FEATURE ARTICLE
Nosiheptide A-Ring Lessons
1309
Azido Thioester 23a
1H NMR (400 MHz, CDCl3): δ = –0.02, 0.00 [s, 3 H, Si(CH3)2],
0.89 [s, 9 H, SiC(CH3)3], 8.09 (s, 1 H, H5), 1.42 [s, 9 H,
CO2C(CH3)3], 2.45 (dd, J = 4.7, 8.3 Hz, 2 H, H2′), 4.43 (dd, J = 4.1,
8.2 Hz, 1 H, H3′), 4.83 (dt, J = 1.3, 5.8 Hz, 2 H, CH2CH=CH2),
5.23–5.05 (m, 3 H, H1′, CH2Ph), 5.28 (dq, J = 1.2, 10.4 Hz, 1 H,
CH=CHH), 5.39 (dq, J = 1.5, 17.2 Hz, 1 H, CH=CHH), 5.81 (d,
J = 7.8 Hz, 1 H, NH), 6.01 (ddt, J = 5.8, 10.4, 16.2 Hz, 1 H,
CH=CH2), 7.42–7.29 (m, 5 H, Ph).
Freshly activated Zn powder49 (2.0 g, 30.7 mmol) was added to di-
ester 22a (515 mg, 0.86 mmol) in THF (35 mL) and 1 M KH2PO4
(5 mL) was added. The mixture was sonicated for 16 h, filtered on
a sintered filter and concentrated to remove all THF. The aqueous
phase was dissolved in 5% citric acid soln and extracted with Et2O
(3 × 50 mL). The combined organic phases were washed with sat.
NaCl (30 mL) and dried (MgSO4). Concentration and purification
by column chromatography (silica gel, 50 g, CHCl3–MeOH, 15:1)
gave the acid (341 mg, 0.73 mmol, 85%) as a colorless gum.
13C NMR (100.6 MHz, CDCl3): δ = –5.3, –4.8, 18.3, 25.9, 28.5,
38.9, 50.5, 66.1, 67.2, 69.8, 80.4, 119.0, 127.9, 128.7, 128.8, 132.1,
135.4, 147.2, 155.3, 161.1, 172.8, 174.2.
[α]D20 –25.7 (c 1.0, CHCl3); Rf = 0.25 (CHCl3–MeOH, 12:1).
HRMS (ESI): m/z [M + H]+ calcd for C29H43N2O7SSi: 591.2555;
found: 591.2551.
IR (KBr): 2957 (w), 2858 (w), 1731 (s), 1715 (s), 1505 (m), 1394
(m), 1368 (m), 1166 (s), 840 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 0.02 [s, 3 H, Si(CH3)2], 0.88 [s, 9
H, SiC(CH3)3], 1.42 [s, 9 H, CO2C(CH3)3], 2.23–2.09 (m, 1 H, H3),
2.30 (dd, J = 6.8, 14.5 Hz, 1 H, H3), 4.46–4.33 (m, 2 H, H2, H4),
5.15 (s, 2 H, CH2Ph), 5.46 (d, J = 7.2 Hz, 1 H, NH), 7.40–7.30 (m,
5 H, Ph).
13C NMR (100.6 MHz, CDCl3): δ = –5.4, –4.9, 18.3, 25.9, 28.5,
36.0, 51.2, 67.2, 69.8, 80.6, 128.7, 128.8, 135.4, 156.3, 172.9,
176.6.
Bisthiazole 4a
N-Boc-protected amine 24a (325 mg, 0.55 mmol) was dissolved in
CH2Cl2–TFA (5 mL, 7:3) with stirring for 1 h. Toluene was added
and co-evaporated under high vacuum to completely remove TFA
(2 × 10 mL). Amide formation following GP1 with the crude
amine, carboxylic acid 18 (281 mg, 0.52 mmol), HOBt (120 mg,
0.78 mmol), Et3N (0.11 mL, 0.78 mmol), and EDC·HCl (125 mg,
0.65 mmol) followed by after column chromatography purification
(silica gel, 30 g, PE–EtOAc, 4:1) gave 4a (312 mg, 0.30 mmol,
58%) as a colorless foam.
HRMS (ESI): m/z [M + Na]+ calcd for C23H37NO7SiNa: 490.2232;
found: 490.2227.
[α]D20 +3.6 (c 1.0, CHCl3); Rf = 0.19 (PE–EtOAc, 2:1).
Anal. Calcd for C23H37NO7Si: C 59.1; H 8.0; N 3.0. Found: C 58.8;
H 8.0; N 2.6.
IR (KBr): 3387 (br w), 2976 (m), 2857 (m), 1726 (s), 1696 (s), 1532
(m), 1488 (s), 1228 (s), 813 (s), 758 cm–1 (m).
Et3SiH (0.52 mL, 3.3 mmol) was added to allyl (R)-2-azido-3-
(tritylthio)propanoate (1.29 g, 3.0 mmol) in CH2Cl2–TFA (20 mL,
9:1) and the mixture was stirred for 10 min at r.t. The volatiles were
removed, and co-evaporated with toluene under high vacuum. The
resulting free thiol was dissolved in CH2Cl2, treated with glutamic
acid prepared above (1.18 g, 2.5 mmol), HOBt (574 mg, 3.8 mmol),
Et3N (0.52 mL, 3.8 mmol), and EDC·HCl (600 mg, 3.1 mmol) fol-
lowing GP1. Purification by column chromatography (silica gel,
150 g, PE–EtOAc, 9:1) gave 23a (1.36 g, 2.1 mmol, 86%) as a col-
orless oil.
1H NMR (400 MHz, CDCl3): δ = 0.00, 0.01 [s, 3 H, Si(CH3)2], 0.89
[s, 9 H, SiC(CH3)3], 1.20 (d, J = 6.4 Hz, 3 H, H4′′′′), 1.35 [s, 9 H,
OC(CH3)3], 1.88 (d, J = 7.2 Hz, 3 H, H3′′′), 2.78–2.61 (m, 2 H, H2′),
4.32–4.23 (m, 2 H, H3′′′, Fmoc-CH), 4.47–4.41 (m, 3 H, Fmoc-
CH2, H2′′′′), 4.49 (dd, J = 4.6, 8.1 Hz, 1 H, H3′), 4.85 (dt, J = 1.4,
5.8 Hz, 2 H, CH2CH=CH2), 5.09 (d, J = 12.1 Hz, 1 H, CHHPh),
5.14 (d, J = 12.1 Hz, 1 H, CHHPh), 5.30 (dq, J = 1.2, 10.4 Hz, 1 H,
CH=CHH), 5.41 (dq, J = 1.5, 17.2 Hz, 1 H, CH=CHH), 5.75 (td,
J = 5.1, 8.9 Hz, 1 H, H1′), 6.04–5.98 (m, 2 H, CH=CH2, Fmoc-NH),
6.70 (q, J = 7.1 Hz, 1 H, H2′′′), 7.38–7.29 (m, 7 H, Fmoc, Ph), 7.42
(t, J = 7.5 Hz, 2 H, Fmoc), 7.62 (d, J = 7.3 Hz, 2 H, Fmoc), 7.78 (d,
J = 7.5 Hz, 2 H, Fmoc), 7.95 (d, J = 8.8 Hz, 1 H, 1′-NH), 8.06 (s, 1
H, H5′′), 8.12 (s, 1 H, H5), 8.67 (s, 1 H, 1′′′-NH).
[α]D20 –53.5 (c 2.0, CHCl3); Rf = 0.50 (PE–EtOAc, 2:1).
IR (KBr): 3366 (br m), 3068 (w), 2931 (s), 2118 (s), 1505 (m), 1457
(m), 1392 (m), 1169 (m), 840 (s), 783 cm–1 (s).
1H NMR (400 MHz, CDCl3): δ = 0.02, 0.04 [s, 3 H, Si(CH3)2], 0.90
[s, 9 H, SiC(CH3)3], 1.45 [s, 9 H, CO2C(CH3)3], 2.32–2.00 (m, 2 H,
H3′), 3.17 (dd, J = 7.9, 13.9 Hz, 1 H, CHHS), 3.35 (dd, J = 5.4,
13.8 Hz, 1 H, CHHS), 4.06 (dd, J = 5.4, 7.9 Hz, 1 H, CHN3), 4.37
(dd, J = 3.0, 8.9 Hz, 1 H, H2′), 4.46 (td, J = 3.8, 8.7 Hz, 1 H, H4),
4.76–4.62 (m, 2 H, CH2CH=CH2), 5.14 (s, 2 H, CH2Ph), 5.43–5.22
(m, 2 H, CH=CH2), 5.55 (d, J = 7.9 Hz, 1 H, NH), 5.92 (ddt, J = 5.8,
10.4, 16.2 Hz, 1 H, CH=CH2), 7.40–7.30 (m, 5 H, Ph).
13C NMR (100.6 MHz, CDCl3): δ = –5.2, –4.8, 14.3, 17.2, 18.4,
25.9, 28.5, 39.3, 47.4, 47.9, 59.1, 66.1, 67.0, 67.2, 67.3, 69.5, 76.4,
119.0, 120.2, 123.8, 125.3, 126.6, 127.3, 128.0, 128.1, 128.3, 128.6,
128.8, 132.1, 135.5, 141.6, 143.9, 147.0, 149.7, 156.3, 160.9, 161.1,
167.2, 168.4, 171.9, 173.0.
HRMS (ESI): m/z [M + H]+calcd for C54H66N5O10S2Si: 1036.4015;
found: 1036.4031.
13C NMR (100.6 MHz, CDCl3): δ = –5.3, –4.8, 18.3, 25.9, 28.5,
30.3, 36.5, 58.4, 61.5, 66.9, 67.3, 69.7, 80.7, 119.7, 128.8, 131.3,
135.4, 155.3, 168.4, 172.6, 200.8.
HRMS (ESI): m/z [M + H]+ calcd for C29H45N4O8SSi: 637.2722;
found: 637.2719.
Benzyl Ester 57a
The free amine 26a (32 mg, 39 μmol) was added to the stirred soln
of free acid 56 (64 mg, 52 μmol), DEPBT (74 mg, 0.25 mmol) and
NaHCO3 (40 mg, 0.48 mmol) in anhyd THF (0.5 mL), the mixture
was stirred for 19 h at r.t. (TLC monitoring). The mixture was dilut-
ed with pH 7.0 phosphate buffer (20 mL) and extracted with CH2Cl2
(3 × 30 mL), and the combined organic layers were dried (Na2SO4)
and concentrated. Purification by column chromatography (silica
gel, 20 g, CH2Cl2–MeOH, 50:1) gave the coupling product 57a
(69 mg, 34 μmol, 87%) of as a colorless glass, suitable for further
elaboration. Rigorous purification by preparative HPLC gave the
coupling product (37.7 mg, 19 μmol, 47%) as a colorless glass.
Thiazole 24a
The crude thiazoline was obtained by GP2 from thioester 23a
(859 mg, 1.3 mmol) and Ph3P (530 mg, 2.0 mmol). After removal
of the volatiles, the residue was oxidized with DBU (0.6 mL,
4.0 mmol) and BrCCl3 (0.2 mL, 2.0 mmol) following GP3. Purifi-
cation by column chromatography (silica gel, 150 g, PE–EtOAc,
6:1) gave 24a (735 mg, 1.2 mmol, 92%) as a colorless oil.
[α]D20 +4.8 (c 0.8, CHCl3); Rf = 0.59 (CH2Cl2–MeOH, 10:1).
[α]D20 –33.4 (c 1.0, CHCl3); Rf = 0.27 (PE–EtOAc, 4:1).
1H NMR (400 MHz, CD3OD): δ = –0.05 (s, 3 H, TBS), –0.03 (s, 3
H, TBS), 0.85 (s, 9 H, TBS), 1.08, 1.10 (21 H, TIPS), 1.26 (t,
J = 4.6 Hz, 3 H, CH3), 1.32 (s, 9 H, t-Bu), 1.90 (d, J = 7.2 Hz, 3 H,
CH3), 2.29 (s, 3 H, CH3), 2.65 (dd, J = 8.0, 5.2 Hz, 3 H, CH, CH2),
2.73 (dd, J = 9.0, 5.6 Hz, 1 H, CH), 4.15 (dd, J = 5.2 Hz, 1 H, CH2),
IR (KBr): 3355 (w), 3093 (w), 2931 (m), 2858 (w), 1715 (s), 1505
(m), 1367 (m), 1174 (m), 840 cm–1 (s).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1300–1311