Synthesis of enantiopure 2-C-methyl-d-erythritol-4-phosphate

Article abstract of DOI:10.1016/j.tetlet.2007.10.129

The synthesis of enantiopure 2-C-methyl-d-erythritol-4-phosphate is disclosed. A 1,3-diol possessing a quaternary stereogenic centre, prepared stereoselectively from an acyclic tri-substituted alkene, has been utilized as a key intermediate.

Full text of DOI:10.1016/j.tetlet.2007.10.129

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Tetrahedron Letters 48 (2007) 9090–9092
Synthesis of enantiopure 2-C-methyl-D-erythritol-4-phosphate
Sadagopan Raghavan* and T. Sreekanth
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 20 September 2007; revised 23 October 2007; accepted 26 October 2007
Available online 30 October 2007
Abstract—The synthesis of enantiopure 2-C-methyl-D-erythritol-4-phosphate is disclosed. A 1,3-diol possessing a quaternary stereo-
genic centre, prepared stereoselectively from an acyclic tri-substituted alkene, has been utilized as a key intermediate.
Ó 2007 Elsevier Ltd. All rights reserved.
Nature employs two biosynthetic pathways for the syn-
thesis of one of the most diverse groups of natural prod-
ucts, terpenes. In addition to the mevalonate-dependent
pathway,1 the 2-C-methyl-D-erythritol-4-phosphate
(MEP, 1) pathway2 has recently been found in chloro-
plasts, algae, cyanobacteria, eubacteria as the source
of isopentenyl diphosphate (IPP). The MEP pathway
while absent in animal cells, is present in many organ-
isms, causing diseases such as tuberculosis, sexually
transmitted infections, infections of the upper respira-
tory tract, toxoplasmosis and malaria.3 The inhibition
of the MEP pathway would provide opportunities to de-
velop anti-parasitic and herbicidal agents.4 Seven differ-
ent enzymes are involved in the MEP pathway; the
intermediates in the pathway are considered important
for the mechanistic study, development of specific inhib-
itors and therapeutic leads. Enzymatic preparation of 15
and cyclodiphosphate 2,6 Scheme 1, has been described.
tiomerically pure MEP utilizing a recently disclosed
methodology describing the regio and stereoselective
preparation of tertiary alcohols from acyclic tri-substi-
tuted alkenes.10 Propargyl ether 3 on reaction with
methyl chloroformate followed by conjugate addition
using Corey’s protocol,11 on the resulting ester 4 (74%
yield), furnished ester12 5 (80% yield), which was
reduced using alane to yield alcohol 6 (80% yield).
Oxidation using Swern protocol13 yielded aldehyde 7,
Scheme 2. The effective synthesis began with the conden-
sation of the lithio anion of (R)-methyl p-tolyl sulfoxide
814 with the unsaturated aldehyde 7 to furnish allyl
alcohol 9 as an equimolar mixture of readily separable
isomers (90% yield).15 The syn isomer 9s was oxidized
using DMP16 to afford the corresponding b-ketosulf-
oxide, which was reduced diastereoselectively using
25
DIBAL-H17 to furnish 9a (80% overall yield, ½aꢀD +87
(c 1.5, CHCl3)).
The reported chemical methods utilize asymmetric epox-
idation,7 asymmetric dihydroxylation,8 and chiral pool
precursors.9 We report herein a novel approach to enan-
The reaction of 9a with NBS proceeded cleanly to yield
25
10 (80%, ½aꢀD ꢁ33.3 (c 1.65, CHCl3)).18 Treatment of 10
with anhydrous potassium carbonate afforded a mixture
of epoxides 11 and 12 in a 3:1 ratio, Scheme 3. To pre-
pare an epoxide chemoselectively using the secondary
carbinol, bromodiol 10 was transformed into 1,2-aceto-
nide 13 (70% yield) using DDQ19 and subsequently trea-
ted with anhydrous potassium carbonate to afford epoxy
sulfoxide 14 (91% yield). Reductive elimination of 14
using Na–Hg20 proceeded less cleanly in comparison
to the corresponding sulfone 15 (89% yield) to yield anti
1,2-diol derivative 16 (70% yield). Protection of the hy-
droxyl group as its benzyl ether 17 (90% yield) followed
by a one-pot oxidative cleavage of the alkene furnished
aldehyde,21 which without isolation was reduced in the
same pot to yield alcohol 18 (70% yield). Conversion
to the corresponding phosphate 19 (70% yield) using
O O-
P
O
O
Me OH
Me
P
2-
O-
OPO3
O
OH OH
OH OH
1
2
Scheme 1.
Keywords: 2-C-Methyl-D-erythritol-4-phosphate; Quaternary stereo-
genic centre; 1,3-Diol; Sulfoxide; NBS.
*
Corresponding author. Tel.: +91 040 27160123; fax: +91 040
27160512; e-mail: sraghavan@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.129

S. Raghavan, T. Sreekanth / Tetrahedron Letters 48 (2007) 9090–9092
9091
BuLi, ClCO2Me
MeO2C
OPMB
Me2CuLi, Ether
THF
MeO2C
OPMB
Me
OPMB
4
5
3
(COCl)2, DMSO
CH2Cl2
AlH3, Ether
HOH2C
OPMB
OHC
OPMB
Me
Me
6
7
OPMB
OPMB
Me
O
S
LDA, THF, -78 oC
O
S
O
S
OH
OH
OHC
OPMB
+
p-Tol
Me
p
-Tol
p
-Tol
+
Me
Me
9s
8
7
9a
DMP, CH2Cl2
DIBAL-H, THF
Scheme 2.
NBS, H2O
Toluene
HO
O
S
HO
O
O
O
Me
Me
K2CO3, MeOH
OPMB
S
OPMB
+
p-Tol
9a
p
-Tol
p
-Tol
OPMB
OH
S
Me
Br
10
O
OH
12
11
H
PMP
Na-Hg, Na2HPO4
MeOH
HO
O
O
O
S
O
DDQ, CH2Cl2
Me
n
K2CO3, CH3CN
O
S
10
p
-Tol
p
-Tol
O
Me
O
Br
13
PMP
H
14, n = 1
15, n = 2
mCPBA, CH2Cl2
OsO4, NaIO4,
2,6-Lutidine, t-BuOH, H2O
then NaBH4
OBn
OP
H2, Pd(OH)2/C
EtOH
Me OH
2-
PO
O
O
H
OPO3
Me
O
Me
O
PMP
OH OH
PMP
H
1
16, P = H
18, P = H
ClP(O)(OBn)2,
-BuLi, THF
NaH, BnBr
THF
n
19, P = P(O)(OBn)2
17, P = Bn
Scheme 3.
dibenzylphosphorochloridate22 and subsequent hydrog-
enolysis by treatment with Pd/C under an atmosphere of
thank Dr. A. C. Kunwar for the NMR spectra and Dr.
M. Vairamani for the mass spectra.
hydrogen yielded 1 (81% yield). The NMR spectra as
25
well as the optical rotation of synthetic 1 ð½aꢀD +7.2
(c 0.2, H2O) were consistent with those reported for
an enzymatically prepared sample.5a
References and notes
In summary, we report a straightforward approach to
enantiopure MEP. Also using appropriate reducing
agents, C4 labelled derivatives can be prepared.
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S.R. is thankful to Dr. J. M. Rao, Head, Org. Div. I, for
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CSIR, New Delhi for a fellowship. Financial assistance
from DST (New Delhi) is gratefully acknowledged. We

9092
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