Total syntheses of eburnamonine, quebrachamine, vincadine and epivincadine
4023
extracted with ether. The extract was washed with water, dried
(Na:CO3) and evaporated. Preparative tic of the residue
on silica gel and development with EtOAc yielded 1.35 g (78%) of
solid lactone 8:22 IR (CHCI3) NH 2.90 (m), C=O 5.74 (s) g.;
~HNMR 8 0.78 (t, 3, .I= 7Hz, Me), 1.2-t.8 (m, 6, methylenes),
2.1-3.1 [m, 8, COCHz, benzyl Hz, (NCH2h], 5.06 (s, 1, NCH),
6.9-7.5 (m, 5, aromatic I-Is), 8.36 (s, 1, NH); role 312 (M+, 18%),
239 (40). 218 (10), 182 (base), 138 (72). (Found: m/e 312.1843.
Calcd. for C~gH24OaN:: role 312.1838).
( + )-Eburnamonine (1), Pyrolysis of a sample of lactone 8 in a
Kugelrohr apparatus at 250° (0.01Tort) for 0.5 hr led to a dis-
tillate which crystallized spontaneously, giving a 60% yield of
pure (±) 1: m.p., m.m.p. 200~ (lit.7~ m.p. 200-202°); IR, UV and
Ill NMR spectra identical with those of an authentic sample7~
Hemiacetats 11. Diisobutylaluminum hydride (1.60mmol in
toluene) was added dropwise over a 5 min period to a sth'ring
soln of 6 (243 mg; 1.43 mmol) in 5 ml dry ether at - 78° under N2.
After 1 hr the mixture was warmed and I M HCI (10 ml) added.
The mixture was extracted with ether and the extract washed
with sat NaHCO3aq, dried (NazSO4) and evaporated. Shorl-path
vacuum distillation of the residue, 246 mg (99%) of pure (by tic)
liquid, yielded a ca. I :1 mixture of lla and b: IR (neat) OH 2.93
(m) ~t; tH NMR 8 0.83, 0.84 (t, total 3, J = 7Hz, Me), 1.0-2.1 (m,
8, methylenes), 3.3-3.7 (m, 2, OCH2), 4.66 (s, I, OCHOR), 4.98 (s,
1, OCHOH); ~3C NMR 8 values on formulas lla16 and b; ride 171
(M*-I, 2%), 154 (13), 149 (48), 108 (58), 9.7 (60), 69 (38), 55 (56), 43
(59), 41 (base). (Found: C, 63.03; H, 9.13. Calcd. for C9H~603:
C, 62.77; H, 9.36%).
Dihydrofuran 13. A mixture of AgCO~ (37.5g) and Celite
(0.57 g/retool of oxidizing agent) in 500 ml benzene was refluxed
under N2 in the absence of light, while 100ml solvent was
removed by a Dean-Stark trap. Alcohol 12, 2.00 g, was added and
the mixture refluxed for another 2.5 hr. The hot mixture was
filtered and the residue washed thoroughly with hot benzene.
Evaporation of the combined filtrate and washings left an oil,
whose distillation yielded 1.70 g (86%) of colorless, liquid enol
ether 13: IR (neat) C=C 6.20 (m) ~; )HNMR 8 0.88 (t, 3,
J = 7Hz, Me)) 1.2-1.9 (m, 6, methylenes), 3.3-4.1 (m, 20CH2),
4.74 (d, 1, J = 3 HZ, olefinic H), 5.33 (s, I, OCHO), 6.40 (d, 1,
J = 3 Hz, olefinic OCH); )3C NMR 8 values on formula 13; role
154 (M*, 19%), 125 (base), 97 (54), 95 (52), 83 (57), 67 (41).
(Found: C, 70.17; H, 9.22. Calcd. for CgH)(O:: C, 70.10', H,
9.15%).
Carbinolamine ethers 14a and b. A mixture of 13 (2.178) and
tryptamine hydrochloride (3.608) in 20ml 10% aqueous AcOH
was stirred for 7 hr. NaOAc (752 rag) was added to the red
mixture and stirring continued for 40 hr. After basification with
10% NazCO3aq the mixture was extracted with CHzCh and the
extract dried (NazSO(), passed through a short, deactivated alu-
mina column (for the removal of excess tryptamine) and
evaporated. Chromatography of the residue on alumina (activity V)
and elution with 1 : t hexane-CH2Cl2 yielded 2.81 g (67%) of solid,
thermally labile, air-sensitive, acid-sensitive carbinolamine ethers
14a and b in three fractions (the second being a 157 mg mixture of
the two substances). Fraction I. 1.39g (33%), was pure 14a: IR
(CHCI~) NH 2.88 (m), C=C 6.18 (m), ~; ~HNMR (~ 0.89 (t,
3, J = 7 Hz, Me), 1.2--1.8 (m, 8, methylenes), 2.5-3.8 (m, 6, OCH2,
NCHz, benzyl CH2), 4.20 (s, 1, OCHN), 4.40 (t, 1, J = 7 Hz, NCH),
7.0-7.6 (m, 4, aromatic Hs); "C NMR 6 (acetone-ds)~ values are on
formula 14a. (Found: m/e 296.1883. Calc. for C)gHz(ON2: m/e
296.1888).
(m) #: 'HNMR 8 (DMSO-d6) 0.84 (t, 3, J =7Hz, Me), 1.1-2.2
(m, 8, methylenes), 2.3-3.2 [m, 6, (NCHzh, benzyl CHz], 3.30 (m,
2, OCH2), 3.96 (t, 1, J = 7 Hz, NCH), 6.7-7.5 (m, 4, aromatic Hs);
" C N M R ~'~ values on formula 15a. (Found: m/e 298.2040.
Calcd. for Ct9H~sONz: role 298.2045).
The same treatment and work-up for ether 14b gave a 93% yield
of 15b: m.p. 169--170°(from CHzCI2) (lit. 14 m.p. 168-170~); IR (KBr)
OH, NH 2.94 (w). 3.07 (m) p.; fH NMR 6 (DMSO-d6) 0.71 (t, 3,
J - 7 Hz, Me), 1.0-2.2 (m, 8, methylenes), 2.3-3.3 [m, 6, (NCH2h,
benzyl CH2], 3.45 (m, 2, OCH2), 3.98 (t, I, J = 7 Hz, NCH), 6.8-7,5
(m, 4, aromatic Hs); J3C NMR 8~ values on formula 15b. (Found:
m/e 298.2040. Calcd. for Cj9H~ON2: role 298.2045).
A
mixture of 11 (467mg) and tryptamine hydrochloride
(800 rag) in 5 ml 10% aqueous AcOH was stirred under N2 for
7 hr. NaOAc, 150 rag, was added and stirring continued for 40hr.
The mixture was made basic with 10% NatCO~aq and extracted
with CHzCIz. The extract was dried (Na2SO4), passed through a
short column of alumina (grade V) and evaporated. A mixture of
the residue and sodium cyanoborohydride (210 rag) in 10 ml 10%
aqueous AcOH was stirred for 10 min, then made basic with 10%
Na:CO3aq and extracted with CH2CI2. The extract was dried
(Na:SO~,), passed through 158 of alumina (grade V) and
evaporated, yielding 750 mg (93%) of a foamy, ca. 1:1 mixture of
pure 15a and b. The two alcohols were separated by crystal-
lization of 15a from EtOAc and partitioning the mother liquor by
the above chromatographic procedure.
Dihydro/uran ester 19. A soln of ethyl diazopyruvate (3.77 g) in 4
(10 ml) and CH2Ch (2 ml) was added slowly (ca 1 drop/3 sec) to a
stirring mixture of freshly prepared copper bronze (0.60g) in 4
(5.00 g) kept at 95o under N2. Heating was continued for 0.5 hr
and the then cooled mixture filtered. Distillation of the filtrate at
60Tort led to the recovery of starting dihydropyan. Finally,
Kugelrohr distillation (ca. 90°/0.2 Tort) of the distillation residue
yielded colorless, liquid ester 19 (5.00 g; 83%): IR (neat) C=O 5.75
(s), C:C 6.10 (m) p.; ~HNMR ~ 0.90 (t, 3, J = T H z , Me of Et),
1.33 (t, 3, J = 7 Hz. Me of OEt), 1.0-2.2 (m, 6, methylenes), 3.71
(m, 2, OCHz), 4.25 (q, 2, l = 7 Hz, OCH2 of Et), 5.48 (s, t, OCH),
5.78 (s, l, olefinic H); ~C NMR ~ values on formula 19; role 226
(M+, 0.9%), 169 (3), 153 (4), 141 (3), 125 (73), 29 (base). (Found:
C, 63.47; H, 7.87. Calcd. for C~:H~sO4; C, 63.70; H, 8.02%).
Esters 20. Ester 19, 4.50g, was added dropwise to fluoroboric
acid (.50 ml of cone acid in 30 ml water) and the mixture stirred at
room temp for 50hr, It then was saturated with NaCl and
extracted exhaustively with CH:CIz. The organic soln was
extracted with 10%Na2CO3aq and the extract acidified with
cone HCI. The aqueous soln was extracted with CH2Ch and the
extract dried (Na~SO4) and evaporated. The residual organic
acid, 3.20g (74%), crystallized in the refrigerator. Diazomethane,
liberated from Diazald (5.0 g), was distilled into an ice-cold soln
of the acid in 75 ml ether up to the point of persistence of a
yellow color. The excess diazomethane was evaporated under a
slow stream of Nz. The soln then was dried (NazSO4) and
evaporated, yielding 3.37g (99%) of a liquid 3:2 ester 20 isomer
mixture: IR (neat) OH 2.93 (m), C=O 5.74 (s) tz; li,i NMR 6 0.89
(t, 3, J = 7 Hz, Me), 1.0-2.5 (m, 8, methylenes), 3.40 (m, 2, OCH2),
3.80, 3.82 (s, 3 total, OMe), 4.93, 5.04 (s, I total, OCH); "C NMR
6 major (minor) isomer OCH2 61.7 (61.5), pyran ~8-CH2 20.5
(20.2), pyran '),-CH2 26.5 (26.6), pyran ~8-C 41.1 (42.1), OCH 107.0
(106.0), Me of Et 8.3 (8.3), CH2 of Et 27.8 (28.0), CO 171.1
(170.2), CO a-C 100.0 (99.8), CO ~8-CH2 42.8 (41.9), OMe 52.8
(52.8); role 230 (M', 0..5%), 125 (3), 97 (45), 96 (40), 95 (35), 83
(74), 69 (65), 67 (95), 57 (83), 55 (base). (Found: role 230.1148.
Calcd. for CHH~sO~: role 230.1154).
Fraction 3, 1.268 (30%), was pure 1~: IR (CHCI~) NH 2.88
(m), C=C 6.18 (m), 6.27 (m) p.; ~H NMR 6 (acetone-d~) 0.78 (t, 3,
J = 7 Hz, Me), 1.0-3.4 (m, 14, methylenes), 4.27 (s, I, OCHN),
4.63 (t, 1, J = 7 Hz, NCH),6.9-7,~ (m, 4, aromatic Hs); 13C NMR
(acetone-d~)" values are on formula 14b. (Found: role 296.1880.
Calcd. for C~gH~ONz: role 296.1888).
Alcohols 15a and b. A mixture of 14a (345 mg) and sodium
cyanoborohydride (73 mg) in 5 ml 50% aqueous AcOH was stir-
red for 10min. It was made basic with 10% Na~CO~aq and
extracted with CH~Ch. The extract was dried (NazSO4) and
evaporated. Chromatography on alumina (grade V) and elution
with EtOAc yielded 276 mg (79%) of 15a; m.p. 169-169.5° (from
EtOAc) (lit.~m.p. 166-167°); IR (KBr) OH, NH 2.99 (w), 3.00
Carbinolamine ether esters 21a and b. A soln of 2 drops of
glacial AcOH in 5 m] dry MeOH was added to a soln of 20
(3.40 g) and tryptamine (3.50 g) in 125 ml CHzCh and the mixture
stirred at room temp for 72 hr. Solid Na:,CO3 (0.208), was added
and the solvent evaporated. Chromatography of the residue on
silica gel and elution with 2 : 1 hexane-EtOAc yielded 4.00 g (76%)
of a partially crystalline mixture of esters 21a and b. Separation
of the solid and crystallization from hexane-EtOAc gave crys-
talline 2in: m.p. 187-188°; IR (KBr) NH 2.97 (s), C=:O 5.88 (s) ~;
tH NMR 6 0.83 (t, 3, J = 7 Hz, Me), 0.9-3.7 (m, 14, methylenes),
3.70 (s, 3, OMe), 4.31 (s, 1, OCHN), 6.9-7.6 (m, 4, aromatic Hs);