Total synthesis of the plasmoidal pigment physarorubinic acid, a polyenoyl tetramic acid

Article abstract of DOI:10.1039/a904921e

The total synthesis of physarorubinic acid, a polyenoyltetramic acid plasmoidal pigment from Physarum polycephalum, is described in a series of steps from (E)-3-iodoacrylic acid 6 and employs aminolysis of the pentaene thioester 11 as a key synthetic step. Lacey-Dieckmann cyclisation and subsequent deprotection then affords physarorubinic acid 1 in high yield and purity.

Full text of DOI:10.1039/a904921e

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Total synthesis of the plasmoidal pigment physarorubinic acid, a
polyenoyl tetramic acid
Darren J. Dixon, Steven V. Ley* and Deborah A. Longbottom
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
Received (in Cambridge) 21st June 1999, Accepted 20th July 1999
The total synthesis of physarorubinic acid, a polyenoyltetra-
mic acid plasmoidal pigment from Physarum polycephalum,
is described in a series of steps from (E)-3-iodoacrylic acid
6 and employs aminolysis of the pentaene thioester 11 as a
key synthetic step. Lacey–Dieckmann cyclisation and
subsequent deprotection then affords physarorubinic acid
1 in high yield and purity.
convenient and efficient method using copper() catalysis to
facilitate the same transformation in good yield and purity.
Propiolic acid was heated to reflux in an excess of aqueous
hydrogen iodide with copper iodide catalyst for 30 minutes. Fol-
lowing cooling to room temperature, filtration, washing with
water and drying, the vinyl iodide 6 was afforded in 71% yield
directly from the reaction mixture (Scheme 1). Treatment of 6
Naturally occurring tetramic acids (4-hydroxy-3-pyrrolin-2-
ones) are of considerable interest to the synthetic organic
chemist, not least because the majority of compounds isolated
exhibit some biological function. The spectrum of biological
activity displayed by the family is remarkable in its diversity and
includes potent antibiotic, antiviral and antiulcerative proper-
ties, cytotoxicity and mycotoxicity, the inhibition of tumours as
well as fungicidal action.1
A notable member of this group of natural products is
physarorubinic acid 1 which was first isolated and characterised
by Nowak and Steffan in 1997.2 As well as containing an
N-methylserine derived acyltetramic acid terminus, physaro-
rubinic acid contains a central fully conjugated all-(E)-pentaene
chain attached to a terminal carboxylic acid. This kind of poly-
enoyltetramic acid framework has been studied previously by
our group during the total syntheses of fuligorubin3 and
erythroskyrine.4 Here we wish to report a further development
of this chemistry in the first total synthesis of physarorubinic
acid 1.
Our analysis of the synthetic problem suggested a convergent
approach involving three main fragments, namely the amino
ester 2, a β-keto thioester fragment 3 bearing a tributyltin group
at its terminus and the vinyl iodide 4 (Fig. 1). Fragment 2 was
readily available from (S)-N-methylserine while the middle
tetraene portion was obtained from the phosphonate ester 9
and β-tributylstannylacrolein unit 10. The remaining fragment
4 could be obtained using a literature route.5
Scheme 1 Reagents and conditions: i, CuI (0.6%), HI (57% aq.),
130 ЊC, 30 min; ii, tBuOAc (10 eq.), CF3SO3H, CH2Cl2, RT, 60 min.
with tert-butyl acetate and a catalytic amount of triflic acid in
dichloromethane at room temperature resulted in formation of
the tert-butyl ester 4, in 73% yield.
Synthesis of amino ester 2 was readily achieved starting from
commercially available (S)-N-methylserine 7, which was con-
verted to the methyl ester hydrochloride salt by heating it to
reflux in methanolic hydrochloric acid. Recrystallisation from
acetone afforded 8 in 83% yield (Scheme 2). tert-Butyldimethyl-
silyl protection of the alcohol was then carried out in
N,N-dimethylformamide. Imidazole (2.2 eq.) was added to a
solution of the amino ester hydrochloride salt 8 at room
temperature followed by tert-butyldimethylsilyl chloride and
the reaction was stirred overnight. Following work-up, 2 was
afforded in 85% yield.
Although high yielding, the existing literature conditions for
preparation of the vinyl iodide used high pressures and temper-
atures, and long reaction times.5 For this reason we developed a
Fig. 1
J. Chem. Soc., Perkin Trans. 1, 1999, 2231–2232
2231

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Scheme 2 Reagents and conditions: i, CH3COCl (10 eq.), MeOH,
reflux, 12 h; ii, Imidazole (2.2 eq.), TBSCl (0.98 eq.), DMF, RT, 8 h.
Having gram quantities of both the vinyl iodide 4 and tert-
butyldimethylsilyl protected (S)-N-methylserine methyl ester 2
in hand, the preparation of the polyene thioester fragment 3
was carried out following our previously established method.4
Compound 3 was prepared as a mixture of keto and enol forms
in the ratio 1:2.
The key Stille coupling of vinyl iodide 4 with the tributyl
stannane 3 was next investigated.6 Thus, treatment of stannane
3 with an excess of the iodide 4 (1.5 eq.) and bis(trifuryl-
phosphine)palladium() chloride (0.15 eq.) in (N,N)-dimethyl-
formamide at room temperature for one hour afforded
isomerically pure all-(E)-pentaene 11, existing mainly in the
enol form in 67% yield as a golden powder (Scheme 3).
With the carbon framework intact, all that remained was the
conversion of the thioester to tetramic acid and subsequent
deprotection to physarorubinic acid 1. Aminolysis of the tert-
butyl thioester with O-protected (S)-N-methylserine methyl
ester (3 eq.) occurred readily, mediated by silver trifluoroacetate
(2 eq.) in tetrahydrofuran at 0 ЊC following a modification of
our previously reported procedure to give β-keto amide 12 in
93% yield and high purity.7 The Lacey–Dieckmann cyclisation
of the ester 12 to acyltetramic acid 13 proceeded well under
standard conditions.7 The ester was dissolved in methanol and
warmed to 25 ЊC at which point it was treated with sodium
methoxide (0.5 M in methanol, 5 eq.). After 2 minutes saturated
ammonium chloride was added to quench the reaction mixture
and aqueous work up afforded essentially pure acyltetramic
acid 13. No further purification was attempted on this material.
The final deprotection to physarorubinic acid
1 was
achieved using a 9:1 trifluoroacetic acid–water mixture. This
was added at room temperature and immediately removed in
vacuo. The process was repeated and was particularly useful
due to the fact that all side products and excess reagents were
volatile. Purification of the crude product by size exclusion
chromatography on Sephadex LH-20 afforded pure physaro-
rubinic acid 1 as a deep red–orange powder in 78% yield.
1
The H and 13C NMR, IR, UV, negative APCI-MS and CD
spectra were all in agreement with the reported data for the
natural product.2
In summary, we have reported an efficient route to the poly-
enoyltetramic acid physarorubinic acid 1 using chemistry pre-
viously developed in our laboratory in the synthesis of tetraene
3. A new method has also been developed for a much more
convenient and efficient synthesis of vinyl iodide 6 than those
previously existing in the literature.
Scheme 3 Reagents and conditions: i, 4 (1.5 eq.), [P(Fur)3]2PdCl2 (0.15
eq.), DMF, RT, 60 min; ii, 2 (3 eq.), Et3N (2 eq.), CF3COOAg (2 eq.),
THF, 0 ЊC, 30 min; iii, MeONa (5 eq.), MeOH, 25 ЊC, 120 s; iv,
CF3CO2H:H2O 9:1, 10 min (×2–solvent removed in vacuo).
2 A. Nowak and B. Steffan, Liebigs Ann./Recl., 1997, 1, 1817.
3 S. C. Smith, S. V. Ley and P. R. Woodward, Tetrahedron, 1992, 48,
1145.
4 D. J. Dixon, S. V. Ley, T. Gracza and P. Szolcsanyi, J. Chem. Soc.,
Perkin Trans. 1, 1999, 839.
5 T. Zoller and D. Uguen, Tetrahedron Lett., 1998, 39, 6719 and refer-
ences cited therein.
Acknowledgements
We thank the EPSRC (to D. J. D. and D. A. L.), the Novartis
Research Fellowship (to S. V. L.) and Pfizer Inc USA for
financial support.
6 J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508.
7 R. N. Lacey, J. Chem. Soc., 1954, 850.
Notes and references
1 For an excellent review, see B. J. L. Royles, Chem. Rev., 1995, 95, 1981
and references cited therein.
Communication 9/04921E
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J. Chem. Soc., Perkin Trans. 1, 1999, 2231–2232