A synthetic route to α-substituted butenolides: Enantioselective synthesis of (+)-ancepsenolide

Article abstract of DOI:10.1002/ejoc.201100491

A variety of α-substituted butenolides was efficiently synthesized starting from commercially available tetronic acid and carboxylic acids in four steps. The effectiveness of this approach is illustrated in the short synthesis of one of the first butenoli

Full text of DOI:10.1002/ejoc.201100491

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100491
A Synthetic Route to α-Substituted Butenolides: Enantioselective Synthesis of
(+)-Ancepsenolide
Cynthia Ghobril,[a] Jérémy Kister,[a] and Rachid Baati*[a]
Keywords: Total synthesis / Asymmetric synthesis / Butenolides / Vinyl triflate / Reduction
A variety of α-substituted butenolides was efficiently synthe-
sized starting from commercially available tetronic acid and
carboxylic acids in four steps. The effectiveness of this ap-
proach is illustrated in the short synthesis of one of the first
butenolide acetogenins: (+)-ancepsenolide.
Introduction
Results and Discussion
The α-alkylbutenolide substructure is found in a variety
of natural products and other biologically active com-
pounds such as pinusolide, gomphostinin, annomolon A,
and several gorgonian lipids.[1] Typical of these derivatives
is a high incidence of biological activity including anti-
biotic, antiviral, antineoplastic, and anticoagulant effects.[2]
In addition, α-substituted butenolides are valuable interme-
diates in the synthesis of other important targets, including
a host of antimicrobial and herbicidal lactones.[1a] Given
their prevalence in nature and as synthetic intermediates,
many methods have been developed for their de novo prep-
aration[3] from both acyclic and oxacyclic precursors.[1a]
This note describes a new and practical four-step procedure
to α-substituted butenolides starting from readily available
tetronic acid (1; Scheme 1).
The first step of our strategy consists in the initial C(3)
acylation of 1 with carboxylic acid 2, followed by in situ
regioselective ketone reduction to afford α-alkylated te-
tronic acids 3. Subsequent enol activation with triflic anhy-
dride and palladium-catalyzed reduction of the resulting
enol triflate leads to α-substituted butenolides 5 in good
overall yield of 30–35% over four steps. To date, three meth-
ods have been reported for the C(3) acylation of tetronic
acids: (i) Stepwise Lewis acid catalyzed 4-(O)-acylation with
acyl chloride followed by a Fries rearrangement.[4] (ii) Di-
rect lithiation of O-methyltetronic acids at C(3) (with LDA)
or Br/Li exchange followed by reaction with acyl donors.[5]
(iii) In situ O-acylation using carboxylic acids followed by a
Fries rearrangement under basic catalysis conditions (Et3N/
DMAP/DCC).[6]
Although the former Friedel–Crafts reaction has been
widely used to synthesize tetronic acids such as carolic ac-
id,[4c] this technique is apparently not suitable for substrates
having sensitive functional groups. As a consequence, the
reported yields are low to moderate.[4b–4g] The second
method, which uses O-alkyltetronic acids, requires a
hydroxy group protection–deprotection sequence and af-
fords usually variable yields for the acylation step.[5] On the
other hand, the third method reported by Yoshii et al. al-
lows a one-pot C(3) acylation procedure involving a
DMAP-mediated Fries rearrangement of the kinetic O-
acylation product, with very good yields (55–94%). We
therefore decided to apply this sequence for the acylation of
tetronic acid with commercially available carboxylic acids 2
(Table 1). The C(3)-acylated tetronic acid intermediates
were then directly reduced in situ by using sodium cyano-
borohydride to afford α-substituted tetronic acids 3a–g in
good yields (50–80% over two steps; Table 1), except when
2f was used (Table 1, Entry 6). In this particular case, the
methyl ketone function was also reduced under the same
conditions to give the corresponding alcohol.
Scheme 1. New synthetic route to α-substituted butenolides 5.
[a] Université de Strasbourg, Faculté de Pharmacie, CNRS/UMR
7199, Laboratoire des Systèmes Chimiques Fonctionnels,
74 route du rhin, B. P. 60024, 67401 Illkirch, France
Fax: +33-3-68854306
E-mail: baati@bioorga.u-strasbg.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100491.
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Eur. J. Org. Chem. 2011, 3416–3419

Enantioselective Synthesis of (+)-Ancepsenolide
Table 1. One-pot C(3) acylation of tetronic acid (1) with carboxylic
acid 2 and ketone reduction.
Table 2. Synthesis of triflate butenolides 4.
Entry Substrate
R
Product
Yield [%][a]
1
2
3
4
5
6
3a
3b
3c
3d
3e
3g
(CH2)2Ph
4a
4b
4c
4d
4e
4g
74
67
75
72
70
73
Entry Substrate
R
Product
Yield [%][a]
CH2CH=CHCH3
(CH2)2CϵCH
CH2OCH2Ph
CH2(CH2)2CO2Me
CH2(CH2)2CϵCH
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
(CH2)2Ph
3a
3b
3c
3d
3e
3f
56
60
50
62
71
0
CH2CH=CHCH3
(CH2)2CϵCH
CH2OCH2Ph
CH2(CH2)2CO2Me
CH2(CH2)2COMe
CH2(CH2)2CϵCH
[a] Isolated yield.
2g
3g
80
in only trace amounts along with decomposed side prod-
ucts, even though the conversion of 4a was complete after
12 h. The same reaction conducted with the following sys-
tem Pd2(dba)3/PPh3/Bu3SnH in THF at room tempera-
ture[7a] increased the yield of 5a up to 42% after 12 h. Fi-
nally, when increasing the amount of Bu3SnH up to 2 equiv.
and the reaction temperature to 50 °C in THF, the desired
compound was obtained in a satisfactory 84% yield after
4 h (Table 3, Entry 1).
[a] Isolated yield.
Our next goal was to validate the reduction of the C(4)
hydroxy group that is usually catalyzed with palladium, a
transformation only reported with C(4)-iodo- and C(4)-bro-
mobutenolide derivatives.[7]
Thus, we first tested enol function activation with model
butenolide substrate 3a by substituting the hydroxy group
with an iodide or a bromide group. We investigated the sub-
stitution by using iodine and triphenylphosphane in ben-
zene at room temperature for 24 h.[8] Unfortunately, the de-
sired iodobutenolide derivative was not obtained, and start-
ing material 3a was recovered unchanged after a reaction
time of 24 h. The use of oxalyl bromide reported to substi-
tute efficiently the OH function of butenolides by a bromine
atom[9] gave the expected bromobutenolide only in a poor
yield (20%) along with an unidentified major compound.
In conclusion, bromination or iodination conditions re-
ported in the literature were not suitable in the case of our
C(3)-substituted butenolide.
Table 3. Palladium catalyzed reduction of triflate butenolides 4.
Finally, we tested the activation of the enol function by
preparing the corresponding enol triflates upon treatment
with triflic anhydride, a reaction previously reported for
butenolides.[10] These conditions were efficient for 3a and
allowed the formation of desired compound 4a in 74% of
isolated yield after a reaction time of 1 h (Table 2, Entry 1).
Thus, these conditions were then applied to all tetronic
[a] Isolated yield.
We then applied these optimized conditions to butenol-
acids 3b–e and 3g synthesized in this study, and triflate but- ide derivatives 4b–e and 4g bearing sensitive groups such as
enolides 4a–e and 4g were formed in good yields (67–75%, an (E)-disubstituted alkene (i.e., 4b), a terminal alkyne (i.e.,
Table 2).
4c and 4g), a benzyloxy group (i.e., 4d), and an ester func-
With these molecules in hand, we then studied the metal- tion (i.e., 4e) to evaluate the scope and limitations of the
catalyzed reduction step. To the best of our knowledge, the methodology. The results are summarized in Table 3. As
palladium-catalyzed reductions of the enol triflate function mentioned earlier, the reduction of nonfunctionalized but-
of C4-(OTf)-butenolides has no literature precedent. How- enolide 4a was effective and led to the expected alkylated
ever, it is well known and documented that vinylic and aro- butenolide 5a in 84% yield (Table 3, Entry 1). Under the
matic triflates can be efficiently reduced in the presence of same reductive experimental conditions [Pd2(dba)3/PPh3/
palladium catalysts and hydride sources.[11] We first tried Bu3SnH], substrates 4b, 4d, and 4e were compatible and
the reported conditions for the reduction of triflate butenol- the respective α-alkylated butenolides 5b, 5d, and 5e were
ide 4a by using Pd(PPh3)4 as catalyst, LiCl as additive, and obtained in good yields (Table 3, Entries 2, 4, and 5). We
Bu3SnH as reducing agent in THF under reflux condi- did not observe any trace amounts of over-reduced prod-
tions.[12] However, α-substituted butenolide 5a was obtained ucts or any isomerized side compounds. The use of func-
Eur. J. Org. Chem. 2011, 3416–3419
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C. Ghobril, J. Kister, R. Baati
SHORT COMMUNICATION
tionalized substrates with terminal alkynes 4c and 4g did 0.4, CHCl3)} in an increased 50% yield (method B). It is
not afford desired products 5c and 5g. Indeed, when triflate noteworthy to point out that the conditions of method B
butenolide 4c was subjected to the reductive conditions, 6- are suitable for large-scale synthesis because of the use of
exo-dig-cyclized product 6 was isolated instead in 45% yield PMHS, a nontoxic and cheap hydride source.
(Table 3, Entry 3). The same conditions applied to triflate
butenolide 4g gave a complex mixture of products difficult
to identify (Table 3, Entry 6). As a preliminary conclusion,
four α-substituted butenolides (i.e., 5a, 5b, 5d, and 5e) were
synthesized in a four-step procedure with good overall
Conclusions
To conclude, a general and efficient four-step protocol
for synthesizing α-substituted butenolides has been devel-
yields by using the novel reducing conditions for the ex-
oped. Furthermore, the effectiveness of this route was dem-
cision of the enol triflate function.
onstrated by the efficient short synthesis of (+)-ancepsenol-
ide (11; six steps, 8% overall yield).
To further illustrate the usefulness of this chemistry, (+)-
ancepsenolide was chosen as a target. This compound rep-
resents one of the first butenolide acetogenins,[13] plant me-
tabolites that have shown interesting antitumoral, antima-
larial, immunosuppressive, as well as pesticidal activities.[14]
To date, two enantioselective syntheses of (+)-ancepsenolide
have been reported by Trost et al. in 1994[13] and by Iriye
et al. in 2001.[15]
Experimental Section
General Method for the Synthesis of α-Alkylated Butenolides 5a–
e: To a suspension of tetronic acid (10 mmol), carboxylic acid 2
(11 mmol), 4-DMAP (3 mmol), and DCC (12 mmol) in dichloro-
methane (25 mL) was added DIPEA (11 mmol) at 0 °C. The reac-
tion mixture was stirred at room temperature overnight. The solu-
tion was then filtered, and the solid was washed with CH2Cl2. The
filtrate was concentrated, and the residue was taken up in EtOAc.
The organic phase was washed with a solution of 1 n HCl followed
by a saturated solution of NaCl, then dried with magnesium sul-
fate, filtered, and concentrated in vacuo to yield a brownish solid
that was used directly in the reduction step. The crude was dis-
solved in acetic acid (25 mL) and NaBH3CN (20 mmol) was added
portionwise at 10 °C. The reaction mixture was stirred for 4 h at
room temperature and then poured into a solution of 1 n HCl. The
aqueous phase was extracted with EtOAc. The collected organic
phases were washed with H2O and brine, dried (MgSO4), filtered,
and concentrated in vacuo. The crude was purified by flash
chromatography to yield compound 3. To a solution of compound
3 (2.33 mmol) in dichloromethane (8 mL) was added DIPEA
(3.49 mmol) at room temperature. The reaction was cooled to
–78 °C and triflic anhydride (2.79 mmol) was added dropwise. The
reaction was stirred for 1 h at –78 °C and then CH2Cl2 was added.
The organic phase was washed with 1 n HCl, H2O, and brine, dried
with magnesium sulfate, filtered, and concentrated in vacuo. The
crude was then purified by flash chromatography to afford com-
pound 4.
Our route to (+)-ancepsenolide (11) started with the acyl-
ation of commercially available (S)-ethyl lactate as reported
in the literature[16] (Scheme 2). Lactonization of 7 provided
key building block 8 in excellent yield.[17] Subsequent C(3)
acylation with commercially available dicarboxylic acid 2h
and in situ reduction afforded butenolide 9 {[α]2D0 = +45.68
(c = 0.43, DMSO)}, which was activated with triflic anhy-
dride to deliver butenolide 10. Finally, palladium-catalyzed
reduction of the enol triflate under the conditions of
method A gave (+)-ancepsenolide (11) in only 20% of yield.
This result prompted us to test other reductive conditions
on model substrate 4a to improve the yield of the isolated
product.[18] Finally, we found that the use of poly(methylhy-
drosiloxane) (PMHS) as reducing agent with Pd(OAc)2/
dppp in DMF at 60 °C for 24 h allowed the isolation of 11
{[α]D20 = +45.53 (c = 0.43, CHCl3), ref.[13] [α] = +39.6 (c =
Reduction Procedure Using Pd2(dba)3/PPh3/Bu3SnH as Reductive
Agent (Method A): A suspension of Pd2(dba)3 (0.01 mmol) and
PPh3 (0.1 mmol) in THF (4 mL) was stirred at room temperature
(green color). After 5 min, a solution of compound 4 (0.7 mmol)
in THF (3 mL) was added followed by Bu3SnH (1.4 mmol) (brown
color). The reaction mixture was heated at 50 °C for 4 h (black
color), then cooled to room temperature and poured on H2O. The
aqueous phase was extracted with diethyl ether. The collected or-
ganic phases were washed with a saturated solution of NaCl, dried
with magnesium sulfate, filtered, and concentrated in vacuo. The
crude was purified by flash chromatography using silica gel + 5%
KF to afford compound 5.
Scheme 2. Synthesis of (+)-ancepsenolide (11). Reagents and condi-
tions: (a) pyridine, acetic anhydride, r.t., 24 h (70%); (b) LiHMDS,
THF, –78 °C, 2 h (91%); (c) 1. HO2C(CH2)10CO2H (2h), DCC,
DMAP, DIPEA, CH2Cl2, r.t., 16 h; 2. NaBH3CN, CH3CO2H, r.t.,
2 h (50% over two steps); (d) Tf2O, DIPEA, CH2Cl2, –78 °C, 1 h
(50%); (e) Method A: Pd2(dba)3, PPh3, Bu3SnH, THF, 50 °C, 4 h
(20%); Method B: Pd(OAc)2, dppp, PMHS, DMF, 60 °C, 24 h
(50%).
Reduction Procedure using Pd(OAc)2/dppp/(TES)H or Pd(OAc)2/
dppp/(TMS)3SiH or Pd(OAc)2/dppp/PMHS as Reductive Agent
(Method B): To a solution of 4 (1 equiv.), Pd(OAc)2 (0.05 equiv.),
and dppp (0.05 equiv.) in DMF (0.2 m) at 60 °C was added (TES)
H (2.5 equiv.) or (TMS)3SiH (2.5 equiv.) or PMHS (2.5 equiv.). The
stirring was continued for the designated time. After dilution with
ether, the mixture was successively washed with water, a saturated
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Enantioselective Synthesis of (+)-Ancepsenolide
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(MgSO4), filtered, and concentrated in vacuo. The crude was puri-
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compound 5.
Supporting Information (see footnote on the first page of this arti-
cle): General remarks, compound characterization data, and NMR
spectra of all products.
Acknowledgments
This work was supported by the Ministère Délégué à l’Enseigne-
ment Supérieur et à la Recherche (Grant to C. G. and J. K.).
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Pd(OAc)2/PPh3/HCO2H/Et3N, DMF, 40 °C, 5 h (5a obtained
in 94% of yield); Pd(OAc)2/dppp/(TES)H, DMF, 60 °C, 5 h
(5a, 52%); Pd(OAc)2/dppp/(TMS)3SiH, DMF, 60 °C, 5 h (5a,
40%); Pd(OAc)2/dppp/(TMS)3SiH, DMF, 60 °C, 24 h (5a,
44%); Pd(OAc)2/dppp/PMHS, DMF, 60 °C, 5 h (5a, 57%);
Pd(OAc)2/dppp/PMHS, DMF, 60 °C, 24 h (5a, quant.). The
last conditions afforded desired reduced compound 5a in quan-
titative yield. These conditions were then applied to butenolide
10 in the last step of the synthesis of (+)-ancepsenolide (11).
Received: April 7, 2011
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Published Online: May 18, 2011
Eur. J. Org. Chem. 2011, 3416–3419
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