Synthesis of highly substituted γ-hydroxybutenolides through the annulation of keto acids with alkynes and subsequent hydroxyl transposition

Article abstract of DOI:10.1039/c6cc01554a

An efficient synthesis of highly functionalized γ-hydroxybutenolides through BF₃-catalyzed annulation of keto acids with alkynes is described. Many advantages such as the use of routine reagents, easy operation, and a 100% atom efficiency are demonstrated in the method. The reaction can be readily scaled up to gram quantities, offering good practicality.

Full text of DOI:10.1039/c6cc01554a

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DOI: 10.1039/C6CC01554A
Journal Name
COMMUNICATION
Synthesis of Highly Substituted γ-Hydroxybutenolides through the
Annulation of Keto Acids with Alkynes and Subsequent Hydroxyl
Transposition
Received 00th January 20xx,
Accepted 00th January 20xx
Wenbin Mao,a and Chen Zhu*,a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
An
efficient
synthesis
of
highly
functionalized
γ-
hydroxybutenolides through BF3-catalyzed annulation of keto
acids with alkynes is described. Many advantages such as the use
of routine reagents, easy operation, and a 100% atom efficiency
are demonstrated in the method. The reaction can be readily
scaled up to gram quantities, offering a good practicality.
γ-Hydroxybutenolides are important structural motifs
extensively found in natural products and have exhibited a
wide range of biological activities. Ianthellidone G is isolated
from a southern Australian marine sponge, Ianthella sp. and
treated as a candidate of BACE inhibitors.1 Moreover, a series
of terpenoids from marine sponges, such as manoalide,
cacospongionolides, and petrosaspongioides, have remarkably
anti-inflammatory properties (Figure 1).2 On the other hand,
γ-
hydroxybutenolides are versatile synthetic intermediates for
the assembly of complex natural products and bioactive
molecules.3 Therefore, the rapid and efficient construction of
Figure 1. Natural products including
structural motif.
-hydroxybutenolides
alkynes, namely oxa-Pauson-Khand reaction (Scheme 1, eq
importance in both fields of synthetic and medicinal chemistry. 3).15 Although this approach produced a variety of highly
highly functionalized γ-hydroxybutenolides is of considerable
substituted
γ-hydroxybutenolides in modest yields, the
The construction of the five-membered lactone is the key
step in the synthesis of γ-hydroxybutenolides, and has made a
employment of harsh reaction conditions and costly transition-
great progress over the past few decades. Among these metal catalyst and ligand significantly limited its applications.
methods, there are two common strategies: a) intermolecular
aldol reaction between α-bromoketone and acetic acid
followed by air oxidation (Scheme 1, eq 1),4-8 and b) aldol
condensation between γ-ketoester and aldehyde (Scheme 1,
eq 2).9-14 However, the former requires the use of preformed
Herein, we describe an efficient and practical approach to
highly functionalized γ-hydroxybutenolides through the Lewis
acid-catalyzed annulation of keto acids with alkynes (Scheme 1,
eq 4). The transformation affords an atom efficiency of 100%,
and only routine reagents are applied. Remarkably, the gram-
scale preparation of γ-hydroxybutenolide explicitly illustrates
the practicability of this protocol.
perishable
-bromoketones; the latter harnesses the multi-
step prepared γ-ketoesters which are sometimes hard to make.
Very recently, Shishido et al. reported the intermolecular
carbonylative cycloaddition of aldehydes with
Recently, we disclosed the cyclization of keto acids with
tertiary alcohols to generate butenolides, in which the
.
combinational use of pTSA.H2O and BF3 Et2O was crucial to the
a.Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, 199 Ren-Ai
Road, Suzhou, Jiangsu 215123, China. Email: chzhu@suda.edu.cn
b.Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
reaction outcome, and exhibited a good catalytic
performance.16 Inspired by these findings, we hypothesized
that in the presence of acid catalyst, the annulation of keto
acid
1 with alkyne 2 in lieu of tertiary alcohol would give a-
hydroxylactone
4
as the expected product (Scheme 2).
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Table 1. Reaction Condition Survey a
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DOI: 10.1039/C6CC01554A
Scheme 1. Preparation of -Hydroxybutenolides
entry
1
solvent
ratio (1a: 2a: A: B) yield(%)b
toluene
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.2
1: 2: 2: 0.3
1: 2: 2: 0
46
76
46
78
< 5
< 5
< 5
< 5
54
93
< 5
92
Surprisingly, the unexpected γ-hydroxybutenolide
hydroxyl-transpositional isomer of , was generated in the
reaction. Regarding the possibly mechanistic pathway, we
postulated that after the formation of , the acid-promoted
protonation and dehydration of led to the intermediate
Subsequently, the cation-driven nucleophilic addition of H2O to
gave rise to the product
Encouraged by these preliminary results, we set out to
3, a
2
benzene
4
3
chlorobenzene
fluorobenzene
DMF
4
4
4
a.
5
6
DMSO
a
3.
7
CH3CN
optimize the reaction conditions for the annulation of keto
acid 1a with alkyne 2a (Table 1). Initially, we examined
different solvents in the presence of combined acids of
8
THF
9
DCE
10
fluorobenzene
fluorobenzene
fluorobenzene
.
pTSA.H2O and BF3 Et2O (entries 1-9). Fluorobenzene was found
11
12c
to be the most efficient one, delivering a better yield than
other solvents (entry 4). Raising the quantity of BF3 Et2O from
.
1: 2: 0: 0.3
a
1a (0.3 mmol), 2a (0.6 mmol, 2 equiv), pTSA.H2O (as shown),
0.2 to 0.3 equiv appreciably improved the chemical yield of 3a
(entry 10). Finally, it was noted that pTSA.H2O was unnecessary
to the transformation, and singly using 30 mol % of BF3 Et2O
.
o
b
and BF3 Et2O (as shown) in 2 mL solvent at 70 C. Yields of
isolated product. c 5 h.
.
could give the comparably high yield (entry 12). The structure
of 3a was unambiguously assigned by single crystal X-ray
analysis.17
With the optimized reaction conditions in hand, we set
about assessing the generality of this protocol. Firstly, we
investigated a variety of keto acids (Scheme 3). Both electron-
rich and deficient keto acids were compatible with the
conditions, affording good chemical yields. While aryl keto
acids were readily converted into the desired products (3a and
3b), the reaction of heteroaryl keto acid was more sluggish and
resulted in moderate yield (3c). The steric hindrance seemed
to have considerable impact on the reaction outcome, as the
ortho-substituted keto acids usually led to lower yields and
longer reaction time
(3h and 3n). Notably, a pair of
atropisomers of 3h with 1.3:1 ratio was observed by NMR
spectra at rt, and disappeared at 80 oC in DMSO. Even the
substrate with strong electron-withdrawing group, such as CF3,
Scheme 2. Proposed Mechanism for the Annulation of Keto
Acid with Alkyne
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6CC01554A
Scheme 3. Variation of Keto Acids a,b
1 (0.3 mmol), 2a (0.6 mmol, 2.0 equiv), and BF3 Et2O (0.09
a
.
o
b
mmol, 0.3 equiv) in 2 mL fluorobenzene at 70 C. Yields of
Scheme 4. Variation of Alkynes a,b
.
isolated product. c BF3 Et2O (0.12 mmol, 0.4 equiv).
a
.
1
(0.3 mmol),
2
(0.6 mmol, 2.0 equiv), and BF3 Et2O (0.09
o
b
mmol, 0.3 equiv) in 2 mL fluorobenzene at 70 C. Yields of
was well tolerated to give high yield (3i). The examples of 3l-3n
c
.
.
isolated product. BF3 Et2O (0.18 mmol, 0.6 equiv). d BF3 Et2O
were noteworthy, since the presence of bromide provided the
platform for later product modification through cross-coupling
reactions. It should be mentioned that alkyl keto acids and
glyoxylic acid were incompatible with the reaction conditions.
Afterward, we turned to evaluate the scope of alkynes
(Scheme 4). Firstly, symmetrical diaryl acetylenes bearing
either electron-donating or withdrawing groups were suitable
(0.12 mmol, 0.4 equiv).
The practicality of this method was demonstrated by the
gram-scale reaction. Under the standard reaction conditions,
1.5 gram of phenyl keto acid 1a (10 mmol) was readily
converted into γ-hydroxybutenolide 3a in 92% yield (eq 1).
substrates to afford the desired products in good yields (3o-3t).
The reaction provided a precise discrimination for the steric
hindrance. For example, the use of unsymmetrical diaryl
acetylene led to a single adduct 3u, in which the bulky o-tolyl
group was positioned outside to avoid the steric repulsion
from aryl keto acid. The annulation with the carbonyl-
activated acetylenes also resulted in solely isomeric products
(
3v and 3w). Notably, the unique regioselectivities were
unexpectedly achieved even in the reaction with siyl- or alkyl-
substituted phenylacetylenes (3x 3z).
In summary, a BF3-catalyzed intermolecular annulation of
keto acids with alkynes has been described. An unexpected
hydroxyl transposition occurs after the annulation. A variety of
highly functionalized γ-hydroxybutenolides are efficiently
-
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B. Tobias, H. Hallak and A. M. Doherty, J. Med.VCiehweAmrti.c,le1O9n9lin7e,
obtained. The method demonstrates many advantages such as
the use of routine reagents, easy operation, unique
regioselectivity, and a 100% atom efficiency, and can be
readily scaled up to gram quantities, thereby providing a
practical approach for the synthesis of γ-hydroxybutenolides.
We are grateful for the financial support from Soochow
University, the National Natural Science Foundation of China
(Grant no. 21402134), the Natural Science Foundation of
Jiangsu Province (Grant no. BK20140306), and the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PAPD). We thank Dr. Xiaodi Yang of Fudan
University for help with the single crystal X-ray analysis of
40, 1063.
DOI: 10.1039/C6CC01554A
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DOI: 10.1039/C6CC01554A
O
R1
R3
O
R3
.
BF3 Et2O (cat.)
O
+
R1 COOH
R2
OH
R2
26 examples
100% Atom efficiency
Broad substrate scope
Routine reagents
High product diversity
Easy operation
A BF3-catalyzed, practical synthesis of highly functionalized γ-hydroxybutenolides
with a 100% atom efficiency is described.