Synthesis of Fragments of Petriellin A
627
After 10 min, solid sodium bicarbonate (a spatula tip) was added
and stirring was continued for 5 min. The reaction mixture was
then filtered to remove trichloroacetamide, and the filtrate was
concentrated at reduced pressure. The residue was purified by
column chromatography (silica, 20% ether/hexane elution) to
give the ester 58 as a clear colourless gum (1.22 g, 90%).
[α]2D4 +20.0 (c 1.0 in CHCl3). (Found: C 74.2, H 7.1, N 2.6.
C31H35NO5 requires C 74.2, H 7.0, N 2.8%.) νmax (NaCl)/cm−1
3089, 3066, 3032, 3003, 3000–2800, 1740, 1702, 1479, 1452,
1400, 1369, 1313, 1249, 1140, 1109, 1088, 1067, 1054, 1030,
987, 757, 740, 697. δH (rotamers) 7.78–7.24 (13H, m, ArH),
4.95–4.22 (7H, m, CHCH2, ArCH2, CH3CH, NCHCO), 3.14–
3.05 (3H, m, NCH3), 1.46 (9H, s, But), 1.22 and 1.13 (3H, 2d,
J 6.4 and 6.3, CH3CHO). δC (rotamers) 168.9, 168.7, 157.6,
156.4, 144.1, 143.9, 141.3, 138.4, 138.2, 128.2, 127.9, 127.6,
127.3, 127.2, 127.1, 127.0, 125.0, 124.9, 119.9, 81.8, 81.6,
75.5, 74.5, 71.6, 71.5, 67.7, 67.5, 63.6, 63.4, 47.2, 33.0, 32.7,
28.0, 16.0.
by TLC (silica, 20% EtOAc/hexane, ∼1 h to completion). The
mixture was then filtered through Celite with MeOH (5 mL) as
eluent and the combined filtrates were concentrated to dryness
under vacuum. The residual amine 49 was combined with the
acid 61 in CH2Cl2 (5 mL), to which was added PyBroP (111 mg,
0.24 mmol) and the mixture was cooled to 0◦C with an ice bath.
To the cooled solution was added Pri2NEt (113 µL, 0.65 mmol)
and stirring was continued at 0◦C for 30 min, when the ice
bath was removed, and the reaction mixture was left overnight.
The solution was diluted with EtOAc (50 mL) and it was then
washed successively with dilute HCl (10 mL), water (10 mL),
5% NaHCO3 solution (10 mL), and brine (10 mL). The organic
phase was dried (MgSO4), filtered, and concentrated under vac-
uum to give a residue, which was filtered through a plug of silica
with 30% EtOAc/hexane as eluent to afford the crude tetramer 8.
Further elution with 60% EtOAc/hexane gave the tetramer 62.
The tetramer 8 was further purified by column chromatography
(silica, 20% Et2O/hexane, then 40% Et2O/hexane) to give the
tetramer 8 (82 mg, 45%) identical in all respects with the mate-
rial described below. The crude tetramer 62 was also purified
by column chromatography (silica, 70% Et2O/hexane) and was
isolated as a clear colourless gum (224 mg, 15%). m/z (ESMS)
771 ([M + K], 10%), 755 ([M + Na], 100), 731 ([M + H], 28),
532 (55), 500 (10), 419 (26), 329 (8). δH (rotamers) 7.75–7.24
(8H, m, ArH), 5.40–4.18 (8H, m, NH, CHCH2, C=CHCH3,
NCHCO × 3), 3.40–2.96 (9H, m, NCH3 × 3), 2.39–0.77 (26H,
m, CH(CH3)CH2CH3, C=CHCH3, CH3CHCH3 × 2).
(2S,3R)-tert-Butyl 2-((S)-2-(((9H-Fluoren-9-yl)methoxy)
carbonylamino)-N,3-dimethylbutanamido)-
3-(benzyloxy)butanoate 60
The ester 58 (520 mg, 1.0 mmol) was dissolved in 33%
Et2NH/DMF solution (6 mL) for 1 h and then the mixture was
concentrated at reduced pressure to give crude amine 44, which
was used directly. The amine 44 was taken up in CH2Cl2 (6 mL)
and the acid 59 (457 mg, 1.4 mmol) was added, followed by
PyBroP (630 mg, 1.4 mmol).The solution was stirred and cooled
to 0◦C with an ice bath, and then Pri2NEt (540 µL, 3.1 mmol) was
added and the reaction mixture was stirred overnight at 0◦C. The
reaction mixture was then diluted with Et2O (30 mL) and the
ethereal solution was washed successively with water (15 mL),
5% citric acid solution (15 mL), brine (15 mL), 5% NaHCO3
solution (15 mL), and brine (15 mL). The organic phase was
dried (MgSO4), filtered, and concentrated under vacuum. The
residue was purified by column chromatography (silica, 20%
EtOAc/hexane) to give the dipeptide 60 (510 mg, 82%) as a clear
colourlessgum. [α]D22 +16.0(c 1.0 inCHCl3). νmax (NaCl)/cm−1
3302, 3089, 3066, 3038, 3000–2800, 1727, 1643, 1525, 1506,
1499, 1479, 1451, 1369, 1299, 1247, 1160, 1110, 1080, 1030,
758, 738, 698. δH 7.75–7.24 (13H, m, ArH), 5.81 (1H, d, J 9.2,
NH), 5.43 (1H, q, J 4.2, CH3CHO), 4.72–4.20 (7H, m, CHCH2,
ArCH2, NCHCO × 2), 3.30 (3H, s NCH3), 2.20–2.09 (1H, m,
CH3CHCH3), 1.44–1.39 (9H, m, But), 1.17, 1.08 and 1.01 (9H,
3d, J 6.2, 6.6 and 6.6, CH3CHCH3 and CH3CHO). δC 173.6,
168.2, 156.2, 143.7, 143.6, 141.0, 138.1, 128.0, 127.4, 127.2,
127.0, 126.8, 124.9, 124.1, 119.7, 81.5, 75.0, 71.4, 66.7, 60.9,
55.4, 46.9, 33.9, 31.0, 27.8, 27.6, 19.2, 17.4, 15.7.
(5S,8S,11S)-tert-Butyl 5-((R)-1-(Benzyloxy)ethyl)-11-sec-
butyl-1-(9H-fluoren-9-yl)-8-isopropyl-4,7,10-trimethyl-
3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate 65
The amine 49 (0.8 mmol) was taken up in CH2Cl2 (4 mL) and
the acid 57 (429 mg, 1.0 mmol) was added, followed by PyBroP
(450 mg, 1.0 mmol). The stirred reaction mixture was cooled to
0◦C with an ice bath and Pri2NEt (420 µL, 2.4 mmol) was added.
The mixture was stirred at 0◦C for 20 min and then the ice bath
was removed, and stirring was continued overnight.The solution
was diluted with Et2O (20 mL) and it was then washed succes-
sively with brine (10 mL), 5% citric acid solution (10 mL), brine
(10 mL), 5% NaHCO3 solution (10 mL), and brine (10 mL). The
ethereal layer was then dried (MgSO4), filtered, and concen-
trated at reduced pressure to leave a pale yellow residue that was
purified by column chromatography (silica, 40% Et2O/hexane)
to afford the tripeptide 65 (340 mg, 57%) as a clear colourless
gum. [α]2D8 −150.4 (c 1.0 in CHCl3). (Found [M + H] 742.4439.
C44H60N3O7 requires [M + H] 742.4431.) νmax (NaCl)/cm−1
3088, 3066, 3030, 3000–2800, 1731, 1705, 1643, 1472, 1454,
1394, 1369, 1300, 1258, 1163, 1094, 1088, 757, 740, 697, 666.
δH (rotamers) 7.76–7.13 (13H, m, ArH), 5.14–3.81 (9H, m,
CHCH2, CH3CHO, ArCH2, NCHCO × 3), 3.03–2.11 and 2.00–
1.91 (11H, 2 m, NCH3 × 2, CHCH3, CH3CHCH3), 1.45–1.41
(9H, m, But), 1.25–1.17 and 0.98–0.68 (17H, 2 m, CH3CHO,
CH(CH3)CH2CH3, CH3CHCH3). δC (rotamers) 170.6, 170.5,
170.0, 169.9, 169.7, 169.2, 168.9, 168.7, 157.0, 156.6, 144.1,
144.0, 143.7, 141.4, 141.1, 138.24, 138.2, 128.2, 127.6, 127.5,
127.3, 125.0, 124.84, 124.8, 124.4, 119.9, 119.6, 119.5, 81.2,
71.1, 70.5, 70.4, 70.2, 67.5, 66.5, 60.9, 60.6, 60.4, 60.2, 59.9,
59.1, 57.8, 57.5, 47.3, 47.1, 33.4, 32.8, 32.7, 31.8, 31.1, 31.0,
30.4, 30.2, 29.8, 29.6, 29.5, 29.3, 28.0, 27.9, 27.4, 24.6, 24.5,
19.2, 19.0, 18.1, 17.6, 17.2, 16.4, 16.3, 16.2, 15.9, 14.0, 11.7,
10.6. Further elution gave the dehydro tripeptide 66 (35 mg, 7%).
m/z (ESMS) 634 ([M + H], 100%).
(5S,8S,11S,14S)-tert-Butyl 8-((R)-1-(Benzyloxy)ethyl)-
14-sec-butyl-1-(9H-fluoren-9-yl)-5,11-diisopropyl-
7,10,13-trimethyl-3,6,9,12-tetraoxo-2-oxa-
4,7,10,13-tetraazapentadecan-15-oate 8
(Convergent Approach)
The dipeptide 60 (130 mg, 0.22 mmol) was dissolved in 50%
TFA/CH2Cl2 (2 mL) for ∼1 h. The solution was then concen-
trated at reduced pressure and the residue was taken up in toluene
(10 mL) and reconcentrated to leave the acid 61, which was
left under high vacuum overnight. Meanwhile, the dipeptide 54
(100 mg, 0.22 mmol) was dissolved in MeOH (3 mL) and 10%
Pd-on-C catalyst (20 mg) was added. The reaction mixture was
stirred in an H2 atmosphere and the reaction was monitored