lation to afford jenamidines A1/A2 model 24 in 69% overall
yield. The spectral data of the ring portion of 24 correspond
very closely to those of the natural product, supporting the
assignment of 3 as the revised structure of jenamidines A1/
A2.
Scheme 5
The side chain was then prepared by a modification of
Adam’s procedure for the ethyl ester.11 Reaction of ylide
2512 with aldehyde 2613 in CH2Cl2 for 2 h provided ester 27
in 67% yield (see Scheme 4). Deprotection with pyr‚HF gave
Scheme 4
ing group for the side chain alcohol that would be cleaved
by the 9:1 CH2Cl2/TFA used for hydrolysis of the tert-butyl
ester. Unfortunately, such a protecting group would not be
compatible with acid chloride 31, and we were unable to
cleanly acylate 19 with mixed anhydrides.
We then examined more base labile ester protecting
groups.14 Dichloroacetate acid chloride 31b was prepared
analogously, but reaction with 19 afforded 32b in only 29%
yield. Fortunately, hydrolysis of 32b with NaHCO3 in MeOH
for 30 min at 25 °C gave jenamidines A1/A2 (3) in 71% yield.
Reaction of chloroacetate 31c with 19 afforded 32c in a still
unacceptable 31% yield, which could also be cleaved by
NaHCO3 in MeOH for 1 h at 25 °C to give jenamidines
A1/A2 (3) cleanly.
hydroxy ester 28 in 99% yield. Initially, we chose to protect
the side chain alcohol as an acetate ester. Reaction of 28
with AcCl, DMAP and pyridine in THF gave 29a in 99%
yield, which was deprotected with 9:1 CH2Cl2/TFA to give
acetoxy acid 30a in 99% yield. Stirring 30a in oxalyl chloride
gave crude acid chloride 31a, which was used without
purification.
The best compromise was the methoxyacetate protecting
group. Acid chloride 31d was prepared in high yield from
hydroxy ester 28. Coupling of 31d with 19, hydrolysis of
the tert-butyl ester, decarboxylation with 9:1 CH2Cl2/TFA,
and flash chromatography on silica gel gave 32d in 39%
yield and jenamidines A1/A2 (3) in 18% yield. Partial
cleavage of the methoxyacetate occurs on chromatography.
Hydrolysis of 32d with Na2CO3 in MeOH for 6 h at 0 °C
provided 3 in 56% yield (70% based on recovered 32d) and
18% of 33 resulting from cleavage of the amide. Hydrolysis
of 32d with NaHCO3 in MeOH for 20 h at 25 °C afforded
only 33 indicating the sensitivity of the amide side chain to
basic hydrolysis. The most efficient procedure involved
hydrolysis of crude 32d with Na2CO3 in MeOH for 24 h at
0 °C to give jenamidines A1/A2 (3) in 45% overall yield from
19 and 32d in 11% overall yield from 19.
Reaction of 19 with NaH and 31a followed by hydrolysis
and decarboxylation with 9:1 CH2Cl2/TFA as described
above for the preparation of 24 afforded jenamidines A1/A2
acetate (32a) in 84% yield (see Scheme 5). Unfortunately,
we were unable to cleave the acetate protecting group of
32a without also cleaving the side chain amide to give a
complex mixture containing some 33. Since the nitrogen of
the amide of 32a is part of a vinylogous urea, the amide is
a vinylogous acyl urea and is therefore easily cleaved under
basic conditions. We considered using an acid-labile protect-
(8) Prasit, P.; Falgueyret, J.-P.; Oballa, R.; Rydzewski, R.; Okamoto, O.
PCT Int. Appl. WO 2001077073; Chem. Abstr. 2001, 135, 318414j.
(9) For similar syntheses of keto esters from esters, see: (a) Honda, Y.;
Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4, 447-
449. (b) Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K.
Tetrahedron Lett. 2003, 44, 3163-3166.
The spectral data of synthetic 3 are identical to those of
the natural product, which is also an approximately 1:1
mixture of diastereomers. Even though 19 was prepared from
(S)-proline and aldehyde 26 was prepared from (S)-lactic
acid, we obtained 3 as a mixture of diastereomers. The ring
fusion hydrogen is readily epimerized and this stereocenter
is lost in the formation of the bis acylated intermediate
(10) For similar compounds, see: (a) Zhao, M.-X.; Wang, M.-X.; Huang,
Z.-T. Tetrahedron 2002, 58, 1309-1316. (b) Ceder, O.; Stenhede, U. Acta
Chem. Scand. 1973, 27, 2221-2223.
(11) Adam, W.; Renze, J.; Wirth, T. J. Org. Chem. 1998, 63, 226-227.
(12) Giner, J.-L. Tetrahedron Lett. 2002, 43, 5457-5459.
(13) (a) Hirama, M.; Shigemoto, T.; Itoˆ, S. J. Org. Chem. 1987, 52,
3342-3346. (b) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem.
1983, 48, 5180-5182.
(14) Kocien˜ski, P. J. Protecting Groups, 3rd ed.; Georg Thieme Verlag:
Stuttgart, 2005; pp 333-337.
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