Expedient synthesis of complex γ-butyrolactones from 5-(1-arylalkylidene) meldrums acids via sequential conjugate alkynylation/Ag(I)-catalyzed lactonization

Article abstract of DOI:10.1021/ol502811j

The conjugate alkynylation of alkylidene Meldrums acids with alkynylalanes and alkynyl Grignards allows for the formation of propargylic all-carbon quaternary stereocenters in high yields. Ag₂CO₃-catalyzed intramolecular cyclization

Full text of DOI:10.1021/ol502811j

Letter
pubs.acs.org/OrgLett
Expedient Synthesis of Complex γ‑Butyrolactones from 5‑(1-
Arylalkylidene) Meldrum’s Acids via Sequential Conjugate
Alkynylation/Ag(I)-Catalyzed Lactonization
Siawash Ahmar and Eric Fillion*
Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
S
* Supporting Information
ABSTRACT: The conjugate alkynylation of alkylidene Mel-
drum’s acids with alkynylalanes and alkynyl Grignards allows
for the formation of propargylic all-carbon quaternary
stereocenters in high yields. Ag2CO3-catalyzed intramolecular
cyclization of propargylic Meldrum’s acid derivatives offers a
two-step entry into complex γ-alkylidene butyrolactones
containing an all-carbon quaternary center at the C-4 position.
group has reported the SN2′ addition of alkynylalanes to allylic
espite recent advances in the formation of all-carbon
Dquaternary centers bearing alkyl and/or alkenyl groups phosphates resulting in enantiopure 1,4-enynes adducts.12
through conjugate addition,1−3 the number of analogous
However, to date and to the best of our knowledge, no
general 1,4-conjugate alkynylation strategy for the formation of
propargylic all-carbon quaternary centers has been reported.
Herein, we present two general complementary methods for
the 1,4-conjugate alkynylation of alkylidene Meldrum’s acid
derivatives 1 using either dimethyl aluminum or Grignard
alkynylides (Scheme 1). Adducts 2 were readily transformed to
highly functionalized γ-butyrolactones 3 by Ag(I)-catalyzed
cyclization (Scheme 1).
methods for the formation of propargylic all-carbon quaternary
centers remains limited. Strategies employed to achieve 1,4-
regioselectivity in the conjugate addition of alkyl or alkenyl
groups to α,β-unsaturated carbonyl compounds, such as the use
of Cu(I) salts, has been hindered by the inertness of the Cu−
C(sp) bond.4 Since the first report on the conjugate
alkynylation of α,β-ketones by Hooz and Layton,5 synthetic
chemists have addressed the chemo- and regioselective transfer
of alkynes to electron-deficient olefins on several different
fronts. Highly electrophilic reagents such as alkynylboranes and
alkynylalanes have been utilized.6,7 Alkynylalanes have been
shown to add to acyclic4 and cyclic enones, where the latter
requires special conditions to overcome the unreactive nature
of the s-trans conformation. For these acceptors, either an
adjacent hydroxyl-directing group7c or a transition metal
catalyst7b was required to allow for the conjugate addition.
More recently, enantioselective conjugate alkynylations to α,β-
unsaturated ketones for the formation of tertiary propargylic
centers have been disclosed.6a,7a,8
Scheme 1. General Strategy
Alternatively, highly electrophilic acceptors have also been
employed in conjunction with transition metals in the presence
of chiral catalysts to access enantioenriched adducts.9
Carreira10c and Fillion10b independently reported the use of
alkylidene Meldrum’s acid as excellent acceptors in the
enantioselective Cu- and Rh-catalyzed conjugate alkynylation
reactions, respectively. Cui and Walker10a also reported the
conjugate addition of Zn-alkynylides in the presence of a chiral
amino alcohol to Meldrum’s acid alkylidenes. Moderate to high
yields and enantioselectivities were achieved in the formation of
tertiary carbon centers in each of these methods. Propargylic
all-carbon quaternary centers have been prepared by Alexakis’
group via the enantioselective copper-catalyzed 1,4-addition of
alkyl Grignards to cyclic enynones.2c,11 As well, Hoveyda’s
Initial attempts to add Li-alkynylides to 1a resulted in nearly
quantitative recovery of starting material (<5% yield). We
postulate that the higher basicity of the Li-alkynylides leads to
γ-deprotonation at the methyl position resulting in isolation of
starting material 1a upon aqueous workup. On the other hand,
the analogous Grignard reagent gave the desired 1,4-adduct.
After optimization of reaction conditions two complementary
protocols were developed (Table 1).13 The electronic character
Received: September 23, 2014
© XXXX American Chemical Society
A
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Table 1. Conjugate Addition of Metal Alkynylides to
Alkylidene Meldrum’s Acids 1a−r
a
AlMe ,
ab2
,
MgCl yield
(%)
entry
alkylidene (R1/R2)
product (R3)
1
Ph/Me (1a)
TMS (2a)
TMS (2b)
TMS (2c)
TMS (2d)
TMS (2e)
TMS (2f)
TMS (2g)
TMS (2h)
TMS (2i)
TMS (2j)
TMS (2k)
TMS (2l)
TMS (2m)
TMS (2n)
TMS (2o)
TMS (2p)
TMS (2q)
TMS (2r)
H (2s)
83
77
91
85
75
88
82
84
NR
NR
39
NR
76
72
66
64
69
94
N/A
75
77
87
85
82
92
83
84
89
85
76
NR
NR
27
NR
84
74
83
77
81
92
86
85
81
85
2
4-MeC6H4/Me (1b)
4-(MeO)C6H4/Me (1c)
4-ClC6H4/Me (1d)
4-FC6H4/Me (1e)
4-(F3C)C6H4/Me (1f)
3-MeC6H4/Me (1g)
3-(MeO)C6H4/Me (1h)
2-ClC6H4/Me (1i)
2-(BnO)C6H4/Me (1j)
2-FC6H4/Me (1k)
1-naphthyl/Me (1l)
2-naphthyl/Me (1m)
2-furyl/Me (1n)
Ph/i-Pr (1o)
3
4
5
The nucleophilic scope of metal alkynylides was also
investigated (Table 1). Good yields were obtained for both
alkyl- and aryl-substituted alkynylides (entries 19−22).
Propargyl and homopropargyl alcohols were added in moderate
to good yields without the need for protection (entries 23−24).
Next, the lactonization of adducts 2s−u was investigated,
since the γ-butyrolactone structural motif is found throughout a
vast number of naturally occurring products.14 Transition-
metal-catalyzed cyclization of acetylenic compounds offers a
direct and attractive route to the formation of γ-butyrolac-
tones.15 Ag(I), Au(I), and Au(III) salts were screened, where
Ag2CO3 led to highly regio- and stereoselective cyclizations
(Table 2).16 Ag(I) salts gave 5-exo-dig products in high yields.
Propargylic Meldrum’s acid 2s readily cyclized to afford γ-
alkylidene butyrolactones containing an ester (3b) or carboxylic
acid (3c) moiety adjacent to the stereogenic center (entries 3
and 4). Cyclization of alkyl- and aryl-substituted propargyl
Medrum’s acids, 2t and 2u respectively, were more sensitive to
reaction conditions (entries 5−10). Regio- and stereoselective
E-3d and E-3e isomers were isolated in a more polar and Lewis
basic solvent such as THF (entries 5 and 7). In benzene, a less
polar solvent, mixtures of E/Z isomers were isolated (entries 6
and 8). Compound 2u afforded product Z-3f exclusively in a
solution of benzene and water as the cosolvent (entry 9).
Transition-metal-catalyzed cyclization of some alkynoic acids
have been reported to give a mixture of E/Z isomers,15b,c and
was rationalized by the authors to be a result of isomerization of
the Z isomer.15c Attempts to isomerize E-3e or Z-3f by
subjecting these products to Ag-salts in their respective reaction
conditions over 24 h did not lead to any isomerization.
Similarly, subjecting a mixture of E/Z isomers to the same
reaction conditions did not change the relative ratio of the
isomers formed.17 These results suggest the possibility of
competing pathways (Scheme 2). Path I accounts for the
formation of the Z isomer, where anti- attack of the carbonyl-O
onto the alkyne-coordinated Ag(I) complex gives rise to the 5-
exo-dig intermediate Ia. The E-isomer may result from a syn-
carbometalation of the carbonyl-O and Ag(I) ion across the
triple bond giving rise to the 5-exo-dig intermediate IIa.
Thermally induced cycloreversion of Ia and IIa resulted in the
formation of acylketene intermediates Ib and IIb respectively,18
followed by nucleophilic attack of the corresponding solvent
affording the γ-alkylidene butyrolactone. Reactions ran in water
at room temperature gave rise to the carboxylic acid γ-
alkylidene butyrolactone 3c. Compounds 2t and 2u subjected
to identical reaction conditions gave mixtures of carboxylated
and decarboxylated butyrolactones. However, upon gentle
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ph/c-Hex (1p)
Ph/cyclopropyl (1q)
Ph/CO2Me (1r)
Ph/Me (1a)
Ph/Me (1a)
n-Bu (2t)
Ph/Me (1a)
Ph (2u)
Ph/Me (1a)
c-Hex (2v)
CH2OH (2w)
CH2CH2OH (2x)
c
c
Ph/Me (1a)
72
c
54
c
Ph/Me (1a)
69
50
a
b
c
Isolated yield. THF as the solvent furnished comparable results. 4
equiv were used.
of the aromatic group had no significant effect on the overall
reactivity where both electron-withdrawing and -donating
substituents resulted in good to excellent yields (Table 1,
entries 1−8). Detrimental effects were observed for ortho
substituted derivatives (entries 9−10, 12). We had previously
observed similar reactivity of ortho-substituted 5-(1-arylalkyli-
dene) Meldrum’s acids in our enantioselective conjugate
alkylation protocol.2e It is interesting to note that ortho
substitution with the smaller fluorine atom 1k yielded the
desired adduct 2k (entry 11), albeit in modest yields,
suggesting that steric properties governed the overall efficiency
of the reaction. The aromatic groups furyl and naphthyl were
also well tolerated (entries 13−14).
Increasing the steric bulk of the alkyl moiety from Me to the
i-Pr and c-Hex group resulted in lower yields for the
alkynylalanes than for the alkynyl Grignards (Table 1, entries
15−17). Excellent yields were achieved with the aryl-ester
group at the electrophilic center (Table 1, entry 18). Addition
of alkynylide AlMe2 led exclusively to the delivery of the alkyne
moiety, and no Me transfer was observed in all cases.
Next the formation of indenylidene Meldrum’s acid 5a−b
were briefly examined and good yields were obtained for both
methods, eqs 1 and 2.
B
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Table 2. Ag(I)-Catalyzed Formation of γ-Alkylidene
Butyrolactones
Scheme 2. γ-Alkylidene Butyrolactones Formation
Mechanism
heating to 85 °C decarboxylated γ-alkylidene butyrolactones
were exclusively formed (Table 2, entries 1, 5, and 9). Further
evidence for the acylketene intermediate was observed when
cyclization reactions were run in the absence of a nucleophilic
solvent. No cyclized products were observed as a result of rapid
decomposition of the unstable acylketene intermediate.3c
In summary, the versatility of alkylidene Meldrum’s acids as
excellent acceptors in conjugate addition reactions has been
expanded to give rise to propargylic all-carbon benzylic
quaternary centers under mild reaction conditions. Two
complementary practical protocols allow for the formation of
a wide range of propargyl Meldrum’s acid derivatives that can
be readily converted to complex γ-alkylidene butyrolactones.
These unprecedented butyrolactones display a stereogenic all-
carbon quaternary center at the C-4 position. Current efforts
center on developing enantioselective versions of these
protocols.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of new com-
pounds including NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: efillion@uwaterloo.ca.
a
b
c
Notes
Isolated yield. Reaction ran at 85 °C for 2 h. Reaction ran at rt for
18 h.
The authors declare no competing financial interest.
C
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(16) AgNO3 gave the 5-exo-dig product but in lower yields. AuCl
gave a varying mixture of the 5-exo-dig and 6-endo-dig products
depending on reaction conditions. AuCl3 resulted in the formation of
complex mixtures.
(17) Determined by comparing the chemical shift of vinylic protons
of γ-alkylidene butyrolactones. No change was observed in their crude
1H NMR spectrum.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the
Government of Ontario (ERA to E.F.), the Canadian
Foundation for Innovation (CFI), the Ontario Innovation
Trust (OIT), and the University of Waterloo.
(18) Sato, M.; Ban, H.; Kaneko, C. Tetrahedron Lett. 1997, 38, 6689.
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