S. Oishi et al. / Tetrahedron 60 (2004) 2971–2977
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stirred solution of amino ester 14 (2.00 g, 5.20 mmol), in
THF (25 mL) was added 1 N LiOH (15.6 mL, 15.6 mmol)
at 0 8C, and stirring was continued overnight at room
temperature. The mixture was acidified with saturated citric
acid solution, concentrated under reduced pressure and
extracted with EtOAc. The extract was washed with H2O
and brine, and dried over MgSO4. Concentration and
recrystalization from Et2O–MeOH (5:1) gave 15 as color-
less crystals (1.90 g, 98% yield): mp 183–185 8C; [a]D22
þ22.8 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3) d
1.42 (s, 9H), 2.10 (ddd, J¼13.6, 10.5, 6.8 Hz, 1H), 2.53
(m, 1H), 2.84 (m, 2H), 2.94 (d, J¼17.1 Hz, 1H), 3.31
(d, J¼16.8 Hz, 1H), 4.79 (br, 1H), 6.95 (d, J¼8.0 Hz, 1H),
7.27 (m, 2H). 13C NMR (400 MHz, CDCl3) d 24.6, 28.1,
56.6, 77.9, 118.3, 128.2, 130.5, 131.3, 133.5, 137.7,
155.0,175.4. FABMS m/z 370 (MHþ). Anal. calcd for
C16H20BrNO4; C, 51.90; H, 5.44; N, 3.78. Found: C, 51.90;
H, 5.47; N, 3.66.
300 mg) in EtOAc (100 mL) under an H2 atmosphere.
After filtration through Celite and concentration under
reduced pressure, purification by flash chromatography over
silica gel with CH2Cl2–MeOH (10:1) provided 18 as a
colorless powder (1.51 g, 99% yield): mp 75–77 8C; [a]D22
þ7.19 (c 0.67, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.33
(t, J¼7.0 Hz, 6H), 1.42 (s, 9H), 2.14 (m, 1H), 2.51 (m, 1H),
2.91 (m, 2H), 3.07 (d, J¼17.3 Hz, 1H), 3.43 (d, J¼17.3 Hz,
1H), 4.13 (m, 4H), 4.87 (br, 1H), 7.17 (dd, J¼7.8, 4.1 Hz,
1H), 7.53 (dd, J¼12.9, 7.8 Hz, 1H), 7.59 (d, J¼14.1 Hz,
1H). 13C NMR (400 MHz, CDCl3) d 16.3, 25.1, 28.2, 37.8,
57.6, 62.3, 80.6, 124.7, 126.6, 129.1, 129.6, 132.4, 135.4,
138.0, 155.6, 177.0. FABMS m/z 428 (MHþ). Anal. calcd
for C20H30NO7P: C, 56.20; H, 7.07; N, 3.28. Found: C,
56.07; H, 7.10; N, 3.22.
3.1.12. Boc-(a-Me)Phe(4-PO3Et2)-Ac6c-Asn-(CH2)3-(1-
naphthyl) (20). To a stirred solution of 9 (215 mg,
0.518 mmol) in dry DMF (2 mL) was added TFFH
(136 mg, 0.518 mmol) at room temperature. After 10 min,
amine 1925 (200 mg, 0.471 mmol) and Pr2i EtN (0.180 mL,
1.03 mmol) were added to the above mixture at room
temperature, and stirring was continued for 24 h at 50 8C.
The mixture was extracted with EtOAc, and the extract was
washed successively with saturated citric acid solution,
brine, saturated NaHCO3 solution and brine, and dried over
Na2SO4. Concentration followed by flash chromatography
over silica gel with CH2Cl2–MeOH (100:0 to 10:1) gave 20
as colorless semisolid (282 mg, 71% yield): 1H NMR
(400 MHz, CDCl3) d 1.20–1.53 (m, 21H), 1.58–1.77 (m,
3H), 1.82 (m, 1H), 1.90–2.11 (m, 4H), 2.17 (m, 1H), 2.65
(dd, J¼15.3, 5.1 Hz, 1H), 2.90 (d, J¼13.6 Hz, 1H), 3.04 (dd,
J¼15.3, 5.6 Hz, 1H), 3.12 (m, 2H), 3.35 (m, 1H), 3.41 (m,
1H), 3.51 (d, J¼13.6 Hz, 1H), 4.14 (m, 4H), 4.66 (s, 1H),
4.71 (m, 1H), 5.35 (br, 1H), 6.22 (br, 1H), 7.04 (m, 3H),
7.34 (m, 2H), 7.43 (m, 2H), 7.53 (t, J¼5.6 Hz, 1H), 7.66
(m, 3H), 7.79 (m, 1H), 7.85 (d, J¼8.3 Hz, 1H), 7.93 (d,
J¼8.3 Hz, 1H). FABMS m/z 822 (MHþ). Anal. calcd for
C43H60N5O9P·0.5H2O: C, 62.15; H, 7.40; N, 8.43. Found:
C, 62.00; H, 7.38; N, 8.37.
3.1.9. Benzyl (S)-2-(tert-butyloxycarbonyl)amino-1,2,3,4-
tetrahydro-6-bromo-2-naphthalenecarboxylate (16). To
a stirred solution of 15 (1.88 g, 5.07 mmol) in DMF
(5.5 mL) were added BnBr (0.664 mL, 5.58 mmol) and
Pri2EtN (1.06 mL, 6.09 mmol) at 0 8C and stirring was
continued for 24 h at room temperature. The mixture was
extracted with EtOAc, and the extract was washed with
saturated citric acid solution, H2O, 5% NaHCO3 solution
and brine, and dried over Na2SO4. Concentration under
reduced pressure followed by flash chromatography over
silica gel with n-hexane–EtOAc (7:1) provided 16 as
colorless crystals (2.27 g, 97% yield): mp 89–91 8C; [a]D22
þ16.9 (c 0.92, CHCl3); 1H NMR (400 MHz, CDCl3) d 1.37
(s, 9H), 2.12 (ddd, J¼13.6, 9.7, 7.5 Hz, 1H), 2.46 (m, 1H),
2.79 (m, 2H), 2.92 (d, J¼16.5 Hz, 1H), 3.26 (d, J¼16.6 Hz,
1H), 4.75 (br, 1H), 5.18 (s, 2H), 6.91 (d, J¼8.0 Hz, 1H),
7.21–7.27 (m, 2H), 7.29–7.38 (m, 5H). 13C NMR
(400 MHz, CDCl3) d 25.1, 28.2, 37.6, 57.7, 67.2, 120.0,
128.1, 128.2, 128.5, 129.2, 130.9, 131.5, 135.6, 137.2,
149.1, 154.8, 173.5. FABMS m/z 460 (MHþ). Anal. calcd
for C23H26BrNO4: C, 60.01; H, 5.69; N, 3.04. Found: C,
59.64; H, 5.70; N, 2.92.
3.1.13. Boc-Atc(6-PO3Et2)-Ac6c-Asn-(CH2)3-(1-naph-
thyl) (21). Using a procedure similar to that described for
the preparation of peptide 20 from 19, coupling of 18
(200 mg, 0.471 mmol) with 19 provided 21 as a colorless
semisolid (282 mg, 71% yield): 1H NMR (400 MHz,
CDCl3) d 1.21–1.43 (m, 18H), 1.52–1.84 (m, 5H), 1.85–
2.09 (m, 5H), 2.22 (m, 1H), 2.39 (m, 1H), 2.57–2.91 (m,
5H), 3.08 (m, 2H), 3.25 (d, J¼17.0 Hz, 1H), 3.34 (m, 2H),
4.13 (m, 4H), 4.79 (dt, J¼8.2, 5.8 Hz, 1H), 4.81 (s, 1H), 5.35
(br, 1H), 6.36 (br, 1H), 7.02 (dd, J¼7.8, 4.1 Hz, 1H), 7.20
(br, 1H), 7.30 (m, 2H), 7.40 (m, 2H), 7.50 (dd, J¼17.9,
7.5 Hz, 1H), 7.55 (m, 2H), 7.64 (m, 1H), 7.80 (m, 2H), 8.01
(d, J¼8.3 Hz, 1H). FABMS m/z 834 (MHþ). Anal. calcd for
C44H60N5O9P·H2O: C, 62.03; H, 7.34; N, 8.22. Found: C,
62.29; H, 7.30; N, 8.32.
3.1.10. (S)-2-(tert-Butyloxycarbonyl)amino-1,2,3,4-tetra-
hydro-6-(diethylphosphono)-2-naphthalenecarboxylic
acid benzyl ester (17). Treatment of 16 (2.21 g, 4.80 mmol)
with diethyl phosphite using a procedure similar to that
described for the preparation 8 from 7, gave 17 as a colorless
1
oil (1.91 g, 93% yield): [a]2D2 þ9.30 (c 1.13, CHCl3); H
NMR (400 MHz, CDCl3) d 1.33 (t, J¼7.0 Hz, 6H), 1.38 (s,
9H), 2.15 (ddd, J¼13.6, 9.2, 7.3 Hz, 1H), 2.45 (m, 1H), 2.86
(m, 2H), 3.04 (d, J¼17.3 Hz, 1H), 3.40 (d, J¼17.0 Hz, 1H),
4.11 (m, 4H), 4.79 (s, 1H), 5.19 (s, 2H), 7.15 (dd, J¼7.8,
4.3 Hz, 1H), 7.28–7.38 (m, 5H), 7.49–7.60 (m, 2H). 13C
NMR (400 MHz, CDCl3) d 16.3, 25.1, 28.2, 28.9,
38.0, 57.7, 62.0, 67.2, 125.2, 127.1, 128.1, 128.2, 128.5,
129.1, 129.5, 132.4, 135.3, 135.6, 137.7, 154.8, 173.5.
HR-FABMS m/z calcd for C27H37NO7P (MHþ) 518.2308,
found: 518.2264.
3.1.14. tert-ButO-(CO)2-(a-Me)Phe(4-PO3Et2)-Ac6c-
Asn-(CH2)3-(1-naphthyl) (22). Protected peptide 20
(93 mg, 0.113 mmol) was treated with TFA-anisole (10:1,
5.5 mL) for 2 h at room temperature then the reaction
mixture was concentrated and dissolved in dry DMF
(1 mL). To this were added tert-butyl oxalyl chloride
3.1.11. (S)-2-(tert-Butyloxycarbonyl)amino-1,2,3,4-tetra-
hydro-6-(diethylphosphono)-2-naphthalenecarboxylic
acid [Boc-Atc(6-PO3Et2)-OH] (18). Benzyl ester 17
(1.84 g, 3.55 mmol) was treated using Pd·C (10%,