pantothenic acid has resulted in the development of a
number of synthetic and biochemical routes for its
production.4
taking advantage of the imide olefination methodology
developed recently in our group.14,15
Retrosynthetically, we envisioned both pantothenic
acid and CJ-15,801 as originating from a common ena-
mide intermediate 4, which could be generated through
the olefination of imide 5. Imide 5 could in turn originate
from the N-formylation of amide 6. Amide 6 could be
obtained efficiently from the ammonia mediated opening
of pantolactone 7 (Scheme 1).
Biologically, pantothenic acid is the starting substrate
in the biosynthesis of coenzyme A (2, CoA), an enzyme
cofactor necessary for a number of metabolic processes
including the citric acid cycle.5 Coenzyme A plays a major
role in the biosynthesis of many important metabolites
such as fatty acids, cholesterol, and acetylcholine.6
Numerous studies have shown that a range of parasites
are unable to synthesize pantothenate and are therefore
dependent on the uptake of pantothenic acid from their
environment for the synthesis of CoA.7-9 This depen-
dence is exhibited in the malarial parasite P. falciparum.10
Blood cells infected by plasmodia utilize new permeability
pathways to bring in small molecules such as pantothe-
nate, whereas uninfected cells do not exhibit these mole-
cule permeability pathways.10
Scheme 1
CJ-15,801 (3) is a pantothenic acid analogue isolated
from Seimatosporum sp. CL28611.11 Structurally, CJ-
15,801 differs from pantothenate only in the fact that it
has a double bond in the β-alanine moiety. Biologically,
CJ-15,801 has shown selective activity against P. falciparum
and multidrug-resistant S. aureus with MIC values be-
tween 30 and 230 μM without affecting mammalian
cell lines.11 This makes CJ-15,801 3 an interesting lead
for the generation of potential new antiparasitic therapies
(Figure 2).
Synthetically, treatment of D-pantolactone 7 with neat
liquid ammonia generated the desired amide 8, which was
then protected as the corresponding acetonide. N-For-
mylation of the amide intermediate then afforded the key
N-formyl imide intermediate 9 in good yield over the
3-step sequence (Scheme 2).
Scheme 2
Figure 2. Antiplasmodial agent CJ-15,801 (3).
The combination of its promising biological profile,
coupled with its interesting enamide unit, has made CJ-
15,801 an attractive synthetic target, with a total synthe-
sis reported by Porco12 and a formal synthesis reported by
Nicolaou.13
Synthesis of Pantothenate. The key imide intermediate 9
having been accessed, the choice of enamide unit to be
generated was considered carefully. It was rationalized
that by employing the correct choice of ester derivative it
might be possible to simultaneously reduce the enamide
unit and liberate the carboxylic acid unit.
We would like to report our efficient and divergent
synthesis of both pantothenic acid (1) and CJ-15,801 (3)
Olefination of imide 9 with benzyltriphenylphosphorany-
lidene acetate gave the desired benzyl ester 10 in good yield
and as a 3:1 mixture of E:Zisomers. With the desired enamide
10 at hand, the tandem hydrogenation-hydrogenolysis se-
quence was attempted. Gratifyingly, treatment of (Z)-ena-
mide 10Z with 10% palladium on carbon under a hydrogen
atmosphere cleanly gave the reduced carboxylic acid 11 in
excellent yield (Scheme 3).
Having successfully shown the feasibility of the reduc-
tion-deprotection sequence, the decision was taken to
carry out this transformation as the final stage of the
synthesis for ease of compound handling. Thus, enamide
10E was treated with BiCl3 to generate the free diol 12 in
good yield. Treatment of enamide 12 under the same
hydrogenation-hydrogenolysis conditions used previously
(5) Daugherty, M.; Polanuyer, B.; Farrell, M.; Scholle, M.; Lykidis,
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(6) Russell, D. W. Cardiovas. Drugs Ther. 1992, 6, 103.
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32, 56.
(8) Saliba, K. J.; Horner, A. H.; Kirk, K. J. Biol. Chem. 1998, 273,
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(9) Saliba, K. J.; Kirk, K. J. Biol. Chem. 2001, 276, 18115.
(10) Saliba, K. J.; Ferru, I.; Kirk, K. Antimicrob. Agents Chemother.
2005, 49, 632.
(11) Saliba, K. J.; Kirk, K. Mol. Biochem. Parasitol. 2005, 141, 129.
(12) Han, C.; Shen, R.; Su, S.; Porco, J. A. Org. Lett. 2004, 6, 27.
(13) Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005,
44, 5992.
(14) Mathieson, J. E.; Crawford, J. J.; Schmidtmann, M.; Marquez,
R. Org. Biomol. Chem. 2009, 7, 2170.
(15) Villa, M. V. J.; Targett, S. M.; Barnes, J. C.; Whittingham,
A.; de Crecy-Lagard, V.; Osterman, A. J. Biol. Chem. 2002, 277, 21431.
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