10548
L. M. Mikkelsen et al. / Tetrahedron 59 (2003) 10541–10549
þ
6 equiv. of (S)-Alpine-Hydride (740 mL, 0.5 M in THF).
Flash chromatography (EtOAc–pentane, 3:1) afforded 14
C H N O [MþNa ]; calculated: 527.2522, found:
3
0 36 2 5
527.2548.
1
(
CDCl ) d (ppm) 7.38–7.12 (m, 14H), 6.33 (br s, 1H), 5.57
20.7 mg, 69%) as a colorless syrup. H NMR (400 MHz,
4.1.9. (2S)-((4S,5S)-5-Benzyloxycarbonylamino-8-tert-
butoxycarbonylamino-4-hydroxy-octanoylamino)-4-
methyl pentanoic acid methyl ester (17). The alcohol 17
was prepared from the ketone 13 according to the procedure
outlined in Section 4.1.3, with the following quantities:
ketone 13 (32.9 mg, 0.06 mmol) and 4.2 equiv. of SmI2
(2.5 mL, 0.1 M in THF). Flash chromotography (EtOAc–
3
(
br s, 1H), 5.32 (dd, 1H, J¼4.8, 8.0 Hz), 5.08 (d, 1H, J¼
1
1
1
2.4 Hz), 5.01 (d, 1H, J¼12.4 Hz), 4.98 (br s, 1H), 4.60 (m,
H), 4.46 (br s, 1H), 3.82 (dt, 1H, J¼7.2, 8.4 Hz), 3.15 (dd,
H, J¼5.6, 16.0 Hz), 2.95–2.88 (m, 3H), 2.48 (m, 1H), 2.28
1
3
(
m, 1H), 2.03 (m, 1H), 1.85 (m, 1H). C NMR (100 MHz,
CDCl ) d (ppm) 175.1, 156.8, 140.3–124.5 (multiple peaks,
3
1
1
8C), 73.2, 72.0, 66.8, 58.1, 57.2, 39.8, 38.8, 34.2, 30.6.
þ
found: 511.2222.
pentane, 5:1) afforded 17 (9.1 mg, 28%) as a yellow oil. H
NMR (400 MHz, CDCl ) d (ppm) 7.34 (m, 5H), 6.11 (br s,
1H), 5.16–5.05 (m, 3H), 4.62–4.57 (m, 2H), 4.08 (br s, 1H),
HRMS C H N O [MþNa ]; calculated: 511.2202,
2
9
32
2
5
3
3
.73 (s, 3H), 3.65 (br d, 1H, J¼7.6 Hz), 3.59 (br d, 1H,
4
.1.7. (4S,5S)-N-((1S,2R)-2-Hydroxy-indan-1-yl)-5-benzyl-
oxycarbonylamino-7-methyl-4-hydroxy-octane amide
15). The alcohol 15 was prepared from the ketone 11
J¼7.6 Hz), 3.12 (br d, 2H, J¼5.2 Hz), 2.45–2.39 (m, 2H),
1.89–1.79 (m, 1H), 1.78–1.69 (m, 2H), 1.66–1.61 (m, 2H),
1.6–1.49 (m, 2H), 1.43 (s, 9H), 0.93 (d, 6H, J¼6 Hz).
1
3
(
C
NMR (100 MHz, CDCl ) d (ppm) 173.9, 173.7, 157.0,
according to the general procedure outlined for 8, with the
following quantities: ketone 11 (31.5 mg, 0.070 mmol) and
3
156.3, 136.8, 128.7 (2C), 128.3, 128.2 (2C), 79.3, 73.0,
66.9, 55.3, 52.6, 51.1, 41.7, 40.5, 33.6, 30.2, 30.1, 28.6 (3C),
26.9, 25.1, 23.0, 22.2. HRMS C H N O [MþNaþ];
calculated: 574.3104, found: 574.3127.
5
Flash chromatography (EtOAc–pentane, 3:1) afforded 15
equiv. of (S)-Alpine-Hydride (696 mL, 0.5 M in THF).
2
8 45 3 8
1
(
19.0 mg, 60%) as a colorless syrup. H NMR (400 MHz,
CDCl ) d (ppm) 7.36–7.23 (m, 9H), 6.39 (br d, 1H, J¼
3
8
1
4
3
2
1
.0 Hz), 5.35 (dd, 1H, J¼4.8, 8.0 Hz), 5.21 (br d, 1H, J¼
0.0 Hz), 5.09 (d, 1H, J¼12.4 Hz), 5.04 (d, 1H, J¼12.4 Hz),
.94 (br d, 1H, J¼8.4 Hz), 4.62 (m, 1H), 4.06 (br s, 1H),
.82–3.61 (m, 2H), 3.15 (ddd, 1H, J¼3.2, 4.8, 16.4 Hz),
.93 (dd, 1H, J¼1.2, 16.4 Hz), 2.56–2.34 (m, 2H), 1.88–
.81 (m, 2H), 1.6–1.60 (m, 1H), 1.39–1.27 (m, 2H), 0.92
4.1.10. (2S)-2-Benzyloxycarbonylamino-5-tert-butoxy-
carbonylamino-pentanethioic acid S-pyridin-4-yl ester
(18). A solution of the a-N-Cbz- and d-N-Boc-protected
ornithine derivative (472 mg, 1.29 mmol) and 4-mercapto-
pyridine (144 mg, 1.29 mmol) in dry distilled dichloro-
methane (15 mL) was cooled to 08C. EDC (296 mg,
1.54 mmol) was added and the solution was stirred for
10 min at 08C and then warmed to 208C followed by stirring
for an additional 2 h. The solution was diluted with
dichloromethane and then washed four times with water
and once with brine. After drying (Na SO ) and evaporation
1
3
(
(
d, 3H, J¼4.4 Hz), 0.90 (d, 3H, J¼4.4 Hz). C NMR
100 MHz, CDCl ) d (ppm) mixture of rotamers, 175.0,
3
1
1
6
3
74.5, 157.2, 157.1, 140.6, 140.5, 140.4 (2C), 136.8, 136.6,
28.8–124.6 (multiple peaks, 18C), 74.6, 74.5, 73.6, 73.4,
7.2, 67.0, 58.1, 58.0, 54.4, 53.8, 39.8 (2C), 36.6, 35.8, 34.3,
2
4
3.7, 30.6, 30.6, 23.8, 23.4, 22.4, 21.8, 20.2, 19.1. HRMS
þ
to dryness, the residue was purified by column chroma-
tography (Pentane–EtOAc, 2:3) affording 338.4 mg (57%
C H N O [MþNa ]; calculated: 477.2365, found:
2
6 34 2 5
1
4
77.2347.
yield) of 18 as colorless crystals. H NMR (400 MHz,
CDCl ) d (ppm) 8.63 (d, 2H, J¼4.8 Hz), 7.39–7.33 (m, 7H),
3
4
.1.8. (4S,5S)-N-Methyl-N-((1R,2R)-2-hydroxy-1-
5.68 (br s, 1H), 5.18 (s, 2H), 4.60 (br s, 1H), 4.54 (m, 1H),
3.16 (m, 2H), 1.97 (m, 1H), 1.73 (m, 1H), 1.68 (m, 2H), 1.44
methyl-2-phenyl-ethyl)-5-benzyloxycarbonylamino-6-
phenyl-4-hydroxy-hexane amide (16). The alcohol 16 was
prepared from the ketone 12 according to the general
procedure outlined for 8, with the following quantities:
ketone 12 (290 mg, 0.58 mmol) and 6 equiv. of (S)-Alpine-
Hydride (7 mL, 0.5 M in THF, 3.5 mmol). Flash chroma-
tography (EtOAc–pentane, 3:2–6:1) afforded 16 (220 mg,
1
3
(s, 9H). C NMR (100 MHz, CDCl ) d (ppm) 197.4, 156.4,
3
156.3, 150.2, 138.6, 136.3, 128.8, 128.5, 128.4 (2C), 79.6,
67.6, 61.5, 40.0, 28.6 (3C), 26.6. HRMS C H N O S
2
3 29 3 5
þ
[MþNa ]; calculated: 482.1726, found: 482.1819.
7
5%) as a colorless syrup. Mixture of rotamers; major¼a,
1
minor¼b: H NMR (400 MHz, CDCl ) d (ppm) 7.40–7.15
Acknowledgements
3
(
m, 15Ha, 15Hb), 5.51 (br d, 1Hb, J¼9.4 Hz), 5.35 (br d,
1
Ha, J¼9.4 Hz), 5.10–5.01 (m, 2Ha, 2Hb), 4.98 (br s, 1Ha
or 1Hb), 4.67 (br s, 1Ha or 1Hb), 4.62–4.58 (m, 1Ha or
Hb), 4.54–4.51 (m, 1Ha, 1Hb), 3.95 (dq, 1Ha or 1Hb,
We are grateful to the Danish National Science Foundation,
the University of Aarhus, the Leo Pharmaceutical Research
Foundation and the Carlsberg Foundation for generous
financial support.
1
J¼6.8, 7.1 Hz), 3.82–3.76 (m, 1Ha, 1Hb), 3.57–3.56 (m,
1
2
7
1
1
0
Ha, 1Hb), 3.46 (br s, 1Ha, 1Hb), 2.96–2.79 (m, 2Ha, 2Hb),
.90 (s, 3Ha), 2.81 (s, 3Hb), 2.58 (ddd, 1Ha or 1Hb, J¼4.0,
.2, 16.8 Hz), 2.53 (t, 2Ha or 2Hb, J¼6.8 Hz), 2.31 (ddd,
Ha or 1Hb, J¼4.0, 9.2, 16.8 Hz), 2.04–1.81 (m, 1Ha,
Hb), 1.70–1.61 (m, 1Ha, 1Hb), 0.99 (d, 3Ha, J¼6.8 Hz),
References
1
3
.94 (d, 3Hb, J¼6.8 Hz). C NMR (100 MHz, CDCl )
1. Blakskjær, P.; Høj, B.; Riber, D.; Skrydstrup, T. J. Am. Chem.
Soc. 2003, 125, 4030.
3
d (ppm) 176.0, 175.5, 156.7 (2C), 142.0, 141.3, 138.8,
1
7
3
38.6, 136.9, 136.8, 129.7–126.3 (multiple peaks, 30C),
6.3, 75.6, 71.5, 71.2, 66.7, 66.6, 58.8, 57.3 (3C), 39.1,
9.0, 32.0 (3C), 31.1, 30.1, 29.6, 15.5, 14.5. HRMS
2. For a recent review on proteinase inhibitors as drugs, see
Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000,
43, 305.