Pathway-divergent coupling of 1,3-enynes with acrylates through cascade cobalt catalysis

Catalytic cascade transformations of simple starting materials into highly functionalized molecules bearing a stereochemically defined multisubstituted alkene, which are important in medicinal chemistry, natural product synthesis, and material science, are in high demand for organic synthesis. The development of multiple reaction pathways accurately controlled by catalysts derived from different ligands is a critical goal in the field of catalysis. Here we report a cobalt-catalyzed strategy for the direct coupling of inexpensive 1,3-enynes with two molecules of acrylates to construct a high diversity of functionalized 1,3-dienes containing a trisubstituted or tetrasubstituted olefin. Such cascade reactions can proceed through three different pathways initiated by oxidative cyclization to achieve multiple bond formation in high chemo-, regio- and stereoselectivity precisely controlled by ligands, providing a platform for the development of tandem carbon-carbon bond-forming reactions.

Acrylates are feedstocks that are produced over three million tons annually.In this context, catalytic cascade reactions of alkynes and acrylates to construct a stereochemically defined trisubstituted or tetrasubstituted olefin with the simultaneous introduction of a stereogenic center and/or other functional groups is an attractive strategy, as a catalytic stereoselective synthesis of multisubstituted alkenes are nontrivial and such moieties widely exist in biologically active molecules (Fig. 1c).We envisioned that a streamlined approach for direct incorporation of two molecules of acrylates into the alkynes through oxidative cyclization followed by different elementary processes would enable divergent editing of the carbon skeleton of the alkyne, converting the alkyne to an alkene associated with the formation of two carbon-carbon single bonds or an alkane with two newly generated carbon-carbon double bonds or single bonds (Fig. 1d).Several factors impeded the development of such processes.Firstly, a multifunctional catalyst has to accurately control the chemo-, regioand stereoselectivity of each step.It is challenging to introduce two molecules of electrophilic acrylates into the alkynes, as alkynes are intrinsically more prone to undergo oxidative cyclization with themselves and insertion into the metallacycle intermediates compared with acrylates due to its higher affinity to the metal center and lowerlying LUMO.For instance, examples of metal-catalyzed coupling of 1,6diynes [22][23][24][25] and alkenes and 1:2 coupling of unsaturated hydrocarbons with carbonyls have been reported 26,27 .Moreover, for the combination of 1,3-enynes and acrylates, the regioselectivity of oxidative cyclization (four possibilities) and the selectivities for subsequent transformations are difficult to tune.Secondly, in comparison with the previous report on tandem reactions of 1,3-enynes with ethylene, much more possible reaction pathways of the metallocycle intermediates could complicate the transformations with acrylates.It is nontrivial to achieve multiple reaction modes.We considered that the development of a distinct reactivity paradigm for oxidative cyclization and nontraditional subsequent pathways for the metallocycle intermediates as well as proper choices of ligands and a metal center would address these longstanding critical issues.
Cobalt is an inexpensive earth-abundant transition metal of low toxicity 28 .Development of cobalt-catalyzed transformations to produce useful building blocks through the unique reactivity of organocobalt complexes fulfills the increasing demands for sustainable chemistry.Recently, we have successfully developed a cobalt-catalyzed protocol for enantioselective coupling of 1,1-disubstituted allenes and aldehydes through oxidative cyclization, generating three different sets of products from the same starting materials 29 .We reasoned that the combination of reaction design and judicious choices of chiral ligands enabled pathway-divergent oxidative cyclization and subsequent transformations [30][31][32][33] .We imagined that different ligands might be able to control the reaction pathway of the metallocycle intermediates formed from oxidative cyclization of 1,3-enynes and acrylates (Fig. 1e) [34][35][36] .We speculated that β-H elimination and protonation of the metallocycle would afford a highly reactive triene intermediate containing two 1,3-diene systems that might undergo a second oxidative cyclization with acrylates.A cobalt-based catalyst was expected to selectively react with one, furnishing highly functionalized products bearing a trisubstituted alkene and a stereogenic center (pathway a).In addition, direct insertion of the acrylates to the C-Co bond of the metallocycle would provide an approach for stereoselective formation of tetrasubstituted olefins (pathway b).Furthermore, trapping the intermediate generated from β-H elimination of the metallocycle containing a primary alkyl (R 1 = primary alkyl) with acrylates would trigger a series of cascade processes, delivering multifunctional building blocks (pathway c).In each pathway, competitive second oxidative cyclization with 1,3-enynes and insertion with 1,3-enynes have to be suppressed and chemoselective reactions with a second molecule of acrylate have to be precisely controlled by the catalysts.Here we report pathway-divergent coupling of readily available 1,3-enynes and acrylates by cascade cobalt catalysis to furnish highly functionalized 1,3-dienes bearing multisubstituted alkenes, accurately editing the carbon skeleton by constructing multiple carbon-carbon bonds.

Reaction optimization
Our studies commenced with reaction of 1,3-enyne 1a containing a tertiary alkyl group with benzyl acrylate 2a in the presence of Co complexes derived from various chiral phosphine ligands (Fig. 2).Although no reaction occurred with the Co complexes derived from phosphinooxazoline 3a (entry 1), bisphosphines bearing axial stereogenicity 3b (entry 2), ferrocene skeleton 3c (entry 3), and chiral phospholane fragments 3g (entry 7), several phosphine ligands (3d-f, 3h-j) induced high enantioselectivity (entries 4-6, 8-10).Only product 4a that incorporate two molecules of benzyl acrylate 2a was afforded, and a single stereoisomer of the trisubstituted alkene was obtained.Performing the transformation in DMA led to a slight improvement of efficiency (entry 11).Screening of reductants revealed that Mn was equally effective (entry 12).Lowering the catalyst loading didn't reduce the efficiency (entry 13).

Cascade coupling to generate tetrasubstituted alkenes
Tetrasubstituted alkenes containing four carbon-based substituents are not only common units in biologically active molecules, but also important intermediates that are versatile platforms to introduce a variety of functional groups into the carbon skeleton.Although catalytic double functionalization of internal alkynes constitutes a direct strategy for the introduction of two carbon-based substituents, significant limitations remained unsolved 37 .In particular, it is challenging to achieve simultaneous reactions of two molecules of alkenes with alkynes in the presence of a proton source, as protonation of the carbon-metal bond is competitive to the carbon-carbon bond forming reaction.Moreover, it is unknown the application of such strategy to the transformation of 1,3-enynes.

Cascade coupling to generate products bearing two trisubstituted alkenes
Editing the carbon skeleton of alkynes by direct introduction of two carbon-carbon bonds constitutes a powerful strategy for the construction of complex molecules.Few examples of saturating the triple bond by formation of two carbon-carbon σ-bonds have been reported, whereas catalytic approaches for connecting the two carbons of the alkyne with two π-bonds from two molecules of alkenes remained unsolved.Although enyne metathesis enabled saturation of the alkyne by generation of two π-bonds with one molecule of alkene, protocols for cascade reaction of two molecules of alkene to establish two trisubstituted olefins stereoselectively are in high demand 38 .We envisioned that tuning relative rates of β-H elimination, protonation and insertion with acrylate by a proper choice of ligand would provide a cascade pathway that might achieve this goal.We found that the reaction of primary alkyl-substituted 1,3-enyne 1b with benzyl acrylate 2a in the presence of Co complex derived from 3k furnished the desired product 10a in 79% yield (Fig. 4b) (supplementary materials).A wide range of functional groups such as halogen (10c), free alcohol (10d), ester (10e), and amide (10f, 10i) are well compatible.1,3-Enynes bearing an aryl (10g) and heteroaryl (10h) were converted into the dienes in high efficiency as a single stereoisomer.Modification of complex natural product α-tocopherol afforded 10j in 78% yield.Enol ether 10k was formed as well through this protocol.Acrylates derived from methanol (11a), cyclohexanol (11b), and phenol (11c) served as suitable substrates.It is worth mentioning that only one isomer of the two trisubstituted alkenes was obtained.We also tested the three reaction pathways mentioned above for vinyl ethyl ketone, providing a complex mixture of unidentified products.Acrylamides and acrylonitrile were not reactive under three different reaction conditions above.In addition, 1,3-enynes bearing a 1,2-or 1,1-disubstituted alkene were not able to participate in the reactions for three different pathways.

Scalable reactions and functionalization
The reactions can be performed on gram scale, affording 4a in 77% yield with 93:7 er and 8a in 90% yield (Fig. 5a).The multifunctional products generated from cascade coupling of 1,3-enynes and acrylates can be transformed into a variety of useful building blocks that are otherwise difficult to access.Rh-catalyzed diastereoselective 1,4-arylation of chiral diene 4a with phenyl boronic acid provided 12 in 89% yield with 87.5:12.5 dr and 13 in 95% yield with 90:10 dr (Fig. 5b) 39 .The stereochemistry of the products was solely controlled by the chiral ligands.Treatment of 4a with B 2 (pin) 2 and MeOH in the presence of NHC-Cu complex 14 followed by oxidative work-up furnished 15 as a single diastereomer (Fig. 5b) 40 .Diastereoselective 1,4-arylation of 6a induced by chiral Rh complex derived from (S,S)−3e produced 16 in 81% yield and 87.5:12.5 dr associated with 9% 1,6-arylation product (Fig. 5c).We attempted developing a method for chemoselective transformation of one of the two ester groups in the product.Treatment of 6a with PhSO 3 H in t-BuOMe gave 17 in 65% yield without erosion of enantioselectivity (Fig. 5c).Chemoselective hydrolysis of the methyl ester moiety with subsequent Curtius rearrangement afforded unnatural amino acid derivative 18 in 53% overall yield and 97:3 er 41 .Selective epoxidation of the tetrasubstituted alkene in diene 8a delivered 19 as a single diastereomer (Fig. 5d) 42 .Ru-catalyzed Eselective cross metathesis with the terminal alkene in 8a furnished highly functionalized 1,3-dienes 20-22 in 62-70% yield 43 .

Preliminary mechanistic studies
To gain some mechanistic insight, we conducted a series of experiments.For the enantioselective cascade coupling pathway, we performed the reaction of 1,3-enyne 1c with acrylate 2a in deuterated water (Fig. 6a).The incorporation of deuterium at the stereogenic center indicated that protonation of the alkenyl-Co in the metallocycle generated from the first oxidative cyclization occurred (III→IV, Fig. 7a).Reaction with deuterated acrylate 2a-D with H 2 O provided product with methyl substituted with one deuterium, suggesting the hydrogen for formation of the methyl group originated from the acrylate and β-H elimination provided the hydrogen (Fig. 6b).Conducting the cascade double alkylation of 1,3-enyne 1d with acrylate 2a or 2a-D in H 2 O or D 2 O implied that protonation at α position of both esters was involved and none of the C-H bonds in the acrylate was cleaved (Fig. 6c, d).We also surveyed the reason for the formation of a Z/E mixture of the tetrasubstituted alkenes with secondary alkyl-substituted 1,3-enynes (supplementary materials).EPR experiments suggested that an alkenyl radical might be generated through homocleavage of the alkenyl-Co intermediate.Compared with primary alkyl-substituted 1,3-enynes, the more sterically congested secondary alkyl groups might decelerate the rate of    insertion of the acrylate to the alkenyl-Co species, leading to competitive homocleavage of the alkenyl-Co(III) bond and subsequent isomerization.For the pathway that generated 1,3-dienes bearing two trisubstituted olefins, we found that similar to the other two pathways, both protonation of α position of esters and transfer of the hydrogen on the acrylate to the terminal alkene to form the methyl group occurred (Fig. 6e, f), whereas the propargyl hydrogen of the 1,3-enyne was rearranged to afford the methylene adjacent to methyl group (Fig. 6g).
Based on all the observations above, we proposed possible catalytic cycles for each pathway (Fig. 7).Co(I) complex underwent regioselective oxidative cyclization to afford metallocycle III that was converted to a triene intermediate (IV) chelated to the Co center by protonation and β-H elimination (Fig. 7a).A second regio-and enantioselective oxidative cyclization followed by protonation provided allyl-Co(III) species VI.With aryl-substituted 1,3-enynes (R 1 = aryl), reductive elimination furnished VIII, whereas allyl isomerization occurred preferentially to generate IX with more sterically congested alkyl-substituted 1,3-enynes (R 2 = alkyl).For the pathway of double alkylation, regioselective oxidative cyclization of 1,3-enyne and acrylate to access metallocycle XII, which underwent insertion of a second molecule of acrylate followed by protonation to release the product 8 (Fig. 7b).For 1,3-enynes bearing a secondary alkyl group, the larger steric hindrance of the secondary alkyl retarded the insertion of a second molecular acrylate.Homocleavage of the alkenyl-Co(III) bond generated an alkenyl radical intermediate, leading to isomerization of the tetrasubstituted alkene (XII→XV→X-VI→XVII, Fig. 7b).For the pathway to generate 10, unlike the pathway shown in Fig. 7b, selective β-H elimination of the metallocycle XXI formed from oxidative cyclization occurred in advance of acrylate insertion (Fig. 7c).Protonation of intermediate XXIII provided a triene that chelated to the Co center (XXIV).Isomerization through Co-H addition and β-H elimination provided a thermodynamically more stable triene bearing two trisubstituted alkenes (XXIV→XXV→XXVI, Fig. 7c).Chemo-and regioselective Co-H addition followed by protonation afforded the product 10.
In conclusion, a cobalt-catalyzed protocol for cascade coupling of 1,3-enynes with acrylates through divergent pathways to furnish highly functionalized molecules bearing a multisubstituted alkene and/or a stereogenic center in high chemo-, regio-and stereoselectivity has been developed.The transformations proceeded through three distinct reaction modes for cobalt catalysis accurately controlled by ligands.Here we achieve the catalytic pathwaydivergent coupling of one molecule of 1,3-enynes with two molecules of electrophilic substituted olefins, reversing the inherent reactivity preference of substrates.The starting materials are inexpensive feedstocks or easily accessible.The tandem reaction pathways enabled the rapid construction of multiple carbon-carbon bonds, editing the carbon skeletons of 1,3-enynes precisely and divergently.The catalysts are derived from inexpensive sustainable cobalt salts and commercially available bisphosphines.The synthetic utility was demonstrated by diverse functionalization of the products, affording a series of useful enantioenriched building blocks that are otherwise difficult to access.Mechanistic studies were conducted to elucidate the reaction mechanisms, revealing that different ligands were able to induce divergent transformations of the metallacycles generated from oxidative cyclization in high chemo-, regioand stereoselectivity.Such discoveries unveiled unique reaction pathways for cobalt catalysis and domino processes through oxidative cyclization, opening up opportunities for designing cascade reactions promoted by Co-based catalysts, providing a toolbox for complex molecule synthesis, and pushing forward the advancement of organocobalt chemistry.Further investigations on other Cocatalyzed tandem reactions through oxidative cyclization are underway.

General procedure
In a N 2 -filled glove box, an oven-dried 8-mL vial equipped with a stirring bar was charged with CoI 2 (6.3 mg, 0.02 mmol, 10 mol %), 3e (8.5 mg, 0.02 mmol, 10 mol %), Mn powder (44.0 mg, 0.8 mmol, 4.0 eq) and DMA (0.8 mL).The vial was sealed with a cap (phenolic cap with red PTFE/white silicone septum) and the solution was allowed to stir at room temperature for 30 min.1a (49.7 mg, 0.4 mmol, 2.0 equiv.),2a (64.9 mg, 0.4 mmol, 1.0 equiv.),H 2 O (14.4 mg, 0.8 mmol, 4.0 equiv.)and DMA (0.2 mL) were added to the solution.Then the vial was sealed with a cap (phenolic open-top cap with red PTFE/white silicone septum), and removed from the glove box.The mixture was immediately moved to a thermostatic bath and allowed to stir at 60 o C for 12 h.Upon cooling to room temperature, the reaction mixture was washed with brine (3 × 15 ml), eluted with Et 2 O (20 mL), dried over MgSO 4 , filtered, and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE:EA = 40:1) to afford the 4a as a colorless oil (82.8 mg, 92% yield).
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Fig. 1 |
Fig. 1 | Background and reaction design.a Catalytic enantioselective double functionalization of alkynes by sequential reactions.b Catalytic coupling of alkynes and activated alkenes through oxidative cyclization promoted by low-valent Ni or Co complexes.c Representative target molecules bearing multisubstituted alkenes.dEditing the carbon skeleton of the alkyne through a streamlined approach by introducing multiple C-C bonds.e Our cascade strategy for pathway-divergent coupling of 1,3-enynes with two molecules of acrylates to generate multifunctional 1,3-dienes.

Fig. 2 |
Fig. 2 | Optimization of reaction conditions.a Yield of isolated product.b Enantiomeric ratios (er) were determined by analysis of HPLC spectra.c Not available.d The reaction was performed in DMA. e Mn was used as reductant.f The