Synthesis of the Aspidosperma Alkaloid Na-Formyl-16-ÃŽÂ±-Hydroxyaspidospermidine
ABSTRACT The first total synthesis of Na-formyl-16ÃŽÂ±-hydroxyaspidospermidine and its isomer via (Ã‚Â±)-vincadifformine is described and their structure elucidation using different methods of analysis is reported.
Molecules 2001, 6, 803-814
Synthesis of the Aspidosperma Alkaloid Na-Formyl-16-α α α α-
Fatiha Belferdi and Abdelhamid Belattar*
Department of Chemistry, Faculty of Science, Constantine University, 25000, Algeria.
* Author to whom correspondence should be addressed; e-mail: email@example.com
Received: 1 April 2001; in revised form 6 September 2001 / Accepted: 8 September 2001 / Published:
30 September 2001
Abstract: The first total synthesis of Na-formyl-16α-hydroxyaspidospermidine and its
isomer via (±)-vincadifformine is described and their structure elucidation using different
methods of analysis is reported.
Keywords: Aspidosperma alkaloid, Rhazia stricta, strictanine, spegazzinine
The indole alkaloid strictanine (1b) was recently isolated from the fruit of Rhazia stricta Decsne
 which is an indigenous medicinal plant abundantly found in Pakistan. This medicinal plant has
long been used for the treatment of various diseases [2, 3]. We report here the first total synthesis of
this compound starting from (±)-vincadifformine (2), which was previously prepared from tryptamine
hydrochloride by an adaptation of Kuehne’s biomimetic synthesis [4, 5]. This prompted us to extend it
to more oxygenated alkaloids such as spegazzinine (10a) and spegazzinidine (10b) .
Results and Discussion
The existing literature method for the conversion of the readily available (±)-vincadifformine (2)
into the key intermediate 16-hydroxyindolenine (3) showed that the latter compound is particularly
Molecules 2001, 6
( 8 )
( 9 )
( 7 ) a. y : 90%
( 6 ) a. 16B - OH
b. 16a - OH
( 2 )
( 5 ) a.
( 3 )
( 4 )
( 10 ) a.R1= H, R2=OH
b. R1=OH, R2=OH
b. 16a - OH
( 1 ) a. 16B - OH
unstable [7, 8]. Similarly, photo-oxygenation  of 2 in the presence of Rose Bengal and sodium
thiosulphate as reducing agent to give 16-hydroxyindolenine (3) resulted in low yields of the desired
compound. The other product was mainly recovered starting material. This is undoubtely due to the
different tungsten lamps used (2x150W). Le Men and co-workers  also achieved this convertion in
vitro through a multi-step procedure involving the prior oxidation with peroxyacids to afford the 16-
hydroxy-1,2-dehydrovincadifformine-Nb-oxide (4) in which the Nb centre was blocked to avoid any
Molecules 2001, 6
Reaction of vincadifformine (2) with m-chloroperbenzoic acid in dry benzene gave, after
evaporation of the solvent, a variable yield of 16-hydroxyindolenine-Nb-oxide derivative 4. However,
an essentially quantitative yield of 4 was obtained after solvent removal under reduced pressure (t bath <
40°C) when vincadifformine was treated with 3 equivalents of m-chloroperbenzoic acid in the dark for
36h under a nitrogen atmosphere.
The molecular ion was observed at m/z 370, in agreement with the empirical formula C21H26N2O4
which was also supported by microanalysis. The UV spectrum in methanol gave maxima at 223 and
270 nm and the IR spectrum indicated a non conjugated ester at 1738 cm-1 (in contrast with the
absorptions at νmax 1670 and 1610 cm-1 in the starting material) and a hydroxy group at 3450 cm-1. The
1H-NMR spectrum showed a multiplet at 8 ppm (OH), a doublet due to the C-9 proton at 7.6 ppm, a
multiplet at 7.5-7.1 (3 ArH), the methoxycarbonylmethyl group at 3.95 ppm and the C-18 methyl
group as a triplet at 0.5 ppm. Subsequent hydrolysis with 1.25M sodium hydroxide solution, followed
by decarboxylation under acidic conditions (pH = 1) at 100°C for 20 min, produced the desired
product 5a as a yellow amorphous solid in 98% yield. The presence of the carbonyl function in 5a was
confirmed by the long wavelength absorption observed in the UV spectrum [λmax 218, 243 (sh), 300
nm] typical of the indolinic compound and by the absorption in the IR spectrum at 1720 cm-1 (CO).
The molecular ion in the mass spectrum was observed at m/z 312 and was consistent with the
molecular formula C19H24N2O2.
m/z 239m/z 110 m/z 130
a, m/z 268m/z 124 ( 18.1 %) c, m/z 138( 100 %)
b, m/z 268
7 // 21
Molecules 2001, 6
Attempts to reduce the N-oxide group with palladium-hydrogen gave a low yield (32%) of 5b
whereas Adam’s catalyst (PtO2) and hydrogen at atmospheric pressure afforded a good yield (80%).
However, the major mass spectral fragment of 5b was not observed at m/z 124 as for vincadifformine
and its derivatives. Instead, the molecule exhibits a M+-28 peak at m/z 268 and shows its most intense
peak at m/z = 138, which is also observed in the 16-dehydrospegazzinidine dimethyl ether 8 .
Consequently, the retro Diels-Alder fragmentation is less important in compound such as 5b with a
carbonyl group at C-16 which thus alters the typical aspidospermine mass spectral fragmentation
pattern. The molecular ion decomposes by expulsion of carbon monoxide to give species b
(m /z=268). Subsequent fission of the C-5, C-6 bond therefore produces not the anticipated ion at m/z
124, but rather the ion c (m/z 138, 100%) as the major fragment (Scheme 1).
16-Oxoaspidospermidine 5b, when subjected to reduction with sodium borohydride in ethanol,
followed by heating, gave a mixture of C-16 epimers, which were separated by column
chromatography on kieselgel G using chloroform – methanol (9:1) as eluent. The major product (less
polar, 72.5%) was 16α-H,16β-OH aspidospermidine 6a, obtained as colourless plates (m.p. 55 °C),
which exhibited UV absorptions at λmax 212, 244 and 300 nm. The exact structure of this compound
was deduced from its 1H-NMR spectrum which exhibited signals clearly indicating that a coupling
constant (J = 4 Hz) of H - 2 (d, 3.77 ppm) and H – 16 (m, 4.85 ppm) that is compatible with a cis
configuration (2α - H, 16α-H). Irradiation of 16-H gave C-2 as a singlet at 3.75 ppm. Therefore the
configuration of the hydroxyl group is β. The 13C-NMR spectrum showed nineteen resonances with
the C-16 atom giving rise to the resonance at δ 67.65 ppm. The more polar product (6b, 12.5%) was
found to be epimeric at C-16 and was compared with that also obtained by Le Men et al.  from the
indolenine 9. Reaction of 16β-hydroxyaspidospermidine 6a with formic acid and acetic anhydride
afforded the N,O-diformyl derivative 7a in 90% yield as colorless plates (m.p.70-72 °C). The infrared
spectrum indicated the presence of two characteristic absorptions at 1720 (OCHO) and 1670 cm-1
(NCHO) with no free NH group. In the 1H-NMR spectrum, the two singlets which correspond to the
two formyl functions (OCHO) and (NCHO) were observed at 8.9 and 8.6 ppm respectively. Data from
the 13C-NMR spectra are reported in Table 1 for comparison.
Table 1. 13C -NMR Data.
Molecules 2001, 6
When sodium carbonate was added to a solution of the diformyl 7a compound in methanol the
reaction produced Na-formyl-16β-hydroxyaspidospermidine (1a) in 98% yield (m.p. 66-68 °C). The
spectroscopic data suggested that the correct relative stereochemistry had been obtained. In the IR
spectrum a broad absorption was seen at 3400 cm-1 (OH) and a strong absorption at 1680 cm-1 which
was assigned to the Na –formyl group. The UV spectrum in methanol is found to be essentially
identical to that reported by Atta –Ur- Rahman  for the alkaloid strictanine (1b). The mass spectrum
shows the anticipated fragmentation pattern (Scheme 2).
+ m/z 158
m/z 282m/z 124(100%)