Stereoselective Remote Functionalization via Palladium‐Catalyzed Redox‐Relay Heck Methodologies

Abstract Exploration of novel, three‐dimensional chemical space is of growing interest in the drug discovery community and with this comes the challenge for synthetic chemists to devise new stereoselective methods to introduce chirality in a rapid and efficient manner. This Minireview provides a timely summary of the development of palladium‐catalyzed asymmetric redox‐relay Heck‐type processes. These reactions represent an important class of transformation for the selective introduction of remote stereocenters, and have risen to prominence over the past decade. Within this Minireview, the vast scope of these transformations will be showcased, alongside applications to pharmaceutically relevant chiral building blocks and drug substances. To complement this overview, a mechanistic summary and discussion of the current limitations of the transformation are presented, followed by an outlook on future areas of investigation.

Abstract: Exploration of novel, three-dimensional chemical space is of growing interesti nt he drug discoveryc ommunity and with this comest he challenge for synthetic chemists to devisen ew stereoselective methods to introduce chirality in ar apid and efficient manner.T his Minireview provides a timely summary of the development of palladium-catalyzed asymmetric redox-relay Heck-type processes. These reactions represent an important class of transformation for the selec-tive introduction of remote stereocenters, and have risen to prominence overt he past decade. Within this Minireview, the vast scope of theset ransformationsw ill be showcased, alongside applications to pharmaceutically relevant chiral buildingb locks and drug substances.T oc omplementt his overview,amechanistic summary and discussion of the current limitations of the transformation are presented, followed by an outlook on future areas of investigation.

Introduction
Over the past two decades, the over-reliance on al imited set of reactions in drug discoveryh as led to chemical libraries that are denselyp opulated with molecules rich in sp 2 character. [1] In recent years however,increased interest in expanding chemical space, particularly the exploration of three-dimensional structures, has been fueled by the evolution of synthetic chemistry methodology in the pharmaceutical industry via thei mplementation of high throughput experimentationa nd directed evolution screening platforms. [2] Increasing the fraction of sp 3 carbonsi sa ppealing from as tructural diversity perspective because ah igher degree of three-dimensionality provides access to new target classes. From an industrial standpoint, such approaches can lead to ac ompetitive advantage. [1] Incorporation of as tereocenter offers multiple benefits, such as enhanced solubility,p harmacokineticsa nd selectivity by providing more complementary binding to the active sites of proteins. [2a, 3] This observation is supported by the greater proportion of chiral molecules that progress in clinical trials. [4] Stereoselectivity is am ajor theme in the discovery,d evelopment and launch of new drugs because chirald rug molecules are almost exclusively marketed as singlee nantiomers. [5] In addition, development and sales of chiral drugs continuet o grow. [6] As ar esult,t here has been an increased interest in developingr obust, cost-efficient stereoselective processes for the large scale synthesis of activep harmaceutical ingredients (APIs) containing one or more stereogenic centers. [7] Despite these efforts, major challenges remain. For instance, few,i fa ny, drug molecules currently on the market have quaternary stereocenters installed via chemical synthesis. [2a, 8] Consequently, the development of broad, practical methodologies which can providea ccess to novel chiral motifs that are useful for drug design,w ith the added potentialt os treamline the synthesis of APIs, are of high value to industry and the synthetic community in general. [9] 1.1 Synthesis of remote stereogenic centers Asymmetric catalysis is al ong-standing field of organic synthesis. [10] The stereoselective a-a nd b-functionalization of carbonyls hasb een extensively studied, [11] but significantly less attention has been directed at the stereoselective synthesis of remote tertiary and quaternary stereocenters. [12] This Minireview describes the development of palladium-catalyzed asymmetric Heck-type transformations. Other transition metalsc an also be applied, but these complementary methods are beyondt he scope of the present article. Specifically,t his review focuses on stereoselective synthetic transformations generating remote tertiary and quaternary stereogenic centers via ar edox-relay mechanism (Scheme1). The two-step sequenceo ft his methodology,i nstallation of ar emote group with high stereoselectivity and subsequent oxidationo fa na lcohol linked by the redox-relay mechanism,e nablesn on-trivial retrosynthetic disconnections to be considered. Herein, remote functionalization is defined as functionalization beyondt he bposition (g, d, e etc.), and a relay is defined as migration over more than one bond. However,w here appropriate, seminale xamplesn ot fulfilling the aforementioned criteria have been included to provide context. [13] 1.2 Redox-relay chain walking systems Alkenem igration using palladium as ac atalyst has been knowns ince 1926. [14] This methodology,a lso known as chain walking,i sc ommon in polymer chemistry, [15] and is now becomingm ore prevalent in small molecule synthesis. [16] Of interest to the topic of this review is the use of palladium catalysts to facilitatea lkene migration in allylic alcohol systems to generate carbonyls in as ingle step, thereby avoiding the need for furthero xidation state manipulations. [17] Such at ransformation, also referred to as a redox-relay event, formally repositions the unsaturation from an alkene to an alcohol. Ag eneral chain walking mechanismo fa llylic alcohol 1 is summarized in Scheme 2. [17] An initial migratory insertion of the alkenei nto the palladium hydride bond yields 2.S ubsequent b-hydride elimination leads to enol 3,w hich can either tautomerize( path a), or undergo am igratory insertion/oxidative deprotonation sequence( path b). During this final step, the alcoholr edoxa cceptor is convertedt ot he corresponding carbonyl product 4, which serves as athermodynamic sink.

Heck reaction-Seminal redox-relay studies
The CÀCb ond forming Heck, or Mizoroki-Heck, reactioni sa palladium-catalyzed coupling of an unsaturated halide (or triflate) with an alkene to generateasubstituted alkene. [21] The reactionw as independently discovered by Mizoroki and Heck, and their co-workers, in 1971 and 1972, respectively. [22] Since these initial reports, the reaction has undergone considerable development, andt oday represents one of the foremost CÀC coupling processes applied in organic synthesis. This reaction class has proven useful due to the mild conditions employed, together with the tolerance of ab road range of functional groups. [23] During early investigation into the scope of this reaction, the formation of unexpected products was observed when using allylic alcohols as the alkene partner.S pecifically,a rylation of primary-and secondary-allylic alcohols (12 and 13)r esulted in the formation of 3-aryl aldehydes (14)a nd ketones (15), respectively (Scheme 5). [24] Primary-ands econdary-homoallylic alcohols were subsequently examined, and these also resulted in the formationo ft he corresponding aldehyde and ketone products,a lbeit in lower yield. [24a,b, 25] It was hypothesized that a' chain walking' mechanism may be occurring, where the double bond migrates along the alkyl chain by iterative b-hydride elimination/migratory insertion steps, until captured by the alcohol moiety to form the carbonyl. In support of this proposal,t he propensity for palladium migration in other Heck-type transformations has been well-documented. [26] Further optimization of the chain walking methodology broadened the scope of the reaction so that various unsaturated alcohols afforded the corresponding aldehyde/ketone,r egardless of how remotelyt he centero fu nsaturation was located away from the hydroxyl group. [27] In 1987, studies into a possible enantioselective variant of the reaction were conducted using chiral allylic alcohols, [28] and concludedt hat the extento fc hirality transfer was limited under the conditions employed. [29] 2. The Redox-Relay Heck Reaction

Preliminary work
From 2010, Sigman and co-workersb egan investigations into Heck transformations with the aim of developing ag eneral, operationally simple and highly regioselective set of reaction conditions for the arylation of electronically non-biased alkenes. [30] Applying the group'sp reviously optimized reaction conditions on allylic alcohol 16,a nd using aryl diazonium salts as coupling partners, an approximately1 :1 ratio of the styrenyl Heck product 17 and ketone 18 was obtained, with the latter referredt oa st he relay Heck product (Scheme 6). [30b, 31] Sigman's finding, coupled with the fact that limited success in an enantioselective variant of this transformation had been achieved thus far,prompted furtherinvestigation into the reaction. The authorsh ypothesized that ar egio-and enantio-selective transformationc ould be achievedb yc areful selection of a chiral catalyst that coulde lectronically differentiate between the CÀHb onds leadingd own the two relay pathways, whilst also sterically differentiating the two faces of the alkene. [31] Scheme5.Unexpected chain walking productso bserved when exploring the scope of the Heckreaction.

Arylation
Since the redox-relay Heck reaction was thought to proceed via successive b-hydride elimination/migratoryi nsertions teps, followinga ni nitial migratoryi nsertion of the aryl-metal complex into the alkene, it was postulated that an electrophiliccatalyst would promote binding of the catalyst to the alkene of the substrate over competing dissociation. [31] It was also noted that aryl diazonium salts may be incompatible with commonly used chiral phosphines, and so alternative chiral ligands were investigated. [30][31][32] The arylation of allylic alcohol 19 in the presence of pyridine-oxazoline (PyrOx) ligand L1 ( Figure 1) was found to generatet he correspondingk etone 20 in 93:7 e.r. (Scheme 7). The high enantioselectivity achievedw as attributed to the chelating ligand generating aw ell-defined environment for asymmetric induction. [31] Since this initial publication,arange of empirically-derived PyrOx and related pyrazine and pyrimidine bisoxazoline ligands have facilitated the vast expansiono ft his methodology ( Figure 1). [33] More recently,n ovel, computationally-deriveda dditions to the ligand series have been derived using multivariate regression analyses to build predictive correlation models based on substrate and catalyst parameterization. [33,34] Ac ombination of electronic (naturalb ond orbital, NBO, charges, and IR frequencies and intensities) and steric (Sterimol and Buried Volume) descriptors have been used to this end. It has been found that am ore negative NBO chargeo nt he oxazoline nitrogena tom of the PyrOx ligand correlates with increased enantioselectivities and the regioselectivity of arylation across the alkene is strongly correlated with all steric dimensions of the oxazoline 4-substituent, as quantified by Sterimol and Buried Volume.
Subsequenti nvestigation into the generation of remote tertiary stereocenters demonstrated that highere nantioselectivities were generally achieved when bulkier or more branched substituents on the saturated side of the allylic alcohol were used (Entry 1v s. 2i nT able 2). [31] It was also observed that when (Z)-alkenes were subjected to the same conditions, the reactionp roceeded in high enantioselectivity to give the antipodal ketone product (Entries 2a nd 3, and 4a nd 5). In all cases, racemic allylic alcohols (21)a fforded the corresponding ketones (22 a/b)i nh igh enantioselectivity,s trongly suggesting catalystc ontrol over the stereochemical outcomeo ft he transformation.T he reaction was also selective with primary and secondary homoallylic-and bis-homoallylic-alcohols, in terms of both enantio-and regio-selectivity (Entries 6-9), favoring the regioisomer resulting from CÀCb ond formationa tt he distal alkene carbon relative to the alcohol. The effect of distance between the alcohol and the alkene in the substrate, termedt he chain length,w as also examined. Whilst enantioselectivities remained high, diminished yields were observed over longer chain lengths (Compare Entries1,7and 9).
Correia and co-workers have also utilized aryl diazonium salts in the redox-relay Heck methodology to generate quaternary stereocenters. The authors reported that the use of tetrafluoroborate diazonium salts (23)e nabled operationally simplified conditions to be developed, compared to the corresponding hexafluorophosphates, for the efficient arylationo f( Z)-diols (24). [35] In this sequence, the resulting aldehyde (25), reacts intramolecularly to generate lactone 26 (after oxidation). The substrate scope primarily consisted of b-functionalized lactones,w ith as ingle example of g-lactone formation (Scheme 8), [35b] and all proceeded with excellent enantioselec-  Scheme6.Preliminarywork on the Heck reaction.

Alkenylation
The electron-deficientn ature of alkenyl triflates (31)w as proposed by Sigman and co-workerst of avor the desired redoxrelay mechanism, achieving site-selective b-hydride elimination followingm igratory insertion. [39] Ap owerful protocol using PyrOx L1 was developed fort he selectivea ddition to disubstituted alkenols (32)( Scheme 10). Both (E)-and (Z)-alkenols can be used in the reaction, with the different alkene geometries leadingt oo pposite enantiomersa st he major product. In all cases,h igh enantiomeric ratios werea ttained irrespective of the electronic nature of the substrate or the chain length. [39] The redox-relay Heck alkenylationo fa lkenols has also been demonstrated in the synthesis of chiral buildingb lock 34,p resent in bioactive molecules such as elisabethin A, elisapterosin B and colombiasin A. [39] Application of the alkenylation methodology to trisubstituted alkenols (36)w as initially unsuccessful. [40] It was hypothesized that the greaters teric demand of the trisubstituted alkene was impeding the migratory insertion of the electrondeficient alkenyl triflate. Evaluation of electron-rich alkenyl triflates revealed that am ore electrophilic ligand (L4,F igure 1) was required to enhanceb inding of the chiral ligand and substrate, which in turn increased the rate of migratory insertion (Table 3). [40] In general, high enantioselectivities were achieved, regardless of the electronic nature of the alkenyl triflate (35). In contrastt ot he disubstituted alkenols ystems, only (E)-alkenyl triflates can be used in the trisubstituted system,w hicht he Scheme9.Phthalide synthesis and applications.  [b] [a] From (Z)-alkene. [b] From (E)-alkene.
It was later shown that alkenyl benzene derivatives (42)c an successfully undergo chain walking eventsi nt he redox-relay Heck coupling with alkenyl triflates (41). [42] Here, the relay terminatest og ive the corresponding styrene products (43)i n high enantiomeric ratios irrespectiveo ft he electronic nature of either coupling partner (Scheme 12). Whilst exploring the possibility of remote difunctionalization, it was noted that use of para-methoxyphenyl boronic acida sa na dditive resulted in enhanced yields, although no difunctionalization was observed. Increasing the chain length led to as lightr eduction in yield and enantioselectivity with each methylene addition. The site selectivities remained at 2.6:1 distal:proximal up to tris-homoallylic alkenyl benzenes, but this diminished with addition of af urther methylene unit.

Indoles
Indoles can be functionalized at the C2-position via ar edoxrelay Heck reaction by use of the correspondingt riflate (Scheme 13). [43] Only ethyl carbamate-protected indoles (44) were successfully utilized, with methyl-, phenyl-or acetyl-protected indoles all resulting in either no product formation or decomposition. All substrates that coupled did so with high enantioselectivity,i ncluding one example with as econdary al-cohol, which led to the formation of the corresponding ketone (47). These C2-activated indole triflates could also be coupled to ene-lactams( 48)a nd disubstituted alkenes containing a remote carbonyl moiety,w hich results in formationo ft he corresponding a,b-unsaturatedp roduct (49), in high enantiomeric ratios. [43]

Cyclic systems
In 2019, the alkenylation of cyclic ene-lactams (51)w as reported (Scheme 14). [44] Various N-protectingg roups were tolerated, generating the corresponding 6-alkenyl substituted a,b-unsaturated d-lactam 52 in excellent yields and enantioselectivities. Electron-deficient alkenyl triflates could also be coupled successfully in high enantiomeric ratios. Attemptsa te xpanding the scope to larger,s even-membered ring systems sawe nan-tioselectivity maintained on ar educed set of substrates, albeit with diminished yields, which could be recovered with increasedc atalyst loadings and longer reactiont imes.

The Redox-Relay Oxidative Heck Reaction
The expansion of coupling partners beyonda ryl diazonium salts led to the development of an effectivec omplementary redox-relay oxidative Heck variant. [45] This oxidative Heck process uses ap alladium(II)c atalyst, and boronic acids replacet he established unsaturated halides or triflates,t hus making the first step of the catalytic cycle transmetallationa so pposed to oxidative addition (Scheme 15). [29] The term 'oxidative' relates to the requirement for oxidation of Pd 0 to Pd II to regenerate the activec atalytic species, and thusa no xidant is required in this case to achievet he desired transformation. [29,46] This methodology has allowed more complex systemst ob ee ffectively cross-coupled under milder conditions without the addition of base. [46b, 47]

Arylation
The seminalp ublication on the redox-relay process by Sigman and co-workersr eportedt he addition of ab road scope of aryl boronic acids to ar ange of (Z)-alkenols (53), forming the correspondinga ldehyde( 54/55)o rk etone in high yield and enantioselectivity. [45] When examining the impact of chain length, a similart rend to the redox-relay Heck (see Section 2) was observed,w here the site selectivity decreased with increased separationb etween the alkene and the alcohol, but enantioselectivity remained high (Table4).
Formation of the (R)-stereocenter was favored at the distal alkene carbon. In contrast, for the minor product of the reaction, formedv ia insertion into the proximal carbon of the alkene,t he (S)-enantiomer was formed, implying that opposite faces of the alkene are presentedt ot he palladiumc atalyst, as illustrated in Scheme 16. [45] This rationales upports the high enantioselectivity observed experimentally for both products. It is worth noting that formationo ft he minor product also proceeds in high enantioselectivity despite migration occurring through the newly formed (S)-stereocenter.
Replacing the alcohol with ac arbonyl group (56)r esulted in enhanced site selectivity for the corresponding a,b-unsaturated products (57), compared to previouss tudies on systems of identicalc hain length (Table 5). [48] Ap ositive solvente ffect was identified using DMA, resulting in d:g site selectivity as high as 15:1 (compared to 5.2:1 with DMF), whilst also increasingt he Scheme15. The oxidative Heck catalytic cycle. Scheme16. Addition of boronic acids to acyclic alkenols in the redox-relay oxidative Heck. yield and maintaining excellent enantioselectivity.T he reaction performed well even in the absence of ac o-oxidant (meaning no additional solid oxidant was used), with comparable site selectivities to those reported previously.E laboration of the carbonyl from as imple aldehyde (Entry 1) to ketones (Entry 2), carboxylic acids (Entry 3) and esters (Entries4-6) was well tolerated. However,w ith increasing chain length, the site selectivity and yield werefound to decrease (Entries 8-10).
The scope was later expanded to trisubstituted alkenols (58), forming the corresponding aldehydes (59), containing a remote quaternary stereocenter,i nh ighe nantiomeric ratio (Scheme 17). [49] Unlike the majority of disubstituteda lkenols, trisubstituted alkenols showed high site selectivity (g:b ! 15:1) regardless of the electronic natureo ft he boronic acid. This enhanced selectivity is attributed to the more nucleophilic nature of the alkenol. For these systems, high site-and enantio-selectivity was also achieved irrespectiveo fthec hain length. The degree of enantioselectivity was found to be the same regardless of alkene geometry,b ut with the formation of opposite enantiomers as the major product. Ar ationale for this was proposed based on the transition state for migratory insertion, in which the binding orientation of the alkene is unchangedf or both alkene configurations(Scheme 17). [49,50] Arylation of trisubstituted (Z)-alkenols (60)c ontaining af luorine substituent on the alkene has also been demonstrated, althought he majority of the investigation focusedo nb-functionalization. [51] Substantially higher catalyst loadings were requiredt og eneratem ore remote fluorinated tertiary stereogenic carbon centers (61), but thesew ere found to proceedi ne xcellent enantioselectivity,w hich diminished slightly with increased chain length (Scheme 18). This methodology enables the straightforward access to enantio-enriched fluorinated buildingb locks, which, in some cases, are knownt oc onfer favorable physicochemical properties in drug molecules. [52] The presence of quaternary stereocenters alongt he acyclic chain is incompatible with the intrinsic mechanism of chain walkinge vents. Inspired by their earlier work, Marek and coworkers exploited the possibility of halting the migration by installing ac yclopropane ring bearing aq uaternary stereocenter along the chain. [53] Thise nabled ar ing-opening event during migration, generating acyclics ystems bearing multiple congesteds tereogenic elements (63)i nf our steps, with ah igh degree of stereocontrol( Scheme19). [54] Although the chiral vinylcyclopropyl carbinol precursor (62)g overned the stereochemicalo utcome, PyrOx L5 (Figure 1) was found to promote am ore selectivem igratory insertion, which led to increased yields.
Di-and tri-substituteda lkenes were compatible with this process, producing tertiary and quaternary stereocenters, respectively.H owever,t he authors found that bulkier chains on the alkene led to slightly diminished diastereo-and regio-selectivities. 1,1,2,2,3-Pentasubstitutedv inylcyclopropyl carbinols (62,w here R 5 ¼ 6 H) were also amenable to this protocol, generating products with three stereogenic centers, withoute pimerization att he a-stereocenter.I nt erms of boronic acid scope,a varietyo ff unctional groups at the para-a nd meta-position Scheme17. Impact of alkene geometry of trisubstituted alkenols on enantioselectivity.
were tolerated, including ethers, halides, esters, ketones and nitro groups,w hereas, ortho-substituted substrates provedi nefficient, and heteroaryl boronic acids proceeded in lower yield. This methodology is also compatible with triflatesa nd indoles as couplingp artners. The reaction is stereospecific, meaningt hat diastereomeric products can be accessed by altering the alkene geometry.T his powerful feature of the process was fully exploited in the synthesis of all four diastereomers (64 a to 64 d)o fprecursor 62 (Scheme19). Identical levels of selectivity were observed for both alkene geometries.

Indoles
The enantioselective N-alkylation of indoles (65)t o( Z)-alkenols (66)h as recently been reported by Sigman and co-workers (Scheme 20). [55] This transformation can be formally classified as an intermolecular aza-Wacker reaction,w hereby selective bhydride elimination prevents the formation of the corresponding enamine and instead leads to aldehyde 67 via chain walking migration. Mechanistic experiments carriedo ut by the authors support a syn-amino-palladation pathway.T he majority of substrates generated using this methodology demonstrate b-functionalization.A lthough high stereoselectivities are consistently achieved, an excess of 66 is required in order to ensure reaction conversion.
Ac omplementary C3-functionalization of indole 68 via ad ehydrogenative redox-relay oxidative Heck strategy to generate quaternary stereocenters ( 70)h as also been developed (Scheme21). [34] Again, the majority of the scope focused on bfunctionalization, buts elected examples demonstrate more remote functionalization. Whilst both alkene isomers resulted in comparable yields, the enantioselectivitiesw ere significantly greater for(Z)-alkenes.

Cyclic systems
In 2018, Sigman and co-workers began to investigate the redox-relay oxidative Heck reaction with cyclic systems, focusing on lactams (71). [56] Regioselective insertion using PyrOx L1 led to the monoarylated ene-lactam product (72)( Scheme 22). This procedure was compatible with av ariety of nitrogen protectingg roups (Boc, Bn, Ts,M ea nd PMB) as well as the unprotected lactam, with high enantioselectivities (95:5-> 99:1 e.r.) achieved in all cases. Application of ar ange of electron-rich and electron-deficient aromatics proceeded to give the corresponding d-lactam product in high yield and enantiomeric ratios, although heteroaromatic and electron-rich boronic acids generally correlatedw ithlower enantioselectivities.
Expanding the ring size to produce e-lactams required higher catalystl oadings due to the diminished activity of these substrates. This produced the desired products in high enantiomeric ratio but lower yield. The scope of this methodology also encompassed the formation of quaternary stereogenic centers from trisubstituted ene-lactams bearing am ethyl substituent. Excellent enantiomeric ratios were demonstrated in all cases, regardless of the electronic nature of the boronic acid substrate. More sterically demanding trisubstituted ene-lactams did not yield any of the desired product. Chiral building blocks for av ariety of drug molecules, such as aCGRP receptor antagonist and am odulator of TNF a-signalling, have been generated from the arylation of ene-lactamsi nh igh yield and with no erosiono fe nantioselectivity over subsequent steps. [56] In ac omplementary study,t etrafluoroborate iodonium salts (73)w ere found to be most efficacious for the alkenylation of ene-lactams (74), allowing electron-rich alkenyl groups to be used (Scheme 23). [44] Given the challenging nature of this transformation the yields and enantioselectivities achieved were remarkable.
Investigationi nto the redox-relay oxidative Heck methodology has since progressed ontoless biaseds ystems, such as symmetricalc ycloheptenones (76)( Scheme24). [57] In this case, remote arylation proceeded in highy ield and enantioselectivity.O fn ote, longerr eactiont imes or greater equivalents of boronic acidl ed to increased levels of the diarylated product. Alkenylation was also possible with alkenyl triflates, using as tandard redox-relay Heck protocol, albeit in lower yields and more modeste nantiomeric ratios. Attempts to explore unsymmetrical cycloalkenones resulted in poor site selectivity.

Mechanistic Investigations
Since their discovery, considerable efforts to develop af undamental understanding of both redox-relay Heck and oxidative Heck transformationsh ave been undertaken. [50,58] The reaction is thought to proceed via migratory insertion of the aryl (or vinyl) coupling partner onto the distal carbon of the alkene, relative to the alcohol. Successive b-hydride elimination/migratory insertion steps then lead to the product. Mechanistic studies, reinforced by computational calculations, have been carried out to support ap roposed catalytic cycle for alkenol substrates( Scheme25). [50,58]

Oxidative addition or transmetallation
Initially,the palladium(0) catalyst undergoes ligand substitution with the chiral PyrOx ligand. [58a] The catalytic cycle then begins with either the oxidativea ddition of the aryl diazonium salt to the palladium(0) catalysti nt he Heck reaction, or transmetallation of the aryl boronic acid to the palladium(II) catalysti nt he oxidative Heck reaction, forming palladium(II) species A.Apcomplex with the alkene of the alkenoli st hen formed (species B). [50, 58a] Computational studies have found that both the oxidative addition of aryl diazonium salts in the Heck reaction; the transmetallation of aryl boronic acids in the oxidative Heck;a nd the subsequenta lkene coordination steps, are all energetically facile. [59] Kinetic studies for the oxidative Heck indicate af ast transmetallation of the boronic acid prior to rapid alkene binding. [60] Af easible low energy associativemechanism for isomerization of B in the presenceo fD MF wasf ound,i ndicating that both cis-a nd trans-isomers of B exist in rapid equilibrium via at rigonal bipyramidal intermediate (Scheme 26). [50]

Migratory insertion
It is proposed that with rapid isomerization of B,t he subsequent syn-migratory insertion of the alkenols hould be under Scheme23. Alkenylationofe ne-lactamsu sing electron-rich iodonium salts.

Scheme24. Arylation of cycloheptenones.
Scheme25. Proposed catalytic cycle for the redox-relay Heck (path a) and oxidative Heck( path b) reactionsb ased on empirical and computational studies.
Curtin-Hammett control, determined by the relative energy of insertiont ransition states that exist for both isomers. The large (10.7 kcal mol À1 )e nergy barrier for migratory insertion suggests that this step in the mechanism is responsible for determining the site-and enantio-selectivity of the product. [50] It was found that the redox-relay pathwayi so fl ower energy,t herefore favoring this process over the traditional Heck manifold. [50, 58a] It was also noted that the traditional Heck pathway is reversible.

Redox-relay chain walking
Experimental observations on the systemss tudied are suggestive of palladium chain walking events. [49,56] Similar observations have previously been made with systemsi nvolving the cycloisomerization of 1,n-dienes. [20] This is also in agreement with the computational studies, which indicate that, following the formation of C,s ite-selective b-hydride elimination leads to intermediate D. [50, 58a] The large free energy of activation calculated suggests that this step is turnover-limiting. [58a] This b-hydride elimination is accompanied by solventm ediated cis-trans isomerization in the lower energy pathway to relieves train. Calculations to determine if displacement of the cationic palladium from the alkene occurs, resultedi na ne ndothermic pathway,s uggesting that this process is unlikely.T he authors postulate that this is due to the electrophilic nature of the chiral ligand,reinforcing that this property is key to the development of an efficient transformation. In addition, the lack of as trong base in this methodology prevents deprotonation, thus allowing reinsertion to occur,f ormingi ntermediate E.Afurther bhydridee limination resultsint he formation of enol F.
The aforementioned chain walking events (C to F)h ave low calculated energy barriers, suggesting that such steps may be reversible. [49,50,58] Deuterium-labelling experimentsw ere also carried out to furtherp robe this aspect of the mechanism. Retention of g-a nd b-deuteriuml abels in 78 was observed experimentally,i mplying preferential migration of the catalyst towards the alcohol in formation of the major product (80) (Scheme 27 a). This observation is in agreement with the computationally-determined mechanism.
[58b] For the minor product of the reaction( 79), only deuterium incorporation at the distal carbon of the alkenew as observed, agains uggesting that the relay is uni-directional. Deuterium labellingo ft he terminal methyl of the alkenol( 81)a lso resulted in the same conclusion for g-arylation (83) ( Scheme 27 b). However,f or b-arylation, deuterium scrambling waso bserved (82 a and 82 b), indicating that migration through as terically-hindered benzylic position enablesr eversible chain walking that still ultimately leads to migration towards the alcohol redox acceptor,f orming the observed carbonyl product. [58b] The reaction of trisubstituted alkenol 84,w hich contains a pre-installed stereocenter on thea lkyl chain, in the presence of either enantiomer of the chiral PyrOx ligand (L1 or ent-L1), resulted in formation of the same product (85)i nh igh enantioselectivity and identicaly ield (Scheme 28 a). [49] The integrity of the pre-installed stereocenter was preserved, implyingt hat the catalystr emains associated on the same face of the alkenol substrate during the relay process. Repeating these control experiments with alkenol 86 resulted in high diastereoselectivity, but giving different diastereomers as the major product (87 and 88)( Scheme 28b). This observation supportsacatalystcontrolled face selection of the alkene. Further deuterium labellings tudies identified that the palladium species remains associated with the alkenol during migration, thereby providing additional evidencet hat reinsertion of the palladium occurso nt he same face of the alkene. [58a]

Dissociationofp roduct
Several theories have been proposed to rationalize the final dissociation step of the mechanism. [50,58] Sigman and co-workers suggested that reinsertion of the palladium hydride forms hydroxyalkyl-palladium species G,w hich acts as at hermodynamic sink in the chain walking mechanism (Scheme 29). [61] The authors state that the presence of the palladium species G rules out ap ossible tautomerization mechanism of the enol to Scheme27. Deuterium labelling experiments as evidence for the uni-directional nature of chain walking events. the carbonyl proposed by Wang andc o-workers. [58b] It has been found that with successive migratory insertion/b-hydride elimination steps, as the palladium speciesm igrates closer towards the oxygen of the alcohol, the energy barrierd ecreases. This shallowp otential energy surfacer epresents an energetically downhill process, and is proposed to be due to af avorable interaction between the partial negative charge of the palladium-bound carbon andt he partial positive charge of the oxygen-bound carbon. [50, 58b] Formation of G is then followed by an oxidative deprotonation of the alcohol by DMF,w hich leads to formation of the carbonyl product bound to the regenerated Pd 0 ,s pecies H. [50] Dissociation of the catalyst releases the product I,c ompleting the catalytic cycle for the redoxrelay Heck. For the redox-relay oxidative Heck, the palladium(0) speciesi st hen re-oxidizedt oP d II by an oxidantt oc omplete the catalytic cycle.

Further mechanistic exploration
Performing the redox-relay methodology on diol 89 enabled furthers tudy of the relay mechanism. [60] Specifically,t he presence of two alcohols of varying distance from the alkene, stemming from ab ranch point in substrate 89,w ould allow any electronic influence of each alcohol on the migration to be probed. It was found that the catalyst migrates preferentially towards the closest alcohol, resulting in the formation of aldehyde 90 over 91 in ar atio of 6.8:1 (Scheme30). This observation was supported by computational studies, where ap rogressivelyl ower energy barrierw as observed as the palladium center migrates towards the alcohol. [50,58,60]

Enantioselectivity
Computational studies suggest at urnover-determining arylation step, followed by successive b-hydride elimination and migratory insertion steps before releaseo ft he product. [58a] As discussed in Section 4.2, it is the initial migratory insertion of the arene which was determined to be both the enantio-and regio-determining step. [50, 58a, 60] The broad substrate scope demonstrated in the literaturef or these reactions supports the notiont hat the electronic and sterica ttributeso fb oth the alkenol and arene coupling partners have little effect on enantioselectivity. [49] The enantioselectivity is instead believed to be controlled by steric repulsion between the alkenol and the tert-butyl group on the chiral PyrOx ligand (L1), as wella sa stabilizing CÀH p interaction of the pyridinyl ring of the chiral ligand and the arene (Figure 2). [50, 58a] The trans influence is also assumed to operate, with the naturalb ond orbitalc hargeo f the oxazoline nitrogen thought to make it as tronger s-donor than the nitrogeno ft he pyridine. [58a] The computationally calculated enantioselectivities (> 99 %) are in good agreement with experimentally determined values.
In further studies on alkenols ystems, it has also been found that polarization of the alkyl chain, as ar esult of the distance between thea lkene and the alcohol, aids in faced iscrimination of the boronic acid substrated uring the rate-determining migratory insertion step. [62] As enantioselectivity was found to decrease with increasingc hain length for this system, it was proposed that al one pair-p interaction between the alcohol and the aryl group on the oxazoline ring is predominantly responsible for the high levels of enantioselectivity. This favorable interaction is weakened with increasing chain length, leadingt o lower enantioselectivities.

Site selectivity
Whilst the electronic and steric properties of the coupling partners do not have as trong influence on enantioselectivity,t hey were found to govern the site selectivity.F or alkene insertion, the aryl group can be either cis or trans in relation to the oxazoline group of the chiral ligand. [50] For these configurations, the aryl group can insert at either the g-(distal) carbon or b-(proximal)carbon from either face of the alkene, leading to (R)or (S)-stereochemistry in the product.
It was determined that the site selectivity is controlled by the differencei ne lectronic structureb etween the two sp 2 -carbons of the alkene. [49,50] Interaction with the electrophilic palladium leads to polarizationo ft he alkene in the transition state ( Figure 3). [50, 58a] This results in the carbon atom of the nascent PdÀCb ond being more negativelyc harged, whilst there is as imultaneousb uild-up of positive chargeo nt he adjacent carbon atom where the aryl group will subsequently insert. [45, 50, 58a, 63] This site selectivity also aids in minimizing steric repulsion,a st he bulky palladium catalyst is situated on the less hindered alkene carbon. This theory is in agreement with experimental evidence that site selectivity increases with decreas-  ing electron density of the arene, increased steric demand aroundt he alkene, andashorter chain length. Other factors, such as the reactionsolvent, have also been found to influence the observed site selectivity. [48]

Applications in Synthesis
While reports on redox-relay (oxidative) Heck reactions have frequentlya pplied these methods to pharmaceutically relevant structurest oh ighlight their potential utility,t here have been fewer examples of widespread application beyondt hose used to showcase the specific developed methodology.
Baran and co-workers have employedt he redox-relay oxidative Heck in the 11-step synthesis of natural products (À)-teleocidin B-1 to B-4( Scheme 31). [64] The coupling of intermediate boronic acid 92 with (E)-alkenol 93 resulted in construction of ak ey quaternary stereocenter in the synthesis. By using both enantiomers of PyrOx ligand (L1 and ent-L1)i nt urn, it was possible to synthesize both diastereomers of the product (94 and 95). Subsequent formation of the second quaternary stereocenterm eant that all four diastereomers (B-1t oB -4) could be synthesized from the same startingm aterials. Compared to prior reports, [49] significantly higher catalyst and ligand loadings were required, as well as an increased excess of the alkenol to be coupled. Addition of 2,6-di-tert-butylpyridine (2,6-di-tBu-py) was also required, to reduce an undesired protodeborylation side reaction.
Scheme33. Application of the Catellaniredox-relay Heck reaction in natural product and drug synthesis. ! 7steps), showcasing that more complex quaternary benzylic stereocenters, prevalent in an umber of bioactive molecules, can be generated efficiently.L ater,amodified set of conditions were employed in the three-step total synthesis of (AE)-ramelteon (previously ! 4steps). [67] Attempts to establish an asymmetric variant of this methodology have been initiated, sof ar with only limited success andm oderate enantiocontrol (Scheme 33).

Summary and Outlook
Since the seminal publicationf irst reporting the unexpected chain walkingr eaction in 1968, the field of palladium catalyzed redox-relay Heck migration has evolved significantly.O ver the past decade the comprehensive development of asymmetric redox-relay Heck reactions and itso xidative variant using PyrOx ligands has led to an ever-increasing understandingo f their synthetic potential. Such transformations typically exhibit high levels of regio-a nd enantio-control, thus providing easy access to novel chiral building blocks bearing remote tertiary or quaternary stereocenterst hat would otherwise be challenging to synthesize.
Whilst substantial advances are being made in the field to make this methodology more widely applicable, extensive work will undoubtedly be required to understand the subtleties of the migration on more complex and non-biased systems. In time, these discoveries should aid in making new, complex transformations more predictable and reliable. This is am ajor research focus, and efforts towards predictinge nantioselectivities have already been reported. [68] The potential scalability of this transformation has also yet to be thoroughly investigated, and detailed studies from this perspective may encourage industrial uptake of the methodology. [69] For the redox-relay Heck reaction, additional considerations need to be taken for the use of diazonium salts in palladium catalysis, [70] whilst there is added complexity in the redox-relay oxidative Heck reaction based on the greater number of additives, which could make it more challenging to understand the role of all reaction components. In addition, the use of oxygen is undesirable on scale. [71] Another avenue which may provide new synthetico pportunities include one-pot sequential catalysis, whereby the in situ generated redox-relay product could be subsequently cross-coupled. [72] From as ynthetic utility viewpoint, the expansion of scope to aw ider range of heterocycles, as well as additional redox acceptors capable of driving the chain migration such as sulfones and sulfonamides, would maket his transformationm ore broadly applicable for the synthesis of bioactive small molecule libraries in drug discovery. [73] Another limitation is the synthesis of quaternary stereocenters, which is currently restrained by the steric hindrance of the alkene substituents. [8d, 56] It is worth noting that there have been multiple reports on redoxrelay (oxidative) Heck b-functionalization using carbamates as coupling partners; [74] protected alcohols to furnish the corresponding carbonyl products, via in situ deprotections trategies; [61,75] or alkynes to generate C sp -C sp 3 stereocenters. [76] Expansiono ft hesem ethodologies for more remote functionali-zation would also be of great value. It is our hope that the synthetic utility of the transformations and applications described in this Minirevieww ill inspiref uture research in this field and in turn help address the currentl imitations discussed.