Transition Metal Catalysis

Cross-coupling reactions are essential tools in target molecule synthesis. However, the use of highly reactive organometallic reagents limits their applicability. Here, we present a mechanochemical Pd-catalyzed cross-coupling reaction between aryl halides and organozinc pivalates that can be carried out under ambient temperature and atmosphere. This operationally simple procedure affords a wide range of biaryl and aryl-heteroaryl derivatives in high yields and short times. The reaction tolerates various functional groups and can be realized on a synthetically useful scale. Its practical value was demonstrated in the short synthesis of the pharmaceutical diflunisal.
T. Čarný, T. Peňaška, S. Andrejčák, R. Šebesta, Chem. Eur. J. 2022, e202202040 DOI: https://doi.org/10.1002/chem.202202040
Heterocycles possessing multiple substituents and stereogenic centers are important structural motifs in many compounds of interest. We present here stereoselective tandem transformation based on Cu-catalyzed conjugate addition of Grignard reagents to heterocyclic Michael acceptors, which is followed by one-pot trapping of in situ formed enolates with stabilized carbocations or their equivalents. The transformations are highly enantio- and diastereoselective with Josiphos-type ferrocene ligand. The reaction of chiral metal enolates with onium compounds allows the installation of structurally attractive substituents on chromenone or piperidinone core. Moreover, cycloheptatrienyl and benzodithiolyl substituents can be further modified, thus expanding synthetic possibilities of this methodology.
B. Mudráková, P. Kisszékelyi, D. Vargová, D. Zakiewicz, R. Šebesta, Adv. Synth. Catal. 2022, 364, 1337 - 1344.
DOI: https://doi.org/10.1002/adsc.202101485
The search for mild, user-friendly, easily accessible, and robust organometallic reagents is an important feature of organometallic chemistry. Ideally, new methodologies employing organometallics should be developed with respect to practical applications in syntheses of target compounds. In this short review, we investigate if organozirconium reagents can fulfill these criteria. Organozirconium compounds are typically generated via in situ hydrozirconation of alkenes or alkynes with the Schwartz reagent. Alkyl and alkenylzirconium reagents have proven to be convenient in conjugate additions, allylic substitutions, cross-coupling reactions, and additions to carbonyls or imines. Furthermore, the Schwartz reagent itself is a useful reducing agent for polar functional groups.
I. Némethová, R. Šebesta, Synthesis 2021, 53, 447-460. DOI: 10.1055/s-0040-1706055
Access to enantiopure complex molecular structures is crucial for the development of new drugs as well as agents used in crop-protection. In this regard, numerous asymmetric methods have been established. Copper-catalyzed 1,4-additions of organometallic reagents are robust C–C bond formation strategies applicable in a wide range of circumstances. This review analyses the syntheses of natural products and pharmaceutical agents, which rely on the application of asymmetric Cu-catalyzed conjugate additions of various organometallic reagents. A wide range of available organometallics, e.g. dialkylzinc, trialkylaluminum, Grignard, and organozirconium, can now be used in conjugate additions to address various synthetic challenges present in targeted natural compounds. Furthermore, efficient catalysts allow high levels of stereofidelity over a diverse array of starting Michael acceptors.
D. Vargová, I. Némethová, R. Šebesta,  ​Org. Biomol. Chem. 2020, 18, 3780-3796. DOI: https://doi.org/10.1039/D0OB00278J
Chiral amines are important as medicines or agrochemicals. They are often assembled by nucleophilic addition to corresponding compounds featuring CN bond. Pre-made organometallics are typical nucleophiles in this reaction. In this work, we describe asymmetric reductive alkylation of imines with alkenes. Hydrozirconation of these alkenes generated organozirconium species in situ. The transformation is catalyzed by Cu-Segphos complex and affords chiral amines in enantioselectivities up to 93% ee.
I. Némethová, D. Vargová, B. Mudráková, J. Filo, R. Šebesta, J. Organomet. Chem. 2020, 908, 121099. DOI: https://doi.org/10.1016/j.jorganchem.2019.121099
This review comprises two major parts, which have chiral metal-enolates in their focus. In the first part, we discuss transition metal catalyzed conjugate additions leading to chiral enolates, which are then subsequently functionalized by reactions with electrophiles, both further catalyzed or uncatalyzed. The second part deals with base generated enolates and their use in the asymmetric transition metal catalyzed processes.
D. Vargová, I. Némethová, K. Plevová, R. Šebesta, ACS Catal. 2019, 9, 3104-3143; DOI: 10.1021/acscatal.8b04357.
Asymmetric conjugate addition of organozirconium species to N-heterocyclic Michael acceptors is presented in this paper. High yield of products was obtained with α,β-unsaturated lactams which are highly unstable, that is why enantioselectivity did not surpass 64% ee. On the other hand protected 2,3-dihydropyridine-4(1H)-ones provided in the same catalytic system desired products in low yields but in enantioselectivity up to 84% ee.
I. Némethová, S. Bilka, R. Šebesta, J. Organomet. Chem. 2018, 856, 100-108; DOI: 10.1016/j.jorganchem.2017.12.042.
In this paper we present first Zr-enolate trapping, initiated by Cu-catalysed CA, by naked organic cations and also by other Michael acceptors. The enantioselective version of this reaction was studied as well, unfortunately the yields of the trapping products were rather low, due to the low reactivity of intermediate species.
I. Némethová, Z. Sorádová, R. Šebesta, Synthesis, 2017, 49, 2461-2469; DOI: 10.1055/s-0036-1588968.www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0036-1588968
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We are interested in these reactions with Grignard reagents as nucleophiles for conjugate addition to produce chiral magnesium enolates. As electrophile we choose:
Preparation of silylated ferrocenyl derivatives we enabled through Retro-Brook rearrangement on O-silylated ferrocenyl alcohol initiated by Br-Li exchange. [see Chem. Eur. J. 2015, 21, 13445-13453]