enantiomerically pure compounds related to chiral hydroxy acids derived from renewable resources
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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
184.R= -CH2CH2C6H3(OCH3)2
185.R= -CH2CH2NHBoc
COOCH3
N R
O
O
H
HO
HO
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
COOCH3
N R
O
O
H
HO
HO
186.R = -CH2C6H5
187.R= -CH2C6H4OCH3
188.R= -CH2CHCH2
189.R= -CH2C6H3(OCH3)2
190.R= -CH2CH2C6H3(OCH3)2
191.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
192
COOCH3
N R
O
O
H
HO
HO
193.R = -CH2C6H5
194.R= -CH2C6H4OCH3
195.R= -CH2CHCH2
196.R= -CH2C6H3(OCH3)2
197.R= -CH2CH2C6H3(OCH3)2
198.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
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
Chiral intermediates
45
6
OO
H
CH2OH
O
O
O
CCl3
202
Chiral intermediates
45
6
OO
H
CH2OH
O
O
O
CCl3
203
Chiral intermediates
45
200
O
O
O
OH
HO
204
Chiral intermediates
45
202
O
OO
O
H
OH
205
Chiral intermediates
45
200
OO
OH
H
OH
COOCH3 206
Chiral intermediates
45, 216
149
O
O H
COOR
COOR 207
Chiral butenolide
46, 266, 268-269
7
OO
H
CH2OH
OH
CH2OH 208
Chiral intermediates
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
Biologically active molecules
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
Biologically active molecules
45, 300, 301
6
OO
H
COOH
COOH
H
Isocitric Acid
226
Biologically active molecules
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: i.ibnusaud@gmail.com b Department of Chemistry, Vanderbilt University, Nashville,Tennessee, 85
37235, United States, Fax: (615) 322-4936; Tel: (615)322-2836; E-mail:
Prasad.L.Polavarapu@vanderbilt.edu 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: henri.kagan@icmo.u-90
psud.fr.
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