A new synthesis of (±)-homosarkomycin ethyl ester

Article abstract of DOI:10.1016/S0040-4039(00)02238-3

A new and efficient synthesis of (±)-homosarkomycin ethyl ester 6, an antitumor antibiotic is described. The successful synthetic approach to 6 uses β-ketophosphonate 5 as a key intermediate.

Full text of DOI:10.1016/S0040-4039(00)02238-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1273–1274
A new synthesis of ( )-homosarkomycin ethyl ester
Ali Samarat,a Vale´rie Fargeas,b Jean Villie´ras,b Jacques Lebretonb and Hassen Amria,*
aLaboratoire de Chimie Organique et Organome´tallique, Faculte´ des Sciences, Campus Universitaire, 1060 Tunis, Tunisia
bLaboratoire de Synthe`se Organique, UMR-CNRS 6513, Faculte´ des Sciences et de Techniques, BP 92208-2,
rue de la Houssinie`re, 44322 Nantes-Cedex 3, France
Received 25 October 2000; accepted 26 November 2000
Abstract—A new and efficient synthesis of ( )-homosarkomycin ethyl ester 6, an antitumor antibiotic is described. The successful
synthetic approach to 6 uses b-ketophosphonate 5 as a key intermediate. © 2001 Elsevier Science Ltd. All rights reserved.
Sarkomycin is known to display a powerful inhibitory
effect on Ehrlich ascites tumors in mice.1 As a result
of the biological activities associated with sarkomycin
and some analogues, among them homosarkomycin,2
many syntheses of these targets have been reported as
multi-step syntheses3–5 with low overall yields. We have
previously described a short large-scale synthesis of
( )-sarkomycin esters6 and derivatives7 including a cyclic
b-ketophosphonate as a key intermediate. In continua-
tion of our interest in the synthesis of biological com-
triethyl phosphonoacetate 1 and ethyl bromobutyrate
leads to the functional phosphonate 2 in 65% yield.
Methylenation of 2 by the Wittig–Horner reaction using
paraformaldehyde and potassium carbonate as a base,
provides in an excellent yield (98%) the desired diethyl
a-methylene adipate 3. The addition of diethyl phosphite
salt to diester 3 affords the Michael adduct 4 (81%), which
was cyclized using tBuOK in anhydrous tetrahydrofuran
to give the key b-ketophosphonate intermediate 5. Intro-
duction of the exocyclic methylene group was performed
by means of the Wittig–Horner reaction under heteroge-
neous liquid–liquid conditions in the presence of aqueous
formaldehyde (30%) and potassium carbonate to give
( )-homosarkomycin ethyl ester 6 in 58% yield. Spectro-
scopic data9 are in accord with the structure 6.
pounds,8 we report herein,
a short synthesis of
( )-homosarkomycin ethyl ester 6 using low cost prod-
ucts and methodology (Scheme 1).
At first, the coupling between commercially available
Scheme 1. Reagents and conditions: (a) NaH, Br-(CH2)3-COOEt, THF, reflux, 8 h; (b) (HCHO)n, K2CO3, THF, reflux, 4 h; (c)
t
(EtO)2P(O)H, K2CO3, 75°C, 16 h; (d) BuOK, THF, 0°C, rt, 2 h; (e) HCHO (30%), K2CO3, THF/H2O, rt,1 h.
Keywords: ( )-homosarkomycin ethyl ester; phosphonic acid derivatives; Wittig reactions; Michael reactions.
* Corresponding author. Fax: +216 1 885 008; e-mail: hassen.amri@fst.rnu.tn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02238-3

1274
A. Samarat et al. / Tetrahedron Letters 42 (2001) 1273–1274
jczyk, M.; Zurawinski, R.; Kielbasinski, P. Tetrahedron
Lett. 1989, 30, 1143–1146.
6. Amri, H.; Rambaud, M.; Villie´ras, J. Tetrahedron Lett.
1989, 30, 7381–7382.
7. Beji, F.; Besbes, R.; Amri, H. Synth. Commun. 2000, 30,
3947–3954.
In summary, a simple and efficient synthesis of ( )-
homosarkomycin ethyl ester was accomplished in only
five steps in 22% overall yield from commercially avail-
able phosphonate 1. Studies directed towards the
synthesis of ( )-homosarkomycin analogues (from sub-
stituted v-bromobutyrates or from v-bromopen-
tanoate) are in progress, as well as the biological
evaluation, the results of which will be reported in due
course.
8. Chamakh, A.; M’hirsi, M.; Villie´ras, J.; Lebreton, J.;
Amri, H. Synthesis 2000, 2, 295–299.
9. Synthesis of homosarkomycin ethyl ester 6: To a mixture
of b-ketophosphonate 5 (3.06 g, 10 mmol) in 10 mL of
THF and 30% aqueous formaldehyde (2 mL) is added a
gelatinous solution of potassium carbonate (2.76 g, 20
mmol) diluted in water (2 mL). The heterogeneous reac-
tion mixture is stirred for 1 h at room temperature then
treated with water. The solution is then extracted with
ether. The combined organic layers are dried over anhy-
drous magnesium sulfate, filtered and concentrated. The
residue is purified by column chromatography on silica gel
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6
. Spectroscopic data: H NMR (200 MHz,
CDCl3): 1.25 (t, 3H, J=7 Hz); 2.36 (m, 6H); 3.64 (m, 1H);
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