Synthesis of Benzolactams
J. Am. Chem. Soc., Vol. 118, No. 8, 1996 1853
ratio of 1:3) 0.87 (m, 3H, (CH2)7CH3), 1.20-1.40 (br, 12H, -(CH2)6-
CH3), 1.62 (s, 9H, Boc), 2.20-2.30 (m, 2H, CHdCHCH2), 3.04 (m,
1H, ArCH2), 3.19 (m, 1H, ArCH2), 3.69 (m, 1H, CH2OH), 3.73 (m,
1H, CH2OH), 3.99 (m, 1H, CH2CH), 5.03 (br, 1H, ArCHdCH), 5.79
(dt, 1H, J ) 7, 12 Hz, ArCHdCH), 6.36 (bd, 1H, J ) 12 Hz, NH),
7.3-7.5 (m, 2H, ArH), 7.85 (bs, 1H, ArH); HRMS calcd for
C24H42N2O3 406.3195, found 406.3179.
Amino Alcohol 39. The procedure was the same as that used for
the preparation of 20, employing 2.32 g (5.7 mmol) of 38, 200 mg of
10% Pd-C, and 20 mL of ethanol for 7 h at room temperature under
H2. Recrystallization from n-hexane afforded 2.04 g of 39 as colorless
prisms (94%): mp 72-73 °C; 1H-NMR (CDCl3) 0.88 (t, 3H, J ) 7Hz,
(CH2)7CH3), 1.25 (br, 14H, -(CH2)7CH3), 1.46 (s, 9H, Boc), 1.57 (m,
2H, CH2(CH2)7CH3), 2.66 (dd, 1H, J ) 10, 14 Hz, ArCH2), 2.84 (dd,
1H, J ) 5, 14 Hz, ArCH2), 2.49 (t, 2H, J ) 8 Hz, CH2(CH2)8CH3),
3.58 (m, 2H, CH2OH), 3.73 (m, 1H, CH2CH), 5.13 (bd, 1H, J ) 8 Hz,
NH), 6.54 (s, 1H, ArH), 6.58 (d, 1H, J ) 8 Hz, ArH), 6.93 (d, 1H, J
) 8 Hz, ArH); HRMS calcd for C24H42N2O3 406.3195, found 406.3179.
N-(Methylamino) Alcohol 40. A solution of 39 (2.04 g, 5.02 mmol)
in 30 mL of THF was added at 0 °C to a mixed anhydride solution
(prepared by addition of 1.21 g of formic acid to 2.60 g of acetic
anhydride at 0 °C, followed by heating for 2 h at 60-70 °C). After
having been stirred for 6 h at room temperature, the mixture was
concentrated under reduced pressure. The residue was poured into
saturated NaHCO3(aq), and the whole was extracted with AcOEt. The
extract was washed with water and brine and dried over MgSO4.
Concentration and purification by column chromatography on silica
gel with AcOEt/n-hexane ) 1/1 afforded 1.75 g of the N-formate as a
pale yellow oil (80%). To a solution of 1.61 g (3.71 mmol) of the
formate in 100 mL of THF was added dropwise 16 mL of 1.0 M BH3
in THF solution at 0 °C, and the mixture was stirred for 4 h at 0 °C.
The reaction was quenched by the addition of 10 mL of 10% citric
acid, and the whole was extracted with AcOEt. After concentration,
the residue was poured into brine and extracted with AcOEt. The
organic layer was washed with water and brine and dried over MgSO4.
Concentration and purification by column chromatography on silica
gel with AcOEt/n-hexane ) 1:2 gave 1.30 g of 40 as colorless prisms
(89%): 1H-NMR (CDCl3) 0.86 (t, 3H, J ) 7 Hz, (CH2)7CH3), 1.24
(br, 14H, -(CH2)7CH3), 1.44 (s, 9H, Boc), 1.56 (m, 2H, CH2(CH2)7-
CH3), 2.52 (t, 2H, J ) 8 Hz, CH2(CH2)8CH3), 2.61 (dd, 1H, J ) 10,
14 Hz, ArCH2), 2.78 (dd, 1H, J ) 4, 14 Hz, ArCH2), 2.85 (s, 3H,
NCH3), 3.60 (m, 2H, CH2OH), 3.67 (m, 1H, CH2CH), 5.08 (br, 1H,
NH), 6.45 (bs, 1H, ArH), 6.49 (d, 1H, J ) 7 Hz, ArH), 6.88 (d, 1H, J
) 7 Hz, ArH); HRMS calcd for C25H44N2O3 420.3352, found 420.3315.
(m, 2H, ArH), 7.01 (m, 2H, ArH), 7.09 (m, 1H, ArH), 7.26 (m, 3H,
ArH); HRMS calcd for C37H58N2O5 610.4346, found 610.4332.
Activated esters 42. The diastereomeric esters 41 (950 mg, 1.56
mmol) were converted into 917 mg (96%) of 42 by the same method
as that used for the preparation of 31. The product was unstable and
was used without further purification.
Benzolactam-V8-310 (6) and epi-Benzolactam-V8-310 (43). Tri-
fluoroacetic acid (18 mL) was added to a solution of 1.28 g (8.62 mmol)
of 42 in 35 mL of CH2Cl2 at 0 °C with stirring. The mixture was
stirred for 2 h at room temperature, and then the solvent was removed
under reduced pressure below 30 °C. The residue was dissolved in 2
L of AcOEt, and then 120 mL of saturated NaHCO3(aq) was added
and the mixture was refluxed for 6 h with vigorous stirring. The organic
layer was separated, washed with brine, dried over MgSO4, and
concentrated. The crude product was separated by column chroma-
tography with AcOEt to give 394 mg of 4 (48%) and 359 mg of 43
(43%). 4: colorless needles (from AcOEt/n-hexane); mp 107-108
°C; IR (KBr) 1660 (NHCO); 1H-NMR (CDCl3) 0.88 (m, 6H, (CH2)7CH3,
CH(CH3)2), 1.05 (d, 3H, J ) 7 Hz, CH(CH3)2), 1.26 (br, 14H, -(CH2)7-
CH3), 1.57 (bs, 2H, CH2(CH2)7CH3), 2.41 (m, 1H, CH(CH3)2), 2.52
(br, 2H, CH2(CH2)8CH3), 2.77 (d, 1H, J ) 17 Hz, ArCH2), 2.79 (s,
3H, N-CH3), 3.04 (dd, 1H, J ) 8, 17 Hz, ArCH2), 3.46 (d, 1H, J ) 9
Hz, NCHCO), 3.52 (m, 1H, CH2OH), 3.69 (m, 1H, CH2OH), 4.03 (bs,
1H, CH2CH), 6.81 (s, 1H, NH), 6.83 (bs, 1H, ArH), 6.90 (d, 1H, J )
7 Hz, ArH), 6.94 (d, 1H, J ) 7 Hz, ArH); 1H-NMR (CD3OD) 0.89 (t,
6H, (CH2)7CH3), 0.94 (d, 3H, CH(CH3)2), 1.09 (d, 3H, J ) 7 Hz, CH-
(CH3)2), 1.27 (br, 14H, -(CH2)7CH3), 1.57 (bs, 2H, CH2(CH2)7CH3),
2.39 (m, 1H, CH(CH3)2), 2.53 (dd, 2H, J ) 6, 8 Hz, CH2(CH2)8CH3),
2.75 (s, 3H, NCH3), 2.85 (dd, 1H, J ) 9, 16 Hz, ArCH2), 2.99 (dd,
1H, J ) 4, 16 Hz, ArCH2), 3.44 (d, 1H, J ) 7 Hz, NCHCO), 3.49 (dd,
1H, J ) 7, 11 Hz, CH2OH), 3.59 (dd, 1H, J ) 5, 11 Hz, CH2OH),
4.48 (bs, 1H, CH2CH), 6.76 (dd, 1H, J ) 1, 7 Hz, ArH), 6.95 (d, 1H,
J ) 7 Hz, ArH), 6.96 (d, 1H, J ) 1 Hz, ArH). Anal. Calcd for
C25H42N2O2 C, 74.58; H, 10.51; N, 6.96; found, C, 74.57; H, 10.68, N,
7.14. 43: colorless flakes (from AcOEt/n-hexane); mp 117-118 °C;
1
IR (KBr) 1660 (NHCO); H-NMR (CDCl3) 0.88 (m, 6H, (CH2)7CH3,
CH(CH3)2), 0.97 (d, 3H, J ) 7 Hz, CH(CH3)2), 1.26 (br, 14H, -(CH2)7-
CH3), 1.57 (bs, 2H, CH2(CH2)7CH3), 2.42 (m, 1H, CH(CH3)2), 2.55
(m, 2H, CH2(CH2)8CH3), 2.83 (d, 1H, J ) 16 Hz, ArCH2), 2.90 (dd,
1H, J ) 6, 16 Hz, ArCH2), 2.93 (s, 3H, N-CH3), 3.19 (d, 1H, J ) 9
Hz, NCHCO), 3.73 (m, 3H, CH2CH, CH2OH), 6.66 (bd, 1H, J ) 4
Hz, NH), 6.76 (dd, 1H, J ) 1, 8 Hz, ArH), 6.91 (d, 1H, J ) 1 Hz,
ArH), 6.98 (d, 1H, J ) 8 Hz, ArH); 1H-NMR (CD3OD) 0.89 (t, 3H, J
) 7 Hz, (CH2)7CH3), 0.85 (t, 3H, J ) 7 Hz, CH(CH3)2), 0.98 (d, 3H,
J ) 7 Hz, CH(CH3)2), 1.27 (br, 14H, -(CH2)7CH3), 1.57 (bs, 2H,
CH2(CH2)7CH3), 2.37 (m, 1H, CH(CH3)2), 2.53 (m, 2H, CH2(CH2)8-
CH3), 2.71 (dd, 1H, J ) 7, 16 Hz, ArCH2), 2.88 (d, 1H, J ) 16 Hz,
ArCH2), 2.90 (s, 3H, NCH3), 3.23 (d, 1H, J ) 11 Hz, NCHCO), 3.69
(m, 3H, CH2CH, CH2OH), 6.75 (dd, 1H, J ) 1, 8 Hz, ArH), 6.94 (d,
1H, J ) 1 Hz, ArH), 7.01 (d, 1H, J ) 8 Hz, ArH). Anal. Calcd for
C25H42N2O2 C, 74.58; H, 10.51; N, 6.96. Found: C, 74.33; H, 10.68;
N, 7.11.
Diastereomeric esters 41. The N-methylamino alcohol 40 (1.27
g, 3.02 mmol) was converted into a diastereomeric mixture of esters
41 by the same method as that used for the preparation of 31 from 30,
using 1.84 g of the triflate and 1.05 g of 2,6-lutidine in 30 mL of
CH2ClCH2Cl. Purification by column chromatography on silica gel
with CH2Cl2/AcOEt ) 20/3 gave 1.62 g of diastereomeric esters 41 as
a colorless oil (80%). To confirm the structure, a small portion of the
mixture was separated by using PTLC. 41A (the stereochemistry
1
Benzolactam-V8-310 Acetate. The procedure was the same as that
used for the preparation of 3-acetate, employing 60 mg (0.15 mmol)
of 6 to afford 54 mg of benzolactam-V8-310 acetate (82%) as a
corresponds to that of BL-V8-310): colorless oil; H-NMR (CDCl3)
0.87 (t, 3H, J ) 7 Hz, (CH2)7CH3), 0.91 (d, 3H, J ) 7 Hz, CH(CH3)2),
1.16 (d, 3H, J ) 7 Hz, CH(CH3)2), 1.23 (bs, 14H, -(CH2)7CH3), 1.45
(s, 9H, Boc), 1.50 (bs, 2H, CH2(CH2)7CH3), 2.27 (m, 1H, CH(CH3)2),
2.45 (t, 2H, J ) 8 Hz, CH2(CH2)8CH3), 2.76 (dd, 1H, J ) 6, 13 Hz,
ArCH2), 2.84 (s, 3H, NCH3), 2.97 (dd, 1H, J ) 10, 13 Hz, ArCH2),
3.27 (bd, 1H, CH2OH), 3.33 (d, 1H, J ) 10 Hz, NCHCO), 3.44 (bd,
1H, CH2OH), 3.76 (bs, 1H, CHCH2OH), 4.82 (d, 1H, J ) 12 Hz,
ArCH2O), 4.95 (d, 1H, J ) 12 Hz, ArCH2O), 5.40 (bd, 1H, J ) 8 Hz,
NHCOO), 6.92 (bd, 2H, J ) 8 Hz, ArH), 7.00 (m, 2H, ArH), 7.16 bd,
1H, J ) 8 Hz, ArH), 7.25 (m, 3H, ArH); HRMS calcd for C37H58N2O5
610.4346, found 610.4335. 41B (the stereochemistry corresponds to
that of epi-BL-V8-310): colorless oil; 1H-NMR (CDCl3) 0.87 (m, 6H,
(CH2)7CH3, CH(CH3)2), 1.15 (d, 3H, J ) 7 Hz, CH(CH3)2), 1.23 (s,
14H, -(CH2)7CH3), 1.37 (s, 9H, Boc), 1.50 (m, 2H, CH2(CH2)7CH3),
2.29 (m, 1H, CH(CH3)2), 2.45 (t, 2H, J ) 8 Hz, CH2(CH2)8CH3), 2.59
(dd, 1H, J ) 4, 13 Hz, ArCH2), 2.87 (s, 3H, NCH3), 2.91 (d, 1H, J )
13 Hz, ArCH2), 3.25 (d, 1H, J ) 10 Hz, NCHCO), 3.50-3.67 (br, 2H,
CH2OH), 3.72 (m, 1H, CHCH2OH), 4.87 (d, 1H, J ) 12 Hz, ArCH2O),
4.99 (d, 1H, J ) 12 Hz, ArCH2O), 6.04 (bd, 1H, J ) 3 Hz NH), 6.92
1
colorless oil: IR (neat) 1740 (Ac), 1660 (NHCO); H-NMR (CDCl3)
0.88 (t, 3H, J ) 7 Hz, (CH2)7CH3), 0.93 (d, 3H, J ) 7 Hz, CH(CH3)2),
1.07 (d, 3H, J ) 7 Hz, CH(CH3)2), 1.26 (m, 14H, -(CH2)7CH3), 1.56
(m, 2H, CH2(CH2)7CH3), 2.10 (s, 3H, COCH3), 2.43 (m, 1H, CH(CH3)2),
2.53 (m, 2H, CH2(CH2)8CH3), 2.77 (s, 3H, N-CH3), 2.96 (d, 2H, J )
6 Hz, ArCH2), 3.43 (d, 1H, J ) 8 Hz, NCHCO), 3.96 (dd, 1H, J ) 8,
12 Hz, CH2OH), 4.20 (dd, 1H, J ) 4, 12 Hz, CH2OH), 4.56 (bs, 1H,
CH2CH), 5.68 (bd, J ) 5 Hz, NH), 6.75 (dd, 1H, J ) 1, 8 Hz, ArH),
6.87 (d, 1H, J ) 1 Hz, ArH), 6.93 (d, 1H, J ) 8 Hz, ArH); HRMS
calcd for C27H44N2O3 444.3352, found 444.3331.
epi-Benzolactam-V8-310 Acetate. The procedure was the same
as that used for the preparation of 3-acetate, employing 94 mg (0.23
mmol) of 43 to afford 92 mg of epi-benzolactam-V8-310 acetate (98%)
as a colorless oil: IR (neat) 1740 (Ac), 1665 (NHCO); 1H-NMR
(CDCl3) 0.88 (t, 3H, (CH2)7CH3), 0.89 (d, 3H, J ) 7 Hz, CH(CH3)2),
0.96 (d, 3H, J ) 7 Hz, CH(CH3)2), 1.26 (br, 14H, -(CH2)7CH3), 1.57
(m, 2H, CH2(CH2)7CH3), 2.11 (s, 3H, COCH3), 2.45 (m, 1H, CH(CH3)2),