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1.
J Am Chem Soc ; 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853359

RESUMO

Aminoboronic acids represent a class of significant compounds that have attracted significant attention in the fields of drug discovery and organic synthesis. Despite notable progress in their synthesis, the efficient construction of chiral ß-aminoboronic acids with alkyl side chains remains a challenging endeavor. Here, we introduce an unprecedented nickel-catalyzed asymmetric borylalkylation of enamides, employing a simple chiral diamine ligand, readily available B2pin2, and alkyl halides as coupling partners. This reaction serves as an efficient platform for assembling a diverse range of ß-aminoboronic acid derivatives with flexible alkyl side chains, displaying exceptional regio-, stereo-, and enantioselectivities. Moreover, this transformation exhibits a broad substrate scope and remarkable tolerance toward various functional groups. Theoretical calculations demonstrate that the benzyl group on the ligand is the key to the high enantiocontrol in this transformation. Additionally, we exemplify the practical application of this strategy through the concise synthesis of complex bioactive molecules.

2.
Nat Rev Chem ; 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822206

RESUMO

Six-membered rings are ubiquitous structural motifs in bioactive compounds and multifunctional materials. Notably, their thermodynamically disfavoured isomers, like disubstituted cyclohexanes featuring one substituent in an equatorial position and the other in an axial position, often exhibit enhanced physical and biological activities in comparison with their opposite isomers. However, the synthesis of thermodynamically disfavoured isomers is, by its nature, challenging, with only a limited number of possible approaches. In this Review, we summarize and compare synthetic methodologies that produce substituted six-membered rings with thermodynamically disfavoured substitution patterns. We place particular emphasis on elucidating the crucial stereoinduction factors within each transformation. Our aim is to stimulate interest in the synthesis of these unique structures, while simultaneously providing synthetic chemists with a guide to approaching this synthetic challenge.

3.
Acc Chem Res ; 56(22): 3246-3259, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37910401

RESUMO

ConspectusChain-walking offers extensive opportunities for innovating synthetic methods that involve constructing chemical bonds at unconventional sites. This approach provides previously inaccessible retrosynthetic disconnections in organic synthesis. Through chain-walking, transition metal-catalyzed alkene difunctionalization reactions can take place in a 1,n-addition (n ≠ 2) mode. Unlike classical 1,2-regioselective difunctionalization reactions, there remains a scarcity of reports regarding migratory patterns. Moreover, the range of olefins utilized in these studies is quite limited.About five years ago, our research group embarked on a project aimed at developing valuable migratory difunctionalization reactions of alkenes through chain-walking. Our focus was on carboboration of alkenes utilizing nickel catalysis. The reaction commences with the migratory insertion of an olefin into a Ni-Bpin species. Subsequently, a thermodynamically stable alkyl nickel complex is generated through a chain-walking process. This complex then couples with a carbon-based electrophile, leading to the formation of an alkylboron compound. It is worth highlighting that the success of these transformations relies significantly on the utilization of a bisnitrogen-based ligand and LiOMe as a B2pin2 activator. Synthetically, these migratory carboboration reactions establish a robust platform for the rapid and efficient synthesis of a wide range of structurally diverse organoboron compounds, which are not facially accessed by conventional methods. The incorporation of a versatile boron group introduces a wealth of possibilities for subsequent diversifications, significantly enhancing the value of the resulting products and allowing for the creation of a broader range of valuable derivatives and applications.This Account provides a comprehensive overview of our research efforts and advancements in the field of migratory carboboration of unactivated alkenes using nickel catalysis. We begin by outlining the development of a series of 1,1-regioselective carboboration reactions of terminal alkenes. A significant focus is placed on the initial integration of boronate, which not only triggers the formation of thermodynamically stable metal species but also exerts control over remote stereochemistry in reactions involving substituted methylenecyclohexenes. Continuing our exploration, remarkable success is achieved in 1,3-regio- and cis-stereoselectivity when dealing with cyclic alkenes. Remarkably, nickel chain-walking catalysis enables heterocyclic alkenes to be viable coupling partners within our transformations. Moreover, it grants us the ability to achieve regioselectivity for cyclohexenes that was previously unattainable, thus expanding the horizons of regiochemical control in these reactions. Lastly, we present the evolution of ligand-modulated regiodivergent carboboration of allylarenes. By gaining insights into the underlying mechanisms driving regiodivergence, we lay a strong foundation for tackling challenges related to selecting specific sites in chain-walking reactions, especially when dealing with multiple stable factors. We anticipate that our findings, coupled with the mechanistic insights we've gained, will not only advance the realm of nickel chain-walking catalysis but also contribute to the broader understanding of selectivity control in reactions of this nature. This advancement will also catalyze the synthesis of intricate functional molecules, contributing to the creation of complex and valuable compounds in the realm of organic chemistry.

4.
Nat Commun ; 14(1): 7670, 2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-37996492

RESUMO

Organosilicon compounds have shown tremendous potential in drug discovery and their synthesis stimulates wide interest. Multicomponent cross-coupling of alkenes with silicon reagents is used to yield complex silicon-containing compounds from readily accessible feedstock chemicals but the reaction with simple alkenes remains challenging. Here, we report a regioselective silylalkylation of simple alkenes, which is enabled by using a stable Ni(II) salt and an inexpensive trans-1,2-diaminocyclohexane ligand as a catalyst. Remarkably, this reaction can tolerate a broad range of olefins bearing various functional groups, including alcohol, ester, amides and ethers, thus it allows for the efficient and selective assembly of a diverse range of bifunctional organosilicon building blocks from terminal alkenes, alkyl halides and the Suginome reagent. Moreover, an expedient synthetic route toward alpha-Lipoic acid has been developed by this methodology.

5.
J Am Chem Soc ; 145(34): 18722-18730, 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37582178

RESUMO

Selective transformation of alkyne triple bonds to double bonds serves as an efficient platform to construct substituted alkenes. While significant advances have been made in its spatiotemporal regulation, achieving a multicomponent enantioselective reaction that requires multifaceted selectivity issues to be overcome is still uncommon. Here, we report an unprecedented asymmetric anti-stereoselective borylcarbofunctionalization of terminal alkynes by nickel catalysis. The utilization of an inexpensive chiral diamine ligand enables the three-component cross-coupling of terminal alkynes, a diboron reagent, and prochiral alkyl electrophiles with high levels of regio-, stereo-, and enantioselectivities. This reaction provides an efficient protocol to access enantioenriched alkenyl esters bearing an α-stereogenic center, is remarkably practical, and has a broad scope and an outstanding functional group compatibility. In addition, the value of this method has been highlighted in a diversity of follow-up stereoretentive derivatizations and the stereoselective concise synthesis of complex drug molecules.

6.
Angew Chem Int Ed Engl ; 62(35): e202308041, 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37428115

RESUMO

While chain-walking stimulates wide interest in both polymerization and organic synthesis, site- and stereoselective control of chain-walking on rings is still a challenging task in the realm of organometallic catalysis. Inspired by a controllable chain-walking on cyclohexane rings in olefin polymerization, we have developed a set of chain-walking carboborations of cyclohexenes based on nickel catalysis. Different from the 1,4-trans-selectivity disclosed in polymer science, a high level of 1,3-regio- and cis-stereoselectivity is obtained in our reactions. Mechanistically, we discovery that the base affects the reduction ability of B2 pin2 and different bases lead to different catalytic cycles and different regioselective products (1,2- Vs 1,3-addition). This study provides a concise and modular method for the synthesis of 1,3-disubstituted cyclohexylboron compounds. The incorporation of a readily modifiable boronate group greatly enhances the value of this method, the synthetic potential of which was highlighted by the synthesis of a series of high-valued commercial chemicals and pharmaceutically interesting molecules.

7.
J Am Chem Soc ; 145(25): 13603-13614, 2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37279247

RESUMO

Chiral boronic esters are a class of versatile building blocks. We describe herein an asymmetric nickel-catalyzed borylative coupling of terminal alkenes with nonactivated alkyl halides. The success of this asymmetric reaction is ascribed to the application of a chiral anionic bisoxazoline ligand. This study provides a three-component strategy to access α- and ß-stereogenic boronic esters from easily accessible starting materials. This protocol is characterized by mild reaction conditions, wide substrate scope and high regio- and enantioselectivity. We also showcase the value of this method in simplifying the synthesis of several drug molecules. Mechanistic studies suggest that the generation of enantioenriched boronic esters bearing an α-stereogenic center results from a stereoconvergent process, while the enantioselectivity-controlling step in the generation of boronic esters with a ß-stereocenter is switched to the olefin migratory insertion step due to coordination of an ester group.

8.
Angew Chem Int Ed Engl ; 61(37): e202209076, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-35861349

RESUMO

We report herein a modular catalytic method for the efficient enantioselective synthesis of chiral allylboronates from abundant feedstock chemicals through an asymmetric 1,1-difunctionalization of alkenes. This protocol is distinguished by its use of an inexpensive chiral catalyst, mild and convenient reaction conditions, wide substrate scope, scalability and practicality. The utility of this method is demonstrated by the rapid synthesis of key intermediates of complex drug molecules. Mechanistic studies reveal that ß-H elimination is a highly regioselective step and the reversible homolysis and convergance to the lower energy pre-reductive elimination intermediate is the enantio-determining step.


Assuntos
Alcenos , Alcenos/química , Catálise , Ciclização , Estrutura Molecular , Estereoisomerismo
9.
Science ; 376(6594): 749-753, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35549424

RESUMO

Substituted six-membered cyclic hydrocarbons are common constituents of biologically active compounds. Although methods for the synthesis of thermodynamically favored, disubstituted cyclohexanes are well established, a reliable and modular protocol for the synthesis of their stereoisomers is still elusive. Herein, we report a general strategy for the modular synthesis of disubstituted cyclohexanes with excellent kinetic stereocontrol from readily accessible substituted methylenecyclohexanes by the implementation of chain-walking catalysis. Mechanistically, the initial introduction of a sterically demanding boron ester group adjacent to the cyclohexane is key to guiding the stereochemical outcome. The synthetic potential of this methodology has been highlighted in late-stage modification of complex bioactive molecules and in comparison with current cross-coupling techniques.

10.
Chem Sci ; 13(5): 1390-1397, 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35222923

RESUMO

While chiral allylic organophosphorus compounds are widely utilized in asymmetric catalysis and for accessing bioactive molecules, their synthetic methods are still very limited. We report the development of asymmetric nickel/Brønsted acid dual-catalyzed hydrophosphinylation of 1,3-dienes with phosphine oxides. This reaction is characterized by an inexpensive chiral catalyst, broad substrate scope, and high regio- and enantioselectivity. This study allows the construction of chiral allylic phosphine oxides in a highly economic and efficient manner. Preliminary mechanistic investigations suggest that the 1,3-diene insertion into the chiral Ni-H species is a highly regioselective process and the formation of the chiral C-P bond is an irreversible step.

11.
J Am Chem Soc ; 143(48): 20027-20034, 2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34734714

RESUMO

Whereas there is a significant interest in the rapid construction of diversely substituted saturated heterocycles, direct and modular access is currently limited to the mono-, 2,3-, or 3,4-substitution pattern. This Communication describes the straightforward and modular construction of 2,4-substituted saturated heterocycles from readily available materials in a highly stereo- and regioselective manner, which sets the stage for numerous readily accessible drug motifs. The strategy relies on chain walking catalysis.

12.
Sci Bull (Beijing) ; 66(6): 570-577, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-36654427

RESUMO

Synthesis of organosilanes from alkenes is a very important topic owing to their wide applications. A Ni/Cu dual metal-catalyzed arylsilylation of terminal alkenes, featuring migratory selectivity, has been developed. A wide diversity of aliphatic silanes have been prepared from terminal alkenes, aryl halides and Suginome's reagent. This protocol is highlighted by excellent regioselectivity, mild reaction conditions and good functional group tolerance. In addition to benzylic positions, carbon-carbon bonds can also be constructed at allylic positions. Preliminary mechanistic studies suggest that the copper cocatalyst promotes the transmetalation of Suginome's reagent, and the addition of a PyrOx ligand inhibits the formation of side-products from the carbon-Heck pathway. Moreover, studies toward the nature of the PyrOx ligand revealed that the steric hindrance of the oxazoline moiety greatly affects the chain-walking process, but not the arylation step.

13.
Nat Commun ; 11(1): 417, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964876

RESUMO

Cross-coupling reactions have developed into powerful approaches for carbon-carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki-Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process.

14.
Chem Sci ; 11(38): 10461-10464, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34094304

RESUMO

The selective cross-coupling of activated electrophiles with unactivated ones has been regarded as a challenging task in cross-electrophile couplings. Herein we describe a migratory cross-coupling strategy, which can overcome this obstacle to access the desired cross-coupling products. Accordingly, a selective migratory cross-coupling of two alkyl electrophiles has been accomplished by nickel catalysis. Remarkably, this alkyl-alkyl cross-coupling reaction provides a platform to prepare 2°-2° carbon-carbon bonds from 1° and 2° carbon coupling partners. Preliminary mechanistic studies suggest that chain-walking occurs at both alkyl halides in this reaction, thus a catalytic cycle with the key step involving two alkylnickel(ii) species is proposed for this transformation.

15.
Angew Chem Int Ed Engl ; 59(21): 7990-8003, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-31800977

RESUMO

The direct difunctionalization of alkenes, a cheap and abundant feedstock, represents one of the most attractive strategies for increasing molecular complexity in synthetic organic chemistry. In contrast with the 1,2-difunctionalization of alkenes, recent advances showcase alkene 1,n-difunctionalizations (n≠2) involving metal migration is an emerging and rapidly growing area of research. This promising strategy not only opens a novel avenue for future development of alkene transformations, but also significantly expands upon the bond disconnections available in modern organic synthesis. This Minireview summarizes recent progress in the migratory difunctionalization of alkenes, with an emphasis on the driving force for metal migration.

16.
iScience ; 22: 369-379, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31812807

RESUMO

A novel nickel/Brønsted acid-catalyzed asymmetric hydroamination of acyclic 1,3-dienes has been established. A wide array of primary and secondary amines can be transformed into allylic amines with high yields and high enantioselectivities under very mild conditions. Moreover, our method is compatible with various functional groups and heterocycles, allowing for late-stage functionalization of biologically active complex molecules. Remarkably, this protocol exhibits good chemoselectivity with respect to amines bearing two different nucleophilic sites. Mechanistic studies reveal that the enantioselective carbon-nitrogen bond-forming step is reversible.

17.
Org Lett ; 21(11): 3968-3971, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31074286

RESUMO

A novel nickel-catalyzed 1,2-arylboration of vinylarenes is reported. A variety of 2-boryl-1,1-diarylalkanes, which constitute a class of significant pharmacophores, are efficiently prepared from readily available olefins and aryl halides in the presence of bis(pinacolato)diboron under mild reaction conditions. The success of this three-component cascade is mainly attributed to the redox-active nitrogen-based ligand. Moreover, this method exhibits good functional group tolerance and excellent chemo- and stereoselectivity.

18.
Angew Chem Int Ed Engl ; 58(26): 8872-8876, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31056806

RESUMO

An unprecedented nickel-catalyzed 1,1-alkylboration of electronically unbiased alkenes has been developed, providing straightforward access to secondary aliphatic boronic esters from readily available materials under very mild reaction conditions. The regioselectivity of this reaction is governed by a unique pyridyl carboxamide ligated catalyst, rather than the substrates. Moreover, this transformation shows excellent chemo- and regio-selectivity and remarkably good functional-group tolerance. We also demonstrate that under balloon pressure, ethylene can also be utilized as a substrate. Additionally, competence experiments indicate that selective bond formation is favored at the α-position of boron and preliminary mechanistic studies indicate that the key step in this three-component reaction involves a 1,2-nickel migration.

19.
Angew Chem Int Ed Engl ; 58(14): 4612-4616, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30740847

RESUMO

An unprecedented arylboration of unactivated terminal alkenes, featuring 1,n-regioselectivity, has been achieved by nickel catalysis. The nitrogen-based ligand plays an essential role in the success of this three-component reaction. This transformation displays good regioselectivity and excellent functional-group tolerance. In addition, the incorporation of a boron group into the products provides substantial opportunities for further transformations. Also demonstrated is that the products can be readily transformed into pharmaceutically relevant molecules. Unexpectedly, preliminary mechanistic studies indicate that although the metal migration favors the α-position of boron, selective and decisive bond formation is favored at the benzylic position.

20.
Angew Chem Int Ed Engl ; 57(38): 12425-12429, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30014554

RESUMO

This report widens the repertoire of emerging PdI catalysis to carbon-heteroatom, that is, C-S bond formation. While Pd0 -catalyzed protocols may suffer from the formation of poisonous sulfide-bound off-cycle intermediates and lack of selectivity, the mechanistically diverse PdI catalysis concept circumvents these challenges and allows for C-S bond formation (S-aryl and S-alkyl) of a wide range of aryl halides. Site-selective thiolations of C-Br sites in the presence of C-Cl and C-OTf were achieved in a general and a priori predictable fashion. Computational, spectroscopic, X-ray, and reactivity data support dinuclear PdI catalysis to be operative. Contrary to air-sensitive Pd0 , the active PdI species was easily recovered in the open atmosphere and subjected to multiple rounds of recycling.

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