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4 Mechanism Problems from Reactions Give Expected Products288
was dissolved in CHCl
3
and washed with saturated aqueous NaCl and 1% NH
4
OH
and then dried over anhydrous Na
2
SO
4
. Removal of the solvent afforded the residue,
which was subjected to a silica gel column (9:1 CHCl
3
/MeOH) to give compound 3
(0.4 mg).
The Mechanism
This describes a modified Polonovski reaction [340]. Initially, the tertiary amine 1 is oxi-
dized to the N-oxide A using mCPBA. Subsequent trifluoroacetylation of A is followed
by an intramolecular attack of the hydroxy group at C13 on the ketone at C5, leading to
the formation of hemiketal C. This step is accompanied by the cleavage of the C4─C5
bond, resulting in the formation of a lactone ring between C5 and C13. Another lac-
tone ring, E, may form through intramolecular transesterification. The rigid fused
tetracyclic ring system of serratinine (1) is anticipated to facilitate fragmentation via
the Polonovski reaction. Reduction of the unstable iminium intermediate D or E with
NaBH
3
CN proceeds with hydride addition from the R-face of the molecule due to steric
hindrance, ultimately generating an R-configuration at C4.
4.8.6. Vincamine
Problem 121: Preparation of Vincamine from Tabersonine
(+)–Vincamine (4) exhibits valuable cerebrovascular and cerebroprotective activ-
ities. One of the preparation in a patent application is the transformation of relatively
abundant natural product tabersonine (1) to 4 by the following process [341].
Please provide a mechanism for the transformation from 3 to 4.
O
O
N
H
H
OH
N
O
OH
OH
H
1
mCPBA
N
+
O
OH
OH
H
O
–
TFAA
N
+
O
OH
H
O
CF
3
O
CF
3
CO
2
–
HO
OH
H
O
O
O
O
H
OH
H
O
O
H
HO
TFA
A
B
C
E
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
D
HO
H
2
O
O
H
N
H
p-TsOH
transesterification
Transesterification
O
O
3
N
+
CF
3
CO
2
–
CF
3
CO
2
–
CF
3
N
+
NaBH
3
CN
NaBH
3
CN
CF
3
CO
2
–
N
+
4.8 Miscellaneous 289
Experimental Procedure (from patent CN 2020, 110950859 A*)
Example Name 1.1.1.7. Once the final reaction step was completed, the temperature
was maintained under 30 °C. Glacial acetic acid (4.1 kg) was slowly added followed
by triphenylphosphine (3.7 kg) to the reaction solution. The reaction was continued
at 35–45 °C for 16–20 hours, the temperature was checked every 2 hours. After the
reaction was completed, the solvents were evaporated under vacuum, bath temper-
ature was controlled at 45–55 °C. DCM (30.0 kg) was added to the residue, the pH
was adjusted to 8–10 with 15% sodium hydroxide solution at a temperature below
35 °C. Layers were separated, the organic phase was concentrated under vacuum
at 45–55 °C. Anhydrous methanol (6.0 kg) was added to the residue, and the mix-
ture was stirred at room temperature for 0.5 hours to crystallize. After centrifugal
filtration, the filter cake was rinsed with anhydrous methanol (2.0 kg) to give crude
vincamine 4. The crude vincamine was added to the spin flask and anhydrous meth-
anol (4.0 kg) was added. The crystal was spin washed at room temperature for 0.5
hours. The product was collected by centrifugal filtration, rinsed with 2.0 kg of
anhydrous methanol to afford pure vincamine 4.
The reported characterization data of (+)–vincamine (4) in another article [342]
are listed as follows. White crystals: mp 230–232 °C; [ɑ]
22
D
+44.0 (c = 1.4, pyridine);
IR (KBr) 3400–2400, 1748 cm
1
;
1
HNMR (200 MHz) δ 0.91 (t, J = 7.5 Hz, 3H), 1.30–
1.80 (m, 5H), 2.10 (d, J = 14.3, 1H), 2.24 (d, J = 14.2, 1H), 2.27 (m, 1H), 2.42–2.70
(m, 3H), 2.90–3.10 (m, 1H), 3.20–3.40 (m, 2H), 3.82 (s, 3H), 3.92 (s, 1H), 4.64 (s, 1H),
7.08–7.18 (m, 3H), 7.45–7.52 (m, 1H);
13
CNMR (50 MHz) δ 7.6 (CH
3
), 16.8 (CH
2
),
20.8 (CH
2
), 25.1 (CH
2
), 28.9 (CH
2
), 35.1 (C), 44.4 (CH
2
), 44.6 (CH
2
), 50.9 (CH
2
), 54.2
(CH
3
), 59.1 (CH), 81.9 (C), 105.9 (C), 110.3 (CH), 118.4 (CH), 120.2 (CH), 121.6
(CH), 129.0 (C), 131.4 (C), 134.4 (C), 174.4 (C). Anal. Calcd for C
21
H
26
N
2
O
3
: C, 71.16;
H, 7.33; N, 7.90. Found: C, 71.05; H, 7.40; N, 7.80.
* This was translated from Chinese by the author of this book.
N
H
N
O
O
H
N
H
N
O
O
H
H
2
, Pd-C, THF
rt, 18 h
1 (Tabersonine)
2 (Vincadifformine)
95%
N
N
+
O
O
H
O
–
OH
Ph
3
P, HOAc
35–45 °C, 16 h
N
N
HO
O
O
H
4 (vincamine)
mCPBA
THF, <35 °C
3
4 Mechanism Problems from Reactions Give Expected Products290
The Mechanism
The first stage should be the reduction of the N-oxide 3 to free amine A by Ph
3
P.
Acid-catalyzed rearrangement of A to B is followed by ring-opening to form C, and
subsequent recyclization yields product 4.
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