Cobalt‐Catalyzed Diastereo‐ and Enantioselective Reductive Coupling of Cyclobutenes and Aldimines

A dual photoredox/cobalt‐catalyzed protocol for chemo‐, regio‐, diastereo‐ and enantioselective reductive coupling of 1,1‐disubstituted allenes and cyclobutenes through chemo‐, regio‐, diastereo‐ and enantioselective oxidative cyclization followed by stereoselective protonation promoted by a chiral phosphine–cobalt complex is presented. Such process represents an unprecedented reaction pathway for cobalt catalysis that enables selective transformation of the less sterically congested alkenes of 1,1‐disubstituted allenes with cyclobutenes, incorporating a broad scope of tetrasubstituted alkenes into the cyclobutane scaffolds in up to 86 % yield, >98 : 2 chemo‐ and regioselectivity, >98 : 2 dr and >99.5:0.5 er. Functionalization delivered a variety of enantioenriched cyclobutanes that are otherwise difficult to access. Preliminary mechanistic studies revealed that the reactions proceeded through oxidative cyclization followed by protonation and protonation might be the rate‐determining step.

A dual photoredox/cobalt-catalyzed protocol for chemo-, regio-, diastereo- and enantioselective reductive coupling of 1,1-disubstituted allenes and cyclobutenes through chemo-, regio-, diastereo- and enantioselective oxidative cyclization followed by stereoselective protonation promoted by a chiral phosphine-cobalt complex is presented. Such process represents an unprecedented reaction pathway for cobalt catalysis that enables selective transformation of the less sterically congested alkenes of 1,1-disubstituted allenes with cyclobutenes, incorporating a broad scope of tetrasubstituted alkenes into the cyclobutane scaffolds in up to 86 % yield, >98 : 2 chemo- and regioselectivity, >98 : 2 dr and >99.5:0.5 er. Functionalization delivered a variety of enantioenriched cyclobutanes that are otherwise difficult to access. Preliminary mechanistic studies revealed that the reactions proceeded through oxidative cyclization followed by protonation and protonation might be the rate-determining step.

Catalytic regio-, diastereo- and enantioselective reductive coupling of 1,3-dienes and aldehydes through regio- and enantioselective oxidative cyclization followed by regio- and diastereoselective protonation promoted by a chiral phosphine-cobalt complex is presented. Such processes represent an unprecedented reaction pathway for cobalt catalysis that enable selective transformation of the more substituted alkene in 1,3-dienes, affording a broad scope of bishomoallylic alcohols without the need of pre-formation of stoichiometric amounts of sensitive organometallic reagents in up to 98 % yield, >98 : 2 regioselectivity, >98 : 2 dr and 98 : 2 er. Application of this method to construction of axial stereogenicity and deuterated stereogenic center provided a wide range of multifunctional chiral building blocks that are otherwise difficult to access. DFT calculations revealed the origin of regio- and stereoselectivity as well as a unique oxidative cyclization mechanism for cobalt catalysis.

Catalytic diastereo- and enantioselective functionalization of cyclobutenes represents a general and modular strategy for the construction of enantioenriched complex cyclobutanes. However, all precedents focused on reactions of cyclobutenes with nucleophilic organometallic intermediates, whereas transformations of cyclobutenes with electrophiles remained unknown. Herein, we report an unprecedented cobalt-catalyzed protocol for diastereo- and enantioselective reductive coupling of unactivated cyclobutenes and aldehydes. This process enabled access to a broad range of densely functionalized enantioenriched cyclobutanes and the introduction of a chiral functionalized alkyl group with high efficiency and stereoselectivity. Mechanistic studies revealed that diastereo- and enantioselective oxidative cyclization of cyclobutenes and aldehydes followed by stereoselective protonation might be involved. DFT (Density Functional Theory) calculations elucidated the origin of stereoselectivity. This study provides a new platform for modular synthesis of enantioenriched cyclobutanes and reveals new reactivity for cobalt catalysis, pushing forward the advancement in organocobalt chemistry.

Catalytic reductive coupling of unsaturated hydrocarbons with carbonyl compounds provides a streamlined alternative to stoichiometric organometallic additions, yet asymmetric variants that directly engage unactivated alkenes remain limited. Here we report a diastereo- and enantioselective nickel-catalyzed intramolecular reductive cyclization of unactivated alkenes and aldehydes. Using a chiral monodentate phosphoramidite ligand and triethylborane as the terminal reductant, the method delivers substituted cyclic alcohols as single diastereomers in up to 98% yield and up to 99% ee, with broad functional-group tolerance including halides, free alcohols, esters, and boronic esters. Applications to bioactive-molecule synthesis are demonstrated, and DFT studies support an enantiodetermining oxidative cyclization pathway.

Tricyclic furan derivatives with multiple chiral centers are ubiquitous in natural products. Construction of such tricyclic scaffolds in a stereocontrolled, step-economic, and atom-economic manner is a key challenge. Here we show a nickel-catalyzed highly enantioselective synthesis of hydronaphtho[1,8-bc]furans with five contiguous chiral centers via desymmetrization of alkynyl-cyclohexadienone by oxidative cyclization and following formal [4 + 2] cycloaddition processes. Alkynyl-cyclohexadienone was synthesized in one step from easily accessible phenols. This reaction represents excellent chemo-selectivity, regio-selectivity, diastereo-selectivity, and enantio-selectivity (single diastereomer, up to 99% ee). An extraordinary regioselectivity in the formal [4 + 2] cycloaddition step with enones revealed the diverse reactivity of the nickelacycle intermediate. Desymmetrization of alkynyl-cyclohexadienones via oxidative cyclization on nickel was supported by the isolation of a nickelacycle from a stoichiometric reaction. Enantioenriched tricyclic products contain various functional groups such as C=O and C=C. The synthetic utility of these products was demonstrated by derivatization of these functional groups.

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first t...

The mitomycins, a family of bioactive natural products, feature a compact 6/5/5‐fused polycyclic ring structure densely decorated with highly reactive and/or fragile quinone, amino ketal, and aziridine as well as carbamate moieties. It is this striking feature that has defeated numerous synthetic attempts towards these apparently small molecules, rendering them one of the most formidable targets for total synthesis. We herein report the first enantioselective synthesis of (+)‐mitomycin K, a representative of G series mitomycins. The key step of this synthesis is an enantioselective oxidative cyclization catalyzed by a palladium/(+)‐sparteine system that had previously been developed by our group. The robustness of this method bodes well for further applications in the asymmetric total synthesis of natural products, particularly those with characteristic 6/5/5‐fused pyrroloindole skeletons.

A chiral aryl iodide promotes the enantioselective oxidative cyclization of 1-naphtholic sulfonamides, albeit in moderate ee and low yield. The products tend to crystallize as conglomerates. Recrystallization thus increases their ee to > 99% ee. This highly enantioenriched material provides seed crystals for the resolution of the racemate (prepared in high yield by oxidative cyclization with (diacetoxyiodo)benzene in trifluoroacetic acid) by coupled preferential crystallization. This enables the production of significant quantities of highly enantioenriched products, despite the low efficiency of the enantioselective reaction.

The mitomycins, a family of bioactive natural products, feature a compact 6/5/5-fused polycyclic ring structure densely decorated with highly reactive and/or fragile quinone, amino ketal, and aziridine as well as carbamate moieties. It is this striking feature that has defeated numerous synthetic attempts towards these apparently small molecules, rendering them one of the most formidable targets for total synthesis. We herein report the first enantioselective synthesis of (+)-mitomycin K, a representative of G series mitomycins. The key step of this synthesis is an enantioselective oxidative cyclization catalyzed by a palladium/(+)-sparteine system that had previously been developed by our group. The robustness of this method bodes well for further applications in the asymmetric total synthesis of natural products, particularly those with characteristic 6/5/5-fused pyrroloindole skeletons.

Shou-Fei Zhu of Nankai University developed (Angew. Chem. Int. Ed. 2014, 53, 13188) an iron catalyst that effected the enantioselective cyclization of 1 to 2. Bypassing diazo precursors, Junliang Zhang of East China Normal University used (Angew. Chem. Int. Ed. 2014, 53, 13751) a gold catalyst to cyclize 3 to 4. Taking advantage of energy transfer from a catalytic Ir complex, Chuo Chen of University of Texas Southwestern carried out (Science 2014, 346, 219) intramolec­ular 2+2 cycloaddition of 5, leading, after dithiane formation, to the cyclobutane 6. Intramolecular ketene cycloaddition has been limited in scope. Liming Zhang of the University of California Santa Barbara found (Angew. Chem. Int. Ed. 2014, 53, 9572) that intramolecular oxidation of an intermediate Ru vinylidene led to a species that cyclized to the cyclobutanone 8. James D. White of Oregon State University devised (J. Am. Chem. Soc. 2014, 136, 13578) an iron catalyst that mediated the enantioselective Conia-ene cyclization of 9 to 10. Xiaoming Feng of Sichuan University observed (Angew. Chem. Int. Ed. 2014, 53, 11579) that the Ni-catalyzed Claisen rearrangement of 11 proceeded with high diastereo- and enantiocontrol. The relative configuration of the product 12 was not reported. Robert H. Grubbs of Caltech showed (J. Am. Chem. Soc. 2014, 136, 13029) that ring opening cross metathesis of 13 with 14 delivered the Z product 15. Mn(III) cyclization has in the past required a stoichiometric amount of inorganic oxidant. Sangho Koo of Myong Ji University found (Adv. Synth. Catal. 2014, 356, 3059) that by adding a Co co- catalyst, air could serve as the stoichiometric oxidant. Indeed, 16 could be cyclized to 17 using inexpensive Mn(II). Matthias Beller of the Leibniz-Institüt für Katalyse prepared (Angew. Chem. Int. Ed. 2014, 53, 13049) the cyclohexene 20 by coupling the racemic alcohol 18 with the amine 19. Paultheo von Zezschwitz of Philipps-Universität Marburg added (Chem. Commun. 2014, 50, 15897) diethyl zinc in a conjugate sense to 21, then reduced the product to give 22. Depending on the reduction method, either diastereomer of the product could be made dominant. Nuno Maulide of the University of Vienna dis­placed (Angew. Chem. Int. Ed. 2014, 53, 7068) the racemic chloride 23 with diethyl zinc to give 24 as a single diastereomer.

Co(nmp)2 is an efficient catalyst for the aerobic oxidative cyclization of pent-4-en-1-ols to give 5-hydroxymethyl trans-tetrahydrofurans (THFs) as single diastereomers in high yield. The trans-THF pharmacophore is of interest because it is found in many biologically active natural products. The three-step synthesis of Co(nmp)2 described here gives the catalyst as a fine powder in 80–85% overall yield on 10-gram scale. The use of the catalyst in a representative oxidative cyclization is also described.

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

Transition-metal catalyzed asymmetric cyclization of 1,6-enynes has emerged as a powerful method for the construction of carbocycles and heterocycles. However, very rare examples worked under electrochemical conditions. We report herein a Co-catalyzed enantioselective intramolecular reductive coupling of enynes via electrochemistry using H2O as hydride source. The products were obtained in good yields with high regio- and enantioselectivities. It represents the rare progress on the cobalt-catalyzed enantioselective transformation via electrochemistry with a general substrate scope. DFT studies explored the possible reaction pathways and revealed that the oxidative cyclization of enynes by LCo(I) is more favorable than oxidative addition of H2O or other pathways.

The reaction of [RhCl(COD)]2 (COD = 1,5-cyclooctadiene) with racemic PPh2(CH(Ph)CH2CHO) and pyridine (py) led to the oxidative addition of the aldehyde, and a single geometric isomer of [RhHCl(PPh2(CH(Ph)CH2CO))(py)2] (1), with hydride trans to chloride, was obtained as a mixture of two diastereomers in a 95 : 5 ratio; this was in agreement with density functional theory (DFT) calculations. In a chloroform solution, the exchange of hydride by chloride yielded [RhCl2(PPh2(CH(Ph)CH2CO))(py)2] (2) as a mixture of a kinetically preferred species, trans-py-2a, and two diastereomers, cis-Cl-2b' and cis-Cl-2b, with cis pyridines and a chloride trans to acyl; as predicted by the DFT calculations, the latter was the major species. Complex 1 reacted with racemic PPh2(CH(Ph)CH2CHO) or PPh2(o-C6H4CHO) to afford [RhHCl(PPh2(CH(Ph)CH2CO))(κ1-PPh2(CH(Ph)CH2CHO))(py)] (3) or [RhHCl(PPh2(o-C6H4CO))(κ1-PPh2(CH(Ph)CH2CHO))(py)] (4), respectively, both with a dangling alkylaldehyde. Diastereomeric mixtures with the ratios 3a/3a' = 80 : 20 and 4a/4a' = 50 : 50 were obtained. Complex 4 reacted with N-donors to afford cationic [RhH(NN)(PPh2(o-C6H4CO))(κ1-PPh2(CH(Ph)CH2CHO))]BPh4 (NN = 1,10-phenanthroline, 5; 2,2'-bipyridine, 6) or with 8-aminoquinoline (aqui) or 2-(aminomethyl)pyridine to yield imination products with terdentate ligands: [RhH(PPh2(o-C6H4CO))(κ3-PNN)]BF4 (PNN = PPh2(CH(Ph)CH2CNC9H6N), 7 and PPh2(CH(Ph)CH2CNCH2C5H4N), 8, respectively. Compounds 5-8 were obtained as equimolar a/a' mixtures of diastereomers. Moreover, 5a and 5a' could be separated. [RhCl(NBD)]2 reacted with racemic PPh2(CH(Ph)CH2CHO) and N-donors to provide nortricyclyl (Ntyl) derivatives [RhCl(NN)(Ntyl)(PPh2CH(Ph)CH2CO)] (NN = phen, 9 and bipy, 10) as an a/a' = 75 : 25 mixture of diastereomers. By reacting [RhCl(NBD)]2 with PPh2(CH(Ph)CH2CHO) and quinoline-8-carbaldehyde in methanol, the phosphino-ester complex [RhCl(Ntyl)(C9H6NCO)(κ2-PPh2CH(Ph)CH2CO(OCH3)] 11 was obtained. The initial equimolar mixture of two diastereomers readily transformed into a single diastereomer, which was found to be thermodynamically most stable by the DFT calculations. Furthermore, single crystal X-ray diffraction analysis of cis-Cl-2b, 5a, 7a, 10a and 11 is reported.