Success Story pager The Halichondrin and E 7389 1986 HalichondinB isa macroycte polyether inal isle from the sponge Halichondsia kadai received in 1986, 1992 11 was aceped for pestinicl development by NCL in 1992 ater was found ob highly cytotoxin mine leukemia cells. Dyin collecting suicient ms al for developmental studies slowed the progress ofthis interesting materia 1998 the dr wosived ane ease on if wth he development ofa synthetic method in 1998 by De. Yoshito Kishi of Harvard University and the discovery that its activity resides inthe macroey-lic lactone C1-C38 moiety. The way was now open for development ofa simplified synthetic analog. Researchers at Eisai Research Institute, who licensed the synthetic technology from Harvard, accomplished the synthesis of the resulting drug, E7389, £7389 was presented to the DDG for pectin development in 198 738, ik its parent atl compounds classified tubulin mew Rewer INSTITUTE Adepolymerizer, and it shows activity at least equal to the naturally ‘occurring chemical. I wets te disrupt the polymerization ofthe microtubules necessary in mitosis, This general characerstic places E7389 in the group of drugs that includes Vinea alkaloids, dolastatins, on cryplophycin, and so forth, bu its tubulin interactions appear to be unique, and it as found to have greater activity against lung ad breast tumors in ‘animal studies than either the parent halichonetin B or paclitaxel 2002 £7389 entered phase { clinical trials in 2009 global phase III study results show E7389 meets primary endpoint of overall survival. E7388 is now in their final stage to be approved shorty (This text was cited from NCI homepage: @ Le Inuman health care Ce ee eee aa 2 A rete et mes | OCMULIN Cee een ee ca eribulin; £7389's generic name1. Introduction Set ox, -Isolated from the sponges Halichondria okada (Hirata and Uemura, 1986), Axinella species (Pettit et al, 1994), and Lissodendorys species (Litaudon et al, 1897) -posesess an unusual steucture; 2,6 Sttrioxatricycio[3.3.2.O]decane ring system, as well as ‘4 22-membered macrolactone ring, two exocycic olefins, and an array of polyoxygenated pyran and furan rings - Only 12.5mg of Halichondrin B was isolated from 600kg of wet sponge ~ showed the impressive biological activity Co of 0.093 ng /ml against B-16 melanoma cells. noncompetitive inhibitors of vinca alkaloids that occupy the vinca- binding domain on tubulin, suppress the growth of ‘microtubules, and inhibit polymerization, thereby inducing cell cycie arrest and apoptosis - Synthesized by Kishi and co-workers first in 1992, second by Philips and co-workers in 2009. ‘Synthetic work by Burke, byYonemitsu and Horita, and by Salmon but none of them have yet to report the completition of the synthesis, 2. Total Synthesis of Norhalichondrin B by Kishi and Co-workers ‘Total Synthesis of Halichondrin B and Norhalichondrin B ope Thomas D. Aicher, Keith R. Buszek, Francis G. Fang, A Ground-Breaking Piece of Work | Cre! Porayih Sun Ho Jung, Yosnto Kish Michael C. Matelich, Paul M. Scola, Denice M. Spero, and ‘Suk Kyoon Yoon J. Am. Chem, Soc, 1992, 114, 3162-3164 2-1. The Kishi's Strategy2-2. C1-C13 Subunit Synthesis ae “a PO gsretitbiann 2 ge Re TS, ticle 2H OHS > 3 mow Fae ‘ona ok Sp iaminos ome OR Stan arya 2 he phon aos i Be: sal 5S Sbucttos Nett es SER. ° 7 On aeaanad co ae oe a sane *.. mecca ciate his 1 2-3. C14-C26 Subunit Synthesis hi Tinta SAB ye co eye an “Oe SE ae SS SC ee 7 = cara “Stee: PF, ef ae wg Ste ton ae * ‘meme x Bee = omy g IY __ sane Teepe Es, Tees + rater werk. prc ee 2c. cae Woe “Si iat “estes2-4, C27-C38 Subunit Synthesis ° oo Hptear "Us CHR ot “ ime 5) BE eye ten Tear Zot Tes Eaves x ree a" jacrrngone . se ote tage Cate Haina yeh imstithue mye o0 ‘ amen Oe iy PaO i eee e = @ Pea " ate . oie ae greg 0 cS ag scr oo 5 bub aeS" SP on es ee moore MeOAc eR and apr wy Yoae Kb ter mpi mrceenuase a 7 DINER so toh AK 0, 995, Se Te —_— as Ig 2-5-1, C39-C54 Subunit Synthesis usc THF 5% 7” ct 1 PMB KH. THE ‘OTBORS 2 60% AcOH. THF ou Hs 74% (2 secs tanger og, on TREE oe Gem Poo = AY TLOATHE TESOL 20, a Za he tart2-6. Subunit Couplings and Completionof the Synthesis3. The Discovary and Development of E7389 ‘On completion of the total synthesis of halichondrin B, norhalichondrin B, and homohalichondrin B, we asked the late Dr. Suffness at the National Cancer Institute (NCI) and Dr. Littlefield at Eisai Research Institute (ERI) to test the in Vitro and in ViVo antitumor activities of the totally synthetic halichondrins as \well as several synthetic intermediates. The results were sensational: theirexperiments clearly demonstrated that the antitumor activities of hhalichondrin B reside in the right portion of the molecule. With this crucial information, a massive drug discovery effort was undertaken by ERI, resulting in two exceptional drug candidates, one (E7389) of which is currently in the late stages of phase Ill clinical trials. Kishi ef af J. AM. CHEM. SOC. 2009, 121, 1563615641 [E7389(generic name; eribulin) |. a synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B - ended clinical trials and now in their final stage to be approved shortly its tumor cell proliferation in association with G2-M arrest It binds to tubulin and inhibits microtubule polymerization(Figure2) Figue 2. €7380inducd fomaton of £7389 (Eribulin) OBA SEA {uoun opgugatesesdotomnas by eacuor rcoeopy Arno dug, micmues mth Tongrscensggaoeet tide 8 teal 1208 ‘ase a ‘oe ainte! of mona oe atchonarn i sence Gnd tare were lage munours ot “Sats pe yr = ae eS ae | ae “90% yield (entries 1-3) - only a small amount of dimer 8 (0396) was observed; thus, the coupling reached completion even with a 1:1 molar ratio of 5 and 6 (S)-sulfonamides 22,0 (entries 1-5 vs entry 9) - the coupling rate was slightly higher at a substrate concentration of (0.8 M than at 0.4 M, but no significant difference was noticed in the coupling ylelds (entry 1 vs entry 2) +) Cat and cet compensated om sone 28 = uch). (CHI comps dre am ese tera a 243) Sl eps Ue Bs sd th seal Bands fe SS ne Oe |e (entries 1,2, 4, and 6). eegpmmanrer me - the asymmetric induction by 1a,b- CrC12/NiCi2 was practically identical OR sensi with that by the corresponding previous Cr catalysts derived from Pe f | te frmaton of dmerbypredut: keep a low rao of Nit Cr sas =a slight exess((ypically 1.5 equiv) of an alkenyl halide is needed to Scheme 3.€26-G27 and C19-C20 Bora Formations scour whrtec hee te Teo oan mayeabe endags ersings eral aia are. Pedides from Vinylsilanes cf their first synthesis of C1-C13 subunit synthesis Problem; recovered startind material or decimation of the substrate by highly reactive iodinating reagents, e.g, IC, 1Br, and IBk ee eae u ACI. 2. ‘a method which utlizes an electrophilic Iodine source with Scovinies @ seunydacs Gast s simsauatieawa cs mcigcyar « fight reactivity but does not generate too reactive intermeciate was needed. with bulkier allylic carbons, better overall retention ‘of olefin geometry; scheme2 Stcuntaiasetinaien ' cis-selectivity, scheme mop ne mm mone oe ee oblem; - nucleophilic attack of ammonia can take place at the 1- or 2-position, that is, +=2 versus t=3 ‘ =the resultant 1.2-amingalcohols 2 can react with the stating material 1,0 yield the corresponding secondary amines 4. | sommes eae A Schcete ciee wiDat eerie aca (yeottestraea ee Panis Higon equ to) sao i : Weaaye sa Isao —— wy aoe 2 YaoMtyetho al ess) * » Youoryatto ess) » ? yornestt0 1 yan) » » t Eoin ten) > » ” Mod Sou « % = MoH seanny » ” t NICH Seguny a » a None equ) o 24-4, Opera nally Simple and Efficient Workup Procedure for TBAF-Mediated Desilylation Crea pons ‘ [com Dreininsa wom Ho = cosh) wae Figure 4. (2) Anibeste RA 400 (OMe) column (inter = 5 an.) en Rexyn 101 (H*) column (diameter = 5 mm). (c) Basic Al,O; (Baker) filter hemsual (diameter = 5 mm) with glass wool dividers. (4) Sepum. (@) Teflon ree ‘connector tube. (f) Teflon tubing. Pump: FMI QGS50. For a 40 mg-scale ‘experiment, approximately 04 ea of Amberlite IRA 400, 04 em of Rexjn aoe, rnin TA EAs tage we 10}, and 01 cm? of alumina were placed im each column. The otal voime — eee ‘of solvent was ca. 4 mL (c = ca, 0.01 M) and the flow-rate was ca. 2 ml pet min ofthe TBAF Warkap occ" ccc Par Te BeOS, acidic ion-exchange resin; Michael adition and acetal formation ieee Polycyclic ketal 5 mete eG strc cn gid een, ee). ‘gat Oo sgn) HE rane 28 Cac, DONE ORS ‘Bese TEoeten econed tas HNO yes eae SSipend eet tebe 5) eau cane "TAF yd Co) TSAF Cal Table 1. Subsnies ed to Tes the Fenslity and ficiency oc was4-5. Refined Approach to a Number of Fragments 4--5-1. C1-C13 Subunit Synthesis Kishi's C1-C13 Subunit Synthesis. 2.2. First generation(1987); 31 steps, 4% overall ylela( ref. (34) 5-1-1, Second generation(1992);16 steps(ref. (36) 5-1-2, Third generation(1996); 12 steps, 11% overall ylela(ret.(37)) 4-5-1-1. Kishi's Second Generation Approach to the C1-C13 Subunit woe SO Tsao oonABaqeys SdiNIYd OUL “1S (600z)s0410m-79 pue 1q @ UUpUoYD!|eYJON Jo sISOLRUAS [e101 °scon Efe ree av “beees Kata pesa iiernas mye Sakae sisouts yungng g¢9-129 ‘5-9sisatpukg otf Jo Uone|dwog pue sBulidnog wUNgng “9-5