別紙41 (課程博士(英文))Date of submission (month day, year)

Feb,27,2020

Depadment

Applied chemistly andSludcntlD N山れberDB3416
Kazutaka sl〕ibatomi

Life scienceSupeτνisols

Seijilwasa
PP11Canl's name

Kazumasa Kitah砥'aAbst"act (Dodo")
Catalytic AsymmetTic synthesis ofchiralHaloge】徐ted compounds andIitle oflhesis

Their steTeospeci6C 11'ansformation(キラルハロゲン化合物の触媒的不斉合成法および立体特異的変換反応の朋発)

Approx,80o words
St磁'eoselective syntl〕esis of halogenated sn]a11 0lganic lnolecules is highly in〕portant in synthetic
OTganic chelnistry because resultlng cl〕Ⅱ'al organohalides can be easily convelted into various cl〕iral

molecules by sN2 reaction, Furthermore, recently, not only auorinated c01〕1Pounds but also cl〕iralCI〕10rinated and bron)inated con〕poundS 釧'e expected as potent dTugs because bi010σica11y active
natural colnpounds often contain C1110rine or bronline atolns on sta'eooenic cm'bon centers. Despited〕e extraoldlnm'y lnt剖'est in practical syntheuc n)ethod010gies toW釦'ds chh'al hal0σenatedCompounds, the n)ethod010gy for t11e construction of chh'al halogenated sta'eogenic cm'bon center
have not estabHSI)ed we11.11〕troduction of halogen aton〕s onto tertiary carbon center have been n〕osdy11n〕1ted to halogenation of active nlethylene con〕pounds such aS β・keto esters.11] alis rese砥'ch,11igl〕1yenatioselective synthesis of tertiary l]alides was carried out. Furthermore, synt11etic utility of l'esultinσter{i飢、y haHdes was explored by subsequel]t st引'eospecific derivatizationsFirst, enantioselective syntl〕esis of tertiary fluoTide 、vas acl}ieved by auorination of a、bral〕C11ed
aldehydes 、V111〕 a newly developed cl〕iral prin]m'y an〕ine catalyst. Enantioselective auorination ofaldel〕ydes 、Ⅳlth chilal second飢'y alnlne catalyst is a higl〕1y useful n]̲ethod to il〕t丁oduce a auorine atonl

On a stereogenic cm'bon center. Although tl〕is n〕ethod yields a‑auoroaldehydes witl〕 11igh
enantioselectivity when a・alkylaldehydes、vere

employed as substrates, auorination ofα,α・dialkylaldehydes (α・brancl〕ed aldehydes) with secondary ol plimary amine catalysts exabits
Unsatisfactory results. Accolding to tl〕ese situations, a ne、v chh'al primm'y an〕i11e catalyst 圦ノasdeveloped and used for enantioselective auorination of a‑branched aldel〕ydes. As a result, various
tertiary auorides wele synthesized in good yield with l】igh enantioselectivity (up t0 95ツ0 ee).
Resulting te11iary auorides 、入lete converted into chh'a1 3・auoropropenes and auolinated analogue of
bioactive conlpounds such as Flurbiprofen. Fultl〕ern〕ore,α・Huoroaldehydes were converted intoα・1〕ydrxyaceta1 νia C飢'bon・Fluorine bond cleavage on a st引'eospecitic n〕anner [up to >99% es, esenantiospecificity whicl) is calculated by (ee of product)/(ee of subsh'ate)]. After the confirn〕ation of
Stereochelnish'y,北 Was confirn)ed t11at this reaction ploceeded via sN2 type reaction
Second, enantioselective syntl】esis of tettiaTy chloride

入N'asachieved by decm'boxylativeCI)10rination of β一keto carboxylic acids in the presence of chital priln雛'y amine catalyst andelectrophilic chlorinating reagent. Although th釘'e is no asymmetric halogenation has been achieved,
Seva'al enantioselective decm'boxylative carbon‑carbon bond fornlation reactions of β・O×0
Carboxylic acids have reported ti11 date. According to these successful examples,β・O×o carboxyHC
acids can work as an enolate equivalent by decm'boxylation of cm'boxyHc acid moiety. Herein,enantioselective halogenation was developed by using β・keto cm'boxyHc acids 、vith chiral an〕ine
Catalyst and electrophilic chlorinating reagent. This reaction afforded varlous secondary and tertiary
α、chloroketones with high enantioselectivity (up t0 98% ee). Furtha'n)ore, resuHing tertiary
Chloroketone was subjected to S入^2 teactions and tl〕is reaction afforded correspondlng a‑surfenyl orα、azide ketones without loss of enantiopurity (up to >99% es). The absolute configuration of tl)e
Substrate and the pToduct were determined by x・ray crysta110graphy and it was conflrmed that
inversion of stereochen〕istry surely occun'ed. Decm'boxylative chlonnation was also appHcable toasymn〕etric syntl〕esis of a・chloro・α・auoroketones by asyn〕n〕etrlc decarboxylative chlorination of
α、auoro、β・keto carboxylic acids in the presence of chiral amine catalyst. This reaction afforded son〕e
Products with high enantioselectivity (up t0 90ツ0 ee). However, nloderate t0 10、v enantioselectivity
Was observed with indanone・derived and acyclic substrates.1hen, resulting a・chloto・α・auoroketone
圦lasSubjected toSN2

reactlonandit yielded

theCm'responding

Chiralα、functionaHzed・α・auoroketones with almost retained enantiopurity (up to >99% es).

Fina11y, asymmetric synthesis of chiral auoroalkenes was achieved by sN2' reaction of chiral
3‑chloro‑3・auropropenes. Fluoroalkene is an imp011ant substlucture especia11y ln nledicina11y・relevant
Chemistry because auoroalkenes sometinle act as peptide bioisost飢'S. Th飢'efore, development of efficientmethods for the pl'epal'ation of auoroalkenes have att↑acted attention in recent yeal'S. paquin'S I'esearchgroup recendy reported an ef丘Cie川 Synthetic method of chⅡ'al auoroalkenes by sN2' 1'eaction of3,3、diauoropropene. on the other hand, our resem'ch 即'oup previously reported ena11tioselective synthesis ofα、chloro、α、auoroaldehydes by organocatalytic enantioselective auorination of a・chloroaldehydes.1nspiredby these wotks, novel synd〕etic route for chiral auoroalkenes was designed by using sN2' 1、eaction of3、chloro‑3・auoropropens which

arePrepm'ed by H0111er・XNadswortl)・Elnmons reaction of chⅡ'al

α一chloro、α、auoroaldehydes. Aftet S仇'eening of reaction conditions, it was revealed that sN2' reaction
affm'ded the desh'ed chiral auroalkene in good yield xvith aln〕ost retained enantioputity (up to >99% es).