In another route, the secondary
amine 8 was directly condensed
with maleic anhydride by refluxing
in toluene. The acid 11 was ob-
tained and converted to ester 12,
which can be converted to the key
intermediate 13 (Scheme 4).
Scheme 5. One-pot approach to allokainic acid. Reagents and conditions:
a) 1) Methyl vinyl ketone, EtOH, rt, 2) maleic anhydride, 3) SOCl2, rt, 95%.
The methodology was further
simplified by achieving the entire
sequence in a one-pot manner. The
starting materials, PMB and MVK, were mixed in ethanol and stirred for few minutes. Maleic anhydride
was then added and stirred for about 30 min followed by the addition of thionyl chloride. The inter-
mediate 12 was isolated in 95% yield and could be transformed to 13, the precursor for allokainic acid
(Scheme 5).
Diastereoselective Routes to Dexoxadrol, Epidexoxadrol, Conhydrine, and
Lentiginosine
In continuation of the asymmetric synthesis of natural products, we undertook the synthesis of a very
important N-methyl-d-aspartate (NMDA) receptor antagonist, dexoxadrol, which was first synthesized
by Hardie et al. in 1960 as an anesthetic drug along with etoxadrol. The subsequent clinical trials re-
vealed that these compounds are efficient NMDA receptor antagonists by binding with 1-(1-
phenylcyclohexyl)piperidine (PCP) cites and are found to be more efficient than the available drugs
memantine and amantadine (Figure 3). The detailed study on the biological behavior of these mole-
cules showed that the presence of a secondary amine, piperidine ring, five-membered oxygenated
ring, and the (S, S) stereochemistry altogether play a crucial role for its enhanced activity.
Our synthesis involved the classical synthetic conversion of pipecolinic acid to olefin 14a. The olefin
14a was then subjected to dihydroxylation via the Upjohn method delivering the diols 15a and 16a
in the proportion of 3:2 (Scheme 6) determined using high-performance liquid chromatography
(HPLC).
The Sharpless “binding pocket” effect for our novel monosubstituted terminal olefin attached to a pi-
peridine system was studied and found to be consistent with this effect. A better discrimination of dia-
stereoselectivity was achieved using hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2PYR)
and hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)2PYR).
We then proceeded with the synthetic approach to accomplish the total synthesis of dexoxadrol
(Scheme 7). Upon hydrogenolysis followed by reaction with dimethoxybenzophenone and p-toluene-
sulfonic acid (PTSA) in isopropyl alcohol held at reflux, 15a (16a) produced dexoxadrol (epidexoxa-
drol). Incidentally this is the first asymmetric synthesis of (À)-epidexoxadrol.
Figure 3. NMDA receptor antagonists.
Scheme 6. Upjohn dihydroxylation. Reagents and conditions: a) OsO4, N-methylmorpholine N-oxide, acetone/H2O (9:1), rt,
80%.
ChemistryOpen 2015, 4, 192 – 196
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