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5

Recent Advances in Biomimetic Synthesis

Involving Cyclodextrins

Y V D Nageswar, S Narayana Murthy, B Madhav and J Shankar

Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500607,

India

1 Introduction

Modern bioorganic chemistry is interested in the mimicking of enzymes in their capability

to bind substrates selectively and catalyze chemical reactions since biochemical selectivity will be superior to chemical selectivity in various aspects Laboratory organic chemistry differs from that used in living systems to perform biochemical reactions In general, organic chemists allow small reactive reagents to attack a free substrate randomly in a solution The selectivity that is achieved is a result of selective reactivity of a particular region of the substrate or steric crowding or blocking certain approach directions In contrast, biochemical reactions involving enzymes bind and then orient the reactants Biochemical selectivity usually reflects such orientation, rather than the intrinsic reactivity of the substrate molecule For instance, it is common to observe the selective oxidation of an unreactive region of a substrate molecule in an enzymatic reaction while much more reactive segments are left untouched Enzymatic processes frequently achieve higher levels of selectivity which are not attainable by simple chemical means Most enzyme catalyzed reactions are stereoselective, or in the choice of substrates, selective either in the type of chemical reactions performed and selective in the region of the molecule to be attacked However, regioselectivity and stereoselectivity, in particular the formation of pure product enantiomers from achiral precursors, are aspects of enzymatic chemistry which are to be admired and imitated by synthetic chemists

Biochemical selectivity is the result of the geometry of enzyme-substrate complexes, in which only certain substrates can fit in the enzyme and only certain points in the substrates are then in a position to be attacked Geometric control was attained by using the reagent-substrate complexes in which a relatively rigid reagent would direct the attack into a particular region of the substrate and this is called “biomimetic control” The term

“biomimetic” has since come into wider use, generally referring to any aspect in which a chemical process imitates a biochemical reaction

Certain supramolecular hosts, with their cavities have the potential to perform novel chemical transformations, mimicking the biochemical selectivity exhibited by enzymes Binding of substrates to these supramolecular hosts involving intermolecular interactions of

non covalent nature such as hydrogen bonding, van der Waals forces, etc results in host

guest complexation akin to biological receptors and substrates The formation of such inclusion complexes involves molecular recognition capability of the supramolecular hosts

In fact molecular recognition involves both binding and selection of the substrate by the

host In addition if the host bears reactive functionalities, it results in the activation of the guest molecule to under go chemical transformation of the bound substrate, wherein the role played by the intermolecular forces is significant

These supramolecular hosts have excited interest as enzyme models catalyzing chemical reactions involving the reversible formation of host-guest complexes Cyclodextrins acquired prominence as supramolecular hosts as they modify the properties of the included molecules Hence they are used in a variety of industrial applications, analytical techniques and as reaction mediator (Szejtli & Osa, 1996)

α-CYCLODEXTRIN

β-CYCLODEXTRIN

γ-CYCLODEXTRIN

O OH HO

OH O

O HO

HO OH O

O HO OH OH

O O

O

OH

OH HO

HO

O

O OH HO

OH O

O OH

O

O OH

OH OH O

O

HO O O

OH OH

OH HO O

O HO

HO

O

O OH HO

OH O

O OH

O

O OH

OH OH O

O

OH O

O OH OH HO

O OH HO HO O

O OH HO

HO

O

O OH OH HO

in the rigid 4C1-chair conformation, giving the macrocycle the shape of a hollow truncated cone The cone is formed by the carbon skeletons of the glucose units with glycosidic oxygen atoms in between The primary hydroxyls of the glucose units are located at the narrow face

of the cone and the secondary hydroxyls at the wider face The primary hydroxyls on the

Recent Advances in Biomimetic Synthesis Involving Cyclodextrins 105 narrow side of the cone can rotate to partially block the cavity In contrast the secondary hydroxyls are attached by relatively rigid chains and as a consequence they can not rotate The primary and secondary hydroxyls on the outside of the cyclodextrins make cyclodextrins water-soluble Cyclodextrins are insoluble in most organic solvents

Because of the relatively apolar cavity in comparison to the polar exterior, cyclodextrins can form inclusion compounds with hydrophobic guest molecules in aqueous solutions predominantly due to intermolecular interactions In aqueous solution, the cyclodextrin cavity is occupied by water molecules in an energetically unfavorable polar-apolar association and the driving force for complex formation is the displacement of high energy water molecules by the hydrophobic guest molecule The most important factor in complexation appears to be the “steric fit” ie., geometric compatibility between the host and the guest However the stability of the resulting complexes varies with the size of both the

guest and the host The Stoichiometry of the guest to host in inclusion complexation is

usually 1:1 in aqueous solution Complexes can also be formed in DMF and DMSO, but they are less stable However, in some cases complexation can also be formed in solid state Cyclodextrins with their hydrophobic cavities mimic enzymes in their capability in binding substrate selectively and catalyze the chemical reactions involving supramolecular catalysis Cyclodextins became prominent as micro vessels for performing a variety of biomimetic synthetic reactions Growing interest in different aspects of cyclodextrins resulted in steady increase in original research articles as well as reviews Various methods that determine the host-guest complex formation include X-ray, fluorimetric measurements, NMR, circular dichroism, ESR, polarography, colorimetry, diffusion across semipermeable membranes and surface strain measurements Among these methods X-ray and NMR have been established

as important and reliable methods to determine molecular encapsulations Some of the applications of CDs to attain higher selectivities in a variety of organic reactions including multi component synthesis of heterocycles are discussed

In view of the significance attached to green chemistry and its relevance to the present day problem of global warming, the development of novel, simple, cleaner synthetic protocols is attracting attention in both academic and industrial research, resulting in an ever increasing number of publications or reports on this topic Designing environ friendly synthetic strategies in water, minimizing the use of harmful, toxic, and flammable organic solvents and hazardous reagents/catalysts, is attaining the priority over other issues Water has the status of universally acceptable solvent since it is economically affordable, readily available and nontoxic

However the fundamental problem of performing organic reactions in water is that many organic substrates are hydrophobic and insoluble These problems can be addressed if the reactions can be planned and executed by following biomimetic approaches through supra- molecular catalysis, involving host-guest complexation, in aqueous medium

In the present context and of particular interest are water soluble hosts with hydrophobic cavities, which can mimic the enzyme-receptor relationship (enzymatic biochemical reactions) Among various possibilities, cyclodextrins offer wider scope for designing and conducting organic reactions in hydrophobic environment following microencapsulation of the substrate molecules

To overcome the drawbacks associated with the existing synthetic methodologies, many organic transformations were attempted successfully, by using cyclodextrin as a recyclable activator in aqueous medium Presently, it is attempted to bring some of the very recent research reports, including certain unpublished results, into this article, focusing mainly on

construction of heterocyclic moieties, utilizing cyclodextrin mediated biomimetic approach,

in view of the significance attached to heterocyclic chemistry

2 Furanones

Furan-2(5H)-ones are prominent structural motifs, widely present as a subunit in many natural products isolated from a variety of sources like algae, sponges, plants, insects and animals, Literature survey indicates that butenolide substructure is present in more than 13,000 natural products and is the core structural unit responsible to induce a wide range of biological properties such as antimicrobial, antifungal, anti-viral HIV-1, anti-inflamatory, and anticancer (De Souza, 2005) It is found in many biologically active natural products such as sarcophine and rubrolide etc., which are isolated from Ritterela rubra, (Miao & Andersen, 1991; Kotora & Negishi, 1997) a colonial tunicate It is also present in synthetic drug molecules like benfurodil hemisuccinate (Eucilat)

Br

Br HO

COOH O

O

benfurodil hemisuccinate (Eucilat®)

The significant biological activity associated with butenolide synthon, attracted the attention

of many researchers to develop numerous synthetic approaches for furan-2(5H)-one derivatives The preparation of 2(5H)-furanone was also reported by refluxing furfural with hydrogen peroxide followed by oxidation resulting in a mixture of 2(3H) and 2(5H)-furanones (Cao et al., 1996) Chunling Fu et al described a new method for the synthesis of 4-iodofuran-2(5H)-ones, involving iodolactonisation of allenoates with molecular iodine (Fu

Nageswar et al., during their efforts towards developing biomimetic organic synthetic protocols through supra molecular catalysis, utilizing recyclable activator like β-CD, reported a simple, one pot three component, methodology for the synthesis of 3,4,5-

Recent Advances in Biomimetic Synthesis Involving Cyclodextrins 107 substituted furan-2(5H)-one derivatives from various substituted anilines, benzaldehydes and DEAD in water, in presence of β-CD This is the first report on the biomimetic synthesis

of 3, 4, 5- substituted furan-2(5H)-ones, by the supra molecular catalysis of β-CD, in water (Murthy et al., 2009)

N H O

H 3 C

O

β-CD(10 mol%) water 60-70 o C

COOEt

COOEt

R 1 R

R = 4-CH 3 ;4-CH 2 CH 3 ;4-OCH 2 Ph;4-OCH 3 ;4-OCH 2 CH 3 ;4-Cl;

R 1 = 4-CH 3 ;4-Cl;4-F;4-I;4-nC 4 H 9 ;3-Cl;

Synthesis of 3, 4, 5- substituted furan-2(5H)-ones, in presence of β-CD as a supra

molecular catalyst in water

Initially, a model reaction was carried by the insitu formation of β-cyclodextrin complex of aniline in water at 50oC, followed by the addition of diethylacetylenedicarboxylate and benzaldehyde while stirring at 60–70oC to obtain ethyl 2,5-dihydro-5-oxo-2-phenyl-4-(phenylamino) furan-3-carboxylate in almost quantitative yield (85%) No product formation was observed, when the reaction was conducted in neat or in presence of water even after prolonged reaction times The scope of this novel and interesting transformation

to synthesize 3, 4, 5-substituted furan-2(5H)-one derivatives with various substituted anilines and substituted aldehydes was studied by keeping diethylacetylenedicaboxylate as

a common substrate All the reactions were clean, and the products were obtained in high yields (78-88%), with good amount of catalyst recovery The results indicated that the substitution on the aromatic ring has a substantial role in governing the reactivity of the substrate as well as product yield The reaction with electron donating groups like methyl, butyl on aniline gave good yield, where as in case of electron withdrawing groups, such as para-chloro and para-fluoro yields decreased The reaction was observed to be sluggish with aliphatic amines, such as benzyl amines and n-alkyl amines Structural identification of these products was established by spectral data No lactone formation was observed in the absence of β-cyclodextrin, even after longer reaction times, establishing the role of β-CD The formation of 3, 4, 5-substituted furan-2(5H)-ones, catalysed by β-CD was supported by

1H NMR studies of the inclusion complex between aniline and β-CD The hydrophobic environment in the cavity of β-CD facilitates the completion of the reaction via aniline/diethylethylenedicarboxylate carbanion, which is stabilized by the primary and secondary –OH groups of β-CD This stabilized carbanion further reacts with aldehyde resulting in the formation of 3, 4, 5-substituted furan-2(5H)-one

These reactions were conducted with a catalytic amount (10 mol %) of β-CD in water Inclusion complex was prepared by taking β-CD and aniline in 1:1 ratio for the purpose of NMR studies NMR spectrum of β-CD/aniline inclusion complex indicated upfield shift of aromatic protons as well as amine protons of aniline, due to the inclusion of aniline inside β-

CD cavity Apart from the upfield shift of aniline protons due to the incorporation of an aromatic ring inside the β-CD cavity, the protons located in the hydrophobic cavity of β-CD

cavity (C3–H and C5–H) were also shifted upfield due to magnetic anisotropy, caused by the aniline molecule (Grigoras & Conduruta, 2006) β-CD was recovered and reused for further runs of these reactions

This biomimetic methodology for the synthesis of furanone derivatives involving CD as a supramolecular catalyst in aqueous medium may have wider applications in green chemistry protocols

3 Pyrroles

The pyrrole structural motif widely occurs in nature and represents itself in many biologically important molecules such as porphyrins, alkaloids and coenzymes (Sundberg, 1996) Due to its application in many important areas, pyrrole skeleton has attracted the attention of many researchers globally Paal-Knorr synthesis, Knorr pyrrole synthesis and Hantzsch synthesis were some of the classical approaches for the preparation of pyrrroles Though over the years numerous synthetic strategies were reported for the preparation of pyrrole derivatives (Shindo et al., 2007; Cyr et al., 2007; Binder & Kirsch, 2006), most of them involve multistep synthetic processes, which reduce the overall yields Even though recently a few one-step syntheses (Shiraishi et al., 1999) are reported for the preparation of pyrrroles, these suffer from several drawbacks such as use of toxic flammable organic solvents, costly transition metal catalysts and longer reaction times To overcome these shortcomings associated with the existing methodologies, developing mild and environmentally benign synthetic protocols involving water as solvent for the synthesis of pyrrroles is desirable Use of a recyclable catalyst as a part of green chemistry approach will

be an additional advantage Nageswar et al during their efforts towards developing novel β-cyclodextrin-promoted synthetic strategies attempted for the first time simple versatile biomimetic approach for the synthesis of substituted pyrrroles from readily available building blocks in aqueous medium under supramolecular catalysis (Murthy et al., 2009)

N

F NH

O

O

Cl

N H

Initially, phenacyl bromide is solubilised in aqueous solution containing β-CD at 500 C To this β-CD-phenacyl bromide complex was added pentane-2, 4-dione followed by aniline The entire reaction mixture was stirred at 600 C-700 C till the reaction goes for completion, giving the 1, 2, 3, 5-substituted pyrrole in excellent yield (86%) To study the scope of this interesting one pot three component biomimetic approach for the preparation of pyrrole derivatives, several reactions were carried out under similar reaction conditions, changing the amine component 4-Methyl; 4-methoxy; 3, 4-dimethoxy; 4-chloro; 4-fluoro; 4-n butyl anilines, benzyl amine, 3-methoxy benzyl amine and 3-bromo benzyl amine were also utilized as reactants

Recent Advances in Biomimetic Synthesis Involving Cyclodextrins 109

O

β-CD/H 2 O 7-8 hrs

R = Ph; 4-Chloro phenyl;4-Methyl phenyl; 4-Fluoro phenyl; 4-Methoxy phenyl;

3,4-Dimethoxyphenyl; 4-n-Butylphenyl;Benzyl;3-Bromo benzyl;

3-Methoxy benzyl; 2,6-Diethyl phenyl

Synthesis of substituted pyrrole derivatives by one-pot three component approach using

β-cyclodextrin as a recyclable catalyst:

It was observed that aromatic amines with electron-donating groups in p-position gave excellent yields, where as electron- withdrawing groups in p-position gave relatively

reduced yields The reactions with aliphatic amines resulted in still lower yields

The role of β-cyclodextrin in these reactions was to solubilise and activate phenacyl bromides through hydrogen-bonding interactions, thereby promoting the reaction with pentane-2, 4-dione to complete the reaction sequence with an amine Reaction was not observed in the absence of β-CD β-CD was recovered and used to run subsequent cycles of the reaction A reaction mechanism via the formation of β-CD/phenacyl bromide complex was suggested, which was further supported by the preparation and characterization studies on β-CD/phenacyl bromide inclusion complex, which was obtained by taking β-cyclodextrin and phenacyl bromide in equimolar quantities.1H-NMR studies of the inclusion complex between β-CD and phenacyl bromide indicated the upfield shift of H-C(3) and H-C(5) of β-CD

This novel, simple, and environmentally benign methodology following the biomimetic approach, reported for the first time involving β-cyclodextrin as a recyclable activator by Nageswar et al., may be a useful application to pyrrole chemistry

4 Oxindoles

Oxindole chemistry has been extensively investigated, as it is an intermediary system between indole and isatin, two prominent structural frame works in organic chemistry Isatin was converted to oxindole via dioxindole, first by Baeyer, establishing the relationship between the compounds Reduction of isatin can be effected with a wide range of reducing agents such as sodium amalgam, zinc in acetic acid or zinc in hydrochloric acid or nickel catalyst Oxidation of indoles and its derivatives by various oxidizing agents such as KMnO4, HNO3, H2SO4, etc result in oxindole skeleton

N H

O O

N H O

OH

N H O

The Baeyer’s first total synthesis of oxindole from phenyl acetic acid via 2-nitrophenyl acetic acid was further modified and improved by different researchers such as Hahn, Hinsberg as well as Brunnes

Recently a series of substituted oxindole derivatives were synthesized and evaluated for growth harmone releasing activity (Tokunaga et al., 2001) Gallagher et al., synthesized and reported 4-[2-(Di-n-propyl amino) ethyl]-2(3H)-indolone (SK&F 101468) as a potent and selective prejunctional dopamine receptor agonist (Gallagher et al., 1985) A series of N-(3-piperidinyl)-2-indolines were synthesized and evaluated as a new structural class of nociceptin receptor (NOP) ligands (Zaveri et al., 2004) Spirotrypro statins A&B, isolated from the fermentation broth of Aspergillus fumigatus exhibited cell cycle inhibition and some of their biologically promising analogues were also reported (Edmondson et al., 1999) The spirooxindole is a prominent structural component present in a number of natural products, such as coerules-cine, elacomine, horsfiline, welwitindolinone A, spirotryprostatin

A, alstonisine, and surugatoxin These compounds exhibit potent cytotoxic activity and are also known as estrogen-receptor modulators, h5-HT6 serotonin receptors, oxytocin antagonists, and antiproliferative agents Due to their significant biological activity several synthetic methodologies have been developed for the construction of spirooxindole system

In view of the growing focus on environ friendly processes, Rao et al revisited the synthesis

of spirooxindoles by utilizing the supra molecular catalytic biomimetic approach (Sridhar et al., 2009)

Literature reports on the synthesis of spirooxindole described so far by the three component condensation reaction of isatin, malononitrile or methyl cyanoacetate, and 1, 3-dicarbonyl compounds have certain limitations as they involve the use of hazardous organic solvents,acidic or basic conditions, transition metal catalysts, surfactants, and microwave irradiation Consequently the development of environ-friendly approaches for these spirooxindoles derivatives under neutral conditions using a recyclable activator in water is desirable

A Rao et al explored the aqueous-phase synthesis of spirooxindole derivatives by the three component reaction of isatin, malononitrile, and dimedone under neutral conditions catalysed by β-cyclodextrin

In general, these reactions were conducted via the formation of β-CD complex of isatin in water This was followed by the successive addition of malononitrile and dimedone, and stirring at 600 C The corresponding spirooxindole derivatives were obtained in excellent yields (84%–91%) after 4–6 h This simple methodology reported by Rao et al was compatible with several substituted isatins having different functionalities such as bromo,

Recent Advances in Biomimetic Synthesis Involving Cyclodextrins 111 methyl, nitro, phenyl, and benzyl groups It was observed that reaction of methyl cyanoacetate with isatin and dimedone under similar conditions resulted in the expected product in very good yields All these reactions proceeded efficiently without any byproduct formation β-cyclodextrin can be easily recovered and reused

R = H, 4-Br, 6-Br, 5-CH 3 ,5-NO 2

R 1 = CH 3 ,CH 2 Ph,Ph

R 2 = CN, COOMe

β-CD-catalyzed one-pot multi-component synthesis of spirooxindoles:

The scope of this methodology has been extended to the reaction of 4-hydroxy coumarin and barbituric acid under similar reaction conditions to obtain spirooxindole derivatives in impressive yields Isolation of β-CD-isatin complex confirmed the complexation process It was observed from 1H NMR studies (D2O) of β-CD, β-CD-isatin complex, and freeze-dried reaction mixture of isatin-malononitrile-dimedone, that there was an up-field shift of H3 and H5 protons of cyclodextrin in the β-CD–isatin complex as compared to β- CD.This proves the formation of an inclusion complex of isatin with β-CD from the secondary side

of cyclodextrin Authors observed that the spectra of the reaction mixture of the β-CD–isatin complex after the addition of malononitrile and dimedone after 2 h, showed an upfield shift

of the CD H6 proton This confirms that the reaction proceeded by the complexation of malononitrile and dimedone from the primary side of cyclodextrin and that isatin is ideally placed for the condensation with malononitrile and dimedone in the cyclodextrin cavity

In the absence of cyclodextrin, the reaction was observed to proceed in lower yields even after longer reaction times During complexation with β-CD the reactivity of the keto group

of isatin increased due to intermolecular hydrogen bonding with the CD-hydroxyl groups This facilitated the Knoevenagel condensation with malononitrile to form an isatylidene malononitrile, which undergoes the established sequence of reactions successively such as Michael addition of dimedone, and the cycloaddition of hydroxyl group to the cyano moiety

to form the desired spirooxindole derivatives

This neutral aqueous phase one-pot three-component biomimetic synthesis of various spirooxindole derivatives by the reaction of isatin and 1, 3-dicarbonyl compounds, is an impressive addition to green chemistry

B α-Hydroxyphosphonates are prominent class of biologically active compounds as well as useful reactive intermediates(Maryanoff & Reitz, 1989) In view of significant biological importance associated with α-hydroxy phophonates, this synthon has attracted enhanced research interest These are extensively used in pharmaceutical applications such as enzyme inhibitors of renin, HIV protease and EPSP synthase (Patel et al., 1995) They also exhibited potential biological activities, such as antibacterial, antiviral, anti-inflammatory, laxative,growth hormonal, and anticancer activities (Stowasser et al., 1992) They are also

used in the synthesis of 1, 2-diketones from acid chlorides, ketophosphonates and aminophosponates (Kaboudin, 2003; Firouzabadi et al., 2004; Iorga et al., 1999)

α-Generally the synthesis of α-hydroxy phosphonates involve the reaction of aldehydes or ketones with dialkyl or trialkyl phosphites in the presence of acidic or basic catalysts α-Hydroxy phosphonates can also be synthesised from Tris(trimethylsilyl) phosphite but it requires elevated temperature under anhydrous reaction conditions However, these methodologies suffer from several drawbacks such as the use of hazardous solvents, acidic conditions and metal catalysts Consequently, the development of environfriendly biomimetic approach under neutral conditions for the synthesis of α-hydroxy phosphonates

is desirable Aqueous phase organic synthesis has recently become the focus in the development of green synthetic protocols, and it can be made more sophisticated if they can

be performed under supramolecular catalysis

OR 2

OR 2

OH or

α-Initially a reaction was conducted by the insitu formation of the β-CD complex of the isatin

in water followed by the addition of dialkyl or trialkyl phosphite The reaction mixture was stirred at room temperature to give the corresponding α1-oxindole-α-hydroxy phosphonates

in impressive yields (86-94%) Scope of this reaction was extended to involve various substituted isatin Reactions performed under similar conditions proceeded efficiently without the need of any metal or acid catalyst Even though the reactions occurred in presence of α-CD and γ-CD,with lesser yields, inexpensive and easily accessible β-CD was selected as the mediator.Different substituted oxindoles synthesised by this simple and practicable methodology were characterized by their spectral data

The catalytic efficiency of cyclodextrins for these reactions was established as no reaction was observed in the absence of cyclodextrin Evidence for complexation between the isatin and cyclodextrin was deduced from NMR studies A comparison of the 1H NMR spectra (D2O) of β-CD, β-CD: isatin complex revealed, the upfield shift of H3 and H5protons of cyclodextrin in the β-CD: isatin complex as compared to β-CD This confirmed the formation

of an inclusion complex of isatin with β-CD.During complex phenomenon the keto group of isatin will be activated due to the inter molecular hydrogen bonding between CD-hydroxyl