Synthesis of jenamidines A1/A2

Article abstract of DOI:10.1021/ol0518784

(Chemical Equation Presented) Addition of the enolate of tert-butyl acetate to cyanamide methyl ester 17 followed by treatment with LHMDS afforded vinylogous urea 19 in 27% yield. Vinylogous urea 19 was also obtained from 37 and tert-butyl cyanoacetate in

Full text of DOI:10.1021/ol0518784

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4519-4522
Synthesis of Jenamidines A1/A2
Barry B. Snider* and Jeremy R. Duvall
Department of Chemistry MS 015, Brandeis UniVersity, Waltham, Massachusetts
02454-9110
snider@brandeis.edu
Received August 4, 2005
ABSTRACT
Addition of the enolate of tert-butyl acetate to cyanamide methyl ester 17 followed by treatment with LHMDS afforded vinylogous urea 19 in
27% yield. Vinylogous urea 19 was also obtained from 37 and tert-butyl cyanoacetate in 50% yield. Acylation of 19 with acid chloride 31d,
followed by hydrolysis of the tert-butyl ester and decarboxylation with 9:1 CH2Cl2/TFA and very mild basic hydrolysis of the methoxyacetate
ester, afforded jenamidines A1/A2 (3) in 45% yield. This first synthesis confirms our reassignment of the jenamidines A1/A2 structure.
Three bicyclic alkaloids, jenamidines A-C, were recently
isolated from the culture broth of Streptomyces sp. (strain
HKI0297).1 Jenamidine A inhibited proliferation of the
chronic myeloid leukemia cell line K-562 (GI50 ) 1.9 µg/
mL). Structure 1 was originally proposed for jenamidine A
(see Figure 1). We prepared model 2, which underwent a
facile retro-Mannich reaction and had spectral data quite
different from jenamidine A, suggesting that structure 1 is
not correct.2 Reexamination of the spectral data of the natural
product led to revised structures for the two diastereomers
of jenamidines A1/A2 (3), the two diastereomers of jena-
midines B1/B2 (4), and jenamidine C (5).2 Bohemamine (6),
whose structure was determined by X-ray crystallography
in 1980,3 and the cell-cell adhesion inhibitor NP25302 (7),4
whose structure was reported very recently, have the same
ring system as the revised structures of jenamidines 3-5.
We next turned our attention to the preparation of
jenamidines A1/A2 (3), which required the development of
new methods for the preparation of the novel N-acyl
vinylogous urea in the right-hand ring. We initially explored
the Pd-catalyzed coupling of triflate 8 with an amide since
(1) Hu, J.-F.; Wunderlich, D.; Thiericke, R.; Dahse, H.-M.; Grabley, S.;
Feng, X.-Z.; Sattler, I. J. Antibiot. 2003, 56, 747-754.
(2) Snider, B. B.; Duvall, J. R.; Sattler, I.; Huang, X. Tetrahedron Lett.
2004, 45, 6725-6727.
(3) Doyle, T. W.; Nettleton, D. E.; Balitz, D. M.; Moseley, J. E.; Grulich,
R. E.; McCabe, T.; Clardy, J. J. Org. Chem. 1980, 45, 1324-1326.
(4) Zhang, Q.; Schrader, K. K.; ElSohly, H. N.; Takamatsu, S. J. Antibiot.
2003, 56, 673-681.
Figure 1. Structures of jenamidines and related natural products.
10.1021/ol0518784 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/27/2005

a broadly applicable Pd-catalyzed amidation of enol triflates
was recently reported.5 Unfortunately, reaction of known keto
lactam 96 with NaH and Tf2O gave only the unstable pyrrole
bis triflate 10. Use of excess NaH and Tf2O gave crude (90%
pure) 10 in 91% yield, which was isolated in pure form in
only 17% yield (see eq 1). Although we were able to cleanly
couple 2-methyl-2-butenamide7 with the enol triflate prepared
from 5,5-dimethyl-1,3-cyclohexanedione, initial attempts at
Pd-catalyzed couplings of amides with 10 were unsuccessful.
Attempted preparation of vinylogous urea 33 (see Scheme
5) by reaction of keto lactam 9 with NH3 led to complex
mixtures.
allowing the alkoxide to add to the cyanamide to form 13.
We thought that a simple ester might be a better choice
because the tetrahedral intermediate should rapidly form the
cyanamide keto ester 18, which could then cyclize to form
the desired product 19. Fortunately, this proved to be the
case. Cyanamide methyl ester 178 was added to a solution
of the lithium enolate of tert-butyl acetate (2.3 equiv) in THF
at -45 °C.9 The solution was stirred for 1 h at -45 °C,
treated with 1.2 equiv of LHMDS in THF, and stirred at
25 °C for 2 h to give the desired product 19 (27%) (see
Scheme 2). Byproduct 21 (24%) was formed by addition of
Scheme 2
We then turned our attention to preparing the vinylogous
urea by addition of an enolate to a cyanamide. Hydrolysis
of the Boc group of Weinreb amide 11 and reaction of the
liberated amine with CNBr and NaHCO3 in EtOH afforded
cyanamide 12 in 84% yield (see Scheme 1). Addition of the
the enolate to the cyanamide to give 20, which then cyclized
to the methyl ester to form the alkylidene imidazolidinone
21.10 The methyl ester of 17 is less electrophilic than the
Weinreb amide of 12 so that the enolate added to both the
methyl ester and the cyanamide.
Scheme 1
Vinylogous urea 19 has the ring system of jenamidines
A1/A2 with an additional carboxylic acid, which we hoped
that we could remove by hydrolysis and decarboxylation
either before or after the introduction of the side chain.
Reaction of 19 with 9:1 CH2Cl2/TFA effected hydrolysis but
did not provide the desired vinylogous urea 33 (see Scheme
5).
Acylation of 19 with 2.5 equiv of NaH and 2.2 equiv of
tigloyl chloride for 2 h afforded a mixture of the desired
amide 22 and the bis-acylated product pyrrole 23 (see
Scheme 3). Treatment of the crude mixture with 9:1
CH2Cl2/TFA for 15 h effected hydrolysis of the tert-butyl
esters of 22 and 23 and the enol ester of 23 and decarboxy-
lithium enolate of tert-butyl acetate to 12 provided 30% of
the enol tautomer of urea â-keto ester 16, 21% of imidazo-
lidinone 15, and 32% of imidazolone 14. Presumably the
lithium alkoxide of the initially formed tetrahedral intermedi-
ate adds to the cyanamide to give 13. Workup affords urea
keto ester 16, which can undergo cyclodehydration to give
14 and 15. Imidazolone 14 is the thermodynamic product
since treating a solution of 15 in CDCl3 with one drop of
TFA cleanly isomerized 15 to 14.
Scheme 3
The Weinreb amide appeared to be a poor choice because
the initially formed tetrahedral intermediate was stable,
(5) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante, R. P. Org. Lett.
2003, 5, 4749-4752.
(6) (a) Murray, A.; Proctor, G. R.; Murray, P. J. Tetrahedron 1996, 52,
3757-3766. (b) Galeotti, N.; Poncet, J.; Chiche, L.; Jouin, P. J. Org. Chem.
1993, 58, 5370-5376.
(7) Miyata, O.; Shinada, T.; Ninomiya, I.; Naito, T.; Date, T.; Okamura,
K.; Inagaki, S. J. Org. Chem. 1991, 56, 6556-6564.
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Org. Lett., Vol. 7, No. 20, 2005

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.
Org. Lett., Vol. 7, No. 20, 2005
4521

analogous to 23, which will give a mixture of diastereomers
on hydrolysis. In the proton NMR spectrum of 3 in CD3OD,
the ring fusion hydrogen, H-7a, integrates for only ∼0.5,
suggesting that partial deuterium exchange has occurred. C-2
and C-7 absorb as four peaks since a separate peak is
observed for the H-7a and D-7a isomer of each diastere-
omer.15 H-2 slowly exchanges with CD3OD over several
hours as was noted for the natural product.2 The optical
rotation of synthetic 3, [R]D 4.2, is very similar to that of
the natural product, [R]D 6.8.1 Therefore, natural jenamidines
A1/A2 (3) could also be a mixture of isomers at the ring
fusion and the (S)-isomer on the side chain. However, since
both rotations are for mixtures of isomers, it is also possible
that the natural product is a mixture of isomers on the side
chain.
Scheme 6
gave crude 38, which was hydrogenated (1 atm) over 10%
Pd/C in MeOH for 2 h to give crude 39 with a very complex
NMR spectrum. Fortunately, crude 39 cyclized on standing
for 1 d to give 19 in 50% overall yield from 37. Using this
sequence, which has not been fully optimized, jenamidines
A1/A2 (3) are now available in 23% overall yield.
In conclusion, addition of the enolate of tert-butyl acetate
to cyanamide methyl ester 17 followed by treatment with
LHMDS afforded vinylogous urea 19 in 27% yield. Viny-
logous urea 19 can be obtained more easily from 37 and
tert-butyl cyanoacetate in 50% yield. Acylation of 19 with
acid chloride 31d, followed by hydrolysis of the tert-butyl
ester and decarboxylation with 9:1 CH2Cl2/TFA and very
mild basic hydrolysis of the methoxyacetate ester afforded
jenamidines A1/A2 (3) in 45% yield. This first synthesis
confirms our reassignment of the jenamidines A1/A2 struc-
ture. Extension of this approach to the syntheses of jena-
midines B1/B2, jenamidine C, and NP25302 is currently in
progress.
The three-step sequence from vinylogous urea 19 and acid
chloride 31d to jenamidines A1/A2 (3) proceeded in accept-
able yield, given the instability of the amide linkage. The
one-pot preparation of 19 from cyanamide 17 provided
adequate quantities of material, but the 27% yield left room
for improvement. Coupling of various N-acetyl amino acid
derivatives 34 with ethyl cyanoacetate has been reported to
give 35, which cyclized on treatment with 8% HCl in EtOH
at reflux to provide 36 in 18-51% overall yield (see Scheme
6).16 The reported spectral data of 36 are comparable to those
of 19. We examined variations of this procedure because
the acid-catalyzed cyclization used to convert 35 to 36 is
not compatible with the tert-butyl ester of 19.
Reaction of Cbz-proline N-hydroxysuccinimide ester (37)
with tert-butyl cyanoacetate and NaH in benzene for 3 h
(15) For discussion of deuterium-induced 13C NMR shifts, see: (a)
Morales-Rios, M. S.; Cervantes-Cuevas, H.; Salgado-Escobar, I.; Joseph-
Nathan, P. Magn. Reson. Chem. 1999, 37, 243-245. (b) Dziembowska,
T.; Hansen, P. E.; Rozwadowski, Z. Prog. Nucl. Magn. Reson. Spectrosc.
2004, 45, 1-29.
(16) (a) Igglessi-Markopoulou, O.; Sandris, C. J. Heterocycl. Chem. 1982,
19, 883-890. (b) Sauve´, G.; Le Berre, N.; Zacharie, B. J. Org. Chem. 1990,
55, 3002-3004. (c) Gola, A.; Samartzi, E.; Bardakos, V.; Petroliagi, M.;
Igglessi-Markopoulou, O.; Markopoulos, J.; Barkley, J. V. J. Heterocycl.
Chem. 2000, 37, 681-686. (d) Petroliagi, M.; Igglessi-Markopoulou, O. J.
Heterocycl. Chem. 2001, 38, 917-922. (e) Detsi, A.; Gavrielatos, E.; Adam,
M.-A.; Igglessi-Markopoulou, O.; Markopoulos, J.; Theologitis, M.; Reis,
H.; Papadopoulos, M. Eur. J. Org. Chem. 2001, 4337-4342. (f) Hamilakis,
S.; Tsolomitis, A. Synth. Commun. 2003, 33, 4313-4319. (g) Detsi, A.;
Emirtzoglou, P.; Prousis, K.; Nikolopoulos, A. N.; Skouridou, V.; Igglessi-
Markopoulou, O. Synlett 2004, 353-355.
Acknowledgment. We thank the NIH (GM50151) for
generous financial support. We thank Prof. Isabel Sattler for
helpful discussions.
Supporting Information Available: Full experimental
details and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0518784
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