WO2024263718A1 - Synthesis of (-)-trans-δ9-tetrahydrocannabivarin and analogs thereof - Google Patents

Abstract

A method is provided for the synthesis of (-)-trans-Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) and analogs thereof starting from a resorcinol reactant, such as divarinol, and a p-menthadienol reactant and proceeding through Δ⁸-THCV as intermediate. The initial step of the reaction between the resorcinol reactant and the p-menthadienol reactant is carried out in a solvent at elevated temperature in the presence of a Brønsted acid to form the Δ⁸ isomer. The Δ⁸ double bond is halogenated and the halogenated intermediate thus formed treated with a strong base to effect dehydrohalogenation and provide the desired product, Δ⁹-THCV, in high yield, with minimal or no remaining Δ⁸-THCV.

Description

- -- -⁹- o a meresennvenon reaesenerao cannanos, an morearcuar reaes as ueonoer ceemsc oa me sncnees,zn cannanos an cannano anaos.envenon armaceuca manuacurn. mecna cemsr,eraeucs, an cemca an eraure.eocrae c reacnennas,nasv recueavea enx ceannsnvae anoenonne mea ane scenc avaanaveeen researce anrooseor ussesona meanro mmecenannas sava. an cannanosncue como a conexs.ese cannac uns suc as cannao , cannano ⁹, erarorcoamnennaeoro, canna,eorca acrocanna,verarocannanoc ac - , ac , w an oarcuarneresar.n , anerarocannavarnc -somer:

-somer:

- - - arueeo soeecnacn meeraccnoan wroerees o an an re oceeorr ssm asa wre can asna mnos are receors oe enocannano ssem.₁ese re₂ an oer rououe cenra anerer ceors areocaeneran an arcuar,easonon o aena ne crvcouasse s ascevms. ancvaocona oe oe voa₁ ree-coeeorrs,n cacum cannes,ere suressn neurona exca a aenon.s a resu,ase n seroonn neuroransmsson oena u nreamen oene suresessoen, neuaro caonncaanoseassesa, c arcovae₁ receorsave sceross,aucoma, an oer conons. nca⁹n, mue erarocannavarn: a comme ee, e..,oe e a. , "- oes ana nar onoenaeraeuceneore manaemen o comounors ae e nees reu," ara.ann men₁ o aans oaeoens.s:-a.as asoeenroose as aeraeuc eaees a s an oes-assocae meaocsorers suc as roecsnouseco-seernveoeraensceencowmaaczuem e ae.s , a "aenrsanroocaansnmavarn resseveomen aneucesnammaonurn oe cecuum aren e a. , "e cannano comoun⁹ ness,"noc. :- ameoraesnsun sensvnwo m -erarocannavarn e a. , "cac a ouse moes o oes,"ur.aees:eaoon aramee nae oannao anerarocannavarn oncemc an nrsnea. sens w eaees...,"aeesare⁸:⁸- --rans-⁹-"⁹-ava"saonmerrsmmaroe ocuccaurrs s arsucuere-s- sraonwsn- a-o"-⁸" an a consera weaer anaonsane⁹som ve, wesomersomers cane exrace₁rome er.ee aoremenone save asoeen aeme.esee.n saova resuann, m ae reaocsonorr coeumcc caom sonseosnznavn asonmecrasns rerouorerono o oaenesusrees⁹-rae.⁸somer,owever, an searaon oewo - - - 9- cscoomrern, w,ereeres a neene aror a meooreerena sneszee esreroucn ne an,nevao mvee ao wou, amon oeresre avanaes,rovee reaens an sovens, ane rea sc maenm ua noumroevr oe a s veas,e us mea ennuvarocnumrennaroceesns.n meoore snnvenesoznns⁹r-ece aon aen aaoovse-meerneoo,n wee nreeenne mee aro anroroves a avanaes reaveorornown meos o sneszn⁹-.e novev mees noumerous reonceeasoroue sness o⁸-, or an anaoereo, as annermeae, wc⁹ssomernenaee a.ee m-eosoons, somowee an seroaoenaonoveeesre snec ses mae carre ou uner m rearacono corwnar wou necessan mue enn reaens an sovens an maememene aaroen ssc rees on envronmena conex.n aon,e meo mae reaaoreo snesazee annaoe ms oanu⁹acurn we as⁹- er se usn arorae susu - as eren. e reacans as weescrenea srucuren o aorrsm eumaomen, a meo Rs²roveor sneszn a comounavne )_m w conann¹esr se -ene:cerorcoam

r,- an ₁-₁₈rocar,eeroaom- 2s₁ se₁e₈cerom,ro suxs, caureoxe,eroaom-conann₁-₁₈rocar an₁-₆ a susue w rox, carox,₂ o-r₆ aacoox,₂-₆ aoxcaron,₁-₆ a, - - -ao³s seecerom_1-6 a an_1-6 a susue w rox, carox, or m onann⁴ss z se -ereoc,e or rorcoamr,, s₁u-s₁₈uerocaer, susue₁-₁₈rocar,eeroaom-uonucnonoa ar₁o₁₈ er acuens, w careroenn a,om mss ma,eenaeen⁴oaom-conann₁-₁₈rocar, an o meaeeroeo sramm ae c orcc serren weren, an⁴ ve-memere rn an a sx-memere r ucure seecerom emere or sx-memere rn, n, oonauseo an aonave-eeroaccc, anave zeroo w none-renroee rnn sus asreu areonmsa anc, a zeccc,eeroaromac, or 5s seecerom,- rocar, susue-rooeeroaoms anonann- rocar, s₁us₁₈uee ₁₁₈rocar,eeroaom-unconar₁ou₁₈ eroaom-conann₁-₁₈rocar, an w aaer rseeans, rene ac a m an reeaco avonn c momxe surrs ree uc cs:oumrersn OH oormua )_m a secon reacan

R² _OH a a c soavaencaore

a acc, an - - - mxure w a aer meonare ra seoconn reea racnane o a aonu.e:rs reacan areresenne reaconnermeaeavne srucure o o aou.:,ererovn ars Ro²rmua m aoenaon reaen

avne s corunacn w a R² X cure oormua seconnce cronacn

eecveoeroaoenae nn s soom mme ee e ea mme oommeennss,, s seess. a, anc are aso carre oun a soven. n some emome , anc are carre oune same soven. emera ns, se s carre oun a reacon mxureas cooeo a nu n sre soome meo e ew em a moou ommeen° nss,. , srescs aso carre ou a eevaeemeraure. se. nermeaes use wousoaon orurcaonnn secn some emomens, seconnermeaes use wousoaon orurcaon soven an. n someae eemorormoenrsa, rueaac aanon a on reernse ac are comne we n some emomens: acan oorme reacon mxure. - - - conann¹s s-eecerorcom₁-₁₂rocar, susue₁-₁₂rocar,eeroaom- 2s₁ se₁e₂ceroamr,, anro suxs, caureeeroaom-conann_1-12rocar 3s- a ox, an₁-₆ a ms ze₁r₆ 4s seo or 5s seeecceerom,rox, an carox an conann- rorcoamr,, s₁u-s₁₂urocar, susue₁-₁₂rocar,eeroaom- unconar₁ou₁₂s eeeroaom-conann₁-₁₂rocar, an s⁹-n som oer a e. nm anoaomenes,¹s n-ro, suca s⁸- or an anaoereo an n some emomereo. menaeno, sucanss,⁸-ers r aenacanss⁹-varn.o ane secon reacans- .eno.ns anomencaure: meann cnoemsmsen oeera nn ue: n oerseorwose, a oneec on ocran aanr s scenncee arrmso u wsecereennvaevnee erans.eccermnoo oarcuarmor onnvenonse anceoeescron oeresenncuenurs sneecceaowon. ane aene cams,e snuarorms "a," "an" an "e" .a reemerecns unesse conex cearcaes oerwse. s useeraermnoo: neneoemenn, anes ursaese "naven seormua" or "avne srucure"s no eerm "rocar" reersoamreoc waararoues oerrmn "caomersn"s use. caron aoms,cao caron aoms,ncunnear,rancs ceon, cacnnc, so aou an unsaurae seces, suc as arous, aenrous, arrous, aneaeu.rae, - - - "rouuss,u aneereorcmar "e"e rreoearosmo-conraocnanr suroscarue" r wee one or more susueneas one caron aoms reace w aeeroa rsorocarn wc a "rocar"soenerree as om.ness oerwsencae,eerm rocar ncun susue anoreeroaom-conann rocaroe m neorrme ou "aes."ca as u aseoueren no re neercsesosa arra cnocnean onr unora ancoue sa cuarrae suc as me, e, n-ro,soro, n-u,sou,-u, oc on aoms, we as ccoarous suc as ccoen, ccoex ,ec, anee, as no necessar, arouseren co , anee.enera, aou aan o caron aoms, nano caron aoms, e..,o caron aoms, "usue a o caron aoms,o caron aoms oro caron aoms. erms "eeroaom" r-ecoenrsanon a a su"s anu "ee weroa one" o rre meorreo s ausnu wencro auesa, ane caron aoms reace w aeeroaom, asescrenurer s onencae,eerm "a"ncuesnear,ranc eanra. no oerwse eeroaom-conann a e, ccc, unsusue, susue, anor rou oeoe armou "aen car" a. osn u aseomse croenna renenrs aoe aasne oanre,roance, or cccrocaron roen,soroen, n-uen,souen, ueon, suc as een, n- ecosen,eracos ocen,ecen,eraecen,exaecen, aoms, e.., en, anee.enrouserenca conano caron aoms oroo car coanr aoonm aso.mse,erom "c cacroaone anom"sn,enos a ca crconc a aoemns,ro caron avno caron aoms.eerm "susue aen" reerso ou,ca one or more susuenrous, aneerms "eer aen susue w "eeroaen" reero aenn wc aea oaom-conann aen" an eeroaom. no oerwsencae s one caron aoms reace w a unsusue, s ,eerm "aen"ncuesnear,rance, ccc, eermu "saune", a asn useoreeroaom-conann aen. o caron aoms conann aeaesre onne rererseoo ann, seuacr or as erancne, n-rroocanro,n anroue o - - - aoem.se, en.er.a,,o ao cuaro ana anom nos, necoessa crar,o an anomsr,ouose cren conano caron aoms oro caron aoms.eerm "sus aron aoms,o caron one or more susuenrous, a ue an" reerso an susue w "eeroan" reero a neerms "eeroaom-conann an" an eeroaom. no oernn wc aeas one caron aoms reace w a unsusue, wsencae,eerm "an"ncuesnear,rance, eer smu "saouxe", a asn useoreeroaom-conann an. ermna eernaeas eren reerso an arouounrou a sne, asene ao , an "aox"rou mae reresene as --a were as roox,soroveo.x,o-xuroouxs, euc.snceuerems "-ae anooxx"ro auns "a sucn aso mxe" aox, eox, n- anaoous manne reenen an susuene coermr ".ar" as useeren, an uness oerwse sece, reerso an aromac recne,n oarnnnre ac snne aeromsuacc rna ore muereen ar aormomaac rcn rnss aare areouunseooeer, commonrou suc as a meene or eene moe.reerre arr a caron aoms, anarcuarreerre arrous c ous conano arrous conan one aromac onano caron aoms.xemar na ,en,enee rn orwouse orne aromac rns, e..,en, ar" reerso an r,enamne,enzoenone, anee. "usue "e ar moe susue w one or more susuenrous, aneerms careorno aaoomm-cso rneaancen w ar" a ane "ereoaeroomar, as" w reereo aersc susuen,n wc aeas one oerwsencae,eerm "ar"ncues u renurereanra. no conann aromac sus nsusue, susue, anoreeroaom- ermna eeeerrmn "aare,o wx"u e ae resn unss "e. ar"erse ans reeernseo a ano avre.rouounrou a sne, reresene as --ar were ars asene a n "arox"rou mae caron aoms, anarcu ove.reerre aroxrous conano xames o aroxrousarncuree,e wrreo auromxarooun,s coennoaxn, o-oao- carenoonx a,o mm-s.ao- - - - meneoxox,--aeon-oxe,no,x,,- or-mmeeooxx--eennooxx, m-meox-enox,-meox-enox,,- aneereme "ramra "a"a rre"er rseeors ano a an a sru ssuus, an enuene asae. sus susue w an arou, weren "ar" an "a" are asene aove sue w an arrou, o caron aoms, ana .reerre aar an ararous conan exame, aarrousncruceu,aorr exraemerree, a-mraerouens c,on,-anmeo ceanro,n a-oms.or c ancoeexe.enra,,-roumesncnuae, w,ou-ccmooaconna,enz,,--een-c-ecoe,n-a-,-ene, -en-u,-en-en,-enccoex,-enzccoex, en-ro, "areancoxco" reexermoe su,s-ueennzs occoeeoxrmmuea -, a wnereene.s aeerms- "aarox" an asuse ar or ara, resecve, --araene ,e ar. nm "ace"er reerso susuensavneormua --a, --ar, or - -ar, m "acox" reerso susuensavneormua - -a, e oerr -m "cc-acr"a ree,r wsoer aecn "cac or," a "roarma, acn su "asrauen" asre asene aove. susue anoreeroaom conann, ana ma a ma or ma noe eerm "accc"s usene co e monoccc,ccc, oroccc. moe ma, ase ooseo a nvenona senseo reero an aac ccc an n aromac ccc moe, an mae monoccc,ccc,occc, romo,uoeroer ,r omrse o ". oao su" asnu "eaoen" are usene convenona senseo reero a coro, erme a "eeeerrmoa "e"eroroauom o-cn ro an. "aenenro"a asomn a "eeroaom-conann arou"aso "eeroar"rou reerso -conann arrou"asoerme a a a moecue,nae, or susuenn wc one or more caron oro smsco anre, recaace n wro aenn, a ooxme on, oeran caron, e.., nroen, oxen, suur,osorus, erm "eeroa" reerso an a sur ssuuuer,nreaerase nerrooaeonm o-rco onxaennn.,mearer,me - - - " "eeeerroocarc"c a"n reeerseoro aar comcac scu" rsesueecnvea reseeroaom-conann,eerms areeeroaom-con ero "ar" an "aromac" susuensa asuan ann, anee.xames oeeroarousncue aoxar, susu-susue a,-aae amno a, anee.xames oeeroar ,,-ensncuerro,rron,rn,unon,no,rmn,mazo, rroranzoo, m,oreraozo, ec., an exames oeeroaom-conann acccrous are "s no,erazno,erno, ec. n some oue asoruemeen" aosnne "suesnuoens, as m,e"a "nsusaunee a ar,", a anr, oer oe,e as aueoeas oneroen aomouno a caronor oer aoms r r moe, a roen susuens.xames o suc s eace w one or more non- rocar mo usuensncueunconarous an unconeaes. sruc rousa ma reresen susuensne susue moecuar aoxu,res- an a seomxeans,er-eo anceuneo,x w,o-u amanoonx:,ao-, arroxox, s,u acnrc,u₁-n₁₈ ac₂ar₁o₈n--a₂ an₁₈- arcar₂on₁₈--ar, a_{518 2}- a₁₈oxcaron---a,-₆₁ a₈roxcaro cox--ac,₂-₁₈ weresao,- acar₆ona₁₈o---n---ar,aocaron-- carox- , c₂ar₁₈oxa -a,₆-₁₈ arcaronao----ar, caramo-- -o--, caramo--₂, mono-₁-₁₈ a-susue a , mono-- a₁r₁₈ a,-₁-₁₈ a-susue caramo--₁-₁₈ cara_{2 518}-susue caramo---ar,-₅-₁₈ ar-susue ocamo--ar₂,--₁-₁₈ a,-₅-₁₈ ar-susue caramo⁺, --ºra,msooca-nao--₂--, c⁺aºr¯a-m,soo-oc-ana-o-₂-,º can,o az-ºo-,soc⁺ano-º¯-, canao oorm--, amno-, mono-- a-susue am=nº¯,orm--, susue amno, mono--₂ ar-sus₁u₁e₈ amn o,-₁-₁₈ a- 1=₈ aroamen,o--- a,-a₅ -,₁₈ ar₆-,₁₈ a-ra am o,-₅-₁₈ ar-susue amno,₂- aor-,--ar,mno-= were were=ro₁e₁n₈,₁-₁₈ a₅₁₈,₅-₁₈₆ ar₁₈,₆-₁₈ a₆a-r₁₈, ar₆a-₁₈, a erac., a, ec.m, anrom-n=oa, - - - --=, narro,so w-ere,= suoro-en-,₁-,₁ s₈u aona,o₅--₁₈ a-r-,,₆-_-18 aar,₆-₁₈ ara, ec., nro e₅rm₂e "a o", arsuan₂--ar aso _{2 118} asuan--a aso -os₁₈ aornosu-n--,aro,s₁-on₁₈a aosuonerm-e "₂a-ar,o"₅,-_{11 8}- a₁r₈ asuosnun--₂-ar-a,, anosno-.₂ca,roca-r m-o₂e,eosnao- -,oso-₂, accc,aveo₂ caron sne aoremenoneunconarous, e aoremenoneu anocmos, we ccc,aveo caron aoms. susue w one o narous ma, aarcuarrouerms,eurer moe r more aonaunconarous or w one or morerocar encomesa ssusecs a as sucose secca enumerae aove, aneerm "unconarou"neneeaneeeerrmmns a "sauncses. oue" aearsroro as oosse susuerous,s "susue a, aen ever memer oarou.or exame,erase aroerno, a ans s ousosusee ar, an ee." a roanraomo"s -ocouo nse a,n wn neenrre rouee se,r ams " s "su neees nrouae eom a-acon, ea sunens"u aeears ever memer oarou.or exame,erase "eeroao rm a o an ar"soenerree as "eeroaom- m-conann a, aen, susue conann a, susue aen, an uersn " a nar onna." eo or" m oo are co remsoeucns.so ornnesanace,a as c ao smruocuunre a snm aanr aonaoa oee comoun w reseco an aom, a susuenwc ma or ma noe a reo maer moecuar semen.n anao ma or ma noe unconarou, or a erverome comoun or mae a "ervave" oe comoun mae reacans.n "a neenen sneszerom one or moreeren e anaoernao a" re maeane a u "nomeo.o.,ue" o a comoun, meannae comoun an ome oe comou a meenerou. anve rseo enanomers,nasseesrecromeers,e orre on mear s ceorneoan one or more asmmerc ceners maeneorm o a sne sereosomer,.e.,e "sereososommeerrccaormusr.e,"u ocr c ao cnomaneounn a - - - m oxwuore oasweroeo omr merosr aen serweoo esonmaers, e..,woasereomers,wo enanomers, or a mxure sece,o awreevner,e⁹-oown an co annanoo urasmer oes nr.eoen, azos rerearnre nuoeren an uness oerwse 11 mern convenonncue: 9 3’ .e noeven snecece meo:

wc ars reacan, e.o.,varno, uneroe comrsna anna sen menaeno,orove a s reacon w⁸ a secon reac⁸an, e..,- secon se,n wce⁸rsouneermoneaeneorm o- or a- anao a aoen aomsounoe-caro oersnermeaesaoenae, suca anermeae anc an n aom,eaoenae comoun servn as a secon a suae reae a se,n wce seconn ure oormua: ⁹ermeaes⁹eroaoenae w rereseneneo srurocveeesrerouc,.e.,- or a- anao, R^{2 )} _m n conann¹ ssr su -eceucree:

rocar,- an susueeeroaom-c₁o-n₁₈annroca-r,eeroaom- 2s₁ se₁e₈cerom,rox, carox,- acox,- a₁ox₁₈rocar an₁-₆ a susue w rox, carox,₂ or₆ao ₂₆ caron,₁-₆ a, - - - ao³s seecerom_1-6 a an_1-6 a susue w rox, carox, or ms zero,, or conann⁴s s-eecerrom,₁-₁₈rocar, susue₁-₁₈rocar,eeroaom- unconar₁ou₁₈s, wocar, susueeer⁴oaom-conann₁-₁₈rocar, an 4ouno aacen cearerno,n a mos,ene maee same oreren weren, an an rom ave-memere rn an am ss maeaenoeeroorm a ccc srucure seece memere or sx-memere rn, wx-mereemere rn, oonauseo an aonave- eeroaccc, anave zeroo ne rns are aromac, accc,eeroaromac, or 5s seecerom,- non-rocraoren, s suusuens an zerooeeroaoms an conann- rocar, s₁us₁₈ueeeroaoms-cue₁-₁₈rocar,eeroaom- uncona₁₁₈ onann₁-₁₈rocar, an erous. rnsen acea arn: e caom sene one a s sonvenesso,r reace raenacan an a caaca eecve amoun o a eaeo aemeraurene rane o aou°o aso aune°,rnscea acn, we racsen aou°o aou°.e reaconsenera ne o seece a carre ou a reux, we soven eanocrc soerverna m,n.e.,avn aonon wne aoremenone ranes.er comoson an connuuens, reeaacnan sraua ae,ormn a reacon mxure Ro²r ameero eecveoroveersnermeae m we

¹s n-ro or a⁸- anao. - - - rane o aeo muoa.r: raoo a oo rueac.an:, as ao r raeaoc oaunsen oes re raanceon w mxuresenerane e oeesrerouc, resun unwane serou enoecreasee n eecvernse ac cane cs, anorncrease overa cos. rnse acserenncue useo caazesna reacon se.uae mea , woumaon, suonc acs suc as-ouenesuonc ac, ac,neenszuenoesnuc aocnc, a eca,ne-esuonecn azcene,su-eoxanesuonc ac,ruoromeanesuonc camorsuonc ac caro nc ac,,-naaenesuonc ac, an a xc acs suc asrcoroacec ac,ruoroacec ac, oxac sucu,rucm acarc, n acrc, ac,a anc aco,s anorocrm acc ac ann acoracn recs ancss suc asrocorc ac, suonc acenesr aan carereorxrec arcnss.en s aocmes emereon amreen ors,anc. acs,ncuno oranc susue or unsusueenzenesuon e oranc suonc acs a oeren as "os c ac suc as-ouenesuonc acaso reerre e reacoen mrxncs a urec e, e a. .c" ., aouca w re.resoe ansoune w ra.n,e a oo auou w. w.o aoo aou w. o aou w.o aou w., o u w., or n suae soven cama aou w.. rnse ac,rov ne useas eecveossovee reacans ane reacon mxure comeonean oren soevreenre woes noe aevserrese re aaceocn a.ne reraecans or oer a cane usencue,u are nomeo, arom senave sovens enzene, an xenes aane acrocarons, e..,ouene, e eone,eeone, mes s nu-cro as cceooneexa,n aceeoeoneneso,n ee., a.,n ace cocnoe,e mxaenone encunnear,o an ccc eers suc ase eer,-n-ro eers, me-u eer, e n-ro eer,me,me,eraro eer,-n-u eer, ,-oxoaneower- acoos, e.., m uran,,-oxane, an ouano ₁₆ eano, eano, n-roano,soroano,somers sovens su,cso amsersm oeenoarnmoa,m eeene,com,erooxeeneaneco, an,mceeroa acnea omeer - - - , a,ce-monererroeo,n ee ace,ameescu,o axnero coroormcoromeane more sovweon osr m maor oer s moaven nos caen seee ccomenroemneo a sne soenveen car sosneame,. wereewo or n some emomens,enermeaeo rreons. woeunounrcaonn se, esunroms se mae use conv aoenaon, or maesoae anure usn ea me:ans, e.., suc asaescrenxame. recen see sn,.ee.,ss⁸-enrocee⁸sromersnermeae,⁸ sneszene aoenae w a or a- anao.ns se,eoueons oormua aoenaon reaenorove a seconnermeaeavne srucure R² X )_m wr.erse mnae

, an reaesn asaoen aom,ca or aom ae-oson oe moecu seeceo aeaoen reuremenor aon o a onee w-oosuonaoreecnuaens ae usee o-oasooenn.e suc as orr, wc wouve rseo aon reaens ccor_{2 2} orr onoe-caron ane-caron. aen-os,oen aano aenaroone rena aeonm seece sou resune aon o aaoen aom ors reacona acevesnen ae reesu-o asreon.reresenaveaoenaon reaens ac r, w arcuarreerre as a cornaono rceaorecn a.ceao anenaorno rromc canorena comne w a seconar aena ser eaen c ves as an acvaor or caas, e..,n₂n a aoenanon r onsea re sc aeo e,n nn ca aer nrrme ,e o aeau re w aousss mseoe nvuexam esno ae a suoua.e s movneunes a oon s wrrn,ee se soeuceon - - - as coouoe -°o aoe amouera°ur,e aeouow - a°ouo ao°u, e.°.,,n aoeu ra -n°e oo aou -°o aou°, °. assennroucenoe mxuressene aou°, oma aou oneun asnoe souon or an arra, aou no necessar, oxane.rrns connue a eassoven a soven, suc as o r e aoremenoneemeraureor a reaconme eecven uensuer anneesrerouc,e seconnermeae.e reaconsca comee secene s roeu eur. are:m aenns soovrene sovenns se aree same ase reuremens e c or soven comnaon use soussovee reacans annenomea reace won or a an com reaocnaenn.s oe soev reenac seonec mexuorer wou averse aecne necessar, seeceromes o reres s sesca, aou no a. sou asoe n enave sovensroveore reacon o se s sece woeae same soven cane useoro sea an se. urcaonn sec, reseco sea,enermeae mae use wou convenona eroaoenaon, or maesoae anure usn e mce:ans, e.., asescrenxame. eronaosennaao sne rea oe sness,eaoenaenermeaesreae w a a-emna en eecveo removee aeaoen aom ae-osonn caron aomos.n reascso an aanse-c reasauzen a neewrooramoeenoauone reoanceweene- an- reacon oeaoenaenermeae on, norma necessan euvaens o a suae w aeaswo, aeasree, or aeasour roxe, soum eoxaes,e,oraesseruam- au soroxneaseu suc, o ars soeume.ero rexace,oassum carre ou a amenemeraure or a a somewa ee on mae emeraures areenera vaeemeraure suae reacon aou°o aou°,ne rane o aou°o aou°, aou°o aou°, roceura, se aco cuane° co aou°, an oma a aou°. reaen we seece soven,eaarnreo ouee csorme rneanconeeemerroauareo,en naecoenssar, - - - a senec aen reaceonaeomenearaenermeaeorove a reacon mxureas srre ae rouc.e soven useureno sre amces seuroec suoceen samoeroveeesre reacon w rearo sesa a reuremensscusse aove rea n,rovea wenus use aseeroaoenaon soveenn.,-eu soanvoen m saeecee avanaeous use ase soven or mae aeo anoer e nove sness re msuas orn m aa rea ncooneroe suacme co amsa seeceor sesa an. oe⁹someroe⁸s: orreaer, e.., aeas.:, aoseaosnn: w, acease m.o:a,r o raoeas.:.n somensances,e moar raos r a .o.,:o., o ne rane o:o.:, e..,.:o.:, anuree r aesacesonrerr .o.uco.,..e.,e⁹- somer or an anaoereo, maesoae . an secone r reeaceoancoronurcoucs:⁹- or an anaoereo, we srucures oers one examee,acaennsen aen reac coonsenorear⁹eeesre reaconrouc.as, as menaeno are seece as reacansrou acns,- resecevre se,.eneveasrrneo an-s a⁹- anao,eneren ¹²³ rea⁴co⁵nroucne reaca reacans an are use w,,,,, an m 1nrosu seec⁵e ano m co arrereseonneo aoev susuensesrene reac¹onrou⁵c. asoows enecon, wreerre rou an m conann¹:s s-eecerorcoamr₁,- a₁n₂ suroscaure, suesue₁-₁₂rocar,eeroaom- 2s₁ se₁e₂c eroaom-conann₁-₁₂rocar 3 erom,rox, carox, an₁-₆ a mss z₁-₆ a 4s seereoc oerrom,rox, an carox an - - - conann⁵s s-eecerorcoamr,, s₁u-s₁₂uerocaerero,a suoms-cuonea₁-₁₂rocar,eeroaom- uncona₁₁₂ nn_1-12rocar, an conann soromues e.momens,en,¹s an oona susue, oonaeeroaom- eeneerroaano nmo-₁c- mon₁₂ oraennrocar an₁- mo ,₈careoc na, orc m ma oroee an a. o n,eon e.ea .r,oa s noumess r arueere,s oenonaere are eeroaoms areca seecerom,, an. nroane oo, ane wn armar, seconar, ore eneeroaom mae conane as an ame rar amnorou ornae, wn aunconarou suc rro,rr oor a snu,onarmne,, oru wnonn a,nn arooma,cr orm acnc,cm rna szuoc, as seces suc as erazo, morono,erazno, anerno.n o ,,-razo, wn aroxrou, an aoxrou, xeneeroaom mae conane an eernae, or auran,erarou ar caanr,onra mno,eerea..,rno anr easner, oro axmane, onrae, mnoraeo, an sou ronn,a eec.rou su, aunreeeroaeo.m meanee wronc aaro oereernae, a suonae rocar moe¹s susue,e nonroen eroaom-conann eunconarous seor susuens areenera seecerom ca susuens unereenon o "susue"nar os secon. su ncue, woumaon,ao, carox, ao¹x, amo, amno, aonam,o-, a accenc,ro anus, a-n a aromna,c surosuus.eor wns zaenrcoe,o muane seecerom₁- r₁o_{8 81}mao,₂₁₈rox, carox,₂₁₈ conarous seece e a-₈ a ₁-₈ aox,₂-₈ acox,₂-₈ aoxcaron, amno, mono- reo.-su-ssuuseu cear aammnoo,,--_{1 1}--_{8 8} a a s-suussuuee a cmarnoam,o₂-,₈ a an caommon,a moonnso-₁- o soro,₁-m₁e e axamee.s., o-¹nc aue,, w-o aum, orao-n: a, suc as me, e, n-ro, 2- n-_{8 18}u ae,nsou₁ e..,,-_{12 2}-u₁₂ a, n-₁ enen₁₀ ,₂,- c₁c₀ aoeex₁ n,₈ o arn₂-e₈ aeen - - - 2- a ₆-_{1 18 8} a aranee....,,₅₂--₆₁₂ a ar-snus,₂u-e₁₀ a₁-n₁₂ a or₂ o-r₈ a_5-6n ar-susue_1-8 susue₄-₁₆eeroarae..,₃-₆eeroar-susue₁-₁₀ a or₃-₆eeroar- -₁-a₈ aoa, we.e.r,en-e ceoeroroaar, susuen mae saurae or unsaurae uoroa_{118 112 1}-₁₀ coroa,₁-₈ coroa,₁-_{12 1}-,₁-₁₀ -₁₈aoraouxor eaoa nee, .. or_1-8uoroa .,.,-₁-₁₂ corrooaxaen,,₁--₁₀ corrooxaaen,, or-₁-₈roxa 2-₁₂uo₂ -ro₁a₈eanoa,₂-n₁₀e.uo_{212 210 28} coroaen, .roaen or₂-₆uoroaen 2-₁₂uo₂ro₁a₈n,-uo,roa₂-₁₂n c oorroa-nuo,ro₂-a₁₀n coroan,₂-₈ coroan, susu₂e-₁₈ a-ox aa₂₁₀ , une.su.,s₁-u₈e a oorx₂ s-su₆sue₁-₁₂ a or₁-₈ aox- susu₂e-₁₈ a₁o₈xaene..,₁-₈ aouxs-suues wue an a₂-₁₂ aonaen₂- or₁₈ a₁-o₈x aaox- susu₂e-₁₂ a₂- 2-o₈x a aaen nne..,₁-₈ aox-susue₂-₁₂ an or₁-₈ aox- 2--₁₈ c caar₈ rooxxaaene.e.,..₂-₁₂ caroxa,₂-₁₀ caroxa, or₂-₈ caroxa, caroxa₃₁₈ ,₃-₁₂ caroxaen,₃-₁₀ caroxaen, or₃-₈ --₁-en₁-₈ a, a, e. o.,₁-₁₂ a, susue w mono-₁-₈ a-susue caramo -₁ a₈enr-₁-₈ a-susue caramo--₁-₈ a₂ caramo₂-₁₈-, e-.., a₂-₁₂ o aren-,- su asu-esu wsu meon coa-r₁a-₈ a-susue a_{2 18 18} mo--₁-_{12 1 2}- 1-₁₈ a -_{1 18 8} a aen, e. , e., e., .,..₁,-_{1 1}-_{2 1}-₂ a 2 a₁₂ a, ,e s snus us, suue w₂-₈ aamo---a useu we - w-_{2 1}--_{8 8} a aam or -o-₁--₈ a-a₂en - - - 2 ₁- 2_-18 a -₁₈ aen, e., e.,..,_-2- a₁₂ a,e snus, suuseu we w- - a-su₁-o₈n a- or- -₁-₈ a₂ -₁₈ a aen, e., e.,..₁,₁ -₂-₂ a₁₂ a,e snus, suuseu we w₁₈ - s₁-₈ asuon₂-a₂-a a _{118 112 08}uonamo-₂-₂ or -₂- a ₂-₁₈ aen, e..,₂-₁₂ aen, susue w₀-₈ suonamo-₂-₂ or -₂- ae nr₁o-₁e₈n a aom, e o.., a n₁-ro₁₂ aen, susue w oxan, morono,aznan,enera enera₂- aen, e..,- aeeenro,c suces, asune m wor ooxanno a,n morazonanno, oarznan, n a₁₈ oe nerooreeno anom₂ re o₁₂ re as nroen¹eerocce, asn morono anaznan. one or more aona susuensenaa mvea o sru msa nuoense mae saemeur asere su sussue w ene aove.xames o suc¹ susuensncue uens arou- a, or- arous a₁-₁₈ aroue.., a₁-₁₂ raovun sues₁ sruuce₁₀ ur we o-ne₁ a oro m₈ xor-esu₂-s₁₈ aueoxuasue - arou w ,s w, ee.r. o e,r a a n₂-₂- e₁₂ a₁₈o axaoxarou susue w an a₁o₆na- aoxa₁rou₁₂, a ₁-₁₂ as xames o¹ susue₂n₁s₂ncue, wa o exnamee. --₂₃, -₂---₂, ----e, -₂,- -----₃, --₂- 2-₄-₃, -₂₃₂₂-₃, --₂₂--₃,- --₂₂₂-_{3 24}-₃, --_{2 2}-₃, -₂ -₂₂-₃₃ , ---₂ -₂₂-₃, -₂₂,- -_{3 2},₂ -₃- 3, -₂-- 2₂-- -₂₂₂ -₃, -₃, -₂,-₂₃ ----- -₂₂-₃, -_{2323 2}-₃, - , --_{2 23}-₃ -₃-₃, ---₂₃ , -₂₂-₂₃ --₃, -₃, -₂ -_{2 2}-₃ ,₂--- - -- , -₂₂₃--₂₂ , -₂₃₃--₂₃ , -₃-₂₃-,₂ -₃- 2₂₂-_{3 23 3},, -₂₃, -₂₂₃ -_{2 22 3}-₂- -_{2 2}-₂-_{23 2} -_{2 23 33 3},₃ , -₃,₂ -₃₃ -_{2 22 3}-₂-₂ -_{2 2}-₂-_{3 242} -_{2 24 43 3},, -₃,₄ -_{3 22}-_{2 2}-_{2 3}, -_{3 22}-_{2 2}- -_{2 23}--₂₂---₃, -₃, -₂₃-₂-₂-₂-- - - - 2 -_{2 2-3}, - 3--₂₂₂- -_3-, -₂- 2₂- 3₂,-₂ -_{22 2-3}, 3-- - -_{22 2}- -₃,₂ --₂-₂,-₂₄ -_2-3, -- -₂₂- -_24-3,₂ --₂-₃,-₃, - -₂-₂ -_-2- -₃, -₃, --₂-_--, -₃, -₂---_-23,, - -_{2 2}--- ₂₂ -₂₂₃, -₃ , -_{2-2-3 2} -₂-₃₃, -₂ ,_{2-4-3 2432}, -₂₂--₃, -₂₂--_{23 22 223 22 233} -₂₂--₂₄₃, --_{23 3}, --_{3 23},₂ -₃-_{22 23 3},, - --₂₃-₂-,₂ -₂-₃, -₂₃,- ---₂-₃-₃, -, --₂₃---₂₄,₃, --₂₃-, -- -, ---₃-₃, --₂₄₃- ₂, --₃-₂₂,₃ -- -₃, --₂₄--_{3 2}, --₂₃--₂₂,₂ --₃-_{23 2},₃ --₂₃-₂₃, --₂--₂₂₃, --₂₂--₂₂₃, -_{23 223} --₂₃-₂₂₃, --₂--₂-₂,₃ - _{22 223}-₂₃-₂₂₃, 3₂, -₃-₂₃ -₃, -₂ --_{2 22}-_{3 3}, --_{2 3},- --₂ -_{2 22 2}-_{3 3}-₂- , -₃, -- --₂₂ -₂-_{3 2}-_{3 3}-, - 3, a₃,₂ n ---- e₂₂₃ o₄-- own-₃, - :₃, -₂---- C^H ₂ ^O _{(CH2)2 O (CH2)3 O CH2} ^N _{O (CH2)2} ^N _O

- - - C_H2 ^N _(CH2)2 ^N _{(CH2)3 N CH2} ^{N NH} O

rox, ca , -u, anroexe, as w₁e₆ as ccoarous suc, a n- , 3s- a, anus asoncuese aos ccoen an ccoex. me, e,₁ n-₆ro,soro ve-menoneosses,ncun or. , n-u,sou,-u, ccoen, ccoex, an so noe eareern, mssc,a a non-roxro oern car⁴ souxs.ueenneras,resoewne oneen rn, an, as 4 susuensresen. ver, ms zero, meanna no - - - cona⁵s seecerom,₁-₁₂rocar, susue₁-₁₂rocar,eeroaom- unconnna₁-₁₂rocar, susueeeroaom-conann_1-12rocar, an man masr n mouas. eeeuceromeaeescron,eresen meos useuor encomasse reen sr cuocmuouns,ncun nous er se annown anaos ormua w¹,²,³,⁴r,e⁵ o,ormua,u aso new anaosavne srucure o rove aove an m encomasse an seeceromeenons reaconoroowucn. , c coommoeunon o m sanees mso aneneraon o comoun aseesre ecnuesnownoose o ornar snee, aesre,oroveurer anaos, usn exs, oreveoeerenaer. r,escreneerneneraure an numer os soecec u enmerosomoensa __ , w____ eoe___ ree__ on_ nv_e_n___ eso_ crn___a_ os__ ne_ ase_n wees acsree enx conuncon w a areneneousrae an n amesaoow aens,aenuome scoe oenvenon. arencororae reerencencaeorn es,nreeraeusr.e reerences, an oer maeras ceeren : aceonreevaons useneoown exames: ::ccooroeane :meromaemane c: e aceanorne eacac:errc ace :₃ : ressureeauceo cnraoemaor 3 meoumru a a: s car eoneare - - -::er-amerourroone :naoueern cran :- esroumoano craore aness o :ness ovarnoromoroucno OH,,-rs--ouenesuonenzene O:Ts 3x TsCl, 3x NEt₃, 0.1x DMAP mnm ao,

m annureeamne.en a co-waera anos cores., mmo, eus.eas was onseoree aon omeamnorne.,. mmo,v.. was aen eo sr overaseoreen wase wrne,re o euv..eascenrae on roar evaoraorwaera°o a vera₂₄, aneceou coumn cromaora :o:or arown o..e o was c crsaze as a weower .. exanes:cove a cooress aon o,,-r 1o.4s eqa ne-preonpyzle MnegBr: OTs 5.5 V THF OTs 2.68 equiv NMP e,,-

. are aeo a eeoasor emu a ceear s wou aon m.ecoanec sao surorenr, aen an a. eounvu annnerx vac₂ cces -r^oro anon seare w. n erouven a.re a n-ero une₃r nrro.en e.uev sosu soown-s c coaoreeo - - - cormoueone as mononoruenne.e reacon souons srreorr a -^o a^on reacon rea e souonsen srre overn a -.en,^oeacon souonsue w anuence w . euv. a.e mcn.eeem orearnacuraesenrauancreaseo amenemeraure an srreor aou successve wasee wrs searaea ourom,e aueou, asaer.e orancrouc souonsaers concenrae on a roar evao₃raor a₂°ovne crurnee-ro.-e wase oranc meenzensuonae as an ora ,-enenes- so wcse ne o.rsazaon oe o weanes. es a rouc,osanereva arn rooom.emeerraouurec usn eexre vacuumoveere so susanaree o conamnans.e comoun macee aso aaee a onreuareer oarn use an e nex s assn ce.eosaon O oTs: OH 10 equiv NaOH .m.n a ,.,

,.mmo,eu as,-u ae. conenser was aacevo. ane r ceraucsoenas an.e, re.acmmo, euv. were aron.e reacon wase ^o on wasace uner exane aeo reuxn.er mnues o reuxn, : anes sovenc w saosw reemovee cons ruomon oe sarn maera.e reacon was soen cm an wase w ar evamor.aoen. reace roenac moxnu rresue wasen ressove xm.omne orancaers werere overa₂₄ an conceen waras eexr oanc ae ro war c e ova.orea crourewaera^oo aor crue-roenzene-,-o,.e.,varno, as aac oveeurroeuces wraes suroeucce,ovarnuo. coumn cromaora :exanes c - - - enera meos annsrumen:aon ⁹- aeras: cemcas wer usens exame: mee,cenc,aesar,xecreomm, comvmerca sourcesma-rc,acem, urcaserom commerca sourcesma-ranceemec anua. sovens were reacons wereerormensosae scnacon,sercenc,mnov, ancros. ass.crew cas an cone sea wererom mem ora mass vas, or roun-oom srnes... mm, m srnes... mm, m srsnsese.c.enc.es. mmso,sae m srnes... mm, an m srnes... mm m ec. wereromorm-ec anen- romrescossoane neee™.esoer xmcee. mesm x x mm” w anere x. mm x mm were soers x mm wererom , we seeve soersrommr-me w™e.rerome seeve an reua-ea sea wereromema me, r aomumaonurma se:esn-aer cromasos.ra waserorme onerccae se an vsuaze w nm ann₄oowe ¹ean. reorenarscerra m weoren oane on aruer- or- secrome ¹er. ss are m.uces are reorem as roeaowvse: sonee ress,uoa sovenea :: =. , muem,oue oo ue,re,uare,ene ssnme ues,oue ores anre ooues. eas.onu one coanss wasonease one cemca ss, muces, anneras oe aouna onsvar arneo re anore,n--zm.ena-,-en--o-menaeno

- - - raeo a m m, m romuno-, aonomoueanse was aevarno., mmo,osc ac mono °.er mnues o srrn,e souon w.e mn,rom. a sues reeancon mxure waseaeo ereanor mnues,,--mena-,-en--o.son,o a mmomoo weaneous mxure. rowse over mnues usn a srneum. s ae e reacon we er mnues o menaeno aon, was comee,ne rreoamc oornan waesoeaerown w aascarrown o.ere aon reacon,e souon was orane an moosr o aeornoawno oursa a re-°.se en oe urcaon:e reacon m sovene souon. sauraea s xure wasue we eer, wase w an concenrae₃no vuacuoon., an wase wrne.e orancaer wasre overa₂₄ scae usn cex aes c mruoee o waasse.ssosv aeorneeaener anure on aa o o. ouc as a cear,-eo . –.n,am,cae ,a. w .aor,⁸-: ¹ z,oroorm- ., =.z,, =.,.z,, =.z,,.s,,. , =.,.z,,. , . –.m,,. –.m,,. –.m,,. –.m,,.s,, ornao.n:s,,.s,,., =.z,. e mnexure m m

oue was, snrre₂.or, m.nu memsoe,o. euv., an- ., m wmo, euv.. erowse re coono °. as euv.,enerae e reacon w aas aoonw oe₂o s₄r aoa °, woras menuenoe souon over mnues. coro-,,-rme--ro-a,,,,,a-neuxaes.roe- rea-ceonnrouc,a,a-- ,oes no neeoeure,u cane userecnezocroccroomrnean-o-no se-c. - - - wase wo snaauraurecaaon o sou-:e reacon mxuresue weane, a an concenraen va₃cuo.on, an wase wrne.e orancaersre over cr₂om₄aorao aoreesreer corue o caneure va auomaeas coumn ernave cornaon reacon:uoc a asa ame-r-eeow m o va. eu,e we a. sr-ar was ae. nn . m,. m ⁸ manec . mmo, euv.n ₂ mo,. euv., an- ., eore coono °.. mn aonxanrousouene.e mxure was srreor mnues reacon was warmeo roomemeera.ur m,. mmo,. euv. was ae, ane roucs o e an srre overn.er woru,eesre naancea as aeow o.¹, e. ,. , =.a,a.orz,-,.:, =.,.zz,,o,ro.orm –-.m.,s,,.,.,s, .z,,. –.m,,.s,,. –.m,,.s,, = ,.s,,., . –.m, cness o⁹ =-.zr,om.-: uoxe. m

,. . va waseru- w aron aneaeo °.- .,. mmo, eu se use wouurcaonn anrousouene. m was aeov. oe sarnren snou aon e reacon was aoweo sroro n, an saurae suorucaono on:e re.aceo onr manxcuru aers w. era wsasu waes we wearnnee anuence w a concenraen vacuo.₄e crue o wasure va aase so,re overa₂₄, an c:⁸e-ane rsaoo a.oreesrerouc as arown o .r m sc,aue, -:⁹- - - - ,.n,a =c.aaz,aor,.⁹-,: = ¹.z,,.z,s,oro,o.rm-, =..,,. =z.,z,. –.m,,. –.m,,. , =.,.,.,.z,,. ,,.,.z,,.s,,.s,,.s,,., =.z,. = - -

Claims

- : . meoor sneszn a co Rm²ounavne srucure oormua n wc: _m conann¹s se-ecerom

- rocar,eer an₁-₆ m,rox, carox,_2-6 acox,- aox-caronroocaom- 2s s₁ee₁₈cero ₁₁₈ ,ar- a, ao³ as s susue w rox, ca₁r₆ox, orao _{26 16} eecerom₁-₆ a an- a susue w rox, carox, or m conann⁴ss z seer -eoc,e, or rroom₁-₁₈rocar, susue₁-₁₈rocar,eeroaom- unconar₁ou₁₈s, wercearn,, m suss,ueeneeer⁴o maaom-econeann₁-₁₈rocar, an 5s seecerom,- rocar, sus same oreren an conann- roc ₁₁₈ ue₁-₁₈rocar,eeroaom- uncon₁₁₈ ar, susueeeroaom-conann₁-₁₈rocar, an warous, aerene meo comrses: arsea renac aan reacavonn mxe surreuc coumrersn: O oHormua )_m a secon reacan

- - - R² _OH a a caaca ee e ran w so e oerveen ano ouere

a acc, an s.ec:ono a reaocuan.:, anereersrov reacnan ars anreerrmesen a a moar raon srucure oormua R² eaeavne m e srucu croen oa

orove a seconnermeaeavn m werenc cson orr

secon acv a eecveoeroaoenae °o a.oue me°o. o cam, werene sovenas aononne rane o aou aou.°.e meo o cam, wereneononsne rane o aou°o - - - .e meo o cam, weren anc are carre oune soven. .e meo o cam, werens use wousoaon anurcaonn. .e meo o cam, werens use wousoaon anurcaonnc. .e meo o cam, werenernse acs an oranc ac. .e meo o cam, werene oranc acs a suonc ac or a caroxc ac. oue.e meo o cam, werene oranc acs a suonc ac seecerom- ruonreosmueonacn aecsu,o mnec aacne,suenoznence ascu,o encanesuonc ac,-exanesuonc ac, naaenesuonc ac, an camorsuonc a acc,.-eenzenesuonc ac,,- .e meo o cam, werene oranc acs-ouenesuonc ac. aou°..e meo o cam, weren se s carre ou a aemeraure oessan .e meo o cam, wereneaoenaon reaens a cornaon reaen. ac an a. coer mee sao s oee ccaemro,m wnere₂,ne c₂, aonrn aa coomn renaaeonn comereros.esrocorc s use re.avee moeo. o cam, weren aeas. euvaens oeaoenaon reaen - - - o..e meo o cam, weren aeasour euvaens oeases use reave .e meo o cam, wereneasesoassum-uoxe. conann¹.s seee mceeorom o c₁a-m₁₂, wroecraern:, susue₁-₁₂rocar,eeroaom- 2s s₁e-e₁₂cerroocmar,, anro sxu,s caruoex,e aneroaom-conann₁-₁₂rocar 3s- 5s seec o a _1-6 a ms ze₁ro₆ er,r aonm w,en- ms,ro⁴casr see,cerom,rox, an carox an conann₁- rocar,₁ su₁s₂ueeero sauosm-cuoenan₁-n₁₂-rocarroc,aree,ro aanom- unconarou₁₂s. ₁₁₂ ereo..e meo o cam, weren¹s n-ro, sucas⁹- or an anao reacans.-mee mneaoen oo c, saumc,a wersen⁹-ers. reacansvarno ane secon we so.vene m aenoea oe carmo, weren reacan anernse ac are comne mxure. roraua aon o reacan oorme reacon - -