Control of Absolute Stereochemistry in Transition‐Metal‐Catalysed Hydrogen‐Borrowing Reactions

Abstract Hydrogen‐borrowing catalysis represents a powerful method for the alkylation of amine or enolate nucleophiles with non‐activated alcohols. This approach relies upon a catalyst that can mediate a strategic series of redox events, enabling the formation of C−C and C−N bonds and producing water as the sole by‐product. In the majority of cases these reactions have been employed to target achiral or racemic products. In contrast, the focus of this Minireview is upon hydrogen‐borrowing‐catalysed reactions in which the absolute stereochemical outcome of the process can be controlled. Asymmetric hydrogen‐borrowing catalysis is rapidly emerging as a powerful approach for the synthesis of enantioenriched amine and carbonyl containing products and examples involving both C−N and C−C bond formation are presented. A variety of different approaches are discussed including use of chiral auxiliaries, asymmetric catalysis and enantiospecific processes.


Introduction
Alkylation is af undamental process in organic synthesis and is typicallyamongst the first reactions taught to chemistryundergraduate students. [1] Aw ide variety of amine and enolate nucleophiles can be employed, enabling CÀNo rC ÀCb ond formation with halide or pseudohalide electrophiles (Scheme 1A). However,i np ractice, this process suffers from significant drawbacks. For example, the electrophiles employed are typically highly toxic and the reactions produce stoichiometric quantities of waste which mustb es eparated after the reaction. [2] Moreover,t he alkylation of amines is often complicated by the formationo fo ver-alkylated side-products. [3] In the case of enolate alkylation, reactions with primary electrophiles typically proceede fficiently,b ut the analogous reactions of secondary electrophiles are often sluggish and can be hampered by competing elimination processes. Hydrogen-borrowing catalysis has emerged as ap owerful alternative alkylation strategy, which solves many of these problems( Scheme 1B). [4] This approach relieso nacatalyst that oxidizes the alcohol starting materialtothe corresponding carbonyl compound, temporarily storing the hydrogen which is produced. The aldehyde or ketone then condenses with the nucleophilic partner (usually an amine or enolate), eliminating water to form an intermediate which is finally reduced by the stored hydrogen to form the alkylated product and regenerate the active catalyst. This reactionp roduces water as the sole by-product and enables non-activated alcohols to serve as electrophiles, therebyn egating the requirement for toxic alkyl halide electrophiles. Using this approach, amines can be reactedw ithout over-alkylation and secondary alcohols can be employed. However, ak ey question still remains, namely,h ow can absolutes tereochemistry be controlled in such ar eaction?R ecently,anumber of reports have emerged that address this important challenge and this is the focusoft his Minireview. [5] The majority of asymmetrich ydrogen-borrowing processes that have been developed involve reactions between an ucleophile 1 and ar acemic secondary alcohol 2 bearing two different groups (R 1 ¼ 6 R 2 ). This process results in the formation of a chiral product 4 (Scheme 2), the stereochemistry of which is established during the step in which hydrogen is returned to achiral intermediate 3.T his provides au nique opportunity to induce asymmetry by controlling the facial selectivity of the reductions tep. In practice, two distinct strategies can be envisaged to direct such ap rocess: (i)diastereoselective reduction of an enantiopure substrate, for example, by introduction of a chiral auxiliary;( ii)addition of an externalc hiral ligand (L*) which mediates ac atalytic asymmetric reduction. Highly enantioselective hydrogen-borrowing processes which employ both of these strategies have been developed and will be discussed in this Minireview.A dditionally,s everalr elated processes will be presentedw hich enables tereochemistry to be controlled at sites adjacent to the reacting alcohol, for example via dynamic kinetic asymmetric transformationo re nantiospecific alkylation.
Overall, the aim of this Minireview is to present the current state of the art in transition-metal mediated asymmetrich ydrogen-borrowing catalysis. The focus is upon processes that form an ew CÀCo rC ÀNb ond and examples involving asymmetric transfer hydrogenation or redox shuttlesa re not covered. A wide variety of approaches to achieve stereocontrol will be discussed including the use of chiral auxiliaries, transition-metal catalysis and enantiospecific processes.

CÀNBond Formation
Amines are hugely important buildingb locks, with extensive applicationsi nm aterials science, natural product synthesis and in the pharmaceutical industry.H ydrogen-borrowingc atalysis is aw ell-established method for N-alkylation and is widely employed for the synthesis of important racemic and achiral amine containing materials. As an illustrative example of ah ydrogen-borrowing process which targets an achiral product, Pfizer have disclosedakilogram-scale hydrogen-borrowing al-kylationb etween alcohol 5 and substituted benzylamine 6 (Scheme3A). [6] This process was catalysed by 0.0325 mol %o f [Cp*IrCl 2 ] 2 ,p roducing amine 7 in 76 %y ield, which could be converted to the anti-schizophrenic medicine PF-03463275 in a single step. Mechanistically,t his typeo fr eactionp roceeds by metal-mediated oxidation of the alcohol to give the respective ketoneo ra ldehyde as well as am etal hydride species (Scheme 3B). The carbonyl then undergoes condensation and the resulting imine is reduced by the metal hydride to give the amine and the regenerated metal catalyst.
In order to carry out an asymmetric amination reaction, the facial selectivity of the final reduction of the imine (or iminium) intermediate must be controlled. This section will discusst hree main strategies to induce asymmetry in this chemistry, namely: (i)Use of chiral substrates;( ii)Use of chiral ligandsi nt ransition metal catalysis;a nd (iii)Use of enzymes. These strategies are detaileds equentially in the following sub-sections.

Enantiopure amines
Various chiral aminen ucleophilesh ave been used to induce diastereoselectivity in hydrogen-borrowing alkylation processes and Ellman's chiral tert-butanesulfinamide auxiliary has proved to be particularly effective in this context. This strategy was pioneered by Dong,G uan, and co-workers in 2014, who employed ac ommercially available ruthenium(II) PNP-type pincer catalyst( Ru-Macho) to achieve diastereoselective alkylation with ar ange of benzylic and aliphatic secondary alcohols (Scheme 4A). [7] Ad ifference in steric bulk between the two groups flankingt he secondary hydroxyl group was required for good diastereoselectivity-a trend consistent with that observed by Ellman and others in the reduction of sulfinylimines. [8] Very high diastereoselectivity was achieved fort he majority of alcohol substrates, whichi sp articularly impressive considering the high reaction temperature (120 8C). Notably, no epimerization of the chiral sulfinimide was observed, enabling the synthesis of the alkylated products in enantiopure form. Subsequently,X ia, Zhang,a nd co-workers developed a related process mediated by iridium catalyst Ir-1 (Scheme 4B). [9] Ar ange of secondary alcohols underwent highly diastereoselective alkylation, including relativelyh indered examples such as 1-phenyl-1-propanol. It was also demonstrated that the chiral auxiliary could be cleaved to obtain the corresponding enantiopure primary amines.
In the same year,L ei, Xiao, Wang, and co-workers made the surprising discovery that as imilar alkylation reaction can be conducted in the absence of any transition-metal catalyst (Scheme5). [10] It was shown that by instead adding as mall quantity( 15 mol %) of the ketone which would result from alcohol oxidation, highly diastereoselective N-alkylation was observed. The method was also used to preparee nantioenriched deuterium-labelled amines 12 from the correspondingr acemic a-deuterated alcohols. The products werei solated with very high levelso fd euterium incorporation. Thea uthors suggest that the mechanism of this process is initiatedb yc ondensation of amine 9 with ketone 13.T he proposed key step in-volvesM eerwein-Ponndorf-Verley-type reduction of the resulting imine 14 by sodium alkoxide 15 via ac helated transition state TS-1.T his hypothesis is supported by the observation that the reactionp rogressively stalls when increasing quantities of 15-crown-5, ac rown ether knownt os equester Na + ,a re added.
Yamaguchi, Fujita and co-workersh aver eported that enantiopure (R)-a-methylbenzylamine (99.5:0.5 e.r.)c an undergo double hydrogen-borrowing alkylation with ad iol to form piperidine 18 (Scheme 6A). [11] Thep roduct was formed in 96:4 d.r.w ith as light erosion in enantiopurity( 93:7 e.r.a nd 96.5:3.5 e.r.f or the major andm inor diastereomers, respectively). The major diastereomer was suggested to have arisen from hydride delivery to the less hindered face of intermediate 21; the smalla mount of racemization was attributed to benzylic deprotonation of this intermediate. The benzyl group readily underwent hydrogenolysis to unveilt he secondary amine 20. This strategy was later employed by Trudell and co-workers as the keys tep in at otal syntheses of noranabasamine (Scheme 6B). [12] Diol 22 was prepared in two steps and then subjected to Yamaguchi's hydrogen-borrowinga nnulation together with either 17 or ent-17 to separatelyg ive either 23 or ent-23.T hese intermediates could be converted to (À)-or (+ +)-noranabasamine in three steps.
Interestingly,e nantiopure a-methylbenzylamine derivatives do not always undergo racemization in hydrogen-borrowing reactions. Indeed, Williams and co-workers have shown that (R)-a-methylbenzylamine (17)c an undergo hydrogenb orrowing with ap rimary alcohol 24 under ruthenium-catalysed conditions with complete stereochemical integrity (Scheme 7A). [13] As imilarr eaction with a1 ,4-diol also generated the corresponding piperidine 27 without racemization. As imilar process has been reported by Hultzsch and co-workers which utilized a manganese-catalysed hydrogen-borrowing alkylation as ak ey step to prepare the hyperparathyroidism medication, cinacalcet, from an enantiopure naphthyl substituteda mine (Scheme 7B). [14] Yan, Feringa, and Barta have reported as ystem for the N-alkylation of unprotected amino acids with alcohols using the Shvo catalyst (Scheme 8). [15] The choice of catalystw as essential-theS hvo catalysti scapable of bifunctional activationo f the alcohol without the need fore xternalb ase that could result in racemization of either the starting materials or products. Aw ide variety of amino acids were successfully N-alkylated under these conditions with excellent yields. Surprisingly, even serine which bears af ree hydroxyl group was ac ompetent substrate that gave the desired product in quantitative yield. For the alkylation of alanineand serine (31 d and 31 e,respectively), as mall amount of racemization was observed, but in the majority of cases the productsw ere obtained with near perfecte nantiospecificity. [16] Cumpstey,M artín-Matute and co-workers have shown that alcohols and amides which are both derived from carbohydratesc an be coupled under hydrogen-borrowingc onditions to afford amino sugarss uch as 34 (Scheme 9). [17] Both the amine anda lcohol partners reactedw ithoute rosiono fs tereochemistry to afford the products with complete diastereoselectivity.

Enantiopure alcohols
Diastereoselectivityc an also be inducedb yu sing chiral alcohol substrates. This strategy was employed by Jacolot, Popowycz and co-workerst oc arry out iridium-catalysed aminationso f isohexides (Scheme 11). [19] Using conditions adapted from those reported by Zhao (vide infra), highly diastereoselective alkylation could be achieved affordingb icyclic amines 37.A lthoughachiral catalyst was used in this process, the diastereoselectivity appearst ob ear esult of substrate control.I ndeed, during reactiono ptimization it was shown that complete diastereoselectivity was also observed using achiral iridium catalysts.
Chen and co-workersh ave reported an intramolecular hydrogen-borrowing alkylation of glucose-derived 1,5-hydroxamines (Scheme 12). [20] The reaction proceeded in moderate yields (up to 42 %) but afforded high diastereoselectivity at the newly formed stereogenic centera tC 5. The relative stereochemicalo utcome of this process is somewhat surprising as it is not consistent with axial addition of iridium hydride to a half-chair iminium species. The authors propose that the high temperature of the process (180 8C) may enable an alternative pathway involving ab oat-like transitions tate to become viable.
Donohoe andc o-workers have reported an iridium-catalysed synthesis of saturated aza-heterocycles via ah ydrogen-borrowing annulation between amines and multi-substituted diols (Scheme 13). [21] This reaction is thought to proceed via am echanism involving two successive hydrogen-borrowing alkylations, the final step of which would be the reduction of a cyclic iminium species 42.T he diastereoselectivity of this process was systematicallyi nvestigatedb yi ntroducing as econd substituent at each possible positiona roundt he heterocyclic core leading to piperidines 41 a-d in high yields.F or 41 a-c the relative stereochemistry is consistent with axial addition of iridium hydride to ah alf-chair bearing an equatorial (or pseudoequatorial) substituent. [22] For 41 d,i tw as proposed that A 1, 3 strain forces the methyl group into apseudoaxial conformation leadingtot he cis-diastereoisomer.
In the same work, the authors also developed as ynthesis of enantioenriched C3-substituted pyrrolidinesa nd piperidines from enantiopure1 ,4-and 1,5-diols (Scheme 14). [21] Under typical conditions employedf or the iridium-catalysed amine alkylation, significant racemization was observed, presumably as a consequence of deprotonation of cyclic iminium intermediate 44 to the corresponding enamine 45.B yc arrying out the reaction in water,t his undesired racemization pathway could be almoste ntirely suppressed enabling the isolation of highly enantioenriched C3-substituted piperidines and pyrrolidines.

Use of chiral additives and transition-metalcatalysts
Asymmetric transition metal catalysis has also been widely used as as trategy to achievea symmetrich ydrogen borrowing. The most common of examples involvec ontrol of the same stereocenter at which the new CÀNb ond is formed.O ther examplesi nvolve control of as tereocenter that is remote to the new CÀNb ond being formed. These two sub-classifications will be discussed separately.

Controlling the stereocenteratw hich the CÀNb ond is formed
The concept of employing ac hiral transition-metal catalystt o perform asymmetrich ydrogen-borrowing alkylation of amines has been pioneered by Zhao and co-workers, who in 2014 reportedadual-catalytic system that employedachiral iridium Scheme11. Diastereoselective hydrogen-borrowing amination of isohexides.
Chem. Eur.J.2020, 26,12912 -12926 www.chemeurj.org 2020 The Authors. Published by Wiley-VCH GmbH catalyst Ir-2 in conjunction with chiral Brønsted acid 49 (Scheme 15). [23] These conditions enabledt he alkylation of anilines 47 with racemic secondary alcohols 46 in high yields and excellent enantioselectivities.T he use of ac hiral Brønsted acid was essential for both yield and enantioselectivity;b oth the chirality of the iridium catalyst and phosphorica cid catalyst were important in the process and high enantioselectivities were only observed for the matchedc ase-when the acid was removede ntirely,n oc onversion was observed. Mechanistically, it was proposed that the iridium complex Ir-2 is first protonated by the phosphoric acid. The resulting iridium phosphate undergoes ligand exchange with the alcohol followed by oxidation to generate the corresponding ketone,w hich in the presenceo ft he acid catalystc ondenses with the aniline.T he resultingp rotonated iminium speciesi ss ufficiently reactive to be reduced by iridium hydride, generating the enantioenriched amine product and regenerating the active catalyst.
The Zhao group subsequently discovered that chiral phosphoric acids alone can induce high levels of enantioselectivity in intramolecular hydrogen-borrowing alkylation reactions (Scheme 16). [24] An achiral Ir catalyst Ir-3 in conjunction with chiral phosphoric acid catalyst 51 and could be employed to preparearange of substituted tetrahydroquinolines 52 in excellent yields with enantioselectivities of up to 98.5:1.5 e.r.
Ta ng, Zhou and co-workersh aved eveloped an earth-abundant catalyst system employing Ni(OTf) 2 with (S)-binapine to catalysea na symmetrich ydrogen-borrowing reaction between racemic benzylic alcohols and benzhydrazides (Scheme 17). [25] The products could be convertedt ot he free benzylamines by reduction with SmI 2 or Raney nickel. Non-asymmetric examples employing aliphatic alcohols as substrates were also successful, suggesting that the reaction operates via a" true" hydrogen pathway,a so pposed to an alternate mechanism involving a h 3 -benzylnickel species 56.D euterium labellings tudies using a-deuterated benzyla lcohol gave results that corroborated a hydrogen-borrowingp athway;t he resulting benzylamine product only had 68 %d euterium incorporation-this deuterium loss is consistent with in situ washout of deuterium via H/ De xchange of ac ationic Ni-D intermediate with protons of acids and alcoholic solvents.
Beller and co-workers have developed ah ighly enantioselective hydrogen-borrowing reaction that enables the synthesis of chiral oxazolidin-2-ones 59 from 1,2-diols and urea (Scheme 18). [26] The process is catalysed by ac ombination of commercially available Ru 3 (CO) 12 and (R)-(+ +)-MeO-BIPHEP, and is thought to proceed via initial nucleophilic substitution of urea with the less sterically hindered primary hydroxyl group of the diol. This generatesa mino alcohol 58 in situ, which then undergoes au nimolecular asymmetrich ydrogen-borrowing alkylation. The enantio-determining step is asymmetric reduction of acyl imine 61,w hich proceeds in up to 96.5:3.5 e.r.T his high Scheme15. Enantioselectiveamination of racemic alcohols via cooperative catalysis by achiral iridium complex andachiralp hosphoric acid. level of enantioselectivity is particularlyr emarkable given the high reaction temperatures required forthis reaction (150 8C).
Very recently,Z hang, Xia, Zhao and co-workers reporteda highly enantioselective Ir I -bisphosphine-catalysed process in which racemic epoxides and 1,2-diaminobenzenes were converted to enantioenriched tetrahydroquinoxalines (Scheme 19). [27] That epoxides instead of more conventional alcohols were used as the non-nitrogen-containing partner makes this findingp articularly noteworthy.T he reaction is initiated by Zn(OTf) 2 -catalysed epoxide opening, which occurs at primary endo ft he epoxide to generate a1 ,5-amino alcohol which cyclizes via an enantioselective hydrogen-borrowing alkylation.A lthough numerous aliphatic epoxides reacted efficiently,ap reliminary experiment involving an aryl-substituted epoxide gave nearly racemic product. This result was rationalized via an inversion in the regioselectivity of Lewis acid mediated epoxide opening-epoxide openinga tt he benzylic position would be expected to afford racemic product. However, this problemc ould be solved by using enantiopure aryl-substituted epoxides in conjunction with am atched chiral catalyst.

Controlling stereocenters adjacent to the site of CÀNb ond formation
The examples discussed thus far have predominantly focused upon hydrogen-borrowing reactions which controlt he stereogenic center whichi sf ormed at the site of CÀNb ond formation (i.e.,b ys tereoselective reduction). However,s everal additional processes have been developed which enable control over as tereogenic centerl ocated adjacent to the amination site.
The first such example was reported by Oe and co-workers, who developed an asymmetric hydrogen-borrowinga pproach for the synthesis of b-amino alcohols from 1,2-diols (Scheme 20 A). [28] This reactionw as mediated by [RuCl 2 (pcymene)] 2 in conjunction with ac hiral Josiphos ligand, which resulted in selective amination at the primary site of the diol. Modest,b ut promising levels of enantiocontrol were observed at the newly forged b-stereogenicc enter( up to 88.5:11.5 e.r.). Zhao, Zhang and co-workers subsequently reportedt hat introductiono fa na chiral Brønsted acid additive significantly boosts the enantioselectivity of the process (Scheme 20 B). [29] A wide range of b-aminoa lcohols and amines couldb er eacted in excellent yields and with very high levels of enantioselectivity (up to 97:3 e.r.). Mechanistically,t he Zhao group proposed a pathway involving oxidation of the diol followedb yc ondensation of the resulting aldehydew itht he amine. The resulting iminium intermediate 77 could rapidlye quilibrate with its enantiomer ent-77 by reversible deprotonation/reprotonation via the intermediacy of enamine 78.T he chiral ruthenium hydride can then selectively reduce ent-77 (rather than 77)l ead-ing to efficient dynamic kinetic asymmetric amination. [30] The authorss uggest that benzoica cid accelerates the iminium racemization pathway.I nterestingly,i nt heir initial publication, Oe and co-workersp roposed ad ifferent mechanism involving enantio-determining reduction of ak eto-amine( e.g. 79). To rule out this pathway in their acid-catalysed process, Zhao, Zhang andc o-workerss ynthesized and resubjected amino ketone 79 to the standardc onditions. The product was obtained in significantly lower enantioselectivity (both with and withoutb enzoic acid), implying that this alternative ketone reductionpathway is not operative.
The use of asymmetrichydrogen borrowing to control multiple stereocenters is also mechanistically intriguing-such a processw ould doubly stereoconvergent and could funnel up to four diastereomers towards as inglep roduct that is both diastereomerically and enantiomerically pure. Such ac oncept underpins the Zhao group's work on the asymmetric amination of alcohols to form a,b-branched amines (Scheme 21). [31] This reaction is proposed to proceed via as imilar pathwayt o the analogousr eactiono f1 ,2-diols, but in this case, the chiral iridium catalyst simultaneously controlst he b-stereogenic center by dynamic asymmetrict ransformation alongw ith the facial selectivity of iminium reduction. Very high levels of both diastereo-and enantioselectivity were observed in this process. The substrate scope was remarkably broad and aw idev ariety of aromatic, aliphatic anda lkoxy substituents could successfully be introduced at the b-position (R 1 /R 2 ).
It is also possible to employ asymmetric hydrogen-borrowing catalysis to controla na djacent axis of chirality.F or example, Zhang and Wang have reportedah ighly atropselective amination of biaryl alcohols 87 (Scheme 22). [32] This reactioni s mediated by ac hiral iridium(III) catalysti nc onjunction with an achiral Brønsted acid. The reactioni sp roposed to proceed via iridium-mediated oxidation of the racemic biaryl alcohol to the correspondinga ldehyde 91,w hich then condenses with the amine to form imine 92.T his intermediate can undergo reversible cyclizationt of rom cyclic hemiaminal 93,w hich is expected to have al ow barrier to biaryl rotation due to the "bridged biaryl" effect discovered by Bringmann. [33] This allows interconversion between the enantiomerso ft he biaryl iminium (92$ent-92)e nabling ad ynamic kinetic resolution in which only one enantiomer undergoes reduction to form 90 with very high enantioselectivity.I tw as shown that the biaryl amine products have av ery high barriert or acemization (DG°r ot = 129.0 kJ mol À1 , t 1/2 rac = 157.6 hat8 08C).

Use of enzymes
Biocatalysis can offer au seful alternative approach for hydrogen-borrowing amination in whiche ach elementary step is catalysed by an individual enzyme. Such reactions are amenable to low operating temperatures and, in several cases, enzymatic catalysis hasb een conducted with racemic secondary alcohols to give enantiopure amines. [34] As ar epresentative example,T urner andc o-workers have reported an elegant enzymatic process for the asymmetrica lkylation of ammonia (Scheme 23). [35] The first step involves ap air of alcohol dehydrogenase enzymes (AD), which oxidiset he alcohol to the corresponding ketone along with concomitantc onversion of NAD + to NADH and H + (two AD enzymes are required, one to oxidise each enantiomer of the racemic alcohol). The resulting ketone then condenses with ammonia to form an imine, which is reduced by an amine dehydrogenase (AmDH) to generate the chiral aminep roduct. This step also converts NADH back to NAD + ,t hereby completingt he catalytic cycle. This method can be employed to preparea na ssortmento fa mines with excellent levels of enantioselectivity.T he Turner group and others have subsequently reported exciting developments in this field, including streamlining the process to use as ingle non-stereoselective AD enzyme, [36] and expanding the scope to other amine nucleophiles. [37] Recently,i th as even been shown that amination is possible in E. coli cells. [38] As this chemistry does not involvet ransition-metal catalysis, ac omprehensive discussion lies outside the scope of this Minireview,b ut enzymatic chemistry can offer au seful alternative to transitionmetal-catalysed methods.

CÀCBond Formation
The formation of carbon-carbonb onds under hydrogen-borrowing conditions is aw ell-established methodt hat has been successfully applied to the alkylation of ketones, esters and nitriles. As ar epresentative example of an on-stereoselective process, Ishii andc o-workers have shown that variousk etones can undergo a-alkylation with primary alcohols to form alkylated products 99 in excellent yields (Scheme 24 A). [39] Mechanistically,t hese reactions are analogous to the corresponding amine alkylation reactions, proceeding via catalyst-promoted oxidation of the alcoholt ot he corresponding carbonyl compound along with formation of at ransition-metal hydride (Scheme 24 B). The aldehyde or ketone then undergoes ab asemediated aldol condensation with an enolate, followed by conjugate reduction of the resulting enone to deliver the saturated product and regenerate the active catalyst. This section will discuss severals trategies for induction of asymmetry including carbonyl reduction, enzymatic catalysis, organocataly-sis andc atalytic asymmetric enone reduction.T hese strategies are detailed sequentially in the following sections.

Asymmetricc arbonyl chemistry
Krische and co-workersh ave pioneered ap owerful new approach for asymmetric carbonyl addition which relies upon hydrogen-borrowing catalysis (Scheme 25). In this chemistry,a n alcohol 100 and a p-unsaturatedp artner 101 can undergo redox-neutral coupling, enabling the highly enantioselective synthesis of homologated alcohol products 102.M echanistically,t his chemistry is distinct from all other examples presented thus far-the process is stilli nitiated by transition-metal-mediated oxidationo fa na lcohol, but the metal hydridew hich is produced directly reacts with the p-unsaturated partner, converting it to an organometallic nucleophile 103 in situ. The enantio-determining step involves recombination of the carbonyl and organometallic partners. The process is remarkably general and has been appliedt oc ouplings of alcohols with an extensive array of p-unsaturated partners (selected examples are showni nS cheme 25 and include allenes, alkynes, dienes, styrenes, and av ariousa llylic electrophiles). [40] This is ar apidly developing area of research and has previously been reviewed elsewhere. [41] Af ull discussion lies outside the remit of this Minireview,b ut this chemistry represents an extremely useful approachfor enantioselective redox-neutral synthesis. Several groups have investigated asymmetric carbonyl reductionw ithin the context of hydrogen-borrowing catalysis.
This area was pioneeredb yN ishibayashi and co-workers, who in 2006, reported ao ne-pot process for the alkylation of acetophenones (104)w ith primary alcohols (105)y ieldings econdary alcohols (106)i ng ood yields and with excellent enantioselectivities (Scheme 26). [42] The first step of the process is at ypical iridium-catalysed hydrogen-borrowing alkylation to generate achiral ketone 109.I nt he second step, ruthenium-catalysed asymmetrict ransfer hydrogenation of ketone 109 with isopropanol as as acrificial hydride source sets the benzylic stereocenter generating chiralalcohols 106 in up to 99:1 e.r.
This method was subsequently developed by Adolfsson and co-workers. [43] Thea uthors reported that as ingle ruthenium catalystc an promote both the hydrogen-borrowing alkylation and asymmetric reduction step( Scheme 27). Ac ombination of [Ru(p-cymene)Cl 2 ] 2 with chiral ligand 110 gave reduced products 106 at moderate reactiont emperatures and with good levels of enantioselectivity.I nt his case, an excess of the alcohol partner 105 (3 equiv) served as the terminal reductant for the transfer-hydrogenation step. The authors observed that addition of substoichiometric amountso fl ithium chloride increasedt he reaction rate as well as the enantioselectivity.T he positive effect of lithium chloride on the catalytic activity of similar ruthenium-based transfer hydrogenation catalysts had been established previously and can be rationalizedb yr eaction via transition state TS-2 wherein the lithium ion aids the hydride transfer by coordination to both the substrate and catalyst. [44] Suzuki and co-workersh ave reported an interesting hydrogen-borrowing alkylation between meso-diol 111 and benzaldehydes (Scheme 28). [45] The authors proposed that the absolute stereochemistryi ss et in the first step, which involves oxidative desymmetrization of diol 111.T his is followed by at ypical hydrogen-borrowing pathway involving condensation with benzaldehydea nd diastereoselective enone reduction. The product 113 was obtained in excellent diastereo-and enantioselectivity,b ut the yield was low (33 %) due to poor conversion in the final reduction step. However,i tw as discovered that addition of isopropanol as as acrificial reductant after 30 minutes could ensure that complete reduction takes place enabling the isolation of products 113 in up to 88 %y ield, still with very high levelsofstereoselectivity.

Biocatalysis
Several elegant biocatalytic enolatea lkylation procedures have been developed. Ad etailed discussion of this chemistry is beyondt he remit of this Minireview,b ut this can be au seful alternative to transition-metal based approaches. As ar epresentativee xample, Gotor and co-workers have reported ah ydrogen-borrowing alkylation of a-cyano ketones (116)w ith primary alcohols catalysed by the fungus Curvularia lunata (Scheme 29). [46] The productsw ere obtained in good to excellent stereoselectivity and useful yields from ap reparative synthetic viewpoint. The observation that tetradeuterated product 117d was isolatedw hen hexadeuteroethanol was em-ployed supports the proposed hydrogen-borrowing mechanism for this transformation.

Conjugate addition
Quintard, Rodriguez, and co-workers have pioneered af undamentally different approach to inducee nantioselectivity in hydrogen-borrowing catalysed reactions.T he authors reported a dual-catalytic process mediated by ac ombinationo fa na chiral iron complex along with achiralproline-derived organocatalyst (Scheme 30). [47] Under these conditions, b-ketoesters 118 could be reacted with primary allylic alcohols (119)t oe fficientlyg enerate chiral alcohols 121 with high levelso fd iastereo-and enantioselectivity.T his reactioni st hought to operate by initial activation of Knçlker complex Fe-1 with trimethylamine Noxide to give catalytically active species Fe-2 along with CO 2 and trimethylamine as by-products. This iron complex can oxidise the allylic alcohol 119 to form a,b-unsaturated aldehyde 122 along with iron hydride Fe-3.I nasecond catalytic cycle the aminocatalyst 120 condenses with aldehyde 122 to form iminium 123,f ollowed by asymmetricc onjugate addition of the b-ketoester nucleophile. Hydrolysis of addition product 124 results in aldehyde 125 and regenerates organocatalyst 120. Finally,f acile reduction of the saturated aldehyde by Fe-3 closes the hydrogen-borrowing cycle and delivers the chiral alcohol product 121.I tw as subsequently shown that the enantioselectivity of this reaction can be enhanced by the addition of Cu(acac) 2 as an additional co-catalyst. [48] Treatment of the hydroxyester products (121)w ith DBU (1,8-diazabicycloundec-7-ene)r esulted in lactonization to generatearange of enantioenriched cyclic derivatives (126).
Quintard, Rodriguez, and co-workers have also reported that 1,3-diketones can be employed as nucleophiles under similar reactionc onditions (Scheme 31). [49] In this case, the intermediate hydroxyketonei ntermediates 128 underwent as pontaneous C-to O-acyl shift to deliver synthetically useful protected alcohols 129.Aseries of examples were prepared in high yields with excellent levels of enantioselectivity (for example  129 a-129 b). The authors demonstrated that the reduction of saturated aldehydes, by iron hydride Fe-3 is much more facile than the corresponding reaction with unsaturated aldehydes, suggesting as ynergistic link between the two catalytic cycles.
Very recently,D ydio andc o-workers reported ar elated methodi nw hich primary allylic alcohols were again transiently activated via oxidation with Knçlker's complex (Scheme 32). [50] In this case, the a,b-unsaturated aldehyde intermediates were captured in ah ighly enantioselective Rh-BINAP-catalysed conjugate addition reaction with aryl boronic acids, enabling the synthesis of g-functionalized alcohols in good yields and excellent enantioselectivities.I tw as also shown that RuH 2 (PPh 3 ) 4 can be used in place of Knçlker'sc omplex and in somec ases gives higher yields and selectivities, whereas Fe-1 tolerates a wider substrate scope.

Selectiveenone reduction
The most direct methodt oc ontrola bsolute stereoselectivity within hydrogen-borrowing enolate alkylation reactions would be to control the facial selectivityo ft he final enone reduction step. However, remarkably few examples of such asymmetric processesh ave been reported. There are two problemsw hich have limited the development of such asymmetric reactions: (i)the strongly basic conditions required to promote aldol condensation typically lead to racemization at the a-stereogenic center;( ii)iti se ssential to controlt he geometry of the enone intermediate in order to obtain high levels of enantioselectivity.H owever,ahandfulo fa symmetrice nolate alkylation processes have been developedt hat overcome these challenges.
This area was pioneered by Williams andc o-workers, who in 2007 reported an asymmetric hydrogen-borrowing reaction between benzyl alcohol and stabilized Wittig ylide 133 (Scheme 33). [51] This reactiono perates via as imilar mechanism to as tandard hydrogen-borrowing process, except that the aldol step is replaced by aW ittig olefination. This was key to the success of the process as it ensured that enone intermediate 136 was formed as as ingle E isomer and also enabled the reactiont op roceed in the absence of base, limiting the possibility of racemizationo ft he newly formed a-stereogenic center in 134.E mploying an Ir I -BINAP system, 134 was isolated in 58 %y ield with very high enantioselectivity (93.5:6.5 e.r.).
Donohoe and co-workers have shown that pentamethylphenyl( Ph*) ketones can be alkylated with aw ide varietyo f primary or secondary alcohols and diols. [52,53] The Ph* group is pivotalf or these transformations-because the aryl group is orthogonal to the carbonyl, the ortho-methyl groups protect it from undesired reduction and homodimerization processes. Moreover,t he Ph* group can readily be converted to aw ide range of functional groups (e.g.,e sters, amines, acidsa nd alcohols) by retro-Friedel-Crafts acylation. [52] Donohoe and coworkers recently reported that pentamethylacetophenone 137 can undergo ahighly enantioselective hydrogen-borrowing annulationw ith diols 138 to synthesize enantioenricheds ubstituted cyclohexanes 139 (Scheme 34). [54] It is thought that the enantiodeterminings tep involves iridium hydride mediated reductiono facyclic enone intermediate via transition state TS-3.T he cyclic nature of the enonei ntermediate enforces a single alkene geometry,t hereby enabling highly enantioselective reduction to form acyl-cyclohexane products such as 139 a-139 b.T he Donohoe group had previously shown that enantiopure g-substituted 1,5-diols react withoutr acemization, [52c,d] and it was found that by matching or mismatching the chiral ligand complex diastereomerically enriched products such as 139 c could be synthesizedi nv ery high yield and diastereoselectivity.
Donohoe and co-workers subsequently reported that pentamethylacetophenone 137 can also undergo asymmetric hydrogen-borrowing alkylation with methyl-substituted secondary alcohols 140 (Scheme 35). [55] This processo perates via a typical hydrogen-borrowing mechanism and the key step therefore involves asymmetric reduction of acyclice nones 143. For high enantioselectivityt ob eo bserved, it wase ssential for the second alcohols ubstituent (R L )t ob es ignificantly larger than am ethyl group-for example, enantioselectivities of 58:42 e.r. and 90:10 e.r.w ere obtained for R L = Et and tBu, respectively.Itwas proposed that when the substituents are sterically well-differentiated, as ingle geometricali somer of the enone intermediate 143 could form, whichw as essential to achieve efficient asymmetrici nduction. The absolute stereochemicalo utcome of the reduction step was analogoust ot he related reduction of cyclic enones discussed above (i.e. via TS-4). Scheme33. Ap ioneeringe xample involving aW ittig reaction embedded within an asymmetrichydrogen-borrowing process.

Conclusion
Transition-metal-catalysed asymmetrich ydrogen-borrowing catalysis is rapidly emerging as ap owerful methodf or the formation of both CÀNa nd CÀCb onds. Various strategies have been developed to achieve such reactions, including asymmetric reduction,d ynamic kineticr esolution, enantiospecific reactions and desymmetrization. Metals from across the d-block can be employed in these reactions, and examples are presented involving catalysis by iridium, ruthenium,r hodium,i ron, nickel and manganese complexes, including several examples which also employo rganic co-catalysts. These methods enable efficient access to aw ide range of useful enantiopure amine and carbonyl containing materials. The field of asymmetrich ydrogen-borrowing catalysis is currently in ap hase of rapid development and the possibility for further advances and applications of theseprocesses is very exciting.