2019 Publications

 Adly, F. G.; Marichev, K. O.; Jensen, J. A.; Arman, H.; Doyle, M. P. “Enoldiazosulfones for Highly Enantioselective [3+3]-Cycloaddition Reactions with Nitrones Catalyzed by Copper(I) with Chiral BOX Ligands” Org. Lett. 2019, 21, 40-44. (DOI: 10.1021/acs.orglett.8b03421)

Enoldiazosulfones undergo [3 + 3]-cycloaddition with nitrones when catalyzed by copper(I) catalysts, but not with dirhodium(II) catalysts. Under mild reaction conditions with chiral bisoxazoline ligands, copper(I) catalysts produce 1,2-oxazine-sulfone derivatives in high yields and enantioselectivities. Dirhodium(II) catalysts form stable donor–acceptor cyclopropenes that undergo uncatalyzed [3 + 2]-cycloaddition reactions with nitrones.

Marichev, K. O.; Doyle, M. P. “Catalytic asymmetric cycloaddition reactions of enoldiazo compounds” Org. & Bio. Chem. 201917, 4183–4195. (DOI: 10.1039/C9OB00478E)

This review describes catalytic asymmetric cycloaddition reactions of silyl-protected enoldiazo compounds for the construction of highly functionalized carbo- and heterocycles which possess one or more chiral center(s). The enoldiazo compound or its derivative, donor–acceptor cyclopropene, form electrophilic vinylogous metal carbene intermediates that combine stepwise with nucleophilic dipolar reactants to form products from [3 + 1]-, [3 + 2]-, [3 + 3]-, [3 + 4]-, and [3 + 5]-cycloaddition, generally in high yield and with exceptional stereocontrol and regioselectivity.

 Dong, K.; Marichev, K. O.; Xu, X.; Doyle, M. P. “High Stereocontrol in the Preparation of Silyl-Protected γ-Substituted Enoldiazoacetates” Synlett 2019, 30, 1457-1461. (DOI: 10.1055/s-0037-1611865)

A robust and efficient synthesis of TIPS-protected γ-substituted enoldiazoacetates with excellent Z-stereocontrol using LiHMDS as a base and TIPSOTf as a silyl-transfer reagent is reported. Despite their increased size compared to previously TBS-protected γ-unsubstituted enoldiazoacetates, a high product yield with exceptional stereocontrol has been achieved in copper-catalyzed [3+3]-cycloaddition reaction with nitrones using a chiral indeno bisoxazoline ligand.

Zheng, H.; Doyle, M. P. “Catalytic Desymmetric Cycloaddition of Diaziridines with Metalloenolcarbenes. The Special Role of Donor-Acceptor Cyclopropenes” Angew. Chem. Int. Ed. 2019, 58, 10343-10346. (DOI: 10.1002/anie.201906754)

A chiral copper(I) complex catalyzes reactions of symmetric diaziridines with enol diazo compounds, which react through N−N bond ring opening in a formal [3+3] cycloaddition to form four chiral centers with high stereocontrol. A broad spectrum of bridged dinitrogen heterocycles were obtained in high yields and excellent diastereo and enantioselectivities from γsubstituted enol diazoacetates, while their geometrical isomers gave different enantioselectivities. Donor–acceptor cyclopropenes formed from the geometrical isomers of the γsubstituted enol diazoacetates underwent catalytic ring opening to give only the Z isomer of the metalloenolcarbene intermediate, provided excellent yields and selectivities for the 1,5diazabicyclo[n.3.1]non2ene derivatives.

Dong, K.; Marichev, K. O.; Doyle, M. P. “The Role of Donor-Acceptor Cyclopropenes in Metal Carbene Reactions. Conversion of E-Substituted Enoldiazoacetates to Z-Substituted Metallo-Enolcarbenes” Organometal. 2019. (DOI: 10.1021/acs.organomet.9b00427)

The influence of geometrical isomers of silyl-protected γ-substituted enoldiazoacetates has been examined in transition-metal-catalyzed vinylcarbene cycloaddition reactions. These reactions often occur with the intervention of donor–acceptor (D-A) cyclopropenes that can serve as metal carbene sources. Pathways to cycloaddition products that occur with and without D-A cyclopropene involvement have been identified. E-γ-Substituted enoldiazoacetates do not undergo cycloaddition reactions unless they first form D-A cyclopropene intermediates. When cycloaddition reactions occur from the metallocarbene only after formation of the D-A cyclopropene, E-γ-substituted enoldiazoacetates are converted to Z-γ-substituted metallo-enolcarbenes, and both geometrical isomers of silyl-protected γ-substituted enoldiazoacetates result in the same product selectivity.

Su, Y.-L.; De Angeles, L.; Doyle, M. P. “Discussion Addendum for: Allylic Oxidation Catalyzed by Dirhodium(II) Tetrakis[e-caprolactamate] of tert-Butyldimethylsilyl-protected trans-Dehydroandrosterone” Org. Synth. 2019, 96, 300-311. (DOI: 10.15227/orgsyn.096.0300)

In summary, dirhodium(II) caprolactamate is a selective and efficient catalyst for TBHP oxidations of the allylic C-H bond. The method features high selectivity, low catalyst loading (usually 0.025 mol%-1 mol%), mild conditions, and a broad substrate scope. The limitations appear to be allylic oxidations of acyclic olefins, but not eneones. Its application to allylic oxidations in the total synthesis of natural products demonstrates its suitability. 

Marichev, K. O.; Wang, K.; Dong, K.; Greco, N.; Massey, L. A.; Deng, Y.; Arman, H.; Doyle, M. P. “ Synthesis of Chiral Tetrasubstituted Azetidines from Donor-Acceptor Azetines via Asymmetric Copper(I)-Catalyzed Imido-Ylide [3+1]-Cycloaddition with Metallo-Enolcarbenes” Angew. Chem. Int. Ed. 2019, 58, 16188-16192. doi: 10.1002/anie.201909929. Highlighted in Synfacts 2019, 15(12), 1393. DOI: 10.1055/s-0039-1691111

In summary, dirhodium(II) caprolactamate is a selective and efficient catalyst for TBHP oxidations of the allylic C-H bond. The method features high selectivity, low catalyst loading (usually 0.025 mol%-1 mol%), mild conditions, and a broad substrate scope. The limitations appear to be allylic oxidations of acyclic olefins, but not eneones. Its application to allylic oxidations in the total synthesis of natural products demonstrates its suitability. The all-cis stereoisomers of tetrasubstituted azetidine-2-carboxylic acids and derivatives that possess three chiral centers have been prepared in high yield and stereocontrol from silyl-protected Z-γ-substituted enoldiazoacetates and imido-sulfurylides by asymmetric [3+1]-cycloaddition using chiral sabox copper(I) catalysis
followed by Pd/C catalytic hydrogenation. Hydrogenation of the chiral p-methoxybenzyl azetine-2-carboxylates occurs with both hydrogen addition to the C=C bond and hydrogenolysis of the ester.

 

Neff, R.K., Su, Y.-L., Liu, S., Rosado, M., Zhang, X., Doyle, M.P. “Generation of Halomethyl Radicals by Halogen Atom Abstraction and Their Addition Reactions with Alkenes” J. Am. Chem. Soc. 2019, 141, 16443-16450. doi: 10.1021/jacs.9b05921

a-Aminoradicals undergo halogen atom abstraction to form halomethyl radicals in reactions initiated by the combination of tert-butyl hydroperoxide, aliphatic trialkylamine, halocarbon, and copper(I) iodide. The formation of the electrophilic a-aminoradical circumvents preferential hydrogen atom transfer in favor of halogen atom transfer, thereby releasing the halomethyl radical for addition to alkenes. The resulting radical addition products add the tert-butylperoxy group to form a-peroxy-b,b-dichloropropylbenzene products that are convertible to their corresponding b,b-dichloro-alcohols and to novel pyridine derivatives. Computational analysis clearly explains the deviation from traditional HAT of chloroform and also establishes formal oxidative addition/reductive elimination as the lowest energy pathway.

Marichev, K. O.; Dong, K.; Massey, L. A.; Deng, Y.; De Angelis, L.; Wang, K.; Arman, H.; Doyle, M. P. “Chiral donor−acceptor
azetines as powerful reactants for synthesis of amino acid derivatives” Nature Communications 2019
10(1):5328. doi: 10.1038/s41467-019-13326-8.

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These
transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon-oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the
intervention of a catalyst. Herein, we report the synthesis of chiral donor−acceptor azetines by highly enantioselective [3+1]-cycloaddition of enoldiazoacetates with aza−ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.