8
RESEARCH ARTICLE ORGANIC CHEMISTRY Delayed catalyst function enables direct enantioselective conversion of nitriles to NH 2 -amines Shaochen Zhang 1 *, Juan del Pozo 1 *, Filippo Romiti 1,2 *, Yucheng Mu 1 , Sebastian Torker 1,2 , Amir H. Hoveyda 1,2 Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine. Successful implementation requires that competing copper-based catalysts be present simultaneously and that the slower-forming and less reactive one engages first. This challenge was addressed by incorporation of a nonproductive side cycle, fueled selectively by inexpensive additives, to delay the function of the more active catalyst. The utility of this approach is highlighted by its application to the efficient preparation of the anticancer agent (+)-tangutorine. F acile and economical access to amines in high diastereomeric and enantiomeric pu- rity is crucial to future advances in chemistry, biology, and medicine. Despite substantial progress (1), however, several key limita- tions remain. There are just a handful of methods for catalytic enantioselective preparation of unprotected a-secondary amines RNH 2 (25). N-activated or -protected starting materials must otherwise be used, resulting in manipulations that increase waste generation and diminish effi- ciency. Synthesizing an unprotected a-secondary amine frequently necessitates (at times strongly) acidic, oxidizing, or reducing conditions that can be low or moderate yielding (6); in some instances, up to three chemical steps must be dedicated to protecting group manipulations alone (79), and/or excess amounts of a costly reagent (e.g., SmI 2 ) might be required (10). The conditions needed for removal of an N-protected unit can lead to side reactions occurring at other sites in a multifunctional molecule (11). Another major issue is that alkyl-substituted N-protected imines, relevant to synthesis of numerous bioactive molecules, tend to be unstable (versus aryl- or heteroaryl variants) and difficult to purify (on account of fast hydrolysis upon exposure to mois- ture and/or enamine or aminal formation), and must therefore be used as mixtures, which leads to low yields. Some of these complications may, in principle, be resolved by the use of N-H aldimines, but these are also unstable, and reports regarding their productive reactivity are scarce and restricted in scope (12). Moreover, when diastereomers can be generated, often only one of them can be accessed (1316). An enantioselective strategy should ideally be diastereodivergent (17). An attractive way to generate an enantiomeri- cally enriched amine would be by converting a readily accessible unsaturated hydrocarbon to an intermediate, which can then react in situ with an imine. An example is the recent protocol (Fig. 1A) for synthesis of N-p-methoxyphenylprotected homoallylic a-secondary amines (15). However, the method is confined to aryl imines (18), and conversion to an N-H amine not only demands harsh oxidative conditions, it is low yielding as well (19). The above shortcomings recently thwarted our efforts to conceive a scalable, diastereo- and enantioselective synthesis of tangutorine, a natu- rally occurring anticancer agent. Our initial plan included the intermediacy of tertiary lactam a (Fig. 1B), to be derived from a protected form of homoallylic amine b. Removal of an N-protecting group, however, under acidic or basic conditions, proved to be compromising for two reasons: first, untimely and rapid cyclization to secondary amide c, which rendered subsequent N-alkyl formation severely inefficient; second, premature unmask- ing of the allylic alcohol, seriously complicating downstream chemoselective amide activation needed for generation of the polycyclic frame- work. It might therefore not be surprising that the only reported enantioselective synthesis of tangutorine (20) is 26 steps long (21), with seven operations relating to protecting-group manipulations and another nine devoted to oxidation-state alterations. We needed to access secondary amine d, probably through merger of unprotected amine e with the appropriate aldehyde; d could then be easily converted to cyclic lactam a, en route to tangutorine. The question thus became: How does one generate N-H amine e efficiently and with high distereo- and enantioselectivity? Sequential additions to a nitrile An unprotected a-secondary amine might be synthesized by nucleophilic addition to a nitrile followed by reduction of the resulting N-H keti- mine (Fig. 1C). Many nitriles are either com- mercially available (unlike aldimines) or can be accessed by an increasing number of protocols (22, 23). Additionally, aldehyde synthesis by oxi- dation or reduction of more readily available and robust starting materials, N-protection to gener- ate a suitable aldimine, and subsequent unmask- ing would be obviated. Without an N-activating unit, enamine formation would be a much less likely pitfall. The prerequisite for high diastereo- and enantioselectivity aside, the idea of synthesiz- ing unprotected amines by sequential, one-pot, addition to a nitrile presented several challenges. Nitriles are generally considered inert; they are better known as ligands (24) for transition metals (including copper) than as electrophiles. After all, acetonitrile is a common solvent and the preferred medium for catalytic allyl additions to N-phenyl aldimines (25). Carboxylic esters, even sterically hindered ones, can be reduced selec- tively in the presence of a cyanide unit (26). To the best of our knowledge, nitriles are yet to be utilized in a catalytic enantioselective reaction with a carbon-based nucleophile. Pursuant to our original studies with alde- hydes and ketones serving as electrophiles, and as recently adopted for additions to N-protected aldimines (Fig. 1A), we chose to focus on multi- functional Cuallyl complexes, conveniently accessed in situ by the addition of a CuB(pin) (pin, pinacolato) species to a monosubstituted allene (27) (Fig. 1C). A related transformation would be applicable to the projected tangutorine synthesis (Fig. 1B). It would be preferable for the nucleophile to add first, as the alternative sequence of nitrile reduction or Cuallyl addition would proceed via problematic N-H aldimines. It would be equally advantageous for the ketimine to be reduced before its reaction with another Cuallyl molecule to give an achiral a-tertiary amine. There was furthermore the question of finding a way to reduce the ketimine interme- diates diastereodivergently (f to g or h, Fig. 1C). We suspected that the boryl and the C=N units would be internally chelated, and the attend- ant structural rigidity would be conducive to diastereoselective reduction (addition from the RESEARCH Zhang et al., Science 364, 4551 (2019) 5 April 2019 1 of 7 1 Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467, USA. 2 Supramolecular Science and Engineering Institute, University of Strasbourg, 67000 Strasbourg, France. *These authors contributed equally to this work. Corresponding author. Email: [email protected] or [email protected] on May 24, 2020 http://science.sciencemag.org/ Downloaded from

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RESEARCH ARTICLE◥

ORGANIC CHEMISTRY

Delayed catalyst function enablesdirect enantioselective conversionof nitriles to NH2-aminesShaochen Zhang1*, Juan del Pozo1*, Filippo Romiti1,2*, Yucheng Mu1,Sebastian Torker1,2, Amir H. Hoveyda1,2†

Accessing enantiomerically enriched amines often demands oxidation-stateadjustments, protection and deprotection processes, and purification proceduresthat increase cost and waste, limiting applicability. When diastereomers can beformed, one isomer is attainable. Here, we show that nitriles, largely viewedas insufficiently reactive, can be transformed directly to multifunctional unprotectedhomoallylic amines by enantioselective addition of a carbon-based nucleophileand diastereodivergent reduction of the resulting ketimine. Successful implementationrequires that competing copper-based catalysts be present simultaneously and thatthe slower-forming and less reactive one engages first. This challenge was addressedby incorporation of a nonproductive side cycle, fueled selectively by inexpensiveadditives, to delay the function of the more active catalyst. The utility of thisapproach is highlighted by its application to the efficient preparation of the anticanceragent (+)-tangutorine.

Facile and economical access to amines inhigh diastereomeric and enantiomeric pu-rity is crucial to future advances in chemistry,biology, and medicine. Despite substantialprogress (1), however, several key limita-

tions remain. There are just a handful ofmethodsfor catalytic enantioselective preparation ofunprotected a-secondary amines RNH2 (2–5).N-activated or -protected startingmaterials mustotherwise be used, resulting in manipulationsthat increase waste generation and diminish effi-ciency. Synthesizing an unprotected a-secondaryamine frequently necessitates (at times strongly)acidic, oxidizing, or reducing conditions that canbe lowormoderate yielding (6); in some instances,up to three chemical steps must be dedicated toprotecting group manipulations alone (7–9),and/or excess amounts of a costly reagent (e.g.,SmI2) might be required (10). The conditionsneeded for removal of an N-protected unit canlead to side reactions occurring at other sites ina multifunctional molecule (11). Another majorissue is that alkyl-substitutedN-protected imines,relevant to synthesis of numerous bioactivemolecules, tend to be unstable (versus aryl- orheteroaryl variants) and difficult to purify (onaccount of fast hydrolysis upon exposure tomois-

ture and/or enamine or aminal formation), andmust therefore be used asmixtures, which leads tolow yields. Some of these complications may, inprinciple, be resolved by the use ofN-Haldimines,but these are also unstable, and reports regardingtheir productive reactivity are scarce and restrictedin scope (12).Moreover, when diastereomers canbe generated, often only one of them can beaccessed (13–16). An enantioselective strategyshould ideally be diastereodivergent (17).An attractive way to generate an enantiomeri-

cally enriched amine would be by converting areadily accessible unsaturated hydrocarbon to anintermediate, which can then react in situwith animine. An example is the recent protocol (Fig. 1A)for synthesis of N-p-methoxyphenyl–protectedhomoallylic a-secondary amines (15). However,the method is confined to aryl imines (18), andconversion to an N-H amine not only demandsharsh oxidative conditions, it is low yielding aswell (19).The above shortcomings recently thwarted

our efforts to conceive a scalable, diastereo- andenantioselective synthesis of tangutorine, a natu-rally occurring anticancer agent. Our initial planincluded the intermediacy of tertiary lactam a(Fig. 1B), to be derived from a protected form ofhomoallylic amineb. Removal of anN-protectinggroup, however, under acidic or basic conditions,proved to be compromising for two reasons: first,untimely and rapid cyclization to secondary amidec, which rendered subsequentN-alkyl formationseverely inefficient; second, premature unmask-ing of the allylic alcohol, seriously complicatingdownstream chemoselective amide activation

needed for generation of the polycyclic frame-work. It might therefore not be surprising thatthe only reported enantioselective synthesis oftangutorine (20) is 26 steps long (21), withseven operations relating to protecting-groupmanipulations and another nine devoted tooxidation-state alterations. We needed to accesssecondary amine d, probably through mergerof unprotected amine e with the appropriatealdehyde; d could then be easily converted tocyclic lactam a, en route to tangutorine. Thequestion thus became: How does one generateN-H amine e efficiently and with high distereo-and enantioselectivity?

Sequential additions to a nitrile

An unprotected a-secondary amine might besynthesized by nucleophilic addition to a nitrilefollowed by reduction of the resulting N-H keti-mine (Fig. 1C). Many nitriles are either com-mercially available (unlike aldimines) or can beaccessed by an increasing number of protocols(22, 23). Additionally, aldehyde synthesis by oxi-dation or reduction of more readily available androbust starting materials, N-protection to gener-ate a suitable aldimine, and subsequent unmask-ing would be obviated. Without an N-activatingunit, enamine formation would be a much lesslikely pitfall.The prerequisite for high diastereo- and

enantioselectivity aside, the idea of synthesiz-ing unprotected amines by sequential, one-pot,addition to a nitrile presented several challenges.Nitriles are generally considered inert; they arebetter known as ligands (24) for transitionmetals(including copper) than as electrophiles. Afterall, acetonitrile is a common solvent and thepreferredmedium for catalytic allyl additions toN-phenyl aldimines (25). Carboxylic esters, evensterically hindered ones, can be reduced selec-tively in the presence of a cyanide unit (26). Tothe best of our knowledge, nitriles are yet to beutilized in a catalytic enantioselective reactionwith a carbon-based nucleophile.Pursuant to our original studies with alde-

hydes and ketones serving as electrophiles, andas recently adopted for additions to N-protectedaldimines (Fig. 1A), we chose to focus on multi-functional Cu–allyl complexes, convenientlyaccessed in situ by the addition of a Cu–B(pin)(pin, pinacolato) species to a monosubstitutedallene (27) (Fig. 1C). A related transformationwould be applicable to the projected tangutorinesynthesis (Fig. 1B). It would be preferable forthe nucleophile to add first, as the alternativesequence of nitrile reduction or Cu–allyl additionwould proceed via problematic N-H aldimines. Itwould be equally advantageous for the ketimineto be reduced before its reaction with anotherCu–allyl molecule to give an achiral a-tertiaryamine. There was furthermore the question offinding a way to reduce the ketimine interme-diates diastereodivergently (f to g or h, Fig. 1C).We suspected that the boryl and the C=N unitswould be internally chelated, and the attend-ant structural rigidity would be conducive todiastereoselective reduction (addition from the

RESEARCH

Zhang et al., Science 364, 45–51 (2019) 5 April 2019 1 of 7

1Department of Chemistry, Merkert Chemistry Center, BostonCollege, Chestnut Hill, MA 02467, USA. 2SupramolecularScience and Engineering Institute, University of Strasbourg,67000 Strasbourg, France.*These authors contributed equally to this work.†Corresponding author. Email: [email protected] [email protected]

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less hindered C=N face to give g). Still, it wasunclear whether we would be able to retainN→B chelation during ketimine reduction and,if so, how the alternative diastereomer h wouldthen be accessed. Besides, although the largeB(pin) moiety could help reduce the rate of ad-dition of a second Cu–allyl complex, we wereconcerned that the Lewis acidic boryl groupmight facilitate epimerization at the sensitivea-stereogenic center of the b,g-unsaturated ke-timine (f, Fig. 1C).We began by examining the reactions involving

phenyl cyanide or acetonitrile (1a or 1b; Fig. 2A),monosubstituted allene2a, B2(pin)2, and t-BuOHtogether with 5.0 mol % of an NHC–Cu (NHC,N-heterocyclic carbene) copper complex (NHC–Cu-1). Ketimine4awas formed after just 3 hours,indicating that a Cu–allyl complex can react read-ily with an aryl or an alkyl nitrile (1b). We laterobtained the x-ray structure of Cu–ketimide 3cby reacting equivalent amounts of acetonitrile,NHC–Cu-2 [Ar = 2,6-(i-Pr)2C6H3], B2(pin)2, and2a (see supplementarymaterials for details). The11B nuclearmagnetic resonance (NMR) spectrumfor b-boryl ketimine 4a bears an upfield peak(9.7 parts per million), which suggests a largelysp3-hybridized boron atom and C=N→B(pin)coordination.

To probe the feasibility of efficient anddiastereoselective ketimine reduction, we treateda sample of catalytically generated 4a (not iso-lable, detectable by spectroscopy) with inexpen-sive polymethylhydrosiloxane (PMHS; 3.0 equiv.),NaOt-Bu (50mol%), and t-BuOH (1.7 equiv.; Fig.2A), thus generating the corresponding Cu–Hcomplex in situ. There was 78% conversion to amixture of compounds after 1.5 hours, amongwhichwe detected a 20:80mixture of the desiredhomoallylic amine 5a, generated as a singlediastereomer (>98% syn), and allylic amine 6a(>98% E or trans). In all likelihood, owing tohigher acidity of the allylic C–Hinab,g-unsaturatedketimine, alkene isomerization occurs prior toC=N reduction; this is supported by swift iso-merizationof4aand4b (Fig. 2B) toa,b-unsaturatedketimines7a and 7b, respectively (10 min, 22°C;>98% E), with just 10 mol % NaOt-Bu. The iden-tity of ketimine 7b was confirmed by x-ray crys-tallography (Fig. 2B). The latter data imply thatketimine reductionmust occur readily and undermild conditions, otherwise olefin isomerizationbecomes dominant. Another key observation wasthat there was minimal imine reduction when4a or 4b was subjected to PMHS without anyNaOt-Bu, showing that a metal alkoxide mustbe available for efficient regeneration of a Cu–H

catalyst [i.e., LCu(H)N–C→LCu(Ot-Bu)→LCuH;see vii→i → vi, Fig. 2E]. Follow-up investi-gations confirmed that, although Cu–H additionto a ketimine is fast, a metal alkoxide must bepresent for Cu–N bond cleavage and productrelease (see the supplementary materials fordetails).Several other findingsmerit note.Unlike b-boryl

ketimines4a and4b (or 7a and 7b), which under-went reduction easily, there was no reactionwiththe N-H ketimine derived from propiophenone(<2% under the same conditions, 24 hours; Fig.2C). Thismeans that C=N→B(pin) chelationmustbe retained for facile reduction. Also, reaction of1a and allene 2a in the absence of B2(pin)2 led tothe formation of a-tertiary amine 8 (Fig. 2C);none of the single-addition product was gen-erated (<2%). Consequently, without a B(pin)moiety double addition becomes dominant, in-dicating that processes with only a Cu–H com-plex [that is, no Cu–B(pin) species (28)] cannot beused to synthesize these and related homoallylicamines (see below).

Delayed catalysis

The capacity of a metal alkoxide to facilitateolefin isomerization (Fig. 2, A and B), togetherwith the necessity for CuH-catalyzed ketimine

Zhang et al., Science 364, 45–51 (2019) 5 April 2019 2 of 7

Fig. 1. The state-of-the-art in enantioselective multicomponentsynthesis of secondary amines, the key problems, and a possiblegeneral solution. (A) Synthesis of homoallylic a-secondary amines fromN-protected imines and allenes as latent nucleophiles, although highlyenantioselective, is limited in scope, requires inefficient N-deprotection,and is not stereodivergent. (B) (+)-Tangutorine might be prepared

concisely without N-protection. (C) One-pot nucleophilic addition orketimine reduction involving a nitrile would be more efficient. Althoughposing several challenges, enantioselective addition and diastereoselectiveC=N reduction would be effected in situ by simultaneously presentCu–B(pin) and Cu–H catalysts. PMP, p-methoxyphenyl; pg, protectinggroup; pin, pinacolato.

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reduction (Fig. 2A), posed the question of howto obtain the desired homoallylic amines withminimal olefin isomerization. Early investigations(Fig. 2A) had shown that generating a Cu–Hcomplex after the C–C bond is formed, despiteNaOt-Bu being added last, leads to substantialamounts of the allylic amine (6a; ~80%). How-

ever, the latter experiment involved a 10-fold ex-cess of NaOt-Bu compared to the Cu–H catalyst(50 versus 5.0 mol %), rendering alkene isom-erization more competitive (versus C=N reduc-tion). Additionally, exploratory studies revealedthat subjection of the intermediate ketimine tostoichiometric amountsofdifferent reducingagents

does not afford the desired syn isomer with highdiastereoselectivity [versus >98:2 diastereomericratio (d.r.), with NHC–Cu–H] and/or is onlymod-erately efficient (~50% yield; see the supple-mentary materials for additional details). Wesurmised that the low d.r. is probably becausesyn selectivity is possible only if hydride addition

Zhang et al., Science 364, 45–51 (2019) 5 April 2019 3 of 7

Fig. 2. Managing the reactivity order of competing catalysts.(A) Addition of a Cu–allyl complex to a nitrile is efficient, but ketiminereduction causes alkene isomerization and byproduct formation.(B) A metal alkoxide promotes olefin isomerization but is required forCuH-catalyzed ketimine reduction. (C) Without a neighboring boryl group,ketimine reduction is slow and double addition dominates. (D) Reactivities

of a Cu–B(pin) and Cu–H complex are competitive, with Cu–H formingand reacting somewhat faster. (E) By incorporating a nonproductive sidecycle, homoallylic amines might be generated more efficiently. (F) Relativelyefficient formation of syn-5a is achieved by incorporating a side cycle.NHC, N-heterocyclic carbene; TBS, t-butyldimethylsilyl; PMHS,polymethylhydrosiloxane. See the supplementary materials for details.

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does not require the disruption of the N→Bchelation; subsequent studies later verified thishypothesis (see below). In searching for a solution,we posited that if the Cu–B(pin) and Cu–H com-plexes were generated concurrently, the rel-atively rapid CuH-catalyzed ketimine reductioncould occur as soon as the b,g-unsaturated keti-minewas formed. Ketimine reductionwould thenhave to be faster than alkene isomerization, despiteincreased metal alkoxide availability.It was unclear whether the relative rates of

formation and reactivity of a Cu–B(pin) and aCu–H complex would favor the desired sequenceof events. To understand these factors better, weperformed the experiments shown in Fig. 2D(conditions reflect the catalytic process in Fig.2A). We determined that with equal amounts ofB2(pin)2 and PMHS, a Cu–H complex is generatedsomewhat faster than a Cu–B(pin) species (Fig.2D, a) and that it adds somewhat more readilyto a monosubstituted allene (Fig. 2D, b). Neitherfactor is favorable to the desired sequence ofevents [i.e., Cu–B(pin) addition to allene, fol-lowed by CuH-catalyzed reduction]. Still morediscouraging, the Cu–allyl species derived fromCu–H addition to 2a added to PhCN (1a) atnearly the same rate as the Cu–allyl intermedi-ate formed by Cu–B(pin) addition to the sameallene (Fig. 2D, c). Similar observations werelater made when the same investigations in-volved a bis-phosphine–Cu complex (see below).We therefore needed to conceive of a strategy

that would favor Cu–B(pin) addition to the alleneeven in the presence of the Cu–Hspecies. Despitemany examples of multicatalytic transforma-tions (29), those involving catalysts that possesscompeting functions are relatively uncommon(30, 31), especially when the one that is formedmore slowly and is less reactivemust nonethelessparticipate first.Use of excess B2(pin)2 (versus PMHS) would

not favor Cu–B(pin) (versus Cu–H) addition toan allene; this would only slow down ketiminereduction and cause more alkene isomerization.Instead, we envisioned modulating the relativerate of Cu–H versus Cu–B(pin) addition to anallene by exploiting the efficiency with which themetal hydride can react not only with a ketiminebut also—in a nonproductive manner—with analcohol. By feeding the reaction mixture suffi-cient amounts of inexpensive t-BuOHandPMHS,neither of which react rapidlywith Cu–B(pin), wesought to engage the Cu–H complex in a sidecycle (see i→vi→i, Fig. 2E). We argued that thiscould raise the relative Cu–B(pin) concentra-tion sufficiently to favor its addition to allene(ii→iii) and onward to nitrile (→iv). The suc-cess of this plan hinged on whether reaction ofCu–H with the alcohol would preempt its un-desired addition to the allene but still allow itsreaction with ketimine to outcompete alkeneisomerization. Otherwise, higher PMHS con-centration would simply favor reaction betweenthe allene and the Cu–H complex. Subsequentprotonolysis and CuH-catalyzed ketimine reduc-tion would give vii followed by viii en route tosyn-ix (Fig. 2E).

Treatment of PhCN (1a),2a, andB2(pin)2, with5.0 mol % NHC–Cu-1 and 50 mol % NaOt-Bualong with 3.4 equivalents of t-BuOH (versus1.7 equiv.) and 5.0 equivalents of PMHS (versus3.0 equiv.) afforded homoallylic amine syn-5ain 46% yield and >98:2 d.r. (Fig. 2F). There wasjust 7% (versus 80%) of the isomerized byproductformed (6a, readily separable from 5a; see belowfor discussion on diastereoselectivity). Althoughmore PMHS leads to higher Cu–Hconcentration,concomitant increase in alcohol concentrationstimulates the nonproductive side cycle, allowingCu–B(pin) addition to the allene to compete ef-fectively. The combined influence of higher PMHSand t-BuOH amounts was confirmed by the factthat with only excess silane (5.0 equiv. versus 1.7equiv. t-BuOH), nearly 50% of the product mix-ture consisted of 6a, and there was 30 to 35% ofunreacted nitrile (insufficient alcohol to feed theentire process). When only more t-BuOH wasused but the amount of silane was kept the same(3.4 equiv.; 3.0 equiv. PMHS), a 66:34 ratio ofallylic:homoallylic amine was observed (5a:6a);under these conditions the process slows down,allowing for increased olefin isomerization (moreon this later). A control experiment correspond-ing to that shown in Fig. 2Da, but involving largeramounts of PMHS [versus B2(pin)2 to emulatethe catalytic conditions], showed that formationof a Cu–H complex is significantly more efficientunder such conditions [15:85 Cu–B(pin):Cu–H;see the supplementarymaterials for details]. Thatis, the nonproductive side cycle delays the ac-tion of a Cu-based complex that is clearly formedfaster.We then set out to identify an effective chiral

ligand with the hopes that we would also im-prove efficiency (versus NHC–Cu-1, Fig. 2F).With benzodioxole-based phos-1 (Fig. 3A) andferrocenyl-based phos-2, there was appreciablenitrile consumption (48% and 92% conversion,respectively), but only different byproducts, prin-cipally a,b-unsaturated ketimine7a, were formed(<5% 5a). By contrast, with phos-3, which bearsa PCy2 coordination site (versus PPh2) but isotherwise identical to phos-2, 5awas isolatedin 76% yield (versus 46% yield withNHC–Cu-1), >98:2 syn:anti ratio, and 95:5 e.r. (enanti-omeric ratio). We could detect only 2% allylicamine 6a.Most achiral or chiralNHC– andbisphosphine–

Cu–B(pin) complexes facilitated C–C bond for-mation, but those that also gave rise to a Cu–Hcomplex capable of efficient ketimine reduc-tionwere far less common; the boryl and hydridespecies derived fromNHC–Cu-1 and phos-3 aretwo such rare instances. The three bisphosphine–Cu complexes catalyze C–C bond generationefficiently and enantioselectively (to give 4a;Fig. 3B), but it is only with phos-3–Cu–H thatcatalytic reduction is efficient (to give 5a). Thismay be attributed to higher Lewis basicity ofdialkylphosphinemoieties and enhanced reduc-ing ability of the derived Cu–H species (versusone dialkylphosphine and one diarylphosphine,phos-2). Use of a combination of alcohols ledto better yields of the syn-homoallylic amines

(Fig. 2; versus when only MeOH or t-BuOHwas used). The smaller MeOH can induce fasterprotonolysis of the Cu–N bond (leading to therelease of the N-H ketimine intermediate), butit can also react faster with the Cu–H complex,decreasing its concentration too rapidly in theside cycle (Fig. 2E). The latter hypothesis is sup-ported by the observation that there was partialketimine reduction (~50%) when only MeOHwas used.Themethod iswidely applicable (Fig. 3C). Aryl-

substituted homoallylic amines (5b to 5h) wereisolated in 62 to 87% yield with complete synselectivity (>98:2 d.r.), and 93.5:6.5 to 96:4 e.r.Nitriles containing a sterically demanding o-tolylmoiety (5b), one or more halides (5e and 5f),or a strongly electron-donating or -withdrawinggroup (5g and 5h, respectively) proved to besuitable substrates. In contrast to a carboxylicester, however, an aldehyde competitively reactswith a Cu–allyl species; a ketone, though remain-ing intact during the first stage of the process, iscompetitively reduced. Heterocyclic nitriles maybe used (5i to 5k). A Lewis basic pyridyl ring,evenwith the ring nitrogen at the ortho position(see 5i), where it can serve as part of a bidentateCu-based chelate with the C=N unit, does notnegatively affect yield or stereoselectivity. Otherstarting materials of note consisted of an a,b-unsaturated nitrile (5l), a b,g-unsaturated nitrile(5m), and an enantiomerically pure benzyl (5n)compound; in the latter instance, reaction withthe alternative (mismatched) substrate enanti-omer was less efficient and stereoselective (53%yield of partially pure homoallylic amine, 91:9 d.r.,83:17 e.r. versus 90% yield, >98:2 d.r., 98:2 e.r. for5n). Reactions with acetonitrile (5o) or the muchlarger tert-butyl nitrile (5p) were similarly high-yielding and selective. Allenes containing a smallermethyl group could be used (5q), and althoughthe reactionwith phenylallene afforded 5r in 42%yield, diastereoselectivitywas complete (>98:2 d.r.)and enantioselectivity high (97:3 e.r.). In mostcases, ≤8% of the allylic amine products wereobserved (percent yield values in Fig. 3 corre-spond to pure homoallylic products). Accessing5l to 5n is especially notable, as the corresponding(N-protected or otherwise) aldimines are difficultto use owing to their instability (4, 32), namely,dimerization by cycloaddition (33) for 5l, alkeneisomerization for 5m, and enamine formationfor 5n. We know of just two examples of catalyticenantioselective nucleophilic addition to a benzyl-substituted aldimine (34, 35).A rationale for the high diastereo- and enantio-

selectivitymay be proposed on the basis of stereo-chemical models derived from density functionaltheory (DFT) calculations (Fig. 3D). In the tran-sition state leading to the major ketimine en-antiomer (I), while the nitrile associates fromthe rear of the copper-based complex, the allylnucleophile is oriented such that the stericallydemanding B(pin) group can be situated belowa t-butyl group of the P(t-Bu)2 moiety. As shownin the side view projection of I (Fig. 3D), thiscauses the t-butyl group that is closer to the(pin)B-substituted allyl unit to tilt upward. The

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less favorable transition state II suffers fromsteric repulsion between the B(pin) group and acyclohexyl (Cy) substituent of the PCy2 moiety.Further destabilizing II is the interaction be-tween the alkenyl substituent (Me) and a prox-imal t-butylphosphine moiety, which causescontraction of the C−Cu−P angles (106.9° and124.2° versus 117.2° and 114.2° in I). The majordiastereomer arises from Cu–H addition to theless hindered face of a boryl-chelated ketimine,similar to the way such a complex would react

with an alkene, namely, without any interactionbetween the transition metal and the nitrogenatom (iii, Fig. 3D).

Achieving stereodivergency

Since syn-selective ketimine reduction proceedsvia an internally chelated ketimine, the alter-native anti diastereomer would have to be gen-erated by disruption of the same interaction. Wereasoned that by using a Lewis acid capable ofrupturing N→B chelation with ensuing ketimine

reduction, we might access the desired homo-allylic amine diastereomers. The same B(pin)group, this time as the largest substituent in aFelkin-Anh–type addition mode (IV, Fig. 4A),would again play a key role. Screening studieswith phos-2 as the chiral ligand (for maximalefficiency and e.r. versus phos-3; see Fig. 3B) ledus to determine that Al(OTf)3 and LiBH4 are aneffective Lewis acid–metal hydride combination.Accordingly, anti-homoallylic amines 9a to 9h(Fig. 4A) were obtained in 55 to 81% yield, 88:12

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Fig. 3. Multicatalytic four-component diastereo- and enantio-selective processes. (A) Synthesis of unprotected homoallylica-secondary amines is most efficient with phos-3. (B) Whereasother chiral Cu complexes promote C–C bond formation enantio-selectively, only phos-3–Cu–H is efficient in ketimine reduction.

(C) The catalytic process has considerable scope. (D) DFTcalculations (MN15/def2-TZVPP//M06L/def2-SVP) provide astereochemical model for the observed diastereo- and enantio-selectivities. Mes, 2,4,6-trimethyphenyl (mesityl). See thesupplementary materials for details.

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to >98:2 d.r., and 96:4 to 99:1 e.r. Although thehigh yield for 9f is notable, considering the abil-ity of LiBH4 to reduce a carboxylic ester, thelower d.r. for the reaction of the less bulky nitrilesmight be due to a competing mode of addition(seeV, Fig. 4A). There were no isomerized allylicamine byproducts detected (<2%).Use of CuMes (Mes, mesityl) (36), a robust and

commercially available organometallic reagentthat may be used without purification, in thisprotocol is preferable partly because of its higher

solubility (versus copper halides) in organic sol-vents, allowing for greater reproducibility. Addi-tionally, because copper alkoxide is generated byreaction of CuMes with an alcohol, there is noneed for additional amounts of sodium alkoxidethat could give rise to alkene isomerization. Thisis particularly important in the synthesis of anti-homoallylic amines, where formation of b,g-unsaturated N-H ketimines must be completedbefore C=N reduction (see 9a to 9h, Fig. 4A). Forthe synthesis of anti-homoallylic amines, it

was necessary to remove Et2O and replace itwith MeOH before adding LiBH4 to ensure opti-mal diastereoselectivity.

Application to natural product synthesis

The final question was whether the advancesdescribed above might enable concise synthesisof gram quantities of diastereo- and enantiomer-ically enriched tangutorine. Multigram amountsof nitrile 10 (Fig, 4B) and allene 11were preparedin three (52% overall yield) and two steps (68%

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Fig. 4. Scope and utility. (A) By altering the conditions for ketimine reduction, the anti-homoallylic N-H amines can be accessed.(B) Utility is highlighted by a nine-step diastereo- and enantioselective gram-scale synthesis of tangutorine, affording the natural productin 28% overall yield (versus 26 steps and 10% overall yield, previously). See the supplementary materials for details.

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overall yield), respectively, from commerciallyavailable starting materials. The two-catalyst,four-component process, carried out at reducedloading (2.0 mol %), afforded 2.68 g of synhomoallylic amine 12 in 82% yield, >98:2 d.r.,and 95:5 e.r. This transformation was performedat –5°C (versus –50°C) because reactions of alkyl-substituted nitriles are generally less sensitive tovariations in temperature; control experimentsindicate that this might be because the derivedketimines are less prone to epimerization (versusaryl- or heteroaryl-substituted cases). Furthermore,5.0 mol % NaOMe, which can still cause con-siderable alkene isomerization if ketimine re-duction is not facile, was sufficient under theseconditions. Use of i-PrOH proved to be as effec-tive as a MeOH/t-BuOH mixture (see above).The boryl group was excised catalytically to

furnish monosubstituted alkene 13 (Fig. 4B).Subsequent reductive coupling with aldehyde14, prepared in a single step from tryptophol(73% yield), gave the desired alkylamine, whichwas used directly (without purification) to ac-cess 1.9 g of 15 (80% overall yield for three stepsfrom 12). Catalytic ring-closing metathesis withMo-1 afforded 1.62 g of 16 (91% yield). Severalissues regarding these latter transformations(12 →16) merit brief note. (i) At first glance, itmight appear that a more economical strategyfor synthesis of 13 would entail a multicom-ponent process that includes Cu–H addition[versus Cu–B(pin)] to a monosubstituted allene[i.e., no C–B-to-C–H conversion (i.e., 12→13)].In practice, however, this is not the case. Apartfrom inhibiting the addition of two identical allylmoieties (see Fig. 2C), without the sizable B(pin)group and the internal N→B chelation, not onlywould ketimine reduction not occur but alkeneisomerization would dominate (see Fig. 2C, 3,and 4). In brief, the C–B bond is muchmore thana mere C–H placeholder. (ii) The high efficiencyof catalytic C–B-to-C–H conversion indicates thatother types of cross-coupling are feasible andunlikely to be adversely affected by the presenceof Lewis basic amine and/or adventitious lactamformation. We have already shown that oxida-tion of the alkenyl–B(pin) to the correspondingb-amino ketone in the presence of an N-H amineis high yielding (32). (iii) As was noted (Fig. 1C),generating primary amine 13under relatively neu-tral conditions—without cyclic lactam formation—was crucial (inefficient subsequent N-alkylation).The intermediacy of an N-protected variant of 13would thus be undesirable. (iv) Ring-closingmetathesis proceeded to completion withRu-1,but repeated purification of 16, was needed (toremove residual transition metal salts), result-ing in diminished yields (65% versus 91% yieldwith Mo-1).Subjection of 16 to 17 and triflic anhydride

(37, 38) and then NaBH4 in MeOH delivered1.05 g of the anticancer agent (92% yield) as asingle diastereomer. The stereochemical iden-tity of synthetic (+)-tangutorine was confirmedby x-ray crystallography (formerly only that ofracemicmaterial was reported, despite the abso-lute stereochemical identity being known). The

nine-step route, involving commercially availableligands, catalysts, and reagents, provided the finaltarget in high diastereo- and enantiomeric purityand in 28% overall yield. This route, which is read-ily amenable to gram-scale synthesis, is nearlythree times more concise and efficient than theformerly disclosed alternative [26 steps, 10%overall yield (21)]. Although tangutorine belongsto an alkaloid family that occurs in nature typ-ically in the racemic form, higher activity hasbeen observed with enantiomerically enrichedmaterial (21).Moreover, separation of tangutorineenantiomers requires HPLC (high performanceliquid chromatography) techniques (39) and istherefore nontrivial, especially on larger scale.

Outlook

The ability to preparemultifunctional homoallylicamines efficiently, stereodivergently, and enantio-selectively, by the use of readily available catalysts,directly from nitriles, and without any protectionand deprotection steps, will have substantial im-pact on the accessibility of bioactiveN-containingcompounds. We expect the approach to be ap-plicable to protocols for synthesis of other typesof unprotected amines through the use of alter-native classes of organocopper compounds. Forinstance, diastereodivergent additions of carbon-based nucleophiles to enantiomerically enrichedketimines would provide easy access to a-tertiaryhomoallylic amines, valuable entities that can begenerated by only a small number of protocols(32, 40). Ketimine hydrolysis may lead to other-wise difficult-to-prepare enantiomerically en-riched b,g-unsaturated ketones. In a broadersense, this may be the first step toward designingtransformations that involve multiple catalysts,where the sequencewithwhich they are requiredto enter the reaction fray differs from whatwould be expected on the basis of their inherentreactivity. Controlling the order in which dif-ferent catalysts react productively by selectivelydelaying one of themwith a nonproductive sidecycle is a concept that could find widespreaduse in future research in reaction development.

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ACKNOWLEDGMENTS

Funding: Financial support was provided by the NIH (grantsGM-47480 and GM-57212) and the Alfonso Martin EscuderoFoundation (postdoctoral fellowship to J. d. P.). We thankDr. B. Li for his invaluable assistance in securing X-raystructures. Author contributions: S. Z., J. d. P., and F. R.developed the method and its applications. Y. M. investigatedand optimized the olefin metathesis process in Fig. 4B, andS. T. carried out the DFT studies. A. H. H. directed thestudies, and wrote the manuscript. Competing interests: Theauthors declare no competing financial interest. Data andmaterials availability: X-ray crystallographic data forcompounds 3b, 3c, 6a, 7b, 9e, and synthetic (+)-tangutorine,are freely available from the Cambridge CrystallographicData Centre (CCDC 1885227, 1885257, 1885259, 1885233,1885258, and 1885261, respectively). Copies of the data can beobtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available in the main text or thesupplementary materials.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/364/6435/45/suppl/DC1Materials and MethodsFigs. S1 to S27Tables S1 to S8References (41–85)NMR Spectra

18 December 2018; accepted 6 March 201910.1126/science.aaw4029

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-amines2Delayed catalyst function enables direct enantioselective conversion of nitriles to NHShaochen Zhang, Juan del Pozo, Filippo Romiti, Yucheng Mu, Sebastian Torker and Amir H. Hoveyda

DOI: 10.1126/science.aaw4029 (6435), 45-51.364Science 

, this issue p. 45Sciencefast-reacting hydride at bay until needed.relative to a competing copper hydride. By adding an innovative delay cycle, the authors succeeded in keeping the

slowreducing that next intermediate to the amine. However, formation and reaction of the copper-boryl complex were too was charged with successively borylating the allene, coupling the intermediate to the nitrile, and then enantioselectivelydeveloped an amine synthesis in which allenes and nitriles are coupled under reductive conditions. A copper catalyst

et al.Concurrent operation of two or more catalytic cycles requires a delicate balance of relative rates. Zhang Amines emerge, as copper bides its time

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