Multicomponent and multicatalytic asymmetric synthesis of furo[2,3-b]pyrrole derivatives: further insights into the mode of action of chiral phosphoric acid catalysts

Mul icomponen and mul ica aly ic asymme ic syn hesis o u o[2,3-b]py ole de i a i es: u he insigh s in o he mode o ac ion o chi al phospho ic acid ca alys s†‡ La a Cala, § a Ped o Villa , § b ´ Angel R. de Le a, b F ancisco J. Fa˜ nan´ as, a Rosana ´ Al a ez * b and F´ elix Rod ´ ıguez * a Mul icomponen and mul ica aly ic eac ions a e hose p ocesses ha y o imi a e he way he enzyma ic machine y ans o ms simple building blocks in o complex p oduc s. The de elopmen o asymme ic e sions o hese eac ions is a s ep o wa d in ou d eam o mi o ing he exquisi e selec i i y o biological p ocesses. In his con ex , he p esen wo k desc ibes a new eac ion o he asymme ic syn hesis o u o[2,3-b]py ole de i a i es om simple 3-bu ynamines, glyoxylic acid and anilines in he p esence o a dual ca aly ic sys em, o med om a gold complex and a chi al phospho ic acid. Compu a ions, aimed o unde s and he excep ional pe o mance o 9-an h acenyl-subs i u ed BINOL- de i ed phospho ic acid ca alys , sugges a undamen al ole o non-co alen in e ac ions being es ablished be ween he ca alys and he eagen s o he ou come o he mul icomponen p ocess. The linea geome y o he an h acenyl subs i uen along wi h he p esence o an elec on-wi hd awing g oup in he aniline and an a oma ic subs i uen in he 3-bu ynamine de i a i e seem o be key s uc u al ac o s o explain he expe imen al esul s and, pa icula ly, he high s e eoselec i i y. In oduc ion Ca alysis has become, wi hou ques ion, a majo subjec o mode n chemis y. In adi ional ca aly ic s a egies, a single ca alys in e ac s wi h a eagen lowe ing he ene ge ic ba ie o he subsequen eac ion wi h ano he eagen . Al hough his s a egy has deli e ed as numbe s o new eac ions o e many decades, new di ec ions in he eld o ca alysis a e necessa y in o de o add ess he demands o sus ainabili y and global well- being o ou socie y. In his con ex , mul ica aly ic eac ions (one-po ca alysis), dened as hose p ocesses whe e se e al eac ions occu in a single ask as a esul o he ac ion o mul iple ca alys , ha e become a powe ul syn he ic ool. 1 On he o he hand, mul icomponen eac ions, which a e hose p ocesses whe e se e al s a ing ma e ials eac oge he o yield a p oduc ha e ains he majo i y o a oms o he eac an s, ha e also become o signican in e es in he eld o o ganic syn hesis. 2 As a esul o me ging bo h ools, mul icomponen and mul ica aly ic eac ions ha e ecen ly eme ged as one o hose new concep s in he a ea o ca alysis. 3 In hese p ocesses, h ee o mo e s a ing ma e ials eac by means o wo o mo e ca alys s (all p esen om he onse o he eac ion) o p oduce s uc u ally and unc ionally complex p oduc s (Scheme 1a). These eac ions y o mimic he way he enzyma ic machine y (mul ica aly ic sys em) ans o ms in Na u e a se ies o simple molecules (mul icomponen sys em) in o in ica e s uc u es. The exquisi e s e eoselec i i y o biosyn he ic eac ions is pa icula ly difficul o imi a e and hus, he de elopmen o asymme ic mul icomponen and mul ica aly ic eac ions emains challenging. 4 In his con ex and based on p e ious wo ks o m ou labo- a o ies, 5 we en isioned ha he mul icomponen coupling o alkynamines 1, glyoxylic acid 2and anilines 3in he p esence o a mul ica aly ic gold/chi al B øns ed acid sys em could deli e enan ioen iched u o[2,3-b]py ole de i a i es 4comp ising h ee con iguous s e eocen e s (one o hem qua e na y; Scheme 1b). We hough ha he gold-ca alysed cyclo- isome iza ion eac ion o alkynamines 1should deli e he enamine in e media es I. 6 Mo eo e , he condensa ion eac ion be ween glyoxylic acid and amines 3should gi e imines II. Fu he asymme ic eac ion be ween hese in si u o med a Ins i u o Uni e si a io de Qu´ ımica O ganome ´ alica “En ique Moles”, Cen o de Inno aci´ on en Qu´ ımica A anzada (ORFEO-CINQA), Uni e sidad de O iedo, Juli´ an Cla e ´ ıa, 8, 33006-O iedo, Spain. E-mail: od iguez@unio i.es b Depa amen o de Qu´ ımica O g´ anica (CINBIO), Uni e sidade de Vigo, As Lagoas- Ma cosende, E-36310 Vigo, Spain. E-mail: [email p o ec ed] †In memo y o ou iend P o esso Kilian Mu˜ niz (1970–2020). ‡Elec onic supplemen a y in o ma ion (ESI) a ailable: Expe imen al p ocedu es, ull compound cha ac e iza ion and compu a ional de ails. CCDC 1550279. Fo ESI and c ys allog aphic da a in CIF o o he elec onic o ma see DOI: 10.1039/d0sc03342a §These au ho s con ibu ed equally o his wo k. Ci e his: Chem. Sci., 2020, 11,9181 All publica ion cha ges o his a icle ha e been paid o by he Royal Socie y o Chemis y Recei ed 16 h June 2020 Accep ed 11 h Augus 2020 DOI: 10.1039/d0sc03342a sc.li/chemical-science This jou nal is © The Royal Socie y o Chemis y 2020 Chem. Sci.,2020,11,9181–9190 | 9181 Chemical Science EDGE ARTICLE Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online View Jou nal | View Issue in e media es would lead o ou desi ed u o[2,3-b]py ole de i a i es 4, which a e a ge s o in e es owing o he p e a- lence o his s uc u al mo i in nume ous biologically pha - macopho es and na u al p oduc s. 7 In addi ion o epo ing he de elopmen o his p ocess, we a e also p esen ing compu a ional s udies aimed o s uc u ally jus i y he o igin o he e y high dias e eo and enan iose- lec i i ies obse ed wi h jus a single ca alys o he se ies o phospho ic acids su eyed, hus p o iding new is as o a io- nalize he beha iou o chi al phospho ic acids in asymme ic p ocesses. 8 Resul s and discussion A he ou se o his s udy, we selec ed e -bu yl[4-(4- chlo ophenyl)-3-bu yn-1-yl]ca bama e 1a, glyoxylic acid 2and 3-ni oaniline 3a as model eagen s in o de o nd op imal eac ion condi ions. As mul ica aly ic sys em, we chose a combina ion o AuMe(JohnPhos) and a B øns ed acid (HB; pa icula ly, phospho ic acid de i a i es). Ini ial expe imen s we e pe o med a oom empe a u e, in oluene as sol en and in he p esence o 4  A molecula sie es (Table 1). To check he iabili y o ou p oposal, we  s ly ied he eac ion in i s acemic e sion by using diphenyl hyd ogen phospha e [DPP, (PhO) 2 PO 2 H] as he acid ca alys . Al hough he eac ion led o he desi ed p oduc in high yield (91%), un o - una ely, an almos equimola mix u e o he wo dias e eoiso- me s 4a and dias -4a was ob ained (d. . ¼1 : 1.5; Table 1, en y 1). Conside ing ha ou objec i e was he de elopmen o a uly selec i e eac ion (dias e eo and enan ioselec i e), his p elimina y esul was highly discou aging since we suspec ed ha he use o chi al phospho ic acid-de i ed ca alys s (CPAs) o pe o m he asymme ic e sion o he eac ion, could in u n lead o he same dias e eoselec i i y p oblems. In ac , when we ied he eac ion wi h BINOL-de i ed phospho ic acids subs i u ed a C3- and C30-posi ions wi h 3,5-bis( i- uo ome hyl)phenyl (CPA A ), 2,4,6- iisop opylphenyl (CPA B )o iphenylsilyl (CPA C ) g oups, we also obse ed he o ma ion o oughly equimola amoun s o he wo dias e eoisome s 4a and dias -4a (Table 1, en ies 2–4). Fu he mo e, he low le els o enan ioselec i i y ound in bo h 4a and dias -4a we e addi ional discou aging issues a his poin . Al hough he same p oblems o dias e eoselec i i y we e obse ed when using he phenan h yl-subs i u ed BINOL- de i a i e CPA D and he VAPOL-de i ed phospho ic acid CPA E (d. . ¼1.9 : 1 and 1 : 1.4 espec i ely; Table 1, en ies 5 and 6), a leas in hese cases one o he dias e eoisome s was ob ained wi h high enan ioselec i i y [e. .(4a)¼99 : 1 wi h CPA D ; e. .(dias -4a)¼96 : 4 wi h CPA D ]. Ne e heless, none o he abo e men ioned phospho ic acid ca alys s led o sa is ac o y esul s in e ms o selec i i y. Su p isingly, when he eac ion was pe o med wi h he 9-an h acenyl-subs i u ed BINOL- de i ed phospho ic acid CPA F , we only obse ed he o ma- ion o compound 4a in almos quan i a i e yield (98%) and, mo e impo an ly, wi h comple e s e eoselec i i y (d. . > 20 : 1; e. . ¼99 : 1). The ex ao dina y pe o mance o ca alys CPA F should be ema ked. Thus, while all o he acid ca alys s (achi al o chi al) Scheme 1 Mul icomponen and mul ica aly ic eac ions. Concep and ou p oposal. Table 1 Sc eening o B øns ed acid ca alys s En y HB Yield a (%) d. . (4a :dias -4a) b e. . (4a) c e. . (dias -4a) c 1DPP 91 1 : 1.5 —— 2CPA A 88 1.3 : 1 86 : 14 36 : 64 3CPA B 91 1.3 : 1 49 : 51 32 : 68 4CPA C 95 1 : 1 74 : 26 50 : 50 5CPA D 92 1.9 : 1 99 : 1 47 : 53 6CPA E 87 1 : 1.4 19 : 81 4 : 96 7CPA F 98 >20 : 1 99 : 1 — a Based on 1a. b De e mined by 1 H NMR analysis o he c ude eac ion mix u e. c De e mined by HPLC using a chi al s a iona y phase. 9182 |Chem. Sci.,2020,11,9181–9190 This jou nal is © The Royal Socie y o Chemis y 2020 Chemical Science Edge A icle Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online p oduced basically equimolecula mix u es o wo dias e eo- isome s, CPA F p o ed unique in pe o ming his ans o ma ion in a highly dias e eoselec i e way. The e y high enan iose- lec i i y achie ed wi h his ca alys (only one enan iome was obse ed) should also be no ed. Thus, om he eigh possible s e eoisome s, we only obse ed he o ma ion o one o hem. Once we had e ied ha he 9-an h acenyl-subs i u ed BINOL-de i ed phospho ic acid CPA F was an op imal acid ca alys o pe o m he desi ed asymme ic mul icomponen and mul ica aly ic p ocess, we add essed he scope o he ans o ma ion. Thus, a ange o expe imen s we e pe o med by mixing diffe en 4-a ylbu -3-yn-1-amines 1, glyoxylic acid 2 and aniline de i a i es 3in oluene (0.1 M) wi h 4  A molecula sie es a oom empe a u e in he p esence o a mix u e o AuMe(JohnPhos) (5 mol%) and chi al phospho ic acid CPA F (10 mol%; Scheme 2). We we e deligh ed o nd ha , unde hese condi ions, a se ies o u o[2,3-b]py ole de i a i es 4wi h di e se subs i u ion pa e ns we e ob ained in excellen yields, as single dias e eoisome s and wi h e y high enan ioselec i - i ies in mos cases. Alkynamines 1subs i u ed a he iple bond wi h diffe en a oma ic ings likewise pe o med efficien ly and led o he co esponding p oduc s 4wi h e y high selec i i y. 9 Rega ding he subs i u ion on he ni ogen a om, e -bu ox- yca bonyl (4a–h) and me hoxyca bonyl g oups (4i–k) we e used. Anilines 3bea ing elec on-wi hd awing subs i uen s we e app op ia e subs a es. Howe e , he eac ion did no p oceed when simple aniline o aniline de i a i es con aining elec on- dona ing g oups we e used. The eac ion wi h alkylamine de i a i es ins ead o anilines was unsuccess ul. The s uc u e and absolu e congu a ion o 4a was unambiguously de e - mined by X- ay c ys allog aphic analysis. 10 The absolu e congu a ion o he emaining u o[2,3-b]py ole de i a i es 4 was assigned by analogy. A mechanis ic p oposal o explain his mul icomponen and mul ica aly ic eac ion is shown in Scheme 3. We conside ed he ini ial cycloisome iza ion o amine de i a i e 1 o gi e he enamine 7in a p ocess p omo ed by he ca ionic gold(I) complex gene a ed om AuMe(JohnPhos) by eac ion wi h he B øns ed acid (DPP o CPA). Thus, he ini ial coo dina ion o he gold ca alys o he iple bond o 1leads o in e media e 5. In amolecula addi ion o he amino g oup o he dis al ca bon o he ac i a ed alkyne gene a es in e media e 6. Finally, a p o- odeme alla ion p ocess, likely assis ed by he anion (B  ), affo ds he enamine de i a i e 7 egene a ing he gold ca alys and closing he  s ca aly ic cycle. Simul aneously, he B øns ed acid ca alys (HB) p omo es he condensa ion o glyoxylic acid 2and aniline de i a i e 3 o o m imine 8. Bo h in e media es gene a ed in he wo p e ious indepen- den p ocesses, namely he N-p o ec ed 2,3-dihyd o-1H-py ole 7and he 2-(a ylimino)ace ic acid 8, en e a hi d ca aly ic cycle whe e he h ee s e eogenic cen es o he nal p oduc 4a e s e eoselec i ely gene a ed. Being bo h componen s achi al, he Scheme 2 Scope o he eac ion. Scheme 3 Mechanis ic p oposal. This jou nal is © The Royal Socie y o Chemis y 2020 Chem. Sci.,2020,11,9181–9190 | 9183 Edge A icle Chemical Science Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online chi al B øns ed acid ca alys (HB) should be in ol ed in his p ocess. Thus, eac ion o he imine 8wi h he acid affo ds ac i a ed imine de i a i e 9. The subsequen eac ion o his in e media e wi h enamine 7could occu h ough a conce ed mechanism o di ec ly deli e in e media e 11, which e ol es p o iding he nal p oduc 4and egene a ing he acid ca alys . Al e na i ely, in e media e 11 could be o med h ough a s ep- wise p ocess ini ia ed by a Mannich- ype addi ion o p oduce iminium ion in e media e 10 ollowed by a cycliza ion eac ion. Rega dless o he mechanism, conce ed o s epwise, he ex ao dina y efficiency o he chi al acid ca alys CPA F should be ema ked because i a ou s he eac ion h ough a single ace o he ac i a ed imine 9and a single ace o he enamine 7 o o m all h ee s e eogenic cen es o he nal p oduc 4wi h exquisi e selec i i y. The high specici y exhibi ed by ca alys CPA F is p obably he mos ema kable ea u e o he eac ion he e desc ibed. Wi h his ca alys , we obse ed e y high dias e eo and enan- ioselec i i ies. On he con a y, basically equimolecula mix u es o dias e eo and/o enan iome s we e obse ed wi h he o he ca alys s used (Table 1). Al hough a ia ions in s e - eoselec i i y alues a e usually obse ed upon changing he subs i uen s a he 3- and 30-posi ions o BINOL-de i ed phos- pho ic acids (CPA), he con as ing diffe ences we obse ed a e unusual. Appa en ly, he specici y exhibi ed by he 9-an h acenyl-subs i u ed BINOL-de i ed phospho ic acid CPA F canno be jus a ibu ed o s e ic effec s because o he ca alys s con aining la ge g oups a 3- and 30-posi ions, i.e. he iphenylsilyl-subs i u ed CPA C , did no pe o m sa is ac o ily. I is also su p ising ha phenan h yl-subs i u ed chi al phos- pho ic acid CPA D , appa en ly e y simila o CPA F , beha es so diffe en ly. In igued, we wonde ed why he 9-an h acenyl- subs i u ed BINOL-de i ed phospho ic acid CPA F was so specic, and we conside ed pe o ming a compu a ional s udy o nd he pa icula ea u es o his ca alys in ou eac ion. In a mo e gene al sense, we also pu sued wi h his in es iga ion o be e unde s and he beha iou o BINOL-de i ed phospho ic acids in asymme ic p ocesses. In his con ex , he eac ion o me hyl 5-phenyl-2,3-dihyd o- 1H-py ole-1-ca boxyla e 7a and imine 8a de i ed om he condensa ion o glyoxylic acid and 3,5-bis( iuo ome hyl)phe- nylaniline was selec ed as model o pe o m DFT calcula ions (Scheme 4). 11 This model eac ion, wi h bo h eagen s in hei mo e s able s- ans con o ma ion, mimics he hi d ca aly ic cycle o he mechanism shown in Scheme 3 whe e all s e eo- cen e s o he nal p oduc 4a e gene a ed. Ini ially, he eac ion wi h he achi al acid ca alys dime hyl hyd ogen phospha e (DMP; Scheme 5) was s udied. Fo ma ion o a bina y complex (aDC), in which he acid in e ac s wi h he imine 8a in he s- ans con o ma ion h ough wo hyd ogen bonds in a bi unc ional ac i a ion ashion, was conside ed o be he mos likely. Two al e na i e mechanisms, namely conce ed and s epwise, o he eac ion o he bina y complex aDC wi h enamine de i a i e 7a o gi e he nal acemic p oduc s ac-4l o ac-dias -4l we e e alua ed. Fo he conce ed [3 + 2]- cycloaddi ion mechanism, and p io o bond o ma ion, we conside ed he o ma ion o wo possible h ee-componen complexes (aTC endo and aTC exo ), which would be c ea ed when aDC and 7a app oach each o he . These wo h ee- componen complexes diffe by he o ien a ion o he phenyl g oup o he enamine 7a when acing aDC [inwa ds (endo)o ou wa ds (exo) he ca aly ic egion]. Fo ma ion o ac-4l o ac- dias -4l om aTC exo o aTC endo p oceeds h ough ansi ion s a es aTS exo o aTS endo , espec i ely. Despi e ou effo s, only he conce ed exo-app oach could be cha ac e ized, and an- si ion s a e aTS exo was ound o be highly asynch onous wi h a compu ed ac i a ion ene gy o 15.9 kcal mol 1 ( o de ails see he ESI‡). De ailed s uc u al analysis o aTS exo allowed o iden i y a s abilizing C A H–pin e ac ion (3.12  A), he so-called T-shaped edge- o- ace in e ac ion (Scheme 5; blue s and in aTS exo ). 12 Taking in o accoun ha his a ene–a ene in e ac ion is elec os a ic, he p esence o he iuo ome hyl subs i uen s con ibu es o dec ease he elec on densi y o he C A –H bonds a ou ing he men ioned in e ac ion. We also no iced ha he o ien a ion o he 3,5-bis( iuo ome hyl)phenyl g oup appea s o be con olled by hyd ogen bonding in e ac ions be ween one o he hyd ogen a oms a he o ho-posi ion and one o he oxygen a oms o he phospho ic acid (2.23  A, Scheme 5, g een s and in aTS exo ). In con as , he endo-app oach does no allow simila a ene– a ene s abilizing in e ac ions and ha migh explain why we we e unable o nd he al e na i e conce ed endo-app oach pa hway. The s epwise mechanism o he [3 + 2]-cycloaddi ion could ake place h ough wo al e na i e o ien a ions o he enamine 7a ela i e o he bina y complex aDC (syn-o an i-app oaches; Scheme 5). The eac ion was conside ed o s a wi h he s e - eode e mining nucleophilic addi ion o enamine 7a h ough i s C3-posi ion (C c ) o he elec ophilic ca bon (C b ) o he iminium ion o he aDC complex. Diffe en o ien a ions o he enamine 7a and complex aDC, as well as he s-cis and s- ans con o ma- ions o he imine 8a we e aken in o conside a ion. Se e al ansi ion s a es, which showed diffe en con o ma ions a ound he dihed al angle C a C b C c C d and he s-cis and s- ans con o me s o he ca bama e, we e op imized and u ned ou o be almos isoene ge ic (DDG¼2.0–0.1 kcal mol 1 ). The lowes ene gy ansi ion s a e o each app oach (aTS-Isyn and aTS-Ian i) we e selec ed and ound o ha e e y simila ac i a- ion ene gies (15.9 and 15.8 kcal mol 1 espec i ely). Once he  s in e media es aIn -Isyn and aIn -Ian i a e o med (no e ha hese in e media es a e simila o 10 in Scheme 3), Scheme 4 Model eac ion selec ed o he compu a ional s udies. 9184 |Chem. Sci.,2020,11,9181–9190 This jou nal is © The Royal Socie y o Chemis y 2020 Chemical Science Edge A icle Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online a con o ma ional change by bond o a ion o dihed al angles C a C b C c C d and C a C b NC e should occu o allow he nucleophilic a ack o he ca boxyla e on o he iminium ion (Scheme 5). Ini ially, we assumed ha he ene gy equi ed o he con o - ma ional change om aIn -I o aIn -II could no compe e wi h he ene gy equi ed o he C–C bond o ma ion. Fo he syn app oach, we we e able o cha ac e ize he in e media e aIn -IIsyn and he ansi ion s a e aTS-IIsyn co - esponding o he o ma ion o he C–O bond. Howe e , he ene gy o his ansi ion s a e (6.7 kcal mol 1 ) is lowe han ha o in e media e aIn -IIsyn (7.5 kcal mol 1 ), sugges ing ha , unde s anda d condi ions, he second bond o ma ion is a ba ie less p ocess. In e es ingly, o he al e na i e an i- app oach, he co esponding in e media e aIn -IIan i and he subsequen C–O bond o ma ion ansi ion s a e aTS-IIan i could no be cha ac e ized and we obse ed he di ec o ma- ion o he nal p oduc om aIn -Ian i in a ba ie less p ocess. Mos likely, he p oximi y o he elec ophilic iminium ca bon (C d ) and he ca boxyla e a ou s he collapse and as o ma ion o he C–O bond. Conside ing he global s udy, he a e-de e mining s eps o he p ocesses going h ough aTSexo (15.9 kcal mol 1 ), aTS-Ian i (15.8 kcal mol 1 ) and aTS-Isyn (15.9 kcal mol 1 ) we e iso- ene ge ic and he e o e, a low an i/syn dias e eoisome ic a io was p edic ed (d. . ¼2.1 : 1) o he o ma ion o he u o[2,3-b] py ole de i a i es ac-4l o ac-dias -4l. This is in comple e ag eemen wi h ou expe imen al esul s (see Table 1, en y 1). This ini ial s udy pe o med wi h he achi al ca alys s dime hyl hyd ogen phospha e (DMP) se ed no only o e i y he ag eemen be ween he compu a ional esul s and he expe imen al da a bu also o show ha ou eac ion could p oceed h ough al e na i e conce ed and/o s epwise mecha- nisms. Wi h his in o ma ion in hand, we aced he mo e challenging s udy on he o igin o he dias e eo and enan io- selec i i y o he o mal [3 + 2]-cycloaddi ion when pe o med wi h he chi al 9-an h acenyl-subs i u ed BINOL-de i ed phos- pho ic acid ca alys CPA F . Mo e p ecisely, we e alua ed he eac ion be ween he enamine de i a i e 7a and a chi al bina y complex (cDC), i sel o med by he in e ac ion o he imine 8a wi h CPA F . The wo possible dias e eome ic chi al bina y complexes Re-cDC and Si-cDC, gene a ed by he in e ac ion o chi al acid CPA F and imine 8a (Fig. 1) we e hen analysed. These wo complexes diffe by he acial o ien a ion o he imine owa ds he phospho ic acid. Whe eas in Re-cDC, he Re- ace o Scheme 5 DMP-p omo ed eac ion o 8a and 7a by conce ed and s epwise mechanisms compu ed a he [wB97XD/DEF2TZVPP(SMD, o- luene)//wB97XD/DEF2SVPP(SMD, oluene)] le el o heo y. T ansi ion s a e aTS exo wi h dis ances indica ed in  A, compu ed a he le el shown abo e, is highligh ed. This jou nal is © The Royal Socie y o Chemis y 2020 Chem. Sci.,2020,11,9181–9190 | 9185 Edge A icle Chemical Science Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online he imine is a ailable o he subsequen eac ion wi h enamine 7a,inSi-cDC is he Si- ace. In bo h cases, he imine is s abilized by hyd ogen bonding in e ac ions h ough a bi unc ional ac i- a ion mode and by pa allel-displacemen (PD)–p-s acking in e ac ions. Bina y complex Si-cDC was ound o be 2.7 kcal mol 1 mo e s able han Re-cDC. The g ea e ela i e s abiliza ion o Si-cDC is likely due o he mo e effec i e o e lap o he an h acenyl p-o bi als o he ca alys and he a yl ag- men o he imine (PD- ype; blue and g een s ands in Fig. 1). As shown, he dis ance be ween he 3,5-bis( iuo ome hyl)phenyl and he used benzene ings o he an h acenyl g oup is sho e o Si-cDC ela i e o Re-cDC (3.68 and 3.81 s. 3.95  A, espec- i ely). Addi ionally, he bis( iuo ome hyl)phenyl g oup o he imine appea s o be con o ma ionally es ained due o he hyd ogen bonding in e ac ions es ablished be ween one o he hyd ogen a oms a he o ho-posi ion and one o he oxygen a oms o he phospho ic acid (wi h dis ances o 2.39  A o Si- cDC and 2.44  A o Re-cDC). The coplana o ien a ion o he imine and he an h acenyl g oup, a ou ed by he PD–pin e ac ions es ablished be ween he la e and he 3,5-bis( iuo ome hyl)phenyl g oup, con ibu es o shield one o he enan io opic aces o he imine, hus lea ing he opposi e one ully accessible o he eac ion wi h enamine de i a i e 7a. 13 These non-co alen in e ac ions we e e alua ed using he NCI-index based on elec on densi y desc ibed by Yang and co-wo ke s, 14 and we ound ha hey we e pa icula ly ele an o he bina y complex Si-cDC ( o de ails, see he ESI‡). The pa icula geome y o he an h acenyl g oup wi h h ee ings a anged in a linea sequence appea s o be c i ical o he s abiliza ion o he bina y complexes, and pa icula ly o Si- cDC, by he abo e-men ioned s abilizing p-in e ac ions. The ex ao dina y esul s we ob ained wi h an h acenyl-subs i u ed BINOL-de i ed phospho ic acid CPA F could be associa ed o his unique s uc u al ea u e o he an h acenyl g oup. 15 Fo he sake o compa ison, we pe o med a simila analysis o he bina y complexes de i ed om o he chi al phospho ic acids wi h diffe en a yl subs i uen s, in pa icula he 2,4,6- iisop opylphenyl-subs i u ed and he 9-phenan h yl- subs i u ed BINOL-de i ed phospho ic acids (CPA B and CPA D , espec i ely). Fo hese skele ons, he non-co alen in e ac ions appea o be less impo an and he compu ed ene gy alues p edic ed a poo o modes s e eoselec i i y o he o ma ion o he nal p oduc , in ag eemen wi h ou expe imen al esul s ( o de ails, see he ESI‡). We had expe imen ally ound ha elec on-wi hd awing g oups a he a yl ing o he imine (i.e. a he s a ing aniline 3) we e equi ed in o de o ob ain good esul s. This obse a- ion was compu a ionally add essed by e alua ion o he p e iously men ioned p-s acking in e ac ions o he bina y complexes as a unc ion o he subs i uen s a he imine a yl ing. In his ega d, i has been p e iously sugges ed ha he p- s acking in e ac ion is enhanced when one o he a oma ic ings con ains elec on-wi hd awing subs i uen s because he associa ed dec ease o he elec on densi y o he a oma ic ing diminishes he elec os a ic epulsion be ween he a yl g oups. 16 Ou compu a ions con med ha he absence o he iuo ome hyl subs i uen s led o a weakened p-in e ac ion be ween he an h acenyl and he a yl g oup o he imine ( o de ails, see ESI‡). Specically, we e alua ed he elec on densi y dis ibu ion o Si-cDC (wi h a 3,5-bis( iuo ome hyl)phenyl g oup) in compa ison wi h ha o Si-cDC_Ph (wi h a phenyl g oup). This s udy allowed us o con m he supe io elec onic complemen a i y when he 3,5-bis( iuo ome hyl)phenyl g oup was in ol ed. This can be easily obse ed in he molec- ula elec os a ic po en ial (MESP) ep esen a ion shown in Fig. 2. 17 Once he bina y complexes o med by coo dina ion o he imine 8a o he 9-an h acenyl-subs i u ed BINOL-de i ed phospho ic acid CPA F we e analysed, we add essed hei subsequen [3 + 2]-cycloaddi ion eac ions wi h enamine de i a i e 7a (Fig. 3). Since 7a can eac wi h bina y complexes Fig. 1 Rep esen a ion o bina y complexes Si-cDC and Re-cDC compu ed a he wB97XD/DEF2TZVPP(SMD, oluene)//wB97XD/ DEF2SVPP (SMD, oluene) le el o heo y o (R)-3,30-bis(9-an h a- cenyl)-1,10-binaph hyl-2,20-diyl hyd ogenphospha e as CPA F . Fig. 2 Rep esen a ion o compu ed molecula elec os a ic po en ial (MESP) o bina y complex Si-cDC and Si-cDC_Ph. Colou codes: 0.04 a.u. (blue colou ) o 0.04 a.u. ( ed colou ) (compu a ions a he wB97XD/DEF2SVPP(SMD, oluene) le el). 9186 |Chem. Sci.,2020,11,9181–9190 This jou nal is © The Royal Socie y o Chemis y 2020 Chemical Science Edge A icle Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online Re-cDC and Si-cDC h ough i s Re-o Si- ace, ou possible e na y complexes (Re,Re-cTC,Si,Si-cTC,Si,Re-cTC and Re,Si- cTC) we e cha ac e ized. Conside ing ou p e ious s udies wi h he achi al dime hyl hyd ogen phospha e (DMP; see Scheme 5), we expec ed o be able o analyse he e olu ion o hese in e - media es h ough he wo possible mechanis ic op ions, namely he conce ed and he s epwise. Howe e , despi e ha ing cha - ac e ized se e al ansi ion s a es o he  s bond o ma ion o he s epwise mechanism, bo h he size and he s uc u al igidi y o he chi al pocke o phospho ic acid CPA F hinde ed he con o ma ional changes equi ed o he o ma ion o he C–O bond in he second s ep o he p ocess. Thus, he s epwise pa hway was disca ded o his complex sys em, and we ocused on he conce ed mechanism. Fo his mechanism, wo ansi ion s a es o each o he ou acial app oaches (ReRe,ReSi,SiRe and SiSi), which diffe by he con o ma ion o he ca bama e (s-cis o s- ans), we e cha ac- e ized. Al hough we we e able o loca e all he ansi ion s a es, only he esul s wi h he mo e s able con o me will be shown (i.e. Re,Re-cTS,Si,Si-cTS,Si,Re-cTS and Re,Si-cTS; Fig. 3). In e es ingly, he app oaches o 7a o he mos s able bina y complex Si-cDC leading o 4l o dias -4l we e a ou ed o e he al e na i e pa hways in ol ing Re-cDC (Fig. 3). Thus, he (ReSi)- cTS and (SiSi)-cTS (13.4 and 16.2 kcal mol 1 , espec i ely) we e ound o be highly a ou ed when compa ed o he dias e eo- isome ic (SiRe)-cTS and (ReRe)-cTS ansi ion s a es (19.1 and 22.5 kcal mol 1 , espec i ely). The s onges p-in e ac ions be ween one o he an h acenyl g oups and he a yl g oup o imine 8in (ReSi)-cTS and (SiSi)-cTS when compa ed o he same in e ac ion in (SiRe)-cTS and (ReRe)-cTS seems o jus i y he p e e en ial pa hways leading o 4l and dias -4l. In o he wo ds, i seems ha he highly s abilizing p-in e ac ions we had obse ed in he bina y complex Si-cDC, s uc u ally associa ed o he pa icula geome y o he an h acenyl g oup, a e main- ained along he cou se o he eac ion, con ibu ing o u he s abilize he co esponding ansi ion s a es (ReSi)-cTS and (SiSi)-cTS. As in he achi al model sys em, he global p ocesses shown in Fig. 3A a e highly exe gonic, being he eac ion ene gy alues o 17.5, 19.6, 17.5 and 22.2 kcal mol 1 o en -dias -4l, dias -4l,en -4l and 4l, espec i ely. F om he ansi ion s a e ene gies compu ed o his mul icomponen eac ion, he Cu - in–Hamme p inciple p edic s ha he expec ed dias e eo- me ic a io 4l/dias -4l would be ca. 99 : 1, and he enan iome ic Fig. 3 (A) Reac ion ee ene gy p ofiles (in kcal mol 1 ) and ep esen a ion o ansi ions s a es o he conce ed pa hway o he [3 + 2]- cycloaddi ion (A ¼3,5-(CF 3 ) 2 –C 6 H 3 ) ca alysed by CPA F compu ed a he wB97XD/DEF2TZVPP(SMD, oluene)//wB97XD/DEF2SVPP(SMD, o- luene) le el. The ReSi (g een), SiRe ( ed), ReRe (blue) and SiSi (pu ple) pa hs a e shown. CPA F has been emo ed o cla i y. (B) Rep esen a ion o compu ed ansi ion s a es o he ou app oaches (i ele an hyd ogen a oms ha e been emo ed o cla i y). This jou nal is © The Royal Socie y o Chemis y 2020 Chem. Sci.,2020,11,9181–9190 | 9187 Edge A icle Chemical Science Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online a io 4l/en -4l would be >99 : 1, which is in excellen ag eemen wi h he expe imen al esul s. In ou eac ion, he dias e eoselec i i y ( o ma ion o 4l o en -4l e sus dias -4l o en -dias -4l) is de e mined by he o ien a ion o he enamine 7a upon eac ion wi h he bina y complexes Si-cDC o Re-cDC (endo o exo app oaches). As shown, ansi ion s a es (SiSi)-cTS and (ReRe)-cTS, in which he phenyl g oup o enamine 7a is o ien ed owa ds he ca aly ic pocke (a o mal endo-cycloaddi ion), a e des abilized ela i e o he (ReSi)-cTS and (SiRe)-cTS (a o mal exo-cycloaddi ion) due o se e e s e ic in e ac ions be ween he phenyl subs i uen o he enamine 7a and one o he an h acenyl g oups o he ca alys . Thus, i seems ha he s e ic ac o s play an impo an ole in de e mining he dias e eoselec i i y o he eac ion. A his poin , he ac i a ion s ain model was used o p o ide u he semi-quan i a i e insigh in o he s e eoinduc ion and he compu ed ene gies a e shown in Table 2. 18 These esul s p o ide addi ional suppo o he assump ion ha dias e - eoselec i i y is de e mined by he dis o ion in he ansi ion s a e, a o ing hose ha show lowe alues. This is eec ed in DDE s ain o (ReRe)-cTS and (SiSi)-cTS, namely 2.92 and 1.76 kcal mol 1 , espec i ely, which is ela ed o he abo e- men ioned s e ic in e ac ions be ween he phenyl g oup o 7a and he an h acenyl agmen . The enan ioselec i i y o he p ocess ( o ma ion o 4l e sus en -4l,o o dias -4l e sus en -dias -4l), appea s o mainly be de e mined by elec onic ac o s. Thus, (ReSi)-cTS (13.4 kcal mol 1 ) leading o 4l is a ou ed o e (SiRe)-cTS (19.1 kcal mol 1 )affo ding en -4l) due o he s onge p-in e - ac ions no iced in he o me and being es ablished be ween one o he an h acenyl g oups and he 3,5-bis( iuo ome hyl) phenyl g oup o he imine 8(see Fig. 3). The same end can be no iced when compa ing (SiSi)-cTS (16.2 kcal mol 1 ) leading o dias -4l wi h (ReRe)-cTS (22.5 kcal mol 1 ) gene a ing en -dias -4l (see Fig. 3). As p e iously no ed, hose s ong p-in e ac ions can ul ima ely be associa ed o he pa icula linea geome y o he an h acenyl g oup. Finally, some o he pa icula ea u es o ansi ion s a e (ReSi)-cTS ha leads o 4l should be ema ked. In addi ion o he p e iously commen ed s ong p-in e ac ion be ween one o he an h acenyl g oups and he 3,5-bis( iuo ome hyl)phenyl g oup o he imine 8, ano he s ong T-shaped edge- o- ace C A H–pin e ac ion be ween he 3,5-bis( iuo ome hyl)phenyl g oup o imine 8and he phenyl g oup o he enamine 7a was obse ed (see Fig. 3B). This is in ag eemen wi h ou expe i- men al obse a ion ha showed ha an a yl subs i uen a he e minal posi ion o he alkyne o amine 1(e en ually, an a yl subs i uen in enamine 7) was equi ed in o de o ge good esul s. 9 To u he analyse all hese non-co alen in e ac ions, we s udied he opological dis ibu ion o elec on densi y in he op imized geome ies o he ou ansi ion s a es using QTAIM (see he ESI‡). 19 Fo he ansi ion s a e o lowe ac i a ion ene gy, namely (Re,Si)-cTS, wo addi ional in e ac ions be ween 7a and Si-cDC (c and g, Fig. 4) could be iden ied along wi h hose al eady no ed be o e (a, b and d– , Fig. 4). In pa icula , he iuo ome hyl subs i uen a o s he H o ho –pin e ac ions. The BCP o p–pand H–X (X is N o O) in e ac ions we e ound o be in he ange o 0.014–0.005 au and 0.093–0.046 au espec i ely. Fo he lowes ene gy ansi ion s a e, he p–p in e ac ion be ween he imine and he an h acenyl agmen becomes 0.006 au. This is consis en wi h he lowe DDE in p edic ed o his ansi ion s a e using he ac i a ion s ain model (Table 2). In con as , he lowe numbe o non-co alen in e ac ions p edic ed by QTAIM o he less a o ed ansi ion s a e (Re,Re)-cTS (see he ESI‡), ansla es in o highe DDE in (2.34 kcal mol 1 ; Table 2). O e all, he compu a ional s udy indica es ha he p e e - en ial o ma ion o compounds 4o e he al e na i e isome s (en -4,dias -4 and en -dias -4) appea s o be a summa ion o key ac o s ela ed o he specic s uc u e o he an h acenyl- subs i u ed BINOL-de i ed phospho ic acid ca alys CPA F and he eagen s. Thus, he pa icula geome y o he an h acenyl g oup o he ca alys along wi h he p esence o elec on- wi hd awing g oups in he s a ing aniline allows he op imi- za ion o pa allel-displacemen p-in e ac ions. This s abiliza- ion is less impo an wi h al e na i e enan iopu e phospho ic acids ha ing a sho e bicyclic a oma ic ing (i.e., naph hyl) o o ho- used (i.e. phenan h yl) o analogues wi h o he subs i - uen s (i.e., 2,4,6- iisop opylphenyl o iphenylsilane). The igidi y and s e ic hind ance o he an h acenyl g oups o he ca alys likely con ibu es o he dias e eoselec i i y o he p ocess, since i de e mines he size o he ca aly ic pocke . In his ega d, he s e ic in e ac ions be ween he a yl g oup o Table 2 Ac i a ion s ain model o he ansi ion s a es o he conce ed pa hway o he [3 + 2]-cycloaddi ion ca alyzed by CPA F compu ed a he uB97XD/de 2TZVPP le el (kcal mol 1 ) DDE ‡a DDE s ainb DDE in c (Re,Re)-cTS 9.51 2.92 2.34 (Si,Re)-cTS 6.33 0.64 1.45 (Si,Si)-cTS 2.62 1.76 0.87 (Re,Si)-cTS 0.00 0.00 0.00 a DDE ‡ is he ac i a ion ene gy ela i e o he lowe ene gy ansi ion s a e (Re,Si)-cTS. b DDE s ain is he ela i e o al dis o ion ene gy o he ansi ion s a es. c DDE in is he ela i e in e ac ion ene gy o he ansi ion s a es calcula ed wi h he co ec ed ene gies. Fig. 4 Bond c i ical poin s o he mos impo an non-co alen in e ac ions cha ac e ized (QTAIM) on he (Re,Si)-cTS. 9188 |Chem. Sci.,2020,11,9181–9190 This jou nal is © The Royal Socie y o Chemis y 2020 Chemical Science Edge A icle Open Access A icle. Published on 12 Augus 2020. Downloaded on 2/16/2021 5:54:54 PM. This a icle is licensed unde a C ea i e Commons A ibu ion 3.0 Unpo ed Licence. View A icle Online enamine 7when app oaching he bina y complex o med be ween he ca alys and he imine 8seems o be de e minan o he dias e eoselec i i y o he eac ion. Finally, he excellen enan ioselec i i y o ou p ocess appea s o be associa ed o he s ong p-in e ac ions es ablished be ween he a yl g oup o imine 8wi h one o he an h acenyl subs i uen s o he CPA F ca alys and also wi h he a yl subs i uen o enamine 7. Conclusions We ha e de eloped a dis e eo and enan ioselec i e syn hesis o u o[2,3-b]py ole de i a i es by means o a mul icomponen and mul ica aly ic p ocess. Thus, he eac ion o a 3-bu yn- amine de i a i e wi h glyoxylic acid and an aniline de i a i e in he p esence o a dual ca aly ic sys em, o med by a gold complex and chi al BINOL-de i ed phospho ic acid, led o he o ma ion o he co esponding u o[2,3-b]py ole de i a i e in e y high yield and s e eoselec i i y. These p oduc s, con aining h ee con iguous s e eocen e s, we e selec i ely ob ained only when he BINOL-de i ed phospho ic acid ca alys was subs i u ed a 3- and 30-posi ions wi h an h acenyl g oups (CPA F ). The ex ao dina y and unique pe o mance o his ca alys was compu a ionally s udied in o de o u he unde s and he mode o ac ion o chi al phospho ic acids in asymme ic p ocesses. This s udy u he suppo s he c ucial inuence o non-co alen in e ac ions, es ablished be ween he chi al phospho ic acid and he eagen s, on he con ol o he s e eoselec i i y o asymme ic eac ions. These in e ac ions seem o be a leas as impo an as he usually e e ed s e ic effec s. In he eac ion he e desc ibed, ea u es in ima ely ela ed o hose non-co alen in e ac ions such as he linea geome y o he an h acenyl g oup o he ca alys , he elec on densi y o he aniline, he elec onic complemen a i y o a oma ic ings in ol ed in an de Waals in e ac ions o he p esence o an a yl subs i uen in he s a ing 3-bu ynamine de i a i e seem o be essen ial in o de o jus i y he excellen esul s in e ms o yield, dias e eo and enan ioselec i i y expe imen ally obse ed. The wo k he e p esen ed no only demons a es he powe o asymme ic mul icomponen and mul ica aly ic eac ions o ans o m simple ma e ials in o complex p oduc s, bu also p o ides new is as o be e unde s and how chi al phospho ic acids ope a e in asymme ic p ocesses. Conflic s o in e es The e a e no conic s o decla e. Acknowledgemen s We g a e ully acknowledge nancial suppo om Spanish Minis e io de Ciencia e Inno aci´ on (g an CTQ2016-76794-P and FPU-p edoc o al g an o L. C.), Conseje ´ ıa de Ciencia, Inno aci´ on y Uni e sidad del P incipado de As u ias (g an IDI/ 2018/000231) and Xun a de Galicia (Consolidaci´ on GRC ED431C2017/61 om DXPCTSUG; ED-431G/02-FEDER “Unha manei a de ace Eu opa” o CINBIO, a Galician esea ch cen e 2016–2019), We also hank Cen o de Supe compu aci´ on de Galicia (CESGA) o gene ous alloca ion o compu ing esou ces. No es and e e ences 1 Fo a e iew on one-po ca alysis, see: (a) N. T. Pa il, V. S. Shinde and B. Gajula, O g. Biomol. Chem., 2012, 10, 211–224. Fo he use o mul ica aly ic sys ems comp ising a me al complex and a chi al o ganoca alys , see: (b) Z. Shao and H. Zhang, Chem. Soc. Re ., 2009, 38, 2745– 2755; (c) C. C. Loh and D. Ende s, Chem.–Eu . J., 2012, 18, 10212–10225; (d) H. Pellissie , Te ahed on, 2013, 69, 7171– 7210; (e) Y. Deng, S. Kuma and H. Wang, Chem. Commun., 2014, 50, 4272–4284; ( ) S. M. Inamda and N. T. Pa il, Chem. Commun., 2014, 50, 15124–15135; (g) D.-F. Chen, Z.-Y. Han, X.-L. Zhou and L.-Z. Gong, Acc. 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