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I Chapter - Iii 1 I CHAPTER - III 1 SYNTHESIS OF OPTICALLY ACTIV Ot-ARYLPROPANOIC ACIDS SECTION - 111A : A LITERATURE SURVEY This chapter addresses the problem of asymmetric synthesis of a-arylpropanoic acids.^ These compounds find application as anti­ inflammatory drugs and are widely used in current medical practice. Inflammation has been understood as a host defense mechanism to infections, metabolic stimuli or injury to tissues. The major manifestations of inflammations are recognized as fever, swelling, pain, redness and sometimes the loss of function. The initial sequence of events supposed to be involved in inflammation or injury are, release of inflammatory mediators, vasodilation and increased vascular permeability leading to exudation. Although anti-inflamma­ tory agents are used in the treatment of various diseases, their main use appears to be in the treatment of arthritis. At the outset, anti-inflammatory agents have been grossly classified as steroidal and non-steroidal compounds. CORTICOSTERONE The steroidal agents, as exemplified by Corticosterone and a host of its synthetic analogs, have been in medical practice for over a few decades and they are gradually giving place to non­ steroidal agents. This situation appears to be the result of the various adverse effects of steroidal drugs such as: 1. Change in the mineral balance 2. Suppression of endocrine function especially of the pituitary bodies. @ a-Arylpropanoic acids are also referred to as 2-arylpropanoic acids. 143 3. These drugs, in higher doses, cause gluconeogenesis and are antagonistic to the action of insulin thus leading to disturbances in carbohydrates, protein and fat metabolism. 4. Another serious drawback of the steroidal drugs is the loss of bone calcium leading to osteoporosis. These toxic effects have motivated the discovery of non-steroi­ dal anti-inflammatory agents (NSAI) with comparable therapeutic value and reduced toxicity. DIFLUNISAL ASPIRIN COOH COOH ©COCOCH - INDOMETHACIN IBUFENAC CH30 .CH2COOH I 3 o. COOH J& C=0 a-ARYL PROPANOIC ACIDS :1(a-l) R-^J COOH NSAI agents can be generally classified into three groups based on their chemical structures. a) Benzoic acid derivatives, typically exemplified by acetyl salicylic acid (Aspirin) and Diflunisal. b) Arylacetic acid derivatives, of which Ibufenac and Indomethacin are the most common ones. 144 c) a-Arylpropanoic acids, the most important of which are Ibuprofen and Naproxen. Most of the NSAI agents appear to act by a common mechanism(Scheme-1). SCHEME-1 MEMBRANE PHOSPHOLIPIDS Photpholipose ARACHIDONIC ACID LIPOQXYGENASE ) »{0>*—fCYCLOOXYGENASE i PROSTAGLANDINS THROMBOXANES E, F , I2 etc. TWO MAJOR PATHWAYS OF ARACHIDONIC ACID CASCADE cl ARACHIDONIC ACID —y °°»y9«"o*c ^ END0PER0X|DE •PROSTAGLANDINS COOH THROMBOXANE A2 COOH 6H As pointed out earlier, the processes of inflammation such as vasodilation are primarily caused by prostaglandins and thromboxane 145 A2 (vasoconstrictor and platelet aggregating agent),which are bio- synthesized from arachidonic acid enzymatically. Cyclooxygenase is supposed to be the oxidizing enzyme leading to prostaglandins and Thromboxane A2 • The anti-inflammatory agents employed are supposed to prevent the prostaglandin synthesis at the cyclooxygenase site. BASIC STRUCTURAL FEATURES FOR DRUG ACTIVITY IN g-ARYLPROPANOIC ACIDS. CH3 I 5 •C—H Ar I COOH The medicinal activity of these drugs appears to be related to three basic structural features shown below. 1) The propanoic acid side chain. 2) The substituents on the phenyl ring. 3) An additional hydrophobic group, generally aryl (as seen by the pronounced activity of ii). In addition to these structural features, the stereochemical disposition of the methyl group appears to be intimately connected with the activity. In most of the known a-arylpropanoic acids, the (S)-configuration at the chiral carbon is known to confer enhanced activity. IBUPROFEN (1c) BIOLOGICAL ACTIVITY H HOOCL (RMS) xjd^coo* 1 : 2 (R)-(-) B8Jy,y,tw> (S)-(+) NAPROXEN (1i) HOOC. H COOH (R):(S) 1 : 28 MeO MeO (R)-(-) -•(S)-(+) Body system 146 This correlation of stereochemistry with the enhanced activity can be appreciated in terms of a better structural fit to arachidon- ic acid in the anti-inflammatory action.Thus, the improved activity arising from the absolute configuration of the chiral center has triggered tremendous efforts to realize the enantiomerically pure a-arylpropanoic acids. These acids are being extensively used in current medical prac­ tice as analgesic, antipyretic, anti-inflammatory agents and form the fourth largest selling group of drugs in the world (Table-1). TABLE-1 SOME a-ARYL PROPANOIC ACIDS IN CURRENT WORLD MARKET3 IBUPROFEN O *COOH 1972 BOOTS (U.K.) KETOPROFEN COOH 1973 SPECIA (France) NAPROXEN OTOT C00H 1974 SYNTEX (U.S.A.) MeO COOH FLURBIPROFEN 1977 BOOTS (U.K.) SUPROFEN COOH 1983 JANSSEN(U.K.) 147 SYNTHESIS OF OPTICALLY ACTIVE a-ARYLPROPANOIC ACIDS. AN OVERVIEW OF LITERATURE METHODS. A classical method of obtaining EPC compounds is by their resolution. l) Resolution of (±)-li with (-)-Cinchonidine. Harrison4 et al (1970) (Bcheme-2). (S)-lj. is obtained by preferential crystallization of the diastereomeric salt with (-)-cinchonidine 2_; the salt of the more potent (S)-enantiomer has lower solubility. SCHEME-2 : TWO STEPS H2C=CK M i) Two recrystallizotions from MeOH-Acetone CO OH » MeO ii) dil.HCl U (t)-NAPROXEN (-)-2 COOH MeO (S)-(-r-)-NAPROXEN 100% ee 2) Optically Active ii by Kinetic Resolution. Ruchardt5 and Franc* (1984) (Scheme-3). These authors converted (±)-li to a diastereomeric mixture of its anhydride 2. by treatment with Ac20, the latter on treatment with (S)-(-)-l-(4-pyridyl)ethanol 3 gave (S)-(+)-li with more than 50% ee and 70% yield. The high asymmetric induction is due to the difference in rates of reactions of the pair of diastereomers with 3. (Kinetic Resolution). 148 SCHEME-3 : TWO STEPS CH3 HO-CH—^N CH3 Ac 0 CH3 I 2 s-<-)-a Ar-CH-COOH [_Ar-CH-COJ--0 (±)-1i CH: CH-. CH3 Ar-CH-CO-O-CH—(Jv M + Ar-CH-COOH Ar = CH30 4 (S)-(+)-li 3. Enzymatic Resolution of Arylpropanoates. a) Selective Hydrolysis by HLE. Bloch6 et al (1989) (Scheme-4). The stereospecificity of enzymatic reactions has been advanta­ geously employed in the synthesis of both the enantiomers of lc. The enzyme Horse liver esterase (HLE), used as its inexpensive and commercial acetone powder, catalyses the selective hydrolysis of the ester (-)-2. to afford the acid (R)-(-)-.lc and the unreacted ester (+)-2, which are easily separable. The latter is then hydrolyzed to the acid (S)-(+)-ic. SCHEME-4 : ONE STEP Me HLE H,, ^Me Me. .H H 0,pH7-2, + Ar COOMe 2 Ar^XOOMe R.T. Ar COOH (±)-2 (RM-)-lc IBUPROFEN (S)-(+)-2 Ar b) Selective Hydrolysis by Lipase. Bin7 et al (1986) (Scheme-5). An analogous preferential hydrolysis of the racemic ester (±)-2 of l_i with enzyme Lipase of Candida Cylindracea furnished the enan- 149 tiomerically pure (S)-(+)-ii along with the unreacted ester (R)-(-)-2. SCHEME-5 : ONE STEP Candida Cylindracea-Lipase Ar"' ^C00CH2CH2Cl Phosphate buffer, C2H5SH Polyvinyl alcohol, 12 h , 25°C Ar 'COOH (+>-2 (S)-(+)-1i,98%ee Ar = Ar^XXX)CH2CH2Cl MeO (R)-(-)-2,70%ee c) Separation by Use of a Biocatalytic Membrane. (S)-(+)-lc is also being manufactured8 by a proprietary bioca­ talytic membrane process. The main disadvantages of the resolution method are: 1. The recycling of the undesired isomer. 2. The recovery of the resolving agent. 3. The set up of proper experimental conditions for separation. Although resolutions are practised in industrial synthesis, the method has some inherent disadvantages as mentioned above and hence, from this point of view, the asymmetric synthesis assumes impor­ tance as it does not suffer from the above mentioned disadvantages. Before attempting any synthesis, if one dissects the molecule in terms of feasible organic reactions, one easily gets convenient clues for its synthesis. Such an approach in a gross sense is called the disconnection approach. ASYMMETRIC SYNTHESIS OF IBUPROFEN AND NAPROXEN; DISCONNECTION APPROACH. The three different types of disconnections shown in the following figure bringforth interesting features and suggest the 150 right chemical reactions to be adopted. a) This disconnection immediately suggests two or three distinct asymmetric reactions required viz. asymmetric methylation of a-arylacetic acid, asymmetric hydrogenation of a-aryl acrylic acid, asymmetric epoxidation of styrene or a-methyl styrene and further transformations. b) This type of disconnection suggests the asymmetric hydrofor- mylation/hydrocarboxylation etc. of the appropriate styrene deriva­ tives. c) This disconnection obviously necessitates an aryl-aliphatic carbon-carbon bond formation in a stereoselective manner, indicating a Grignard aryl alkyl coupling reaction and asymmetric alkylation of appropriate aryl compounds. d) Another major class of reactions not included in the above disconnection approach and which has led to industrial methods for the synthesis of a-arylpropanoic acids is the 1,2-aryl migration (rearrangement) reaction as shown below. RCL OR , A >C<X 1'2'Ary' r Jk Ar^Or^r migration Ar COOR A summary of the various approaches directed towards the asymmetric synthesis of this class of compounds is described below: 1. Asymmetric Alkylation. Fuji10 et al (1989) (Scheme-6). The use of Binaphthol (BN) as a chiral auxiliary in asymmetric alkylation has enabled the synthesis of (S)-(+)-i. In this strategy, alkylation of BINAP esters of arylacetic acid with CH3I led to very 151 high ee's of the desired product. A noteworthy feature is that the (S)-binaphthyl ester undergoes a highly stereoselective alkylation reaction. Finally, acid hydrolysis of the ester 6 afforded the a-arylpropanoic acid 1 SCHEME-6 '• THREE STEPS + R COOH _9_ + 3 + (S) -(+)-! 6. >98%ee 90M0 Reagents '• (a) H® (b)LDA,THF,HMPAJCH3I,-78°C ,4h (c) H , H20; Recrystallization 2. Asymmetric Hydrogenation. a) Novori11 et al (1987) (Scheme-7A). A remarkable advance in asymmetric hydrogenation in recent years is the development of extremely effective chiral Ru(II) cata­ lysts.
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