Synthesis of 2-C-methylerythritols and 2-C-methylthreitols via enantiodivergent Sharpless dihydroxylation of trisubstituted olefins

Article abstract of DOI:10.1016/j.tetlet.2012.03.071

The mevalonate-independent pathway (MIP) is an interesting avenue for antimicrobial lead discovery. Here, we present a unified enantioselective synthesis of all four stereoisomers of 2-C-methyltetrol. These are useful building blocks of many bioactive natural products, including 2-C-methylerythritol phosphate (MEP) of the MIP biosynthetic pathway.

Full text of DOI:10.1016/j.tetlet.2012.03.071

Tetrahedron Letters 53 (2012) 2706–2708
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2-C-methylerythritols and 2-C-methylthreitols via enantiodivergent
Sharpless dihydroxylation of trisubstituted olefins
⇑
Shibaji K. Ghosh, Mark S. Butler , Martin J. Lear
Department of Chemistry and Medicinal Chemistry, Program of the Life Sciences Institute, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
The mevalonate-independent pathway (MIP) is an interesting avenue for antimicrobial lead discovery.
Here, we present a unified enantioselective synthesis of all four stereoisomers of 2-C-methyltetrol. These
are useful building blocks of many bioactive natural products, including 2-C-methylerythritol phosphate
(MEP) of the MIP biosynthetic pathway.
Received 7 February 2012
Revised 29 February 2012
Accepted 20 March 2012
Available online 25 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Mevalonate
Erythritol
Threitol
Tetraols
Sharpless
Dudley
Enantiodivergent
Antibiotic
Malaria
Microbial
Parasitic
The identification of novel ways to selectively target invading
parasites or microbes within animal hosts is critical to the develop-
ment of new drug leads and diagnostic probes. In our efforts to
develop natural product based leads and imaging agents,1 we be-
gan searching for biosynthetic differences between animal cell
types and microbial types. Our search soon led us to the mevalo-
nate-independent pathway (MIP) that exists in Gram-negative
bacteria, plant chloroplasts and algae, but not in animals
(Fig. 1).2–4 Indeed, a precedent already exists to support the MIP
pathway as a promising avenue to develop drugs against bacteria
(e.g., Mycobacterium tuberculosis) and malaria.4,5 Fosmidomycin,
approach to synthesize all the stereoisomers of 2-C-methylerythre-
itol (1) and 2-C-methylthreitol (9) of MEP (2) in good to high enan-
tiomeric purity (80–98% ee). To this end, the Sharpless asymmetric
dihydroxylation (SAD) of PMB-O-protected trisubstituted alkeno-
ates was found to be a convenient enantiodivergent tactic.
It should be noted that 2-C-methylerythritol (1) and 2-C-
methylthreitol (9) have previously been prepared in moderate to
good enantiomeric excesses.7–9 A chemo-enzymatic synthesis of
all four isomers has been developed10 and the natural 2-C-methyl-
D
-erythritol enantiomer [(+)-1] has also been prepared using chiral
pool starting materials.11,12 Despite these reported syntheses, we
decided to pursue a unified stratagem to all four isomers from read-
ily available, non-chiral hydroxyacetone 3 (Scheme 1).
an inhibitor of 1-deoxy-D-xylulose-5-phosphate (DXP), is being
evaluated in phase II clinical trials to treat malaria, in combination
with the antibiotic clindamycin, by Jomaa Pharma GmbH and the
medicines for the malaria venture.6
2-C-Methylerythritol phosphate (2, MEP) has been proposed to
be a key intermediate in this pathway (Fig. 1) to generate isopen-
tenyl phosphate (IP) by the reductive-migratory isomerism of DXP,
a condensation product between pyruvate (Pyr) and glyceralde-
hyde-3-phosphate (G3P).4 Herein, we report a unified five-step
CO2
O
O
OH
+
O
2-
-
2-
H
OPO3
G3P
CO2
Pyr
OPO3
DXP
DXP synthase
OH
HO
OH
NADP+
NADPH
HO
2-
OR
2-C
OPO3
⇑
Corresponding author. Tel.: +65 6516 3998; fax: +65 6779 1691.
DXR
OH
2-
(+)-1 (R= H)
2 (MEP, R= PO3
)
IP
E-mail address: Martin.Lear@nus.edu.sg (M.J. Lear).
Present address: Institute for Molecular Bioscience, University of Queensland, St.
Lucia 4072, Queensland, Australia.
Figure 1. Mevalonate-independent pathway (MIP) via phosphorylated tetraol 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.071

S. K. Ghosh et al. / Tetrahedron Letters 53 (2012) 2706–2708
2707
MgO, PhCF3
0 °C to rt, 12 h
10 % Pd-C
(30 % w/w)
HO
LiBH4, THF
0 °C, 1 h
HO
NaH, THF, rt, 20 h
HO
(R)
PMBO
(R)
(+)-7
PMBO
HO
(S)
2-C
(S)
2-C
OH
OH
O
O
H
2 (Balloon)
CO2Et
MeOTf
OH
OH
EtOH, rt, 10 h
3
4
PO(OEt)3
(+)-1 (99%)
(-)-8 (87%)
(75%)
PMBO
N
O
HO
HO
HO
HO
(R)
(R)
(S)
HO
HO
PMBO
HO
(S)
(S)
OH
OH
(R)
OEt
OH
3-C
OH
OH
NMO, citric acid
K2OsO2(OH)4
OH
OH
O
(+)-9
(-)-9
(-)-1 (2-C-L-erythritol)
(2-C-threitols)
( )-6 (90% from 5E)
PMBO
OEt
tBuOH/H2O (1:1)
rt, 12 h
Scheme 3. Synthesis of all dephosphorylated steroisomes 1 and 9 of MEP.
O
HO
PMBO
(3:1 E/Z) - separable
5
3-C
OEt
obtained with the use of AD-mix-
a (95% ee). Not unexpectedly,
(75%)
OH
( )-7 (85% from 5Z)
the enantioselectivities and reaction rates to produce (+)-7 and
(À)-7 were lower for the cis-olefin 5Z as compared to 5E15; the
72–75% yields and 80–85% ee values are based on recovered 5Z
after 72 h.
Scheme 1. Stereodivergent synthesis of thero and erythro esters.
Finally, to form the natural D-isomer (+)-1 of MEP, ethyl ester
To aid mechanistically in a subsequent SAD step,13 we began by
(+)-7 was reduced with LiBH4 to afford triol (À)-8 in 87% yield
(Scheme 3). Deprotection of the PMB group, however, was found
to be problematic under oxidative conditions (e.g., CAN or DDQ)
due to the adjacent and multiple hydroxy functionalities. A practi-
cal solution to this seemingly simply deprotection step was to per-
form hydrogenolysis with Pd–C (30% w/w) in ethanol. This allowed
the smooth generation and isolation of all the tetraols 1 or 9 in near
quantitative yields and high purities.
protecting 3 with a suitable benzyl group. This was surprisingly
difficult to achieve in practice; for example, only moderate yields
(below 40%) were achieved under standard conditions with freshly
prepared benzyl-2,2,2-trichloroacetimidate. Eventually, we settled
for the p-methoxybenzyl (PMB) ether 4, whereby the use of Dud-
ley’s reagent14 gave a consistently good yield, and Horner–Wads-
worth–Emmons olefination with triethyl phosphonoacetate gave
the
mixture.
The pure geometric isomers 5Z and 5E were confirmed by nOe
a,b-unsaturated ethyl ester 5 as a readily separable 3:1 E/Z
In closing, three main advancements are worth noting. Firstly,
each D- or L-isomer of 2-C-methylerythritol (1) or 2-C-methylthre-
itol (9) can be accessed in good to high enantiomeric purity via a
reliable, five-step stereodivergent sequence from readily available
hydroxyacetone 3 in 30–40% overall yields. Secondly, the PMB-
ether/ethyl ester form of the olefin 5 not only improved the enanti-
oselectivity of the SAD reaction, as compared to a related olefin
substrate,8,13 but also 5 could be synthesized in two steps, as com-
pared to four, by virtue of Dudley’s neutral benzylation condi-
tions.14 Thirdly, the title compounds 1 and 9 are useful building
blocks to naturally occurring bioactive molecules, including a sac-
charinic acid lactone (a plant growth regulator),16 potassium
(2R,3R)-4-trihydroxy-2-methylbutanoate (for leaf closing)17 and
potassium aeshynomate (for leaf opening).18 In addition to these
points, we anticipate this work will provide opportunities in the
exploitation of the MIP pathway and in the design of biosynthetic
probes and inhibitors to selectively target microbial or parasitic
infections.
NMR studies. For reference purposes (i.e., future % ee determina-
tion using chiral HPLC) and to check the reactivity of the olefins
5, we synthesized the racemic diols ( )-6 and ( )-7 under Sharp-
less’ modified procedure with citric acid to increase the reaction
rate.15 As anticipated, dihydroxylation of the cis-olefin 5Z was
found to be slower as compared to the trans-olefin 5E.
Next, we studied the proposed enantiodivergent SAD route to
all threo 6 and erythro 7 C-methyldiols by the choice of either
AD-mix-a or -b (Scheme 2). Here, we found both the PMB and ethyl
ester groups to be essential for optimal enantiomeric excesses for
such trisubstituted olefins 5. The substrate 5E under AD-mix-b
conditions gave 98% ee of the threo-diol (+)-6. This is a significant
improvement over the reported 82% ee for a benzyl-ether, methyl-
ester analogue of 5E.8 A similarly high % ee of (À)-6 was also
Acknowledgments
O
AD-mix-β
HO
PMBO
(S)
(R)
OEt
Financial support from the Ministry of Education of Singapore
(AcRF Tier-2 Grant T206B1112) and a PhD scholarship (to S.K.G.)
are greatly appreciated.
CH3SO2NH2
OH
5E
tBuOH/H2O (1:1)
-1 °C, 72 h
(+)-6 (83%, 98%ee)
O
HO
(R)
PMBO
(S)
Supplementary data
OEt
AD-mix-α
AD-mix β
O
OH
PMBO
(-)-6 (79%, 95%ee)
OEt
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
071.
5 (E or Z)
O
HO
PMBO
(S)
(S)
OEt
CH3SO2NH2
tBuOH/H2O (1:1)
-1 °C, 72 h
OH
5Z
References and notes
7
(+)- (75%, 85%ee)
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Scheme 2. Catalytic enantiodivergent syntheses of 6 and 7.
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