The Journal of Organic Chemistry
Article
3451, 2963, 2926, 1455, 1375, 1222, 1178, 1116, 1041 cm−1; 1H NMR
(300 MHz, CDCl3): δ 5.70 (br s, 1H), 4.02−3.91 (m, 2H), 3.56 (dd, J
= 11.3, 2.3 Hz, 1H), 3.47 (dd, J = 11.3, 3.7 Hz, 1H), 2.40 (m, 1H),
2.29 (m, 1H), 1.95 (m, 1H), 1.76 (m, 1H), 1.62−1.59 (m, 3H), 1.39
(s, 3H), 1.07 (d, J = 7.5 Hz, 3H), 0.74 (d, J = 7.5 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 131.6, 123.8, 95.8, 78.5, 71.0, 63.3, 34.6,
34.2, 24.4, 24.0, 18.2, 15.1, 13.3 ppm; HRMS (ESI) m/z calcd. for
C13H22O3Na [M + Na]+: 249.1466, found: 249.1472.
(R,E)-Ethyl-2-methyl-4-((1R,3R,4S,5R)-1,4,8-trimethyl-2,9-
dioxabicyclo[3.3.1]non-7-en-3-yl)pent-2 (24). To a stirred
solution of primary alcohol (320 mg, 1.41 mmol) and solid anhydrous
NaHCO3 (356 mg) in CH2Cl2 (30 mL) at 0 °C was added Dess−
Martin periodinane (900 mg, 2.11 mmol). The resulting reaction
mixture was stirred at 0 °C to room temperature for 1 h. After
completion of the reaction (monitored by TLC), the mixture was
filtered through filter paper. The filtrate was washed with saturated
NaHCO3 solution (20 mL) and CH2Cl2 (30 mL). The organic layer
was separated and the aqueous layer extracted with CH2Cl2 (3 × 30
mL). The combined organic layer was dried over anhydrous Na2SO4,
concentrated under reduced pressure and filtered through a small pad
of silica gel to give aldehyde 23 (286 mg, 90%) as a colorless oil which
was used for the next step without further purification.
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography using
ethyl acetate and hexane (1:9) as mobile phase to afford aldehyde 7
29
(189 mg, 95%) as a pale yellow viscous liquid. [α]D −40.2 (c = 0.7,
CHCl3); IR (neat): ν 3332, 2962, 2927, 1679, 1459, 1379, 1338, 1265,
1193, 1159, 1118 cm−1; 1H NMR (300 MHz, CDCl3): δ 9.46 (s, 1H),
6.75 (m, 1H), 5.71 (br s, 1H), 3.95 (t, J = 6.3 Hz, 1H), 3.53 (dd, J =
10.5, 2.2 Hz, 1H), 2.91 (m, 1H), 2.40 (m, 1H), 1.96 (m, 1H), 1.85 (m,
1H), 1.76 (d, J = 1.5 Hz, 3H), 1.64−1.62 (m, 3H), 1.43 (s, 3H), 1.09
(d, J = 6.8 Hz, 3H), 0.70 (d, J = 6.8, Hz, 3H) ppm; 13C NMR (75
MHz, CDCl3): δ 195.5, 155.1, 139.1, 132.3, 123.2, 95.4, 76.1, 70.8,
35.1, 34.3, 24.1, 24.0, 18.2, 16.4, 13.1, 9.1 ppm; HRMS (ESI) m/z
calcd. for C16H25O3 [M + H]+: 265.1804, found: 265.1801.
2,2-Dimethyl-6-((R,1E,3E)-3-methyl-5-((1R,3R,4S,5R)-1,4,8-
trimethyl-2,9-dioxabicyclo [3.3.1]non-7-en-3-yl)hexa-1,3-dien-
yl)-4H-1,3-dioxin-4-one (5). In a flame-dried, two-necked RB flask,
charged with NaH (39 mg, 60% suspension in mineral oil, 0.99 mmol)
under argon atmosphere, anhydrous THF (5 mL) was added and cool
to 0 °C. To this stirred solution phosphonate 8 (316 mg, 1.1 mmol) in
anhydrous THF (20 mL) was added dropwise at 0 °C and was allowed
to stir for 30 min. Then aldehyde 7 (150 mg, 0.568 mmol) in THF (10
mL) was added at 0 °C. The resulting mixture was allowed to stir for
12 h at room temperature. The reaction was quenched with saturated
aqueous solution of NH4Cl (5 mL), extracted with ethyl acetate (3 ×
10 mL). Combined extracts were dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by silica gel
column chromatography to afford compound 5 (216 mg, 93%) as a
The resulting aldehyde 23 (286 mg, 1.27 mmol) and
(carbethoxyethylidene)triphenyl phosphorane (2.3 g, 6.39 mmol)
were dissolved in toluene (30 mL), heated at 110 °C for 12 h. Toluene
was removed under reduced pressure and the residue was purified by
silica gel column chromatography using ethyl acetate and hexane (1:9)
as mobile phase to afford ester 24 (342 mg, 87%) as a10:1 E/Z
29
colorless liquid. [α]D +4.32 (c = 1.08, CHCl3); IR (neat): ν 3448,
2925, 1724, 1624, 1380, 1269, 1203, 1118, 1015 cm−1; 1H NMR (300
MHz, CDCl3): δ 7.02 (d, J = 15.8 Hz, 1H), 6.11 (d, J = 9.8 Hz, 1H),
5.87 (d, J = 15.8 Hz, 1H), 5.69 (br s, 1H), 5.28 (s, 1H), 3.93 (m, 1H),
3.46 (dd, J = 10.5, 2.2 Hz, 1H), 2.75 (m, 1H), 2.39 (m, 1H), 1.99−
1.87 (m, 2H), 1.81 (d, J = 1.5 Hz, 3H), 1.75 (s, 3H), 1.74 (s, 3H),
1.63−1.60 (m, 3H), 1.42 (s, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.67 (d, J =
6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 164.0, 162.1,143.4,
142.4, 132.8, 132.4, 123.2, 117.0, 106.1, 95.4, 93.7, 76.5, 71.0, 34.9,
34.1, 25.1, 24.8, 24.3, 24.1, 18.3, 17.1, 13.1, 12.0 ppm; HRMS (ESI)
m/z calcd. for C23H32O5Na [M + Na]+: 411.2147, found: 411.2145.
Ethyl-2-((R,4E,6E)-N-(2,4-dimethoxybenzyl)-6-methyl-3-oxo-
8-((1R,3R,4S,5R)-1,4,8-tri-methyl-2,9-dioxabicyclo[3.3.1]non-7-
en-3-yl)nona-4,6-dienamido)acetate (25). Compound 5 (80 mg,
0.21 mmol) and DMB-glycine ester 6 (62.5 mg, 0.25 mmol) were
dissolved in anhydrous toluene (5 mL) in a flame dry RB flask
equipped with a condenser under argon atmosphere. The solution was
heated to reflux at 110 °C for 6 h. The reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using ethyl
acetate and hexane (2:3) as mobile phase to afford compound 25 (119
mg, 99%) as pale yellow oil. [α]D29 −5.2 (c = 1.35, CHCl3); IR (neat):
ν 3449, 2925, 2854, 1744, 1615, 1585, 1507, 1462, 1206, 1120 cm−1;
1H NMR (ketone and enol forms, 300 MHz, CDCl3): δ 14.0 (s, 0.5H),
29
isomers. [α]D −23.1 (c = 0.7, CHCl3); IR (neat): ν 3635, 2963,
2929, 2876, 1710, 1650, 1447, 1375, 1243 cm−1; 1H NMR (500 MHz,
CDCl3): δ 6.86 (dd, J = 10.5, 0.9 Hz, 1H), 5.66 (br s, 1H), 4.22−4.16
(m, 2H), 3.90 (m, 1H), 3.43 (dd, J = 10.5, 1.9 Hz, 1H), 2.68 (m, 1H),
2.37 (m, 1H), 1.95−1.84 (m, 2H), 1.83 (d, J = 0.95 Hz, 3H), 1.62−
1.60 (m, 3H), 1.40 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H), 1.02 (d, J = 6.6
Hz, 3H), 0.67 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
δ 168.2, 142.6, 132.5, 127.8, 123.2, 95.4, 76.2, 71.0, 60.4, 34.9, 34.3,
24.2, 24.1, 18.3, 16.5, 14.3, 13.2, 12.4 ppm; HRMS (ESI) m/z calcd.
for C18H28O4Na [M + Na]+: 331.1880, found: 331.1885.
(R,E)-2-Methyl-4-((1R,3R,4S,5R)-1,4,8-trimethyl-2,9-
dioxabicyclo[3.3.1]non-7-en-3-yl)pent-2-en-1-ol. A stirred sol-
ution of ester 24 (350 mg, 1.13 mmol) in anhydrous CH2Cl2 (10 mL)
was treated with DIBAL-H (2.55 mL of 1 M solution in toluene, 2.55
mmol) at 0 °C and stirred for 3 h. The reaction was quenched with
MeOH (1 mL) and saturated aqueous sodium potassium tartrate
solution (10 mL). The reaction mixture was warmed to room
temperature and stirred for 5 h. The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (2 × 10 mL). Combined
organic layers were dried over Na2SO4, concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography using ethyl acetate and hexane (1:4) as mobile phase
to afford alcohol (266 mg, 88%) as a colorless liquid. [α]D29 −44.36 (c
= 1.0, CHCl3); IR (neat): ν 3455, 2960, 2925, 1456, 1370, 1222, 1175,
7.32 (d, J = 15.8 Hz, 0.5H), 7.13 (d, J = 15.8 Hz, 1H), 7.02 (m, 1H),
6.44−6.39 (m, 2H), 6.22 (m, 1H), 6.01 (d, J = 9.8 Hz, 1H), 5.75 (d, J
= 15.8 Hz 1H), 5.66 (br s, 1H), 5.26 (s, 0.5H), 4.50 (s, 2H), 4.21−
4.09 (m, 2H), 4.07−4.04 (m, 2H), 3.97 (s, 1H), 3.90 (m, 1H), 3.83−
3.78 (m, 6H), 3.43 (m, 1H), 2.71 (m, 1H), 2.35 (m, 1H), 1.91 (m,
2H), 1.79 (m, 3H), 1.60 (s, 3H), 1.30−1.23 (m, 3H), 1.04−0.97 (m,
3H), 0.69−0.63 (m, 3H) ppm; 13C NMR (ketone and enol forms, 75
MHz, CDCl3): δ 193.9, 172.9, 170.2, 169.5, 169.3, 169.0, 168.1, 160.9,
160.5, 158.6, 158.1, 149.8, 145.5, 145.0, 141.2, 140.0, 133.1, 132.7,
132.6, 132.5, 131.4, 130.0, 128.5, 123.5, 123.1, 123.0, 120.4, 116.4,
115.8, 104.2, 103.9, 98.6, 98.5, 98.2, 95.4, 95.3, 88.6, 76.6, 71.0, 61.1.
60.0, 55.3, 55.2, 48.3, 47.2, 47.0, 46.8, 46.6, 34.9, 34.8, 34.3, 34.0, 24.2,
24.1, 18.3, 17.2, 17.0, 14.1, 13.2, 12.1 ppm; HRMS (ESI) m/z calcd.
for C33H45NO8Na [M + Na]+: 606.3042, found: 606.3049.
1
1114, 1041 cm−1; H NMR (300 MHz, CDCl3): δ 5.65 (br s, 1H),
5.57 (d, J = 9.8 Hz, 1H), 4.02 (s, 2H), 3.90 (t, J = 6.8 Hz, 1H), 3.38
(dd, J = 10.5, 2.2 Hz, 1H), 2.56 (m, 1H), 2.36 (m, 1H), 1.68 (s, 3H),
1.62−1.58 (m, 3H), 1.37 (s, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.67 (d, J =
6.8 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 135.2, 132.8, 127.3,
123.3, 95.6, 77.6, 71.3, 69.4, 34.7, 33.1, 24.5, 24.4, 18.5, 17.8, 13.9, 13.6
ppm; HRMS (ESI) m/z calcd. for C16H26O3Na [M + Na]+: 289.1779,
found: 289.1766.
(R,E)-2-Methyl-4-((1R,3R,4S,5R)-1,4,8-trimethyl-2,9-
dioxabicyclo[3.3.1]non-7-en-3-yl)pent-2-ena (7). To a stirred
solution of alcohol (200 mg, 0.75 mmol) and iodobenzene diacetate
(362 mg, 1.12 mmol) in anhydrous CH2Cl2 (10 mL) was added
TEMPO (11.7 mg, 0.075 mmol) at room temperature and stirred for 1
h. After completion of reaction (monitored by TLC), it was quenched
with saturated aqueous solution of NaHCO3 (5 mL) followed by
saturated aqueous solution of Na2S2O3 (5 mL) and stirred for 1 h. The
organic layer was separated and the aqueous layer extracted with
CH2Cl2 (2 × 10 mL). Combined organic layer was dried over
Dimethoxybenzyl (DMB) Protected Tirandamycin C (26). A
stirred solution of diketo compound 25 (50 mg, 0.09 mmol) in
anhydrous THF (2 mL) under argon atmosphere was treated with
TBAF (0.214 mL, 1 M solution in THF, 0.22 mmol) and the resulting
yellow solution stirred for 15 min at room temperature. After
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dx.doi.org/10.1021/jo3016709 | J. Org. Chem. XXXX, XXX, XXX−XXX