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Chapter I Review on Meldrum’s acid 1-1 Introduction
Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione; isopropylidene-
Malonate) 1, prepared by reaction between acetone, malonic acid and acetic
anhydride, was discovered in 1908 by A. N. Meldrum.1,2 Meldrum, infact,
misidentified the structure of this new compound as β-lactone 2 with
carboxylic acid group at position 3, and the correct cyclic acylal structure was
only assigned 40 years later by Davidson and Bernhard3 and compound 1 was
classified as a cyclic acylal. (Scheme 1)
O O
OH OH
O O
OH OAc
Ac2O
-AcOH
O O
O O-AcOH
O
O
O
O
OH
12
3
1
2
1
2
3
45
6
Scheme 1 : Meldrum's acid preparation and its misidentified structure
Acylal 1 is remarkably acidic (pKa 7.3 in DMSO at 25 0C) as compared
to other related dicarbonyl compounds e.g. dimedone (pKa 11.2 in DMSO at
25 0C) and an open-chain analog dimethyl malonate (pKa 15.9 in DMSO at 25 0C)4. The rigid structure, low steric profile as well as high value for C–H
acidity (comparable to acetic acid), accounts for the unique chemical properties
of Meldrum’s acid. The explanation of this facile acidity lies in the stability of
the resultant anion 1a, in which the π-orbitals are rigidly held in the ideal
configuration for overlap whereas Meldrum’s acid is overwhelmingly (>
99.5%) diketo tautomer5.
- 1 -
Chapter I Review on Meldrum’s acid
O O
O O
O O
OO
O O
OO
1a
Meldrum’s acid derivatives have attracted considerable attention as
valuable reagents and intermediates in organic synthesis (Scheme 2). Thus,
acylated Meldrum’s acid of the general formula 3 are the most important class
of Meldrum’s acid derivatives which are widely used for the preparation of
various 1,3-dicarbonyl compounds.6,7 The 5,5-dibromo Meldrum’s acid 4 is a
mild agent for α-bromination of aldehydes and ketones.8 Mono- and di-
substituted alkyl and aryl derivatives of Meldrum’s acid 5 are intermediates in
the modified malonic ester synthesis while 5-methylene Meldrum’s acids 6 are
substrates for selective conjugate addition of nucleophiles and for Diels–Alder
reactions. 5-Thioxo malonate 7 is also a reactive dienophile9 while 5-
alkoxymethylene 8 and 5-aminomethylene 9 Meldrum’s acid are versatile
synthons for various heterocyclizations.10 5-Oximino derivatives 10 have been
employed as synthetic equivalents of nitrosoketenes11 and as reactive
dienophiles.12 Betaine 11 is a stable source of methylene Meldrum’s acid.13
Cyclopropanes 12a and 12b, which are enormously activated by the
spiroconnection to the 1,3-dioxane-4,6-dione system, can react with a variety
of nucleophilic agents under mild conditions.14-16 Lastly, a resin bound cyclic
malonic ester 13 has found application in the solid phase synthesis of various
heterocyclic scaffolds.17-19
This brief survey of synthetic applications of the most important 2,2-
dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) derivatives would not be
complete without mentioning multicomponent and domino reactions that
involve Meldrum’s acid and related compounds.20-25
A domino reaction is usually defined as a process of two or more bond-
forming reactions under identical conditions, in which the subsequent
transformations take place at the functionalities obtained in the former
- 2 -
Chapter I Review on Meldrum’s acid transformation. This principle allows efficient synthesis of complex molecules
such as natural products from simple substrates. A multi-component reaction
(MCR) is a convergent process, in which three or more starting materials react
to form a product, where basically all or most of the atoms contribute to the
newly formed structure. The concepts of domino and MCRs enable rapid
synthesis of various heterocyclic compounds with diverse substitution patterns.
The most commonly cited Meldrum’s acid based MCR is the Yonemitsu
reaction,26-28 involving Meldrum’s acid, an aldehyde and an indole in a one-pot
process, leading to indol-3-ylpropionic acid derivatives (Scheme 3). The latter
have been efficiently used for the synthesis of ellipticine analogs.29
O O
O O
OH R
O O
O O
O O
O O
R
O O
O O
S
O O
O O
OR
O O
O O
NR1R2
O O
O O
NOR
O O
O O
R
O
O
O
O
N
O
O
O
O
Scheme 2 : Meldrum's acid derivatives
4 R1, R2 = Br5 R1, R2 = alkyl, aryl or H
3 6 7 8
9 10 1112a R = H12b R = vinyl
13
+
R1 R2
- 3 -
Chapter I Review on Meldrum’s acid
O
O
O
O
RCHOO
O
O
O
RNH O
O
O
O
R
NH+Catalyst
Scheme 3 : Oikawa-Yonemitsu reaction
In the 1980s, the utility of Meldrum’s acid in the synthesis of natural
products was widely recognized. The unique reactivity of derivatives of
Meldrum’s acid 3–13 has been employed for the synthesis of many complex
targets. This review offers a summary of the transformations of Meldrum’s acid
(and it’s derivatives) towards the synthesis of natural products and their
analogs.
1-2 Applications of Meldrum’s acid in organic synthesis
The chemistry of Meldrum’s acid is dominated by its susceptibility to
nucleophilic attack at position 4 and 6 and to electrophilic attack (via the
anion) at position 5. The simple hydrolysis to malonic acid is a common
example of nucleophilic attack which may be accomplished under acidic or
basic conditions.2 The reaction mechanism has been studied by Pihlaja et al.30
The use of alcoholic hydrogen chloride yields the malonate diester,31,32 (Scheme
4) while ‘solvolysis’ by phenols gives monoaryl esters which can be easily
converted to diaryl esters.33
O
O
O
O COOEt
O
O COOEt
MeO
MeO
Scheme 4 : Methanolic acid hydrolysis of 5,5 di-substituted Meldrum's acid
HCl / MeOH
Reflux
- 4 -
Chapter I Review on Meldrum’s acid
Ketones react with Meldrum’s acid by displacement of acetone to give
2,2-disubstituted-l,3-dioxan-4,6-diones.34 (Scheme 5, route a). It is worth
mentioning that, by the attack of amines at carbonyl carbon, with concomitant
ion of acetone provides a possible or useful route to monoamides of malonic
acids (Scheme 5, route b).
O O
O O
R R'
O
O O
O O
R R'
R-NH2O
NH
O
OH
O
R
CO2 NH
CH3
O
R
Scheme 5 : route a = displacement of acetoneroute b = monoamides of malonic acid
+
+
a
b
1.2 a 5,5-Dialkyl derivatives of Meldrum’s acid
O O
O OR'R
5,5-Dialkyl derivatives are the most important synthetic intermediates.
These derivatives may be made by standard alkylation methods, but the
important alternative routes involve, the reaction of Meldrum’s anion 1a with
alky135 (or activated heterocyclic36) halides in the presence of silver oxide
(Equation a; Scheme 6) and the reaction of meldrum’s acid with various alkyl
halides in [bpy]BF4 ionic liquid at 60-70 0C using triethyl amine as a base
(Equation b; Scheme 6), exclusively these methods give bis-alkylated product.37
- 5 -
Chapter I Review on Meldrum’s acid Interestingly, the reaction of the dibromide is known to furnish corresponding
spiro compound38. Recently, the protocol has been extended for the synthesis of
an indane ester39 via base catalyzed hydrolysis of the spiro intermediate (Scheme
7).
O O
O O
O O
O OMe Me
MeI
Ag2ORCH2X
Et3N
O O
O ORCH2 CH2R
a b
Ionic liquid[bpy]BF4
60-70 oC
Scheme 6 : Synthesis of 5,5 dialkyl derivatives of Meldrum's acid
CH2Br
CH2Br
OMe
O
O
O
O
NaH
OMe
O
O
O
O
OMe
Me
CO2Et
+
1. EtOH / Pyridine2. LDA / MeI
Scheme 7: Synthesis of indane monoester
The hydrolysis of 5,5-disubstituted-l,3-dioxan-4,6-diones proceeds
smoothly under basic or acidic conditions to furnish diester40 (Scheme 4).
1.2 b 5-Methylene derivatives of Meldrum’s acid
O O
O O
X Y
- 6 -
Chapter I Review on Meldrum’s acid The parent 5-methylene compound, 14, is highly reactive and relatively
difficult to prepare (Scheme 8) while other 5-methylene derivatives of
Meldrum’s acid can be prepared by Knoevengel condensation of Meldrum’s
acid with carbonyl compounds. This reaction proceeds easily for aromatic41, 42
or hindered aliphatic aldehydes42 as well as aliphatic ketones,43, 44 while
aromatic ketones require activation by the use of a catalyst.45 (Scheme 9)
O O
O O
X Y
O O
O O
Me
O O
O OMe SePh
ArCO3HPhSeBr
14. X = H, Y = H15. X = H, Y = OEt16. X = H, Y = NHR17. X = Y = NHC6H1118. X = OH, Y = NHR
Scheme 8: Synthesis of parent methylene compound
O O
O O R R'
O O O
O O
R R'
+
R' = alkyl / H
Scheme 9: Knoevengel condensation
A number of functional derivatives of 5-methylene compounds are
known. Thus 15, is readily available from Meldrum’s acid and
triethylorthoformate46, while addition of an amine to this reaction mixture gives
the amino compounds46, 4716. The diamino compound 17, which is an extended
urea, can be made from dicyclohexylcarbodiimide48, and the ‘amides’ 18 from
isocyanates.49
Remarkable properties of 5-methylene derivatives of Meldrum’s acid
are, like that of parent 1,3-dioxan-4,6-dione, they are also unexpectedly strong
acid50. Reduction of 5-methylene-l,3-dioxan-4,6-diones to the corresponding 5-
alkyl compound is possible catalytically38, using lithium aluminium hydride51,
borohydride exchange resin52, Sodium hydrogen telluride53, etc. The resultant
- 7 -
Chapter I Review on Meldrum’s acid 5-alkyl derivatives have also been demonstrated to be useful in the synthesis of
few natural products.
1.2 c 5-Halogeno or nitrogen containing derivatives
Like 5-methylene derivatives as well as 5-alkyl derivatives, 5-halogen
and 5-nitrogen containing derivatives have also been demonstrated to be useful
in organic transformations. 5,5-Dibromo derivatives of Meldrum’s acid can act
as a mild brominating agent54 (Equation a: Scheme 10) and that upon alkaline
hydrolysis furnishes carbon tetrabromide. Simple dissolution in
dimethylformamide yields coupled derivative (Equation b: Scheme 10).
O O
O O
Br22 eqNaOH
O O
O O
Br Br
O
O
O
O
O
O
O
O
b DMF
Br21 eqNaOH
O O
O OR Br
O O
O OR H
NuBr
Nu a
+
Scheme 10 : a = route as a brominating agent b = route for formation of coupled derivative
Meldrum’s acid on reaction with sodium nitrite3 yields an oxime as
unstable solid55 whose reduction over PtO2 provides the only known route to 5-
amino Meldrum’s acid (Scheme 11 route a). Similarly hydrazones are prepared
by coupling of Meldrum’s acid with appropriate diazo compounds56 or
diazonium salts55 (Scheme 11 route b)
- 8 -
Chapter I Review on Meldrum’s acid
a
b
Scheme 11 : Synthesis of 5-nitrogenous derivatives
O O
O O
NaNO2 O O
O O
NOH
PtO2
O O
O OH NH2
O O
O O
NNHAr
i. ArN2+X-
ii. reduction
1.2 d Domino reactions of Meldrum’s acid
Substituted γ-pyrones 20 are useful precursors in the synthesis of
polyacetate- and spiroketal-containing natural products which have been
synthesized using acylated Meldrum’s acid 3 as a starting material. A variety of
acid chlorides and vinyl ethers 19 can be used to prepare mono-, di- and tri-
substituted pyrones.57 (Scheme 12)
3 19
20
O
O
O
O
R'COCl
Pyridine, CH2Cl2
O
O
O
O
R'
OH
C6H6 80 oC, 2h
XO
R'' O
R'
OHO
O
X
OR''
THF, H2OPTSA, Reflux12-16h
O
O
X
R'
Scheme 12 : Synthesis of γ-pyrones
The acylated Meldrum’s acid, 3 can be used in the synthesis of optically
active β-lactams58 22 in excellent yields (Scheme 13). 2-Alkyl and 2-aryl 4-
quinolones 23 can be prepared starting from Meldrum’s acid 1 via their
- 9 -
Chapter I Review on Meldrum’s acid derivatives bisalkylthiolydine as well as alkyl- and arylthioalkylidene59. (Scheme 14)
Scheme 13 : Synthesis of β−lactams
3
21
22
O
O
O
O
R
OH
C6H6 H+
N
S
CO2CH3
CO2CH3
NO
R
O S
Scheme 14 : Synthesis of 2-aryl /alkyl-4-quinolones23
O
O
O
O
+ CS2
1. TEA, DMSO, rt
2 RX, 0oC, rt
O
O
O
O
SR
SR
1. RMgX / THF
2. 5 % HCl
O
O
O
O
SR
R
+
X
NH2
EthanolReflux
O
O
O
OSR
NH
X
240-260 oC
X
NH
O
R
5-Substituted 3-isoxazolols 26 can also be synthesized in a three step
procedure starting from acylated Meldrum’s acid 3. 60 (Scheme 15)
3
24
25 26
O
O
O
O
R
OH NOBocH
boc
R N
OO
OBoc
OBoc HCl
ON
OH
R65 oC
Scheme 15 : Synthesis of 3-isoxazols
- 10 -
Chapter I Review on Meldrum’s acid 1-3 Applications of Meldrum’s acid in multistep synthesis
The chemical synthesis of carbon containing molecules, carbogens, has
been a major field of scientific endeavor for over a century. Nonetheless
subject is still far from fully developed. For example, of the almost infinite
number and variety of carbogenic structures which are capable of discrete
existence only a minute fraction have been prepared and studied with
Meldrum’s acid as a precursor. In addition, for the last century there has been
continuing and dramatic growth in the power of science of constructing
complex molecules which shows no sign of decreasing. The ability of the
chemists to synthesize compounds with Meldrum’s acid as a precursor which
was beyond reach in a preceding 10-20 year period is well documented by this
literature survey.
1.3 a Terpenoids
The high C–H acidity, flat structure and low steric profile of Meldrum’s
acid provide a unique template for various transformations at the active
methylene site. After functionalization of position 5, the Meldrum’s acid can be
converted to an acetic acid or acetic ester group by hydrolysis or alcoholysis,
respectively under mild conditions (Scheme16). The alcoholysis reaction can be
efficiently catalyzed by Ni(acac)2.09
O O
O O
O O
O OR'R''
R' R''
ORO
R = H, alkyl
Ni(acac)2
Scheme 16 : Hydrolysis of 5-substituted Meldrum's acid
- 11 -
Chapter I Review on Meldrum’s acid
This particular observation has been used in the synthesis of a few
sesquiterpenes ar-turmerone 27 and α-curcumene 28 (Scheme 17), the
constituents of some essential oils.61
O
27 28
Scheme 17 : 27 ar-turmerone 28 α−curcumene
Syntheses of both natural products proceeds via the same benzyl
Meldrum’s acid intermediate 30 which is prepared by three different routes as
depicted in (Scheme 18).
O
O
O
O
Me
Me
O
O
O
O
O
TiCl4
O
O
O
O
Me
OHPBr3
NaBH3CN
NaBH4
Me
Br K2CO3
DMF
O
O
O
O
CHO
O
O
O
O
CH3MgI
CuI
O
O
O
O
Scheme 18 : Synthesis of benzyl Meldrum's acid
30
30
30
30
+Methano
Methano
29
31
+
PiperidineAcOH
+
- 12 -
Chapter I Review on Meldrum’s acid
In the first method, acylal 30 was obtained by conjugate addition of
methylmagnesium iodide to p-tolylidene Meldrum’s acid 29. In the second
approach, a highly electrophilic olefin 31, produced by condensation of p-
methylacetophenone with Meldrum’s acid, was selectively reduced with
sodium cyano-borohydride to give 30. In the third approach, compound 30 was
prepared by direct alkylation of Meldrum’s acid with p-tolylethyl bromide.
Compound 30, on decarboxylative hydrolysis in aqueous pyridine,
transformed to carboxylic acid 32, which was further converted to ar-turmerone
27 (Scheme 19). Alternatively, the target compound 27 was prepared from 29
through a sequence of reactions, including acylation with 3,3-dimethylacryloyl
chloride, alcoholysis, and hydrolysis of the β-keto ester 33.
Scheme 19 : Synthesis of ar-turmerone
H2O
-CO2, -EtOH
30COCl
Py, DCM
O
O
O
O
O
EtOH
O
COOEt
-CO2, -Me2CO
O
Py, H20
-CO2, -Me2CO COOH
Li
30
32 27
33
In the synthesis of α-curcumene, 28, the monoalkylated Meldrum’s acid
was subjected to second alkylation with β,β-dimethyl allyl bromide to give
compound 34. This was then converted into α-curcumene (Scheme 20).
- 13 -
Chapter I Review on Meldrum’s acid
Another terpenoid molecule, synthesized with the use of a cyclic acylal
template, is taiwaniaquinol B 35 isolated from a common Taiwanese pine tree
Taiwania cryptomerioides. The noteworthy feature of the synthesis of the target
compound was the selective deprotection of the methoxyl group adjacent to the
carbonyl group and oxidation of the aromatic ring to quinone, which was
catalytically reduced to hydroxy groups, affording Taiwaniaquinol B 35
(Scheme 21).
Br
K2CO3, DMF
O
OO
O
OH
OHO
O
Pb(OAc)4, C6H6
OZn-Hg / HCl
1. NaOH, EtOH2. H+
Scheme 20 : Synthesis of α-curcumene
30
28
34
Diels–Alder reaction often permits the rapid assembly of complex
chemical structures of natural products and certain derivatives of Meldrum’s
acid can be exploited as either ‘ene’ or ‘diene’ components in this reaction. A
recent and very interesting example of such a Diels–Alder reaction is
connected with the synthesis of a tetracyclic quassinoid framework.
Quassinoids exhibit a wide range of biological activities and are a large family
of naturally occurring compounds, which possess the carbon skeleton of the
parent compound Quasin 36 that possess the C20 picrasane framework 37
(Scheme 22). 62
- 14 -
Chapter I Review on Meldrum’s acid
O
OMe
MeO
TiCl4, PyridineO
O
O
O
O
O
O
O
OMe
MeO
O
H
OMe
MeO
O
H
OH
MeO
OH
MeMgBr
THF
TMSOTf
CH3NO2, reflux
Scheme 21 : Synthesis of Taiwaniaquinol B
+
1. BCl3, DCM2. CAN, H2O-MeCN3. H2, Pd/C, EtOAc
1
35
O
O
O
OH
H
H
H
OMe
MeO
O OH H
36 37
Scheme 22 : 36-quassin 37-C20 picrasane framework
- 15 -
Chapter I Review on Meldrum’s acid
Perreault and Spino had synthesized a diene precursor 38 of the C20
picrasane framework.9 and it was envisioned that a [4 + 2]-cycloaddition
involving 38 and a thioxomalonate synthon 39 would give the corresponding
cycloadduct 40 (Scheme 23), suitable for the construction of quassinoid
framework. The choice of dienophile was explained by the known fact that
thiocarbonyls are more reactive with dienes than the corresponding carbonyls
and the sulfide linker is easy to remove.
H
OEt
COOMe
S COOR
COORS
O
H
ROOC
ROOC
OEt
COOMe
+
38 39 40
Scheme 23 : Retro Diels-Alder reaction
After screening a variety of thioxocarbonyls 41, 42 and 7 as dienes, it
was revealed that thioxo Meldrum’s acid 7, generated by thionation of
Meldrum,s acid with phthalimidosulfenyl chloride,63 reacted smoothly with
diene 38 to form the desired cycloadduct 43 with even higher selectivity. The
adduct 43 was subsequently transformed to the targeted molecule9 i.e.
quassinoid precursor 45 through methyl ester 44 and sequence of reactions
(Scheme 24).
Like thioxo Meldrum’s acid, methylene derivatives of Meldrum’s acid
can also behave as reactive hetero-dienes in Diels–Alder reaction. Tietze and
his group worked out an efficient multicomponent domino reaction between a
1,3-dicarbonyl compound, an aldehyde and an enol ether or an alkene in the
presence of a mild base, such as ethylene diammonium diacetate (EDDA).21
The reaction also proceeds on a polymer support and is thus suitable for
combinatorial synthesis.64 (Scheme 25)
- 16 -
Chapter I Review on Meldrum’s acid
O O
O O
S
O
O
O
O
S
O O
OO
S O
H
O
OEt
O
O
O
H
O
OEt
S
O
O
O
H
O
OEtOMeOO
H
O
OEtTBSOH H
COOMe
+
1. Ni(acac)2, MeOH, 98%2. Ni(Raney), THF-H2o
41 42
7 38 43
4445
Scheme 24 : Synthesis of quasinoid precursor
O
O
O
O
H
O
R EDDA O
O
O
O
R
OR'
O
O
O
O
R
OR'
R''OH
-Me2CO
-CO2O OR'
RO
R''O
O
Scheme 25 : Domino Knoevengel-hetero-Diels-alder reaction
+ +
- 17 -
Chapter I Review on Meldrum’s acid
The domino Knoevenagel–hetero-Diels–Alder reaction has been
successfully employed in the syntheses of a number of monoterpenoid
alkaloids and their stereoisomers including dihydroantirhine,65 hirsutine,66
dihydro-corynantheine,66 emetine,67 and tubulosine .68
Coumarins are a class of naturally occurring benzopyrone derivatives,
which are often found in green plants. The pharmacological and biochemical
properties, and therapeutic applications of simple coumarins depend upon the
pattern of substitution.69 7-Hydroxy-4-isopropyl-6-methylcoumarin 47 is
isolated from Macrothelypteris torresiana..70 The short synthesis of this
product, starting from isobutyroyl Meldrum’s acid 46 is depicted in (Scheme
26).71
O
O
OH
O
O
EtOH, refluxOO
EtO
OHOH
Con. H2SO4
O OOH
Scheme 26 : Synthesis of coumarins
r.t. 16 h
46
47
1.3 a Furanones and pyranones
The first example of radical addition of Meldrum’s acid to olefins was
reported from our laboratory in 2001 in the synthesis of norbisabolide 48
(Scheme 27).72 isolated from the root bark of Atalantia monophylla.73 In the first
step of this synthesis, cerium(IV) ammonium nitrate (CAN) oxidized
- 18 -
Chapter I Review on Meldrum’s acid Meldrum’s acid to generate a radical, which added to the exo-double bond of
(R)-(+)- limonene 49, affording the lactone carboxylic acid 50 in good yield.
The regioselectivity of the radical addition can be explained on the basis of a
steric effect where the bulky Meldrum’s acid radical adds to the less hindered
double bond in the side chain. Decarboxylation of 50 on heating with poly- 4-
vinylpyridine in DMF furnished norbisabolide 48 in nearly quantitative yield as
a mixture of diastereomers.
H
O O
OOO
C
O
OO
CAN
HO
O
O
OH
HO
O
Scheme 27 : Synthesis of norbisabolide
4950
48
Poly-4-vinylpyridineDMF, 80oC
Meldrum’s acid is known to react with aldo-pentoses and aldo-hexoses,
providing facile access to C-glycosidic-1,4-lactones.74,75 This reaction is
remarkable due to its high bond forming efficiency, resulting in formation of
the fused lactones in a single step. (+)-Goniofufurone 51 and (+)-7-epi-
goniofufurone 52 are natural anti-tumor lactones, isolated from the
Goniothalamus species (Annonaceae) (Scheme 28). The reaction of D-glucose
with Meldrum’s acid led to triol 53 with the bicyclic goniofufurone framework
- 19 -
Chapter I Review on Meldrum’s acid which furnishes (+)-7-epi-goniofufurone 52 in subsequent sequence of
reactions (Scheme 29).
O
O OOH
OH
PhO
O OOH
OH
Ph
51 52
Scheme 28 : 51 (+)-goniofufurone 52 (+)-7-epi-goniofufurone
O OH
OHOH
OH
OH O O
OO
n-BuNH2, DMF O
O OOH
OH
OH
O
O OOH
OH
Ph
+
40 oC
53
52
Scheme 29: Synthesis of (+)-7-epi-goniofufurone
Pyrones, especially 3-alkylated derivatives, are known to exhibit
significant biological activity however only a few methods are known, and the
majority of these are low yielding. Probably the most convenient and efficient
one is based on the thermal recyclization of acetoacetyl derivatives of
Meldrum’s acid.76 This approach has been applied to the first synthesis of
racemic germicidine 54 (Scheme 30).77,78
- 20 -
Chapter I Review on Meldrum’s acid
54
Scheme 30 : Synthesis of germicidine
O
O
O
O
OH
1. MeOH, reflux2. MeONa, MeOH3. 1N HCl OH
O O
+
O
O
O
O
DCC, Et3N,DMAP, DCM
O
O
O
O
O OH
Toluene, reflux
-CO2
-Me2CO
OH
O
O
O
OH
O O
OH
O
Et
Gelastatin 55 is another natural product containing a partially
unsaturated pyrone ring that has been synthesized using Meldrum’s acid. The
Michael addition reaction of Meldrum’s acid with methyl acrylate yielded
exclusively the mono-substituted derivative 56.79 The latter was alkylated with
allylic bromide 57 to form the key intermediate 58. This can be converted to
Gelastatine 55 through a sequence of reactions. (Scheme 31)
- 21 -
Chapter I Review on Meldrum’s acid
O
O
O
O
COOMeO
O
O
O
COOMe
OTBS
OTHP
Br
K2CO3, DMF
O
O
O
O
COOMe
OTBS
OTHP
OO
OH
O
+
56
57
5855Scheme 31 : Synthesis of gelastatine
- 22 -
Chapter I Review on Meldrum’s acid 1-4 Concluding remarks
The natural environment continues to be an abundant source of
biologically active and structurally diverse compounds. Total syntheses of such
substances not only provide sufficient amounts of material for biological
studies, but also result in novel synthetic methods and strategies. Due to their
unique reactivity, Meldrum’s acid and it’s derivatives have proven to be
valuable reagents and intermediates in the synthesis of complex organic
compounds such as natural products and their analogs. The ability of acyl
derivatives of Meldrum’s acid to generate acylketene species under pyrolysis
conditions is the most fruitful field of their applications. For example, β-keto
thioesters, easily accessible from reaction of thiols with acyl Meldrum’s acids,
can be regarded as analogs of acyl-SCoA and have been exploited in
biomimetic syntheses of polyketide derived natural products. As demonstrated
in the present microreview, cyclic acylals have a potential for application in
stereoselective synthesis of complex organic molecules. Another direction in
their chemistry is the development of novel multicomponent and domino
reactions, producing variously substituted privileged scaffolds. These reactions,
along with Meldrum’s acid based solid phase syntheses, are ideally suited for
parallel and combinatorial processing. Parallelization techniques provide easy
exploration of the chemical space around the biologically active scaffolds,
enabling generation of ‘‘natural product-like’’ libraries for biological screening
and SAR studies.
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