An expeditious synthesis of (±)-desepoxy-4,5-didehydromethylenomycin A methyl ester

Article abstract of DOI:10.1021/ol005742b

A total synthesis of the racemic methyl ester of desepoxy-4,5-didehydromethylenomycin A has been achieved in six steps with an overall yield of 31% starting from diethyl methanephosphonate. The key steps include the Nazarov cyclization of the dienone 7 leading to the α-phosphoryl cyclopentenone 8 and the Horner-Wittig reaction of the latter employed for the introduction of the exocyclic methylene moiety.

Full text of DOI:10.1021/ol005742b

ORGANIC
LETTERS
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Vol. 2, No. 8
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An Expeditious Synthesis of
±)-Desepoxy-4,5-didehydromethylenomycin
1
(
A Methyl Ester
Piotr Balczewski and Marian Mikolajczyk*
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences,
90-363 Lodz, Sienkiewicza 112, Poland
marmikol@bilbo.cbmm.lodz.pl
Received March 1, 2000
ABSTRACT
A total synthesis of the racemic methyl ester of desepoxy-4,5-didehydromethylenomycin A has been achieved in six steps with an overall
yield of 31% starting from diethyl methanephosphonate. The key steps include the Nazarov cyclization of the dienone 7 leading to the r-phosphoryl
cyclopentenone 8 and the Horner−Wittig reaction of the latter employed for the introduction of the exocyclic methylene moiety.
The cyclopentenone skeleton is a common structural motif
in a variety of naturally occurring compounds. Among them,
a family of cyclopentanoid antibiotics known as methyleno-
mycins attracted considerable attention because of a wide
syntheses are not trivial. This is because of the low chemical
stability of these compounds and specific functionalization
of the five-membered ring. Therefore, they became attractive
synthetic targets in numerous laboratories. As part of our
program aimed at development of efficient and versatile
methods for the synthesis of functionalized cyclopentenones
and cyclopentanones using organic phosphorus and sulfur
compounds, we have also been engaged for the past few
years in the synthesis of cyclopentanoid antibiotics and
1
spectrum of biological activity and structural diversity.
Methylenomycin A 1, desepoxy-4,5-didehydromethyleno-
mycin A 2a, and methylenomycin B 3, which have been
isolated from the culture broth of Streptomyces species, show
inhibitory activity against Gram-positive and Gram-negative
2
3
bacteria.
related compounds. Our endeavors resulted in the elabora-
tion of new and efficient synthetic approaches to methyl-
4
5
6
7
enomycin B 3, sarkomycin, isoterrein, rosaprostol, and
(
2) Haneishi, T.; Kitahara, N.; Takiguchi, Y.; Arai, M. J. Antibiot. 1974,
2
7, 386-392. Haneishi, T.; Terahara, A.; Arai, M.; Hata, T.; Tamura, C. J.
Antibiot. 1974, 27, 393-399. Haneishi, T.; Terahara, A.; Hamano, K.; Arai,
M. J. Antibiot. 1974, 27, 400-407.
(3) For a recent summary, see: Mikolajczyk, M.; Mikina, M.; Zurawinski,
R. Pure Appl. Chem. 1999, 71, 473-480.
(
4) Mikolajczyk, M.; Grzejszczak, S.; Lyzwa, P. Tetrahedron Lett. 1982,
2
6
3, 2237-2240. Mikolajczyk, M.; Balczewski, P. Synthesis 1984, 691-
94; 1987, 659-661. Mikolajczyk, M.; Zatorski, A. J. Org. Chem. 1991,
Although the structures of methylenomycins 1-3 are
deceptively simple (they are simplest antibiotics), their
56, 1217-1223. Mikolajczyk, M.; Zurawinski, R. Synlett 1991, 575-576.
Balczewski, P. Heteroatom. Chem. 1997, 8, 67-69.
(5) Mikolajczyk, M.; Zurawinski, R.; Kielbasinski, P.; Wieczorek, M.
W.; Blaszczyk, J. Synthesis 1997, 356-365.
(
1) See, for example: Mathew, J. In Recent Progress in the Chemical
(6) Mikolajczyk, M.; Mikina, M.; Wieczorek, M. W.; Blaszczyk, J.
Angew. Chem. 1996, 108, 1645-1647; Angew. Chem., Int. Ed. Engl. 1996,
35, 1560-1562.
Synthesis of Antibiotics and Related Microbiological Products; Lucakcs,
G., Ed.; Springer-Verlag: Berlin, 1993; Vol. 2, pp 435-474.
1
0.1021/ol005742b CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

8
prostaglandin B1R methyl ester. Continuing our interest in
4 with methyl bromoacetate afforded the corresponding
R-substituted â-oxophosphonate 5. A simple bromination of
the R-phosphonate carbanion of 5 with bromine and subse-
quent dehydrobromination of the resulting bromophospho-
nate 6 using DBU allowed for the preparation of dienone 7,
which is a key intermediate because according to our
synthetic strategy the construction of the cyclopentenone ring
would be accomplished via the Nazarov reaction.
this field, we wish to disclose herein a new total synthesis
of the title compound (()-2b9 using diethyl methanephos-
phonate as a substrate. It is shown in Scheme 1 and briefly
discussed below.
,10
12
Scheme 1a
A newly formed olefinic bond in 7 has the E-geometry as
3
13
indicated by the JH,P coupling constant value of 23.2 Hz.
Additional support for this assignment was provided by NOE
experiments. Thus, irradiation of the olefinic methine proton
at δ ) 6.74 ppm induced an enhancement in absorption
intensity of the phosphorus signal of 4.6%. Interestingly, the
observed NOE between two â olefinic protons in 7 of 16.9%
points to their proximity and to a conformation suitable for
the cyclopentenone ring formation via the Nazarov cycliza-
tion. The latter reaction, which has been found to occur with
structurally related R-phosphoryl dienones in low to moderate
1
4
yields, was a priori the most uncertain step in the whole
synthesis. To our satisfaction, however, the Nazarov cy-
clization of 7 carried out in the presence of iron(III) chloride
in methylene chloride at -30 °C gave cyclopentenone 8 in
9
1% yield and with the trans-situated phosphoryl and
methoxycarbonyl groups as the only product. In accord with
the commonly accepted mechanism of the Nazarov reac-
1
5
tion, formation of the double bond exclusively at C(2) and
C(3) of the cyclopentenone ring may be attributed to a better
stabilization of an intermediate â-ketocarbocation by the two
methyl groups. In the last step, the Horner-Wittig reaction
of 8 with gaseous formaldehyde allowed for the introduction
of the exocyclic R-methylene moiety under mild conditions
and for completion of the synthesis of (()-methyl ester of
desepoxy-4,5-didehydromethylenomycin A 2b in 31% over-
all yield. The spectral data of the product obtained were fully
1
0
consistent with those reported in the literature.
In summary, we have developed a short and efficient
synthesis of the racemic methyl ester of desepoxy-4,5-
(
10) For previous syntheses of (()-2b, see: Sakai, K.; Amemiya, S.;
a
(
a) BuLi, -78 °C, Cu
CO Me, THF, -10 °C f reflux; (c) NaH, 25 °C f 60
, THF, -10 °C; (d) DBU, CH Cl , rt; (e) FeCl , CH Cl
30 °C f rt, 30 h; (f) NaH, CH O‚gaseous, THF, rt.
2
I
2
, THF, -40 °C; (b) NaH, -10 °C f
Inoue, K.; Kojima, K. Tetrahedron Lett. 1979, 25, 2365-2368. Boschelli,
D.; Scarborough, R. M. Jr.; Smith, A. B., III. Tetrahedron Lett. 1981, 27,
rt, BrCH
C, Br
2
2
1
9-22. Mahidol, C.; Thebtaranonth, C.; Thebtaranonth, Y.; Yenjai, C.
°
-
2
2
2
3
2
2
,
Tetrahedron Lett. 1989, 30, 3857-3860. Hong, F.-T.; Lee, K.-S.; Liao,
Ch.-Ch. Tetrahedron Lett. 1992, 33, 2155-2158. Tius, M. A.; Kwok, Ch.-
K.; Gu, X.; Zhao, Ch. Synth. Commun. 1994, 24, 871-885.
2
(11) Tiglic acid chloride was obtained from commercially available trans-
2
-methyl-2-butenoic acid (tiglic acid).
(12) Attempted phenylselenylation of the sodium salt of 4 with phe-
In the first step, the lithium-copper salt of the starting
phosphonate was acylated with tiglic acid chloride to give
nylselenenyl bromide as an alternative way for introduction of the olefinic
bond failed.
(
13) There is a clear-cut relationship between the E and Z geometry of
â-oxophosphonate 4 as a mixture of E and Z isomers in a
3
â-monosubstituted vinyl phosphonates and the value of the JH, P coupling
1
1
2
2:1 ratio. Treatment of the sodium salt of the E isomer of
3
3
constant ( JH,P-trans ∼ 40 Hz; JH,P-cis ∼ 20 Hz): Lehnert, W. Tetrahedron
1
1
974, 30, 301-305. Reetz, M. T.; Peter, R.; von Itzstein, M.; Chem. Ber.
987, 120, 121-122. Nickson, T. E. J. Org. Chem. 1988, 53, 3870. Midura,
(
7) Mikolajczyk, M.; Zurawinski, R. J. Org. Chem. 1998, 63, 8894-
897. Mikolajczyk, M.; Mikina, M.; Jankowiak, A.; Mphahlele, M. J.
Submitted.
W. H.; Mikolajczyk, M.; Tetrahedron Lett. 1995, 36, 2871-2874.
(14) Minami, T.; Nakayama, M.; Fujimoto, K.; Matsuo, S. Phosphorus,
Sulfur, Silicon Relat. Elem. 1993, 75, 135-138. Motoyoshija, J.; Mizuno,
K.; Tsuda, T.; Hayashi, S. Synlett 1993, 237-238.
(15) Krohn, K. In Organic Synthesis Highlights; Mulzer, J., Altenbach,
H.-J., Braun, M., Krohn, K.; Reissig, H.-U. Eds.; VCH: Weinheim, New
York, Basel, Cambridge, 1991; pp 137-144. Habermas, K. L.; Denmark,
S. E.; Jones, T. K. Org. React. 1994, 45, 1-158.
8
(
(
8) Mikolajczyk, M.; Mikina, M.; Jankowiak, A. Submitted.
9) The methyl ester 2b is more stable than the corresponding free acid
2
a. It is also expected to be more biologically active than 2a as was found
in the case of methylenomycin A 1 methyl ester which showed stronger
antibacterial and antifungal activity than methylenomycin A itself.
1154
Org. Lett., Vol. 2, No. 8, 2000

didehydromethylenomycin A. The key steps in this synthesis
involve the highly efficient and regioselective Nazarov
cyclization of R-phosphoryl dienone 7 and the use of the
Horner-Wittig reaction for introduction of the exocyclic
R-methylene moiety. Our synthesis compares favorably in
terms of use of simple reagents and transformations with
the majority of the previously reported syntheses. The
synthesis of optically active 2b is currently under study in
our laboratory.
Acknowledgment. Financial support by the State Com-
mittee for Scientific Research (Grant T09A 128 12) is
gratefully acknowledged.
Supporting Information Available: Full experimental
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL005742B
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