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

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This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 1

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.

Kaganc

Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX 5

DOI: 10.1039/b000000x

An inventory of enantiomerically pure compounds of agrochemical, pharmaceutical and of functional interest derived from naturally occurring chiral α-hydroxy acids have 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 10

classes of compounds have also been presented.

Introduction

Chiral compounds are the key components in modern agro chemical and pharmaceutical industry. Synthesis of both natural and unnatural organic compounds in the enantiomerically pure 15

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 20

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 25

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 function4-6 (for instance, D.frontalis, the natural pheromone was found to be a mixture of two enantiomers in a ratio of 85:15)7-9. The 30

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 FDA were chiral and 75% were single enantiomers and in nine of the top ten drugs, the active ingredients are chiral. This comes 35

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.10-15The economic interests are obvious for the production of enantiomerically pure compounds in a sustainable manner. 40

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) the classical 45

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) 50

traditional methods of resolution of racemic mixture to enantiomerically pure compounds.16-27Production of enantiopure compounds employing microbes-enzymes, and semi-synthetic approach is considered environmentally benign as these approaches reduce the number of chemical steps to reach the final 55

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 60

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 stereo selective transformation of one enantiomer to the desired product.29- 31 65

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 70

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 75

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 80

microbial production of enantiomerically pure compounds, are

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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 5

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 10

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)

H3C COOH

OH

1 (S)-Hydroxybutanedioic acid (Malic

acid)

HOOCCOOH

OH

2

(2R,3R)-2,3-dihydroxybutanedioic acid (Tartaric acid)

HOOCCOOH

OH

OH 3

(R)-2-hydroxy-2-phenylacetic acid (Mandelic acid)

COOHHO

4

(2S, 3R)-tetrahydro-5-oxo-2, 3-furandicarboxylic acid

(Isocitric acid)

HOOC COOH

HOOC

HO

H

H

5

(2S, 3S)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylic acid

(Garcinia acid)

OO

H

COOH

OH

COOH 6

(2S, 3R)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylic acid

(Hibiscus acid)

OO

H

COOH

OH

COOH 7

15

Convenient functionalization makes these acids quite promising. Malic (apple acid), tartaric (grape acid), 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 20

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 25

those having multi 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 30

distributed, hydroxycitric acids. Hence attention has been focused on the use and scope of naturally occurring hydroxy acids including recently identified (2S, 3S) and (2S, 3R)-tetrahydro-3-hydroxy-5-oxo-2, 3-furandicarboxylic acids (Garcinia and hibiscus acids, 6 and 7). The limiting factor for the synthetic scope of 35

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.39-44Our 40

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 the plants are a rich source of enantiomerically pure 45

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 50

vegetables47, respectively.

Table 2 Annual productions of some chiral compounds from the chiral pool

Product World production (tons per annum)

Carbohydrates L-Ascorbic acid 35,000

D-Glucose 5,000,000 D-Sucrose 100,000,000

Hydroxy acids

L-Lactic acid 25,000 L-Tartaric acid 10,000 L-Malic acid 10

Amino acids L-glutamic acid 650,000

D-Alanine L-Cysteine

100 4,750

Alkaloids

Ephedrine 500 Cinchonidine 50

Terpenes

(-)carvone 500 (-)-α-pinene 25,000

Agrochemical, pharmaceutical and functionally 55

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. 60

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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

Crabapple Malic acid Cranberries Citric, malic acids

Currants Tartaric acid. Grapes Malic and

tartaric acids (3:2) Limes Citric, malic acids

Loganberry Malic acid Nectarine Malic acid

Orange Peel Malic acid Passionfruit 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.

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)-2-5

hydroxypropanoic acid [(S)-(+)-Lactic acid], (S)-hydroxybutanedioic acid [(S)-(-)-Malic acid], (2R,3R)-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 10

agents (catalysts, ligands, modifiers or metal based reagents) and building blocks.49-51 This review concerns with the recent applications of chiral α-hydroxy acids in the semi-synthetic pathways, since 2000. The milestone catalysts developed include Ti/DET52-53 (Sharpless, asymmetric epoxidation) (8), DIOP54-56 15

(Kagan, a bidentate phosphine ligand used for the enantioselective hydrogenation of olefins) (9), TADDOLs57-59, (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 20

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. 25

The industrial applications of these acids as chiral selectors for the development of 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, 30

paints, electrochemical coatings, piezoelectronic devices are also

known. Malic diesters are useful as mosquito repellents.

HO

HO

O

O

O

O

DET8

PPh2

PPh2

O

O

DIOP9

OH

OH

O

O

R

R

R R

R R

TADDOLs

10

CAB

11

OMe

OMe

O

O B

O

O COOH O

R

Fig. 1 Milestone ligands or catalysts derived from tartaric acid

Lactic acid 35

H3C COOH

OH

1

(S) - 2-Hydroxypropanoic acid Fig. 2 Three- carbon skeleton with one chiral center

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 40

fermentation. Chemical synthesis often results racemic products,

where as the enantioselective synthesis of D or L form can be obtained by the fermentation using specific microbial strain.75Commercially, lactic acid is produced by the fermentation of carbohydrates. It is currently obtained via bacterial 45

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 50

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 55

biological and synthetic applications.

Malic acid

2

HOOCCOOH

OH

(S)-Hydroxybutanedioic acid Fig. 3 Four carbon skeleton with one chiral center The (S)-(-) malic acid (2, Fig. 3) occurs naturally in apples and 60

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 65

extremely versatile 4-carbon building block possessing carboxyl group at the 4-position that serves as a useful “handle” 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 70

and functional applications.


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

Starting molecules Chiral

Synthons/compounds prepared Applications References

H3C COOH

OH

1

CbzHNOMe

O

OH

12

Synthesis of (+)-Conagenin 81

1

O

O

O

O

13

Preparation of block copolymers 82

1

N

PMBO

O

Me

OMe

14

Synthesis of (+)-macrosphelides

83

1

*O

O

O

O*

O

15

Synthesis of polyether–ester dendrimer

84

H3C COOH

OH

16

PPh2

PPh2

[Rh]

17

1,3–Dipolar cycloaddition of nitrones to methacrolein

85

1

O

OO

O

O

18

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 HO

O

OH

n 19

Biodegradable polymer-medical applications such as tissue engineering

88-91

RH OEt

O

(S)-ethyl lactate

HO

20

OS

O

MeH

PhPh

O

21

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


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HOOCCOOH

HO COOH

22

1

H3C

OH

OH

23

Chiron (high demand in commodity chemicals)

97, 37

1

N

O

O

O CO2H

24

Preparation of aminooxy peptides 98

1

NH

N H

OCOCH3

CH3

25

Enantioselective benzoylation of α- aminoesters

99

1

H3C CO2Et

O

NH2

26

Synthesis of α-aminoxy amino acids and hybrid peptides

100

16

Cl

OHO2C

27

Herbicide 101

1

PPh2

PPh2H3CH

M

M=transition metal

28

Enantioselective Diels–Alder reactions, hydrogenations, Friedel-

Crafts reactions etc 102, 103

H3COCO COCl

CH3

29

N

N

OH

CH3

OH 30

Fungal metabolite 104, 105

1

COOH

OH 31

Chiron 106

1

OHO

N

32

β-blocking agents 107, 108

a


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

Starting molecules Chiral synthons/compounds prepared Applications References

HOOCCOOH

OH

33

O

Ot-Bu

O

COOH

34

Synthesis of (-)-Wikstromol

109

HOOCCOOH

OH

2

OO O

OAc

35

Synthesis of chiral tetronic acids

110

33

TsO OTBDMS

HO

OH

36 and 37

Synthesis of (2S,3S,7S)-3,7-

dimethylpentadecan-2-yl acetate and propionate, the Sex Pheromones of Pine

Sawflies

111

2

O

O

O

HO

11

38 Aculeatin A

O

O

O

HO

11

39 Aculeatin B

High cytotoxicity against KB cancer cells lines as well as antiprotozoal activity against Plasmodium falciparum strains K1 and NF54

112

HOOH

OHH

40

Fe

O

OH

H

MeO

41

Ferrocenes with planar chirality used for the synthesis of chiral ligands in asymmetric catalysis, material chemistry and biology

113

EtOOEt

O

O

OH

42

OO

OH

OHOH

NaHO3PO

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


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43

33

O

OHO

O

O

HO

44

(R)-(-)- and (S)-(+)-homocitric acid lactones

and related a-hydroxy dicarboxylic acids

115

2 Chiral synthons 116-118

2

O

OH

HO

O

O

OH

45

Total synthesis of secondary metabolite xestodecalactone C

119

2

N

46

Methyl pyrrolidine alkaloids 120

2

O

OH 47

A building block of the N-substituent of the

chiral amino alcohol unit

121

OEt

OH

OH O

48

OO

O

OH

HOHO

OH OH 49

Folk medicine for the treatment of fever, pain, snake-bite and lung disease

122

2

O

OTBDPSO

OH

H

F

H

O

OTBDPSO

OH

H

F

H

50 and 51

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

O

O

O

H

OHOH

52

Stereoselective total synthesis of polyrhacitide A which having significant analgesic and anti-inflammatory activities

125

HO

CO2R2

CO2R2

53.R2=H, 54.R2=.Bn, 55.R2=.t-Bu

Total Synthesis of 2-O-Feruloyl-L-malate, 2-

O-Sinapoyl-L-malate and 2-O-5-Hydroxyferuloyl-L-malate

126


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OH

R1 OMe

OCO2H

O

CO2H

56.R1=H,

57.R1=OMe

58.R1=OH

2

OCH3

OCH3

O

O

OH

H3CO

59

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

N

HO

H

O 60

Total synthesis of Grandisine D, which was proposed to be a biogenetic precursor of

Grandisines B and F and (-)-isoelaeocarpiline 128

2

N

N N

N

MeO

NH2

HO

O

61

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

O

OTESO

OTs

OTBS

62

Synthesis of spiroacetal moiety of antitumour

antibiotic ossamycin 130

MeOOMe

O

O

OH

63

BnO

O O

Me Me

H 64

Synthesis of 35-deoxy amphotericin B aglycone,which is having great importance in

medicine 131

2

OOEt

O O

65

Synthesis of (-)-dictyostatin

132

33

Synthesis of antiproliferative Cephalotaxus

esters 133


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Me

Me

O

O

O

OH

66

2

ROO

OR OEt

67.R=H68.R=TBS

Total synthesis of the antitumor agents neolaulimalide, isolaulimalide, laulimalide

134

2

CHO

O O

PMP

69

Synthesis of polyhydroxylated central part of Phoslactomycin B that shows selective PP2A

inhibitory activity. 135

2

HO

O

OH

70

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

O

OH

PivO

71

Asymmetric total syntheses of novel Aspidosperma indole alkaloids, (-)-

subincanadines A and B 137

2

NBoc

OMs

72

Synthesis of novel 3-pyrrolidinyl derivatives of nucleobases

138

2

OH

OH

CH3

73

Synthesis of 6-epiprelactone-V which are poly-substituted chiral δ-lactones used as

building blocks in natural product synthesis 139

2

HN

O

OOMe

O

74

Synthesis of poly(ester amide)s

140

33

N

S

O2S

TMS

MeO

75

Total synthesis of (-)-phorboxazole A, a potent cytostatic agent from the sponge

Phorbas sp.

141

2

O

O

CHO 76

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

143


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O

OR

O

Me

Br

Me

77

from paederus fuscipes.

2

N3 CO2Et

OTBS 78

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

BnOOH

OSCH3

O

79

Chiral building block for the synthesis of

analogues of the antibiotic pantocin B

145,146

2

NHOH

OPMBO

80

Chiral building block for the asymmetric synthesis of (+)-Ioline, a pyrrolizidine alkaloid from rye grass and tall fescue

147,148

2

OO

RO

81

Synthesis of polyhydroxylated pyrrolizidine Alkaloids

149

2

S S

OMe

OMEM OMe

82

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

(2R,3R) - 2,3-dihydroxybutanedioic acid

HOOCCOOH

OH

OH

3

Fig. 4 Four-carbon skeleton with two chiral centers 5

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 10

popularity as a chiral building block. Importance of 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 15

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.

Mandelic acid 20

HO COOH

(R)-hydroxy -2-phenyl acetic acid

4

Fig. 5

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.191-193Commercially, 25

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 30

method.195It has long been known for use as a urinary antiseptic. For example, methenamine mandelate is marketed in the U.S. 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 35


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various biomedical applications such as the 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 5

transformations.196Table 7 shows the important chirons and compounds prepared from mandelic acid and lists their biological and functional applications.

Isocitric acid

HOOC COOH

HOOC

HO

H

H

(2R,3S)-isocitric acid

5

10

Fig. 6 Six-carbon skeleton with two chiral centers

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 Nelson206, who isolated the material as the triethyl ester and as 15

the diethyl ester lactone from blackberries and who found that it was by far the predominating acid of this fruit. Pucher207-210 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 20

Kreb’s tricarboxylic acid cycle, a mechanism that is 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 25

accordingly, a substance of considerable importance to biochemists. 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 30

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 35

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 Yeast are known to 40

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 45

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 (2R, 3S)-isocitric acid by fermentation of sunflower oil in kilogram amounts.216, 217 Table 8 shows the important 50

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 55

are prone to epimerization under acidic and basic conditions. Since the enolisation and subsequent protonation of isocitric acid (and hydroxycitric acids, Scheme 4) offers no guaranty for the stereochemical integrity of the chiral centers during any chemical reaction with these molecules (Scheme 1). 60

2-Hydroxycitric acid (HCA) and related optically active γγγγ-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 (2S,3S) 65

and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2, 3- furan dicarboxylic acids (Garcinia and Hibiscus acids, 6 and 7), are extensively distributed in nature (Scheme 2). However no report is available on the existence of other stereoisomers (2R, 3R) and (2R, 3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furan dicarboxylic 70

acids naturally. The acid 6 is known to be present in 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 75

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

cannabinu39-41,218-222. All these plants are distributed across many countries and the 80

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 85

available under the γ-butyrolactone structure (Scheme 3). However the open structures of 6 and 7 are made available by converting to its triesters (Table 9. No.164-166 and 168-170) It may be noted that the absolute configuration of C3 is fixed and C2 is prone to epimerisation in all the isomers of 90

hydroxycitric acids (Scheme 4) 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 95

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, 100

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 are known since 1960’s, these compounds have not yet appeared in the wide 105

spectrum of asymmetric syntheses, irrespective of the fact that these compounds can easily be made available (from cheap natural sources) as a renewable feedstock.


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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

HOOCCOOH

OH

OH 3

O

O

O

OR

O

O

O

O

H

tBu

OR

O

83 and 84

Pharmaceutical building blocks, dienophile in Diels Alder reaction

152

HOOCCOOH

OH

OH

85

O

O

OH

OBn

86

Synthesis of L-lyxo-phytosphingosine

153

85

O

O

O

OO

O

HOOC

COOHHOOC

COOH

87

NMR solvating agents 69, 70, 154-158

3

C COOCH2

ROCO OCOR

O

NH

Si

O

O

Osilica gel

88

Chiral stationary phase 159-161

3

OH

OH

Ph Ph

Ph Ph

O

O

89

Chiral ligand for Diels-Alder reaction,[2+2]

cycloaddition etc, chiral phase transfer catalyst.

162

3

O

O

H

H

O

O

PPh2

PPh2

90

Chiral ligand for asymmetric

hydrogenations of olefins

163

85

O

O

H

H

PAr2

PAr2

91

Asymmetric hydrogenation of

enamides 164

3

Pharmaceutical co-crystal- phosphodiesterase

IV inhibitor with L-tartaric acid

165


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N N

N

NH

O O

O

HO

OO

O

OOH

OH

92

3

93.R=

HO

HO

trans-caftaric acid

94.R=HO

trans-p-coutaric acid

95.R=HO

O

CH3

trans-fertaric acid

HOOH

O

OH

O

O

RO

O

Pleiotropic biological activity

166

85

CHOSS

O

O

TBSO 96

Synthesis of acyclic C1–C7 fragment of Peloruside

B to set the absolute stereochemistry.

167

85 HO O

O

OH 97

A versatile bridging intermediate en route to

aminocyclitols unit which are found in

valienamine,Conduramines A-1 and E and a key intermediate of (+)-

Pancratistatin

168

85

NH

OHHO

98

Preparation of chiral selector

169

85

N

Ot-But-BuO

O

99

Synthesis of homo-N-nucleoside analogues

170

85 Synthesis of

antiproliferative 171


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N

HN

COOH

R

100

imidazole and imidazoline analogs

for melanoma

3 or 85

O

HO OH

OMe

OH

O 101

Total synthesis and absolute configuration of

the Styryl Lactone Gonioheptolide A

172

3 or 85 Chiral resolving agent 173-175

3

O

O

O

OO

O

102 and 103

Chiral ligand 176

85

O

HOOH

Ph

OMe

O

104

Stereoselective synthesis of antitumor

tetrahydrofuran (+)-goniothalesdiol

177

85

HO

OH

OH

NH2

HO

OH

OH

NH2 105 and 106

Preparations of D-ribo- and L-lyxo-

phytosphingosines 178, 179

3 or 85

OO

OMe

OMe

MeO2CMeO2C

107

Preparation of chiral catalysts

180

3

OO

OH

108

Enantioselective synthesis of (-)-muricatacin, a bio-

active lactone 181

3

O

O

O

H 109

Synthesise of β-lactam-azasugar hybrid

182


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3

O O

NHR2 NHR2

SO2

R=

O

110

Chiral sulfonamide ligand 183, 184

3 or 85

NH

MeONH

Me

111

Synthesis of 3- methoxy-4-methylaminopyrrolidine

for a synthesis of AG-7352 which is a novel

anti-tumour agent

185

3

OO

O

AcO

OAc

112

Chiral synthons 186

3

H3COOCCOCl

OAc

OAc

113

Enantioselective synthesis of (1R)-1-

(hydroxymethyl)-2-acetyl-1,2,3,4-tetrahydro-

β-carboline

187

3

OiPr

OiPr

O

O

OOH

OOH

OH

114

Ligands in chiral acyloxy borane (CAB), catalyst

for enantioselcetive Diels-Alder reaction, hetero

Diels-Alder reaction,allylation,allylation polymerizations,for the

synthesis of chiral depsipeptide dendrimers.

188, 60, 61

O

OMeO

MeO

COSEt

COSEt

115

OO

H3C COOH

116

Construction of enantiomerically

pure γ-butyrolactones 189

3 N

O

Ph

Ph

117

Dynamic kinetic resolution of benzhydryl quinuclidinone which are

used as precursor to substance P antagonist

31

3 or 85 NH

P

O

OEt

OEt

R1

R2

118

Used as an organo catalyst for the synthesis of α-aminophosphonates

190


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

Starting molecules Chiral synthon prepared Applications References

HO COOH

119 (DL- Mandelic acid)

Ph S H

H2NHNOC H CONHNH2

Ph

120

synthesis of 1,1’- diphenylthiodiacetic acid dihydrazide

197

119 O

O CO2H

OHO

On

121

Anti-microbial , contraceptive anti HIV-1 activity

191

HO COOH

122

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

OH

O

OH

123

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 N

OH

H3CO

OH

(H3C)2N

124 and 125

Chiral resolving agent for the preparation of many biologically active compounds example for the resolution of β-amino alcohols,Tramedols etc.

201, 202

4

H3COCO

HO

Ph

Ph

126

Chiral acetate synthons

203

122

H3COCO

HO

Ph

Ph

127

Chiral acetate synthons

203


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4

OH

OH

O

O

O

Ph

O 128

Used for the total synthesis of (+)-Crassalactone A which shows cytotoxic activity against a

panel of mammalian cancer cell lines 204

HOOC OHC HO

OH

OH

HOOC OHO

OH

COOH

HOOC OHC HO

OH

COOH

HO

HOOC OHCO

OH

OHO

HOOC OHC HO

OH

COOH

H

HOOC OHC HO

OH

COOH

H

5129

131

133

130

HOOC OHC HO

OH

COOH

H

134

HOOC OHC HO

OH

COOH

H

5

H

5

132 Scheme I Racemisation of diastereomeric isocitric acids via sequential epimerization 5

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

Starting molecules Chiral synthon prepared Applications References

OO COOH

COOH

135

OO

H2N

COOtBu

136

Non-natural -amino acid synthons 216

135

O

O O

O

O 137

Chiral synthons 216

a


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OO H

COOHCOOH

OH

OO H

COOHCOOH

OH

OO H

COOHCOOH

OH

OO H

COOHCOOH

OH

140138 139 141

1427 143

OO H

COOHCOOH

H

OO H

COOH

COOH

H

OO H

COOHCOOH

H

OO H

COOH

COOH

H

133132

134 5

145144

146 135

HOOC OH

H COOH

HHOOC

HOOC OH

H COOH

HHOOC

HOOC OH

H COOH

HHOOCHOOC OH

H COOH

HHOOC

HOOC OH

HO COOH

HHOOC

HOOC OH

HO COOH

HHOOC

HOOC OH

HO COOH

HHOOC

HOOC OH

HO COOH

HHOOC

6

Scheme 2 Structures of stereoisomers of hydroxycitric acids, isocitric acids and their corresponding lactones

HOOC

HOH

COOH

R'R

OOCOOH

H

R'

R

6. R=-OH, R'=-COOH7. R=-COOH, R'=-OH

138. R=-OH,R'=-COOH139. R=-COOH,R'=-OH

Scheme 3 Natural and lactone forms of garcinia and hibiscus acid 5

HOOC OH

HO COOH

CH

O

OH

HOOC OH

HO COOH

O OH

HOOC OH

HO COOH

COOHH

138 147 138 and 141 Scheme 4 Epimerization of diastereomeric hydroxycitric acids

10


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Table 9 Some important chiral synthons and compounds based on garcinia and hibiscus acids

Starting molecules Chiral synthons/compounds prepared with stereochemistry matching that of

GA and HA

Applications

(Relevant properties of the derived compounds)

References

OO H

COONa

OH

COONa 148

O

O H

COOR

OH

COOR

149.R=CH3

150.R=C2H5

151.R=CH(CH3)2

152R=CH2Ph

Preparation of chiral butenolides, Chiral probe for characterizing chiroptical studies of achiral

surfactants

46, 266-270

O

O H

COONa

OH

COONa 153

O

O H

COOR

OH

COOR

154.R=CH3

155.R=C2H5

156.R=CH(CH3)2

157.R=CH2Ph

Preparation of chiral butenolides 46, 266-269

149

OO H

CH3RO

Quararibea metabolite lactone

158.R=CH3

159.R=C2H5

160.R=CH(CH3)2

161.R=CH2Ph

Subunit in many natural products 45, 246, 248, 271

OO H

COOHCOOH

OH 6

OO

N

O

O

CH2Ph

HO

H

162

Chiron for the synthesis of biologically important chiral

pyrrolidine diones 37, 38, 237, 272, 273

HO COONa

COONa

OH

NaOOC 163

HO COOR

COOR

OH

ROOC

164.R=CH3

165.R=C2H5

166.R=CH(CH3)2

Chiral synthons

41, 42

HO COONa

COONa

OH

NaOOC 167

HO COOR

COOR

OH

ROOC

168.R=CH3

169.R=C2H5

170.R=CH(CH3)2

Chiral synthons

41, 42

148

Chiral synthon 41, 42, 46


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OO

H

COOR

OCH2SCH3

COOR 171

OO H

COOHCOOH

OH 7

OO

H

COOR

OCH2SCH3

COOR 172

Chiral synthons 41, 42, 46

164

COOCH3

N R

O

O

H

HO

HO

173.R = -CH2C6H5

174.R= -CH2C6H4OCH3

175.R= -CH2CHCH2

176.R= -CH2C6H3(OCH3)2

177.R= -CH2CH2C6H3(OCH3)2

178.R= -CH2CH2NHBoc

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

HO COOCH3

COOCH3

OH

H3COOC

179

180.R = -CH2C6H5

181.R= -CH2C6H4OCH3

182.R= -CH2CHCH2

183.R= -CH2C6H3(OCH3)2


185.R= -CH2CH2NHBoc

COOCH3

N R

O

O

H

HO

HO




37, 38, 237, 273-288

168

COOCH3

N R

O

O

H

HO

HO

186.R = -CH2C6H5

187.R= -CH2C6H4OCH3

188.R= -CH2CHCH2

189.R= -CH2C6H3(OCH3)2


191.R= -CH2CH2NHBoc




37, 38, 237, 273-288

HO COOCH3

COOCH3

OH

H3COOC

192

COOCH3

N R

O

O

H

HO

HO

193.R = -CH2C6H5

194.R= -CH2C6H4OCH3

195.R= -CH2CHCH2

196.R= -CH2C6H3(OCH3)2


198.R= -CH2CH2NHBoc




37, 38, 237, 273-288

6

Chiral building block used for the

synthesis of pharmacologically important natural products

37, 38, 42, 289


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O

O O

OAc

HO

O 199

6

OO HCOOCH3

OH

CH2OH 200

Chiral intermediates

44

154

OO

H

COOCH3

OH

CH2OH 201


45

6

OO

H

CH2OH

O

O

O

CCl3

202


45

6

OO

H

CH2OH

O

O

O

CCl3

203


45

200

O

O

O

OH

HO

204


45

202

O

OO

O

H

OH

205


45

200

OO

OH

H

OH

COOCH3 206


45, 216

149

O

O H

COOR

COOR 207

Chiral butenolide

46, 266, 268-269

7

OO

H

CH2OH

OH

CH2OH 208


45, 46, 37, 38

154

Flavor component 46, 246, 248, 271


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N

O

N

OH

H

H

H

OO

HO

(-) Funebrine 209

203

O R

COOH

O

210. R=n-C5H11: (-)-methylenolactocin211. R=n-C13H27:(-)-Protolichesterinic ac

Pharmacological and biological

activities, such as antitumor, antibiotic, antifungal, and

antibacterial.

249-265

202

O R

COOH

O

212. R=n-C5H11: (-)-Phaseolinic acid213. R=n-C13H27:(-)-Nephromopsinic acid

Pharmaceutically important

molecules 249-265

203

O R

COOH

O

214. R=n-C11H23: (-)-Nephrosterinic acid215. R=n-C13H27:(-)-Rocellaric acid

Pharmacological and biological

activities, such as antitumor, antibiotic, antifungal, and

antibacterial.

249-265

203

OO

CO2H

C -75 216

Pharmacological and biological activities, such as antitumor,

antibiotic, antifungal, and antibacterial.

249-265, 290-292

208

OO H

(+)-trans-quercus lactone 217

Aroma components in high quality

alcoholic beverages 46, 293, 294

206

OO NH2

O

OCH3

OH 218

Non-natural lactone-amino ester

45, 216


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200

OO

O

O

H

H

C8H17

(+) Avenaciolide 219

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

O

OO

H

HH

nC8H17

isoavenaciolide

O

220

Biologically active molecules

45, 295-299

200

O

OO

H

HH

C2H5

Ethisolide

O

221


45, 295-299

202

O

OO

H

H O

n-C4H9

H

(-)-canadensolide 222

Inhibition of the germination of fungi, antibacterial and phytotoxic

activities

45, 300, 301

202

O

OO

H

H O

H

C2H5

xylobovide 223

Biologically important molecules

45, 300, 301

202

O

OO

H

H O

nC6H13

H

sporothriolide 224

Biologically important molecules

45, 300, 301

202

O

OO

H

H O

H

nC4H9

(+)-dihydrocandensolide 225


45, 300, 301

6

OO

H

COOH

COOH

H

Isocitric Acid

226


216

206

Chiral synthons

45, 216


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OO

OH

OH

OH 227

O

O OH

OH

OH

228

OO H

CH3

Cis and Trans Whisky Lactones 229

Aroma components in high quality

alcoholic beverages

46, 293, 294

6

OO H

COOH

OH

COOHR'

R''

230. R'= -H, R''= -CH(OH)C11H23231. R'= -OH, R''= -C12H25

Cinatrin C2 and C3

Biologically active molecules molecules. PLA2 inhibitors

239, 302-305

6

OO

N

O

O

H

H

OCH3

CH3OOCH3

Mescaline Isocitrimide Lactone 232

Biologically active, Psychotic

molecule. 37, 42, 306

6

O

O

Japaneese beetle pheromone 233

Sex pheromone for the Japanese beetle, Popillia japonica

37, 7

O

OH

COOR''

R

R'

R=-COOR'',R'=-CH2COOR" 234

O

O

OH

OH

HO

Ar Ar

Ar Ar

Ar Ar

235. Ar=phenyl236.Ar=4-methylphenyl TADDOL derivative

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

O

OH

COOR''

R

R'

R=-CH2COOR",R'= -COOR" 237

O

O

OH

OH

HO

Ar Ar

Ar Ar

Ar Ar

238.Ar=phenyl239.Ar=4-methylphenyl

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

O B

OOO

O

H

O

O

H

-

Na+

240

Chiral reducing agents with poor selectivity

37, 38, 60-62, 307

7 Chiral reducing agents with high 36, 37,


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OB

OOO

O

H

OO

HH

H-

Na+

241

enantio selectivity 59-60, 307

199

OO

O

NH

O

NH(CH2)11

Si

CH3

CH3

O

(H3C)3SiO

(H3C)3SiO

Si

HO

242

Chiral stationary phase 62

a

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 5

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 10

Owing to their importance, in recent years many enantiopure lactones have been the targets of an increasing number of synthetic efforts237 that are notable in their strategic diversities. Compounds like mescaline isocitrimide lactone, avinaciolides, whisky lactones, funebrine, quercus lactones, cinatrins,45,46, 238-248 15

methylenolactocins, paraconic acids,249-265 etc., have a basic carbon framework which is not matching 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 20

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 25

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 30

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 35

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 40

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 change 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 45

solutions are converted from basic to acidic pH. This observation was referred to as 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 50

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 55

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. 60

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 65

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 ~203nm at pH 2.49 in 6 to ~200 nm in its disodium salt (148). Similarly, the 70

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 75

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. As for pH dependence, optical rotation becomes more positive 80

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, (2S, 3S) in 6 and (2S, 3R) in 7, the observed pattern for change in pH dependent variation of optical rotation is in accord with the rule of Clough. 85

90


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5

10

15

Fig. 7 Electronic circular dichroism spectra of Garcinia acid (top panel) and Hibiscus acid under different pH conditions and of their 20

disodium salts.

25

30

35

40

Fig. 8 Optical rotatory dispersion spectra of Garcinia acid (top panel) and Hibiscus acid under different pH conditions and of their disodium

salts. 45

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 agrochemical or pharmaceutical applications and 50

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 (2S, 3S) and 55

(2S,3R) 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 (2R,3R) and (2R,3S) stereoisomers can be obtained by the chemical transformation of the natural isomers. Hence all the 60

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 65

and tartaric acids have been generally used for the synthesis of biologically and functionally active molecules which contain four carbon frame work. Conversion of malic or tartaric acids to molecules with six carbon framework skeleton involves several synthetic steps. Having a six carbon skeleton with unique 70

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. 75

Acknowledgment: I.I., S.H., and P.S.V., 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. 80

Notes and references

a Institute for Intensive Research in Basic Sciences, Mahatma Gandhi

University, Kottayam, Kerala, India. Fax: 0481-2732992; Tel: 0481-

2732992; E-mail: [email protected] b Department of Chemistry, Vanderbilt University, Nashville,Tennessee, 85

37235, United States, Fax: (615) 322-4936; Tel: (615)322-2836; E-mail:

[email protected] c Equipe de Catalyse Moléculaire-ICMMO - Bât 420, Université Paris-

Sud , 15, rue Georges Clemenceau, 91405 Orsay Cedex, France, Fax:

01.69.15.46.80, Tel: 01.69.15.78.95. E-mail: [email protected]

psud.fr.

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

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