Wrona et al.
JOCArticle
and concentrated under reduced pressure. Purification by flash
chromatography (silica, 30% EtOAc/hexanes) gives reproduci-
chloroformate (46.8 μL, 0.50 M solution in methylene chloride).
The reaction mixture was allowed to stir for 30 min at -20 °C
(checked by TLC) before anhydrous ammonia (l) was bubbled
into the solution (until the disappearance of the mixed anhy-
dride by TLC). The reaction was quenched with water and
warmed to room temperature. The aqueous layer was extracted
with methylene chloride (3ꢀ). The combined organic layers were
dried with magnesium sulfate, filtered, and concentrated under
reduced pressure. Purification by flash chromatography (silica,
50% EtOAc/hexanes) provided 60% (2 steps) of the desired
product as a yellow oil and recovered acid in 40%. [R]20D þ10.5
ble 40-89% yields of desired product 33b as a yellow oil. [R]20
D
þ12.2 (c 1.1, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.43-7.28
(m, 5H), 6.94 (s, 1H), 6.91 (s, 1H), 6.71 (s, 1H), 6.66 (t, J=7.4 Hz,
1H), 5.29 (d, J=10.0 Hz, 1H), 4.99 (s, 2H), 4.81 (A of ABq, J=
6.4 Hz, 1H), 4.60 (B of ABq, J=6.4 Hz, 1H), 4.13 (q, J=7.4, 14.6
Hz, 1H), 3.84 (dd, J=3.2, 6.4 Hz, 1H), 3.60 (d, J=9.2 Hz, 1H),
3.40 (s, 3H), 3.38 (s, 3H), 3.28 (s, 3H), 3.20 (m, 2H), 2.64 (dd, J=
5.2, 13.6 Hz, 1H), 2.54 (d, J=2.8 Hz, 1H), 2.51 (m, 1H), 2.24 (m,
3H), 1.94 (m, 1H), 1.81 (s, 3H), 1.72 (m, 1H), 1.61 (s, 3H), 1.54
(m, 1H), 1.28 (ovlp. m, 1H), 1.23 (t, J=6.4 Hz, 1H), 1.14 (m, 1H),
1.06 (d, J=6.4 Hz, 1H), 0.72 (d, J=6.4 Hz, 1H); 13C NMR
(CDCl3, 75.0 MHz) δ 167.8, 159.2, 144.3, 140.9, 136.4, 133.8,
131.4, 128.5, 128.2, 128.0, 127.4, 124.8, 122.3, 115.1, 114.9, 97.3,
81.2, 81.0, 79.4, 78.6, 70.0, 60.3, 58.4, 56.8, 56.0, 44.1, 36.4, 34.4,
30.8, 29.3, 23.9, 18.6, 17.7, 14.2, 12.3; IR (neat) νmax 3457, 2928,
1708, 1448, 1269, 1097, 1030, 697 cm-1; HRMS (CI, NH3) m/z
calcd for C38H55BrO8 [M þ 23]þ 741.2978, found 741.3000.
(2E,6S,7S,8E,10S,12S,14R)-Ethyl 15-(3-(Benzyloxy)-5-bromo-
phenyl)-7-(tert-butyldimethylsilyloxy)-6,12-dimethoxy-11-(meth-
oxymethoxy)-2,8,10,14-tetramethylpentadeca-2,8-dienoate. To a
solution of alcohol 33b (13.0 mg, 0.0173 mmol) in methyl-
ene chloride (200 μL) at 0 °C was added 2,6-lutidine (8.03 μL,
0.0694 mmol) and tert-butyldimethylsilyl trifluoromethanesul-
fonate (7.96 μL, 0.0347 mmol). The reaction mixture was
allowed to stir for 2 h at 0 °C and was quenched by addition
of a saturated solution of sodium bicarbonate. The aqueous
layer was extracted with methylene chloride (3ꢀ). The combined
organic layers were dried with magnesium sulfate, filtered, and
concentrated under reduced pressure. Purification by flash
chromatography (silica, 20% EtOAc/hexanes) provided 95%
1
(c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.41-7.29 (m,
5H), 6.94 (s, 1H), 6.91 (s, 1H), 6.71 (s, 1H), 6.32 (t, J=6.6 Hz,
1H), 5.41 (br s, 2H), 5.13 (d, J=9.6 Hz, 1H), 4.99 (s, 2H), 4.82 (A
of ABq, J=6.8 Hz, 1H), 4.60 (B of ABq, J=6.4 Hz, 1H), 3.94 (d,
J=6.8 Hz, 1H), 3.59 (d, J=9.6 Hz, 1H), 3.43 (s, 3H), 3.38 (s, 3H),
3.27 (s, 3H), 3.18 (d, J=10.8 Hz, 1H), 3.07 (ddd, J=2.4, 6.8,
9.6 Hz, 1H), 2.65 (dd, J=5.2, 13.6 Hz, 1H), 2.46 (m, 1H), 2.21
(m, 3H), 1.92 (m, 1H), 1.80 (s, 3H), 1.71 (ddd, J =3.6, 10.8,
14.4 Hz, 1H), 1.56 (s, 3H), 1.46 (m, 1H), 1.27 (m, 1H), 1.13 (m,
1H), 1.03 (d, J=6.4 Hz, 3H), 0.87 (s, 9H), 0.71 (d, J=6.4 Hz,
1H), 0.05 (s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
171.2, 159.2, 144.5, 137.3, 136.4, 134.9, 130.5, 130.0, 128.6,
128.1, 127.5, 124.9, 122.3, 115.2, 115.0, 97.4, 83.6, 81.1, 80.3,
79.4, 70.1, 59.7, 56.8, 56.1, 44.2, 36.4, 34.3, 30.9, 30.2, 25.8, 24.8,
18.8, 18.1, 17.6, 12.64, 12.56, -4.7, -4.9; IR (neat) νmax 3342,
2954, 2927, 1684, 1457, 1376, 1250, 1110, 1030, 837 cm-1
;
HRMS (CI, NH3) m/z calcd for C42H66BrNO7Si [M þ 23]þ
826.3690, found 826.3662.
(4E,8S,9S,10E,12S,13R,14S,16R)-20-(Benzyloxy)-9-(tert-
butyldimethylsilyloxy)-8,14-dimethoxy-13-(methoxymethoxy)-
4,10,12,16-tetramethyl-2-aza-bicyclo[16.3.1]docosa-1(21),4,10,-
18(22),19-pentaen-3-one (34b). To a solution of amide (10.0 mg,
0.0120 mmol) in toluene (0.800 mL) in a sealed tube was added
potassium carbonate (4.96 mg, 0.0359 mmol). Copper(I) iodide
(1.1 mg, 0.0060 mmol) and N,N0-dimethyl-1,2-ethanediamine
(1.28 μL, 0.0120 mmol) were added sequentially and the tube
was sealed closed. The green suspension was heated to 100 °C for
36 h. The contents were filtered over plug of silica and washed
with ethyl acetate. Concentration of the solvent followed by
of the desired product as a yellow oil. [R]20 þ16.9 (c 1.3,
D
1
CHCl3); H NMR (CDCl3, 400 MHz) δ 7.41-7.29 (m, 5H),
6.93 (s, 1H), 6.91 (s, 1H), 6.71 (s, 1H), 6.64 (dt, J=1.6, 7.4 Hz,
1H), 5.13 (d, J=10.0 Hz, 1H), 4.99 (s, 1H), 4.83 (A of ABq, J=
6.4 Hz, 1H), 4.60 (B of ABq, J=6.4 Hz, 1H), 4.11 (q, J=7.0, 14.2
Hz, 1H), 3.94 (d, J=6.8 Hz, 1H), 3.59 (d, J=9.6 Hz, 1H), 3.44 (s,
3H), 3.38 (s, 3H), 3.26 (s, 3H), 3.18 (d, J=10.8 Hz, 1H), 3.06
(ddd, J=2.8, 7.0, 10.0 Hz, 1H), 2.64 (dd, J=5.2, 13.6 Hz, 1H),
2.46 (m, 1H), 2.23 (m, 3H), 1.93 (m, 1H), 1.79 (s, 3H), 1.73 (m,
1H), 1.56 (s, 3H), 1.46 (m, 1H), 1.30 (m, 1H), 1.21 (t, J=7.2 Hz,
3H), 1.12 (m, 1H), 1.04 (d, J=6.8 Hz, 3H), 0.87 (s, 9H), 0.71 (d,
J=6.4 Hz, 1H), 0.05 (s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3,
75.0 MHz) δ 168.0, 159.3, 144.5, 141.5, 136.5, 135.0, 130.5,
128.6, 128.0, 127.5, 124.9, 122.3, 115.2, 114.9, 97.4, 83.4, 81.0,
80.6, 79.2, 70.1, 60.3, 59.8, 56.8, 56.1, 44.2, 36.4, 30.8, 30.1, 25.8,
24.9, 18.7, 18.1, 17.8, 14.2, 12.5, 12.4, -4.7, -4.9; IR (neat) νmax
2955, 2928, 2856, 2823, 1710, 1448, 1258, 1111, 1031, 837, 776
cm-1; HRMS (CI, NH3) m/z calcd for C44H69BrO8Si [M þ 23]þ
855.3843, found 855.3819.
flash chromatography (silica, 50% EtOAc/hexanes) yields pro-
1
duct 34b in 82% yield. [R]20 þ49.6 (c 1.3, CHCl3); H NMR
D
(CDCl3, 400 MHz) δ 7.41-7.30 (m, 5H), 7.13 (br s, 1H), 6.69
(br s, 1H), 6.55 (s, 1H), 6.36 (s, 1H), 5.85 (t, J=6.0 Hz, 1H), 5.00
(s, 2H), 4.98 (obst. d, 1H), 4.81 (A of ABq, J=6.4 Hz, 1H), 4.65
(B of ABq, J=6.8 Hz, 1H), 3.77 (d, J=7.6 Hz, 1H), 3.54 (d, J=
8.8 Hz, 1H), 3.45 (s, 3H), 3.41 (s, 3H), 3.31 (s, 3H), 3.12 (d, J=
10.0 Hz, 1H), 2.98 (dt, J=3.0 Hz, 7.8 Hz, 1H), 2.78 (dd, J=4.0,
13.2 Hz, 1H), 2.43 (m, 1H), 2.36 (dd, J=6.4, 13.6 Hz, 1H), 2.20
(m, 1H), 2.11 (m, 1H), 1.91 (m, 1H), 1.74 (s, 3H), 1.62 (m, 1H),
1.53 (s, 1H), 1.25 (m, 1H), 1.17-1.08 (m, 2H), 1.04 (d, J=6.8 Hz,
1H), 0.86 (s, 9H), 0.72 (d, J=6.8 Hz, 1H), 0.04 (s, 3H), -0.03 (s,
3H); 13C NMR (CDCl3, 75.0 MHz) δ 173.0, 159.1, 142.1, 139.1,
136.6, 136.1, 134.6, 131.1, 131.0, 128.6, 128.0, 127.5, 118.0,
113.8, 105.7, 97.6, 83.3, 82.4, 82.0, 79.6, 70.0, 60.8, 57.0, 56.2,
42.9, 34.4, 33.5, 31.3, 30.7, 25.8, 23.7, 18.4, 18.1, 17.6, 13.7, 11.0,
-4.7, -4.9; IR (neat) νmax 3300, 2927, 2856, 1664, 1594, 1461,
1111, 1032, 837 cm-1; HRMS (CI, NH3) m/z calcd for
C42H65NO7Si [M þ 23]þ 746.4428, found 746.4434.
(2E,6S,7S,8E,10S,12S,14R)-15-(3-(Benzyloxy)-5-bromophenyl)-
7-(tert-butyldimethylsilyloxy)-6,12-dimethoxy-11-(methoxymethoxy)-
2,8,10,14-tetramethylpentadeca-2,8-dienamide. Into a 10 mL
round-bottomed flask containing ester (12.0 mg, 0.0139 mmol)
was added a mixture of tetrahydrofuran (400 μL), methanol
(400 μL), and water (200 μL). Lithium hydroxide, monohydrate
(11.6 mg, 0.278 mmol) was added and reaction mixture was
allowed to stir for 48 h. The reaction mixture was concentrated
under reduced pressure. The residue was diluted with pH 4.5
NaH2PO4 (10 mL) and extracted with methylene chloride (5ꢀ)
with the aqueous phase saturated with solid NaCl each time.
The combined organic layers were dried with magnesium sul-
fate, filtered, and concentrated under reduced pressure. The
crude acid was used in the next step without further purification.
To a solution of acid (17.0 mg, 0.0203 mmol) in methylene
chloride (1.00 mL) at -20 °C was added sequentially triethyl-
amine (85.4 μL, 0.50 M solution in methylene chloride) and ethyl
(4E,8S,9S,10E,12S,13R,14S,16R)-Carbamic Acid 20-(Benzy-
loxy)-8,14-dimethoxy-13-(methoxymethoxy)-4,10,12,16-tetra-
methyl-3-oxo-2-aza-bicyclo[16.3.1]docosa-1(21),4,10,18(22),19-
pentaen-9-yl Ester. To a solution of TBS ether 34b (13.0 mg,
0.0172 mmol) in tetrahydrofuran (1.30 mL) in a nalgene vial was
added a premixed solution of [pyridine hydrofluoride:pyridine:
THF (1:1:2.5) by volume] (600 μL) dropwise. The reaction
was allowed to run at room temperature for 24 h before another
600 μL of HF mixture was added. The reaction was stirred for
2834 J. Org. Chem. Vol. 75, No. 9, 2010