, 2H), 1.22 (m, 1H),
1.44 (s, 9H), 1.51-1.96 (m, 8H), 2.38 (dd, J ) 13.9, 2.3, 1H),
2.60 (m, 1H), 3.33 (d, J ) 12.1, 1H), 3.57 (d, J ) 12.1, 1H),
3.92 (m, 1H), 4.75 (d, J ) 9.1, 1H), 5.06 (dd, J ) 10.6, 2.3,
1H), 5.85 (d, J ) 8.8, 1H); 13C NMR (125 MHz, CDCl3) 13.5,
17.8, 24.7, 24.9, 28.4, 30.6, 31.1, 33.0, 38.0, 45.5, 51.6, 55.8,
67.1, 80.3, 119.1, 171.4.
The N-Boc hydroxymethyl compound (900 mg, 2.48 mmol)
was dissolved in 60 mL of CH2Cl2, cooled to 0 °C, and treated
with 20 mL of freshly distilled TFA. The deprotection was
complete after 80 min and the mixture was evaporated to
dryness and purified by preparative HPLC (YMC S5 ODS
30 × 100 mm, 18 min gradient 80% A:B to 100% B; solvent A
) 10% MeOH-90%H2O-0.1% TFA, solvent B ) 90% MeOH-
10% H2O-0.1% TFA, collected product from 5.1 to 6.5 min) to
give, after lyophillization from water, 660 mg (71%) of the TFA
salt of 16d as a white lyophilate: 1H NMR (500 MHz,
MeOH-d4) 0.87 (m, 1H), 1.00 (m, 1H), 1.30 (m, 2H), 1.54 (m,
1H), 1.58-1.80 (m, 6H), 2.00 (m, 2H), 2.36 (dd, J ) 14.1, 2.6,
1H), 2.63 (m, 1H), 3.58 (d, J ) 11.0, 1H), 3.64 (d, J ) 11.0,
1H), 3.90 (m, 1H), 4.61 (s, 1H), 5.19 (dd, J ) 10.9, 2.6, 1H);
1-(S)-Adamantan-1-yl-(R)-(2-hydroxy-1-phenylethyl-
amino)acetonitrile (20). 1-Adamantanecarboxylic acid
(10.0 g, 0.0549 mol) was dissolved in Et2O (160 mL) and MeOH
(40 mL), and trimethylsilyldiazomethane (2.0 M in hexane,
30 mL, 0.06 mol, 1.1 equiv) was added. After 3 h at room
temperature, the reaction mixture was concentrated and
purified by flash chromatography (5 × 15 cm silica column,
eluted with 40% CH2Cl2/hexanes) to give the desired ester 19
as a white crystalline solid (10.7 g, 0.055 mol, quantitative):