5292 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Richardson et al.
(2S,3S,4S)-Formylamino-acetic Acid 1-(3-Hexyl-4-oxo-oxetan-
2-ylmethyl)-tetradecyl Ester (15b). Prepared according to the
representative Mitsunobu reaction procedure using ꢀ-lactone 13a
(20.0 mg, 0.0523 mmol), triphenylphosphine (44.4 mg, 0.169
mmol), N-formylglycine (20.4 mg, 0.197 mmol), and DIAD (33
µL, 0.169 mmol) in 0.7 mL of THF. Purification by flash
chromatography on SiO2 (4:1, hexanes:EtOAc) gave ꢀ-lactone 15b
to warm to room temperature and stirred overnight. The mixture
was concentrated in vacuo and purified twice by chromatography
(SiO2, 10 f 30% EtOAc:hexanes) to afford ꢀ-lactone 15f (6 mg,
25%). Rf ) 0.26 (30% EtOAc/hexanes); [R]22 ) -3.68 (c 0.4,
D
CHCl3). IR (thin film) 2926, 2856, 1828, 1740, 1671 cm-1
.
1H
NMR (500 MHz, CDCl3) δ 8.23 (br s, 1H), 5.90 (d, J ) 8.5 Hz,
1H), 5.04 (app quint, J ) 5.5 Hz, 1H), 4.69 (ddd, J ) 5.0, 8.5,
13.0 Hz, 1H), 4.30-4.33 (m, 1H), 3.18-3.22 (m, 1H), 2.19 (app
quint, J ) 7.0 Hz, 1H), 2.00 (dt, J ) 4.5, 19.0 Hz, 1H), 1.64-1.70
(m, 2H), 1.54-1.60 (m, 19H) 1.22-1.32 (m, 6H), 1.042 (dppt, J
) 7.5 Hz, 3H) 0.97 (dd, J ) 1.5, 4.5 Hz, 4H), 0.90 (appt, J ) 7.5
Hz, 3H). 13C NMR (125 HMz, CDCl3) δ 172.2, 169.5, 161.2, 74.7,
73.3, 58.6, 40.4, 39.1, 34.4, 32.2, 30.0, 29.9, 29.8, 29.7, 29.6, 29.5,
25.4, 22.9, 21.1, 14.4, 11.3. HRMS (ESI) calcd for 38C21H45NO5
[M + H], 384.2744; found, 384.2786.
1
(17.8 mg, 73%). H NMR (300 MHz, C6D6) δ 7.72 (s, 1H), 5.16
(br, 1H), 4.94-5.01 (m, 1H), 4.06 (dt, J ) 4.8, 7.5 Hz, 1H), 3.78
(dd, J ) 6.0, 18.0 Hz, 1H), 3.69 (dd, J ) 5.7, 18.0 Hz, 1H), 2.74
(dt, J ) 4.2, 7.5 Hz, 1H), 1.72 (dt, J ) 8.1, 15.0 Hz, 1H), 1.15-1.47
(m, 35H), 0.88-0.94 (m, 6H). 13C NMR (75 MHz, C6D6) δ 170.7,
169.6, 160.9, 74.8, 72.8, 57.6, 40.5, 39.2, 34.8, 32.7, 32.2, 30.53
(2), 30.51, 30.5, 30.4, 30.3, 30.2, 30.1, 29.7, 28.1, 27.3, 25.9, 23.5,
23.3, 14.7, 14.6.
(S)-2-Formylamino-3-phenyl-propionic Acid 1-((2S,3S,4S)-
3-Hexyl-4-oxo-oxetan-2-ylmethyl)-tetradecyl Ester (15c). Pre-
pared according to the representative Mitsunobu reaction procedure
using ꢀ-lactone 13a (20.0 mg, 0.0523 mmol), triphenylphosphine
(44.4 mg, 0.169 mmol), N-formyl-L-leucin (47.3 mg, 0.296 mmol),
and DIAD (49 µL, 0.25 mmol) in 1.0 mL of THF. Purification by
flash chromatography on SiO2 (4:1, hexanes:EtOAc) gave ꢀ-lactone
15c (33 mg, 80%). 1H NMR (300 MHz, C6D6) δ 7.57 (s, 1H),
6.96-7.12 (m, 5H), 5.08 (d, J ) 8.1 Hz, 1H), 4.92-4.98 (m, 1H),
4.87 (q, J ) 7.5 Hz, 1H), 3.93-3.99 (m, 1H), 3.01 (dd, J ) 6.3,
14.1 Hz, 1H), 2.84 (dd, J ) 7.2, 14.1 Hz, 1H), 2.70 (dt, J ) 4.2,
7.8 Hz, 1H), 1.73 (dt, J ) 7.5, 15.0 Hz, 1H), 1.14-1.54 (m, 35H),
0.88-0.95 (m, 6H). HRMS (ESI) calcd for C34H55NO5 [M + Li],
564.4240; found, 564.4166.
(S)-2-Formylamino-4-methyl-pentanoic Acid 1-((2S,3S,4S)-
3-Methyl-4-oxo-oxetan-2-ylmethyl)-dodecyl Ester (15d). Prepared
according to the representative Mitsunobu reaction procedure using
ꢀ-lactone 13a (40.0 mg, 0.105 mmol), triphenylphosphine (88.9
mg, 0.339 mmol), N-formyl-L-histidine (72.3 mg, 0.395 mmol),
and DIAD (66 µL, 0.34 mmol) in 3 mL of THF. Purification by
flash chromatography on SiO2 (2:1, hexanes:EtOAc) gave ꢀ-lactone
15d (10 mg, 17%). 1H NMR (300 MHz, C6D6) δ 7.91 (s, 1H),
7.78 (s, 1H), 6.97 (s, 1H), 6.82 (d, J ) 7.5 Hz, 1H), 4.93-4.99
(m, 2H), 4.82 (quint, J ) 6.6 Hz, 1H), 4.22 (dt, J ) 3.9, 6.3 Hz,
1H), 2.99 (dd, J ) 5.1, 14.1 Hz, 1H), 2.86 (dd, J ) 5.4, 15.0 Hz,
1H), 2.78-2.82 (m, 1H), 1.88 (dt, J ) 6.9, 14.7 Hz, 1H), 1.16-1.63
(m, 31H), 0.87-0.96 (m, 10H).
(S)-2-Formylamino-4-methyl-pentanoic Acid 1-((2S,3S,4S)-
3-Methyl-4-oxo-oxetan-2-ylmethyl)-dodecyl Ester (15e). Prepared
according to the representative Mitsunobu reaction procedure using
the mixture of ꢀ-lactones 13e and 14e (11.9 mg, 0.0418 mmol),
triphenylphosphine (32.8 mg, 0.125 mmol), N-formylleucine (23.2
mg, 0.146 mmol), and DIAD (25 µL, 0.13 mmol) in 1.0 mL of
THF. Purification by flash chromatography on SiO2 (3:2, hexanes:
EtOAc) followed by a second purification by flash chromatography
on SiO2 (0.4:1:3 THF:CHCl3:hexanes) gave the desired ꢀ-lactone
as a mixture of diastereomers. The two diastereomers could be
separated by MPLC (65:35, hexanes: EtOAc), affording ꢀ-lactone
15e (6.8 mg, 38%) and diastereomeric ꢀ-lactone 16b (4.4 mg, 24%).
Major diastereomer (15e): 1H NMR (300 MHz, CDCl3) δ 8.23 (s,
1H), 5.92 (d, J ) 8.7 Hz, 1H), 4.98-5.10 (m, 1H), 4.69 (td, J )
4.8, 8.4, 1H), 4.23 (ddd, J ) 8.4, 4.2, 4.2 Hz, 1H), 3.28 (dq, J )
4.2, 7.8 Hz, 1H), 1.96-2.26 (m, 2H), 1.51-1.75 (m, 5H), 1.40 (d,
J ) 7.8 Hz, 3H), 1.26 (br. s, 18H), 0.98 (d, J ) 6.0 Hz, 6H), 0.89
(t, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.2, 171.4,
160.8, 76.5, 72.8, 51.8, 49.9, 41.8, 38.7, 34.4, 32.1, 29.92, 29.83,
29.75, 29.65, 29.56, 29.51, 25.3, 25.1, 23.1, 22.9, 22.0, 14.3, 12.6.
(S)-((R)-1-((2S,3S)-3-Ethyl-4-oxooxetan-2-yl)tridecan-2-yl)
2-Methanamido-4-methylpentanoate (15f). To a mixture of
hydroxy ꢀ-lactone 13d (17.7 mg, 0.0594 mmol), N-formylleucine
(33.4 mg, 0.209 mmol), and triphenylphosphine (53.4 mg, 0.203
mmol) in a 10 mL round-bottom flask was added 0.5 mL of xylene,
and the mixture was azeotroped in vacuo. After 1.0 h, THF (1.4
mL) was added under N2 and the solution was cooled to 0 °C.
Next, DIAD (37.9 µL, 0.1947 mmol) was added and the reaction
mixture was stirred at 0 °C for 10 min. The reaction was allowed
(2S,3S,4S)-Formylamino-acetic Acid 1-(3-Hexyl-4-oxo-oxetan-
2-ylmethyl)-dodecyl Ester (15g). Prepared according to the
representative Mitsunobu reaction procedure using ꢀ-lactone 13b
(40.0 mg, 0.113 mmol), triphenylphosphine (74.1 mg, 0.283 mmol),
N-formylglycine (40.7 mg, 0.395 mmol), and DIAD (55 µL, 0.28
mmol) in 2 mL of THF. Purification by flash chromatography on
1
SiO2 (4:1, hexanes:EtOAc) gave ꢀ-lactone 15g (43 mg, 87%). H
NMR (300 MHz, C6D6) δ 7.79 (s, 1H), 5.45 (br, 1H), 4.95-5.02
(m, 1H), 4.08 (dt, J ) 5.1, 7.2 Hz, 1H), 3.81(dd, J ) 5.7, 18.0 Hz,
1H), 3.73 (dd, J ) 5.7, 18.3 Hz, 1H), 2.78 (dt, J ) 4.2, 7.8 Hz,
1H), 1.75 (dt, J ) 8.1, 15.0 Hz, 1H), 1.17-1.52 (m, 31H),
0.87-0.94 (m, 6H). 13C NMR (75 MHz, C6D6) δ 170.8, 169.7,
161.1, 74.9, 72.8, 57.6, 40.6, 39.2, 34.8, 32.7, 32.2, 30.47, 30.45,
30.40, 30.3, 30.2, 30.1, 29.7, 28.2, 27.4, 25.9, 23.5, 23.3, 14.7, 14.6.
2-Formylamino-3-methyl-butyric Acid (2S,2R,3S,4S)-1-(3-
Hexyl-4-oxo-oxetan-2-ylmethyl)-hex-4-enyl Ester (15h). Prepared
according to the representative Mitsunobu reaction procedure using
ꢀ-lactone 13h (20.0 mg, 0.0745 mmol), triphenylphosphine (27.4
mg, 0.104 mmol), N-formyl-L-valine (21.6 mg, 0.149 mmol), DIAD
(20 µL, 0.10 mmol) in 1 mL of THF. Purification by flash
chromatography on SiO2 (9:1, hexanes:EtOAc) gave ꢀ-lactone 15h
(13.3 mg, 45%) as a colorless oil as a E/Z-mixture, only peaks for
major olefin isomer are assigned. Rf ) 0.24 (30% EtOAc/hexanes);
[R]22D -7.95 (0.9, CHCl3). IR (thin film) 1823, 1737, 1670 cm-1
.
1H NMR (500 MHz, CDCl3) δ 8.28 (s, 1H), 6.05 (d, J ) 8.0 Hz,
1H), 5.32-5.50 (m, 2H), 5.03-5.08 (m, 1H), 4.64 (ddd, J ) 4.5,
7.5, 16.5 Hz, 1H), 4.30 (dt, J ) 4.0, 8.0 Hz, 1H), 3.23 (dt, J ) 4.5,
7.0 Hz, 1H), 2.06-2.26 (m, 3H), 2.02 (dt, J ) 5.5, 14.5 Hz, 2H),
1.64-1.85 (m, 6H), 1.28-1.48 (m, 9H), 1.01 (d, J ) 6.5 Hz, 3H),
0.93 (d, J ) 7.0 Hz, 3H), 0.89 (t, J ) 6.6 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 171.2, 170.9, 161.0, 129.4, 126.6, 74.8, 72.5, 57.3,
56.1, 38.8, 33.9, 31.7, 31.2, 29.2, 28.4, 27.9, 26.9, 22.7, 19.5, 18.l1,
17.7, 14.2. HRMS (ESI) calcd for C22H37NO5 [M + H], 396.2744;
found, 396.2833.
(S)-2-Formylamino-3-phenyl-propionic Acid 1-((2S,3S,4S)-
3-Hexyl-4-oxo-oxetan-2-ylmethyl)-hex-4-enyl Ester (15i). Pre-
pared according to the representative Mitsunobu reaction procedure
using ꢀ-lactone 13h (20.0 mg, 0.0745 mmol), triphenylphosphine
(27.4 mg, 0.104 mmol), N-formyl-L-phenylalanine (28.8 mg, 0.149
mmol), and DIAD (20 µL, 0.10 mmol) in 2 mL of THF. Purification
by flash chromatography on SiO2 (4:1, hexanes:EtOAc) gave
ꢀ-lactone 15i (yield not determined) as a E/Z-mixture; only peaks
for major olefin isomer are assigned. 1H NMR (300 MHz, CDCl3)
δ 8.18 (s, 1H), 7.17-7.32 (m, 5H), 5.99 (d, J ) 7.8 Hz, 1H)
5.30-5.47 (m, 2H), 4.97-5.05 (m, 1H), 4.91 (q, J ) 6.9 Hz, 1H),
4.28 (dt, J ) 5.1, 7.8 Hz, 1H), 3.06-3.24 (m, 3H), 1.26-2.10 (m,
19H), 0.90 (t, J ) 6.6 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
171.0, 170.9, 160.6, 135.7, 129.5, 129.4, 128.9, 127.6, 126.5, 74.7,
72.7, 57.3, 52.3, 38.8, 38.0, 33.9, 31.7, 29.2, 28.3, 27.8, 26.9, 22.7,
18.1, 14.3. HRMS (ESI) calcd for C26H37NO5 [M + H], 444.2744;
found, 444.2730.
(S)-2-Formylamino-4-methyl-pentanoic Acid 1-((2S,3S,4S)-
3-Hexyl-4-oxo-oxetan-2-ylmethyl)-pent-4-enyl Ester (15j). Pre-
pared according to the representative Mitsunobu reaction procedure
using ꢀ-lactone 13g (80.0 mg, 0.315 mmol), triphenylphosphine
(116 mg, 0.441 mmol), N-formylleucin (126 mg, 0.788 mmol), and