2502
G. P. Aguado et al. / Tetrahedron: Asymmetry 17 (2006) 2499–2503
The solvation by chloroform has been taken into account
through the Generalized Born/Surface Area (GB/SA)
method.16
absorption, 2H), 6.14 (s, 1H), 7.23 (br s, 1H), 9.91 (br
s, 1H). 13C NMR (62.5 MHz, acetone-d6) d for the major
rotamer, 11.35, 16.30, 22.93, 26.84, 27.68, 29.20, 29.92,
39.21, 41.58, 42.68, 47.07, 48.09, 51.41, 53.37, 59.60,
78.37, 108.75, 141.78, 150.99, 155.93, 164.03, 167.40,
171.21, 206.11. HRMS (EI, 70 eV), calcd for C27H42N4O8
[M]: 550.3004; experimental 550.3003. Calcd for C22H34-
N4O6 [MꢀC5H8O2]: 450.2478; experimental 450.2478.
3.2. Methyl (10R,2R,30S)-2-benzyloxycarbonylamino-4-
(30-acetyl-20,20-dimethylcyclobutyl)butanoate, 2
A mixture of substrate 1 (600 mg, 1.6 mmol), prepared
according to Ref. 7, and [(COD)Rh(R,R)-Et-DuPHOS]-
OTf, (R,R)-Et-DuPHOS, (38.4 mg) in EtOH was stirred
under a hydrogen atmosphere at 2 atm pressure for 4 days.
The solvent was removed and the residue was chromato-
graphed (1:1 CH2Cl2–EtOAc as eluent) to afford saturated
2 (548 mg, 91% yield) in >99.9 de as an oil. [a]D = +20.2 (c
1.4, MeOH). IR (film) 3333 (br), 1699 (br) cmꢀ1. 1H NMR
(500 MHz, acetone-d6) d 0.80 (s, 3H), 1.28 (s, 3H), 1.31–
2.21 (complex absorption, 7H), 1.97 (s, 3H), 2.87 (dd,
J = 7.7 Hz, J0 = 9.8 Hz, 1H), 3.67 (s, 3H), 4.19 (m, 1H),
5.03–5.09 (complex absorption, 2H), 6.71 (d, J = 7.7 Hz,
1H), 7.27–7.36 (complex absorption, 5H). 13C NMR
(125 MHz, acetone-d6) d 17.14, 23.75, 26.88, 30.09, 30.69,
30.56, 42.26, 43.51, 52.19, 54.20, 55.03, 66.69, 128.56,
128.60, 129.16, 138.11, 156.99, 173.50, 206.48. Anal. Calcd
for C21H29NO5: C, 67.18: H, 7.79; N, 3.73. Found; C,
66.78; H, 7.78; N, 3.65.
3.4. (10R,2R,30S)-2-[200-tert-Butoxycarbonylamino-100-
[(thymin-1-yl)acetyl]aminoethyl]-4-(30-acetyl-20,20-di-
methylcyclobutyl)butanoic acid, 5
Ester 4 (140 mg, 0.25 mmol) was added to a solution of
K2CO3 (174 mg, 1.3 mmol) in 3:1 MeOH–H2O (2.4 mL)
and the resulting mixture was stirred at room temperature
for 12 h. Methanol was evaporated and the aqueous layer
was washed with ether and, subsequently, 5% HCl was
added to reach a pH of 2. The acid aqueous phase was
extracted with ether (5 · 5 mL). The combined organic
extracts were dried over MgSO4 and the solvent was
removed at reduced pressure to afford acid 5 as a solid that
was purified by crystallization (33 mg, 24% yield). Crystals,
mp 115–121 ꢁC (from ether–pentane). [a]D = +14.5 (c 1.1,
MeOH). IR (film) 3500–2900 (br), 2952 (br), 1672 (br)
cmꢀ1. 1H NMR (250 MHz, acetone-d6) d for the major rot-
amer, 0.80 (s, 3H), 1.28 (s, 3H), 1.22–2.10 (complex absorp-
tion, 7H), 1.41 (s, 9H), 1.80 (s, 3H), 1.97 (s, 3H), 2.72–3.80
(complex absorption, 5H), 4.26–4.41 (m, 1H), 4.59–4.82
(complex absorption, 2H), 6.20 (s, 1H), 7.27 (br s, 1H),
10.02 (br s, 1H). 13C NMR (62.5 MHz, methanol-d4) d
for the major rotamer, 12.20, 17.35, 24.83, 28.20, 28.75,
30.23, 30.89, 40.26, 43.03, 44.48, 48.67, 49.84, 55.04,
62.26, 80.58, 110.84, 143.74, 152.91, 158.34, 166.98,
169.59, 174.22, 210.95. FAB+MS: 559.29 (M+Na+).
3.3. Methyl (10R,2R,30S)-2-[200-tert-butoxycarbonylamino-
100-[(thymin-1-yl)acetyl]aminoethyl]-4-(30-acetyl-20,20-di-
methylcyclobutyl)butanoate, 4 through compound 3
A mixture containing compound 2 (366 mg, 0,89 mmol),
N-Boc-2-aminoacetaldehyde (214 mg, 1.3 mmol) and 10%
Pd/C (30 mg) in 16 mL MeOH was stirred under a hydro-
gen atmosphere at 5 atm pressure for 6 h. The mixture was
then filtered through Celite and washed exhaustively with
MeOH. The solvent was removed under vacuo to afford
crude 3 (230 mg, 67% yield), which was used immediately
in the next step without additional purification.
Acknowledgements
DCC (94.5 mg, 0.46 mmol) was added to a solution of
2-(thymin-1-yl)acetic acid (84.3 mg, 0.46 mmol) and
DhbtOH (74.7 mg. 0.46 mmol) in 0.8 mL dry DMF, and
the mixture was stirred under a nitrogen atmosphere at
room temperature for 40 min. Then a solution of com-
pound 3 (110 mg, 0.29 mmol) in 1.3 mL dry DMF was
added and the resultant mixture was stirred overnight.
The reaction mixture was filtered and the solvent was re-
moved at a reduced pressure. The residue was poured into
10 mL water and extracted with ethyl acetate (4 · 5 mL).
The organic layers were washed with saturated aqueous
NaHCO3 (1 · 10 mL) and this aqueous phase was
extracted with ethyl acetate (2 · 5 mL). The combined
organic extracts were dried over MgSO4 and the solvent
was removed under vacuo. Crude 4 was purified by column
chromatography (4:1 EtOAc–CH2Cl2) to afford 90 mg
(57% yield) of the pure compound as a colourless oil.
[a]D = +33.0 (c 1.0, MeOH). IR (film) 2591 (br), 1667
(br) cmꢀ1. 1H NMR (250 MHz, acetone-d6) d for the major
rotamer, 0.80 (s, 3H), 1.28 (s, 3H), 1.26–2.10 (complex
absorption, 7H), 1.41 (6, 9H), 1.81, (s, 3H), 1.97 (s, 3H),
2.71–2.99 (m, 1H), 3.30–3.77 (complex absorption, 4H),
4.30 (dd, J = 5.9 Hz, J0 = 8.7 Hz, 1H), 4.63–4.81 (complex
´
Financial support from Ministerio de Educacion y Ciencia,
Spain, (PB2001-1907 and CT2004-1067), and from DURSI
(Generalitat de Catalunya, Spain) (SGR2001-182 and
SGR2005-103) is gratefully acknowledged.
References
1. (a) Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O.
Science 1991, 254, 1497; (b) Hyrup, B.; Nielsen, P. E. Bioorg.
Med. Chem. 1996, 4, 5; (c) Nielsen, P. E. Acc. Chem. Res.
1999, 32, 624; (d) Ganesh, K.; Nielsen, P. E. Curr. Org. Chem.
2000, 4, 931; (e) Nielsen, P. E. Curr. Opin. Biotechnol. 2001,
12, 16; (f) Petersen, M.; Wengel, J. Trends Biotechnol. 2003,
21, 74.
2. See, for instance: (a) Gangamani, B. P.; Kumar, V. A.;
Ganesh, K. N. Tetrahedron 1999, 55, 177; (b) D’Costa, M.;
Kumar, V. A.; Ganesh, K. N. Org. Lett. 1999, 1, 1513; (c)
Vilaivan, T.; Khongdeesameor, C.; Harnyauttanokam, P.;
Westwell, M. S.; Lowe, G. Biorg. Med. Chem. Lett. 2000, 10,
2541; (d) Hickman, D. T.; King, P. M.; Cooper, M. A.;
Slater, J. M.; Micklefield, J. Chem. Commun. 2000, 2251; (e)
Puschi, A.; Tedeschi, T.; Nielsen, P. E. Org. Lett. 2000, 2,
4161; (f) Vilaivan, T.; Khongdeesameor, C.; Harnyauttano-