Asymmetric synthesis of dibenzo[b,d]azepines by Cu-catalyzed reductive or borylative cyclization

Asymme ic syn hesis o dibenzo[b,d]azepines by Cu-ca alyzed educ i e o bo yla i e cycliza ion† Pa icia Rod ´ ıguez-Salamanca, a Roc´ ıo Ma ´ ın-de la Calle, a Ve ´ onica Rod ´ ıguez, b Ped o Me ino, c Rosa io Fe n´ andez, * b Jos´ e M. Lassale a * a and Valen ´ ın Ho nillos * ab A coppe -ca alyzed asymme ic in amolecula educ i e cycliza ion o he syn hesis o dibenzo[b,d] azepines is desc ibed. Use o 20- inyl-bia yl-2-imines as subs a es and in si u o med [Cu I /(Ph-BPE)] as he ca alys enables he syn hesis o 7-membe ed b idged bia ylamines con aining bo h cen al and axial s e eogenic elemen s in high yields (up o 98%) and wi h excellen dias e eo- and enan ioselec i i ies (>20 : 1 d. ., up o 99% ee). Mo eo e , he same ca alys was ound o acili a e a ela ed bo yla i e cycliza ion o affo d e sa ile bo onic es e de i a i es. Bo h eac ions p oceed unde mild condi ions ( ) and a e applicable o a a ie y o subs i u ed a oma ic and he e ocyclic de i a i es. In oduc ion The asymme ic syn hesis o bia yl a opisome s has e ol ed in o a s imula ing esea ch eld in o ganic syn hesis owing o he ubiqui ous occu ence o his s uc u al mo i in a a ie y o na u al p oduc s and bioac i e subs ances, and o hei wide- anging u ili ies in ca alys design and ma e ial science. 1 Mos o hese compounds comp ise con o me s wi h es ic ed o a- ion a ound a single bond whose congu a ional s abili y is gene ally de e mined by he numbe and size o he subs i u- en s a he o ho posi ions ela i e o he s e eogenic axis. A less common class o bia yl a opisome s consis o hose whe e he bia yl uni is inco po a ed in o a cyclic sys em, wi h he ypical o ho,o ho0subs i uen s being eplaced by a b idge (Fig. 1). 2 In hese sys ems, he congu a ional s abili y di ec ly co ela es wi h he ing size: in 5- and 6-membe ed ings he o a ion a ound he s e eogenic axis is usually no hinde ed, bu 7-membe ed b idged bia yls exhibi a highe congu a ional s abili y owing o con o ma ional easons and can be oen esol ed as a opisome s. Addi ionally, he in oduc ion o sp 2 hyb idized a oms inc eases he igidi y in he b idging cycle, and he e o e he congu a ional s abili y, 3 while he p esence o s e eogenic cen e s in he b idge is known o impose a specic congu a ion on he bia yl axis by a cen al o axial chi ali y elay e en . 4 No ably, hese p ope ies ha e been ecen ly exploi ed o he cons uc ion o a unidi ec ional o a y molecula mo o based on he o ma ion o bia yl s uc u es ea u ing a se en-membe ed lac one b idge. 5 The mos dis inc i e class o b idged bia yls p esen ing his elay phenomenon comp ises chi al dibenzoazepines. These 7- membe ed cyclic b idged bia yl amines and ela ed analogues ha e ecei ed conside able a en ion due o hei p esence in se e al na u al subs ances and d ugs. Selec ed examples shown in Fig. 2 include e y h i aeine B (A), a dime ic E y h ina alkaloid isola ed om E. a iega e, 6 dipep ide LY-411575 (B) which has demons a ed effec i i y as g-sec e ase inhibi o o he ea - men o melanoma and Alzheime 's disease, 7 RO4929097 (C), ano he po en and selec i e g-sec e ase which a ge s No ch signaling in umo cells, 8 indolobenzoazepinone D, a ubulin polyme iza ion inhibi o exhibi ing an ip oli e a i e ac i i ies in a a ie y o cance cell lines, 9 and paullones E, a amily o cy o oxic compounds which efficien ly inhibi cyclin-dependen kinases (CDKs). 10 The asymme ic syn hesis o axially chi al 7-membe ed b idged bia yl amines has adi ionally elied on chi al Fig. 1 Configu a ional s abili y o acyclic and b idged bia yls. a Ins i u o In es igaciones Qu´ ımicas (CSIC-US), C/Am´ e ico Vespucio, 49, 41092 Se illa, Spain. E-mail: [email protected] b Depa amen o de Qu´ ımica O g´ anica, Uni e sidad de Se illa, C/P o . Ga c´ ıa Gonz´ alez, 1, 41012 Se illa, Spain c Ins i u o de Biocompu aci´ on y F´ ısica de Sis emas Complejos (BIFI), Uni e sidad de Za agoza, 50009 Za agoza, Spain †Elec onic supplemen a y in o ma ion (ESI) a ailable: Expe imen al p o ocols, cha ac e iza ion da a. CCDC 2095490–2095492. Fo ESI and c ys allog aphic da a in CIF o o he elec onic o ma see DOI: 10.1039/d1sc04980a Ci e his: Chem. Sci.,2021,12,15291 All publica ion cha ges o his a icle ha e been paid o by he Royal Socie y o Chemis y Recei ed 8 h Sep embe 2021 Accep ed 8 h No embe 2021 DOI: 10.1039/d1sc04980a sc.li/chemical-science © 2021 The Au ho (s). Published by he Royal Socie y o Chemis y Chem. Sci.,2021,12,15291–15297 | 15291 Chemical Science EDGE ARTICLE Open Access A icle. Published on 10 No embe 2021. Downloaded on 3/22/2022 1:30:42 PM. This a icle is licensed unde a C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence. View A icle Online View Jou nal | View Issue auxilia ies o s a ing ma e ials om he chi al pool, gene ally equi ing mul is ep p ocedu es. 3,11 The con ol o bo h cen al and axial chi ali y elemen s in he mos in e es ing dibenzo[b,d] azepine de i a i es cons i u es a challenge: o da e, only a hand ul o me hods ha e been desc ibed o hei ca aly ic asymme ic syn hesis (Scheme 1). Axially chi al dibenzoazepinones wi h amide b idges ha e been p epa ed by desymme iza ion ia Pd-ca alyzed C–H a y- la ion 12 (Scheme 1A) and, e y ecen ly, by a cyclo- ca bopallada ion-ca bonyla ion cascade eac ion using alcohols o anilines as nucleophiles 13 (Scheme 1B). To ou knowledge, he au ome iza ion o me as able enamines p omo ed by a chi al phospho ic acid ca alys appea s as he only ca aly ic me hod epo ed o ob ain axially chi al dibenzo [b,d]azepines (Scheme 1C). 14,15 Hence, he de elopmen o a modula and s aigh o wa d ca aly ic enan ioselec i e me hod, p o iding access o hese s uc u al mo i s emains as a desi able goal. Resul s and discussion Inspi ed by he wo k o Buchwald 16 and Yun 17 on Cu-ca alyzed cycliza ions using aldimines as elec ophiles, we en isioned ha Schiffbases om o ho- inyl, o ho0-amino bia yls could also be sui able subs a es o pe o m educ i e o bo yla i e cycliza ions o he cons uc ion o axially chi al dibenzo[b,d] azepine de i a i es ea u ing a s e eogenic axis and wo con iguous s e eogenic cen e s (Scheme 1D). P elimina y s udies we e pe o med wi h compound 1Aa, eadily ob ained by condensa ion o 20- inyl-biphenyl-2-amine wi h benzaldehyde, as a model subs a e (Table 1). Using Cu(OAc) 2 as he p eca alys , me hyldie hoxysilane (DEMS) as he hyd ide sou ce and anhyd ous TBME : THF (95 : 5) mix u e as he sol en a oom empe a u e, ep esen a i es o comme cially a ailable chi al biphosphine ligands L1–L6 we e es ed o he syn hesis o he desi ed azepine 2Aa. Poo eac- i i ies we e obse ed wi h BINAP L1, SEGPHOS L2, DUPHOS L3 o he JOSIPHOS ep esen a i e L4 (en ies 1–4), while mode a e ca aly ic ac i i y and enan ioselec i i y we e obse ed wi h MeO- Fig. 2 Selec ed bioac i e dibenzoazepines and ela ed analogues. Scheme 1 Ca aly ic asymme ic syn hesis o axially chi al 7- membe ed cyclic b idged bia yl amines. 15292 |Chem. Sci.,2021,12,15291–15297 © 2021 The Au ho (s). Published by he Royal Socie y o Chemis y Chemical Science Edge A icle Open Access A icle. Published on 10 No embe 2021. Downloaded on 3/22/2022 1:30:42 PM. This a icle is licensed unde a C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence. View A icle Online SEGPHOS L5 (en y 5).Finally, (R,R)-Ph-BPE L6 p o ed o be he ligand o choice, affo ding op imal esul s in e ms o eac i i y, dias e eo- and enan ioselec i i y (99% yield, >20 : 1 d. ., 99% ee, en y 6). Wi h he op imized condi ions es ablished, we examined he subs a e scope o he 20- inyl-biphenyl-2-imine p ecu so s o explo e he gene ali y o his asymme ic educ i e cycliza ion. Subs a es wi h elec on- ich me hyl and me hoxy subs i uen s on he aldimine a yl ing we e ans o med in o he co e- sponding dibenzoazepines 2Ab–ein high yields and excellen enan ioselec i i ies. The s e ic effec o placing subs i uen s on he o ho posi ion o he ing has a negligible effec on eac i i y and enan ioselec i i y as demons a ed o he syn hesis o 2Ab, 2A and 2Ai. Elec on-decien subs i uen s on he phenyl ing o he aldimine we e also ole a ed. Thus, uo ina ed subs a es u nished he co esponding dibenzoazepines 2Ah and 2Ai wi h excellen selec i i ies. Howe e , he enan ioselec i i y d ops when a CF 3 g oup is loca ed a he pa a posi ion o he phenyl ing (2Am). Impo an ly, p oduc s bea ing halide (2A ,2Ag,2Aj and 2Ak), es e (2Al) and ni ile (2An) unc ionali ies we e also Scheme 2 Subs a e scope. Reac ions pe o med on 0.2 mmol scale o a 36 h pe iod a . Yields o isola ed p oduc a e ch oma og aphy. A single dias e eome was obse ed by 1 H NMR in he c ude eac ion mix u es. Ee's we e de e mined by HPLC on chi al s a iona y phases. a Reac ion pe o med on 2 mmol (566 mg) scale. © 2021 The Au ho (s). Published by he Royal Socie y o Chemis y Chem. Sci.,2021,12,15291–15297 | 15293 Edge A icle Chemical Science Open Access A icle. Published on 10 No embe 2021. Downloaded on 3/22/2022 1:30:42 PM. This a icle is licensed unde a C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence. View A icle Online ob ained in good o high yields (66–99%) and mode a e o high enan ioselec i i ies (up o 92%), p o iding syn he ically use ul unc ionali ies o u he ans o ma ions. Mo eo e , he me hod also ole a es a a ie y o he e ocyclic subs a es, leading o u an (2Ap), N-me hyl py ole (2Aq), hiophene (2A ), py idine (2A ) and used he e ocyclic de i a i es (benzo u an 2As,N-me hylindole 2A and hianaph hene 2Au) in good yields and excellen enan ioselec i i ies. The S a ,6S,7Rabsolu e congu a ion o p oduc s 2Ag, and 2Aj was de e mined by X- ay diff ac ion analysis, 18 while ha o o he p oduc s 2was assigned by analogy. Mo eo e , he cen al o axial chi ali y elay phenomenon was con med by a dihed al angle o 39 be ween he wo a yl g oups in bo h compounds. I should be no ed ha he cis-dias e eome s we e exclusi ely o med in all cases. Bia yls deco a ed wi h se e al elec on-dona ing o wi hd awing g oups (e.g. Me, OMe, o F) we e also sui able subs a es o his ans o ma ion, affo ding he desi ed p od- uc s in mode a e o good yields wi h high enan ioselec i i ies (2Ba–2Ea,94–99% ee). We nex explo ed he kine ic esolu ion (KR) o a isubs i- u ed, hence congu a ionally s able, bia ylimine 1Fa ia Cu- ca alyzed hyd ocup a ion/cycliza ion ollowed by educ ion o he un eac ed, enan ioen iched imine (Scheme 3). The eac ion s opped a 50% con e sion, despi e he p esence o a la ge excess (2 equi .) o silane. In his way, dibenzoazepine 2Fa could be ob ained in high enan ioselec i i y unde he p e iously op imized condi ions, while he enan ioen iched s a ing ma e ial was ans o med in o amine (S)-3Fa, ob ained in nea ly enan iopu e o m (>99% ee) ae LiAlH 4 educ ion (s¼98). The bia yl-2-amine 3Fa, ea u ing only axial chi ali y, shows an appealing s uc u e wi h po en ial applica ions in asymme ic ca alysis. Reasoning ha subs a es 1should o m e y simila o ganocoppe in e media es ae inse ion o he inyl g oup in o L*Cu–Bpin ca alys s, we decided o explo e also he Cu- ca alyzed enan ioselec i e bo yla i e cycliza ion o he same subs a es 1as an al e na i e app oach o axially chi al dibenzo [b,d]azepines, in his case deco a ed wi h a bo yl g oup ha should be use ul o u he de i a iza ion o bioconjuga ion (Scheme 4). Using again 1A as a model subs a e in he eac ion wi h bis(pinacola o)dibo on [B 2 (pin) 2 ], he ca alys o med by combina ion o [Cu(MeCN) 4 ]PF 6 wi h biphosphine L2,KO Bu as he base, iP OH as he p o on sou ce and anhyd ous THF as he sol en we e iden ied as he bes condi ions, leading o he bo yla ed axially chi al dibenzoazepine (S a ,6S,7R)-4Aa in 85% yield wi h excellen egio-, dias e eo- and enan ioselec i i y (>20 : 1 d. . 98% ee). Single c ys al X- ay analysis o his compound 18 con med he assigned absolu e congu a ion. Bo yla i e cycliza ion o o he 20- inyl-biphenyl-2-imines p o- ceeded efficien ly unde he same condi ions o affo d p oduc s 4wi h excellen enan iocon ol (>20 : 1 d. ., 92–98% ee). Again, elec on- ich and -decien subs i uen s as well as o ho- subs i u ion in he phenyl ing we e ole a ed. The eac ion also accep s he e oa enes as illus a ed o compound 4A . To explo e he syn he ic po en ial o he me hodology, g am- scale syn hesis and de i a iza ions we e pe o med. Asymme ic in amolecula educ i e cycliza ion o 1Aa on a 2 mmol scale affo ded he desi ed p oduc 2Aa in 93% yield and 98% ee (Scheme 2). As shown in Scheme 5, deme hyla ion o 2Ae Scheme 3 Kine ic esolu ion o ac-1Fa. Reac ion pe o med on 0.2 mmol scale o a 36 h pe iod a . Yields o isola ed p oduc a e ch oma og aphy. Ee's we e de e mined by HPLC on chi al s a iona y phases. Table 1 Sc eening o ligands and op imiza ion o he eac ion En y a Ligand Con . b (%) ee c (%) 1L1,(S)-BINAP <5 nd 2L2,(R)-DTBM-SEGPHOS <10 nd 3L3,(S,S)-Me-DUPHOS <20 nd 4L4,(R)-(S)-JOSIPHOS <20 nd 5L5,(R)-MeO-BIPHEP 42 77 6 d L6,(R,R)-Ph-BPE 99 (99 yield) 99 a Reac ions pe o med on 0.2 mmol scale. b Es ima ed by 1 H-NMR spec oscopy. c De e mined by HPLC on chi al s a iona y phases. d A single dias e eome was obse ed by 1 H NMR in he c ude eac ion mix u e. 15294 |Chem. Sci.,2021,12,15291–15297 © 2021 The Au ho (s). Published by he Royal Socie y o Chemis y Chemical Science Edge A icle Open Access A icle. Published on 10 No embe 2021. Downloaded on 3/22/2022 1:30:42 PM. This a icle is licensed unde a C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence. View A icle Online offe ed he co esponding phenol p oduc 5which can be used as syn he ic handle o u he ans o ma ions. Mo eo e , uo escen labelling o 2Ag was accomplished ia Suzu- kiMiyau a coupling p o iding py ene subs i u ed compound 6 wi h emi ing p ope ies o hei po en ial use in biological s udies. 19 On he o he hand, oxida ion o 4Ah wi h sodium pe bo a e led o chi al p ima y alcohol 7in high yield while in amolecula Suzuki coupling o 4A affo ds cis- e ahy- d odibenzoindenoazepine 8in 56% yield. To assess he congu a ional s abili y o he bia yl axis o p oduc s 2, we calcula ed he o a ion abou he axis o he biphenyl moie y o compound 2Aa. The dibenzoazepine ing can adop boa aand hal -chai bcon o ma ions (Scheme 6). 20 A hi d con o ma ion can be loca ed bu a a conside able highe ene gy. 21 The mos s able con o ma ion o 2Aa was ound o be C1a, ma ching he X- ay s uc u es o analogs 2ag,2Aj and 4Aa. Rema kably, no in e con e sion be ween C1a and C2a con o - ma ions is possible due o s e ic easons. Thus, axial epime i- za ion by biphenyl bond o a ion equi es a p e ious change om a o bcon o ma ions. The in e con e sion o he S a -C1a/ S a -C1b and R a -C2a/R a -C2b con o me s ha e ee ene gy ba ie s o 15.6 and 14.0 kcal mol 1 , espec i ely and he diffe ence be ween ee ene gy o con o me s accoun s o he p e e ed C1a and C2b con o ma ions in each case. The in e con e sion be ween S a -C1b/R a -C2b con o ma ions in ol ing epime iza ion has ee ene gy ba ie s o only 2, 6 and 8.1 kcal mol 1 . Those alues clea ly show ha a as equilib ium is es ablished a 25 C (a ba ie o 15.6 kcal mol 1 co esponds, app oxima ely, o a kine ic cons an o 22.4 s 1 wi h 1/2 o 0.031) and, conse- quen ly, he obse ed popula ion o con o me s depends on hei ela i e s abili y. The calcula ed ela i e ene gies o he mos s able S a -C1a/R a -C2b con o me s co espond o a 2.4 kcal diffe ence, co esponding o a 98 : 2 a io. Conside ing hese alues and he assumed DFT expe imen al e o i is possible o conclude ha , essen ially, only S a -C1a will be obse ed. Low empe a u e 1 H-NMR expe imen s p o ided u he suppo o his conclusion: a single se o peaks is obse ed a empe a- u es as low as 60 C. On he ligh o hese calcula ions, we specula ed on he possibili y o eezing o shiing he con o ma ional equilib- ium by in oducing a bulkie Bu g oup ins ead o he Ph g oup. In e es ingly, he calcula ion p edic s ha R a -C2b is he lowes ene gy con o ma ion in his case (1.7 lowe han S a -C1a). This esul can be a ionalized by he lowe impac o he s e ic effec s in he S a -C1a con o me as a esul o he wo gauche in e ac ions o he R g oup, while he e is only one in R a -C2b.In o de o check whe he a shio he axial chi ali y could be indeed expe imen ally achie ed, pi alaldehyde de i a i e 1Aw was p epa ed and subjec ed o he educ i e cycliza ion p o ocol o achie e p oduc 2Aw in 85% yield and 97% ee (Scheme 7). The R a ,6S,7Rcongu a ion is in his case en a i ely assigned on he basis o he abo e calcula ions and he absence o a NOE obse ed be ween H-7 and he Me g oup, clea ly obse ed o 2Aa (R ¼Ph) due o hei ela i e gauche disposi ion (suppo ed Scheme 4 Coppe -ca alyzed bo yla i e cycliza ion. Reac ions pe - o med on 0.2 mmol scale. Yields o isola ed p oduc a e ch oma- og aphy. A single dias e eome (>20 : 1 d. .) was obse ed as de e mined by 1 H NMR in he c ude eac ion mix u es. Ee's we e de e mined by HPLC analysis. Scheme 5 De i a iza ion eac ions. © 2021 The Au ho (s). Published by he Royal Socie y o Chemis y Chem. Sci.,2021,12,15291–15297 | 15295 Edge A icle Chemical Science Open Access A icle. Published on 10 No embe 2021. Downloaded on 3/22/2022 1:30:42 PM. This a icle is licensed unde a C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence. View A icle Online by he compu a ional analysis o non-co alen in e ac ions, NCI; see ESI†). As in he p eceden case, a single se o signals is isible in he 1 H-NMR spec um upon cooling o 60 C, indi- ca ing he absence o any signican amoun s o mino con o me s. Based on p e ious mechanis ic s udies by Buchwald 22 and Ha wig 23 labo a o ies, we assume ha he hyd ocup a ion o subs a es 1, gene a ing in e media e Ia (Scheme 8) is he s e eode e mining s ep. Ensuing cis-selec i e cycliza ion o affo d complex IIa should hen p oceed ia a well-o ganized ansi ion s a e TS wi h he assis ance p o ided by coo dina ion o he imine ni ogen. Then, he esul ing in e - media e IIa eac s wi h he silane eagen o egene a e he CuH ca alys . A simila model and ca aly ic cycle can be also p oposed o he bo yla i e cycliza ion (X ¼Bpin). Conclusions We ha e success ully de eloped a s aigh o wa d app oach o he enan ioselec i e syn hesis o dibenzo[b,d]azepines ea u ing cen al and axial chi ali y elemen s by means o Cu-ca alyzed asymme ic in amolecula educ i e o bo yla i e cycliza- ions. Bo h eac ions p oceed wi h good yields and excellen dias e eo- and enan ioselec i i ies unde mild condi ions. Axially chi al bia yl-2-amines could also be ob ained in nea ly pe ec enan ioselec i i y h ough a kine ic esolu ion p ocess. Compu a ional wo k indica es ha he axial chi ali y is he - modynamically con olled, and ha he sense o he axial chi ali y depends on he na u e o he imine R g oup. Da a a ailabili y All expe imen al and compu a ional da a associa ed wi h his s udy can be ound in he a icle o in he ESI.† Au ho con ibu ions R. F., J. M. L. and V. H. concei ed and supe ised he s udy. P. R.-S., R. M. C. and V. R. pe o med he expe imen s and analyzed he da a. V. H. and J. M. L. w o e he manusc ip . P. M. pe o med he compu a ional s udies. Scheme 6 Compu a ional analysis o he axial epime iza ion o dibenzoazepines 2A (wb97xd/de 2 z p//wb97xd/de 2s p/cpcm ¼ diisop opyle he ). Rela i e ee ene gies a e gi en in b acke s in kcal mol 1 . Da a o R ¼Ph in plain ex , da a o R ¼ Bu in i alics. Fo de ails see he ESI.† Scheme 7 Syn hesis o e -bu yl-subs i u ed dibenzoazepine 2Aw. Scheme 8 Ca aly ic cycle and s e eochemical model. 15296 |Chem. Sci.,2021,12,15291–15297 © 2021 The Au ho (s). Published by he Royal Socie y o Chemis y Chemical Science Edge A icle Open Access A icle. Published on 10 No embe 2021. Downloaded on 3/22/2022 1:30:42 PM. This a icle is licensed unde a C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence. View A icle Online Conflic s o in e es The e a e no conic s o decla e. Acknowledgemen s We hank he Spanish Minis e io de Ciencia e Inno aci´ on (G an s PID2019-106358GB-C21, PID2019-106358GB-C22, PID2019-104090RB-100, con ac s RYC-2017-22294 o V.H. and BES-2017-081561 o P. R-S), Eu opean unding (ERDF), Jun a de Andaluc´ ıa (G an s P18-FR-3531, P18-FR-644, US- 1262867, and US-1260906), and A agon Go e nmen (G upos E34_20R). Compu a ional esou ces om he supe -compu e s “Memen o”and “Cie zo”p o ided by BIFI-ZCAM (Uni e si y o Za agoza, Spain) a e also acknowledged. We also hank D F ancisco Jos´ e Fe n´ andez de C´ o do a o X- ay s uc u e de e - mina ion o compounds 2Aj,2Ag and 4Aa. No es and e e ences 1(a) G. B ingmann, T. Gulde , T. A. M. Gulde and M. B euning, Chem. Re ., 2011, 111, 563–639; (b) J. E. Smy h, N. M. Bu le and P. A. Kelle , Na . P od. Rep., 2015, 32, 1562–1583; (c) J. Wencel-Delo d, A. Panossian, F. R. Le oux and F. Colobe , Chem. Soc. Re ., 2015, 44, 3418–3430; (d) Y.-B. Wang and B. Tan, Acc. Chem. Res., 2018, 51, 534–547; (e) J. K. Cheng, S.-H. Xiang, S. Li, L. Ye and B. Tan, Chem. Re ., 2021, 121, 4805–4902; ( ) J. M. Lassale a, A opisome ism and Axial Chi ali y, Wo ld Scien ic, New Je sey, 2019. 2 G. B ingmann, A. J. P. Mo ime , P. A. Kelle , M. J. G esse , J. Ga ne and M. B euning, Angew. Chem., In . Ed., 2005, 44, 5384–5427. 3 S. L. Pi a, T. W. Wallace and J. P. G aham, O g. Le ., 2009, 11, 1663–1666. 4(a) S. Supe chi, D. Casa ini, A. Lau i a, A. Ba oso and C. Rosini, Angew. Chem., In . Ed., 2001, 40, 451–454; (b) Y. Zhang, Y.-Q. Liu, L. Hu, X. Zhang and Q. Yin, O g. Le ., 2020, 22, 6479–6483; (c) Y. Guo, M.-M. Liu, X. Zhu, L. Zhu and C. He, Angew. Chem., In . Ed., 2021, 60, 13887–13891. 5 Y. Zhang, Z. Chang, H. Zhao, S. C espi, B. L. Fe inga and D. Zhao, Chem, 2020, 6, 2420–2429. 6 B. Zhang, M. Bao, C. Zeng, X. Zhong, L. Ni, Y. Zeng and X. Cai, O g. Le ., 2014, 16, 6400–6403. 7 G. T. Wong, D. Man a, F. M. Poule , Q. Zhang, H. Josien, T. Ba a, L. Engs om, M. Pinzon-O iz, J. S. Fine, H. J. Lee, L. Zhang, G. A. Higgins and E. M. Pa ke , J. Biol. Chem., 2004, 279, 12876–12882. 8 J. S. Nai , T. Sheikh, A. L. Ho and G. K. Schwa z, An icance Res., 2013, 33, 1307–1316. 9 L. Kelle , S. Beaumon , J.-M. Liu, S. Tho e , J. S. Bignon, J. Wdzieczak-Bakala, P. Dauban and R. H. Dodd, J. Med. Chem., 2008, 51, 3414–3421. 10 W. Zaha e i z, R. Gussio, M. Leos , A. M. Sende owicz, T. Lahusen, C. Kunick, L. Meije and E. A. Saus ille, Cance Res., 1999, 59, 2566–2569. 11 (a) L. A. Saudan, G. Be na dinelli and E. P. K¨ undig, Synle , 2000, 483–486; (b) C. A. Chee ham, R. S. Massey, S. L. Pi a, R. G. P i cha d and T. W. Wallace, O g. Biomol. Chem., 2011, 9, 1831–1838; (c) S. Pos iko a, M. Sabbah, D. Wigh man, I. T. Nguyen, M. Sanselme, T. Besson, J.-F. B ie e, S. Oudeye and V. Le ache , J. O g. Chem., 2013, 78, 8191–8197; (d) P. C. Bulman Page, C. A. Pea ce, Y. Chan, P. Pa ke , B. R. Buckley, G. A. Rassias and M. R. Elsegood, J. O g. Chem., 2015, 80, 8036–8045. 12 (a) T. Sage and N. C ame , Angew. Chem., In . Ed., 2013, 52, 7865–7868; (b) C. G. New on, E. B aconi, J. Kuziola, M. D. Wod ich and N. C ame , Angew. Chem., In . Ed., 2018, 57, 11040–11044. 13 H. Hu, Y. Peng, T. Yu, S. Cheng, S. Luo and Q. Zhu, O g. Le ., 2021, 23, 3636–3640. 14 J. Liu, X. Yang, Z. Zuo, J. Nan, Y. Wang and X. Luan, O g. Le ., 2018, 20, 244–247. 15 Fo he syn hesis o ela ed dibenzo[c,e]azepine de i a i es (N a om no a ached o he bia yl moie y) see: (a) S. P. F ance, G. A. Aleku, M. Sha ma, J. Mangas-Sanchez, R. M. Howa d, J. S eik, R. Kuma , R. W. Adams, I. Slabu, R. C ook, G. G ogan, T. W. Wallace and N. J. Tu ne , Angew. Chem., In . Ed., 2017, 56, 15589–15593; (b) T. Yang, X. Guo, Q. Yin and X. Zhang, Chem. Sci., 2019, 10, 2473– 2477; (c) S. Zhang, F. Chen, Y.-M. He and Q.-H. Fan, O g. Le ., 2019, 21, 5538–5541; (d) T. Kano, H. Sugimo o and K. Ma uoka, J. Am. Chem. Soc., 2011, 133, 18130–18133. See also e . 4b. 16 E. Ascic and S. L. Buchwald, J. Am. Chem. Soc., 2015, 137, 4666–4669. 17 D. Li, J. Kim, J. W. Yang and J. Yun, Chem.–Asian J., 2018, 13, 2365–2368. 18 CCDC 2095490 [(S a ,6S,7R)-2Aj], 2095492 [(S a ,6S,7R)-2Ag] and 2095491 [(S a ,6S,7R)-4Aa].† 19 R. W. Sinkeldam, N. G eco and Y. To , Chem. Re ., 2002, 110, 2579–2619. 20 J. Messinge and V. Buss, J. O g. Chem., 1992, 57, 3320–3328. 21 S. Saebo and J. E. Boggs, J. Mol. S uc .: THEOCHEM, 1982, 87, 365–373. 22 Y. Yang, S.-L. Shi, D. Niu, P. Liu and S. L. Buchwald, Science, 2015, 349,62–66. 23 Y. Xi and J. F. Ha wig, J. Am. Chem. Soc., 2017, 139, 12758– 12772. © 2021 The Au ho (s). Published by he Royal Socie y o Chemis y Chem. Sci.,2021,12,15291–15297 | 15297 Edge A icle Chemical Science Open Access A icle. Published on 10 No embe 2021. Downloaded on 3/22/2022 1:30:42 PM. This a icle is licensed unde a C ea i e Commons A ibu ion-NonComme cial 3.0 Unpo ed Licence. View A icle Online