1896 J . Org. Chem., Vol. 67, No. 6, 2002
Herdemann et al.
1230 cm-1; 1H NMR (CD3CN, 300 MHz) δ 1.17-1.28 (m, 1 H),
1.26 (t, J ) 7.2 Hz, 3 H), 1.55-1.78 (m, 3 H), 1.77 (bs, 3 H),
2.51 (dd, J ) 4.6, 11.8 Hz, 1 H), 2.57-2.86 (m, 2 H), 3.36-
3.57 (m, 2 H), 3.95-4.02 (m, 1 H), 4.17 (q, J ) 7.2 Hz, 2 H),
4.26 (bd, J ) 13.3 Hz, 1 H), 5.01-5.24 (m, 2 H), 5.63 (bs, 1 H),
6.80 (s, 1 H), 7.27-7.44 (m, 5 H); 13C NMR (CD3CN, 63 MHz)
δ 14.6, 20.9, 27.6, 39.0, 40.0, 40.4, 44.1, 52.4, 58.7, 61.3, 67.3,
128.5, 128.8 (2C), 129.4 (2C), 132.5, 132.9, 134.8, 135.3, 138.5,
156.0, 167.5; MS (ES+) m/z (rel intensity) 438 (MK+, 58), 422
(MNa+, 100); HRMS (CI, isobutane) calcd. for C23H30NO5
(MH+) 400.2124, found 400.2103.
4-Meth yl-1,2,3,3a,6,6a,7,8-octah ydr o-3,9-diazacyclopen -
ta [d ]n a p h th a len e-6,9-d ica r boxylic Acid 9-Ben zyl Ester
6-Eth yl Ester (38a ). NaBH4 (16 mg, 0.430 mmol) was added
to a cold solution of imine 33 (17 mg, 0.043 mmol) in CH2Cl2/
MeOH (1:1, 2 mL). The reaction mixture was allowed to warm
to room temperature during 30 min and then poured into an
aqueous HCl solution (25 mL, pH 1-2). Hydrolysis was
achieved by supplementary dropwise HCl (1 N) addition to pH
1. The mixture was basified with a saturated NaHCO3 solution
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were dried over MgSO4 and concentrated in vacuo.
Purification of the residue by preparative TLC (AcOEt/MeOH
100:1, 0.2% NEt3) gave amine 38a (14 mg, 0.035 mmol, 82%
8a -(2-Meth a n esu lfon yloxyeth yl)-7-m eth yl-3,4,4a ,8a -tet-
r a h yd r o-1H-isoqu in olin e-2,5-d ica r boxylic Acid 2-Ben zyl
Ester 5-Eth yl Ester (32). Methylsulfonyl chloride (0.14 mL,
1.765 mmol) and triethylamine (0.49 mL, 3.53 mmol) were
added to a solution of alcohol 31 (141 mg, 0.353 mmol) in
CH2Cl2 (25 mL) at -78 °C. After 5 min, the reaction mixture
was allowed to warm to 0 °C over 30 min and then stirred
during 1 h at the same temperature. H2O (20 mL) was added,
the mixture was basified with a saturated NaHCO3 aqueous
solution (10 mL), and the organic phase was collected. After
extraction of the aqueous phase with CH2Cl2 (4 × 10 mL), the
combined organic fractions were dried over MgSO4 and
concentrated in vacuo. Chromatography on silica gel (heptane/
AcOEt 7/3) of the residue gave mesylate 32 (163 mg, 0.341
mmol, 96% yield): IR (film) 2979, 2939, 1698, 1356, 1274, 1235,
1174 cm-1; 1H NMR (CD3CN, 300 MHz) δ 1.08-1.28 (m, 1 H),
1.26 (t, J ) 7.0 Hz, 3 H), 1.42-1.52 (m, 1 H), 1.58-1.68 (m, 1
H), 1.79 (bs, 3 H), 1.83-1.92 (m, 1 H), 2.53 (dd, J ) 3.5, 12.3
Hz, 1 H), 2.59-2.87 (m, 2 H), 2.94 (bs, 3 H), 3.94-4.04 (m, 1
H), 4.04-4.29 (m, 5 H), 5.00-5.26 (m, 2 H), 5.61 (bs, 1 H),
6.82 (s, 1 H), 7.27-7.48 (m, 5 H); 13C NMR (CD3CN, 75 MHz)
δ 14.5, 20.9, 27.6, 36.0, 37.3, 38.8, 40.1, 43.9, 52.0, 61.4, 67.4,
68.0, 128.7, 128.8 (2C), 129.4 (2C), 132.6, 134.1, 133.1, 135.2,
138.4, 156.0, 167.2; MS (CI, isobutane) m/z (rel intensity) 478
(MH+, 92), 434 (50), 338 (62), 91 (100); HRMS (CI, isobutane)
calcd for C24H32NO7S (MH+) 478.1899, found 478.1877.
4-Meth yl-1,3a ,6,6a ,7,8-h exa h yd r o-3,9-d ia za cyclop en ta -
[d ]n a p h t h a len e-6,9-d ica r b oxylic Acid 9-Ben zyl E st er
6-Eth yl Ester (33 a n d 34). Under a nitrogen atmosphere,
NaN3 (150 mg, 2.3 mmol) was added to a solution of mesylate
32 (110 mg, 0.231 mmol) in DMF (20 mL). The reaction
mixture was stirred during 24 h at 60 °C and then allowed to
cool to room temperature. H2O (200 mL) was added before
extraction with Et2O (5 × 20 mL). The combined etheral
extracts were dried over MgSO4 and concentrated under
reduced pressure. Chromatography on silica gel (heptane/
AcOEt 1/1, 0.1% NEt3) of the residue allowed separation of
the two isomers. Major isomer 33 (38 mg, 0.096 mmol, 42%
yield): IR (film) 3340, 2940, 2876, 1731, 1698, 1436, 1196 cm-1
;
1H NMR (CD3CN, 400 MHz, 60 °C) δ 1.24 (t, J ) 7.1 Hz, 3 H),
1.24-1.34 (m, 3 H), 1.66 (bs, 3 H), 1.72-1.79 (m, 1 H), 2.20-
2.25 (m, 1 H), 2.52 (d, J ) 13.4 Hz, 1 H), 2.57-2.64 (m, 1 H),
2.73-2.81 (m, 1 H), 2.88-2.94 (m, 1 H), 3.10 (bs, 1 H), 3.42-
3.46 (m, 1 H), 4.08-4.20 (m, 4 H), 5.08 (bd, J ) 12.6 Hz, 1 H),
5.14 (bd, J ) 12.6 Hz, 1 H), 5.56 (d, J ) 1.3 Hz, 1 H), 7.30-
7.40 (m, 5 H); 13C NMR (CD3CN, 63 MHz) δ 14.5, 20.8, 25.4,
34.5, 40.5, 42.9, 44.0, 44.3, 47.0, 53.2, 60.1, 61.2, 67.3, 119.8,
128.5, 128.8 (2C), 129.4 (2C), 136.7, 138.5, 155.8, 174.4; MS
(ES+) m/z (rel intensity) 819 ([2M + Na]+, 31), 797 ([2M + H]+,
100), 421 (MNa+, 10), 399 (MH+, 47).
4-Meth yl-1,2,3,3a,6,6a,7,8-octah ydr o-3,9-diazacyclopen -
ta [d ]n a p h th a len e-6,9-d ica r boxylic Acid 9-Ben zyl Ester
6-Eth yl Ester (38b). NaBH4 (32 mg, 0.860 mmol) was added
to a cold solution of imine 34 (34 mg, 0.086 mmol) in CH2Cl2/
MeOH (1:1, 4 mL). The reaction mixture was allowed to warm
to room temperature during 30 min and then poured into an
aqueous HCl solution (50 mL, pH 1-2). The mixture was
basified with a saturated NaHCO3 aqueous solution and
extracted with CH2Cl2 (3 × 20 mL). The combined organic
fractions were dried over MgSO4 and concentrated in vacuo.
Purification of the residue by preparative TLC (CH2Cl2/MeOH
95/5, 0.2% NEt3) gave amine 38b (30 mg, 0.075 mmol, 88%
yield): IR (film) 3333, 2937, 2870, 1731, 1694, 1435, 1220 cm-1
;
1H NMR (CD3CN, 400 MHz) δ 1.22 (t, J ) 7.1 Hz, 3 H), 1.40-
1.47 (m, 1 H), 1.49-1.58 (m, 1 H), 1.59-1.85 (m, 2 H), 1.74
(bs, 3 H), 1.95-2.01 (m, 1 H), 2.15 (bs, 1 H), 2.65-2.80 (m, 2
H), 2.84-3.09 (m, 2 H), 3.15-3.29 (m, 2 H), 3.33 (bd, J ) 11.0
Hz, 1 H), 3.64-3.76 (m, 1 H), 4.12 (q, J ) 7.1 Hz, 2 H), 5.09
(s, 2 H), 5.44 (bs, 1 H), 7.27-7.40 (m, 5 H); 13C NMR (CD3CN,
63 MHz) δ 14.5, 21.8, 26.5, 37.4, 37.7, 41.0, 44.4, 44.9, 45.5,
49.3, 61.5, 64.5, 67.4, 120.3, 128.5, 128.8 (2C), 129.4 (2C), 136.6,
138.4, 156.1, 175.0; MS (ES+) m/z (rel intensity) 797 ([2M +
H]+, 14), 399 (MH+, 100); HRMS (CI, isobutane) calcd for
C
23H31N2O4 (MH+) 399.2284, found 399.2288.
yield): IR (film) 2979, 2940, 2858, 1729, 1698, 1436, 1264 cm-1
;
4-H yd r oxy-4-m e t h yl-1,2,3,3a ,4,6a ,7,8-oct a h yd r o-3,9-
1H NMR (CD3CN, 400 MHz) δ 1.25-1.42 (m, 2 H), 1.27 (t, J
) 7.1 Hz, 3 H), 1.81 (s, 3 H), 2.18 (d, J ) 17.0 Hz, 1 H), 2.33-
2.39 (m, 1 H), 2.61 (d, J ) 13.3 Hz, 1 H), 2.70 (d, J ) 17.0 Hz,
1 H), 2.77-2.84 (m, 1 H), 3.38-3.41 (m, 1 H), 3.88 (dd, J )
2.0, 13.3 Hz, 1 H), 4.10-4.26 (m, 4 H), 5.13 (bs, 2 H), 5.52 (s,
1 H), 7.32-7.41 (m, 5 H), 7.53 (s, 1 H); 13C NMR (CD3CN, 101
MHz) δ 14.8, 21.6, 25.5, 39.1, 43.5, 44.6 (2C), 45.5, 53.1, 61.6,
67.8, 75.1, 118.5, 128.8, 129.0 (2C), 129.7 (2C), 137.4, 138.7,
156.5, 167.0, 174.2; MS (ES+) m/z (rel intensity) 435 (MK+,
28), 419 (MNa+, 100), 397 (MH+, 15); HRMS (CI, isobutane)
calcd for C23H29N2O4 (MH+) 397.2127, found 397.2140. Minor
isomer 34 (23 mg, 0.058 mmol, 25% yield): IR (film) 2936,
d ia za cyclop en t a [d ]n a p h t h a len e-6,9-d ica r b oxylic Acid
9-Ben zyl E st er 6-E t h yl E st er (40). Trifluoroacetic anhy-
dride (0.210 mL, 1.506 mmol) was added slowly, at 0 °C, to a
solution of hydrogen peroxide (50% in H2O, 0.044 mL, 0.753
mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred
during 90 min at 0 °C. To an aliquot of this freshly prepared
peroxide solution (0.75 mL) was added, at 0 °C, a solution of
amine 38a (18 mg, 0.045 mmol) dissolved in a mixture of
trifluoroacetic acid and CH2Cl2 (1:50, 0.45 mL, corresponding
to 0.113 mmol of the acid). The reaction mixture was allowed
to warm to room temperature during 45 min, poured into a
cold saturated Na2SO3 solution, and basified with a saturated
NaHCO3 solution. The two phases were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic fractions were dried over MgSO4 and con-
centrated in vacuo. This freshly prepared crude epoxide was
then taken up in anhydrous EtOH (0.50 mL). A solution of
NaOEt in EtOH (1.50 mL), prepared from Na (42 mg, 1.826
mmol) and anhydrous EtOH (10 mL), was added at 0 °C. After
stirring for 6 h at room temperature the reaction mixture was
poured into cold H2O (20 mL) and extracted with CH2Cl2 (4 ×
20 mL). The combined organic phases were dried over MgSO4
and concentrated in vacuo. The residue was purified by
preparative TLC (CH2Cl2/MeOH 95/5, 0.2% NEt3) to give
amino alcohol 40 (15 mg, 0.036 mmol, 80% yield): IR (film)
2856, 1722, 1698, 1435, 1221 cm-1 1H NMR (CD3CN, 400
;
MHz) δ 1.26 (t, J ) 7.1 Hz, 3 H), 1.45-1.52 (m, 1 H), 1.75-
1.85 (m, 1 H), 1.89-1.95 (m, 1 H), 1.96 (s, 3 H), 2.48 (d, J )
18.0 Hz, 1H), 2.68 (dd, J ) 1.4, 18.0 Hz, 1 H), 3.15 (d, J )
13.3 Hz, 1 H), 3.23-3.31 (m, 2 H), 3.56 (d, J ) 13.3 Hz, 1 H),
3.72-3.80 (m, 2 H), 4.16 (q, J ) 7.1 Hz, 2 H), 5.14 (s, 2 H),
5.49 (s, 1 H), 7.32-7.42 (m, 5 H), 7.46 (s, 1 H); 13C NMR
(CD3CN, 101 MHz) δ 14.7, 22.2, 26.7, 35.8, 41.5, 44.2 (2C),
48.8, 50.0, 61.9, 67.8, 77.5, 120.5, 128.9, 129.1 (2C), 129.7 (2C),
136.5, 138.9, 156.4, 166.1, 175.0; MS (ES+) m/z (rel intensity)
435 (MK+, 31), 419 (MNa+, 100), 397 (MH+, 98); HRMS (CI,
isobutane) calcd for
397.2123.
C
23H29N2O4 (MH+) 397.2127, found