PAPER
(±)-9-epi-Wailupemycin A
385
was added to the mixture and the aqueous layer was extracted with
IR (ATR, neat): 3066 (w), 2957 (w), 2897 (w), 2859 (w), 1724 (m),
1646 (w), 1569 (w), 1454 (w), 1420 (w), 1314 (w), 1250 (m),
1196 (w), 1135 (w), 1102 (m), 997 (w), 919 (m), 897 (m), 842 (s),
Et O (4 × 10 mL). The combined organic layers were washed with
2
brine (20 mL) and dried (Na SO ). The solvent was removed under
2
4
–
1
reduced pressure to give 22 (102 mg, 203 μmol, 80%) as an orange
740 (m), 699 (s), 613 (w), 545 (w), 505 (w), 405 cm (w).
oil. The yield was calculated by NMR analysis; R = 0.66 (pentane–
EtOAc, 2:1).
1
f
H NMR (300 MHz, CD Cl ): δ (cis-isomer) = 7.59–7.55 (m, 2 H,),
.55–7.52 (m, 2 H,), 7.38–7.23 (m, 11 H,), 5.94 (d, J = 2.3 Hz, 1 H),
2
2
7
1
H NMR (300 MHz, CDCl ): δ = 7.93–7.87 (m, 2 H), 7.75–7.61 (m,
5.42 (d, J = 2.3 Hz, 1 H), 5.07 (s, 1 H), 3.97–3.90 (m, 1 H), 3.82 (s,
3 H), 3.04 (d, J = 1.9 Hz, 1 H), 2.86 (d, J = 14.0 Hz, 1 H), 2.65 (t,
J = 11.9 Hz, 1 H), 2.45 (d, J = 13.9 Hz, 1 H), 2.24 (dd, J = 12.2, 4.9
Hz, 1 H), 1.92 (ddd, J = 15.0, 8.4, 2.0 Hz, 1 H), 1.83 (dd, J = 15.0,
5.7 Hz, 1 H), 0.99 (s, 9 H), 0.17 (s, 9 H,), 0.11 (s, 9 H); δ (trans-
isomer) = 7.68–7.59 (m, 4 H), 7.48–7.28 (m, 11 H), 5.80 (d, J = 2.2
Hz, 1 H), 5.40 (d, J = 2.2 Hz, 1 H), 5.35 (s, 1 H), 4.21–4.08 (m, 1
H), 3.80 (s, 3 H), 2.76 (d, J = 14.5 Hz, 1 H), 2.64 (d, J = 14.5 Hz, 1
H), 2.49 (dd, J = 13.8, 5.1 Hz, 1 H), 2.02–1.95 (m, 1 H), 1.95–1.76
3
7
H), 7.47–7.32 (m, 6 H), 4.52 (s, 1 H), 4.42–4.36 (m, 1 H), 3.65 (s,
2
H), 3.01 (dd, J = 14.1, 2.9 Hz, 2 H), 2.92 (dd, J = 14.1, 3.7 Hz, 2
H), 1.00 (s, 9 H).
13
C NMR (75 MHz, CDCl ): δ = 203.4 (2 C), 196.8, 136.3, 135.9 (4
3
C), 134.0, 132.5 (2 C), 130.3 (2 C), 128.8 (2 C), 128.8 (2 C), 128.0
(4 C), 86.3, 65.3, 45.7 (2 C), 45.2, 26.8 (3 C), 19.2.
+
HRMS (ESI): m/z calcd for C H O Si + Na [M + Na] : 523.1911;
3
0
32
5
found: 523.1909.
(
m, 2 H), 1.06 (s, 9 H), 0.16 (s, 9 H), 0.08 (s, 9 H).
1
3
C NMR (125 MHz, CD Cl ): δ (cis-isomer) = 171.4, 164.9, 162.9,
6
-(tert-Butyldiphenylsilyloxy)-2-phenyl-3a,7a-bis(trimethyl-
2
2
silyloxy)-5,6,7,7a-tetrahydrobenzofuran-4(3aH)-one (23)
158.5, 136.1 (2 C), 136.0 (2 C), 134.5, 134.3, 130.0 (2 C), 130.0,
129.9, 128.7 (2 C), 128.0 (2 C), 127.9 (2 C), 126.1 (2 C), 109.4,
103.1, 97.0, 88.1, 87.8, 78.2, 65.1, 56.3, 43.8, 43.1, 40.2, 27.1 (3 C),
19.3, 2.2 (3 C), 2.1 (3 C); δ (trans-isomer) = 171.3, 164.7, 163.2,
157.2, 136.2 (2 C), 136.1 (2 C), 134.8, 134.6, 130.3, 130.0, 130.0,
129.8, 128.7 (2 C), 128.0 (2 C), 127.9 (2 C), 125.9 (2 C), 109.6,
103.2, 99.0, 89.2, 88.0, 76.9, 65.4, 56.3, 43.9, 43.0, 39.7, 27.2 (3 C),
19.4, 2.4 (3 C), 2.1 (3 C).
Aldol 22 (116 mg, 232 μmol) was dissolved in anhydrous CH Cl
2
2
(
5 mL) and cooled to 0 °C. First 2,6-lutidine (110 μL, 926 µmol)
and then Me SiOTf (80.0 μL, 463 μmol) were added dropwise to
3
the cooled solution. The reaction mixture was warmed up to r.t. and
stirred for 12 h. Sat. aq NaHCO (20 mL) was added and the aque-
ous layer was extracted with Et O (3 × 10 mL). The combined or-
ganic layers were washed with H O (10 mL) and brine (20 mL), and
3
2
2
dried (Na SO ). The solvent was removed under reduced pressure
and the crude product was purified by flash chromatography on sil-
ica gel (pentane–EtOAc, 100:3) to give 23 (89.0 mg, 138 μmol,
+
2
4
HRMS (EI): m/z calcd for C H O Si [M] : 784.3283; found:
4
3
56
8
3
7
84.3270.
6
0%) as a white foam; R = 0.22 (pentane–EtOAc, 100:2).
f
9-epi-Wailupemycin A (25)
Alcohol 24 (25.0 mg, 32.0 μmol) was dissolved in THF (0.4 mL)
and a solution of TBAF (1.0 M in THF, 0.19 mL, 191 μmol) and
AcOH (0.04 mL, 732 μmol) were added dropwise. After stirring for
IR (ATR, neat): 3066 (w), 2957 (w), 2898 (w), 2859 (w), 1723 (m),
1
1
9
4
1
642 (w), 1583 (w), 1452 (w), 1426 (w), 1386 (w), 1311 (w),
251 (m), 1197 (m), 1133 (m), 1084 (s), 1053 (m), 995 (w),
19 (s), 896 (m), 839 (s), 736 (s), 698 (s), 612 (w), 503 (m),
3
h at r.t., sat. aq NH Cl (20 mL) was added. The aqueous layer was
4
–1
extracted with CHCl (5 × 10 mL) and the combined organic layers
00 cm (w).
3
were washed with phosphate puffer (pH 7) and brine (10 mL), and
H NMR (300 MHz, CD Cl ): δ = 7.60–7.57 (m, 2 H), 7.56–7.52
2
2
dried (Na SO ). The solvent was removed under reduced pressure
2
4
(
m, 2 H), 7.41–7.37 (m, 2 H), 7.36–7.32 (m, 5 H), 7.31–7.24 (m, 4
and the crude product purified by flash chromatography on silica
gel (EtOAc) to give 25 (11.0 mg, 27.3 μmol, 85%) as a white solid;
H), 5.00 (s, 1 H), 4.17–4.10 (m, 1 H), 2.82 (ddd, J = 18.0, 7.0, 2.0
Hz, 1 H), 2.50–2.44 (m, 2 H), 1.98 (dd, J = 13.3, 11.3 Hz, 1 H), 1.03
mp 175 °C; R = 0.29 (EtOAc).
f
(s, 9 H), 0.16 (s, 9 H), 0.15 (s, 9 H).
IR (ATR, neat): 3355 (w), 2924 (w), 2853 (w), 1723 (m), 1687 (s),
1636 (m), 1557 (s), 1454 (m), 1411 (m), 1356 (w), 1319 (w),
13
C NMR (75 MHz, CD Cl ): δ = 206.2, 158.8, 136.1 (2 C), 136.0
2
2
(
(
2 C), 134.0, 133.9, 130.3, 130.2, 130.2, 129.5, 128.8 (2 C), 128.1
2 C), 128.0 (2 C), 126.2 (2 C), 108.9, 98.5, 90.6, 63.6, 48.0 (2 C),
1
9
6
1
252 (s), 1206 (m), 1145 (m), 1093 (w), 1063 (w), 1033 (m),
96 (w), 939 (w), 906 (w), 862 (w), 819 (w), 747 (w), 686 (m),
47.7 (2 C), 27.1 (3 C), 19.3, 2.6 (3 C), 1.7 (3 C).
–1
40 (w), 600 (w), 548 (m), 493 (w), 409 cm (w).
+
HRMS (EI): m/z calcd for C H O Si [M] : 644.2810; found:
3
6
48
5
3
H NMR (500 MHz, CD CN): δ = 8.02–7.97 (m, 2 H), 7.66–7.61
3
644.2796.
(m, 1 H), 7.54–7.49 (m, 2 H), 6.00 (d, J = 2.2 Hz, 1 H), 5.46 (d, J =
2
.2 Hz, 1 H), 4.38–4.32 (m, 2 H), 4.02 (d, J = 1.4 Hz, 1 H), 3.85 (d,
6
-[(6-(tert-Butyldiphenylsilyloxy)-4-hydroxy-2-phenyl-3a,7a-
J = 16.6 Hz, 1 H), 3.81 (s, 3 H), 3.73 (d, J = 7.8 Hz, 1 H), 3.49 (dd,
J = 16.6, 1.1 Hz, 1 H), 3.12 (dd, J = 13.5, 4.5 Hz, 1 H), 2.92 (d,
J = 14.2 Hz, 1 H), 2.81 (d, J = 14.2 Hz, 1 H), 2.65 (dt, J = 13.5, 2.6
Hz, 1 H), 2.29 (ddd, J = 15.6, 3.7, 1.5 Hz, 1 H), 2.20 (dt, J = 15.6,
2
13
bis(trimethylsilyloxy)-3a,4,5,6,7,7a-hexahydrobenzofuran-4-
yl)methyl)-4-methoxy-2H-pyran-2-one (24)
LDA was prepared freshly by slowly adding n-BuLi (1.6 M in THF)
(1.61 mL, 2.57 mmol) to a solution of i-Pr NH (0.41 mL,
2
.6 Hz, 1 H).
2
.92 mmol) in anhydrous THF (8.5 mL) at –78 °C. The solution
was stirred 15 min at –78 °C and then 5 min at r.t., and then cooled
C NMR (125 MHz, CD CN): δ = 209.0, 198.5, 172.2, 165.1,
3
1
8
to –78 °C. Methylpyrone 6 (369 mg, 2.63 mmol) in anhydrous
THF (10 mL) was slowly added to the LDA solution at –78 °C. The
reaction mixture was stirred 25 min at –78 °C. A solution of enol si-
lyl acetal 23 (404 mg, 0.63 mmol) in anhydrous THF (8.5 mL) was
slowly added to the mixture at –78 °C and stirred for 20 min at this
1
8
62.6, 138.0, 134.6, 129.7 (2 C), 129.5 (2 C), 104.0, 88.6, 83.2,
2.9, 70.5, 57.0, 46.8, 43.9, 40.7, 38.0.
+
HRMS (ESI): m/z calcd for C H O + Na [M + Na] : 425.1207;
found: 425.1206.
2
1
22
8
temperature. Sat. aq NH Cl (20 mL) was added to the mixture with
4
subsequent stirring for 5 min at r.t. The aqueous layer was extracted
Acknowledgment
with CH Cl (5 × 15 mL) and the combined organic layers were
2
2
washed with brine (25 mL) and dried (Na SO ). The solvent was re-
Generous support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
2
4
moved under reduced pressure and the crude product purified by
flash chromatography on silica gel (pentane–EtOAc, 3:1 to 2:1) to
give 24 (254 mg, 322 μmol, 51%) with a dr of 5.9:1 as a white foam;
Rf = 0.69 (pentane–EtOAc, 1:1).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 381–386