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M. Belohradsky et al. / Tetrahedron 58 (2002) 8811–8823
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(m, 16H); 4.99 (s, 2H); 7.34 (m, 5H); 7.54 (bs, 1H); 12.44
(bs, 1H). FAB MS m/z (%): 384 ([MþH]þ, 35%), 340
(40%). Anal. calcd for C18H25NO8: C, 56.36; H, 6.57; N,
3.65. Found: C, 56.45; H, 6.73; N, 3.59.
8c: yield 0.96 g (99%); oil. 1H NMR d (ppm), CDCl3: 3.56–
3.70 (m, 20H); 3.76 (s, 3H);3.90–4.07 (m, 4H) 5.10 (s, 2H);
6.08 (bs, 1H); 7.34 (m, 5H). FAB MS m/z (%): 486
([MþH]þ, 15%); 508 ([MþNa]þ, 100%). Anal. calcd for
C23H35NO10·H2O: C, 54.86; H, 7.41; N, 2.78. Found: C,
55.08; H, 7.31; N, 2.88.
N-Cbz-protected amino acid 6b: 4.1 g (80%); oil. 1H NMR
d (ppm), DMSO-d6: 3.36–3.84 (m, 20H); 4.98 (s, 2H); 6.98
(bs, 1H); 7.34 (m, 5H). FAB MS m/z (%): 428 ([MþH]þ,
35%). Anal. calcd for C20H29NO9·H2O: C, 53.92; H, 7.01;
N, 3.14. Found: C, 53.78; H, 6.95; N, 2.94.
4.2.8. Hydrogenolysis of N-Cbz-protected esters (8a–c).
N-Cbz-protected amino acid methyl ester 8a–c (2 mmol)
was dissolved in methanol (30 mL), 10% Pd/C
catalyst (50 mg) was added and the reaction mixture
was stirred under hydrogen for 5–10 h until the deprotec-
tion was complete (TLC). The catalyst was filtered off,
methanol was evaporated and the oily product was dried in
vacuo.
N-Cbz-protected amino acid 6c: 4.5 g (70%); colorless
crystals; mp 96–978C. 1H NMR d (ppm), DMSO-d6: 3.36–
3.84 (m, 20H); 4.98 (s, 2H); 6.98 (bs, 1H); 7.34 (m, 5H).
FAB MS m/z (%): 494 ([MþNa]þ, 100%); 516 ([Mþ2Na]þ,
54%). Negative ion FAB MS m/z (%): 470 ([M2H]2,
100%). Anal. calcd for C22H33NO10: C, 56.04; H, 7.06; N,
2.97. Found: C, 56.02; H, 7.23; N, 2.91.
1
Deprotected ester 9a: 0.52 g (99%); oil. H NMR d (ppm),
DMSO-d6: 3.45–3.72 (m, 12H); 3.76 (s, 3H); 3.91 (dd, 4H);
8.68 (bs, 2H). FAB MS m/z (%): 264 ([MþH]þ, 100%).
HRMS (FAB) calcd for C11H21NO6: 264.1447. Found:
264.1461.
4.2.6. Hydrogenolysis of N-Cbz-amino acids (6a–c).
N-Cbz-protected amino acid 6a–c (0.5 mmol) was dis-
solved in methanol, 10% Pd/C catalyst (50 mg) was added
and hydrogen was bubbled through the reaction mixture for
3 h. After standing overnight under hydrogen, the catalyst
was filtered off and the solvent was evaporated. The residue
was crystallized from the mixture of methanol and diethyl or
diisopropyl ether.
1
Deprotected ester 9b: 0.65 g (94%); oil. H NMR d (ppm),
DMSO-d6: 3.60–4.39 (m, 23H); 9.44 (bs, 2H). FAB MS m/z
(%): 308 ([MþH]þ, 100%); HRMS (FAB) calcd for
C13H25NO7: 308.1709. Found: 308.1668.
1
Deprotected ester 9c: 0.69 g (98%); oil. H NMR d (ppm),
Free amino acid 7a: yield 0.115 g (92%); colorless crystals;
1
DMSO-d6: 3.28–4.02 (m, 27H); 8.68 (bs, 2H). FAB MS m/z
(%): 352 ([MþH]þ, 100%); HRMS (FAB) calcd for
C15H29NO8: 352.1971. Found: 352.1905.
mp 192–1968C. H NMR d (ppm), DMSO-d6: 3.35–3.85
(m, 16H); 7.42 (bs, 2H). FAB MS m/z (%): 250 ([MþH]þ,
100%). Anal. calcd for C10H19NO6·H2O: C, 44.94; H, 7.92;
N, 5.24. Found: C, 44.72; H, 7.95; N, 5.11.
4.2.9. N-Cbz-protected dipeptides (10a–c). Free methyl
ester 9a–c (1 mmol), N-Cbz-protected amino acid 6a–c
(1 mmol) and benzotriazol-1-yl-oxy-tripyrrolidinophos-
phonium hexafluorophosphate (0.6 g, 1.15 mmol) were
dissolved in diisopropylethyl amine (3 mL) and dry
dichloromethane (3 mL) and the reaction mixture was
stirred gently at rt for 5 days. Solvents were taken off and
the crude residue was subjected to column chromatography
(silica gel; chloroform–methanol 97:3).
Free amino acid 7b: yield 0.130 g (88%); colorless crystals;
1
mp 135–1378C. H NMR d (ppm), DMSO-d6: 3.30–3.82
(m, 20H); 7.20 (bs, 2H). FAB MS m/z (%): 280 ([MþH]þ,
100%). Anal. calcd for C12H23NO7: C, 49.14; H, 7.90; N,
4.78. Found: C, 49.03; H, 7.75; N, 4.90.
Free amino acid 7c: yield 0.155 g (91%); colorless crystals;
1
mp 163–1668C. H NMR d (ppm), DMSO-d6: 3.44–3.78
(m, 24H); 7.13 (bs, 2H). FAB MS m/z (%): 338 ([MþH]þ,
100%). Anal. calcd for C14H27NO8: C, 49.69; H, 8.04; N,
4.14. Found: C, 49.53; H, 8.12; N, 4.11.
10a: yield 0.46 g (73%); colorless crystals; mp 117–1188C.
1H NMR d (ppm), CDCl3: 3.60–4.18 (m, 35H); 5.05 (s,
2H); 5.81 (bs, 1H); 7.33 (m, 5H); 7.82 (bs, 1H). FAB MS
m/z (%): 629 ([MþH]þ, 100%); HRMS (FAB) calcd for
C29H45N2O13: 629.2921. Found: 629.2912.
4.2.7. Methyl esters of N-Cbz-amino acids (8a–c). N-Cbz-
protected amino acid 6a–c (2 mmol) was dissolved in dry
dichloromethane (30 mL) and an excess of diazomethane in
diethyl ether was slowly added. After 15 min the solvents
were evaporated and the residue was dried in vacuo.
1
10b: yield 0.44 g, (61%); oil. H NMR d (ppm), CDCl3:
3.55–4.20 (m, 43H); 5.07 (s, 2H); 6.17 (bs, 1H); 7.33 (m,
5H); 7.51 (bs, 1H). FAB MS m/z (%): 717 ([MþH]þ, 29%);
739 ([MþNa]þ, 100%; HRMS (FAB) calcd for
C33H53N2O15: 717.3446. Found: 717.3342.
8a: yield 0.79 g (99%); oil. 1H NMR d (ppm), CDCl3: 3.52–
3.80 (m, 16H); 3.93 (s, 3H); 5.09 (s, 2H); 5.51 (bs, 1H); 7.34
(m, 5H). FAB MS m/z (%): 398 ([MþH]þ, 100%). Anal.
calcd for C19H27NO8: C, 57.42; H, 6.85; N, 3.52. Found: C,
57.31; H, 6.79; N, 3.54.
1
10c: yield 0.50 g, (62%); oil. H NMR d (ppm), CDCl3:
3.55–4.18 (m, 51H); 5.09 (s, 2H); 6.18 (bs, 1H); 7.34 (m,
5H); 7.61 (bs, 1H). FAB MS m/z (%): 805 ([MþH]þ, 68%);
827 ([MþNa]þ, 100%); HRMS (FAB) calcd for
C37H61N2O15: 805.3970. Found: 805.3932.
8b: yield 0.88 g (99%); oil. 1H NMR d (ppm), CDCl3: 3.60–
3.70 (m, 16H); 3.87 (s, 3H); 3.90–4.10 (m, 4H) 5.11 (s, 2H);
6.03 (bs, 1H); 7.34 (m, 5H). FAB MS m/z (%): 464
([MþNa]þ, 100%). Anal. calcd for C21H31NO9: C, 57.13;
H, 7.08; N, 3.17. Found: C, 56.89; H, 6.91; N, 3.01.
4.2.10. Deprotected dipeptides (11a–c). Prepared by
hydrogenolysis of 10a–c (0.5 mmol) analogously as
described for the amino acid methyl esters 9a–c.