Enantioefficient Synthesis of R-Ergocryptine
1H NMR (CDCl3, 400 MHz): δ 1.52 (9H, s, CMe3), 2.87 (2H, t,
J ) 7.1 Hz, H-4), 3.21 (2H, t, J ) 7.1 Hz, H-4), 7.41 (1H, dd,
J ) 8.3, 8.0 Hz, H-7), 7.57 (1H, br s, H-2), 7.70 (1H, d, J ) 8.3
Hz, H-8), 8.53 (1H, J ) 8.0 Hz, H-8). 13C NMR (CDCl3, 100
MHz): δ 20.7 (C-3), 28.8 (CMe3), 38.6 (C-4), 41.2 (CMe3), 116.3
(C-2a), 119.7 (C-8), 121.38 (C-2), 122.88 (C-6), 125.96 (C-5a),
126.35 (C-7), 133.7 (C-8b), 135.9 (C-8a), 177.2 (NCO), 197.3
(C-5). IR (KBr, cm-1): 2976, 1694, 1671, 1603. HRMS (EI, 70
eV): C16H17NO2 m/z calcd 255.1259, found 255.1264.
N-P iv-4-[N-m eth yl-N-aceton yl(2′,2′-eth ylen edioxy)]am i-
n o-3,4-d ih yd r o-1H-ben zo[c,d ]in d ol-5-on e: Alk yla tion of
5 w ith 4d (6a ). To a solution of 4d (1.12 g, 3.35 mmol) in dry
toluene (35 mL) was added amine 5 (1.1 g, 8.3 mmol) in toluene
(3.5 mL) at room temperature and the solution was stirred
for 48 h. The precipitate formed was filtered off and washed
with toluene and the combined filtrate was evaporated in
vacuo. Purification by chromatography (eluent: EtOAc/hexane,
2:1) afforded 6a (0.43 g, 35%) as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ 1.37 (3H, s, CH3), 1.53 (9H, s, CMe3),
2.69 (3H, s, NCH3), 2.87 (1H, d, J ) 14.8 Hz, NCH2A), 3.02
(1H, d, J ) 14.8 Hz, NCH2B), 3.28-3.33 (2H, m, H-3), 3.94
(1H, dd, J ) 11.3, 6.9 Hz, H-4), 3.9-4.02 (4H, m, OCH2CH2O),
7.43 (1H, dd, J ) 8.3, 7.6 Hz, H-7), 7.58 (1H, dd, J ) 1.9, 1.0
Hz, H-2), 7.69 (1H, dd, J ) 7.6, 0.7 Hz, H-8), 8.50 (1H, dd, J
) 8.3, 0.7 Hz, H-6). 13C NMR (CDCl3, 50 MHz): δ 22.8 (CCH3),
26.4 (C-3), 28.7 (CMe3), 41.02 (NCH3), 41.17 (CMe3), 61.5
(NCH2), 65.1 (OCH2CH2O), 70.0 (C-4), 110.8 (CCH3), 116.6 (C-
2a), 119.7 (C-6), 121.46 (C-2), 122.68 (C-8), 126.55 (C-7), 126.60
(C-5a), 132.7 (C-8a), 135.7 (C-8b), 177. 2 (NCO), 198.4 (C-5).
IR (oil, cm-1): 2979, 2879, 1690, 1606. MS (FAB-NOBA, m/z,
%): 385 (M + H+, 50), 307 (18), 154 (100). HRMS (FAB,
glycerine): C22H28N2O4 m/z calcd 384.2049, found 384.2041.
4-[N-Met h yl-N-a cet on yl(2′,2′-et h ylen ed ioxy)]a m in o-
3,4-d ih yd r o-1H-ben zo[c,d ]in d ol-5-on e (6b). (a ) Alk yla tion
of 5 w ith 4g. To a solution of 4g (7.5 g, 30.0 mmol) in dry
THF (130 mL) was added amine 5 (8.6 g, 65.1 mmol) in THF
(20.0 mL) at room temperature and the solution was stirred
for 24 h. The precipitate formed was filtered off and washed
with THF and the solvent was evaporated in vacuo (bath: 30-
35 °C). The residue was dissolved in a mixture of EtOAc (450
mL) and cold water (180 mL), and the pH was adjusted to ≈3
with aq HCl solution (1 M, 54 mL). The organic phase was
extracted with aq HCl solution (0.5 M, 2 × 60 mL) and water
(50 mL). The aqueous phase was mixed with CHCl3 (450 mL)
and the pH was adjusted to ≈8 with aq saturated Na2CO3
solution (≈40 mL) while the mixture was cooled with an ice
bath. After the phases were separated, the aqueous phase was
washed with CHCl3 (2 × 100 mL). The combined organic phase
was washed with brine (100 mL) and dried. Evaporation
(bath: 30-35 °C) of the solvent provided a crude solid (6.83
g, 76%), which was crystallized from a mixture of EtOAc/
hexane (1:1, 50 mL) to afford 4.727 g (52.4%) of 6b as a cream-
colored solid. A further crop of 6b (0.295 g, 3.3%) was obtained
by chromatography of the mother liquor (eluent: EtOAc/
hexane, 1:1). Mp: 120-124 °C. 1H NMR (CDCl3, 400 MHz): δ
1.39 (3H, s, CCH3), 2.70 (3H, s, NCH3), 2.90 (1H, d, J ) 14.5
Hz, NCH2A), 3.03 (1H, d, J ) 14.5 Hz, NCH2B), 3.31 (1H, m, J
) 15.4, 11.4, 1.6 Hz, H-3A), 3.37 (1H, m, J ) 15.4, 7.3, 0.7 Hz,
H-3B), 4.01 (1H, dd, J ) 11.4, 7.3 Hz, H-4), 3.9-4.06 (4H, m,
OCH2CH2O), 7.07 (1H, dd, J ) 1.6, 0.7 Hz, H-2), 7.25 (1H, dd,
J ) 8.1, 7.3 Hz, H-7), 7.51 (1H, dd, J ) 7.3, 0.6 Hz, H-8), 7.55
(1H, dd, J ) 8.10, 0.6 Hz, H-6), 8.46 (1H, br s, NH). 13C NMR
(CDCl3, 50 MHz): δ 22.8 (CCH3), 26.5 (C-3), 41.0 (NCH3), 61.6
(NCH2), 65.1 (OCH2CH2O), 71.1 (C-4), 110.9 (C-2a), 115.69 (C-
6), 115.85 (C-8), 120.7 (C-2), 123.1 (C-7), 126.7 (C-5a), 131.6
(C-8a), 134.9 (C-8b), 199.7 (C-5). IR (KBr, cm-1): 3133, 3094,
2974, 2950, 1671, 1619, 1600. MS (EI, m/z, %): 300 (M+, 11),
213 (96), 185 (23), 170 (57), 87 (100). HRMS (EI): C17H20N2O3
m/z calcd 300.1474, found 300.1480.
N-P iv-4-br om o-Uh le’s k eton e (4d ). Preparation of 4d was
described in our earlier publication.15
N-P iv-4-b r om o-Uh le’s Ket on e E t h ylen e Ket a l (4e).
Protection of bromoketone 4d was carried out by applying a
commonly used method (4d , 30.0 g, 89.7 mmol; ethylene glycol,
65 mL; p-TSA, 2.7 g; reflux in 0.6 L of benzene, 6 h, water
separating device). After cooling, the mixture was diluted with
EtOAc (2.5 L), crushed ice (1.5 L), and aq NH4OH solution
(25%, 110 mL). The organic phase was washed with water (2
× 0.6 L) and dried. The crude product was crystallized from
ether (100 mL) to afford 27.4 g (81%) of ketal 4e as a cream-
colored solid. Mp: 153-155 °C. 1H NMR (CDCl3, 200 MHz):
δ 1.51 (9H, s, CMe3), 3.46 (1H, dd, J ) 15.6, 6.7 Hz, H-3A),
3.68 (1H, dd, J ) 15.6, 4.2 Hz, H-3B), 4.27 (4H, s, OCH2CH2O),
4.60 (1H, dd, J ) 6.7, 4.2 Hz, H-4), 7.25-7.42 (2H, m, H-6
and H-7), 7.51 (1H, br s, H-2), 8.34 (1H, dd, J ) 7.5, 1.7 Hz,
H-8). 13C NMR (CDCl3, 50 MHz): δ 28.5 (CMe3), 30.8 (C-3),
40.9 (CMe3), 53.0 (C-4), 66.11 and 66.39 (OCH2CH2O), 106.6
(C-5), 114.8 (C-2a), 118.16 (C-6), 118.51 (C-8), 120.4 (C-2),
126.1 (C-7), 127.4 (C-8b), 128.7 (C-5a), 135.0 (C-8a), 176.9
(NCO). IR (KBr, cm-1): 2975, 2879, 1687, 1439. MS (EI, m/z,
%): 377 (M+, 43), 214 (39), 170 (20), 57 (100). HRMS (EI):
C
18H20NO3Br m/z calcd 377.0627, found 377.0622.
4-Br om o-Uh le’s Ket on e E t h ylen e Ket a l (4f). Methyl-
amine gas was introduced into a solution of 4e (18.9 g, 49.9
mmol) in CHCl3 (300 mL) at 10-15 °C for about 3-4 h. The
mixture was washed with water (100 mL) and brine (100 mL)
and dried. The crude product was crystallized from diethyl
ether (50 mL) to yield 13.04 g (88%) of 4f as a cream-colored
solid. Mp: 120-122 °C. 1H NMR (CDCl3, 400 MHz): δ 3.50
(1H, dd, J ) 15.8, 7.2 Hz, H-3A), 3.71 (1H, dd, J ) 15.8, 4.1
Hz, H-3B), 4.28 (4H, s, OCH2CH2O), 4.65 (1H, dd, J ) 7.2, 4.1
Hz, H-4), 6.93 (1H, br s, H-2), 7.17 (1H, dd, J ) 7.1, 0.9 Hz,
H-8), 7.22 (1H, dd, J ) 7.1, 7.7 Hz, H-7), 7.31 (1H, dd, J )
7.7, 0.9 Hz, H-6), 8.0 (1H, br s, NH). 13C NMR (CDCl3, 100
MHz): δ 31.3 (C-3), 54.6 (C-4), 65.95 and 66.40 (OCH2CH2O),
107.2 (C-5), 109.4 (C-2a), 111.4 (C-8), 114.2 (C-6), 119.1 (C-2),
122.9 (C-7), 126.4 (C-8b), 129.0 (C-5a), 133.8 (C-8a). IR (KBr,
cm-1): 3358, 2878. MS (EI, m/z, %): 293 (M+, 76), 293 (75),
214 (100), 170 (95). HRMS (EI):
293.0051, found 293.0055.
C13H12NO2Br m/z calcd
4-Br om o-3,4-d ih yd r o-1H -b en zo[c,d ]in d ol-5-on e (4g;
4-Br om o-Uh le’s Keton e). To a solution of 4f (22.0 g, 74.8
mmol) in acetone (610 mL) at 10-15 °C was added aq HCl
solution (1 M, 110 mL). The mixture was stirred for 3 h while
the temperature was allowed to warm to room temperature.
The organic solvent was evaporated under reduced pressure
(water bath: 30-35 °C). The precipitated product was filtered
off and washed with water (2 × 75 mL) and ether (2 × 50 mL)
to afford 18.0 g (97%) of 4g as a pale brown solid. (The product
proved to be unstable at room temperature but it could be
stored at -20 °C for a few months without any decomposition.)
(b) N-Dea cetyla tion of 6a . Methylamine gas was intro-
duced into a solution of 6a (0.5 g, 1.3 mmol) in benzene (50
mL) at 10-15 °C for about 1 h. The mixture was washed with
water and brine and dried. The isolation of 6b (0.312 g, 80%)
was carried out as described above.
(()-9,10-Did eh yd r o-6-m eth yler golin e-8-on e (7) via Di-
k eton e 6c. In the first step 6b (1.6 g, 5.32 mmol) was dissolved
in aq HCl solution (6 M, 100 mL) and stirred at 37 °C for 1 h,
then cooled in an ice bath. The mixture was mixed with CHCl3
(0.5 L), and the pH was adjusted to ≈7 with aq NaOH solution
(5 M). After the phases were separated, the aqueous phase
was washed with CHCl3 (2 × 100 mL). The combined organic
1
Mp: 119-122 °C. H NMR (CDCl3 + DMSO-d6, 400 MHz): δ
3.60 (1H, dd, J ) 17.5, 3.5 Hz, H-3A), 3.89 (1H, dd, J ) 17.5,
4.8 Hz, H-3B), 4.91 (1H, dd, J ) 4.8, 3.5 Hz, H-4), 7.24 (1H, br
s, H-2), 7.28 (1H, dd, J ) 7.4, 7.6 Hz, H-7), 7.58 (1H, d, J )
7.4 Hz, H-8), 7.64 (1H, d, J ) 7.6 Hz, H-6), 10.79 (1H, br s,
NH). 13C NMR (CDCl3, 100 MHz): δ 31.5 (C-3), 51.5 (C-4),
105.8 (C-2a), 116.87 (C-8), 117.21 (C-6), 122.19 (C-5a), 122.40
(C-7), 123.28 (C-2), 130.7 (C-8b), 134.9 (C8a), 190.2 (C5). IR
(KBr, cm-1): 3400, 1669, 1617, 1598. MS (EI, m/z, %): 249
(M+, 64), 249 (65), 170 (100). HRMS (EI): C11H8NOBr m/z
calcd 248.9789, found 248.9788.
J . Org. Chem, Vol. 69, No. 18, 2004 5997