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W. Szymanski, R. Ostaszewski / Tetrahedron 64 (2008) 3197e3203
4.4.7. BocGly-(R)-Leu-GlyOtBu (6d)
1-hydroxybenzotriazole (22 mg, 0.15 mmol). The solution
was cooled to 0 ꢀC and EDC (21 mg, 0.11 mmol) was added
in one portion. After 4 h the solvent was evaporated and the
residue was taken up in ethyl acetate (15 mL). This solution
was washed with 5% aqueous citric acid solution (2ꢂ5 mL),
saturated NaHCO3 solution (2ꢂ5 mL), and brine (5 mL).
The organic phase was dried (MgSO4) and evaporated to yield
the analytically pure compound. Yield: 58% of colorless oil;
Rf¼0.35 (hexane/ethyl acetate 4:6, v/v); [a]1D9 þ52.0 (c 1.0,
CHCl3). 1H NMR (200 MHz, CDCl3): d 1.43 (s, 9H,
(CH3)3), 2.89 (s, 3H, CH3N), 3.00 (dd, 1H, J¼14.4, 9.2 Hz,
PhCH2CH), 3.34 (dd, 1H, J¼14.6, 6.8 Hz, PhCH2CH),
3.67e3.92 (m, 2H, Gly-CH2), 3.91e4.07 (m, 2H, Gly-CH2),
5.10 (s, 2H, PhCH2O), 5.36 (dd, 1H, J¼9.2, 6.8 Hz,
PhCH2CH), 5.70 (br s, 1H, NHCBz), 6.57 (br s, 1H, NH),
7.18e7.44 (m, 5H, ArH). 13C NMR (50 MHz, CDCl3):
d 28.4, 34.0, 42.3, 58.3, 67.3, 82.6, 112.2, 116.4, 126.9,
127.1, 127.7, 128.4, 128.9, 129.0, 159.9, 168.8, 170.0.
HRMS (ESI, [MþNa]þ) 472.2437 (C23H35N3O6Na:
472.2418). IR (CHCl3) n: 3329, 2930, 1727, 1651, 1531,
Yield: 95% of colorless oil; Rf¼0.30 (hexane/ethyl acetate
5:5, v/v); [a]2D0 þ25.8 (c 1.0, CHCl3). H NMR (200 MHz,
1
CDCl3): d 0.89e0.93 (m, 6H, CH3CH), 1.42 (s, 9H, (CH3)3C),
1.44 (s, 9H, (CH3)3C), 1.52e1.78 (m, 3H, CHCH2), 3.78e
3.92 (m, 4H, 2ꢂGly-2H), 4.48e4.60 (m, 1H, Leu-H), 5.37 (br
s, 1H, NHBoc), 6.82e6.95 (m, 2H, 2NH). 13C NMR
(50 MHz, CDCl3): d 22.2, 23.3, 25.0, 28.4, 28.6, 31.3, 41.3,
42.3, 51.8, 82.5, 156.5, 169.0, 170.1, 172.4. HRMS (ESI,
[MþNa]þ) 424.2423 (C19H35N3O6Na: 424.2418). IR (Nujol)
n: 3251, 1750, 1661, 1528, 1226, 1168 cmꢁ1
4.4.8. CBzGly-(R)-Leu-GlyOtBu (6e)
.
Yield: 99% of colorless oil; Rf¼0.32 (hexane/ethyl acetate
1
5:5, v/v); [a]2D0 þ21.0 (c 1.0, CHCl3). H NMR (200 MHz,
CDCl3): d 0.89e0.93 (m, 6H, CH3CH), 1.44 (s, 9H,
(CH3)3C), 1.52e1.78 (m, 3H, CHCH2), 3.78e4.00 (m, 4H,
2ꢂGly-2H), 4.48e4.61 (m, 1H, Leu-H), 5.10 (s, 2H,
PhCH2), 5.73 (br s, 1H, NHBoc), 6.82e6.88 (m, 2H, 2NH),
7.30e7.40 (m, 5H, ArH). 13C NMR (50 MHz, CDCl3):
d 22.3, 23.2, 25.1, 28.4, 41.4, 42.3, 51.9, 67.5, 82.7, 128.4,
128.5, 128.9, 136.4, 168.0, 169.6, 172.3. HRMS (ESI,
[MþNa]þ) 458.2259 (C22H33N3O6Na: 458.2262). IR
(CHCl3) n: 3300, 2958, 1729, 1652, 1537, 1368, 1236, 1156,
1455, 1368, 1250, 1157 cmꢁ1
.
4.5.2. CBzGly-(N-Me)-(R)-Leu-GlyOtBu (6h)
Yield: 47% of yellow oil; Rf¼0.38 (hexane/ethyl acetate 5:5,
v/v); [a]1D9 þ83.9 (c 0.57, CHCl3). 1H NMR (200 MHz, CDCl3):
d 0.90 (d, 3H, J¼9.6 Hz, CH3CH), 0.93 (d, 3H, J¼9.6 Hz,
CH3CH), 1.44 (s, 9H, (CH3)3C), 1.60e1.78 (m, 3H, CHCH2),
2.90 (s, 3H, CH3N), 3.78e4.05 (m, 4H, 2ꢂGly-2H), 5.05e
5.20 (m, 1H, Leu-H), 5.10 (s, 2H, PhCH2), 5.80 (br s, 1H,
NHBoc), 6.47 (br s, 1H, NH), 7.32e7.47 (m, 5H, ArH). 13C
NMR (50 MHz, CDCl3): d 22.3, 23.4, 25.2, 28.4, 30.0, 36.4,
42.2, 43.3, 55.1, 64.1, 67.3, 113.2, 119.4, 128.4, 128.8, 160.4,
167.5, 167.7, 169.5. HRMS (ESI, [MþNa]þ) 506.2254
(C25H33N3O6Na: 506.2262). IR (CHCl3) n: 3330, 2957, 2932,
754 cmꢁ1
.
4.4.9. Boc-(S)-Ala-(R)-Leu-GlyOtBu (6f)
Yield: 99% of white crystals; Rf¼0.43 (hexane/ethyl acetate
5:5, v/v); mp 185e187 ꢀC (ethyl acetate/hexane); [a]2D0 þ18.4
(c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): d 0.89e0.93 (m,
6H, CH3CH), 1.34 (d, J¼7.0 Hz, 3H, Ala-CH3), 1.42 (s, 9H,
(CH3)3C), 1.44 (s, 9H, (CH3)3C), 1.52e1.78 (m, 3H, CHCH2),
3.78e4.00 (m, 4H, 2ꢂGly-2H), 4.05e4.22 (m, 1H, 2ꢂAla-H),
4.42e4.58 (m, 1H, Leu-H), 5.24 (d, J¼7.0 Hz, 1H, NHBoc),
6.83 (d, J¼9.2 Hz, 1H, Leu-NH), 6.97 (br s, H, Gly-NH).
13C NMR (50 MHz, CDCl3): d 18.5, 22.1, 23.4, 25.1,
28.4, 28.6, 41.0, 42.3, 51.8, 80.6, 82.4, 155.9, 169.0, 172.4,
173.4. HRMS (ESI, [MþNa]þ) 438.2562 (C20H37N3O6Na:
438.2575). IR (Nujol) n: 3290, 3240, 1749, 1677, 1652,
1727, 1651, 1530, 1368, 1251, 1158 cmꢁ1
.
Acknowledgements
This work was financially supported by Polish State Com-
mittee for Scientific Research, Grant PBZeKBN 126/T09/07.
1568, 1532, 1455, 1366, 1226, 1168 cmꢁ1
.
4.5. Synthesis of compounds 6aeh
References and notes
The optimized transformation of alcohols (S)-5a and (S)-5b
into N-methylated amides 6g and h, respectively is further
exemplified by the synthesis of 6g.
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4.5.1. CBzGly-(N-Me)-(R)-Phe-GlyOtBu (6g)
A solution of methanesulfonic acid ester (S)-7a (60 mg,
0.17 mmol) in methanol (containing 5 wt% of methylamine)
was stirred for 24 h in 50 ꢀC. The volatiles were then evapo-
rated and the crude product was purified by flash chromatog-
raphy (silica gel, ethyl acetate/methanol 9:1, v/v). HRMS
(ESI, [MþH]þ) 293.1857 (C16H25N2O3: 293.1860). Obtained
compound (R)-10a was used in further synthesis. To a solution
of amine (R)-10a (28 mg, 0.09 mmol) in CH2Cl2 (4.0 mL)
were added CBz-protected glycine (21 mg, 0.10 mmol) and
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