New Catalytic Routes to Benzofused Seven-Membered Azaheterocycles

Benzazepines, benzodiazepines and benzoxazepines compose a privileged family of natural products and pharmaceuticals. Their remarkable biological activity made them useful drugs to treat a large variety of issues. The design of new catalytic sustainable routes to these nuclei still remains as a main challenge to the organic chemistry. In this thesis the synthesis of these three nuclei upon generation of a key metalp- allyl intermediate through Csp2-H activation, allylic C-H activation, and Rh-hydride catalysis have been successfully accomplished

Palladium-Catalyzed [5+2] Heteroannulation of Phenethylamides with 1,3-Dienes to Dopaminergic 3-Benzazepines

NOTICE: This is the peer reviewed version of the following article: Velasco-Rubio, A., Varela, J. A., Saá, C. (2020). Palladium-Catalyzed [5+2] Heteroannulation of Phenethylamides with 1,3-Dienes to Dopaminergic 3-Benzazepines. Org. Lett., 22, 9, 3591-3595. [doi: 10.1021/acs.orglett.0c01053]. This article may be used for non-commercial purposes in accordance with American Chemical Society Terms and Conditions for self-archivingPhenethyltriflamides react with 1,3-dienes upon treatment with a catalytic amount of Pd(OAc)2 and Cu(OAc)2/O2 as oxidant to afford chemo-, regio- and diastereoselectively 2,3,4,5-tetrahydro-1H-benzo[d]azepines (3-benzazepine derivatives) in good to excellent yields. A DFT study of the [5+2] heteroannulation suggests a mechanistic pathway starting by the formation of the six-membered palladacycle cis-PdX2L2 via a CMD process followed by η2 coordination and insertion of the 1,3-diene unit in a diastereoselective manner.This work has received financial support from MINECO (project CTQ2017-87939R and ORFEO-CINQA network RED2018-102387-T), the Xunta de Galicia (project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund – ERDF). A.V.-R. thanks Xunta de Galicia for a predoctoral fel-lowship (ED481A-2018/34, 2018-2021)S

Direct C–H Allylation of Unactivated Alkanes by Cooperative W/Cu Photocatalysis

Here we report a photocatalytic methodology that enables the direct allylation of strong aliphatic C–H bonds with simple allylic chlorides. The method relies on a cooperative interaction of two metal catalysts in which the decatungstate anion acts as a hydrogen-atom abstractor generating a nucleophilic carbon-centered radical that engages in an SH2′ reaction with an activated allylic π-olefin–copper complex. Because of this dual catalysis, the protocol allows for the functionalization of a range of chemical feedstocks and natural products under mild conditions in short reaction timesFinancial support from the European Research Council (ERC-CoG 863914-BECAME), Agencia Estatal de Investigación (PID2020-118237RB-I00), Xunta de Galicia (ED431C 2018/04; Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03), and the European Regional Development Fund (ERDF) is gratefully acknowledgedS

Enantioenriched alpha-Vinyl 1,4-Benzodiazepines and 1,4-Benzoxazepines via Enantioselective Rhodium-Catalyzed Hydrofunctionalizations of Alkynes and Allenes

Benzofused seven-membered heterocycles such as 1,4-benzo[e]diazepines (1,4-BZDs) and 1,4-benzo[e]oxazepines (1,4-BZOs) were efficiently synthesized by Rh-catalyzed hydrofunctionalization of internal alkynes and allenes in good to excellent yields. The asymmetric hydroamination of (aminomethyl)anilines gave rise to 3-vinyl-1,4-BZDs with excellent enantioselectivities. Orthogonal N-deprotection of 1,4-BZDs allowed an easy entry to an advanced pyrrolobenzodiazepine metabolite of the V2-receptor antagonist Lixivaptan®This work has received financial support from MINECO (project CTQ2017-87939R and ORFEO-CINQA network RED2018-102387-T), the Xunta de Galicia (project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund – ERDF). A.V.-R. thanks Xunta de Galicia for a predoctoral fel-lowship (ED481A-2018/34, 2018-2021).S

Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl Bromides: Access to Fully Substituted α-Amino Ketones

A versatile thermal Overman rearrangement of enantioenriched, cyclic allylic alcohols providing tertiary allylic amines has been developed. The vinyl bromide used to control enantioselectivity in a preceding CBS reduction is utilized as a synthetic handle for the preparation of tertiary α-amino ketones and related derivatives in an asymmetric fashion

Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl Bromides: Access to Fully Substituted α-Amino Ketones

A versatile thermal Overman rearrangement of enantioenriched, cyclic allylic alcohols providing tertiary allylic amines has been developed. The vinyl bromide used to control enantioselectivity in a preceding CBS reduction is utilized as a synthetic handle for the preparation of tertiary α-amino ketones and related derivatives in an asymmetric fashion

Palladium-Catalyzed [5 + 2] Rollover Annulation of 1-Benzylpyrazoles with Alkynes: A Direct Entry to Tricyclic 2-Benzazepines

The first Pd-catalyzed [5 + 2] rollover annulation of 1-benzylpyrazoles with alkynes to assemble 10H-benzo[e]pyrazolo[1,5-a]azepines (tricyclic 2-benzazepines) has been developed. The rollover annulation implies a twofold C–H activation of aryl and heteroaryl Csp2–H bonds (C–H/C–H) of 1-benzylpyrazoles (five-atom partners) and alkynes to give the [5 + 2] annulated compounds.We acknowledge financial support from MICINN (Project PID2020-118048GB-I00 and ORFEO−CINQA Network RED2018-102387-T), the Xunta de Galicia (Project ED431C 2022/27 and Centro Singular de Investigación de Galicia Accreditation 2019−2022, ED431G 2019/03), and the European Union (European Regional Development Fund). A.S.-L. thanks MICINN for a predoctoral contract.S

Recent Advances in Transition-Metal Catalyzed Oxidative Annulations to Benzazepines and Benzodiazepines

NOTICE: This is the peer reviewed version of the following article: Velasco-Rubio, A., Varela J. A., Saá C. (2020). Recent Advances in Transition-Metal Catalyzed Oxidative Annulations to Benzazepines and Benzodiazepines. Adv. Synth. Catal., 362, 22, 4861-4875. [doi: 10.1002/adsc.202000808]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for self-archivingBenzazepines and benzodiazepines, benzofused seven-membered N-heterocycles, compose an important family of natural products and pharmaceuticals. Although certainly important and effectives, classical synthetic methods of these cyclic compounds involve methodologies that often require multistep procedures, with generation of waste materials and lack of sustainability. By contrast, cycloadditions based on transition metal catalyzed C-H bond activations (oxidative annulations) have emerged as appealing strategies for more sustainable synthetic processes. In this review, we focus our attention to describe the state-of-the-art transition-metal catalyzed annulations via C-H activations to benzazepines and benzodiazepines.This work has received financial support from MINECO (project CTQ2017-87939R and ORFEO-CINQA network RED2018- 102387-T), the Xunta de Galicia (project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019- 2022, ED431G 2019/03) and the European Union (European Regional Development Fund – ERDF)S

Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with noncardiovascular death in CKD populations are lacking. The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n ¼ 2185 CKD patients). After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG þ rs2283368 CC/CT þ rs2320762 GG). Among the patients with the three SNPs genotyped (n ¼ 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA þ rs2283368 TT þ rs2320762 GT/TT). All the other combinations [n ¼ 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher fhazard ratio [HR] 3.28 [confidence interval (CI) 1.51-7.12]g and lower [HR 6 × 10- (95% CI 3.3 × 10--1.1 × 10-)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination. Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD