Synthesis of 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate.

Article abstract of DOI:10.1021/ol025661a

[reaction: see text] The synthesis of 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate, a biochemical intermediate in the deoxyxylulose pathway of isoprenoid biosynthesis, was accomplished in four steps. Bisphosphorylation of 2-C-methyl-D-erythritol 1,3-dia

Full text of DOI:10.1021/ol025661a

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1225-1226
Synthesis of 2-C-Methyl-D-Erythritol
2,4-Cyclopyrophosphate
Jose´-Luis Giner* and William V. Ferris, Jr.
Department of Chemistry, State UniVersity of New York-ESF,
Syracuse, New York 13210
jlginer@syr.edu
Received February 4, 2002
ABSTRACT
The synthesis of 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate, a biochemical intermediate in the deoxyxylulose pathway of isoprenoid
biosynthesis, was accomplished in four steps. Bisphosphorylation of 2-C-methyl-D-erythritol 1,3-diacetate, followed by carbodiimide cyclization
and deprotection, led to the title compound in 42% overall yield.
2-C-Methyl-D-erythritol 2,4-cyclopyrophosphate (1) was first
isolated from DesulfoVibrio desulfuricans and Corynebac-
terium ammoniagenes bacteria.1 Its structure was elucidated
by NMR spectroscopy, and its absolute stereochemical
configuration was determined by hydrolysis to the known
2-C-methyl-D-erythritol (2).2 Due to its accumulation in
bacteria under conditions of oxidative stress, its role in the
bacteria was interpreted in terms of a protective function.3
More recently, 1 was shown to be an intermediate in the
newly discovered deoxyxylulose pathway of isoprenoid
biosynthesis.4 This pathway coexists with the mevalonate
pathway in plants and replaces it altogether in many bacteria.5
We have previously reported the syntheses of 1-D-deoxyxy-
lulose and 2.6,7 In this communication we report the chemical
synthesis of 1.
(1) (a) Turner, D. L.; Santos, H.; Fareleira, P.; Pacheco, I.; LeGall, J.;
Xavier, A. V. Biochem. J. 1992, 285, 387-390. (b) Ostrovsky, D.;
Shipanova, I.; Sibeldina, L.; Shashkov, A.; Kharatian, E.; Malyarova, I.;
Tantsyrev, G. FEBS Lett. 1992, 298, 159-161. (c) Ostrovsky, D.; Kharatian,
E.; Malarova, I.; Shipanova, I.; Sibeldina, L.; Shashkov, A.; Tantsirev, G.
BioFactors 1992, 3, 261-264.
Our synthesis of 2 via biomimetic epoxy ester-ortho ester
rearrangement (3 to 4) also resulted in the preparation of
2-C-methyl-D-erythritol 1,3-diacetate (5, 58% yield from 3).7
This compound was used as the starting material for the
synthesis of 1 (Scheme 1). Double phosphorylation of 5 by
the phosphoramidite method led to the benzyl-protected
(2) Ostrovsky, D.; Shashkov, A.; Sviridov, A. Biochem. J. 1993, 295,
901-902.
(3) Ostrovsky, D. N. Biochemistry (Moscow) 1995, 60, 9-12.
(4) (a) Herz, S.; Wungsintaweekul, J.; Schuhr, C. A.; Hecht, S.; Luttgen,
H.; Sagner, S.; Fellermeier, M.; Eisenreich, W.; Zenk, M. H.; Bacher, A.;
Rohdich, F. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 2486-2490. (b) Takagi,
M.; Kuzuyama, T.; Kaneda, K.; Watanabe, H.; Dairi, T.; Seto, H.
Tetrahedron Lett. 2000, 41, 3395-3398. (c) Rohdich, F.; Eisenreich, W.;
Wungsintaweekul, J.; Hecht, S.; Schuhr, C. A.; Bacher, A. Eur. J. Biochem.
2001, 268, 3190-3197. (d) Hecht, S.; Eisenreich, W.; Adam, P.; Amslinger,
S.; Kis, K.; Bacher, A.; Arigoni, D.; Rohdich, F. Proc. Natl. Acad. Sci.
U.S.A. 2001, 98, 14837-14842.
(5) For reviews, see: (a) Eisenreich, W.; Schwarz, M.; Cartayrade, A.;
Arigoni, D.; Zenk, M. H.; Bacher, A. Chem. Biol. 1998, 5, R221-R233.
(b) Rohmer, M. Nat. Prod. Rep. 1999, 16, 565-574. (c) Lichtenthaler, H.
K. Biochem. Soc. Trans. 2000, 28, 785-789.
(6) Giner, J.-L. Tetrahedron Lett. 1998, 39, 2479-2482.
(7) Giner, J.-L.; Ferris, W. V., Jr.; Mullins, J. J. Unpublished work.
10.1021/ol025661a CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/15/2002

Scheme 1. Synthesis of 2-C-Methyl-D-erythritol 2,4-Cyclopyrophosphate (1)a
a (a) 3 equiv of (BnO)2PNi-Pr2, tetrazole, CH2Cl2, rt, 50 min; (b) m-CPBA, rt, 45 min; (c) H2, 10% Pd/C, MeOH/1% NH4HCO3 4:1, rt,
3 h; (d) excess EDC, H2O, rt, 3 d; (e) 1.36 M NH4OH, 30 °C, 4 h; (f) 1.1 equiv of (BnO)2PNi-Pr2, tetrazole, CH2Cl2, rt, 50 min.
diphosphate 6,8 which upon hydrogenolysis gave 2-C-methyl-
D-erythritol 1,3-diacetate 2,4-diphosphate (7). This compound
could be converted into 2-C-methyl-D-erythritol 2,4-diphos-
phate (8) in 75% yield by saponification of the acetate esters
with 0.6 M ammonium hydroxide.
raphy (2-propanol/acetonitrile/1% aqueous ammonium ac-
etate 1:1:1). A similar isomer of 10 has been isolated together
with 1 as an enzymatic product from the malaria parasite.4c
Although a biochemical synthesis of 1 involving up to 15
enzymes has previously been published,12 this represents the
first chemical synthesis of 1.
In an attempt to prepare 2-C-methyl-D-erythritol 4-phos-
phate, another intermediate in the deoxyxylulose pathway,
diol 5 was treated with 1.1 equiv of dibenzyl diisopropyl
phosphoramidite. This did not lead to the desired product;
however, a monobenzylated product was isolated in moderate
yield. A doubling of signals in the NMR spectra suggested
that the product was a 1:1 diastereomeric mixture of cyclic
monophosphates with a chiral center at phosphorus (11).
Hydrogenolysis of the mixture led to a single product
interpreted as being 2-C-methyl-D-erythritol 2,4-cyclophos-
phate 1,3-diacetate (12).
An attempt to form 1 by carbodiimide cyclization of 8
failed as could be expected. However, carbodiimide coupling
of 7 smoothly led to the formation of the protected cyclic
pyrophosphate 9. In these reactions, the carbodiimide used
was not dicyclohexylcarbodiimide as in the synthesis of the
cyclic pyrophosphate methanophosphagen,9 but rather a large
excess of the water-soluble carbodiimide EDC.10 The sub-
stituted urea byproduct of the reaction was removed by cation
exchange chromatography (DOWEX 50WX8-200). The
product (9) thus obtained was mixed with ammonium
chloride and could be further purified by silica gel chroma-
tography (2-propanol/acetonitrile/1% aqueous ammonium
acetate 4:1:1), or used directly for the next step. Deprotection
of 9 by saponification with 1.36 M NH4OH led to 1 in good
yield. Careful control of the saponification reaction was
necessary because 1 rearranges under basic conditions.11 The
product of rearrangement (10) could easily be separated from
the desired cyclic pyrophosphate 1 by silica gel chromatog-
Acknowledgment. We thank the Sigma Xi Scientific
Research Society for financial support.
Supporting Information Available: Experimental pro-
cedures and 1H, 13C, and 31P NMR spectral data for
compounds 6-12. This material is available free of charge
via the Internet at http://pubs.acs.org.
(8) Perich, J. W.; Johns, R. B. Tetrahedron Lett. 1987, 28, 101-102.
(9) (a) Kanodia, S.; Roberts, M. F. Proc. Natl. Acad. Sci. U.S.A. 1983,
80, 5217-5221. (b) Berkessel, A.; Geisel, U.; Herault, D. A. Tetrahedron
Lett. 1996, 37, 355-356.
(10) Tohidi, M.; Orgel, L. E. J. Mol. EVol. 1990, 30, 97-103.
(11) Ostrovsky, D.; Diomina, G.; Shipanova, I.; Sibeldina, L.; Shashkov,
A. BioFactors 1994, 4, 155-159.
OL025661A
(12) Schuhr, C. A.; Hecht, S.; Kis, K.; Eisenreich, W.; Wungsintaweekul,
J.; Bacher, A.; Rohdich, F. Eur. J. Org. Chem. 2001, 3221-3226.
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