Enantioselective Stereodivergent Nucleophile‐Dependent Isothiourea‐Catalysed Domino Reactions

Abstract α,β‐Unsaturated acyl ammoniums generated from the reaction of α,β‐unsaturated 2,4,6‐trichlorophenol (TCP) esters bearing a pendent enone with an isothiourea organocatalyst are versatile intermediates in a range of enantioselective nucleophile‐dependent domino processes to form complex products of diverse topology with excellent stereoselectivity. Use of either 1,3‐dicarbonyls, acyl benzothiazoles, or acyl benzimidazoles as nucleophiles allows three distinct, diastereodivergent domino reaction pathways to be accessed to form various fused polycyclic cores containing multiple contiguous stereocentres.


Introduction
Dominor eaction processes are one of the mostu seful strategies for the rapid generation of molecular complexity in organic synthesis. [1] Enantioselective organocatalysis is particularly suited to the development of complex tandem or domino processesd ue to the wide range of distinct activation modes accessible, the ease with which thesec an be combined, and the high levels of chemo-and stereoselectivity often obtained. [2] Te rtiary amine Lewis base-catalysed functionalisation of substrates at the carboxylic acid oxidationl evel can provide direct access to different catalytic intermediates that have aw ide range of applications ( Figure 1). To this end, enantiomerically pure catalysts based upon eithert he DMAP or PPY scaffolds, [3] cinchonaa lkaloids, [4] or isothioureas [5] are the most widely used. Of the intermediates directlya ccessible at the carboxylic acid oxidation level using these catalysts, acyl ammonium and ammoniume nolates have been the most extensively studied to date and can be utilised in an umber of stereoselective processes. [6] However,t he use of a,b-unsaturated acyl ammonium intermediates generated from stable a,b-unsaturated carboxylic acid derivatives hasr eceived comparatively little attention. Seminalw ork in this area from Fu and co-workers used a,b-unsaturated acyl ammonium intermediates generated from ap lanar-chiral DMAPc atalyst and a,b-unsaturated acyl fluorides in [3+ +2] annulations with silylated indenes to form highly substituted diquinanes with good stereoselectivity( up to 92:8 d.r.and 89:11e .r.). [7] Building on this work, we reported the use of an isothiourea catalysta nd homoanhydrides as a,b-unsaturated acyl ammonium precursors in Michael addition-lactonization reactions with ar ange of 1,3-dicarbonyls to form functionalised dihydropyranones 2,d ihydropyridones,o re sters (upon ring-opening)w ith high enantioselectivity (Scheme 1a). [8a] Recent experimental and computational analysis has revealed the importance of non-bonding 1,5-S···Oi nteractions in governing the chemoand enantioselectivity of annulations of benzothiazoles. [8b] Romo and co-workerss ubsequently used acid chlorides as a,bunsaturated acyl ammoniump recursors in enantioselective isothiourea-catalysedd omino Michael addition-aldol-lactonization reactionsu sing malonate derivatives as nucleophilest of orm functionalised cyclopentanes 4 with high stereoselectivity (Scheme 1b). [9a] Romo has also used a-a nd b-aminomalonates as di-nucleophiles in Michael addition-lactamization processes with a,b-unsaturated acyl ammoniumst of orm substituted glactamsa nd piperidones. [9b] The a,b-unsaturated acyl ammonium intermediate can also serve as an activatedd ienophile in highly enantioselective organocatalytic Diels-Alder reactions to form fused g-a nd d-lactones. [9c] Matsubara and co-workers have recently preparede nantiomerically enriched 1,5-benzo- thiazepines through reactiono f2 -aminothiophenols with a,bunsaturated acyl ammoniumsg enerated from mixed anhydrides and an isothiourea organocatalyst. [10] To date,t hese are the only reported examples investigating the use of a,b-unsaturated acyl ammonium intermediates. [11] Further studies into the reactivity and synthetic applicability of these speciesu sing readily available tertiary amine based catalysts are required to determine their versatility.T od emonstrate the potential of these intermediates,i nt his manuscript we envisioned that introducing as econd Michael acceptor into an a,b-unsaturated acyl ammonium precursor would allow for the development of more complex domino reaction processes (Scheme 1c). Addition of suitablen ucleophiles into such an a,b-unsaturated acyl ammonium would initiate ad omino process that can utilize the latent ammonium enolatea nd acyl ammonium reactivity presentw ithin the system.M oreover, using pro-nucleophiles that contain multiple potentials ites of reactivitym ay further increaset he molecular complexity accessible in these processes. In this case, the challenge is to generate highly chemo-, regio-and stereoselective processes that favour one specific domino reactionp athway over all others. This is particularly difficult given the multiple electrophilica nd nucleophilic sites within the reactants, ands uch domino processes have not been previouslyi nvestigated using tertiary amine based catalysis.
Herein the successful realisation of these ideas is reported using an isothiourea-derived a,b-unsaturated acyl ammonium generated from bench-stable activated ester precursors. To the best of our knowledge,t hese processes are also the first demonstration of using an activated ester as an a,b-unsaturated acyl ammonium precursor.T he exact domino reactionp athway followed is dependento nt he intrinsic reactivity within each class of pro-nucleophile used, which has allowed three distinct and stereodivergent processest ob ed eveloped. The fused polycyclic products obtained contain multiple contiguous stereocentres and have complex molecular topologies. Importantly,i ne ach case the products are formed with high specificity and stereoselectivity.
The absolutea nd relative configuration of 12 a was confirmed by X-ray crystallographic analysis, with all other products in this series assigned by analogy. [19] The use of non-aryl substituted diketones such as acetylacetonel ed to as light drop in product selectivity and as ignificant reduction in enantioselectivity for 13 a (62.5:37.5 e.r.), although the diastereoselectivityr emained high. Ac ontrol experiment in the absence of HyperBTM 1 did not lead to product formation,d emonstrating that ar acemic base-promotedb ackground reaction is not responsible for the observed drop in enantioselectivity.M alonates are also competent nucleophiles in this process, selectively forming fused products 14 a and 15 a with high diastereoselectivity,b ut with slightly reduced enantioselectivity.T he treatment of 5 with non-symmetrical ethyl benzoylacetate gave indane 16 in 74 %y ield, although the additional stereogenic centre was only modestly controlled leadingt oa75:25 mixtureo fd iastereoisomers.
Next, aw ide range of substituted a,b-unsaturated TCP esters was subjected to the previously optimised reactionc onditions using aryl 1,3-diketonesa sn ucleophiles( Ta ble3). The variousT CP esters were readily synthesised in four high-yield-ing steps from the correspondings ubstituted 2-bromobenzaldehyde. Substitution around the benzenoid ring is tolerated, with polycyclic products 17 a-19 a formed with excellent stereoselectivity.V arious alkyl and aryl enone substituents were also successfully incorporated. Aryl rings bearing electron-donating,e lectron-withdrawing and halogen substituents all workedw ell, giving indanes 22 a-25 a with high product selectivity in good yields (up to 69 %) and excellent stereoselectivity in all cases (> 95:5 d.r., up to > 99:1 e.r.). Combinations of substituted a,b-unsaturated TCP esters with different aryl 1,3-diketones were also performed, formingf unctionalised products 26 a-28 a in good yields with the same high selectivity.
The reactionm echanism using 1,3-dicarbonyls as nucleophiles is proposed to proceed through ad omino Michael-Michael-lactonization process (Scheme2a). Nucleophilic addition of HyperBTM 1 into TCP ester 5 generatesa na,b-unsaturated acyl ammonium intermediate 29.M ichael addition of the enolate of 1,3-dicarbonyl 6 onto 29 generates ammoniume nolate 30,w hich undergoes intramolecular Michael addition onto the pendente none. Lactonization of the resulting enolateo nto  the acyl ammonium releases polycyclicp roduct 7a and regenerates the catalyst. The observed stereochemical outcomei s proposed to arise from an initial Michael addition onto the Reface of a,b-unsaturated acyl ammonium 29,w hich is conformationally locked due to as tabilisingn on-bonding O-Si nteraction (n O to s* C-S ), with the Si-face effectively blocked by the stereodirectingg roups on the catalyst. [20] Evidence for such an O-S interaction hasp reviously been obtainedb oth in the solid-state, throughX -ray analysiso fa na,b-unsaturated acyl isothiourea salt, [8] and computationally through DFT calculations of possible transitions tates for aD iels-Alder reaction using an a,b-unsaturated acyl ammonium.
[9c] Subsequent intramolecular Michael addition of ammonium enolate 30 proceeds under substrate control,w ith the 1,3-dicarbonyl, ammonium enolatea nd enone all adopting pseudo-equatorialp ositions in the five-membered pre-transition state assembly 32 (Scheme 2b). Cyclisation under catalyst control is presumably disfavoured due to the presenceo fA 1,3 strain betweent he 1,3dicarbonyl substituent and the ammonium enolate. [21] Reactionsusing acyl benzothiazoles as nucleophiles Having explored the use of various 1,3-dicarbonyls, the use of acyl benzothiazoles as an alternative pro-nucleophilec lass in the domino process was investigated. Reacting a,b-unsaturated TCP ester 5 with 2-phenacyl benzothiazole 34 under the previously optimised conditions using HyperBTM 1 (20 mol %) as the catalystgave aseparable89:11 mixture of functionalised polycyclic products 35 a and 35 b in 53 %y ield (Scheme3). In this case, major product 35 a results from preferentialc yclisation through the benzothiazole nitrogen, which is consistent with previouso bservations using this class of nucleophile. [8] Interestingly,w hilet he diastereo-and enantioselectivity of this processr emainh igh (> 95:5 d.r., 94:6 e.r.), the relative configuration aroundt he fused indane 35 a is different to that observed within the major product from the reaction using 1,3dicarbonyls. The relative configuration of minor product 35 b could not be determined, although it is formed as ar acemate suggesting that it may arise from ab ase-mediated background process. Ac ontrol experiment in the absence of HyperBTM 1 confirmed the presence of ab ase-promoted reactioni nt his case. [22] Intriguedb yt he change in constitution and configuration within the major product, the scope of the domino process using various acyl benzothiazoles as nucleophiles was explored ( Table 4). Substitution within the benzenoid ring of the a,b-unsaturated ester was possible, although the presence of am ethyl substituent led to lower enantioselectivity (82:18 e.r. for 36 a). The presence of an aryl enone substituent worked particularly well, forming indane 38 a in 83 %y ield with high selectivity (93:7 a/b)a nd excellent stereoselectivity (> 95:5 d.r., 97:3 e.r.). Within the acyl benzothiazole, halogen substitution aroundt he benzenoid ring gave products 39 a and 40 a in good yields and high stereoselectivity.Alower yield was obtained for 41 a bearing an electron-donating methoxy substituent (20 %), althought he stereocontrol remained high. The rela-tive and absolutec onfiguration of 41 a was confirmed by X-ray crystallographic analysis, [23] with all other products assigned by analogy.V arious 2-arylacyl benzothiazole substituents were also tolerated, forming polycyclic products 42 a-44 a with high product selectivity and with good diastereo-and enantiocontrol.
The stereodivergence observed in the major products obtained fromt he reactions using 2-acyl benzothiazoles compared with 1,3-dicarbonyls can be rationalised through the operationo fa na lternative dominoM ichael-lactamization-Michael pathway (Scheme 4a). After initial Michael addition onto a,bunsaturated acyl ammonium 29 the resulting ammonium enolate 45 undergoes preferential protont ransfer to give acyl ammonium 46.L actamization of the benzothiazole nitrogen onto the acyl ammonium generates dihydropyridone 47 and releas-Scheme3.Reactionwith 2-phenacyl benzothiazole 34.  Consistent with this alternative mechanism,t reatment of TCP ester 5 with acyl benzothiazole 50 using only 1.5 equiv PS-BEMP gave dihydropyridone 51 as the major product (77 % yield, 88:12 e.r.), with only 11 %o fc yclised product 52 isolated with comparable levels of stereocontrol (Scheme 5). Treating isolated dihydropyridone 51 with PS-BEMPi nt he absence of catalystp romoted furtherc yclisation into 52,w hich was obtained in 86 %y ield as as ingle diastereoisomer in 92:8 e.r.T his demonstrates that 51 is av iable precursor to indane 52 and the stereochemical outcome of the stepwise cyclisation is consistent with that observed in the domino processes.

Reactionsusing acyl benzimidazoles as nucleophiles
As acyl benzothiazoles had given ad istinct domino reaction pathway,t he use of alternative acyl benzazoles was investigated. While treatment of 2-phenyacyl benzoxazole with a,b-unsa-turatedT CP ester 5 under the previously optimised conditions led to ac omplex isomeric mixture, reactionw ith 2-phenyacyl benzimidazole 53 gave as ingle major product isolated in 83 % yield (Scheme6). Further characterisation revealed its structure to be fused polycycle 54 containing three contiguous stereocentres, including one quaternary stereocentre. Although 54 was formed as as ingle diastereoisomer,t he enantioselectivity was low (62:38 e.r.).
Intrigued by this observation and the possibility of accessing another distinct dominop athway,t he reactionw ith 2-phenacyl benzimidazole 53 waso ptimised (Table 5). Ac ontrole xperiment in the absence of catalysta lso led to product 54 in 79 % yield and > 95:5 d.r.( Ta ble 5, entry 1), with X-ray crystallographic analysisc onfirming the structurala ssignment and relative configuration. [24] The presenceo fasignificant racemic base-promoted background reaction accountsf or the low enantioselectivityo bserved in the presence of HyperBTM 1. Consequently,t he racemic base-promoted domino reaction of 5 with 53 was first studied. Weaker organic bases such as i Pr 2 NEt led to no product formation, but addition of DMAP (20 mol %) gave 31 %o f54 (Table 5, entries 2a nd 3). The use of the amidine base DBU led to ac omplex mixture( Ta ble 5, entry 4), therefore PS-BEMP was chosen forf urther study.T he dominop rocess was more efficient in CH 2 Cl 2 compared with either THF or MeCN and the reaction stoichiometry could be reduced to 1.5 equivalents of both 53 and PS-BEMP,g iving 54 in 90 %y ield as as ingle diastereoisomer (Table 5, entries 5-7). The reactionc ould be performed on a3 .5 mmol scale, leading to the isolation of 1.3 go ff used polycycle 54 in 84 %y ield ( Table 5, entry 8).
The scopea nd limitations of this process were explored through variation of both the acyl benzimidazole and the a,bunsaturated TCPe ster (Table 6). Various 2-arylacylb enzimidazoles containing either electron-donating, electron-withdrawing or halogen substituents were tolerated, formingf used indanes 55-60 in generally good yield and excellent diastereoselectivity.I ntroduction of a2 -furyl substituent gave product 61 in 68 %y ield, although the diastereoselectivity was reduced The introduction of substituents within the benzenoid ring of the a,b-unsaturated TCP ester gave the corresponding products 65 and 66 in excellent yield as single diastereoisomers. In contrast with the reactions using acyl benzothiazoles, only an electron-rich aryl enone substituent could be incorporated, formingp roduct 68 in 80 %y ield. The presence of either electron-withdrawing or halogen substituted aromatic rings on the enone led to mixtures of products and lowy ields. Notably,t he pendent enone could be replaced with an a,b-unsaturated methyle ster,g iving the corresponding indane 69 in 79 %y ield with excellents electivity.
Having demonstrated aw ide scope for the diastereoselective dominop rocess using benzimidazoles as nucleophiles, the possibility of an isothiourea-catalysed enantioselective variant was revisited. [25] The reaction of TCP ester 5 and benzimidazole 53 under the previously optimised conditions with the addition of HyperBTM 1 (20 mol %) gave product 54 as asingle diastereoisomer,b ut with low enantioselectivity ( Table 7, entry 1). Lowering the temperature to 0 8Cl ed to an improvement, with 54 formed in 70.5:29.5 e.r.( Ta ble 7, entry 2). Changing the base used also had an impact on enantioselectivity.W hile DBU gave ac omplexm ixture, the use of 2,6-lutidine gave product 54 in an enhanced 83:17 e.r.( Ta ble 7, entries 3a nd 4). Finally, using i Pr 2 NEt allowed 54 to be isolated in 60 %y ield as as ingle diastereoisomer in 88:12e.r.(Ta ble 7, entry 5).  The newly optimised conditions for the HyperBTM 1-catalysed reactionu sing benzimidazolesw ere appliedt ot he enantioselective synthesis of as ubset of the fused polycycles made previously (Table 8). Structural variation within both the benzimidazole and a,b-unsaturated TCP ester was tolerated,f orming the products in generally good yields with excellent diastereoselectivity and comparable levels of enantioselectivity in each case. The absolute and relative configuration of fused indane 55 was confirmed through X-ray crystallographic analysis of ar ecrystallised sample (98.5:1.5 e.r.), [26] with all other products assignedb yanalogy.
Mechanistically,t he reactivity and stereoselectivity observed for the reactions using benzimidazoles can be rationalised by the Michael-lactamization-Michael domino pathway depicted in Scheme7a. Michael addition occurs on the Re-face of a,bunsaturated acyl ammonium 29,w ith subsequent proton transfer and lactamization of the resulting acyl ammonium 71 generating fused dihydropyridone 72 and releasingt he catalyst.
Deprotonation of the benzimidazole followed by intramolecular Michael addition of the enolate formed onto the pendent a,b-unsaturated ketone gives the observed product 54 containing three contiguous stereocentres, including one allcarbon quaternary stereocentre. The diastereoselectivity is rationalised by the enone adopting as terically favoured pseudoequatorial positioni nt he formingi ndane ring during the intramolecular Michael addition (Scheme 7b). An alternative pathway in which the intramolecular Michael addition occurs from acyl ammonium 71 prior to lactamization cannotb er uled out, however the Michael-lactamization-Michael pathway is currently favouredb yd rawing analogy with the reactions using acyl benzothiazoles.
Conclusions a,b-Unsaturated acyl ammonium intermediates generated from an isothiourea catalysta nd bench-stable a,b-unsaturated TCP esters bearing pendent Michael acceptors undergo various  General procedure for the Michael-Michael-lactonization reaction with 1,3-dicarbonyls HyperBTM 1 (20 mol %), PS-BEMP (2 equiv), and the appropriate 1,3-dicarbonyl (2 equiv) were added to as olution of the appropriate a,b-unsaturated TCP ester in anhydrous THF (0.4 m)a tr oom temperature. The reaction mixture was stirred for 48 hb efore being filtered to remove the base and concentrated in vacuo. The crude product was purified by column chromatography (petrol/ EtOAc) on silica gel to give products of approximately 95 %p urity. Analytically pure samples could be obtained through as econd chromatographic purification using CH 2 Cl 2 as eluent.
General procedure for the Michael-lactamization-Michael reaction with acyl benzothiazoles HyperBTM 1 (20 mol %), PS-BEMP (2 equiv), and the appropriate acyl benzothiazole (2 equiv) were added to as olution of the appropriate a,b-unsaturated TCP ester in anhydrous THF (0.4 m)a t room temperature. The reaction mixture was stirred for 48 h before being filtered to remove the base and concentrated in vacuo. The crude product was purified by column chromatography (petrol/EtOAc) on silica gel to give products of approximately 95 % purity.A nalytically pure samples could be obtained through asecond chromatographic purification using CH 2 Cl 2 as eluent.
General procedure for the diastereoselective Michael-lactamization-Michaelreaction with acylbenzimidazoles PS-BEMP (1.5 equiv), and the appropriate acyl benzothiazole (2 equiv) were added to as olution of the appropriate a,b-unsaturated TCP ester in anhydrous CH 2 Cl 2 (0.4 m)a tr oom temperature. The reaction mixture was stirred for 40 hb efore being filtered to remove the base and concentrated in vacuo. The crude product was purified by column chromatography (petrol/EtOAc) on silica gel to give products of approximately 95 %p urity.A nalytically pure samples could be obtained through as econd chromatographic purification using CH 2 Cl 2 as eluent.
Generalp rocedure for the enantioselective Michael-lactamization-Michael reaction with acyl benzimidazoles The appropriate acyl benzimidazole (2 equiv), HyperBTM 1 (20 mol %), and i Pr 2 NEt (2.0 equiv) were added to as olution of the appropriate a,b-unsaturated TCP ester in anhydrous CH 2 Cl 2 (0.4 m)a t0 8C. The reaction was allowed to warm to 10 8Ca nd stirred for 48 h. The reaction was quenched with 0.1 m HCl and extracted with CH 2 Cl 2 ( 3). The combined organic layers were washed with brine, dried over anhydrous MgSO 4 ,f iltered and concentrated in vacuo. The crude product was purified by column chromatography (petrol/EtOAc) on silica gel to give products of approximately 95 %p urity.A nalytically pure samples could be obtained through as econd chromatographic purification using CH 2 Cl 2 as eluent.