Y. Wu et al. / Tetrahedron 57 02001) 3373±3381
3379
C18H20N6O4´1.35 CF3COOH´3/4H2O requires: C, 45.06; H,
4.17; N, 15.23%]; nmax *KBr): 1755, 1679 cm21 *CvO); dH
*300 MHz, d6-DMSO) 10.80 *1H, s, A±NH), 9.45 *1H, s,
NH), 8.66 *1H, s, A±CH*8)), 7.49±7.31 *5H, m, Ph), 5.23
*2H, s, CH2Ph), 4.61 *2H, t, J5.7 Hz, ACH2), 4.10 *2H, s,
NCH2CO), 3.64 *3H, s, OCH3), 3.57 *2H, t, J5.7 Hz,
ACH2CH2); ESI-MS m/z: 385 *100, MH1), 91 *37), 770
*8, 2MH1).
m, CH2CH2N and ±OCH3), 2.90 *3H, 3£s, NCH3), 1.93
*3H, s, T±CH3), 1.45 *9H, s, Boc); FAB-MS m/z: 539 *19,
MNa1), 517 *20, MH1), 417 *32), 339 *35), 176 *42), 105
*100).
3.3.2. N-[,N-tert-Butoxycarbonyl-N-methyl)glycyl]-N-[2-
,thymin-1-yl)ethyl]glycine ,4a). To a solution of the
methyl ester 23a *2.27 g, 4.4 mmol) in acetone *8 mL)
was added NaOH *0.2 M; 8 mL). The solution was left over-
night in a refrigerator, then was evaporated to dryness. The
residue was taken up in water *20 mL) and acidi®ed to pH 2
with 10% KHSO4. The acid was extracted with ethyl acetate
*8£30 mL) and dried over Na2SO4. Evaporation to almost
dryness followed by addition of ether gave a solid, which
was collected by®ltration and washed several times with
ether. After puri®cation by¯ash column chromatography
eluting with 10:2.5:1.5 ethyl acetate/methanol/water, 4a
was obtained as a white foam *1.418 g, 81%): [Found: C,
49.81; H, 6.48; N, 13.71. C17H26N4O7´1/2H2O requires: C,
50.12; H, 6.68; N, 13.75%]; Rf 0.35 *2:1 ethyl acetate/
methanol); nmax *KBr): 1750, 1698 cm21 *CvO); dH
*400 MHz, d-DMSO) 12.78 *1H, s, COOH), 11.32, 11.14
and 11.10 *1H, 3£s, T±NH), 7.57 and 7.39 *1H, 2£s, T±
CH*6)), 4.15, 4.14 and 3.98 *2H, 3£s, CH2COOH), 4.04,
3.89 and 3.87 *2H, 3£s, NCH2CO), 3.80 and 3.73 *2H, 2£m,
TCH2CH2), 3.51 *2H, m, TCH2CH2), 2.73, 2.71, 2.65 and
2.61 *3H, 4£s, NCH3), 1.74 and 1.71 *3H, 2£s, T±CH3),
1.38, 1.32 and 1.30 *9H, 3£s, Boc); FAB-MS m/z: 421 *7,
MNa1), 399 *28, MH1).
3.2.3. N-[2,2-Amino-acetyl-guanine-9-yl)ethyl]glycine
methyl ester ,22). The product 22 was obtained as a
white solid [Found:
C 38.11; H, 3.99; N, 18.14.
C12H16N6O4´1.35 CF3COOH requires: C 38.21; H 3.78; N
18.19%]; nmax *KBr); 1755,1678 and 1614 cm21 *CvO);
dH *300 MHz, d6-DMSO) 11.73 *1H, s, G±NH), 7.99 *1H,
s, G±CH*8)), 4.15 *2H, t, J5.7Hz, GCH2), 3.64 *2H, s,
NCH2CO), 3.46 *3H, s, OCH31H2O), 2.99 *2H, t,
J5.7 Hz, GCH2CH2), 2.19 *3H, s, Ac±CH3); ESI-MS
m/z: 309 *100, MH1), 331 *20, MNa1), 617 *25, 2MH1),
639 *21, 2MNa1).
3.2.4. N-[2-,Thymin-1-yl)ethyl]glycine methyl ester
,11b). The protected peptoid 10 *2.5 mmol) was treated
with 10% HBr in acetic acid *20 mL) at room temperature
for 1 h. The mixture was evaporated under reduced pres-
sure; the residue was triturated with ether washed with
methanol±ether. Recrystallization from ethanol±water
gave a white solid [Found: C 48.94; H, 6.24; N, 16.85.
C10H15N3O4´1/4 H2O requires: C 48.87; H 6.36; N
17.10%]; nmax *KBr); 1689 cm21 *CvO); dH *300 MHz,
d6-DMSO) 11.37 *1H, s, T±NH), 9.21 *1H, m, NH), 7.49
*1H, s, T±CH*6)), 4.03 *2H, s, NCH2CO), 3.96 *2H, t,
J5 Hz, CH2CH2N), 3.75 *3H, s, OCH3), 3.24 *2H, t,
J5 Hz, CH2CH2N), 1.76 *3H, s, T±CH3); EI-MS m/z:
242 *39, MH1), 153 *45), 102 *100); HRMS m/z: Calcd
for C10H15N3O4: 241.24692; Found: 241.106.
3.3.3. N-[,N-tert-Butoxycarbonyl-N-methyl)glycyl]-N-[2-
,N6-benzyloxycarbonyladenin-9-yl)ethyl]glycine methyl
ester ,24a). To a solution of 21 *1.63 g, 4.25 mmol),
N-Boc±sarcosine *0.803 g, 4.25 mmol) and HBTU *2.15 g,
4.67 mmol) in anhydrous DMF *10 mL) and anhydrous
DCM *10 mL) at 08C was added DIPEA *2.2 mL,
12.75 mmol) dropwise. The solution was allowed to warm
slowlyto room temperature and was stirred overnight.
Subsequently, water *40 mL) was added to the reaction
mixture and the resulting aqueous solution extracted with
ethyl acetate *6£50 mL). The combined organic extracts
were washed with 1 M citric acid *2£60 mL), NaHCO3
*2£60 mL) and brine *60 mL), respectively, dried over
Na2SO4 and concentrated in vacuo. Filtration followed by
evaporation afforded a crude product. After puri®cation
using ¯ash chromatographywith 96:4 ethly acetate/
methanol as the eluting solvent, a white solid was obtained
*1.535 g 65%); [Found: C, 55.30, H, 6.01; N, 17.81.
C25H33N7O7 requires: C, 55.24; H, 6.12; N, 18.00%]; Rf
0.25 *25:1 ethyl acetate/methanol); nmax *KBr): 1749,
1693 cm21 *CvO); dH *300 MHz, CDCl3) 8.78 and 8.76
*1H, 2£s, A±CH*2)), 8.12 *1H, brm, A±CH*8)), 7.43±
7.36 *5H, m, Ph), 5.31 *2H, s, CH2Ph), 4.48 *2H, m,
ACH2), 3.92±3.74 *6H, m, NCH2CO, NCH2CO and
ACH2CH2), 3.74 and 3.72 *3H, 2£s, OCH3), 2.87 and 2.83
*3H, 2£s, NCH3), 1.45 and 1.43 *9H, 2£s, Boc); ESI-MS
m/z: 556.7 *100, MH1), 578.5 *14, MNa1), 1111.7 *16,
2MH1), 1133.7 *10, 2MNa1).
3.3. Solution phase synthesis of N-Boc protected
dipeptoids 4a, 6a and 7a
3.3.1. N-[,N-tert-Butoxycarbonyl-N-methyl)glycyl]-N-[2-
,N3-benzoylthymin-1-yl)ethyl]glycine methyl ester ,23a).
To a solution of 11a *1.73 g, 5 mmol) in anhydrous DMF
*25 mL) was added a solution of N-Boc±sarcosine *0.945 g,
5 mmol), BOP *2.43 g, 5.5 mmol) and DIPEA *1.7 mL,
10 mmol) in anhydrous DMF *10 mL). After stirring at
room temperature overnight, the reaction was concentrated
in vacuo and the residue was partitioned between ethyl
acetate *60 mL) and brine *60 mL), and the aqueous phase
was extracted with ethyl acetate *4£60 mL). The combined
organic extracts were washed with 1 M citric acid
*2£30 mL), NaHCO3 *2£30 mL) and brine *2£30 mL),
respectively, dried over Na2SO4 and concentrated in
vacuo. The resulting solid was puri®ed by¯ash column
chromatographyeluting with 1:4 hexane/ethyl acetate to
give 23a *1.625 g, 63%) as a brittle white foam: Rf 0.2
*1:4 hexane/ethyl acetate); [Found: C, 57.61; H, 6.40; N,
10.45. C25H32N4O8´1/4H2O requires: C, 57.63; H, 6.29; N,
10.75%]; nmax *KBr): 1749, 1699 and 1656 cm21 *CvO);
dH *300 MHz, CDCl3) 7.89±8.02 *2H, d, d, J30.0, 7.3 Hz,
benzoyl o-CH), 7.63 *1H, t, J7.3 Hz, benzoyl p-CH), 7.48
*t, 2H, benzoyl m-CH), 7.33±7.35 *m, 1H, T±CH*6)), 3.89±
4.08 *brm, 4H, CH2CH2N and NCH2CO), 3.66±3.76 *5H,
3.3.4. N-[,N-tert-Butoxycarbonyl-N-methyl)glycyl]-N-[2-
,6a).
,N6-benzyloxycarbonyladenin-9-yl)ethyl]glycine
A 1.0 M solution of sodium hydroxide *5 mmol) was
added to a stirred solution of 24a *1.11 g, 2 mmol) in THF