Enantioselective Skeletal Editing

Welcome to this week’s Organic Synthesis Newsletter.

Monday 25^th November – Sunday 1^st December 2024 | Volume 1, Issue 36

HIGHLIGHT OF THE WEEK
Asymmetric Dearomative Single-Atom Skeletal Editing of Indoles and Pyrroles

X. Zhang,^† Q. Song,^† S. Liu,^† P. Sivaguru, Z. Liu,* Y. Yang, Y. Ning, E. A. Anderson, G. de Ruiter & X. Bi*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01680-0)

Heterocycle skeletal editing has recently emerged as a powerful tactic for achieving heterocycle-to-heterocycle transmutation without the need for multistep de novo heterocycle synthesis. However, the enantioselective skeletal editing of heteroarenes through single-atom logic remains challenging. Here, the authors report the enantiodivergent dearomative skeletal editing of indoles and pyrroles via an asymmetric carbon-atom insertion, using trifluoromethyl N-triftosylhydrazones as carbene precursors. This strategy provides straightforward access to enantiomerically enriched six-membered N-heterocycles containing a trifluoromethylated quaternary stereocentre from planar N-heteroarenes. The synthetic utility of this enantiodivergent methodology was demonstrated by a broad evaluation of reaction scope, product derivatization and concise syntheses of drug analogues.

NATURE CHEMISTRY
Unmasking the Reverse Catalytic Activity of “ene”-Reductases for Asymmetric Carbonyl Desaturation

H. Wang,^† B. Gao,^† H. Cheng, S. Cao, X. Ma, Y. Chen & Y. Ye*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01671-1)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-1k5kc) 🔓

Carbonyl desaturation is a fundamental reaction widely practiced in organic synthesis. While numerous methods have been developed to expand the scope of this important transformation, most of them necessitate multi-step protocols or suffer from the use of high loadings of metal or strong oxidizing conditions. Moreover, approaches that can achieve precise stereochemical control of the desaturation process are extremely rare. Here, the authors report a biocatalytic platform for the desymmetrizing desaturation of cyclohexanones to generate diverse cyclohexenones bearing a remote quaternary stereogenic centre, by reengineering “ene”-reductases to efficiently mediate dehydrogenation, the reverse process of their native activity. This “ene”-reductase-based desaturation system operates under mild conditions with air as the terminal oxidant, tolerates oxidation-sensitive or metal-incompatible functional groups and, more importantly, exhibits unparalleled stereoselectivity compared with those achieved with small-molecule catalysts.

NATURE CATALYSIS
Enantioconvergent Copper-Catalysed Difluoromethylation of Alkyl Halides

D. Ding, L. Yin, A. T. Poore, Y.-S. Ho, Y.-H. Cheng, C.-T. Hsieh, S. C. Yachuw, R. M. Knieser, J. A. Krause, S. Tian, M.-J. Cheng & W. Liu*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01253-x)

Stereochemically controlled hydrogen bond donors play essential roles in the pharmaceutical industry. Consequently, organic molecules that bear difluoromethyl (CF₂H) groups at chiral centres are emerging as pivotal components in pharmaceuticals due to their distinct hydrogen-bonding properties. However, a general approach for introducing CF₂H groups in an enantioselective manner has remained elusive. Here, the authors show that enantioconvergent difluoromethylation of racemic alkyl electrophiles, through alkyl radical intermediates, represents a strategy for constructing CF₂H-containing stereocentres with excellent enantioselectivity.

NATURE COMMUNICATIONS
Photochemical 1,3-Boronate Rearrangement enables Three-Component N-Alkylation for α-Tertiary Hydroxybenzylamine Synthesis

P. Zou,^† D. Fu,^† H. Wang,^† R. Sun, Y. Lan* & Y. Chen*

Nat. Commun. 2024, 15, 10234 (DOI: 10.1038/s41467-024-54165-6) 🔓

Hydroxybenzylamines are prevalent in drugs and bioactive molecules, including various antimalarial and anticancer drugs. α-Tertiary alkylation of amines impacts drug-target interactions significantly through their influence on basicity and lipophilicity. Traditional N-alkylation methods, especially for α-tertiary amines, suffer from limitations due to high energy barriers from steric hindrance. In this work, the authors leverage visible light irradiation to enable the organoboronic acid addition to sterically hindered ketimines in the excited state. Notably, it overcomes the limitations of the well-explored Petasis reaction, which is restricted to aldimines due to the high energy barrier associated with ketimines (51.3 kcal/mol). This three-component coupling of aliphatic amines, o-phenolic ketones, and organoboronic acids delivers diverse α-tertiary o-hydroxybenzylamines (77 examples, yields up to 82%) with broad functional group tolerance.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Catalytic Enantioselective Hydrogen Atom Abstraction Enables the Asymmetric Oxidation of meso Diols

N. Y. S. Lam, J. Dhankhar, A. S. K. Lahdenperä & R. J. Phipps*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13919) 🔓

Desymmetrization of meso diols is an important strategy for the synthesis of chiral oxygen-containing building blocks. Oxidative desymmetrization is an important subclass, but existing methods are often constrained by the need for activated alcohol substrates. Here, the authors disclose a conceptually distinct strategy toward oxidative diol desymmetrization that is enabled by catalytic enantioselective hydrogen atom abstraction. Following single electron oxidation of a cinchona alkaloid-derived catalyst, enantiodetermining hydrogen atom abstraction generates a desymmetrized ketyl radical intermediate which reacts with either DIAD or O₂ before in situ elimination to form valuable hydroxyketone products. A range of cyclic and acyclic meso diols are competent, defining the absolute configuration of up to four stereocenters in a single operation.

Highly Efficient and Enantioselective Iridium-Catalyzed Asymmetric Reductive Cycloetherification

Y. Zong,^†* X. Zou,^† H. Tao, Q. Huang, G.-Q. Chen* & X. Zhang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c13709)

A catalytic protocol for the iridium-catalyzed asymmetric hydrogenation (AH) of γ- or δ-hydroxy ketones to rapidly assemble various aliphatic enantioenriched tetrahydrofurans (THFs) or tetrahydropyrans (THPs) is disclosed. A wide range of enantioenriched THFs or THPs were obtained in high yields and excellent enantioselectivities (up to 99% and up to 96.5:3.5 e.r.). The dynamic kinetic resolution asymmetric hydrogenation (DKR-AH) process was also achieved, simultaneously constructing enantioenriched THP scaffolds with two contiguous stereogenic centers with high yields and stereoselectivities (up to 92% yield, up to 98.5:1.5 e.r. and >20:1 d.r.). This catalytic enantioselective approach could be carried out on gram scale and various enantioenriched cyclic ethers were further transformed into an array of useful building blocks for enantioenriched natural products and bioactive molecules.

Stereoselective Glycosylation for 1,2-cis-Aminoglycoside Assembly by Cooperative Atom Transfer Catalysis

H. Li,^† D. Zhang,^† C. Li,^† L. Yin,^† Z. Jiang, Y. Luo & H. Xu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c15084)

The authors report a new catalytic method for exclusive 1,2-cis-α-selective glycosylation that assembles a wide variety of 1,2-cis-aminoglycosidic linkages in complex glycans and glycoconjugates. Mechanistic studies revealed a unique glycosylation mechanism in which the iron catalyst activates a glycosyl acceptor and an oxidant when it facilitates the cooperative atom transfer of both moieties to a glycosyl donor in an exclusively cis-selective manner. This catalytic approach is effective for a broad range of glycosyl donors and acceptors, and it can be operated in a reiterative fashion and scaled up to the multigram scale.

Synthesis of P(V)-Stereogenic Phosphorus Compounds via Organocatalytic Asymmetric Condensation

F. Che,^† J. Hu,^† M. Liao,^† Z. Luo, H. Long, B. Li, Y. R. Chi & X. Wu*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11956)

Enantioenriched phosphorus(V)-stereogenic compounds are crucial in various natural products, drugs and catalysts/ligands. While a handful of stereoselective synthetic approaches have been developed, achieving direct stereocontrol at the phosphorus atom through catalytic generation of phosphorus(V)-heteroatom bonds continues to be a formidable challenge. Here, the authors disclose an organocatalytic asymmetric condensation strategy that employs a novel activation mode of stable feedstock phosphinic acids by the formation of mixed phosphinic anhydride as the reactive species to facilitate further catalyst-controlled asymmetric P–O bond formations, involving a dynamic kinetic asymmetric transformation (DYKAT) process with alcohol nucleophiles via a cinchonidine-derived bifunctional catalyst. The resulting H-phosphinate intermediates allow further stereospecific derivatizations, affording modular access to a diverse library of chiral phosphonates and phosphonamidates with notable antibacterial activity.

Catalytic Asymmetric Transfer Hydrogenation of β,γ-Unsaturated α-Diketones

Z. Zhao,^† W. Dong,^† J. Liu, S. Yang, A. E. Cotman, Q. Zhang* & X. Fang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11070)

Asymmetric transfer hydrogenation (ATH) is a highly valuable strategy that has been widely applied in the industrial production of drug molecules. However, despite the success in ATH of ketones, highly efficient, regio- and stereoselective ATH on enones remains underdeveloped. Moreover, optically pure acyloins and 1,2-diols are useful building blocks in organic synthesis, medicinal chemistry and materials science, but concise asymmetric approaches to different types of acyloins and 1,2-diols have scarcely been discovered. Here, the authors report the first highly efficient ATH of readily accessible β,γ-unsaturated α-diketones. The protocol affords four types of enantioenriched acyloins and four types of optically pure 1,2-diols in highly regio- and stereoselective fashion. The synthetic value of this work has been showcased by the divergent synthesis of four related natural products.

Enantioselective Alkylation of Primary C(sp³)–H Bonds in N-Methyl Tertiary Amine Enabled by Iridium Complex of Axially Chiral β-Aryl Porphyrins

S. Yuan, S.-Y. Li, X.-M. Zhao,* Y.-Z. Lin & S.-C. Zheng*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c12449)

A fine-tuning of enantioselective carbene insertion into primary C(sp³)–H bonds has been realized in challenging substrates, such as N-methyl unblocked aromatic and non-deactivated aliphatic tertiary amines, in which sterically demanding β-axially chiral iridium porphyrin catalysts play a crucial role. This primary C(sp³)–H alkylation with diazo compounds affords a series of β-chiral tertiary amines in high yields with excellent enantioselectivities. Notably, the protocol was successfully applied to the postmodification of chiral bicuculline, yielding the desired derivative with high diastereoselectivity.

Mechanistic Investigation of the pseudo-Halogen Effect in Enantioselective Aminocatalyzed [6+4] and [10+6] Cycloadditions: Enabling Unique Favorskii-Like Rearrangements

C. D. Barløse, R. S. Bitsch, J. Faghtmann, C. D. Escobar, M. E. Casacchia, A. Kristensen & K. A. Jørgensen*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c15353)

A mechanistic investigation into the novel combination of the pseudo-halogen effect with enantioselective aminocatalysis unravels the mechanistic intricacies of [6+4] and [10+6] higher-order cycloadditions and the succeeding new Favorskii-like rearrangements. By introducing the OTf-group into the tropone framework, it can serve both as an activator for the cycloaddition and as a proficient leaving group within the corresponding cycloadduct, thus enabling unprecedented ring-contracting Favorskii-like rearrangements. Integrating the -OTf group creates an electron-deficient 6π-component leveraging the pseudo-halogen effect by enhancing the polarization and introducing new strategic interaction points. This modification complements electron-rich 4π- and 10π-components from amino-activated 2,4-dienals or indene-carbaldehydes. This novel concept results in the experimental isolation of structurally complex products in high peri-, diastereo-, and enantioselectivity with moderate yield.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION
Anomeric Amide-Enabled Alkene-Arene and Alkene-Alkene Aminative Coupling

C. Stein,^† J. L. Tyler,^† J. Wiener, F. Boser, C. G. Daniliuc & F. Glorius*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202418141)

Despite the prominence of C−N bond forming cross-coupling reactions as a strategy to assemble molecular fragments, aminative coupling approaches, in which two fragments are assembled directly at the heteroatom, represents a rarely exploited retrosynthetic strategy. Herein, the authors report the design, synthesis, and implementation of an anomeric amide reagent capable of promoting highly regioselective aminative alkene-arene and alkene-alkene coupling reactions. Due to the simplicity of the protocol and building blocks required, high-throughput experimentation was employed to rapidly and efficiently explore a wide range of chemical space and determine the limits of reactivity. In addition, alternative reactivity modes from the functionalized intermediates delivered by this protocol demonstrate the divergent nature of this aminative coupling strategy.

Visible Light-Mediated [4+2] Annulation of Silylimines with Olefins to 1-Aminotetralins Enabled by Diradical Hydrogen Atom Transfer of C−H Bonds

Q. Liu, Y. Huang, X. Zhou, I. Fernández* & Y. Xiong*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202421464)

A facile photochemical, one-pot synthesis of highly functionalized 1-aminotetralin derivatives (>70 examples) from readily accessible o-alkyl and o-formyl aryl silylimines with olefins is described. A diradical-mediated hydrogen atom transfer (DHAT) of primary, secondary, and tertiary C(sp³)−H bonds of o-alkyl arylsilylimines and C(sp²)−H bonds of o-formyl arylsilylimines enabled a [4+2] annulation with olefins in excellent diastereoselectivity. This protocol is compatible with a variety of functional groups and can be applied to the modification of bioactive molecules.

CHEMRXIV
Concise Synthesis of (–)-Veratramine and (–)-20-epi-Veratramine via Aromative Diels-Alder Reaction

M. D. Zott, D. W. Zuschlag & D. H. Trauner*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-ccrr6-v2) 🔓

A concise and convergent synthesis of the isosteroidal alkaloids veratramine and 20-epi-veratramine has been accomplished. A Horner-Wadsworth-Emmons olefination joins two chiral building blocks of approximately equal complexity and a transition-metal catalyzed intramolecular Diels-Alder cycloaddition-aromatization cascade constructs the tetrasubstituted arene. Other key steps include a highly diastereoselective crotylation of an N-sulfonyl iminium ion and an Eschenmoser fragmentation. The chiral building blocks developed for this synthesis could be used to access a range of additional isosteroidal alkaloids using the authors diversifiable strategy. This work shows that 20-epi-veratramine is not identical with a natural product proposed to have that structure.

The Asymmetric Olefinative Conjugate Addition

F. Vaghi, P. Soppelsa, K. Wurst, G. Licini & M. Orlandi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-zghgx) 🔓

The asymmetric olefinative conjugate addition (AOCA) is presented, which involves an enantioselective conjugate addition to an olefin activated by a traceless electron-withdrawing group, which then allows for an olefinative quench with a carbonyl compound. This approach is demonstrated by the Cu-catalyzed enantioselective conjugate addition of organoboron and organozinc reagents to an alkenyl phosphonate, followed by quenching with a carbonyl compound to yield the corresponding alkene via Horner-Wadsworth-Emmons olefination. This one-pot sequence efficiently produces chiral internal olefins, addressing a common limitation of Cu-catalyzed enantioselective allylic substitutions, which typically only generate terminal alkenes. The versatility of this strategy is showcased through the synthesis of various structurally diverse products with high yields, complete diastereocontrol, and enantiomeric ratios of up to 98:2.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE
Colossal Coral

🔭 Colossal coral. Nature have just released their selection of the best science images in November, featuring a 300-year-old coral near the Solomon Islands in the Pacific. Coming in at 34 × 32 metres, the newly discovered coral—pictured just behind the boat in the image above—is the World’s largest. Composed of nearly a billion coral polyps that function as if they were a single organism, the giant structure can actually be seen from space. With only 8.4% of the ocean protected by government regulations and 77% of coral reef areas subject to temperatures high enough to cause bleaching, finding such a large coral in good health offers promise that other coral colonies may be able to weather the climate crisis.