Synthesis of pulvinic derivatives via TBAF-mediated regioselective opening of an unsymmetrical monoaromatic pulvinic dilactone

Article abstract of DOI:10.1021/jo801817s

(Chemical Equation Presented) The synthesis of the monoaromatic pulvinic dilactone 1 from a tetronic acid derivative is reported. The reaction of 1 with various amines was found to provide the two pulvinamides regioisomers 2a and 2b. Using tetrabutylammonium fluoride (TBAF) as an activator, pulvinamides 2a could be obtained with excellent regioselectivities and good yields. Additions of alcohols to 1 are also studied, leading to similar observations.

Full text of DOI:10.1021/jo801817s

Synthesis of Pulvinic Derivatives via
TBAF-Mediated Regioselective Opening of an
Unsymmetrical Monoaromatic Pulvinic Dilactone
FIGURE 1. Structure of pulvinic (R ) H) and vulpinic (R ) Me)
acids.
Damien Habrant,† Antoine Le Roux,† Ste´phane Poigny,‡
Ste´phane Meunier,*,† Alain Wagner,*,† and
Charles Mioskowski†,§
Laboratoire de Synthe`se Bio-Organique, CNRS-UMR
7175/LC1, Institut Gilbert Laustriat, Faculte´ de Pharmacie,
Illkirch, 67401 France, and Centre de Recherche et de
De´Veloppement Pierre Fabre Dermo-Cosme´tique, 17 Alle´e
Camille Soula, 31320 Vigoulet-Auzil, France
meunier@bioorga.u-strasbg.fr; wagner@bioorga.u-strasbg.fr
FIGURE 2. Reactivity of (a) diaromatic and (b) monoaromatic
dilactones toward nucleophiles (NuH ) H2O, ROH, RR′NH2).
ReceiVed August 14, 2008
SCHEME 1. Synthesis of Monoaromatic Dilactone 1
The synthesis of the monoaromatic pulvinic dilactone 1 from
a tetronic acid derivative is reported. The reaction of 1 with
various amines was found to provide the two pulvinamides
regioisomers 2a and 2b. Using tetrabutylammonium fluoride
(TBAF) as an activator, pulvinamides 2a could be obtained
with excellent regioselectivities and good yields. Additions
of alcohols to 1 are also studied, leading to similar
observations.
The syntheses of symmetrical (Ar ) Ar′) and unsymmetrical
(Ar * Ar′) pulvinic acids were recently the focus of a review
article.4 The pioneering work of Volhardt in 1894 allowed the
preparation of symmetrical pulvinic acids by hydrolysis or
methanolysis of a diaromatic dilactone (Figure 2a, Ar ) Ar′).5
This methodology was improved and extended to the synthesis
of unsymmetrical pulvinic acids by hydrolysis of diaromatic
dilactones (Figure 2a, Ar * Ar′).6 Nevertheless, the formation
of two pulvinic isomers is unavoidable, due to the similar
reactivity of the two carbonyls of dilactones used.
Toward the synthesis of monoaromatic type I and type II
compounds we thought of using a monoaromatic dilactone
(Figure 2b) as a highly advanced intermediate which could lead
in one step to both types of simplified pulvinic derivatives.
Moreover, we found that the reaction of nucleophiles on such
monophenyl dilactone can be tuned toward the selective
formation of type I adducts.
Pulvinic acids (Figure 1) constitute a family of fungi pigments
containing a γ-alkylidene butenolide ring system.1 Members
differ by the aryl groups, often hydroxylated or methoxylated.
Studies in our group demonstrated the antioxidant properties
of several pulvinic derivatives.2 The preparation of simplified
analogues, bearing only one aromatic substituent, could help
us elucidate the origin of the activity. For this purpose, the
preparation of derivatives of types I and II was investigated
(Figure 2b). To the best of our knowledge, one example of type
I product has been described in the literature with very poor
yields,3 and no example of type II product has been reported.
The synthesis of the selected dilactone 1 was achieved as
follows (Scheme 1). A condensation reaction between the
methoxy-protected 4-methoxyphenyl tetronic acid 37 and methyl
pyruvate provided 4 as a mixture of diastereomers (syn/anti:
* To whom correspondence should be addressed. Phone: +33(0)390244297.
Fax: +33(0)39024306.
† Institut Gilbert Laustriat.
‡ Pierre Fabre Dermo-Cosme´tique
§ Deceased June 2007.
(1) For reviews, see: (a) Gill, M.; Steglich, W. Prog. Chem. Org. Nat. Prod.
1987, 51, 1. (b) Rao, Y. S Chem. ReV. 1976, 76, 625.
(2) Meunier, S.; Hane´danian, M.; Desage-El Murr, M.; Nowaczyk, S.; LeGall,
T.; Pin, S.; Renault, J.-P.; Boquet, D.; Cre´minon, C.; Saint-Aman, E.; Valleix,
A.; Taran, F.; Mioskowski, C. ChemBioChem 2005, 6, 1234–1241.
(3) Weinstock, J.; Blank, J. E.; Hye-Ja, O.; Sutton, B. M. J. Org. Chem.
1979, 44, 673–675.
(4) Zografos, A. L.; Georgiadis, D. Synthesis 2006, 19, 3157–3188.
(5) Volhard, J. Justus Liebigs Ann. Chem. 1894, 282, 1–21.
(6) Akermark, B. Acta Chem. Scand. 1961, 15, 1695–1700.
9490 J. Org. Chem. 2008, 73, 9490–9493
10.1021/jo801817s CCC: $40.75 2008 American Chemical Society
Published on Web 11/13/2008

TABLE 1. Effect of Solvent and Temperature on the 9a/10a
Ratioa
TABLE 2. Effect of Additives on the 9a/10a Ratio
entry
additive (equiv)
solvent, T (°C)
9a/10a ratioa
entry
solvent
DCM
DCM
THF
THF
Et2O
acetone
DMF
EtOH
MeCN
hexane
T (°C)
9a/10a ratiob
1
2
3
4
5
6
7
8
PPh3 (0.2)
MeCN, rt
MeCN, rt
MeCN, rt
DCM, rt
MeCN, rt
MeCN, rt
MeCN, rt
DCM, rt
67/33
67/33
66/34
62/38
62/38
69/31
69/31
62/38
64/46
68/32
NaCN (0.2)
DABCO (0.2)
HMPA (0.2)
TMSOTf (0.2)
Ti(OiPr)4 (0.2)
Al(OtBu)3 (0.2)
Al(OtBu)3 (0.2)
Al(OtBu)3(0.2)
Al(OtBu)3 (0.2)
TBAF (2)
TBAF (0.2)
TBAF (1)
TBAF (2)
TBAF (1)
TBAF (2)
1
2
3
4
5
6
7
8
rt
-35
-35
-78
-35
-35
-35
-35
-35
-35
rt
55/45
62/38
66/34
65/35
59/41
67/33
59/41
61/39
69/31
9
DMF, rt
MeCN, -78
THF, rt
10
11
12
13
14
15
16
17
18
19
20
21
22
9
b
/
10
11c
12
13d
14
15
16e
THF, -78
73/27
84/16
86/14
87/13
98/2
76/24
75/25
70/30
68/32
68/32
64/36
70/30
63/37
70/30
67/33
66/34
64/36
THF, -78
H2O
[BMIM][BF4]
MeCN
MeCN
MeCN
5
rt
85
rt
THF, -78
THF, -35
THF, -35 to -78
THF, -35 to -78
THF, -35 to -78
THF, -35 to -78
THF, -35 to -78
THF, -35 to -78
THF, -35 to -78
TBACl (2)
TBACN (2)
TBAI (2)
TMAF (2)
KF (2)
rt
a Addition of 1 to a solution of 8a (1.3 equiv), 15 min of stirring at
the specified temperature, unless otherwise specified. b Determined by
integration in 1H NMR of the crude reaction mixture. c 20 equiv of 8a
was used. d 2.5 equiv of 8a and 48 h stirring were required to reach
completion. e Slow addition of a solution of 8a on 1.
CsF (2)
a Determined from the crude reaction mixture on 1H NMR spectrum.
b No trace of the desired products was observed.
1/1 by 1H NMR). Crude compound 4 was dehydrated8 to yield
alkene 5 as a 70/30 mixture of E and Z isomers (attributed by
NOESY experiments), which could be separated by chroma-
tography, but were typically engaged as a mixture in the next
step. Deprotection of the methyl enol ether of 5 using 1 equiv
of BBr3 was performed at 0 °C for 2 h.9 Some starting material
was recovered after this step, but longer reaction time led to
the partial deprotection of the aromatic methoxy group. Note-
worthy, both E and Z isomers led to a unique isomer of the
monoaromatic vulpinic acid derivative 6 (see the Supporting
Information). The corresponding acid derivative 7 was then
obtained in a quantitative yield by saponification. Finally,
treatment of 7 by acetic anhydride yielded the monoaromatic
dilactone 1. Incidentally, 6 and 7 were the first monoaromatic
type I adducts that we synthesized (Figure 2b). Activation of
acid 7 in the purpose of synthesizing other type I esters or
amides was found to lead exclusively to dilactone 1.
This interesting first result prompted us to optimize the
reaction conditions in the aim to improve the regioselectivity
of the nucleophilic attack. Decreasing of the temperature to -35
°C in DCM (Table 1, entry 2) slightly improved the 9a/10a
ratio. At low temperature, the screening of solvent showed only
minor changes in the ratio (Table 1, entries 2-9). Only hexane
did not allow the reaction (Table 1, entry 10). Neat (Table 1,
entry 11, rt) or aqueous conditions (Table 1, entry 12, 5 °C)
did not improve significantly the 9a/10a ratio, neither did the
use of ionic liquid (Table 1, entry 13, rt). Higher temperatures
(Table 1, entries 14 and 15) or inversion of the addition order
of reactants (Table 1, entry 16) have no effect. Nevertheless,
clean and total conversion of 1 was always observed after 15
1
min as shown by TLC and H NMR.
Then we considered the use of activators. For all reactions
compiled in Table 2, the additive was mixed with the dilactone
1 and dibutylamine 8a (1.3 equiv) was added dropwise. After
15 min at the specified temperature, 1 was always consumed
(by TLC), and reactions were worked up and analyzed by NMR.
The use 0.2 equiv of various Lewis bases (Table 2, entries 1-4)
or Lewis acids (Table 2, entries 5-7) had no effect on the
regioselectivity of the addition of 8a to 1.
Using Al(O-t-Bu)3, the change of solvent (Table 2, entries
8-10) or the reduction of the temperature (Table 2, entry 10)
did not affect the 9a/10a ratio. In the next assay, we found that
the use of 2 equiv of TBAF in THF (Table 2, entry 11) did not
provide the expected amides, but the type I monoaromatic
pulvinic acid derivative 7 instead in a quantitative yield. We
hypothesized that water (5%) present in the TBAF-THF
First, the reaction of 1 with dibutylamine 8a was studied in
different solvents and at different temperatures (Table 1). In
DCM at rt, 1 was consumed after 15 min and a mixture of type
I 9a and type II 10a adducts was obtained in a 55/45 ratio in
favor of type I. The two products could be separated by
chromatography on silica gel with a 86% global yield. Both
products show significant differences in aspect (9a being a
striking yellow solid, as usual pulvinic derivatives while 10a is
1
a pale yellow oil) and in H NMR spectra (see the Supporting
Information, aromatic protons).10
(7) (a) Campbell, A. C.; Maidment, M. S.; Pick, J. H.; Stevenson, D. F.
J. Chem. Soc., Perkin Trans. 1 1985, 1567–1576. (b) Mallinger, A.; Le Gall, T.;
Mioskowski, C. Synlett 2008, 386–388.
(8) Willis, C.; Bodio, E.; Bourdreux, Y.; Billaud, C.; Le Gall, T.; Mioskowski,
C. Tetrahedron Lett. 2007, 48, 6421–6424.
(9) Ahmed, Z.; Langer, P. Tetrahedron 2005, 61, 2055–2063.
(10) Foden, F. R.; Mc Cormick, J.; O’Mant, D. M. J. Med. Chem. 1975, 18,
199–203.
J. Org. Chem. Vol. 73, No. 23, 2008 9491

TABLE 3. Formation of Amides 9 and 10 from Dilactone 1
TABLE 4. Formation of Esters 12 and 13 from Dilactone 1
a Addition of 8 (1.3 equiv) to 1 at -78 °C, 15 min. b Addition of
TBAF (2 equiv) to 1 at -35 °C, then addition of 8 (1.3 equiv) at -78
°C, 15 min. c Isolated yield, using TBAF. d 2.5 equiv of amine was
used.
solution was responsible for the hydrolysis of the dilactone 1.
This hydrolysis reaction is triggered by TBAF (not observed in
pure water, Table 1, entry 11) and regiospecific. Since the
preparation of anhydrous TBAF is not straightforward (see
below; dried TBAF is reported to decompose by E2 elimination
at rt),11 for the ease of the procedure and to avoid the hydrolysis
side reaction we considered the use of a smaller quantity of the
commercially available TBAF-THF solution and/or lower
temperature. The addition of 0.2 equiv of TBAF to 1 at -78
°C prior to the addition of 8a yielded the expected amides in a
73/27 ratio (Table 2, entry 12) and prevented the hydrolysis of
1. An increase to 1 or 2 equiv of TBAF at -78 °C allowed the
ratio to raise to 85/15 approximately (Table 2, entries 13 and
14); a comparable ratio was obtained when the reaction was
performed at -35 °C (Table 2, entry 15). In each case, low
temperature avoided the hydrolysis of 1. Finally, using 2 equiv
of TBAF slowly added to dilactone 1 in THF at -35 °C,
followed by the addition of dibutylamine 8a at -78 °C and
stirring for 15 min (Table 3, entry 16), regioisomer 9a was
obtained almost exclusively. Entries 17-22 of Table 2 are
discussed at the end of this paper.
The optimized reaction conditions (Table 2, entry 16) were
then applied to various amines and compared to reactions
conducted in the absence of TBAF (Table 3). All experiments
were completed after 15 min at -78 °C, but great improvements
of the 9/10 ratio were observed when TBAF was used, affording
products 9 in good to excellent isolated yields. Secondary amines
showed slightly higher selectivity than the corresponding
primary amines (Table 3, entries 1 and 3 versus 2 and 4).
Morpholine (Table 3, entry 5) and propargylamine (Table 3,
entry 6) reacted with total regioselectivity and almost quantita-
tive yield. In the presence of TBAF, aniline reacted as well
regiospecifically (Table 3, entry 7), but only 25% of amide 9g
could be isolated since the hydrolysis adduct 7 was the major
a Except for entry 1, TBAF (or TBAF*) was added to a solution of 1
in THF at -35 °C, then addition of 11, 15 min. b Determined by
integration in 1H NMR of the crude reaction mixture. c Isolated yield.
d i-PrOH was used as solvent. e Product not isolated.
product of the reaction. As a weaker nucleophile, aniline
probably could not compete with water (contained in the
TBAF-THF solution) as efficiently as previous alkylamines.
Surprisingly, without TBAF, aniline afforded a fairly good 9/10
ratio, and 9g could be isolated in 78% yield. Finally, only amides
were obtained when amino alcohols were used, demonstrating
the chemoselectivity of the reaction (Table 3, entries 8 and 9).
Then the additions of alcohols to 1 were studied. In the
absence of activating agent isopropyl alcohol 11a, even used
as the solvent, did not react with 1 at room temperature.
Refluxing 1 in 11a overnight resulted in quantitative lactone
opening with low type I/type II selectivity (Table 4, entry 1).
Using TBAF with 11a, the lactone opening was found to be
very regioselective since only type I, ester 12 or acid 7, adducts
were obtained (Table 4, entries 2-6). With 1 equiv of 11a and
TBAF at -35 °C, the lactone-opening reaction was complete
after 15 min and very regioselective, but the hydrolysis product
7 was formed in the reaction mixture (Table 4, entry 2). As
hypothesized earlier, formation of 7 could be due to a side
reaction with water contained in the TBAF-THF solution;
indeed the use of 2 equiv of the activator solution increased
the proportion of 7 (Table 4, entry 3), whereas the use of an
excess of alcohol 11a reduced it (Table 4, entry 4). Addition of
activated molecular sieves did not avoid the formation of 7
(Table 4, entry 5). Using the commercially available TBAF-THF
solution, our best result was obtained by adding the activator
(2 equiv) at -35 °C and then 11a (10 equiv) at -78 °C for 15
min: specific formation of ester 12a, isolated in 83% yield (Table
4, entry 6). Excess of i-PrOH was evaporated, but this protocol
is not convenient for less volatile alcohols.
(11) (a) Sharma, R. K.; Fry, J. L. J. Org. Chem. 1983, 48, 2112–2114. (b)
Cox, D. P.; Terpinski, J.; Lawrynowicz, W. J. Org. Chem. 1984, 49, 3216–
3219.
9492 J. Org. Chem. Vol. 73, No. 23, 2008

To design an alternative protocol that could prevent the
hydrolysis side reaction anhydrous TBAF was prepared. The
recently reported procedure by DiMagno et al. was applied to
produce anhydrous TBAF (noted TBAF*).12 Using this activator
and the optimized reaction conditions for amines, the addition
of i-PrOH 11a was found to be slightly less selective since 5%
of type II ester 13a was detected by NMR (Table 4, entry 7),
but the ester 12a could be isolated with a good yield (69%)
and the formation of 7 was avoided. The same protocol was
applied to benzyl alcohol 11b, dodecyl alcohol 11c and solketal
11d which showed comparable reactivity and furnished the
corresponding esters 12b-d in good yields (Table 4, entries
8-10). In each case, the use of anhydrous TBAF* prevented
the hydrolysis side reaction leading to 7.
In regard of the mechanism of the reaction with TBAF, we
first envisaged the formation of an acid fluoride intermediate
by the regioselective addition of a fluoride anion on 1. With
the goal to detect such an intermediate, 1 equiv of 1 was mixed
with 2 equiv of TBAF in THF-d8 at -35 °C, and the resulting
solution was analyzed by 19F NMR (200 MHz) at low
temperature (-20, -35, and -78 °C); unfortunately, no peak
was observed that could be related to an acid fluoride (charac-
teristic chemical shift in the range 20-50 ppm).13 Thus, if an
acid fluoride is formed, this intermediate is probably unstable,
has a short lifetime, and reverts to the dilactone 1 in the absence
of a nucleophile. Interestingly, variations of the anion or the
cation of the activator alter a lot the regioselectivity of the
reaction. The larger and more polarizable the anion is, the lower
is the regioselectivity for the addition of 8a on 1 (Table 2, entries
16-19). On the other hand, changing tetrabutylammonium for
a smaller and more coordinating cation alters as well the
nucleophile addition regioselectivity (Table 2, entries 20-22).
It is noteworthy that in all experiments the total conversion of
1 into pulvinamides 9a and 10a was observed. It appears that
a high reactivity of the activator system leads to a high
regioselectivity. This observation, as well as our NMR experi-
ment, does not provide a clear explanation for the striking jump
in regioselectivity observed. Nevertheless, two hypotheses seem
to prevail: the direct reaction of fluoride on 1 that would lead
preferentially to a very reactive type I acid fluoride or the
activation of the nucleophile by fluoride acting as a strong
H-bond acceptor and able to modulate the outcome of the
reaction. The Table 4 results showing a variation in the
selectivity according to the alcohol used (entries 6-10) would
support the second hypothesis, whereas the Table 3 results
showing small selectivity variation when diverse amines were
used support either the first hypothesis or second hypothesis if
the H-bond acceptor effect is very high and equivalent for all
substrates.
In conclusion, the preparation of a monoaromatic pulvinic
dilactone 1 was described. It was found that TBAF was an
efficient activator for the regioselective ring opening of 1 by
amines and alcohols. Our methodology allowed the preparation
of 13 unsymmetrical and monoaromatic pulvinic acid derivatives
that are currently tested for their antioxidant capacities. The
study of the addition of other nucleophiles on 1 and the
preparation of type II monoaromatic derivatives (Figure 2b) are
in progress and will be reported in due course.
Experimental Section
General Procedure for the Regioselective Ring Opening of
Dilactone 1 with Amines. To a solution of dilactone 1 (1 equiv)
in 1.5 mL of THF was slowly added a solution of TBAF (1 M
solution in THF, 2 equiv) at -35 °C. The mixture was stirred for
15 min and then cooled to -78 °C. A solution of amine (1.3-2.5
equiv) in 1 mL of THF was added. After 15 min of stirring at -78
°C, the reaction was completed and the mixture was allowed to
warm to room temperature. After concentration in vacuo, the crude
residue was purified by chromatography on silica gel. Data for
9a: prepared from 1 (19.7 mg, 0.08 mmol) and 8a (9.7 µL, 0.10
mmol) and purified by flash chromatography (CH2Cl2/MeOH: 95/
5) as a yellow solid (31.0 mg, 94%): mp 86-87 °C; 1H NMR (300
MHz, CDCl3) δ 11.3 (brs, 1H), 8.04 (d, J ) 9.0 Hz, 2H), 6.93 (d,
J ) 9.0 Hz, 2H), 3.82 (s, 3H), 3.38 (t, J ) 7.6 Hz, 4H), 2.13 (s,
3H), 1.68-1.53 (m, 4H), 1.38-1.24 (m, 4H), 0.94 (t, J ) 7.1 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 172.1, 167.2, 162.0, 159.2,
159.1, 148.6, 129.1; 122.1, 114.3, 113.9, 104.2, 55.3, 47.6, 29.9,
20.1, 16.2, 13.8; IR 2959, 2932, 2871, 2837, 1759, 1604, 1537,
1432, 1249, 1094, 1072, 827 cm-1; HRMS (ES, pos) calcd for
C22H30NO5 [M + H]+ 388.2118, found 388.2144. Data for 9c:
prepared from 1 (20.2 mg, 0.08 mmol) and 8c (70 mg, 0.19 mmol)
and purified by flash chromatography (CH2Cl2/Et2O: 90/10) as a
yellow solid (38.2 mg, 80%): mp 48-49 °C; 1H NMR (300 MHz,
CDCl3) δ 11.26 (s, 1H), 8.05 (d, J ) 8.9 Hz, 2H), 6.94 (d, J ) 8.9
Hz, 2H), 3.83 (s, 3H), 3.38 (t, J ) 9.0 Hz, 4H), 2.17 (s, 3H),
1.62-1.60 (m, 4H), 1.29-1.24 (m, 36H), 0.88 (t, J ) 6.0 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 172.2, 167.2, 159.2, 159.1, 148.8,
129.1, 122.2, 114.3, 113.9, 104.2, 55.4, 47.9, 32.0, 29.8, 29.7, 29.5,
29.4, 27.9, 26.9, 22.8, 16.3, 14.3; IR 2921, 2850, 1769, 1468, 1454,
1250, 1182, 1079, 828 cm-1; HRMS (ES, pos) calcd for C38H62NO5
[M + H]+ 612.4623, found 612.4631.
Acknowledgment. This work was supported by the Centre
National de la Recherche Scientifique, Laboratoires Pierre Fabre
Dermo-Cosme´tique, and De´le´gation Ge´ne´rale pour l’Armement.
We are grateful to Cyril Antheaume for helpful NMR elucidations.
Supporting Information Available: General information,
analytical data, and 1H and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050–2051.
(13) (a) Lu, C.; DesMarteau, D. D. J. Fluor. Chem. 2007, 128, 832–838. (b)
Cohen, O.; Sasson, R.; Rozen, S. J. Fluor. Chem. 2006, 127, 433–43.
JO801817S
J. Org. Chem. Vol. 73, No. 23, 2008 9493