Enantiomerically pure compounds related to chiral hydroxy acids derived from renewable resources

Simimole Haleema a , Paleapadam Vavan Sasi a , Ibrahim Ibnusaud * a , Prasad L. Polavarapu * b and Henri B. Kagan c
a Institute for Intensive Research in Basic Sciences, Mahatma Gandhi University, Kottayam, Kerala, India. E-mail: i.ibnusaud@gmail.com; Fax: +91 (0)481 2732992; Tel: +91 (0)481 2732992
b Department of Chemistry, Vanderbilt University, Nashville, Tennessee, 37235, USA. E-mail: Prasad.L.Polavarapu@vanderbilt.edu; Fax: +1 (615) 322 4936; Tel: +1 (615) 322 2836
c Equipe de Catalyse Moléculaire-ICMMO - Bât 420, Université Paris-Sud, 15, rue Georges Clemenceau, 91405 Orsay Cedex, France. E-mail: henri.kagan@icmo.u-psud.fr.; Fax: +33 (0)1 69 15 46 80; Tel: +33 (0)1 69 15 78 95

Received 19th June 2012 , Accepted 19th June 2012

First published on 22nd June 2012

Abstract

An inventory of enantiomerically pure compounds of agrochemical , pharmaceutical and of functional interest derived from naturally occurring chiral α-hydroxy acids has been presented. Attention has been focused on the employment of relatively less documented hydroxycitric acids namely isocitric, garcinia and hibiscus acids. Synthetic applications have been reviewed. The chiroptical studies on these new classes of compounds have also been presented.

Introduction

Chiral compounds are the key components in the modern agro-chemical and pharmaceutical industries. Synthesis of both natural and unnatural organic compounds in the enantiomerically pure form is one of the contemporary challenges in organic chemistry. 1

There is a close relationship between biological activities and absolute configurations of synthetic compounds, or natural products, used as drugs , agrochemicals and/or fragrance . 2,3 The self-organization of bio-molecules leading to the properties beyond those of individual molecules relies on the enantiomeric purity of chiral compounds. The two enantiomers of a synthetic chiral drug interact differently with its receptor site and often lead to different biological effects. In several cases undesirable side effects or even toxic effects may occur with the antipode. 4 There are also cases when a particular composition of enantiomers is an essential criterion for the desired biological function 4–6 (for instance, D.frontalis , a natural pheromone was found to be a mixture of two enantiomers in a ratio of 85:15). 7–9 The necessity for the syntheses of enantiomerically pure compounds is evident from structure–activity studies. It is estimated that 80% of small-molecule drugs approved by the FDA were chiral and 75% were single enantiomers and in nine of the top ten drugs , the active ingredients are chiral. This comes close to more than half of all drug sales world-wide in 2006 (which was one third in 2001). It is estimated that about 200 chiral compounds could enter the development process each year. 10–15 The economic interests are obvious for the production of enantiomerically pure compounds in a sustainable manner.

Methods for obtaining enantiopure compounds

There is a surge for the development of efficient methods for gaining access to enantiomerically pure compounds with diverse architectures and varying degrees of complexity. This can be accomplished in three different manners: (a) classical asymmetric synthesis involving chiral catalysts (enzymatic or nonenzymatic) or stoichiometric use of chiral auxiliaries or microbes; (b) the chiral pool approach in which the conversion of an enantiopure compound obtained from the chiral pool to the desired chiral substance (semi-synthetic approach); and (c) traditional methods of resolution of a racemic mixture to enantiomerically pure compounds. 16–27 Production of enantiopure compounds employing microbes–enzymes, and semi-synthetic approaches are considered environmentally benign as these approaches reduce the number of chemical steps to reach the final structures. The outcome of resolutions is often unpredictable (the chance of success for a typical resolution experiment is estimated at 20–30%) 28 and may wastefully consume precious starting materials and reagents that might lead to the wrong enantiomer, which must then be racemised or discarded. Recovery of resolving agents may also be required. However, dynamic kinetic resolution is quite efficient when it is possible to combine a fast in situ racemization of the substrate and slow and fast stereoselective transformation of one enantiomer to the desired product. 29–31

Chiral pool approach towards enantiomerically pure compounds

A wide range of natural products with remarkable skeletal build-up and multiple-functionality can be obtained from renewable resources. The chiral pool approach is extremely attractive when the starting compound is abundant and can be judiciously converted to the desired structure in few steps. However, this strategy is confined to only some selected classes obtained from the chiral pool, as compounds with matching stereo-structure to that of target compounds are not frequently encountered. Usually there is unavailability of the natural products in both enantiomeric forms, although sometimes the rare enantiomer is also natural (in the case of tartaric acid ) or two different plants can give opposite enantiomers (some terpenes for example). However, the major advantages of the chiral pool approach, and microbial production of enantiomerically pure compounds, are that they are environmentally friendly, often economically viable and practically convenient. Hence considerable effort and creativity has been expended for the use of enantiopure, inexpensive compounds such as terpenes , carbohydrates , hydroxy acids, and amino acids obtained directly from the chiral pool for target-oriented syntheses. 9,32–37

There is a renewed interest for the identification, isolation and utilization of natural products in the semi-synthesis of desired chiral compounds to save several synthetic steps. This approach forms an aspect of green chemistry. Naturally occurring chiral hydroxy acids in the enantiomerically pure form are one of the major sources of bioactive molecules or of useful synthetic equivalents (Table 1).

Table 1 Some of the naturally occurring chiral hydroxy acids
Name of the natural product Structure
( S )-2-Hydroxypropanoic acid ( lactic acid )
( S )-Hydroxybutanedioic acid ( malic acid )
(2 R ,3 R )-2,3-dihydroxybutanedioic acid ( tartaric acid )
( R )-2-hydroxy-2-phenylacetic acid (mandelic acid)
(2 S ,3 R )-tetrahydro-5-oxo-2, 3-furandicarboxylic acid ( isocitric acid )
(2 S ,3 S )-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylic acid (garcinia acid)
(2 S ,3 R )-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylic acid (hibiscus acid)

Convenient functionalization makes these acids quite promising. Malic (apple acid), tartaric (grape acid), and citric acids are all structurally related. In a seminal work, Seebach recognized the potential of, especially tartaric acid , as a prime chiral building block for the synthesis of several functionally important compounds. 38 The present review highlights the source of common as well as rare chiral hydroxy acids and attempts to provide a concise and practical source of information on a variety of functionally and biologically useful enantiomerically pure molecules ranging from relatively simple, with only one asymmetric center, to those having multiple chiral centers.

Though natural α-hydroxy acids have been extensively used as a renewable enantiomerically pure source for various aspects of chirality, no attempt has been made to explore the synthetic utility of closely related and less known, but abundantly distributed, hydroxycitric acids. Hence attention has been focused on the use and scope of naturally occurring hydroxy acids including recently identified (2 S ,3 S ) and (2 S ,3 R )-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids (garcinia and hibiscus acids, 6 and 7). The limiting factor for the synthetic scope of hydroxycitric acids could be attributed to the non-availability of any convenient method for a large-scale isolation from complex plant extracts. In order to overcome this hurdle, our laboratory has recently developed practical and economic procedures for the large-scale isolation of both compounds from plant sources with high purity. 39–44 Our recent studies proved that these acids are another class of hydroxy acids with tremendous promise as a source of enantiomerically pure organic compounds. 45,46

Chirality and Plants

Though plants are a rich source of enantiomerically pure secondary metabolites , the number of plants that have been extensively studied is relatively low (only 5%). Often crude extracts of these plant materials are used in medicine. Table 2 and Table 3 show annual production of some chiral compounds from the chiral pool and the major chiral acids present in fruits and vegetables, 47 respectively.

Table 2 Annual productions of some chiral compounds from the chiral pool
Product World production/tons per annum
Carbohydrates
L -Ascorbic acid 35000
D -Glucose 5000000
D -Sucrose 100000000
Hydroxy acids
L -Lactic acid 25000
L -Tartaric acid 10000
L -Malic acid 10
Amino acids
L -glutamic acid 650000
D -Alanine 100
L -Cysteine 4750
Alkaloids
Ephedrine 500
Cinchonidine 50
Terpenes
(−)carvone 500
(−)-α-pinene 25000
Table 3 Major chiral acids present in fruits and vegetables
Source Major acids present
Fruits
Apples Malic acid
Avocados Tartaric acid
Bananas Malic acid
Blackberries Isocitric, malic acids
Cherries Malic acid
Crabapples Malic acid
Cranberries Citric, malic acids
Currants Tartaric acid
Grapes Malic and tartaric acids (3:2)
Limes Citric, malic acids
Loganberries Malic acid
Nectarines Malic acid
Orange peel Malic acid
Passionfruits Malic
Peaches Malic acid
Pears Malic acid
Pineapples Malic acid
Plums Malic acid
Vegetables
Beans Citric, malic acids
Broccoli Malic and citric acids (3:2)
Carrots Malic, citric, isocitric acids
Mushrooms Lactarimic acid
Peas Malic acid
Potatoes Malic acid
Tomatoes Malic acid
Rhubarb Malic acid

Agrochemical , pharmaceutical and functionally important compounds, based on renewable enantiopure hydroxy acids

The use of enantiopure natural products obtained from renewable resources as a source of chirality in synthesis has become routine in the past two to three decades.

Enantiopure hydroxy acids were quickly recognized as a basic source of chirality with highly functionalized structures. 38,48 The naturally occurring chiral compounds, especially ( S )-2-hydroxypropanoic acid [ ( S )-(+)-Lactic acid ], ( S )-hydroxybutanedioic acid [( S )-(−)-Malic acid], (2 R ,3 R )-2,3-dihydroxybutanedioic acid [( R , R )-(+)-Tartaric acid] and Citramalic acid (α-methyl analogue of ( S )-malic acid ; used less often) and their derivatives are well known as enantioselective agents ( catalysts , ligands , modifiers or metal based reagents) and building blocks. 49–51 This review is concerned with the recent applications of chiral α-hydroxy acids in the semi-synthetic pathways, since 2000. The milestone catalysts developed include Ti/DET 52,53 (Sharpless, asymmetric epoxidation ) (8), DIOP 54–56 (Kagan, a bidentate phosphine ligand used for the enantioselective hydrogenation of olefins ) (9), TADDOLs, 57–59 (Seebach, ligand for Lewis acid catalysts in Diels–Alder reactions, [2+2] cycloadditions, etc ) (10), and chiral acyloxy boranes (Yamamoto, a Lewis acid catalyst for the condensation of simple chiral enol silyl ethers of ketones with various aldehydes ) 60,61 (11) (Fig. 1). These examples show that the derivatisation of a quite simple basic structure from the chiral pool may lead to successful enantioselective catalysts in different chemical reactions.

Fig. 1 Milestone ligands or catalysts derived from tartaric acid .

The industrial applications of these acids as chiral selectors for the development of a chiral stationary phase for liquid chromatographic separations, 62–64 chiral NMR discriminating agents, 65–69 chiral solvating agents, 69,70 chiral catalysts , 71–73 chiral liquid crystals, 74 chiral dopants, 74 dental material, ceramics, paints, electrochemical coatings and piezoelectronic devices are also known. Malic diesters are useful as mosquito repellents.

Lactic acid

Lactic acid (1, Fig. 2) occurs naturally in sour milk and in minor amounts in the muscle of animals, including humans. It can be manufactured either by chemical synthesis or by microbial fermentation . Chemical synthesis often results in racemic products, whereas the enantioselective synthesis of the D or L form can be obtained by fermentation using a specific microbial strain. 75 Commercially, lactic acid is produced by the fermentation of carbohydrates . It is currently obtained via bacterial fermentation from corn as a platform chemical for the production of the biodegradable polymer , poly- lactic acid (PLA). 76,77 PLA is used as an environmentally benign substitute for petro-chemically derived plastics as well as in some medical applications. 78 Being a simple hydroxy acid it has been an attractive source from the chiral pool, for the synthesis of several chiral synthons with one chiral centre. It is used for both food and non-food applications including cosmetics , pharmaceuticals , agrochemicals ( Duplosan ) 79 and chemical production. Table 4 shows the important chirons and compounds prepared from lactic acid and lists their biological and synthetic applications.

Fig. 2 Three-carbon skeleton with one chiral center.

Table 4 Important chirons and compounds prepared from lactic acid and its biological and functional applications

Starting molecules Chiral synthons/compounds prepared Applications References
Synthesis of (+)-conagenin 81
1 Preparation of block copolymers 82
1 Synthesis of (+)-macrosphelides 83
1 Synthesis of polyether – ester dendrimers 84
1,3-Dipolar cycloaddition of nitrones to methacrolein 85
1 Chiral tether groups for intra-molecular and diastereoselective [2+2] photocycloaddition reactions. Temporary chiral linker in the total synthesis of (−)-italicene and (+)-isoitalicene 86,87
16 or 1 Biodegradable polymer -medical applications such as tissue engineering 88–91
For the preparation of chiral sulfoxides which are useful auxiliaries in asymmetric synthesis especially in the field of biology and material science, for example in the synthesis of ferroelectric liquid crystals 92–94
1 An intermediate in the biosynthetic pathway of lysine in yeast and some fungi 95,96
1 Chiron (high demand in commodity chemicals) 97,37
1 Preparation of aminooxy peptides 98
1 Enantioselective benzoylation of α-aminoesters 99
1 Synthesis of α-aminoxy amino acids and hybrid peptides 100
16 Herbicide 101
1 Enantioselective Diels–Alder reactions, hydrogenations, Friedel–Crafts reactions etc 102,103
Fungal metabolite 104,105
1 Chiron 106
1 β-Blocking agents 107,108

Malic acid

( S )-(−)-Malic acid (2, Fig. 3) occurs naturally in apples and other fruits and is otherwise known as ‘apple acid’. It is considerably more expensive than the one manufactured industrially by the fermentation of fumaric acid . Also, there are a few synthetic methods which have been developed for the preparation of enantiomerically pure malic acids. 80 It is an extremely versatile 4-carbon building block possessing a carboxyl group at the 4-position that serves as a useful “handle” that is easily manipulated to provide variety of synthetically useful functionalities. 38 Table 5 shows the important chirons and compounds prepared from malic acid and lists their biological and functional applications.

Fig. 3 Four carbon skeleton with one chiral center.

Table 5 Important chirons and compounds prepared from malic acid and its biological and functional applications

Starting molecules Chiral synthons/compounds prepared Applications References
Synthesis of (−)-wikstromol 109
Synthesis of chiral tetronic acids 110
33 Synthesis of (2 S ,3 S ,7 S )-3,7-dimethylpentadecan-2-yl acetate and propionate, the sex pheromones of pine sawflies 111
2 High cytotoxicity against KB cancer cells lines as well as antiprotozoal activity against plasmodium falciparum strains K1 and NF54 112
Ferrocenes with planar chirality used for the synthesis of chiral ligands in asymmetric catalysis, material chemistry and biology 113
Most selective serine / threonine protein phosphatase 2A(PP2A) inhibitor , potent cytotoxic activity in vitro against a range of cancer cells lines, and in vivo antitumor activity toward lymphoid leukemias 114
33 ( R )-(−)- and ( S )-(+)-homocitric acid lactones and related a -hydroxy dicarboxylic acids 115
2 Chiral synthons 116–118
2 Total synthesis of secondary metabolite xestodecalactone C 119
2 Methyl pyrrolidine alkaloids 120
2 A building block of the N -substituent of the chiral amino alcohol unit 121
Folk medicine for the treatment of fever, pain, snake-bites and lung disease 122
2 Synthesis of enantiomerically pure 2,5-disubstituted 3-oxygenated tetrahydrofurans units present in many marine natural products. This structural unit also appears as part of more complex ring systems such as the bicyclo[3.3.0]octane system of (−)-kumausallene 123,124
2 Stereoselective total synthesis of polyrhacitide A which has significant analgesic and anti -inflammatory activities 125
Total synthesis of 2- o -feruloyl- L -malate, 2- o -sinapoyl- L -malate and 2- o -5-hydroxyferuloyl- L -malate 126
2 Synthesis of enantiomerically pure ethyl 2-hydroxy-4-phenylbutanoate which has great biological importance, since it is a versatile key intermediate for the synthesis of a variety of angiotention converting enzyme ( ACE ) inhibitors 127
2 Total synthesis of grandisine D, which was proposed to be a biogenetic precursor of grandisines B and F and (−)-isoelaeocarpiline 128
2 Synthesis of 4-(6-aminopurine-9-yl)-2-hydroxybutyric acid methyl ester (DZ2002), a potent reversible inhibitor of SAHase. DZ2002 is regarded as a promising therapeutic agent for immune-related diseases 129
2 Synthesis of spiroacetal moiety of antitumour antibiotic ossamycin 130
Synthesis of 35-deoxy amphotericin B aglycone, which has great importance in medicine 131
2 Synthesis of (−)-dictyostatin 132
33 Synthesis of antiproliferative cephalotaxus esters 133
2 Total synthesis of the antitumor agents neolaulimalide, isolaulimalide, laulimalide 134
2 Synthesis of polyhydroxylated central part of phoslactomycin B that shows selective PP2A inhibitory activity. 135
2 For investigating the stereochemistry of 2-hydroxyheptanoic acid and to confirm the absolute configuration of verticilide, a 24-membered cyclic depsipeptide isolated from the culture broth of Verticillium sp . FKI-1033 136
2 Asymmetric total syntheses of novel Aspidosperma indole alkaloids , (−)-subincanadines A and B 137
2 Synthesis of novel 3-pyrrolidinyl derivatives of nucleobases 138
2 Synthesis of 6-epiprelactone-V which are poly-substituted chiral δ-lactones used as building blocks in natural product synthesis 139
2 Synthesis of poly(ester amide)s 140
33 Total synthesis of (−)-phorboxazole A, a potent cytostatic agent from the sponge Phorbas sp. 141
2 Synthesis of ( R )-2-methyl-4-deoxy and ( R )-2-methyl-4,5-dideoxy analogues of 6-phosphogluconate as potential inhibitors of 6-phosphogluconate dehydrogenase 142
2 Synthesis of (+)-benzoyl pedamide which is a part of pederin, a potent insect toxin isolated from paederus fuscipes . 143
2 Chiral building block for the total synthesis of a stereoisomer of bistramide C, a new class of bioactive polyethers isolated from the marine ascidian Lissoclinum bistratum 144
2 Chiral building block for the synthesis of analogues of the antibiotic pantocin B 145,146
2 Chiral building block for the asymmetric synthesis of (+)-ioline, a pyrrolizidine alkaloid from rye grass and tall fescue 147,148
2 Synthesis of polyhydroxylated pyrrolizidine alkaloids 149
2 Synthesis of macrolactin A which inhibits B16-F10 murine melanoma cancer cells and mammalian Herpes simplex viruses I and II, and protects human T lymphoblasts against HIV replication 150

Tartaric acid

Natural ( R , R )-(+)-tartaric acid (3, Fig. 4) is one of the cheapest enantiomerically pure organic compounds. It is readily available as a by-product from the wine industry (cream of tartar). It occurs in many fruits (tamarind, grapes etc ) both as the free acid and the salt. The natural abundance of this compound has insured its popularity as a chiral building block. The importance of the C2 symmetry of tartaric acid and some of its derivatives in a variety of chemical and physical processes have been widely appreciated. With the advantage of having two adjacent chiral centers, tartaric acid is also proved to be the most ideal choice for preparing naturally occurring biologically active target compounds bearing two centers of chirality. 37,38,151 The opposite enantiomer of 3 is also present in nature, though in small quantities. Some recent applications are presented in Table 6.

Fig. 4 Four-carbon skeleton with two chiral centers.

Table 6 Important chirons and compounds prepared from tartaric acid and their biological and material applications

Starting molecules Chiral synthons/compounds (material) prepared Applications References
Pharmaceutical building blocks, dienophile in Diels–Alder reactions 152
Synthesis of L - lyxo -phytosphingosine 153
85 NMR solvating agents 69,70,154–158
3 Chiral stationary phase 159–161
3 Chiral ligand for Diels–Alder reactions, [2+2] cycloadditions etc , chiral phase transfer catalyst . 162
3 Chiral ligand for asymmetric hydrogenations of olefins 163
85 Asymmetric hydrogenation of enamides 164
3 Pharmaceutical co-crystal- phosphodiesterase IV inhibitor with L -tartaric acid 165
3 Pleiotropic biological activity 166
85 Synthesis of acyclic C1–C7 fragment of peloruside B to set the absolute stereochemistry. 167
85 A versatile bridging intermediate en route to aminocyclitols units which are found in valienamine, conduramines A-1 and E and a key intermediate of (+)-pancratistatin 168
85 Preparation of chiral selector 169
85 Synthesis of homo- N -nucleoside analogues 170
85 Synthesis of antiproliferative imidazole and imidazoline analogs for melanoma 171
3 or 85 Total synthesis and absolute configuration of the styryl lactone gonioheptolide A 172
3 or 85 Chiral resolving agent 173–175
3 Chiral ligand 176
85 Stereoselective synthesis of antitumor tetrahydrofuran (+)-goniothalesdiol 177
85 Preparations of D - ribo - and L - lyxo -phytosphingosines 178,179
3 or 85 Preparation of chiral catalysts 180
3 Enantioselective synthesis of (−)-muricatacin, a bio-active lactone 181
3 Synthesise of β-lactam-azasugar hybrid 182
3 Chiral sulfonamide ligand 183,184
3 or 85 Synthesis of 3- methoxy-4-methylaminopyrrolidine for a synthesis of AG-7352 which is a novel anti -tumour agent 185
3 Chiral synthons 186
3 Enantioselective synthesis of (1 R )-1-(hydroxymethyl)-2-acetyl-1,2,3,4-tetrahydro-β-carboline 187
3 Ligands in chiral acyloxy borane (CAB), catalyst for enantioselcetive Diels–Alder reactions, hetero Diels–Alder reactions ,allylation, allylation polymerizations, for the synthesis of chiral depsipeptide dendrimers. 188,60,61
Construction of enantiomerically pure γ-butyrolactones 189
3 Dynamic kinetic resolution of benzhydryl quinuclidinone , which are used as precursor to substance P antagonist 31
3 or 85 Used as an organo catalyst for the synthesis of α-aminophosphonates 190

Mandelic acid

Mandelic acid (MDA 4, Fig. 5) is a simple chiral hydroxy acid that has been commonly used as a resolving agent for chiral separation, especially for chiral alcohols . 191–193 Commercially, enantiomerically pure mandelic acid is prepared by a chemical method from benzaldehyde as precursor, using nitrilase enzymes. 194 Also there are reports available for the chemical synthesis of DL -mandelic acid from benzaldehyde and chloroform by using ultrasonic phase transfer catalysis method. 195 It has long been known for use as a urinary antiseptic. For example, methenamine mandelate is marketed in the USA under the name Mandelamine. Recently, polymandelic acid (PMDA) synthesized via the concentrated sulfuric acid treatment of mandelic acid has attracted attention as a viable candidate in various biomedical applications such as contraceptive, antimicrobial activity and as a novel microbicide to prevent the sexual transmission of both human immunodeficiency virus (HIV-1) and herpes simplex virus (HSV). 191 MDA and its derivatives are also useful as chiral auxiliaries for stereo selective transformations. 196 Table 7 shows the important chirons and compounds prepared from mandelic acid and lists their biological and functional applications.

Table 7 Important chirons and compounds prepared from mandelic acid and their biological and material applications

Starting molecules Chiral synthon prepared Applications References
synthesis of 1,1′-diphenylthiodiacetic acid dihydrazide 197
119 Anti-microbial, contraceptive and anti HIV-1 activity 191
Piracetam-( S )-mandelic acid co-crystal Pharmaceutical co-crystal 198
122 Used as tether groups for intramolecular and diastereoselective [2+2] photocycloaddition of 3-oxocyclohexene carboxylic acid derivatives 199
122 Used for the enantiopure synthesis of ( S )-oxybutynin, a muscaronic receptor antagonist for the treatment of urinary frequency, urgency, and urge incontinence 200
4 or 122 Chiral resolving agent for the preparation of many biologically active compounds, for example, β-amino alcohols, tramedols etc. 201,202
4 Chiral acetate synthons 203
122 Chiral acetate synthons 203
4 Used for the total synthesis of (+)-crassalactone A which shows cytotoxic activity against a panel of mammalian cancer cell lines 204

Isocitric acid

Isocitric acid (5, Fig. 6) a chiral acid known since 1890 and racemic isocitric acid were first prepared by Fittig. 205 The natural occurrence of isocitric acid lactone was first demonstrated by Nelson, 206 who isolated the material as the triethyl ester and as the diethyl ester lactone from blackberries and who found that it was by far the predominating acid of this fruit. Pucher 207–210 et al. isolated isocitric acids from Bryophyllum leaf tissue, a rich natural source of this acid. Isocitric acid is one of the components of the series of enzymatic reactions generally referred to as the Kreb's tricarboxylic acid cycle, a mechanism that is as advanced as the explanation for respiration in living cells. As a member of the Kreb's tricarboxylic acid cycle, it is also presumably present, although doubtless only in trace amounts, in all living cells in which this biochemical mechanism for respiration occurs. 211 It is, accordingly, a substance of considerable importance to biochemists.

Fig. 6 Six-carbon skeleton with two chiral centers.

The main disadvantage in the isolation of 5 from natural sources is the separation from its constitutional isomer citric acid , which invariably accompanies it. 212,213 Only from 15 to 30 percent of the isocitric acid present could be isolated as dimethyl isocitrate lactone, the balance of the acid being present in crystallisable oils that were found to be rich in trimethyl isocitrate . The lactone itself cannot be used for isolation because, unlike the synthetic material, the optically active natural substances do not crystallize well in the presence of impurities. However the dimethyl ester has excellent crystallisable properties. 208

Many chiral organic acids in enantiomerically pure form are produced by various microorganisms in sufficient yields for commercial manufacture by fermentation . 214 Yeasts are known to excrete citric acid and isocitric acid in varying proportions when grown on some carbon sources including long chain n -alkanes or glucose . Several reports are available for the improved production of isocitric acid . 215 However, attempts to separate citric acid from isocitric acid have so far been successfully done only on an analytical scale. As a result of the scarce availability of enatiopure isocitric acid , reports on the use of 5 as a chiron are rare. Recently, Giannis et al. have succeeded in the isolation of enantiopure (2 R ,3 S )-isocitric acid by fermentation of sunflower oil in kilogram amounts. 216,217 Table 8 shows the important chirons and compounds prepared from isocitric acid and lists their biological and functional applications. To best of our knowledge, no systematic study has been reported to check the enantiopurity of various isomers of isocitric acids in view of the fact that the C2 and C3 chiral carbon atoms of these molecules are prone to epimerization under acidic and basic conditions. The enolisation and subsequent protonation of isocitric acid (and hydroxycitric acids, Scheme 1) offers no guaranty for the stereochemical integrity of the chiral centers during any chemical reaction with these molecules (Scheme 2).

Scheme 1 Epimerization of diastereomeric hydroxycitric acids.
Scheme 2 Racemisation of diastereomeric isocitric acids via sequential epimerization.

Table 8 Important chirons and compounds prepared from isocitric acid and their biological and material applications

Starting molecules Chiral synthon prepared Applications References
Non-natural amino acid synthons 216
135 Chiral synthons 216

2-Hydroxycitric acid (HCA) and related optically active γ-butyrolactones

2-Hydroxycitric acid (HCA) belongs to the class of organic acids which are widely utilized in medicines and food additives . 214,218–220 Out of the four isomers of 2-hydroxycitric acids, the (2 S ,3 S ) and (2 S ,3 R )-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acids (garcinia and hibiscus acids, 6 and 7), are extensively distributed in nature (Scheme 3). However no report is available on the existence of other stereoisomers (2 R ,3 R ) and (2 R ,3 S )-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic acids naturally. The acid 6 is known to be present in the plant species Garcinia cambogia , which is extensively distributed across southern parts of India. The dried rind of the fruit, popularly known as “Malabar tamarind” is traditionally used as a condiment and is readily available in several markets in many Asian countries. The other isomer 7 is present in the calyxes/leaves of Hibiscus sabdariffa (Mathippuli) and the leaves of Hibiscus furcatus (Uppanacham) and Hibiscus cannabinu . 39–41,218–222

Scheme 3 Structures of stereoisomers of hydroxycitric acids, isocitric acids and their corresponding lactones .

All these plants are distributed across many countries and the plant materials are available in large quantities throughout the seasons. The isolation of 5, 6 or 7 as open tricarboxylic acids , i.e. in the natural form is extremely difficult because of their spontaneous lactonisation during their isolation process due to the presence of a γ-hydroxy group. So these compounds are only available under the γ-butyrolactone structure (Scheme 4).

Scheme 4 Natural and lactone forms of garcinia and hibiscus acid.

However, the open structures of 6 and 7 are made available by converting to its triesters (Table 9, 164–166 and 168–170)

Table 9 Some important chiral synthons and compounds based on garcinia acid (GA) and hibiscus acid (HA)

Starting molecules Chiral synthons/compounds prepared with stereochemistry matching that of GA and HA Applications (relevant properties of the derived compounds) References
Preparation of chiral butenolides , chiral probe for characterizing chiroptical studies of achiral surfactants 46,266–270
Preparation of chiral butenolides 46,266–269
149 Subunit in many natural products 45,246,248,271
Chiron for the synthesis of biologically important chiral pyrrolidine diones 37,38,237,272,273
Chiral synthons 41,42
Chiral synthons 41,42
148 Chiral synthon 41,42,46
Chiral synthons 41,42,46
164 Chiral building blocks used for the syntheses of compounds having potent inhibitory activities against purine nucleoside phosphorylases, aldose reductase inhibitors , antibacterial activity etc. 37,38,237,273–288
Chiral building blocks used for the syntheses of compounds having potent inhibitory activities against purine nucleoside phosphorylases, aldose reductase inhibitors , antibacterial activity etc. 37,38,237,273–288
168 Chiral building blocks used for the syntheses of compounds having potent inhibitory activities against purine nucleoside phosphorylases, aldose reductase inhibitors , antibacterial activity etc. 37,38,237,273–288
Chiral building blocks used for the syntheses of compounds having potent inhibitory activities against purine nucleoside phosphorylases, aldose reductase inhibitors , antibacterial activity etc. 37,38,237,273–288
6 Chiral building block used for the synthesis of pharmacologically important natural products 37,38,42,289
6 Chiral intermediates 44
154 Chiral intermediates 45
6 Chiral intermediates 45
6 Chiral intermediates 45
200 Chiral intermediates 45
202 Chiral intermediates 45
200 Chiral intermediates 45,216
149 Chiral butenolide 46,266,268,269
7 Chiral intermediates 45,46,37,38
154 Flavor component 46,246,248,271
203 Pharmacological and biological activities, such as antitumor, antibiotic , antifungal, and antibacterial 249–265
202 Pharmaceutically important molecules 249–265
203 Pharmacological and biological activities, such as antitumor, antibiotic , antifungal, and antibacterial. 249–265
203 Pharmacological and biological activities, such as antitumor, antibiotic , antifungal, and antibacterial 249–265,290–292
208 Aroma components in high quality alcoholic beverages 46,293,294
206 Non-natural lactone -amino ester 45,216
200 Biological activities such as inhibition of fungal spore germination, antibacterial action, inhibition of glutamate transport in rat liver mitochondria, inhibition of glutamate transport in rat liver mitochondria, irreversible inhibition of vaccinia H1 related (VHR) phosphatase activity 45,295–299
200 Biologically active molecules 45,295–299
200 Biologically active molecules 45,295–299
202 Inhibition of the germination of fungi, antibacterial and phytotoxic activities 45,300,301
202 Biologically important molecules 45,300,301
202 Biologically important molecules 45,300,301
202 Biologically active molecules 45,300,301
6 Biologically active molecules 216
206 Chiral synthons 45,216
Aroma components in high quality alcoholic beverages 46,293,294
6 Biologically active molecules, PLA2 inhibitors 239,302–305
6 Biologically active, psychotic molecule. 37,42,306
6 Sex pheromone for the Japanese beetle, Popillia japonica 37,7
Chiral ligands in Diels–Alder reaction of cyclopentadiene with crotonamides (3-acyl-1,3-oxazolidin-2-ones). Chiral dopant in liquid crystal 38,57,58
Chiral ligands in Diels–Alder reaction of cyclopentadiene with crotonamides (3-acyl-1,3-oxazolidin-2-ones). Chiral dopant in liquid crystal 38,57,58
6 Chiral reducing agents with poor selectivity 37,38,60–62,307
7 Chiral reducing agents with high enantio selectivity 36,37,59,60,307
199 Chiral stationary phase 62

It may be noted that the absolute configuration of C3 is fixed and C2 is prone to epimerisation in all the isomers of hydroxycitric acids (Scheme 1) under acidic or basic conditions. This property can be carefully exploited for the production of the unnatural stereoisomers of hydroxycitric acids (140 and 141). There are a few reports for the synthesis of racemic 6 and 7. 223,224

Natural and synthetic γ-butyrolactones and related bislactones have attracted much attention due to their biological and functional properties. 45,46,57,225–227 Functionalized chiral γ-butyrolactones are important chiral building blocks for the syntheses of many potential drugs ( antibiotics , antileukemics, antifungal etc. ), pheromones , and flavor components. 45,46,228 They are also useful to prepare chiral catalysts , chiral doping agents, chiral calixarenes , chiral stationary phases, etc. Though naturally occurring hydroxycitric acids 6 and 7 have been known since the 1960s, these compounds have not yet appeared in the wide spectrum of asymmetric syntheses, irrespective of the fact that these compounds can easily be made available (from cheap natural sources) as a renewable feedstock.

The physiological and biochemical effects of 2-hydroxycitric acids have been studied extensively for their unique regulatory effect on fatty acid synthesis, lipogenesis, appetite, and weight loss. 217,220,227 The derivatives of 2-hydroxycitric acids ( i.e. in the open form) have been incorporated into a wide range of pharmaceutical preparations in combination with other ingredients for the claimed purpose of enhancing weight loss, cardio protection, correcting conditions of lipid abnormalities, and endurance in exercise. 229–236

Owing to their importance, in recent years, many enantiopure lactones have been the targets of an increasing number of synthetic efforts 237 that are notable in their strategic diversities. Compounds like mescaline isocitrimide lactone, avinaciolides, whisky lactones , funebrine, quercus lactones , cinatrins, 45,46,238–248 methylenolactocins, paraconic acids, 249–265 etc. , have a basic carbon framework which does not match with tartaric acid . Then 2-hydroxycitric acids 6 and 7 could be the most appropriate starting materials in order to minimize synthetic steps and to maximize the synthetic efficiency. The known methods for the synthesis of some concave bislactones, namely (+)-avenaciolide (219), (+)-isoavenaciolide (220), ethisolide (221), (−)-canadensolide (222), xylobovide (223) and sporothriolide (224), are tedious and time consuming. An expeditious semi-synthetic route for the construction of these molecules has been developed from abundantly available 6 and 7. 42,45,46

Also, there are several reports available for the total synthesis of paraconic acids (210–216), a group of highly substituted γ-butyrolactones isolated from different species of moss, lichens, fungi and cultures of pencillium sp ., in both racemic and enantiomerically pure forms. Due to the presence of two stereogenic centres and a γ-butyrolactone moiety, 6 and 7 could be found as versatile starting materials for these classes of molecules. Table 9 shows the important chirons and compounds derived from 6 and 7 and list their biological and functional applications.

Chiroptical properties

Optical rotatory dispersion ( ORD ) and electronic circular dichroism ( ECD ) are widely used to characterize chiral compounds. 308,309 These spectroscopic properties of α-hydroxy acids and their esters can show solvent dependent variations. For example, tartaric acid dimethyl ester is known to exhibit solvent dependent ORD and ECD , because of changes in the composition of its conformations. 310,311 It has been known that the optical rotation of natural amino acids becomes more positive when the solutions are converted from basic to acidic pH. This observation is referred to as the Clough–Lutz–Jorgensen (CLJ) effect. 312 The CLJ effect for natural amino acids was rationalized by Kundrat and Autschbach using quantum mechanical calculations. 313 A similar effect, observed for α-hydroxy carboxylic acids was known as the rule of Clough. 312 According to the rule of Clough, the optical rotation at 589 nm of α-hydroxy carboxylic acids with ( S )-configuration becomes more positive when the medium is changed from basic to acidic. In other words, the optical rotation difference between acidic and basic solutions of a carboxylic acid with ( S )-configuration is positive. Nitsch-Velasquez and Autschbach rationalized this rule using quantum mechanical predictions for some α-hydroxy carboxylic acids . 314 Thus, both solvent and pH dependent variations of chiroptical properties of hydroxy acids are of importance.

Because of their ring structures, which do not have much flexibility, Garcinia and Hibiscus acids (6 and 7) are not expected to show solvent dependence as that observed for non-cyclic α-hydroxy acids (for example, tartaric acid ). There is a possibility for variation in ring puckering angle of 6 and 7 with solvent , but only one ring puckering angle appears to be dominant for these compounds. 43,44 The ECD spectra of 6 and 7 at different pH values are shown in Fig. 7. The corresponding ORD spectra are shown in Fig. 8. The positive ECD band shifts from ∼203 nm at pH 2.49 in 6 to ∼200 nm in its disodium salt (148). Similarly, the positive ECD band shifts from ∼208 nm at pH 2.6 in 7 to ∼202 nm in its disodium salt (153) in water . The ORD spectra of 6 at different pH and those in methanol and DMSO solvent are very similar and drastic influences of solvent or pH are not apparent (Fig. 8). Similarly, the ORD spectra of 7 (see Fig. 8) at different pH are very similar to that of its disodium salt in water . These observations are reflective of robust structural features of 6 and 7, avoiding the complexities associated with conformational freedom as found for non-cyclic α-hydroxy acids.

Fig. 7 Electronic circular dichroism spectra of garcinia acid (top panel) and hibiscus acid under different pH conditions and of their disodium salts.
Fig. 8 Optical rotatory dispersion spectra of garcinia acid (top panel) and hibiscus acid under different pH conditions and of their disodium salts.

As for pH dependence, optical rotation becomes more positive at acidic pH (compared to that at basic pH) (see Fig. 8) both for 6 and 7. Even though these two acids have two chiral centers, (2 S ,3 S ) in 6 and (2 S ,3 R ) in 7, the observed pattern for change in pH dependent variation of optical rotation is in accord with the rule of Clough.

Conclusions

An up-to-date account of enantiopure compounds/intermediates, based on naturally occurring α-hydroxy acids obtained from renewable sources has been attempted. These compounds are of relevance for agro-chemical or pharmaceutical applications and functional properties. The recent publications and patents based on lactic, malic and tartaric acids have been explored to a greater extent and cited. Relatively rare and potentially interesting hydroxycitric acids, namely isocitric and 2-hydroxycitric acids, have been presented in detail for the first time. The (2 S ,3 S ) and (2 S ,3 R ) hydroxycitric acids can be easily made available from cheap plant sources. The structure and stereochemistry of these molecules have been discussed with the help of chirooptical data. The (2 R ,3 R ) and (2 R ,3 S ) stereoisomers can be obtained by the chemical transformation of the natural isomers. Hence, all the stereoisomers of 2-hydroxycitric acids are at the disposal of scientists for applications in the broad area of chirality. Established methods are available for the large scale microbial production of isocitric and hydroxycitric acids by environmentally benign techniques. Hydroxy acids, namely malic and tartaric acids , have been generally used for the synthesis of biologically and functionally active molecules which contain a four-carbon framework. Conversion of malic or tartaric acids to molecules with a six-carbon framework skeleton involves several synthetic steps. Having a six-carbon skeleton with unique structure and stereochemistry, hydroxy acids based on γ-butyrolactone-containing molecules are ideally suited for the synthesis of six-carbon, chiral building blocks, ligands , auxiliaries and resolving agents etc.

Acknowledgements

I.I., S.H., and P.V.S., would like to acknowledge the Department of Science and Technology, Govt. of India, New Delhi, for financial assistance (Project No. SR/S1/OC/54-2007). P.L.P. thanks Ms. Karissa Hammer for assistance in ECD and ORD measurements on garcinia and hibiscus acids.

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