14 Biological Chemistry Part (i) Prostaglandins By R. F. NEWT0N”and S. M. ROBERTSb Chemical Research Gepartment Glaxo Group Research Ware Herts. SG 12 ODJ 1 Introduction The field of prostaglandin research has not been the subject of a Report before. We will concentrate on work that has been published in the last two years with reference to earlier studies where necessary. Some aspects of the biological activities of prostaglandins are presented in order to put the chemical data into perspective. 2 History Nomenclature and Occurrence’ The first report describing the biological effects of prostaglandins was published in the 1930’s. The small quantities of material that were available at that time precluded purification and structure elucidation. It was not until twenty years later that Bergstrom isolated the first crystalline samples of prostaglandins and deter- mined their structures.Nine classes of prostaglandins and two classes of thromboxanes have been discovered to date (Figure 1):the classes differ in the substitution pattern about the five- or six-membered ring respectively. Prostaglandins (PGs) and thromboxanes (TXs) possess two side-chains which contain seven and eight carbon atoms and these are called the a-and w-chains respectively. In the series described in Figure 1the side-chains contain two alkene units and this number is included in the name in the form of a subscript. Other series have been isolated in which the side-chains contain one and three alkene units as described for the PG-E class in Figure 2.All the classes of prostaglandin have three members the I-class is the exception to this rule since PG-I has not been found in nature to date. The numbering of the prostaglandins is conventional and is illustrated for PG-E2 in Figure 2. Prostaglandins D2,E2 and F2aare widely distributed in mammalian tissue but they are present in only very low concentrations. The seminal fluids of sheep and man are two of the richest sources and contain ca. 300 pg 1-’. A coral endogenous to the Caribbean Plexaura homomallu contains large quantities of PG-A2 and onions have been shown to contain PG-A,. Recently the alga Grarciluria fichenoides has been shown to contain PG-F2a and PG-E2. a Address correspondence to this author. * Present address Chemical Research Department Glaxo Group Research Ltd.Greenford Middlesex. R. F. Newton and S. M. Roberts in ‘Fats and Oils Chemistry and Technology’ ed. R. J. Hamilton and A. Bhati Applied Science London 1980 p. 109. 347 R. F.Newton and S. M. Roberts 4.1 0 4-R' aQH R (),R2 0 -2 R' R' R' R' PG-C;? PG-D2 PG-AZ PG-B;? OH R' 9" PG-G2 PG-H;? PG-E;? PG-F;?(Y Figure 1 Structures of PGs and TXs e11 Z ) 3 " Z H /* 15 C5H11 OH 13 9 OH PG-E2 OH Figure 2 Structures of PG-El PG-E2 and PG-E3 Biological Chemistry -Part (i) Prostaglandins 3 Biosynthesis and Metabolism of Prostaglandins' The prostaglandins are unusual in that unlike the hormones and the neurohormones there is no mechanism for their storage.They are biosynthesized from the appropri- ate polyenoic acid in response to a stimulus. For the 2-series prostaglandins arachidonie acid is released from membrane- bound phospholipids by the action of a phospholipase. The free acid is then cyclized to form PG-G2 by a cyclo-oxygenase enzyme system (Scheme 1).The hydroperoxide Cyclo-oxygenase enzyme _7 \/ fi2H 2H Other prostaglandins and thromboxanes Arachidonic acid Scheme 1 unit of PG-G2 is reduced by a peroxidase enzyme to give PG-H2. Except for PGF2a which is the product of an enzymic reduction process all the prostaglandins of the 2-series and TX-A2 are obtained from PG-G2 and/or PG-H2 by enzyme catalysed rearrangements. Prostaglandins of the 1-and 3-series are formed from the corresponding tri- and penta-alkenoic acids respectively by analogous routes.PG-I and TX-A2 are unstable under physiological conditions and rapidly hydrolyse to 6-ketoprosta- glandin Fla (1)and TX-B2 respectively. These decomposition products and the rest of the prostaglandin family are subject to extremely efficient metabolic pro- cesses. The first step is an oxidation of the C-15 hydroxy-group by a dehydrogenase enzyme followed by reduction of the C-13 C-14 alkene unit by a hydrogenase system. Two cycles of p-oxidation of the cy -side-chain and oxidation at the terminus of the w-side-chain produce compounds such as the keto-acid (2) which is the major urinary metabolite of PG-E,. 0 nu OH (1) (2) K. H. Gibson in 'Prostaglandins and Thrornboxanes an Introductory Text,' ed R.F. Newton and S. M. Roberts Butterworths London 1982 p.8. R. F. Newton and S. M. Roberts 4 Biological Activity of Prostaglandins and Thromboxanes Most of the early work on the biological activity of prostaglandins was concentrated on prostaglandins E and F. It became quite clear that both classes displayed potent effects on a number of biological systems3 For example PG-F2a is a potent l~teolytic:~ that is it causes regression of the corpus luteum in experimental animals. Since the corpus luteum is responsible for the maintenance of progesterone levels during implantation and development of a fertilized egg the prostaglandin can cause termination of pregnancy at an early stage.Prostaglandins E relax isolated airway smooth muscle and thus are potentially useful as aids to asthmatic patient^.^ Unfortunately the prostaglandins frequently cause severe irritation of the respiratory tract when administered by aerosol to patients. The natural prostaglandins have found very few therapeutic applications in man mainly as a result of their lack of selectivity and oral activity and their short duration of action. For instance an injection of PG-E causes a fall in blood pressure an increase in gut motility diarrhoea uterine stimulation inhibition of acid secretion and sensitization of pain receptors! The discovery of prostaglandins I and thrombodanes renewed hopes that pros- tanoids would be clinically useful. TX-A is produced from PG-H within the blood platelets and acts to increase the level of Ca2’ within the cytoplasm of the cell.This causes the platelet to deform and release TX-A and other aggregating agents into the blood plasma. Further platelets then deform and aggregate to give a thrombus. In addition TX-A is a potent vasoconstrictor so reducing blood flow even more. Prostaglandin I2 is produced from PG-H2 in the epithelial cells of blood vessels (e.g. artery walls) and released into the blood plasma. Besides acting as a potent vasodilator it also acts at a specific receptor on the blood platelet. This causes an increase in cyclic AMP levels within the cytoplasm which in turn leads to a decrease in the concentration of cytoplasmic Ca” levels. Thus the actions of TX-A and PG-I are directly opposed.In a healthy individual these effects are balanced and blood platelet homeostasis is maintained. In the event of damage to the blood vessels e.g. lesions or fat deposits on arterial walls PG-I production will be impaired whilst TX-A production in the vicinity will be undiminished. Blood platelets then adhere to the damaged vessel and clump together. Breakaway of this mass of platelets at a later time could provide a potentially lethal thrombw6 One possible aid to a patient at risk from thrombosis or stroke would be the administration of a chemically and metabolically stable PG-I analogue which would supplement the low concentration of the natural compound. Alternatively blocking E. W. Horton in ‘Chemistry Biochemistry and Pharmacology of Prostanoids’ ed.S. M. Roberts and F. Scheinmann Pergamon Oxford 1979,p.1. E. W.Horton and N. Poyser Physiol. Rev. 1976,56 595. I. Kennedy in ‘Prostaglandins and Thromboxanes an Introductory Text’ ed. R. F. Newton and S. M. Roberts Butterworths London 1982,p. 19;M.Wassermann J. Pharmacol. Exp. Ther. 1980,214,68. S. Moncada and J. R. Vane Pharm. Rev. 1978,30 293;‘Prostaglandins and Cardiovascular Disease’ ed. R. J. Hegyeli Raven Press 1980;R. J. Gryglewski Crit. Rev. Biochem. 1980,7 291. Biological Chemistry -Part (i) Prostaglandins 351 the production of TX-A2 from PG-H (a thromboxane synthetase inhibitor) or blocking the action effected by binding of TX-A to its macromolecular receptor (a thromboxane antagonist) may provide a remedy by reducing the rate of blood- platelet aggregation.Prostaglandins have been implicated in many other biological processes for example regulation of the onset of fever and the transmission of pain,7 the inflamma- tory response,* control of gastric acid secretion,’ regulation of adrenergic trans- mission,1o cancer,” immunology and allergy,’ and in the central nervous ~ystem.’~ 5 Chemical Synthesis of Prostaglandins Thromboxanes and Analogues Many of the points brought out in the above discussion have direct relevance to the synthesis of PGs TXs and analogues. For instance the abundance of PG-A in a Caribbean coral led to this substance being used as a starting material for other prostanoid syntheses by some group^.'^ The preparation of prostanoids designed to be metabolically stable and orally active has been a principal’goal in the field.Moreover the synthesis of prostanoids with enhanced selectivity of biological activity has been the raison d’etre of many research groups. The recent emergence of prostaglandins I and thromboxanes as highly important natural products has led synthetic chemists to focus their attention on these molecules as target structures. Prostaglandin synthesis has led to the discovery of many reactions and the use of some new protecting groups of general interest.” Early strategies (pre-1977) in prostaglandin synthesis have been reviewed in three excellent textbooks.16 A full review of the synthetic chemistry reported in the primary journals between 1977 and mid-1980 is a~ailab1e.I~ Synthesis of Prostaglandins A-F.-New Routes to the Corey Lactone and Congen -ers. The pioneering work of Corey established the lactone (3)as a key intermediate to PG-El PG-E2 PG-E3 PG-Fla PG-F2a and PG-F3a. Since PGs A-C are available from PGs-E’~ this lactone became a focal point for prostaglandin synthesis. ’S. H. Ferreira Nature (London) 1972,240,200; W. Feldberg in ‘Prostaglandin Synthetase Inhibitors’ ed. H. J. Robinson and J. R. Vane Raven Press New York 1974 p.197. J. R. Vane J. Allergy Clin. Immunol. 1976 58,691. A. Robert in ‘Prostaglandins and the Gastrointestinal Tract’ ed. L. R. Johnson Raven Press 1981 p.1407. lo K. V. Malik Fed. Proc. 1978 37,203. ” G. C. Easty and D. M. Easty Cancer Treatment Rev. 1976 3 217. l2 J. Morley J.L. Beats M. A. Bray and W. Paul J. Royal SOC.Med. 1980 73 443; L. M. Pelus and H. R. Strausser LifeSci. 1977 20,903. l3 F. Coceani Arch. Interm. Med. 1974,133 119. l4 G. L. Bundy W. P. Schneider F. H. Lincoln and J. E. Pike J. Am. Chem. SOC. 1972,94 2123; M. B. Floyd R. E. Schaub G. J. Siuta J. S.Skotnicki C. V. Grudzinskas M. J. Weiss F. Dessy and L. Van Humbeeck J. Med. Chem. 1980 23 903; K. M. Maxey and G. L. Bundy Tetrahedron Lett. 1980,445. M. P. L. Caton Tetrahedron 1979 35 2705. l6 J. S. Bindra and R. Bindra ‘Prostaglandin Synthesis’ Academic New York 1977; A. Mitra ‘The Synthesis of Prostaglandin Derivatives’ J. Wiley and Sons,New York 1978; C. Szartay and L. Novak ‘Synthesis of Prostaglandins’ Akademiai Kiado Budapest 1978. ” S. M.Roberts and F. Scheinmann ‘Recent Synthetic Routes to Prostaglandins and Thromboxanes’ Academic London,1982; see also ‘Aliphatic and Related Natural Product Chemistry’ (A Specialist Periodical Report) ed. F. D. Gunstone The Chemical Society London 1979 (Volume 1) and The Royal Society of Chemistry London 1981 (Volume 2). R. F. Newton and S.M. Roberts (3) R' = H or protecting group R2 = one carbon unit e.g. CHO CHpOR' (4) liv o-fo H02C Br&>o 01x-xii (3) xiii-xv+ 9 OR' OH OR2 C,Hl1 OR21xvi OH PG-F2u q xvii OR2 OR2 (7) R' = p-PhC6H4NHC0 R2 = tetrahydropyranyl (THP) Reagents i HC02H HCHO; ii Jones' reagent; iii HBr AcOH; iv HOOA? NaOAc; v HBr AcOH; vi NaHCO, H,O; vii PhSH pyridine DCC; viii Raney Ni; ix (Et0)2P(0)CH2COC5H,I NaH; x K,C03 MeOH; xi p-PhC6H4NC0 Et,N; xii LiBHBu',; xiii LiOH H,O then CIC02Et CO,; xiv dihydropyran (DHP) H'; xv HAIBu',; xvi Ph3PCH(CH2),CO,-; xvii MeCO,H H20 Scheme 2 Biological Chemistry -Part (i) Prostaglandins 353 The Sutherland-I.C.I.synthesis of the Corey lactone is detailed in Scheme 2.'* The initial Prins reaction on norbornadiene formed a key step in setting up the required stereochemistry in the keto-acid (4). This keto-acid was cleaved regio- and stereo-specifically with hydrobromic acid to give the carboxylic acid (5). Baeyer-Villiger oxidation of (5)led to the formation of the 8-lactone (6),which was readily converted into the Corey lactone. Conversion of this lactoqe into PG-F2a followed the original Corey strategy; thus a Wittig reaction appended the w-side-chain and the 15(S) hydroxy-group could be introduced by a stereocontrol- led reduction process.Partial reduction of the lactone unit to a lactol followed by a 'salt-free' Wittig reaction to introduce the Z-alkene moiety gave the PG-F2a derivative (7),which formed PG-F2a on treatment with acid. ?H OH -0Q OH Cl (8) Simple amendment of this pathway gave cloprostenol (8) which 'is marketed under the trade-name Estrumate as a veterinary aid to maximize the efficiency of artificial insemination. l9 Ghosez's elegant syntheses of the Corey lactone begins with a [2 + 21 addition of the keten (9) to cyclopentadiene (Scheme 3).20The four-membered ring of the . .. iii+ :1KCo2Me[C02Me % 0 II 0 0 \CH(OMe) (9) 1vi vii q0 (3; R1= p-PhC6HaC0 R2 = CHO) 4 viii ii BrQ** OH CH(0Me)Z (13) Reagents i cyclopentadiene; ii Bu",SnH AIBN; iii NaBH, MeOH then NaOMe then HCl HC(OMe),; iv NaOH; v KI,; vi diazabicycloundecene (DBU); vii MeCONHBr H,O;viii p-PhC6H,COCl pyridine; ix H' Scheme 3 l8 N.R. A. Beeley R. Peel J. K. Sutherland J. J. Holohan K. B. Mallion and G. J. Sependa Tetrahedron 1981,37(Supplement l) 411. l9 M. Dukes W. Russell and A. L. Walpole Nature 1974,330. 2o S. Goldstein P. Vannes C. Houge A. M. Frisque-Hesbain C. Wiaux-Zamar L. Ghosez G. Germain J. P. Declercq M. Van Meerssche. and J. M. Arrieta J. Am. Chem. SOC.. 1981 103,4616. R. F.Newton and S. M. Roberts bicycloheptenone (10) is readily cleaved to give the ester (11).Saponification and iodolactonization gave the acetal (12). Elimination of hydrogen iodide followed by stereospecific addition of HOBr gave the bromohydrin (13)which was converted in three steps into the Corey lactone. A [2 + 21 cycloaddition is also featured as the first stage in Fleming's route to the Corey lactone.*' Trimethylsilylcyclopentadiene(14)reacted with dichloroketen to give solely the bicycloheptenone (15). Electrophilic substitution of the silyl moiety with concomitant migration of the double bond gave the ether (16),which was converted into the unsaturated lactone (17) and thence into the Corey lactone by a well-defined series of reactions. SiMe ,oq Me Si c1 -Qcl 0VI 4,q0Ssteps (3) 3 Q**' -Zsteps, Q -OMe OMe The Corey lactone has been prepared from readily available cyclo-octa-l,5-diene.This diene was converted into cyclonona-2,4,7-trien-l-ol(18) in six steps this trienol isomerized to the aldehyde (19) in the presence of potassium hydride (Scheme 4).The derived carboxylic acid (which could be resolved) was iodolacton- ized to give (20) and by further transformations the acetal (12). This compound . nu CHO ?-to Pqo 1'1 Reagents i KH THF; ii Ag20 NaOH H,O; iii I, K2C03. THF H20; iv. 0,. MeOH CHZCIz then Me2S; v H' CH(OMe) Scheme 4 I. Fleming and B. W. Au-Yeung Tetrahedron 1981 37 (Supplement l) 13. L. A. Paquette and G. D. Crouse Tetrahedron 1981,37(Supplement l),281. Biological Chemistry -Part (i) Prostaglandins was converted into the Corey lactone (see Scheme 2) and into the enal (21) a precursor of PG-C216 and TX-B2.The enal (21) has also been prepared from the lactone (22) (available in optically active form23). The carbonylation process was accomplished using an intra-molecular a-amido-alkylation reaction as the key step (23) + (24) (Scheme 5).24 Prostaglandin-D3 has recently been added to the list of naturally occurring prostaglandins available from the Corey la~tone.~~ OCOAr ,fy&iv v 6-f‘ o***y i ii -iii ’ (21) NHMe OH -N \ (22) (23) (24) Me Reagents i MeNH,; ii ArCOCl pyridine; iii CH,O MeNO, CF,CO,H; iv HCl; v Bu‘OCl NaOMe then H’ Scheme 5 The Glaxo Syntheses. Prostaglandin A is available from the optically active ketone (-)-(25) using the sequence described in Scheme 6.26The key step involved $r $‘ lvi LiCuC,H7 -C,H 1 1 OR OR R = SiMezBut (29) Reagents i Br, NaHCO, CCl,; ii LiN(SiMe,),; iii (26) CH,CI,; iv m-ClC,H,CO,H; v DBU; vi Me,NCHO heat Scheme 6 23 N.Ishizuka S. Miyamura T. Takeuchi and K. Achiwa Heterocycles 1980,14 1123. ’* T. T. Li P. Lesko R. H. Ellison N. Subramanian and J. H. Fried J. Org. Chem. 1980,46 111. ” Y.Konishi H. Wakatsuka and M. Hayashi Chem. Lett. 1980 377. 26 M. A. W. Finch S. M. Roberts G. T. Woolley and R. F. Newton J. Chem. SOC.,Perkin Trans. 1 1981 1725. 356 R. F. Newton and S. M. Roberts homoconjugate addition of the cuprate reagent (26)to the bromotricycloheptanone (27). The product norbornanone (28)was transformed in three steps into the late-stage PG-A2 precursor (29).The enantiomeric bicycloheptenone (+)-(25)was converted into the same PG-A2 precursor (29)using a different series of reactions (Scheme 7).27The key transforma- tion involved the cuprate reagent (26)and the epoxyester (30) in an SN'anti reaction to give the lactone (29)directly. A small amount of the isomeric lactone (31)was also isolated. Interestingly the SN2'pathway was found not to predominate when the epoxide (30) underwent reaction with other nucleophiles.28 Reagents i MeC0,H; ii N-bromosuccinimide CCI, hu; iii K,CO, MeOH; iv (26) Scheme 7 n I\ (-)-enantiomer (+)-enantiomer OK0 -a.$1 I 3 steps 3 steps e Q -Qo 0,''- 0 0 QR o-fo # 3 steps 2 steps 9, ' ' LC5Hl1 OH C,Hl1 OR OR OH 3 steps 1 1 PG-E2 &H2Lc02H II PG-FZa 4 IV CJI 1 CJI I HO OH OR % PG-D2methyl ester OH (33) Reagents i (26);ii H'; iii hv H,O,MeCN; iv Ph,PCH(CH,),CO; Scheme 8 27 C.B. Chapleo M. A. W. Finch T. V. Lee S. M. Roberts and R. F. Newton J. Chem. SOC.,Perkin Trans. 1 1980 2084. S. M. Roberts G. T. Woolley and R. F. Newton J. Chem. SOC.,Perkin Trans. 1. 1981 1729. Biological Chemistry -Part (i) Prostaglandins ProstaglandinsEZand Fza are also available from both enantiomers of the ketone (25) as shown in Scheme 8.29These enantiocomplementary routes were based on reaction sequences worked out previously on the racemic A noteworthy feature of the route starting from the ketone (+)-(25) is the high yield photochemical conversion of the cyclobutanone (32) into the y-lactol (33).This route represents the shortest synthesis of prostaglandins E2 and F2a reported to date. In order for the above strategy to be viable an efficient resolution of the ketone (25) is required. Reduction of the ketone (25) with actively fermenting bakers' yeast gave two diastereoisomeric alcohols (34) and (35) of high optical purity and in good chemical yield. The alcohols (34) and (35) were easily separated by distillation and were oxidized to the ketones (+)-(25) and (-)-(25) respectively using Jones' conditions the alcohols (34) and (35) gave the bromohydrins (36) and (37) respectively on reaction with N-bromosuccinimide in aqueous di~xan.~' (34) (35) 1 1 Br I Br 0 (36) (37) Another important feature of the Glaxo route is the direct access to PG-D232 and simple derivative^.^^ Conjugate Addition to 4 -Substituted Cyclopentenones.Two approaches have been explored (Scheme 9). The first involves conjugate addition to a 2-alkyl-4-alkoxy cyclopentenone the second involves conjugate addition to a 4-alkoxycyclopen- tenone and trapping of the enolate ion with a moiety which can be readily transfor- med into the C-7 side-chain. Note that direct alkylation by addition of the complete a-side-chain to the enolate anion has not been achieved. In these strategies the stereochemistry at C-4 of the cyclopentenone establishes the whole substitution pattern required for the prostaglandin E class. Thus nucleophilic addition of the C-8 side-chain takes place on the less hindered face 29 J.Davies S. M. Roberts D. P. Reynolds and R. F. Newton J. Chem. SOC.,Perkin Trans. 1,1981 1317. 30 T. V. Lee S. M. Roberts M. J. Dimsdale R. F. Newton D. K. Rainey and C. F. Webb J. Chem. Soc. Perkin Trans. 1 1978 1176; C. Howard R. F. Newton D. P. Reynolds A. H. Wadsworth D. R. Kelly and S. M. Roberts ibid 1980 859; C. Howard R. F. Newton D. P. Reynolds and S. M. Roberts ibid 1981 2049. 3' R. F. Newton J. Paton D. P. Reynolds S. N. Young and S. M. Roberts J. Chem. SOC.,Chem. Commun. 1979,908. 32 R. F. Newton D. P. Reynolds C. F. Webb and S. M. Roberts J. Chem. SOC.,Perkin Trans. 1 1981 2055. 33 R. J. Cave R. F. Newton D. P. Reynolds and S. M.Roberts J. Chem. SOC.,Perkin Trans.1 1981,646. R. F. Newton and S. M. Roberts 6-L T C5H' 1 OR2 OR2 ' 0R3 R' =(cH2)&02Me or CH2CH:CH(CH2)3C02Me R2=R3=protectinggroup R4 =simple C-1 or C-2 unit Scheme 9 of the cyclopentenone and a trans relationship between the a-and w-side-chains is set up by thermodynamic control. In a series of papers,34 Rickards et al. have demonstrated that phenol can be converted into the acid (38) this acid (which can be resolved) was transformed into the 3-chloroenone (39). Conjugate addition of the C-7 unit followed by elimination of chloride ion and carbonyl group transposition furnished the PG-El precursor (40) (Scheme 10). In an alternative process the chloroenone (39) was OR2 (41) (40) R' =SiMe2Bu';R2 =THP Reagents i Pb(OAc),; ii CrCl,; iii CISiMe,Bu' imidazole; iv BrMg(CH,),OR' CuI Scheme 10 34 R.M. Christie M. Gill and R. W. Rickards J. Chem. SOC.,Perkin Trans. 1 1981,593;M. Gill and R. W. Rickards ibid p. 599; M. Gill and R. W. Rickards Aust. J. Chem. 1981,34 1063. Biological Chemistry -Part (i) Prostaglandins transformed into the stannylcyclopentenediol derivative (41) which reacted efficiently with various electrophiles to give after standard functional group manipulation the required enone (40).35 The PG-E2precursor (42)was obtained from the lactone (22) (which is available in optically active form36) by the series of simple transformations described in Scheme 1l.37 qo OH0,.-0,,*~H2)3c02Me -6,.*ucH2) 3c0 2 Me - - (22) 0 (CH2)3C02Me PG-E2 -wH2)3c02Me + OH OTHP (42) Scheme 11 The preparation of simple derivatives of PG-EI and PG-E from (40) and (42) respectively was achieved using a cuprate reagent (26) or a The enone (43) is readily available.It has been prepared in the optically active Stork prepared (43) in racemic form from cyclopentadiene in two steps. Conjugate addition of the appropriate cuprate reagent followed by trapping of the enolate with formaldehyde gave the hydroxyketone (44).The hydroxyketone (44) was transformed into the a-methylene ketone (45). A second conjugate addition gave the PG-E2derivative (46) (Scheme 12).40 Another successful conjugate addition-enolate trapping sequence was described recently by Davis.41 Two features are noteworthy. First the use of the cuprate reagent (47) and the transformation of the 132,15R configuration of the w-side- chain into the required 13E,15sconfiguration using a subtle sulphenate-sulphoxide rearrangement.Secondly the use of keten bis(methy1thio)acetal monoxide as the enolate trapping agent (Scheme 13). Organozirconium reagents in the presence of a low-valence nickel catalyst can be used in place of the more commonly employed cuprate reagent^.^' ” M. Gill H. P. Bainton and R. W. Rickards Tetrahedron Lett. 1981 22 1437. 36 M. Nara S. Terashima and S. Yamada Tetrahedron,1980 36 3161. ” L. Novak Acad. Chim. Acad. Sci. Hungary 1979,102,91. ’* C. J. Sih R. G. Salomon P. Price R. Sood and G. Peruzotti J. Am. Chem. SOC. 1975 97 857; C. J. Sih J. B. Heather R.Sood P. Price G. Peruzzotti L. F. Hsu-Lee and S. S. Lee ibid 1975 97 865; J. B. Heather R. Sood P. Price G. Peruzzotti S. S. Lee L. F. Hsu-Lee and C. J. Sih Tetrahedron Lett. 1973 2313. 39 K. Ogwa M. Yamashita and G. Tsuchihashi Tetrahedron Lett. 1976 759; S. Miura S. Kurozumi T. Tom,T. Tanaka M. Kobayashi S. Matsubura and S. Ishimoto Tetrahedron 1976 32 1896. 40 G. Stork and M. Isobe J. Am. Chem. SOC.,1975,97,6260. 41 R. Davis and K. G. Untch J. Org. Chem. 1979 44,3755. 42 J. Schwartz and Y. Hayasi Tetrahedron Lett. 1980 21 1497. R. F. Newton and S. M. Roberts iii iv 4-i ii -C5H1 1 C5H11 OR' OR' O'R' OR2 OR2 (43) (44) (45) j/ &2)3cH20R3 RZ = CHZOCHzPh R' CMezPh C,Hll OR' OR2 (46) Reagents i LiCu[CH:CHCH(ORZ)C5H1,],; ii CH,O; iii MsCl pyridine; iv Et,N; v LiCu[CH:CH(CH,),CH,0R3] Scheme 12 ))Me LII vi vii CH 5&C5H1 -(33) OR -, OR OH R = SiMezBu' Reagents i L~CU[CH:CHCH(OCM~~OM~)C,H,,]~ (47); ii H,C:C(SMe)S(O)Me; iii PhSCI Et,N; iv P(OMe),; v chromatography; vi L-selectride; vii HCI Scheme 13 MiscellaneousProcedures.Holton has reported a four-stage synthesisof the lactone (53) starting from cyclopentadiene (Scheme 14).43Thus addition of hydrogen chloride gas to cyclopentadieneand treatment of the resultant chloride with anhy-drous dimethylamine furnished the cyclopentenylamine (48). Reaction of this intermediate with lithium tetrachloropalladate and sodio diethyl malonate followed by addition of di-isopropylamine gave the alkene (50) via the complex (49).The alkene (50) was treated with lithium tetrachloropalladate in a mixture of 2-chloroethanol dimethyl sulphoxide (DMSO),and ethyldi-isopropylamine to give the complex (51) which on reaction with oct-1-en-3-one gave the desired enone (52). Conversion of (52) into the lactone (53) was straightforward. A very interesting route to optically active PG-E has been described by Fuchs. The ally1 sulphide (54) is readily available in optically active form44and was 43 R. A. Holton J. Am. Chem. SOC.,1977 99 8084. 44 J. C. Saddler R.E. Donaldson and P. L. Fuchs J. Am. Chem. SOC.,1981,103,2110. Biological Chemistry -Part (i)Prostaglandins L NMe I ,NMe NMe (48) CH(CO,Et) (49) 1iv NMe, I Reagents i HC1; ii Me,NH; iii lithium tetrachloropalladatc NaCH(CO,Et) then EtNPr’, heat; iv lithium tetrachloropalladate Cl(CH,),OH DMSO EtNPr’,; v C,H,,COCH:CH,; vi L-selectride; vii NaCN; viii MeI; ix KOH Scheme 14 converted in four steps into the sulphone (55).This sulphone reacted stereo- specifically with dimethylamine with displacement of the mesyloxy-group to give a tertiary amine. Quaternization of the amine function and an SN’(syn) reaction with more dimethylamine gave the key sulphone (56). Reaction of (56) with the appropriate organolithium reagent gave the stabilized carbanion (57) which was quenched with the ally1 iodide (58)in the same pot (overall yield 67%). The amine (59) was formed and converted into the amino-acid (60) in four steps. The acid (60) was converted into the oxime (61) and thence into PG-E2 (Scheme 15).45 Thus in the Fuchs’ procedure the cyclopentane ring is connected to the two prostaglandin side-chains in one pot this highly desirable ‘triply convergent’ approach has been used to prepare 11-deoxyPG-E from cyclopentenone (vide infra),but fails to provide PG-E from 4-alkoxycyclopentenones (vide supra).Synthesis of Some Analogues of Prostaglandins A-F. -1 1-Deonyprostaglandin E. The 11-deoxyprostaglandin E class is noteworthy for two reasons. First this class of compound is readily prepared from cyclopentenone. Second some members 45 R. E. Donaldson and P. L. Fuchs,J. Am. Chem.Soc. 1981,103,2108. 362 R.F.Newton and S. M. Roberts QH QH -6 GS0,Ph OSPh QS0,Ph ii-i" SOZPh q 0 OR OR (54) (55) 'Fi CH,CH:CH(CH,)3C0,Me & CSH, C5Hl I OR OR OR OR (59) (57) 4 steps Ho\ &i CH,CH:CH(CH,),CO,H -2 steps &:;;;H aPG-E C31 OR OR OR OR (60) (61) R = SiMe2Bu' Reagents i m-CIC6H4C03H; ii DBU; iii ClSiMe,Bu'; imidazole DMF; iv MeSO,Cl Et3N; v Me,NH; vi FS0,Me; vii LiCH:CHCH(OR)CSHI1; viii ICH,CH:CH(CH,),CO,Me (58); ix CH8 BF,.Et,O Me,CO Scheme 15 of this class exhibit interesting biological activity for example the prostanoid (62) is a highly potent and selective anti-ulcer agent.46 Two methods of synthesis of the 11-deoxyPG-E system are available.Either the w-side-chain can be added to cyclopentenone and a derived enolate alkylated directly (see Scheme 16)47 or a 2-substituted cyclopentenone is prepared and reacted 46 A.K. Banerjee B. J. Broughton T. S. Burton M. P. L. Caton A. J. Christmas E. C. J. Coffee K. Crowshaw C. J. Hardy M. A. Heazell M. N. Palfreyman T. Parker L. C. Saunders and K. A. J. Stuttle Prostaglandins,1981 22,167. 47 J. W. Patterson and J. H. Fried J. Org. Chem. 1974 39 2506; see also A. J. Dixon R. J. K. Taylor and R. F. Newton 1.Chem. SOC.,Perkin Trans. I 1981 1407. Biological Chemistry -Part (i) Prostaglandins ,I3CO2Me / C31 / C,Hl I OR OR R = CMezOMe Reagents i LiCu[CH:CHCH(OR)C,H,,] then CISiMe then Li NH,; ii (58) Scheme 16 with the requisite cuprate reagent to give an 11-deoxyPG-E. The required precursor (65) of 11-deoxyPG-El was prepared by reaction of the aldehyde (63) with the enamine (64) and rearrangement of the first formed product48 or by dialkylation (63) (64) 1 1-deoxy-PG-El of diethyl3-oxoglutarate followed by periodate oxidation hydrolysis decarboxyla- tion cyclization and re-e~terification.~’ C0,Et to-(65) ~2k,co~Et O~lhcozEt + Et0,C C0,Et Et0,C C0,Et C02Et 0 0 The precursor (66) of 11-deoxyPG-Ez can be prepared by thiazolium salt cata- lysed addition of the appropriate aldehyde to methylacrylate followed by cyclization partial reduction and dehydration.” RCH2CH0 + CH2:CHCO2Me + RCH2CO(CHz)2C02Me U 11-deoxy-PG-E2 48 A.Barco S. Benetti P. G. Baraldi and D. Sirnoni Synrhesis 1981 199. 4p Y.Naoshima S. Mizobuchi and Wakabayashi Agric. Bid. Chem. 1979,43 1765. 50 L.Novak G.Baan J. Marosfalvi and C. Szantay Chem. Ber. 1980 113 2939. 364 R. F. Newton and S. M. Roberts The Stork synthesis of optically active 11-deoxyPG-E from 2,3-isopropylidene- L-erythrose (67) is elegant but long. The key step involves reaction of the carbonate (68) with the ortho-ester (69) to give the triester (70) through a Claisen rear- rangement.” Me0,C- Me0,C co Me “0 I 5 steps H nCHz)3COzMe040 (67) Me02C(CH2)3CI C(CH2)2C(OMe)3 (69) (70) 5 steps1 Me0,C C02Me 11-deoxy-PG-E2 sH::3c0z Me R = CH(Me)OEt ‘0R F‘luoroprostaglandina 12-Fluoroprostaglandin FZa (73) (and also the correspond- ing 13,14-dihydro-derivative)are biologically interesting because they show a significant separation of antifertility and smooth muscle stimulating activities in the hamster.’* These fluoroprostaglandins are not substrates for the 15-hydroxy PG-dehydrogenase enzyme.The prostanoid (73) was prepared using the Corey-Suther- land-I.C.I. strategy and the fluorobicycloheptane (72). The latter compound is prepared by fluorination of the bromoester (71).53 14-Fluoroprostaglandin-F2ahas been prepared from the ester (72).54 Me0,C Me0,C F Brho-Br&o e2)3c02Me sye; CSHll OH k 02 02 OH (71) (72) (73) + F C0,Me Br&> 0 ’’ G. Stork and S. Raucher J. Am. Chem. Soc. 1976,98 1583. 52 P.A. Grieco and T.Takigawa J. Med. Chem. 1981,24,839. 53 P.A. Grieco W. Owens C.-L. J. Wang E. Williams W. J. Schillinger K. Hirotsu and J. Clardy J. Med. Chem. 1980,23 1072. 54 P. A.Grieco W. J. Schillinger and Y. Yokoyama J. Med. Chem. 1980,23,1077. Biological Chemistry -Part (i) Prostaglandins 10,10-Difluoro-13,14-dehydroprostaglandin F2a(76) has been prepared by Fried (Scheme 17)" using a strategy that had been used earlier to prepare naturally occurring prostaglandins. The reaction of the epoxide (74) and the alane (75) was highly regioselective due to the influence of the neighbouring primary hydroxy- group. d OH 0 OBu' (75) OR Reagents i Bu'OH H'; ii LDA ICH,CH:CH2; iii HCI; iv FCIO, MeOH KHCO,; v KAIHBu',; vi chromatography; vii 0, MeOH; viii KI, Na2C0, H,O; ix (CF,SO),O pyridine; x KOH MeOH; xi CO then 12; xii KOH then H+; xiii LiAIH4; xiv (75) Scheme 17 Azaprostaglandins The most interesting azaprostanoids have an hydantoin system replacing the cyclopentane ring of the natural compounds.For example the hydan- toin (78) shows very potent anti-aggregatory activity on blood platelets. The active compound is very readily prepared from the acyclic aminodiester (77) as shown in Scheme 18." The diester (77) was converted into other series of heteroprostanoids. The structure-activity relationships suggested that a nitrogen atom at position 10 and the prostaglandin configuration at C-8 are vital for maximum biological activity." The compound (79) prepared by a Pfizer group has been shown to be a potent thromboxane synthetase inhibitor,58 while the 13-azaprostanoid (80) synthesized by Collington et al. is a potent thromboxane antag~nist.'~ Whether any of the " J.Fried D. K. Mitra N. Nagarajan and M. M. Mehrotra J. Med. Chem. 1980,23 234. 56 M. A. Brockwell A. G. Caldwell N. Whittaker and M. J. Begley J. Chem. Soc. Perkin Trans. 1 1981,706. 57 P.Barraclough A. G. Caldwell C. J. Harris and N. Whittaker J. Chem. SOC.,Perkin Trans. 1 1981, 2096. '* M. J. Randall M. J. Parry E. Hawkeshead P. E. Cross and R. P. Dickinson Thrombosis Res. 1981, 23 145. '' R.A. Coleman E. W. Collington H. P. Geisou. E. J. Hornby P. T. A. Humphrey I. Kennedy G. P. Levy P. Lumley P. J. Mc€abe and C. J. Wallis Br. J. Pharm. 1981,72 524. 0 OH (78) Reagents i MeCO,H H,O; ii (MeCO),O; iii porcine renal acylase; iv SOCI, EtOH; v CH2:CHCOC6H11; vi NaBH,; vii HCl KCNO EtOH Scheme 18 compounds(78) (79),or (80)can be used to protect a patient at risk from thrombosis or stroke remains to be seen.A number of aza-11-deoxyprostaglandin E analogues have been described. The 8-a~a-(81),~' and 8,lO-diaza-prostanoid (83)62have been prepared 10-a~a-(82),~~ by standard routes. OCH,Ph N'l (79) 6o P. A. Zoretic J. Jardin and R. Angus J. Heferocycl.Chem. 1980,17,1623. " P.A. Zoretic F. Barcelos J. Jardin and C. Bhakta J.Org. Chem. 1980,45,810. '* S. Saijo M. Wada J. Himizu and A. Ishida Chem. Pharm. Bull. 1980.26,1459. Biological Chemistry -Part (i) Prostaglandins OH OH (82) (83) Recently the synthesis and biological profile of aza-analogues of PG-I2 have been reported. Cassidy et al. converted the aminoester (84) into the amidolactone (85) this lactone gave the aza-prostanoid (86).Preliminary biological results suggest that (86) is a potent inhibitor of collagen- and ATP-induced platelet aggregation in human platelet-rich plasma.63 Synthesis of ProstaglandinsG-I. -PG-G2 and PG-H2have been synthesized from PG-F2a. Mukaiyama's reagent (87) is used to replace the hydroxy-groups at C-9 (2-11,and if required C-15 by halogen atoms prior to substitution with peroxide anion (Scheme 19).64Overall yields are low. CQHHI)~CO#~ 2)3COzMe CSHIl C5H11 OH Br ' OR la-iv PG-H2 CI I .... III.LV I +' Et PG-G2 (87) R = SiMe2Bu' Reagents i (87) Et46Br; ii H'; iii hog pancreas lipase; iv AgO,CCF, H202;v PhCH,&Bu,CI- (87) Scheme 19 63 F. Cassidy R. W. Moore G. Wootton K.H. Baggaley G. R. Green L. J. A. Jennings and A. W. R. Tyrrell Tefrahedron Lett. 1981 22 253. 64 N. A. Porter J. D. Byers K. M. Holden and D. B. Menzel 1.Am. Chem. Soc. 1979 101,4319;N. A. Porter J. D. Byers A. E. Ali and T. E. Eling ibid 1980,102. 1184. R. F.Newton and S. M. Roberts 368 Following the structure elucidation of PG-I2a number of research groups reported the preparation of this material from PG-F2cu.A common strategy was employed namely halogeno- (or mercuri-) etherification of the C-5 alkene unit with intramolecular participation of the hydroxy-group at C-9 followed by base catalysed elimination of hydrogen halide. The required 2-geometry about the enol-ether OH ?$~CHZ)W~M~ '~4,-iik / C5H11 C5H11 OH OH OH OH OH OH liii PG-12 Reagents i KI, Na,CO, H,O; ii DBN benzene; iii NaOH MeOH H,O Scheme 20 HO + 'erythro' isomers OR OR OR OR Reagents i \IJ ,pentane -78 "C; ii KI, Na,CO, H20; iii Bu",SnH; iv m-CIC,H,CO,H; v K,CO, MeOH; vi MeSO,Cl pyridine; vii H'; viii chromatography; ix DBN; x NaOH MeOH H20 Scheme 21 Biological Chemistry -Part (i) Prostaglandins moiety was ensured by the stereochemistry of the addition (trans)and elimination (trans)processes (Scheme 20).65 Recently Newton has reported a total synthesis of PG-I,.The key step in this synthesis involved the reaction of the readily available aldehyde (88)and the lithium enolate of cyclopentanone in a stereocontrolled aldol reaction. The two ‘threo’ diastereomers (89) and (90) were isolated in 70% yield and were independently converted into PG-I2 by a series of high yield reactions outlined in Scheme 21.66 Synthesis of Some Analogues of Prostaglandins H and I.-Prostaglandins-G and -H are very important compounds. Not only do they possess biological activity per se but also all other PGs and TXs are derived from them in viuo. A large number of analogues of PG-H2 have been prepared in order to study the biochemistry and pharmacology of the unstable natural materials. Corey et al. prepared the diaza-analogue of PG-H (91) from the mesylate (92; R’ = R2 = H) by a route closely related to that used by Porter to prepare the natural compound (vide supra). In fact Corey prepared the bis-mesylate (92) from (91) (93) PG-A2 rather than from PG-F2a6’ The dithia-analogue (93) was prepared from the bis-mesylate (92; R’ = Me R2 = THP) in a similar manner.67 (&;72H -,py3C02M‘ OH C,Hl L \ I ’ OH OH OTs OH (94) OH (95) 65 B.De N. H. Andersen R. M. Ippolito C. H. Wilson and W. D. Johnson Prostaglandins. 1980 19 221 and references therein. 66 R. F. Newton S. M. Roberts B. J. Wakefield and G. T. Woolley I. Chem. SOC., Chem. Commun. 1981,922. 67 K. C; Nicolaou G. P. Gasic and W. E. Barnette Angew. Chem. Inr. Ed. Engl. 1978 17 293 and references therein. R. F. Newton and S. M. Roberts 11-HomoPG-E (94) is produced on benzophenone sensitized photolysis of PG-A2 in methanol. The 9,ll-epoxymethano-analogue(95)of PG-H was prepared from (94).6' The endoperoxide analogue (97) was prepared from the Diels-Alder adduct of cyclopentadiene and methyl propynoate (96).The cuprate reagent (26) was used to add the w-side-chain to the @-unsaturated ester function in compound (96).6' The corresponding PG-HI analogue has been prepared using a similar strategy.@ OSiMe3Bu' OH (97) (98) A number of the analogues described above inhibit the synthesis of thromboxane; however they all cause platelet aggregation at low concentrations rendering them unsuitable for consideration as potential anti-thrombotic agents.More interesting from the biological viewpoint is the report by the Upjohn group that the analogue (98)prevents thromboxane synthesis but does not affect PG-1 synthesis nor does it cause aggregation of blood platelets in simple test ~ystems.~' 0 /CO,Me 4QOzMe Cco2Me 0,Ph OR OR 0,Ph O'R o,Ph (99) (100) R = THP 0,Ph OH OH (102) (101) Reagents i NaOH then CH,N,; ii CrOCI, HOBu' pyridine; iii LiCH,CO,Me iv H1.Pd-C; v KOBu' benzene; vi HMPA A Scheme 22 68 M.F. Ansell M. P. L. Caton and P. C. North Tetrahedron Lett 1981 22 1723. 69 F. Fitzpatrick R. Gorman G. Bundy T. Honohan J. McGuire and F. Sun Biochim. Biophys. Acra 1979 573,238. Biological Chemistry -Part (i) Prostaglandins 6,9-MethyleneprostaglandinI (Carba-PG-12). Several groups have made use of Corey intermediates to prepare carba-PG-I (102). For example the lactone (99) was converted into the keto-ester (100)and then via a Dieckmann cyclization into the cyclopentanone (101).The w-side-chain was elaborated in the usual manner and the carboxylic acid side-chain was appended using a ’salt-free’ Wittig reaction (Scheme 22).” Aristoff used the late-stage Corey intermediate (103) and a novel Wadsworth- Emmons-Wittig reaction (104) + (105) to furnish after catalytic reduction the ketone (106). The ketone (106) was converted into carba-PG-I using previously described methods.71 bC H I I OR s+C5HlL -CJII I OR OR OR OR OR (104) (105) R = THP 1 OH (106) The key reaction in an alternative route to carba-PG-I2 involves an intramolecular Michael reaction and the diketoester (107). Transformation of the hydroxyester (108) into the desired PG-I2 analogue closely paralleled the routes described above (Scheme 23).72 n ..I. , 111 iv v --* ---* p+ CO,H C02Et QC0,Et 0 0 Reagents i Jones’oxidation; ii (Et0,CCH,C0,-),Mg2’ (imidazole),CO; iii K,CO,; iv 2-methyl-2- ethyl-1,3-dioxolane H’; v NaBH Scheme 23 ’O Y.Konishi M. Kawamura Y. Arai and M. Hayashi Chem. Lett. 1979 1437. ” P. A. Aristoff J. Org. Chem. 1981 46 1954. ’* A. Barco S. Benetti G. P. Pollini P. G. Baraldi and C. Gandolfi J. Org. Chem. 1980 45 4776. 372 R. F. Newton and S. M. Roberts The enone (109) is a key intermediate in the route to carba-PG-I described by Ikegami. Two routes to this intermediate are a~ailable.’~ Reaction of the enone (109) with the cuprate reagent (26) gave the bicyclo-octanone (110) which was transformed in six steps into the carba-PG-I2 precursor (106) (Scheme 24).The ketone (110) was converted also into A6-~arba-PG-12.74 -7 *T -(106) 6 steps &O & / C5HIl OR OR OR (109) (110) R = SiMe2But Reagents i (26),ether -78 “C Scheme 24 6,9-Thiaprostaglandin 12. The PG-F2a derivative (111)was subjected to two SN2 reactions at C-9to introduce a sulphur atom to this position with retention of configuration. Iodine mediated cyclization and base catalysed trans-elimination of HI gave thia-PG-I (112) from which the sulphoxide (113) was produced on treatment with peroxide (Scheme 25).” 5E-Thia-PG-I sulphoxide and sulphone OH SAC *\C5Hl I *+C5Hl 1 OR OH OR OH (111) li OH O’H OH OH OH (113) (112) R = THP Reagents i NaOMe MeOH then 12 CH2CI,; ii DBU iii HOOBu‘ Scheme 25 ’’M.Shibasaki K. Iseki and S. Ikegami Chem. Lea. 1979 1299; Synrh. Commun. 1980,10,545. 74 M.Shibasaki K. Iseki and S. Ikegami Terrahedron Len. 1980 21 169. ” K.C.Nicolaou W. E. Barnette and R. L. Magolda J. Am. Chem. Soc. 1981,103,3472 3486. Biological Chemistry -Part (i)Prostaglandins 373 (114) are available by a similar strategy.75 A6-Thia-PG-I (116) was prepared from the prostanoid (115).76 (114;n = 1or2) (115) (116) Thia-PG-I is chemically more stable than PG-I,. It is a potent inhibitor of blood platelet aggregation; however it is a substrate for prostaglandin 15-hydroxy- dehydrogenase and hence it is rapidly metabolized in vivo. (117) (118) Homoprostaglandin I,. The PG-Iz analogue (118) has been synthesized from the A4-PG-Fla derivative (117) by a cyclization-elimination procedure similar to those described above.77 The isomeric homo-PG-Iz (119) was prepared from the lactone (99) as indicated in Scheme 26.78 2 OAc 6 steps __* a<-;p 1-(CH2)3COzH z C5Hl I OTHP 0,Ph 0,Ph O’Ac OH OH (99) (119) Scheme 26 Prostaglandin Il.Prostaglandin I1 (121) was prepared from PG-Fza by tri-n- butyltin hydride reduction of the iodo- or seleno-ethers (120).79 76 M. Shibasaki Y. Torisawa and S. Ikegami Chem. Lett. 1980 1247. 77 R.A.Johnson and E. G. Nidy J. Org. Chem. 1980,45,3802. ’I8 W.Skubulla Tetrahedron Lett. 1980 21 3261. 79 R. A. Johnson F. H.Lincoln E. G. Nidy W. P. Schneider J. L. Thompson and U.Axen J. Am. Chem.Soc. 1978,100,7690;K.C.Nicolaou W. E. Barnette and R. L. Magolda ibid 1981,103,3480. R. F. Newton and S. M. Roberts (120) X = I Br or SePh (121) R' = R2 = H or protecting group A total synthesis of 6p-PG-II has been reported by Newton et al. The key reaction involves the bis-Grignard reagent (122) which was alkylated and carboxy- lated in one-pot to give the hydroxy-acid (123). The acid (123) was cyclized in the 'reverse' manner i.e. utilizing an hydroxy-group in the side-chain and an endo-cyclic alkene unit (Scheme 27).80 <+< CHO BrMg(CH2)4MgBr C411Jk+(121) (122) OR CJ,l OR OR OR (88) R = SiMe2Bu' (123) Reagents i (122); ii CO,; iii KI, THF H,O; iv HSnBu",; v H' Scheme 27 Synthesis of Thromboxane B2.-A laboratory synthesis of TX-A2 has not been reported to date.TX-B has been prepared from well-established PG-precursors for example an Upjohn group used the lactone (21) to prepare the key intermediate (21) R. F.Newton,M. A. W. Finch and S.M. Roberts J. Chem. SOC.,Perkin I 1981 1312. Biological Chemistry -Part (i) Prostaglandins (124) in ten stepss1 A second group from the Upjohn laboratories prepared the same intermediate (124) from the lactone (99).82A more efficient synthesis of TX-B2 from the PG-F2a derivative (125) has been described by Schneider and Morge (Scheme 28).83 OAc (CH2)3C02Me (CH2)3C02Me A,,, OAc irr-~\.rn M-(CH2),C02Me ,*'LJcA .,-\ ( C5H1 I OAc L 5H OH C (125) OAc 1 I OAc (125) Reagents i Pb(OAc), C,H,; ii (MeO),CH C,H,N.HCI MeOH; iii HO- H,O; iv phosphoric acid H20 THF Scheme 28 Optically active TX-B2has been obtained from chiral sugars.For example Kelly has converted laevoglucosan (126) into the epoxytosylate (127). Opening of the epoxide ring with displacement of the tosyl group followed by stereoselective reduction of the new epoxide gave the alcohol (128) which was transformed into the TX-B2precursor (124) in three steps (Scheme 29).84 0 OH (126) (127) (128) Reagents i TsCI C,H,N then NaOMe; ii CH2:CHCHZMgCl,CuI THF; iii LiBHEt, THF; iv TsC1 C&N; v RuO, NaIO, H,O Me2CO;vi MeOH H' Scheme 29 The four hydroxy-groups of the simple sugar derivative (129) are fully differenti-ated. Oxidation of the free hydroxy-group followed by a Wittig reaction gave the esters (130),Reduction of the alkene unit hydrolysis of the ester and debenzoylation gave the lactone (1311,which was converted into TX-B2in standard fashion (Scheme N.A. Nelson and R. W. Jackson Tetrahedron Lert. 1976 3275. 82 R. C. Kelly I. Schletter and S. J. Stein Terrahedron Lerr. 1976 3279. 83 W. P. Schneider and R. A. Morge Tefrahedron Lerr. 1976 3283. 84 A. G. Kelly and J. S. Roberts J. Chem. Soc. Chdm. Commun. 1980 228 R. F.Newton and S. M. Roberts OCOPh PhCOO KoR& .dgz2Me -MeO' 0 MeO' 0 MeO" (129) (130) (131) R = SiMe2Bu' Reagents i l-ethyl-3-(3'-dirnethylaminopropyl)carbodi-irnide.HCl, C,H,N.CF,CO,H DMSO; ii (MeO),POCH,CO,Me KOBu'; iii Pd(OH), H,; iv K,CO, MeOH Scheme 30 30)." Another noteworthy route from a simple glucose derivative to TX-B2 has been documented.86 A total synthesis of TX-B2 has been reported by Corey et al.The readily available enone (132) was converted into (133). Reaction of (133) with the aldehyde (134) under carefully controlled conditions led to the diol (135) which cyclized under acid conditions to give the desired product (136) with the a-and w-side-chains trans-oriented. Further transformations gave the acetal (137) and hence TX-B2 (Scheme 31)." BUSfMe-BUSF-SBu SBu BUS SB"oH ' CSHII OH (132) (133) (135) Reagents i LiNPr', THF HMPA then CH,:CHCH,Br; ii LiNPr', THF then (134);iii MeCO,H H,O THF Scheme 31 IsS. Hanessian and P. Lavalle Can. I. Chem. 1981,59 870;see also H.Ohrui and S. Ernoto Agric. Bid. Chem. 1977,41,1773. *' E. J. Corey M. Shibasaki and J. Knolle Tetrahedron Lett. 1977 1625; 0.Hernandez ibid 1978,219. E.J. Corey M. Shibasaki J. Knolle and T. Sugahara Tetrahedron Lett. 1977 785. Biological Chemistry -Part (i) Prostaglandins Synthesis of Some Analogues of Thromboxane-A2.-The dithia-analogue (139) of TX-A2 has been prepared by a series of transformations outlined in Scheme 32.88 I5 steps c- s \ (CHz)zCO,Me (138) 6 steps OMS 2)3C02Me -iii-v ~z)3c02Na / Call / CJll s \ OBz OH (CH2),COzMe (139) Reagents i H2S NaOAc EtOH; ii HSCH,CH,CO,Me EtNPr', DMF; iii KOBu' HMPA; iv NaOMe MeOH; v NaOH THF H,O Scheme 32 0.+CHO -fQ"CN C0,Me OTHP 0 (140) (141) 18 steps a<H2)3c02Me SAC 11 steps HO OH (142) Scheme 33 S.Ohuchida N. Hamanaka and M. Hayashi J. Am. Chem. SOC.,1981,103,4597 R. F. Newton and S. M. Roberts The key stage involves the triple conjugate addition to the enynone (138). The same research group have prepared 9,ll-thia-ll,12-methylene-TX-A2 (142) from the readily available ester (140) via formation of the lactone (141) and thereafter a series of standard transformations (Scheme 33).*' The isomeric analogue (143)" and the 11,12-methylenethrornboxaneA2(146)" were prepared from cis-1,3-disubstituted cyclobutanes. In the former synthesis an intramolecular Michael reaction is employed to form the second six-membered ring (Scheme 34) whereas in the latter synthesis an iodoetherification reaction C0,Me OH (143) Reagents i NaSCH,(OEt), DMSO; ii HAIBu',; iii CH,(CO,Me), AcOH pyrrolidine; iv H'; v AcOH pyrrolidine Scheme 34 CH,OSiMe,Bu' bC0,Et i-iii -0 0 OH OH (146) Reagents i MeOH H'; ii MeC(OEt), EtC0,H then 1N-HCI; iii NaBH, EtOH; iv Hg(OCOCF,), benzene then 1,; v NaN,; vi FS0,Me then pH4 buffer Scheme 35 89 S.Ohuchida N. Hamanaka and M. Hayashi Tetrahedron Len. 1981 22 1349. 90 S. Kosuge N. Hamanaka and M. Hayashi Tetrahedron Lett. 1981,22 1345. 91 E. J. Corey J. W. Ponder and P.Ulrich Tetrahedron Len. 1980 21 137. Biological Chemistry -Part (i) Prostaglandins (under carefully controlled conditions) was involved in the key step (144) + (145) (Scheme 35). 11,12-MethylenethromboxaneA2 (147) has been prepared from PG-A2 using the strategy illustrated in Scheme 36." -HO 2)3 e r z 2 M e ~HCHZNH cH20H C31 OR OR 0 16 steps OH OH OR (147) R = SiMe2Bu' Reagents i Me,SiCN HOC,H,,"eo KCN 18-crown-6; ii LiAIH,; iii HONO; iv (CF,SO,),O; v LiOH THF,H,O Scheme 36 The bicyclo[3.l.l]heptanone (148) is available by two routes starting from readily accessible materials.It has been converted into 9,ll 11,12-dimethylenethrorn-boxane A2 (149) by the route shown in Scheme 37.93 The thrombanoid (149) is a potent TX-A2 antagonist in platelet aggregation assays. Reagents i MeOCHPPh then PhSeCI; ii m-CIC,H,CO,H; iii (26) then K2C0, MeOH Scheme 37 92 K. M. Maxey and G. L. Bundy Terrahedron Lerr.1980 21 445 93 K. C. Nicolaou R. L. Magolda and D. A. Claremon J. Am. Chem. Soc. 1980,102 1404. R. F.Newton and S.M. Roberts The bicyclo[2.2. llderivative (150)94 and the corresponding oxa-compound (151)9s have been synthesized. The norbornane (150) is a weak inhibitor of throm-boxane synthetase. E2)3c02Me c 2 ) 3 c 0 2 H / C,H,I / CSHll OH OH (150) (151) 94 P. Barraclough Tetrahedron Len. 1980 21 1897. 95 T. Kametani T. Suzuki A. Tamino and K. Umo Hererocycles 1981 16 905.