S. Mizutani et al. / Tetrahedron xxx (2016) 1e6
5
form:
.59 (m, 2H), 3.09 (m, 2H), 2.91 (s, 2H); C NMR (100 MHz, CDCl
keto form: 197.2, 166.5, 135.3, 130.6 (2C), 128.0 (2C), 126.7, 109.3,
5.2, 65.1, 49.6, 47.6, 44.0; enol form: 171.7, 171.6, 135.8,130.9 (2C),
d
14.6 (br s, 1H), 7.26 (m, 5H), 6.35 (br s, 2H), 3.09 (m, 2H),
addition of water, and the mixture was diluted with EtOAc. After
the layers were separated, the aqueous layer was extracted with
EtOAc. The combined organic layer was washed with brine, dried
13
3
3
)
d
6
d
over Na
gel column chromatography (hexane/EtOAc¼6/1) to give 17 (1.14 g,
72%) as colorless oil. IR (neat)
max¼3392, 3269, 3020, 2981, 2935,
2985, 1784, 1474, 1713, 1493, 1456, 1394, 1369, 1319, 1234, 1145,
2 4
SO , and concentrated. The residue was purified by silica
1
27.7 (2C), 126.4, 110.0, 88.0, 65.2, 65.3, 44.2, 43.1; HRMS (ESI) m/z
79
þ
calcd for C14
H
16 BrNO
4
Na ([MþNa] ) 364.0155, found 364.0155.
n
ꢂ
1
5: Mp¼110e112 C, IR (KBr)
n
max¼3446, 3299, 3236, 3056,
ꢁ1 1
3
029, 3004, 2962, 2929, 2881, 1737, 1689, 1583, 1496, 1436, 1389,
1078, 1032, 848 cm ; H NMR (400 MHz, CD OD) d 7.22 (m, 5H),
3
ꢁ
1 1
1
(
(
365, 1346, 1313, 1259, 1215, 1145, 1113, 1080, 1059 cm ; H NMR
400 MHz, CDCl 7.27 (m, 5H), 6.72 (br s, 1H), 6.13 (br s, 1H), 3.93
m, 2H), 3.69 (s, 2H), 3.28 (s, 2H), 3.18 (s, 2H); C NMR (100 MHz,
189.8, 165.4, 135.8, 130.8 (2C), 128.0 (2C), 126.7, 109.3, 65.4
3.89 (m, 2H), 3.67 (m, 2H), 3.11 (d, J¼16.0 Hz,1H), 3.04 (d, J¼16.0 Hz,
3
)
d
1H), 3.04 (s, 2H), 1.50 (s, 9H), the peak derived from H-2 was not
13
13
observed; C NMR (100 MHz, CD
3
OD)
d
196.7, 167.2, 152.8, 137.4,
CDCl
3
)
d
131.9 (2C), 128.9 (2C), 127.6, 110.3, 83.9, 66.2, 66.1, 47.7, 44.5, 28.2
7
9
(
2C), 62.6, 43.9, 43.2; HRMS (FAB) m/z calcd for C14
H
15 Br
2
NO
4
Na
(3C), the peak derived from C-2 was not observed; HRMS (ESI) m/z
þ
79
þ
(
[MþNa] ) 441.9260, found 441.9262.
calcd for C19
H
24 BrNO
6
Na ([MþNa] ) 464.0679, found 464.0680.
4
.3.4. (ꢀ)-Berkeleyamide D (1). Triethylamine (9.4
was added to a solution of 10 (23.0 mg, 67.2
butylglyoxal (3) (8.4 mg, 73.6 mol) in a 10:1 mixture of THF and
O (2.2 mL). The mixture was stirred at room temperature for 2 h.
The reaction was quenched by the addition of water, and the
mixture was diluted with CH Cl . After the layers were separated,
the organic layer was washed with water twice, brine, dried over
Na SO , and concentrated to a volume of 2 mL.
A 30% aqueous HClO solution (0.10 mL, 52.8
the solution of the crude product in CH Cl (2 mL) at room tem-
m
L, 67.4
m
mol)
4.3.7. tert-Butyl
tyl}-3-(3-methylbutanoyl)oxirane-2-carbonyl]carbamate
(16). Triethylamine (15.3 L, 0.110 mmol) was added to a solution
of 17 (48.3 mg, 0.109 mmol) and isobutylglyoxal (3) (15.1 mg,
0.132 mmol) in a 10:1 mixture of THF and H O (2 mL). The mixture
was stirred at room temperature for 1.5 h. The reaction was
quenched by the addition of water, and the mixture was diluted
with EtOAc. After the layers were separated, the aqueous layer was
extracted with EtOAc. The combined organic layer was washed
[(2RS,3RS)-2-{2-(2-benzyl-1,3-dioxolan-2-yl)ace-
m
mol) and iso-
m
m
H
2
2
2
2
2
4
4
mmol) was added to
2
2
2 4
with brine, dried over Na SO , and concentrated. The residue was
perature, and the mixture was stirred for 3 days. The reaction was
quenched by the addition of water, and the mixture was diluted
with EtOAc. After the layers were separated, the organic layer was
purified by silica gel column chromatography (hexane/EtOAc¼5/1)
ꢂ
to give 16 (47.8 mg, 92%) as a colorless solid. Mp¼34e38 C; IR (KBr)
n
max¼3276, 2960, 2933, 1788, 1753, 1716, 1493, 1458, 1396, 1369,
1 1
ꢁ
washed with brine, dried over Na
2
SO
4
, and concentrated. The res-
1315, 1236, 1151, 1065, 1032, 854, cm ; H NMR (400 MHz, CD
3
OD)
idue was purified by preparative TLC (hexane/EtOAc¼1/1) to give
d
7.24 (m, 5H), 4.14 (s, 1H), 3.88 (m, 2H), 3.67 (m, 2H), 3.06 (d,
(
ꢀ)-1 (5.1 mg, 23% over two steps) as
a
white solid.
J¼18.0 Hz, 1H), 3.02 (d, J¼18.0 Hz, 1H), 2.89 (d, J¼15.6 Hz, 1H), 2.72
(d, J¼15.6 Hz, 1H), 2.49 (dd, J¼18.0, 7.2 Hz, 1H), 2.45 (dd, J¼18.0,
ꢂ
Mp¼142e143 C, IR (KBr)
n
max¼3396, 3210, 3034, 2951, 1732, 1674,
ꢁ1
1
574, 1454, 1387, 1352, 1277, 1180, 1149, 1126, 964, 852, 817 cm
H NMR (400 MHz, CDCl
;
6.4 Hz, 1H), 2.09 (m, 1H), 1.46 (s, 9H), 0.92 (d, J¼7.2 Hz, 3H), 0.90 (d,
1
13
3
)
d
7.35 (m, 5H), 6.77 (br s, 1H), 5.51 (d,
J¼7.2 Hz, 3H); C NMR (100 MHz, CD
3
OD) d 203.3, 200.0, 166.3,
J¼0.8 Hz, 1H), 5.37 (d, J¼0.4 Hz, 1H), 4.43 (d, J¼10.4 Hz, 1H), 4.02 (d,
152.6, 137.4, 131.9 (2C), 128.9 (2C), 127.6, 110.6, 83.8, 68.9, 66.2, 66.1,
J¼17.6 Hz, 1H), 3.96 (d, J¼17.6 Hz, 1H), 3.06 (d, J¼10.4 Hz, 1H), 1.94
62.0, 50.3, 44.9, 42.9, 28.2 (3C), 24.7, 22.84, 22.80; HRMS (ESI) m/z
calcd for C25
þ
(
m, 1H), 1.88 (m, 1H), 1.61 (m, 1H), 1.02 (d, J¼6.4 Hz, 3H) 1.01 (d,
H33NO
8
Na ([MþNa] ) 489.2099, found 489.2097.
13
J¼6.4 Hz, 3H); C NMR (100 MHz, CDCl
3
) d 199.4,197.8,164.0,133.2,
1
2
3
29.2 (2C), 129.0 (2C), 127.8, 104.4, 95.3, 84.9, 75.2, 45.5, 37.4, 24.0,
4.3.8. (ꢀ)-Berkeleyamide D (1) and (2RS,3RS)-6-benzyl-2-(3-
methylbutanoyl)-1-oxa-5-azaspiro[2.5]oct-6-ene-4,8-dione (19). A
30% aqueous HClO
þ
3.9, 23.8; HRMS (ESI) m/z calcd for C18
54.1312, found 354.1312.
H21NO
5
Na ([MþNa] )
4
solution (0.10 mL, 52.8
mmol) was added to
a solution of 16 (21.4 mg, 45.0
m
mol) in CH
2
2
Cl (2 mL) at room
4
.3.5. tert-Butyl {4-(2-benzyl-1,3-dioxolan-2-yl)-3-oxobutanoyl}car-
temperature, and the mixture was stirred for 3 days. The reaction
was quenched by the addition of water, and the mixture was di-
bamate (18). A solution of 13 (1.54 g, 4.42 mmol) and tert-butyl
carbamate (518 mg, 4.42 mmol) in acetonitrile (45 mL) was stirred
under reflux for 30 min. The mixture was cooled to room temper-
ature and concentrated. The residue was purified by silica gel
luted with CHCl
was extracted with CHCl
with brine, dried over Na
3
. After the layers were separated, the aqueous layer
. The combined organic layer was washed
SO , and concentrated. The residue was
3
2
4
chromatography (hexane/CHCl
3
/EtOAc¼6/3/1) to give 18 (1.41 g,
purified by silica gel column chromatography (hexane/EtOAc¼4/1)
8
8%) as a 2:1 mixture of keto form and enol form as a white solid.
to give (ꢀ)-1 (5.80 mg, 39%) and 19 (3.20 mg, 23%).
ꢂ
ꢂ
Mp¼65e67 C, IR (KBr)
485, 1456, 1371, 1336, 1292, 1232, 1149, 1091, 1064, 1035 cm ; H
NMR (400 MHz, CDCl ) keto form: 7.90 (br s, 1H), 7.26 (m, 5H),
.95 (m, 4H), 3.72 (m, 2H), 3.01 (s, 2H), 2.86 (s, 2H),1.47 (s, 9H); enol
n
max¼3248, 3209, 2978, 2895, 1753, 1622,
19: Mp¼55e62 C; IR (KBr)
n
max¼3479, 3375, 3089, 2958, 1732,
ꢁ1 1
1
1714, 1651, 1612, 1508, 1456, 1421, 1396, 1363, 1340, 1267, 1144, 1030,
818cm ; HNMR(400MHz,CDCl )d7.92(brs,1H),7.63(m, 3H), 7.23
3
ꢁ1 1
3
d
3
(m, 2H), 5.64 (s, 1H), 3.84 (s, 1H), 3.75 (d, J¼16.4 Hz, 1H), 3.69 (d,
form:
d
13.82 (br s,1H), 7.39 (br s,1H), 7.26 (m, 5H), 6.27 (s,1H), 3.95
J¼16.4 Hz,1H), 2.71 (dd, J¼17.2 Hz, 5.6 Hz,1H), 2.66 (dd, J¼17.2, 7.2 Hz,
13
13
(
(
m, 2H), 3.62 (m, 2H), 3.05 (s, 2H), 2.60 (s, 2H), 1.49 (s, 9H); C NMR
100 MHz, CDCl ) keto form: 200.9, 167.9, 150.3, 135.8, 130.7 (2C),
1H), 2.16 (m, 1H), 0.96 (d, J¼6.8 Hz, 3H), 0.92 (d, J¼6.8 Hz, 3H);
C
3
d
3
NMR (100 MHz, CDCl ) d 203.2, 186.3, 167.2, 156.8, 132.6, 129.5 (2C),
1
28.0 (2C), 126.6, 109.2, 82.8, 65.1 (2C), 52.0, 50.6, 43.8, 27.9 (3C);
129.3 (2C), 128.5, 107.0, 68.6, 59.9, 49.4, 40.4, 23.8, 22.8, 22.3; HRMS
þ
enol form:
d
178.1, 172.1, 150.0, 135.9, 130.7 (2C), 128.0 (2C), 126.4,
4
(ESI) m/zcalcd forC18H19NO Na([MþNa] )336.1206, found336.1207.
109.6, 92.6, 82.5, 65.3 (2C), 44.4, 44.2, 28.0 (3C); HRMS (ESI) m/z
þ
calcd for C19
H25NO
6
Na ([MþNa] ) 386.1574, found 386.1574.
2 3 2
4.3.9. Transformation of 16 into 19. PdCl (CH CN) (44.0 mg,
0.170 mmol) was added to a solution of 16 (61.0 mg, 0.128 mmol) in
4
.3.6. tert-Butyl (4-(2-benzyl-1,3-dioxolan-2-yl)-2-bromo-3-
acetone (3 mL) at room temperature, and the mixture was stirred
for 4 days. The reaction was quenched by the addition of water, and
the mixture was diluted with EtOAc. After the layers were sepa-
rated, the aqueous layer was extracted with EtOAc. The combined
oxobutanoyl)carbamate (17). NBS (608 mg, 3.42 mmol) was added
in several portions to a solution of 18 (1.31 g, 3.60 mmol) and
NaHSO
ꢂ
4
(108 mg 0.900 mmol) in THF (50 mL) at 0 C. The mixture
ꢂ
was stirred at 0 C for 15 min. The reaction was quenched by the
2 4
organic layer was washed with brine, dried over Na SO , and