~roorganic & M edicirw l Chemwrry Lefrers, Vol.1, No.4, pp. 201-2134. 1991 0960-894X/91 $3.00 + .OO 0 1991 PmgamcmPress plc baited in Great Britain ENANT~~P~CI~IC SYNTHESIS OF 14S,15S LEUKOTRIENE zyxwvutsrqpon A4 METHYL ESTER A V Rama Rae*, A V Purandare and A K Singh Indian Institute of Chemical Technology, Hyde&ad 500 007, India zyxwvutsrqponmlkjihgfedcbaZYXWV 5 March 1991) (r eceived A practtcaf enanttospecific eicosatetraenoate (14S,I5S cursor has been described. Abstract Since sensitivity then and synthesis of methyl 14S,15S-oxid0-52,82,10E,IZELTA4 methyl ester) from D-glucose as chiral pre- dtscovery’, leukotrrenes mflammatory reactions. 1DE,lZE_eicosatetraenoic chemical to study. clearly that reported report studies investigation. intermediate herem m VIVO or m vitro LTA4 as a crrculatmg so far, an efficient the to probe for large scale (Figure there agent arose direct 14,15-oxldo-52,82, in conver- actions in its own right. are difficult by serum protein This is a question an acute zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM ne e d to synthesize this scarce its physjologIca1 use of an expensrve enantiospecrfrc the et al3 on 5, 6 LTA4 stabilised biochemical Hence in order involved which could be adopted Retrosynthesrs 2 key precursor role of its own. Due to its raprd by Sammueisson and unstable postufated to 8, 15 LTB4 (2) and 14, 15 LTB4 However, further has pro hyper- acid (1%HPETE) converston merits Sammuelsson due to their if 14, 15 LTA4 has pharmacological and brochemical establish prominence acid (14,15 LTA4) (I) as the hypothetrcal sion of 15-hydroperoxyelcosatetraenoic (3). It is not known have acquired startmg approach towards role. The only total materral, synthesrs4, 2-deoxy-D-rrbose. 145,i 5s LTA4 methyl We ester preparation. 1) Indicated epoxyaldehyde (4) and phosp~o~ium salt (5) as the key precursors. IICT Communicatton No. 2786 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 201 A. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFED V. RAMA RAO et zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLK al. 202 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA O xid a tio n c o up ling of w ith mixture of 2 unsa tura te d a c c o m p lishe d The by re q uisite e xte nsio n, nishe d of o le fm 19 in wa s g a ve p re p a re d in the by re fluxmg w ith wa s fo llo w e d Tre a tme nt of (22)7 20 w ith in 80% tre a ting b ro mo e ste r a c e to nitrile und e r a rg o n in yie ld . (22) w ith a lc o ho l yie ld e xc e ss 18.7 a ny furthe r hyd ro - a mo unt, the fur- p re se nc e O THP by re q uire d 15 g a ve Pa rtia l m fo llo w e d d e p ro te c - d ia zo m e tha ne p ho sp ho nium trip he nylp ho sp hm e fo llo w e d d i- c hlo rid e Fo r e q uiva le nt w itho ut the in of (17). Ph3P-C Br4 re a g e nt a tmo sp he re , io d ine O p e ning 8 e the r in w ith Fina lly, - THP a ffo rd 88% of wa s C HC I3). 2): c a ta lyst Jo ne s c is-tra ns iso m e r te tra hyd ro p yra nyl as 19 (1%) 1.0, fro m to nic ke l a lc o ho l b ro m id e hyd ro xy e ste r o xid e , P(I1) (c (Sc he m e p ro te c te d im m e d ia te a a ll-tra ns a mo unt -27.7” by yie ld e d d e sire d c a ta lytic [a ], p re p a re d e thyle ne g a ve a a s fo llo w s using p ro te c te d b ro mo (5) sub se q ue ntly c is-o le fm yie ld . of re a c tio ns wa s b ic a rb o na te , of (14) the to Re p o rte d ’ sa lt of a lkyla te d to 85% so d ium O xid a tio n le nts) wa s e p o xya ld e hyd e p re se nc e C HC I3). se t w hic h a c e tyle ne e ste rific a tio n, (5) 16, 17 of a nhyd ro us no n. e ffic ie nt unsta b le Iso m e risa tio n the 1.2, p ho sp ho nium a nd a lc o ho l g e na tio n9 (4). in (c to fo rm ylm e thyle ne trip he nylp ho sp ho ra ne , a ld e hyd e -27.9” [o r], a sim p le a c e tyle nic c ha in (13) of p ho to c he m ic a lly c hlo ro me tha ne . I5 e p o xya lc o ho l e q uiva le nts b y c o lum n (1.5 sa lt e q uiva - c hro m a to g ra p hic p urific a tio n. Scheme 2 OTHP vi, vii -L/j/=/M Br O THP 20 i) Na NH2 LlNH2, (3 hq . e q ), NH3, C Br4, DC M, e the r, O ” , 1 hr, the sta g e c is-tra ns se t as the (a c ro ss (u-p o ro sil, 1% re so lutio n of 3 hr, viii) fo r sim ila r Ph3P the to C -9) mixture ha s hr. DHP, 75%; units, the re a c tio n a lre a d y of (Sc he m e 155 a c hie ve d (4) The hr, 4 hr, 95%; 85%; v) 85%; vii) p ho sp ho mum c o up ling a l, m e thyl a ra tio by 1 hr, I a nd i.e ., so lve nts LTA4 re ve a le d O”, rt, III) Ph3P, CH 2 N 2’ 80%. et a nd DC M, EtO H, 3). b y Za mb o ni4 14S, been PWNI; a c e to ne , 48 hr, g e ne ra tio n mixture (c a t), e p o xya ld e hyd e re p o rte d mixture IV) 80” , i.e ., PTSA re a g e nt, e q ), C H3C N, as of II) Jo ne s p ho sp ho ra ne Et3N-n-he p ta ne ) this 10 VI) c o up ling c o nd itio ns fo r 75%; -35” , ke y fina l hr, 80%; (1.5 b o th b a se C -S 6 o xid e , rt, p re p a re d wa s -35” , e thyle ne 95%; using silyll-a m id e a NH3, Na HC 03, Ha ving a c hie ve d hq . wa s e ste r Za mb o ni’ , (5), suc c e ssfully lithium -b is-(trim e thyl THF-HMPA of sa lt (4:I); (23).7 c is:tra ns this HPLC a s 80:20. re p o rt to g ive a na lysis Sinc e c o nstitute s 14S,15S Leukotiene 203 A4 methyl ester Figure 1 :- v v 0 OHC CO2R wa BrPh3Pw k. Epoxyaldehyde 15 (4) was synthesized 1): - Trt-0-acetyl-D-glucal 2+ cleavage6 using Hg and acetylatton. Two afforded the 10 with subsequent II led with requtstte m 75% yield. to its carbon dilute eight from D-glucose in the following manner (Scheme < from D-glucose, was subjected to hydrolyttc sulfuric acid, carbon selective Treatment internal prepared’ homologation rearrangement subsequent (6), via skeleton primary hydroxyl of I1 with involvmg mrttal dtsplacement to give o,b-unsaturated Wittig olefination 7 9 m 75% overall protection 1.1 equivalents formation aldehyde followed yield. mesetylene methoxide of an unisolable to give epoxyalcohol (13)7 (8) after hydrogenation Deacetylation furnished of sodium by terminal to trio1 sulfonate in methanol epoxide 12 [aI, -44.2” (c 1.3, CHC13). Gcrl, -44.0’ (c 1.0, CHC13). Reported4 1 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Scheme OAc D-Glucose ,+ i,ii -> , AcO&CHo iii,iv 6R 1 RzH & R=Ac OAc AcOb dAc v’vi > Ro& vii 6H 2 , l_o R=H 11 R=M.st 1) HgS04, THF-HIMPA, H+, Dioxane-H20, rt, 4 hr, 92%; ii) Ac20, -78” O”, 1 hr, 78%; iv) H2, Pd/C, MeOH, rt, 1 hr, 90%; vi) Mesetylenesulfonylchloride (1.1 eq), MeOH, rt, 4 hr, 75%; viti) Cr03-ZPy, (2.2 eq), Toluene, EtOH, Py, rt, 3 hr, 95%; iii) Ph3=CHCH3, 2 hr, rt, (Mst-Cl), Celite, 90%; v) NaOMe (0.5 eq), Py, O”, 36 hr, 75%; vii) NaOMe DCM, O”, I hr, 85%; ix) Ph3PCHCH0 80”, 3 hr, 70%; x) I2 (0.1 eq), h, CH2C12, 2 hr, 95%. , 204 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA A. V. RAMA RAO et al. Scheme i sii C02Me BrPhgP 3 , w 2 23 - zyxwvutsrqponmlkjihgfedcbaZYXWVU I) LHMDS, an a lte rna tive p ho mum the THF-HMPA a nd sa lt 5 synthe sis References a nd 2. Sa mmue lsso n, 3. a) the ir to 5, -78” , the 4 hr, synthe sis Stud ie s c o up ling . hp o xyg e na se “ Le uko trie ne s J., B., Fitzp a tric k, USA, 70% of a re unsa tura te d und e rw a y to a ld e hyd e e xte nd 4 this a nd p ho s- a p p ro a c h to p ro d uc ts. 80, 5425. c ite d Whistle r, Pre ss, R.L. G o nza le z, 7. All the me nta l 8. Eg lmto n, 9. Bro w n, B., J. S. J., Ed .; Else vie r, 1989. 568. J. B~o l. a nd Ro ka c h, a nd F., C he m., Ro ka c h, Sa mmue lsso n, Lig g e tt, 1985, J., B., W., 260, Pro c . Mc G e e , Na tl. J., Bunting , 1983, 24, a nd Yo rk, F., J., SC I., Mo rto n, 11403. Te tra he d ro n Le tt., Wo rlfro n, 1963, Le sa g e , ne w Vo l. 4899 a nd re fe - S. c o m p o und s “ Me tho d s M.L., in C a rb o hyd ra te C he m istry” , G ., Jones, a nd sho w e d E.R.H. a nd AhuIa , A.K., Ac a d e m ic 11, p 263. Pe rlin, A.S., c o nsiste nt C a rb o hyd ra te sp e c tra l d a ta Re se a rc h, a nd g a ve 1975, and Whiting, 3. C he m. M.C., So t., J. C he m. 1973, 553. So t., 1952, 42, sa tisfa c to ry a na lysis. C .A. Ac a d . the re in. Ne w 6. 220, b ) Fitzp a tric k, Mile tte , R., 1983, Ha e g g stro m, a nd Sa mmue lsso n, Za mb o m, a nd Lip o xyg e na se s” , Sc ie nc e , F., 1983, re nc e s 5. to a p p ro a c h ii) and Notes Ro ka c h, D. O ” , 30 m in; e ffic ie nt o f o the r 1. 4. (4:1), 2873. 267. e le -