(-)-Daucic Acid: Revision of Configuration, Synthesis, and Biosynthetic Implications

Article abstract of DOI:10.1002/anie.200352718

The synthesis of dihydropyrans with the D-xylo (1), D-ribo, L-arabino, and D-lyxo (2) configuration by one-carbon-atom homologation of D-mannose or D-galactose, terminal oxidation, and directed β elimination revealed (-)-daucic acid isolated from carrots

Full text of DOI:10.1002/anie.200352718

Communications
Plant Acids
(ꢀ)-Daucic Acid: Revision of Configuration,
Synthesis, and Biosynthetic Implications**
Frieder W. Lichtenthaler,* Katsumi Nakamura, and
Jürgen Klotz
In memory of Friedrich Cramer
(ꢀ)-Daucic acid, a C7-sugar dicarboxylic acid found in carrots
(Daucus carota), sugar beet, wheat, sunflowers, and tobacco,
was first isolated from mature carrots in 1971[1] and later
assigned the structure of a 2,6-anhydro-3-deoxy-d-hept-2-
enaric acid and d-xylo configuration with respect to the three
chiral centers (Scheme 1, 1).[2] The assignment of a dihydro-
Scheme 1. Reactions of (ꢀ)-daucic acid, isolated from Daucus carota,
from which the structure of a 2,6-anhydro-2-deoxyhept-2-enaric acid
was derived; the d-xylo configuration 1 was determined on the basis of
[2]
1HNMR spectroscopic data (60 MHz).
pyran structure was based on the oxidative conversion of its
dimethyl ester into dimethyl chelidonate (2!3), and its
affiliation to the d series of sugars (that is, its configuration at
C6) followed convincingly from the high positive optical
rotation of the furanoid rearrangement product 5 ([a]D =
+79.3 in CHCl3), which correlated well with the equally
high negative [a]D value of the synthetically prepared
l-enantiomer.[2] This assignment was later corroborated by
the isolation of osbeckic acid 6 from Osbeckia chinensis L.,
the dimethyl ester of which proved to be fully congruent
to 5.[3]
[*] Prof. Dr. F. W. Lichtenthaler, Dr. K. Nakamura, Dr. J. Klotz
Clemens-Schöpf-Institut für Organische Chemie und Biochemie
Technische Universität Darmstadt
Petersenstrasse 22, 64287 Darmstadt (Germany)
Fax: (+49)6151-16-6674
E-mail: lichtenthaler@chemie.tu-darmstadt.de
[**] We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for support. K.N. thanks the Alexander von
Humboldt Foundation for a fellowship.
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DOI: 10.1002/anie.200352718
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Chemie
The assignment of the configuration at C4 and C5 was less
conclusive (Scheme 1), as it was inferred from low-resolution
1
(60 MHz) H NMR spectroscopic data for dimethyl daucate
(2) and its di-O-acetyl derivative, primarily from the coupling
constants for 4-H and 5-H and comparison of these with
analogous NMR spectroscopic data for certain 4,5-unsatu-
rated hexuronates,[4] which on close inspection prove unreli-
able.[5] Moreover, the half-chair forms of sugar-derived
dihydropyrans usually exist in complex conformational equi-
libria, which are virtually impossible to predict, thus resulting
in coupling patterns that have little bearing on the actual
configuration. Therefore, the verification of the stereochem-
istry at C4 and C5 of (ꢀ)-daucic acid was deemed imperative,
particularly as reflections on its biosynthetic origin—its
formation from 3-deoxy-d-arabino-heptulosonate 7-phos-
phate (DAHP), an early intermediate of the shikimic acid
pathway,[6] is a likely possibility—would lead one to expect
the d-arabino configuration.
These considerations, together with the notion that daucic
acid is a possible biosynthetic precursor of chelidonic acid (4),
a leaf-closing factor in Cassia mimosoides,[7] prompted us to
devise a stereocontrolled synthesis, which should be practical
enough to furnish sufficient amounts for biological studies.
Accordingly, herein we report expedient syntheses of the
daucic acids with the d-xylo, d-ribo, l-arabino, and d-lyxo
configuration. Our conceptual approach for developing
stereochemically unambiguous access to the d-xylo-heptena-
ric acid 1 and the three alternate configurations of this acid
was based upon the anomeric one-carbon-atom homologation
of suitable d-hexoses (d-galactose or d-mannose), subsequent
oxidation at both termini to the corresponding pyranoid C7
dicarboxylic acids, and controlled b elimination into the
pyranoid ring through the judicious choice of leaving groups.
The synthesis of the dimethyl d-xylo-dicarboxylate 2
started from tri-O-acetyl-2-acetoxy-d-galactal (7), readily
accessible from d-galactose in a three-step, one-pot proce-
dure[8] involving acetylation, treatment with HBr/HOAc, and
dimethylamine-promoted elimination of HBr (Scheme 2).
The acetone-initiated photoaddition of formamide to 7, albeit
complex,[9] is a selective to give the heptonamide 8 as the
major product (54%), which can be converted into the methyl
heptonate 9 by methanolysis under acidic conditions. Oxida-
tion of the primary hydroxy group was effected smoothly with
oxygen in the presence of the Adams catalyst to afford, after
esterification with methanolic HCl, the dimethyl heptarate
10. Although the axial orientation of the 5-OH group in 10
would suggest preferential 5,6-elimination from the corre-
sponding tri-O-acetyl (11) or tri-O-benzoyl derivative, their
exposure to a variety of suitable conditions (e.g. NaOAc/
Ac2O, 70 8C or Al2O3/lutidine, 408C) led to multicomponent
mixtures. Thus, a better leaving group had to be introduced at
C5. Low-temperature benzoylation of the equatorial hydroxy
groups in 10 and subsequent treatment with methanesulfonyl
chloride provided 12. Now 5,6-elimination could be effected
cleanly, either from 12 by briefly heating in NaOAc/Ac2O to
afford the dibenzoate 15 (59%), or from the debenzoylated
product 13 through exposure to NaOMe/MeOH to deliver
dimethyl d-xylo-heptenarate 2 (77%) directly. Gratifyingly,
all products in this reaction sequence were obtained in readily
Scheme 2. Conversion of d-galactose into the d-xylo-heptenarate 2:
a) HCONH2, Me2CO, hn, 3 days, RT, 54%;[9] b) HCl (8%)/MeOH,
reflux, 3 h, 86%; c) Pt/O2, water (pH8), 70 8C, 4 h, then saturated
methanolic HCl, RT, 1 h, 56%; d) BzCl, pyridine, ꢀ408C, 2 h; then
MsCl, ꢀ408C!RT, 2 h, 58%; e) pyridine/Ac2O (2:1), RT, 12 h, 85%;
f) saturated methanolic HCl, reflux, 14 h, 73%; g) NaOMe (0.1n)/
MeOH, RT, 1 h, 77%. Ms=methanesulfonyl.
characterizable, crystalline form; only the di-O-acetyl and di-
O-benzoyl derivatives 14 and 15 have so far resisted
crystallization.
The melting point for the product 2 of this reaction
sequence was close to that of the Daucus carota derived
compound. However, its optical rotation, although similar in
size, was opposite in sign (Table 1). The notion that the
natural product might therefore have the enantiomeric (i.e. l-
xylo) configuration was invalidated by the distinct differences
in the 1H NMR spectroscopic data of synthetic 2 and 14,
compared to those reported for the respective products of
natural origin. The chemical shifts observed for 4-H, 5-H, and
6-H vary by d = 0.3–0.6 ppm in each case, and the coupling
constants J3,4 and J4,5 have significantly different values
(Table 1). Thus, a d-xylo or l-xylo configuration for natural
(ꢀ)-daucic acid can be excluded unequivocally.
Of the remaining possible configurations—d-ribo, d-lyxo,
and d-arabino—the synthesis of the d-ribo analogue 22, the
C5 epimer of 2, was addressed next. We took advantage of the
ready accessibility of heptononitrile 16 from d-mannose
through a two-step, one-pot reaction comprising acetylation
and anomeric cyanation (Scheme 3).[10] Acid hydrolysis
followed by esterification with methanol then provided the
mannosyl-C-carboxylate 17. The Pt/O2 oxidation of the
primary hydroxy group in 17 proved unusually capricious,
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Table 1: Relevant physicochemical data for dimethyl 2,6-anhydro-3-deoxyhept-2-enarates of d-xylo, d-ribo, l-arabino, and d-lyxo configuration and their
diacetates, as compared with those reported for the analogous Daucus carota derived daucic acid derivatives.[2]
Compound
M.p. [8C]
[a]2D0[a]
1HNMR [ppm, Hz]
4-H5-H6-H
J3,4
J3,5
J4,5
J5,6
solvent
(ꢀ)-dimethyl daucate[2]
130–131
oil
ꢀ102[b]
4.51
5.63
4.30
4.66
4.82
4.35
3
2.3
2.6
1
?
1.5
?
?
4.4
2
1.8
1.8
CDCl3
CDCl3
C6H6
diacetate[2]
?
5.73
4.19
5.85
2 R=H133–135
+106
+146
4.60
4.61
4.41
4.8
5.3
5.3
1.3
1.5
1.5
?
2.2
2.2
1.5
1.4
1.0
CDCl3
CDCl3
C6H6
14 R=Ac
syrup
5.13
5.20
5.38
5.57
22 R=Hsyrup
23 R=Ac
+150.4
+171.1
4.32
5.62
4.12
5.71
4.63
4.84
4.74
4.4
3.7
3.8
–
–
0.7
4.3
?
4.2
7.6
6.8
6.3
CDCl3
CDCl3
C6H6
syrup
5.52
29 R=Hsyrup
30 R=Ac
+30.0
+72.1
4.25
5.14
5.22
4.19
5.44
5.58
4.73
5.06
4.89
4.3
5.4
5.3
0.9
1.5
1.5
2.2
2.1
2.3
5.4
2.2
2.6
CDCl3
CDCl3
C6H6
104–106
35 R=H128–129
36 R=Ac syrup
ꢀ98.3
ꢀ54.1
4.50
5.56
4.30
5.81
4.67
4.84
4.27
3.3
2.2
2.3
1.1
1.7
1.7
4.3
?
4.5
2.3
1.4
1.7
CDCl3
CDCl3
C6D6
5.74
[a] Optical-rotation values for the free diols in acetone, for the diacetates in CHCl3. [b] [a]D value at 24.58C.
and the conversion of this compound into the desired
dicarboxylate was instead effected by a TEMPO-catalyzed
oxidation with sodium hypochlorite,[11] to provide, upon
esterification with methanolic HCl, the dimethyl heptarate
18 in high yield. Subsequent protection of the hydroxy groups
at C3 and C4 through acetonide formation (!19), followed
by mesylation (!20), set the stage for the 5,6-elimination of
methanesulfonic acid, which was effected simply by briefly
exposing 20 to Al2O3/lutidine at 408C (!21). Finally, removal
of the isopropylidene group in 21 with aqueous trifluoroacetic
acid smoothly delivered the desired dimethyl d-ribo-hepte-
narate 22, which was acetylated to the di-O-acetyl derivative
23. Both 22 and 23 were isolated as syrups with high positive
optical-rotation values. Substantially smaller negative values
were observed for the Daucus carota derived product. As
distinct differences were also observed in the respective
1H NMR spectroscopic data (see Table 1), the d-ribo and l-
ribo stereochemistry for natural (ꢀ)-daucic acid can also be
excluded.
To finally unravel the stereochemistry of the natural
product—arabino or lyxo configurations were still possible—
we investigated a convergent synthetic pathway from b-d-
galactosyl cyanide 24,[12] under the premise that D2,3 (or D5,6)
unsaturation could be introduced selectively through an
elimination reaction if the 3-OH (or, alternatively, the 5-
OH) group in the C7-dicarboxylate 26 was converted into a
displaceable leaving group (Scheme 4). Indeed, this key
intermediate was prepared in a straightforward manner by
Scheme 3. Synthesis of the d-ribo-heptenarate 22 from d-mannose:
a) pyridine/Ac2O (1.3:1), 08C, 2 days,[10a] then Me3SiCN, BF3·Et2O,
CH3NO2, 358C, 2 h;[10b] b) aqueous HCl (25%), 508C, 24 h, then satu-
rated methanolic HCl, RT, 2 h, 85%; c) TEMPO/NaOCl, H2O/CH2Cl2,
08C, 20 h, then saturated methanolic HCl, RT, 2 h, 83%; d) Me2CO/
H2SO4, RT, 4 h, 75%; e) MsCl, pyridine, 08C, 3 h, 94%; f) basic Al2O3,
lutidine, 408C, 30 min, 75%; g) CHCl3/TFA/water (50:10:1), RT, 1 h,
86%; h) pyridine/Ac2O (2:1), RT, 5 h, 91%. TEMPO=2,2,6,6-tetrame-
thylpiperidinyl-1-oxyl, TFA=trifluoroacetic acid.
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Whereas 29 was obtained as a syrup, its diacetate 30 crystal-
lized well.
A similar sequence of reactions led from the isopropyli-
dene-protected dimethyl heptarate 31 to the corresponding d-
lyxo compounds 35 and 36. Mesylation (!33) and Al2O3/
lutidine-induced elimination gave 34, which was then exposed
to aqueous trifluoroacetic acid to remove the isopropylidene
group.
Unlike the l-arabino-heptenarates 29 and 30, whose
1H NMR spectroscopic data differed markedly from those
of the Daucus carota derived compounds,[2] the d-lyxo
analogues 35 and 36 showed almost perfect agreement, not
only in the sign and magnitude of their optical-rotation values,
but most notably in the chemical shifts and coupling patterns
in their 1H NMR spectra (Table 1). The slight deviations
observed in the coupling constants undoubtedly result from
the different field strengths (60[2] versus 300 MHz) and,
conceivably, from temperature differences. The temperature
affects the equilibrium between the respective half-chair
forms (5H6Q6H5) and hence the NMR coupling patterns
observed. This evidence is cogent enough to allow the
unambiguous assignment of the d-lyxo-configuration to
carrot-derived (ꢀ)-daucic acid.
The synthetic (ꢀ)-dimethyl daucate (35) could be sa-
ponified readily by exposure to aqueous trifluoroacetic acid
(4:1, 2days, 25 8C), to provide the free acid in crystalline form
(m.p. 87–888C, [a]2D0 = ꢀ85 in MeOH, 80%). More vigorous
acid conditions led to the pyran!furan rearrangement
observed previously for the natural product (Scheme 1):[2]
Heating 35 in methanolic HCl afforded dimethyl osbeckate
(5) (60%), whereas heating 35 in water in the presence of a
strongly acidic ion-exchange resin gave the free osbeckic acid
(6; 81%).
Scheme 4. Conversion of d-galactose into dimethyl heptenarates with
the l-arabino (29) and the d-lyxo configuration (35); the stereochemis-
try of 35 corresponds to that of natural (ꢀ)-daucic acid: a) NaOAc/
Ac2O, 1008C, 2 h,[12a] then Me3SiCN, BF3·Et2O in CH3NO2, 358C,
2 h,[12b] 79%; b) 1. NaOMe/MeOH, 2 h, RT; 2. NaOH (6n), 4 h, reflux;
3. saturated methanolic HCl, RT, 2 h, 85%; c) TEMPO/NaOCl, H2O/
CH2Cl2, 08C, 20 h, then saturated methanolic HCl, RT, 2 h, 76%;
d) Me2CO/H2SO4, RT, 4 h, 83%; e) CHCl3/TFA/water (50:10:1), RT,
30 min, then BzCl (1.2 equiv), pyridine, ꢀ408C, 2 h, then MsCl, pyri-
dine, RT, 3 h, 53%; f) saturated methanolic HCl, reflux, 24 h, 86%;
g) NaOMe (0.1n)/MeOH, 15 min, RT, 90%; h) pyridine/Ac2O (2:1),
RT, 14 h, 90%; i) MsCl, pyridine, 08C, 3 h, 85%; j) basic Al2O3, lutidine,
408C, 30 min, 74%; k) CHCl3/TFA/water (50:10:1), RT, 1 h, 83%.
base hydrolysis of 24,[12] esterification (!25), and TEMPO/
NaOCl oxidation in an overall yield of 51%. Attempts to
selectively benzoylate the equatorial OH groups in 26, a
protocol successful with its C2epimer 10 in the synthesis of 5-
O-mesylate 12, failed as a result of the distinctly different
reactivities of the hydroxy groups in 26 and 10. As an
alternate, albeit less direct route to the desired 3,4-di-O-
benzoyl-5-O-mesylheptarate 27, the 4,5-cis-diol in 26 was
protected through isopropylidenation (!31, the key inter-
mediate for the generation of the d-lyxo compounds; see
below), which was followed by benzoylation and acid
hydrolysis of the acetonide. The resulting 3-benzoate of 26,
unlike 26 itself, could be monobenzoylated readily at the 4-
OH at low temperature, and subsequent in situ mesylation
delivered 27 in a tolerable overall yield of 40% for the five
steps from 26. Introduction of the D5,6 unsaturation in the l-
arabino heptenarate 29 was effected by brief exposure of the
de-O-benzoylated heptarate 28 to NaOMe (0.1n)/MeOH.
Not only is the biosynthetic origin of (ꢀ)-daucic acid
intriguing—sedoheptulose 7-phosphate (37) and 3-deoxy-d-
arabino-heptulosonate 7-phosphate (DAHP, 38), both estab-
lished intermediates of the pentose phosphate and shikimic
acid pathways, respectively, are potential precursors—but
also its close structural relationship with chelidonic acid (4).
The elaboration of the g-pyrone system would merely require
oxidation of daucic acid at C4 and 5,6-elimination of water.
Studies on the biosynthesis of chelidonic acid with 14C-
labeled sugars have uniformly shown that d-glucose, and to an
even greater extent d-ribose, are incorporated well,[13,14]
whereas 37 is not.[13] Although the assumption that DAHP
(38) is therefore the likely precursor[14] persisted for 30 years,
it was convincingly disproved recently by quantitative carbon-
flux analyses of 13C-labeled sugars, which suggested a
biosynthetic assembly of chelidonic acid from one molecule
each of pentose phosphate and phosphoenolpyruvate (PEP;
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Unlike in Gram-negative bacteria,
in which the C8 chain of KDO 8-P is
incorporated into the lipopolysacchar-
ides of cell walls,[16] in this case the
terminal carbon is removed by dephos-
phorylation and oxidative decarboxy-
lation. Although only loss of water is
formally required from the resulting
intermediate 40 to give daucic acid, a
direct 3,2-elimination is unlikely—
“cells obey the laws of chemis-
try”[20]—as the hydrogen atom
involved (3-H) is not activated. As
activation is usually provided by a
vicinal carbonyl group—the conver-
sion of d-glucose into kojic acid by
Aspergillus oryzae has been rational-
ized on this basis[21]—the oxidation of
40 at C4 appears plausible as the next
step. Dehydration of the resulting
ketodicarboxylic acid 41 is thought to
proceed spontaneously to give the
dihydropyranone 42, a furcation point
towards these C7 dicarboxylic acids.
Daucic acid is formed from 42 by
reduction (42!43), chelidonic acid
by elimination of water (42!4), and
meconic acid, plentiful in Papavera-
Scheme 5. Possible mechanism for the biosynthesis of C7 dicarboxylic acids in plants from
common precursors. The suggestion is based on the identical configurations in the pyranoid
rings of daucic acid (43) and KDO 8-P (39), the conjecture that the generation of the structurally
similar daucic, chelidonic (4), and meconic acid (44) may occur via a common intermediate, and
on studies[15] on the biosynthesis of 4.
Scheme 5).[15] Such a biosynthetic process is well-established
for Gram-negative bacteria, in which PEP and d-arabinose 5-
phosphate (d-Ara 5-P), in turn generated from d-ribulose 5-
phosphate by isomerization, undergo an aldol-type conden-
sation to form 3-deoxy-d-manno-octulosonate 8-phosphate
(KDO 8-P, 39).[16,17] As the KDO 8-P synthase catalyzed aldol
addition proceeds with exclusive Si attack by PEP to the Re
face of the sugar carbonyl group, the 4R isomer is formed
stereospecifically, so that the product 39 has the d-manno
configuration.[18] The existence of such a KDO 8-P based
mechanism in plants has not yet been proved. However, the
fact that DAH 7-P synthase, a key enzyme of the shikimic acid
pathway[6] and abundant in higher plants, catalyzes the aldol
addition of PEP not only to its natural substrate d-erythrose
4-phosphate, but to d-ribose 5-phosphate (d-Rib 5-P) and d-
Ara 5-P as well,[19] may be regarded tentatively as evidence
that an octulosonate 8-phosphate based pathway is also
operative in plants.
Based on the newly established d-lyxo stereochemistry of
(ꢀ)-daucic acid (37 and 38 as precursors would lead to the d-
arabino configuration), on the conjecture that the biosyn-
thetic elaboration of daucic acid is closely related to that of
chelidonic (4) and meconic acid (44), and on available
evidence[15] about the biosynthesis of 4, a biosynthetic path-
way readily unfolds as depicted in Scheme 5: d-Ara 5-P and
PEP undergo an aldol-type condensation to KDO 8-P (39), in
which the stereochemistry of the pyranoid ring correlates with
the d-lyxo configuration of daucic acid. If d-Rib 5-P was
involved in the aldol addition step, the C8-sugar phosphate
would have the d-altro configuration, thus requiring an
(unnecessary) epimerization at a later stage.
ceae, by oxidation (42!44). The furanoid osbeckic acid is
likely to be formed from daucic acid through ring contraction
and double dehydration (43!6).
The alluring consistency of this proposed biosynthetic
pathway, particularly the configurational identity of KDO 8-P
and daucic acid in their pyranoid rings, clearly calls for the
systematic investigation of higher plants for the occurrence of
a C8-sugar-phosphate pathway with the possible intermedi-
ates 40–42, in particular in those species in which these C7
dicarboxylic acids have been detected: daucic acid in carrots,
sugar beets, wheat, sunflowers, and tobacco, osbeckic acid in
Osbeckia chinensis L., meconic acid in Papaveraceae, and
chelidonic acid in a plethora of plant families.
Received: August 25, 2003 [Z52718]
Published Online: November 18, 2003
Keywords: carbohydrates · chelidonic acid ·
configuration determination · daucic acid · osbeckic acid
.
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Chemie
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