Concise synthesis of enantiopure erythro-saccharinic acid lactone and potassium (2R,3R)-2,3,4-trihydroxy-2-methylbutanoate

Article abstract of DOI:10.1016/j.tetlet.2006.09.156

A short and efficient approach was applied to the total synthesis of erythro-saccharinic acid lactone and the leaf-closing substance potassium (2R,3R)-2,3,4-trihydroxy-2-methylbutanoate from a 2-C-hydroxymethyl-d-erythrose derivative, using a combined str

Full text of DOI:10.1016/j.tetlet.2006.09.156

Tetrahedron Letters 47 (2006) 8479–8481
Concise synthesis of enantiopure erythro-saccharinic acid
lactone and potassium (2R,3R)-2,3,4-trihydroxy-2-methylbutanoate
Alexandros E. Koumbis,* Apostolos D. Kaitaidis and Stefanos S. Kotoulas
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
Received 20 August 2006; revised 20 September 2006; accepted 28 September 2006
Abstract—A short and efficient approach was applied to the total synthesis of erythro-saccharinic acid lactone and the leaf-closing
substance potassium (2R,3R)-2,3,4-trihydroxy-2-methylbutanoate from a 2-C-hydroxymethyl-D-erythrose derivative, using a com-
bined strategy.
Ó 2006 Elsevier Ltd. All rights reserved.
Potassium (2R,3R)-2,3,4-trihydroxy-2-methylbutanoate
(1, Fig. 1), a leaf-closing substance of the leguminous
tropical plant Leucaena leucocephalam, was recently
isolated by Ueda et al.1 In general, most of the plants
belonging to the legume family keep their leaves closed
during the night and open them in the morning.2 This
phenomenon, controlled by their internal biological
clocks, is called nyctinasty.3 Practically, this circadian
rhythmic movement of the leaves is regulated by the
interaction of leaf-opening and leaf-closing bioactive
compounds. Since nyctinasty is very important for
the survival of these legumes and the active factors
usually differ from plant to plant, these compounds
could be used as ecological friendly herbicides.1,4
Specifically, L. leucocephalam poses a serious threat
to the environment because it grows rapidly and inhib-
its the growth of surrounding plants by the secretion of
allelochemicals.5 This results in the disruption of the
ecosystem and a selectively effective herbicide against
it is desirable.
On the other hand, 2-C-methyl-D-erythrono-1,4-lactone
[or erythro-saccharinic acid lactone, (À)-2, Fig. 1] is the
first aldonolactone isolated from plants which, not sur-
prisingly, are members of the leguminosae family:
Astragalus lusitanicus L.6a (a plant which shows a high
degree of toxicity for cattle) and Cicer arietinum L.6b
(a valuable source of protein and oil in semi-arid tropi-
cal regions). Later, the same compound was found in
other plant extracts6c and identified as an oviposition
stimulant of the butterfly Papilio bianor from Orixa
japonica6d and as a metabolite of the 1-deoxy-D-xylulose
biosynthetic pathway of plants.6e Obviously, lactone
(À)-2 is structurally related to butanoate 1 and, in fact,
is probably the natural precursor of the latter. Enantio-
pure (À)-2 is also a potential useful chiral building block
in the synthesis of other natural products.7
Lactone (À)-2 was previously synthesized using either
chiral pool approaches7,8 or via an asymmetric aldol
reaction.9 There was until lately only one precedent syn-
thesis of 1 by Gogoi and Argade, but as the racemate.10
During our on-going synthesis, the same group11 re-
ported the preparation of both 1 and (À)-2 in optically
pure form via an enzyme catalyzed reaction.
O
O
HO
HO
COO-K+
In continuation of our natural product synthesis,
employing acetonides of D- and L-erythroses as starting
materials,12 we report here a new and very efficient
approach for the synthesis of enantiopure 1 and (À)-2.
HO
OH
OH
1
(-)-2
Figure 1. Structures of targeted natural products 1 and (À)-2.
Since 1 could be prepared upon saponification of (À)-2,
we envisaged a retrosynthetic strategy using lactone 3 as
an advanced precursor (Scheme 1). This compound
*
Corresponding author. Tel.: +30 2310 997839; fax: +30 2310
997679; e-mail: akoumbis@chem.auth.gr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.156

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A. E. Koumbis et al. / Tetrahedron Letters 47 (2006) 8479–8481
with those reported in the literature.16 {For (À)-2: [a]D
O
O
O
O
OP
OH
OH
1
(-)-2
À60.2 (c 0.3, H2O), lit.7 [a]D À61.2 (c 0.2, H2O)}.17
O
O
O
O
O
O
Furthermore, there is another point of interest regarding
the above described synthesis. The enantiomer of (À)-2
is equally easy accessible in optically pure form using
the same sequence of reactions but starting from L-arab-
inose.18 This task was also investigated and (+)-2 was
obtained in a similar overall yield.19 {For (+)-2: [a]D
+58.8 (c 0.5, H2O), lit.11 [a]D +58.5 (c 0.5, H2O)}.
3
4
5
Scheme 1. Retrosynthetic analysis.
could derive from the protected lactol 4 (P = a suitable
protecting group), which in turn could derive from
D-erythrose derivative 5. The latter is easily accessible
from D-arabinose and has undoubtedly the correct ste-
reochemistry at the quaternary carbon centre.
In conclusion, the work described in this article presents
a short and efficient synthetic approach towards the
preparation of two natural products, (2R,3R)-2,3-dihy-
droxy-2-methyl-c-butyrolactone [(À)-2] and potassium
(2R,3R)-2,3,4-trihydroxy-2-methylbutanoate (1), mak-
ing use of readily available, multigram quantities of D-
arabinose derived chiron 5 and employing a combined
retrosynthetic chiral pool route. The overall yields for
both targets were approximately 70% in a six-step
sequence involving relatively simple and inexpensive
procedures.
Indeed, hydroxymethyl erythrose 5, available in multi-
gram quantities from D-arabinose,13 was initially deriv-
atized to give tosylate
6 under mild conditions
(Scheme 2). It is noteworthy that under these conditions
the corresponding bis-tosylate was formed only in
traces. Next, the hemiacetal hydroxy group of 6 was
protected yielding a mixture of C-1 epimeric silyl ethers
7 (a and b anomers in a ratio of ca. 3:1). Although it was
very easy to chromatographically separate these two iso-
mers, there was practically no need to do so since both
were equally useful for the on-going synthesis. There-
fore, the mixture of 7 was subsequently reacted with
LiAlH4 in THF under reflux.14 In this way, the 2-C-
methyl-erythrose derivatives 8 were obtained in a very
good combined yield. The removal of the silyl protecting
group was performed under neutral conditions to afford
lactols 9, almost quantitatively. The latter were
smoothly oxidized to give lactone 3.15 The completion
of the synthesis was accomplished by a two-step proce-
dure involving initially, removal of the acetonide group
upon treatment with trifluoroacetic acid [to give (À)-2]
and finally saponification on treatment with aqueous
potassium hydroxide (to yield 1). Both compounds were
found to have identical physical and spectroscopic data
References and notes
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O
O
OH
OR
OTBS
R
i
iii
D
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O
O
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O
5 R = H
6 R = Ts
7 R = OTs
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ii
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v
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9
Scheme 2. Synthesis of (À)-1 and 2. Reagents and conditions: (i) Ref.
13; (ii) TsCl, pyridine, rt, 90%; (iii) TBSCl, imidazole, CH2Cl2, rt, 98%;
(iv) LiAlH4, THF, 60 °C, 96%; (v) TBAF, AcOH, THF, 0 °C to rt,
99%; (vi) CrO3, pyridine, Ac2O, CH2Cl2, rt, 89%; (vii) TFA, H2O, 0 °C
to rt, 95%; (viii) KOH, H2O, 0 °C to rt, 99%.
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17. It was practically impossible to obtain an optical rotation
for 1 in H2O since this compound slowly decomposes at
near neutral pH. See Refs. 1 and 10.
18. For the preparation of the enantiomer of
L-arabinose see Ref. 12b.
5 from
15. Compound 3 was found to have identical 1H and 13C
NMR spectra with those reported in Ref. 7; [a]D À82.0 (c
2.0, acetone).
19. 1H and 13C NMR spectra were identical with those of
(À)-2.