R. Cincinelli et al. / Tetrahedron Letters 52 (2011) 5972–5975
5973
recovery of starting material. Thus, we planned to use (ꢁ)-menthol
as a chiral auxiliary for the asymmetric reduction of -oxo ester.
OAc
4'
H
N
1
OH
a
2
2'
O
3
Compound 3 was obtained by reacting benzaldehyde with pyruvic
3'
O
acid enolate in methanol, followed by acidification with HCl.8 The
1
treatment with
menthol afforded compound 4, that was reduced to
a
,
a
-dichloromethyl methyl ether, TEA and (ꢁ)-
a
-hydroxyes-
Figure 1. Structure of compound 1.
ter 5 (Scheme 1). Very high diastereoselectivity was achieved with
-selectride9 in diethylether at ꢁ78 °C (% de: 97%, determined by
A broad signal that overlapped the olefinic signal at 6.77 ppm,
integrating for one proton, was present in the 1H NMR spectrum.
The absence of any carbon corresponding to this hydrogen in the
HMBC experiment, along with the disappearance of this signal in
the 1H spectrum after exchange with D2O and trifluoroacetic acid,
led us to hypothesize the presence of an amidic bond. In addition,
the analysis of the COSY spectrum showed that the NH group was
coupled with a methylene resonating at 3.60 ppm. (d C 34.9), on its
turn coupled with a second methylene group resonating as a triplet
(J = 5.9 Hz) at 2.66 ppm. The chemical shift and the multiplicity of
this signal suggested that it was linked to a carbonyl group.
The most upfield signal in the 1H spectrum was a singlet at
2.22 ppm, corresponding to a methyl group. Examination of HMBC
and HSQC spectra showed that this methyl resonated at 21.3 ppm
and was close to the carbonyl at 169.6 ppm, thus corroborating the
presence of an acetyl group.
Upon rationalizing the above data we established that the three
carbonyl groups at 168.6, 169.6, and 175.6 ppm corresponded to
an amide, to an acetyl group, and to a carboxylic acid, respectively.
Theaboveinformationallowedthestructureassignmentasdepicted
in Figure 1. The structure was supported by the ESI mass spectra. In-
deed, the ESI positive mass spectrum showed peaks at 314.0997
[M+Na]+, 627.1959 [2M+1]+, and 649.1779 [2M+3Naꢁ2]+ m/z, while
the ESI negative spectrum showed a peak at 290.1024 [Mꢁ1]ꢁ m/z.
Compound 1 is the amide of a substituted glycolic acid with b-
alanine. This appears to be a remarkable occurrence, as, to the best
of our knowledge, the only other example of this kind of product in
plants is the well-known pantothenic acid (vitamin B5),4a the
essential precursor to CoA.4b As several analogues of this metabo-
lite have been demonstrated to exert an antimicrobial effect
against a range of microorganisms,4c evaluation of biological activ-
ity of compound 1 is in progress.
L
300 MHz 1H NMR). However, hydrolysis of the ester to remove
the chiral auxiliary under basic conditions (LiOH, THF) gave partial
racemization (determined by comparison of optical rotation with
that reported in the literature5) whereas under acidic conditions,
(HCl 37% in dioxane, reflux) the isomerized product 610 was
formed. Thus, we turned back to compound 3. An enantioselective
reduction of this ketoacid was performed using a chiral complex
NaBH4-
lute configuration (R) and the enantiomeric excess (92%) of the
L
-proline, prepared as described by Schmutzler.11 The abso-
a
-
hydroxy acid 7 were determined by comparison with the optical
rotation of (R)-2-hydroxy-4-phenylbut-3-enoic acid obtained by
enzymatic resolution.5 Acetylation of (R)-7 performed either with
Ac2O/Py at 0 °C or with AcCl in THF gave partial racemization, con-
firming the sensitivity of this
a-hydroxy acid to acidic and basic
conditions. Finally, it was found that treatment with AcCl as a sol-
vent at room temperature12 gave the desired acetylated compound
without the loss of optical purity. This was condensed with 3-ami-
no-1-propanol at room temperature13 to give compound 9 in good
yield. Oxidation of 9 with Jones reagent14 at 0–5 °C afforded acid 1
in 56% yield and 75% ee. The spectroscopic properties and the sign
of optical rotation matched with those found for the natural com-
pound. As the absolute configuration at C-2 in 7 is (R) and during
the following steps no inversion of configuration occurs, we may
safely deduce that the absolute configuration of the natural com-
pound must be (R). Chiral HPLC analysis15 showed two peaks at
tR = 34.0 min and at tR = 49.2 min. HPLC analysis of the natural
sample using the same conditions showed a single peak at
tR = 34.7 min.
Compound 10 was isolated as a yellow powder, mp 173 °C; ½a D25
ꢀ
ꢁ16.9 (c 0.1, ethanol); 1H and 13C NMR spectra disclosed signals
and correlations for 43 C and 36 H atoms, ten of which were ex-
changed with D2O (Table 2).
To unambiguously confirm the proposed structure, a total enan-
tioselective synthesis of 1 was carried out (Scheme 1). For the syn-
thesis of enantiomerically pure 2-hydroxy-4-phenylbut-3-enoic
acid or close derivatives, numerous strategies have been devised,
including enzymatic resolution of esters5 and diastereoselective
The 13C NMR spectrum revealed two signals at 182.0 and
182.06 ppm, suggesting the presence of two
a,b-unsaturated car-
bonyl groups, whereas the presence of a signal at 170.3 ppm, led
to hypothesize the presence of a carboxylic acid, confirmed by
the solubility in aqueous sodium bicarbonate.
reduction of
a
-oxo esters6 or amides7 using chiral auxiliaries. A
first attempt to prepare E-2-oxo-4-phenylbut-3-enoic acid
The presence of aromatic rings was clearly deduced from a set
following a reported enzymatic resolution5 failed, giving only the
of signals in the region between 7.95 and 6.46 ppm in the 1H
O
O
OH
CHO
a,b
O
c
d
O
COOH
O
O
3
4
2
5
e
f
g
OH
OH
COOH
OH
OH
OH
O
O
7
6
(R)-7
OAc
h
OAc
O
OAc
O
H
H
N
l
N
i
COOH
CH2OH
COOH
(R)-1
(R)-8
(R)-9
Scheme 1. Synthesis of compound 1. Reagents and conditions: (a) Pyruvic acid, KOH, MeOH, 30 °C, 1 h, 70%; (b) HCl 1.6 M, 60%; (c)
1 h, then (ꢁ)-menthol, TEA, CH2Cl2, rt, overnight, 61% (d) -selectride, Et2O, ꢁ78 °C, 1 h, 76%; (e) HCl 32%, dioxane, reflux, 6 h, 29%; (f) LiOH, THF, 60 °C, 4 h, 60%; (g) NaBH4-
proline, dry THF, rt, 24 h, 84%; (h) AcCl, rt, 2 h, 82%; (i) 3-amino-1-propanol, WSC, HOBt, dry THF, rt, overnight, 74%; (j) Jones reagent, acetone, 0 °C, 1 h, 56%.
a,a-dichloromethyl methyl ether, 50 °C,
L
L-