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1.
Chem Sci ; 15(16): 5832-5868, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38665517

ABSTRACT

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C-C, C-H, and C-N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N-H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry.

2.
Org Lett ; 24(29): 5468-5473, 2022 07 29.
Article in English | MEDLINE | ID: mdl-35856291

ABSTRACT

The 1,1a,2,7b-tetrahydrocyclopropa[c]chromene, arising from fusion of chromane and cyclopropane rings is the core of medicinally relevant compounds. Engaging sulfoxonium ylides in enantioselective aminocatalytic reactions for the first time, a convenient entry to this scaffold is presented. Several ring-fused derivatives were obtained in moderate-to-good yields and enantioselectivities and with perfect diastereoselectivity at the cyclopropane, using an α,α-diphenylprolinol aminocatalyst. The versatility of the hemiacetal moiety in the products was leveraged to effect various synthetic manipulations.


Subject(s)
Chromans , Cyclopropanes , Benzopyrans , Cyclopropanes/chemistry , Stereoisomerism
3.
Chem Sci ; 12(30): 10233-10241, 2021 Aug 04.
Article in English | MEDLINE | ID: mdl-34447530

ABSTRACT

Currently, conventional reductive catalytic methodologies do not guarantee general access to enantioenriched ß-branched ß-trifluoromethyl α-amino acid derivatives. Herein, a one-pot approach to these important α-amino acids, grounded on the reduction - ring opening of Erlenmeyer-Plöchl azlactones, is presented. The configurations of the two chirality centers of the products are established during each of the two catalytic steps, enabling a stereodivergent process.

4.
Org Biomol Chem ; 18(43): 8793-8809, 2020 11 12.
Article in English | MEDLINE | ID: mdl-33084717

ABSTRACT

Sulfur ylides first disclosed in 1930 started to gain more attention in the 1960s, thanks mainly to the studies by Corey and Chaykovsky on their use for the preparation of strained rings. More recently, the chemistry of these compounds has experienced important growth, in part due to the similarity of their reactivities with diazo compounds. This short review provides an overview on the great assortment of reactions of sulfoxonium ylides, outlining a comparison between the chemistry of these ylides and their congeners: sulfonium ylides and diazo compounds. Insertion reactions, cyclisation reactions and ring-opening reactions are highlighted, giving particular attention to catalytic asymmetric methodologies.

5.
Chemistry ; 25(68): 15694-15701, 2019 Dec 05.
Article in English | MEDLINE | ID: mdl-31556176

ABSTRACT

The first stereoselective synthesis of enantioenriched axially chiral indole-quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloaddition of 3-alkenylindoles and N-arylimines, followed by an oxidative central-to-axial chirality conversion process, allowing for access to previously unreported axially chiral indole-quinoline biaryls. The methodology is also implemented for the design and the preparation of challenging compounds exhibiting two stereogenic axes. DFT calculations shed light on the stereoselectivity of the central-to-axial chirality conversion, showing unconventional behavior.

6.
ChemMedChem ; 13(17): 1744-1750, 2018 09 06.
Article in English | MEDLINE | ID: mdl-29966045

ABSTRACT

A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5 µm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.


Subject(s)
Antineoplastic Agents/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Central Nervous System Neoplasms/drug therapy , Glioblastoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/pathology , Cycloaddition Reaction , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Signal Transduction/drug effects , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolism
7.
Chem Commun (Camb) ; 54(32): 3977-3980, 2018 Apr 17.
Article in English | MEDLINE | ID: mdl-29610810

ABSTRACT

A new protocol for the enantioselective direct α-heteroarylation of aldehydes with isoquinoline N-oxides, via chiral enamine catalysis, has been successfully developed. High enantiomeric excesses and moderate to good yields were achieved for a variety of α-heteroarylated aldehydes.

8.
Org Lett ; 19(4): 834-837, 2017 02 17.
Article in English | MEDLINE | ID: mdl-28128963

ABSTRACT

Catalytic addition of chiral enamines to azinium salts is a powerful tool for the synthesis of enantioenriched heterocycles. An unprecedented asymmetric dearomative addition of aldehydes to activated N-alkylpyridinium salts is presented. The process exhibits complete C-4 regioselectivity along with high levels of diastereo- and enantiocontrol, achieving a high-yielding synthesis of a broad range of optically active 1,4-dihydropyridines. Moreover, the presented methodology enables the synthesis of functionalized octahydropyrrolo[2,3-c]pyridines, the core structure of anticancer peptidomimetics.

9.
Molecules ; 21(8)2016 Jul 30.
Article in English | MEDLINE | ID: mdl-27483233

ABSTRACT

Given its synthetic relevance, the catalytic enantioselective reduction of ß,ß-disubstituted nitroalkenes has received a great deal of attention. Several bio-, metal-, and organo-catalytic methods have been developed, which however are usually applicable to single classes of nitroalkene substrates. In this paper, we present an account of our previous work on this transformation, which implemented with new disclosures and mechanistic insights results in a very general protocol for nitroalkene reductions. The proposed methodology is characterized by (i) a remarkably broad scope encompassing various nitroalkene classes; (ii) Hantzsch esters as convenient (on a preparative scale) hydrogen surrogates; (iii) a simple and commercially available thiourea as catalyst; (iv) user-friendly procedures. Overall, the proposed protocol gives a practical dimension to the catalytic enantioselective reduction of ß,ß-disubstituted nitroalkenes, offering a useful and general platform for the preparation of nitroalkanes bearing a stereogenic center at the ß-position in a highly enantioenriched form. A transition state model derived from control kinetic experiments combined with literature data is proposed and discussed. This model accounts and justifies the observed experimental results.


Subject(s)
Alkenes/chemistry , Nitro Compounds/chemistry , Thiourea/chemistry , Catalysis , Hydrogen Bonding , Hydrogenation , Molecular Structure , Stereoisomerism
10.
Chemistry ; 21(52): 19208-22, 2015 Dec 21.
Article in English | MEDLINE | ID: mdl-26602867

ABSTRACT

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

11.
Chemistry ; 21(49): 17578-82, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26486074

ABSTRACT

A domino Friedel-Crafts/nitro-Michael reaction between 4-substituted indoles and nitroethene is presented. The reaction is catalyzed by BINOL-derived phosphoric acid catalysts, and delivers the corresponding 3,4-ring-fused indoles with very good results in terms of yields and diastereo- and enantioselectivities. The tricyclic benzo[cd]indole products bear a nitro group at the right position to serve as precursors of ergot alkaloids, as demonstrated by the formal synthesis of 6,7-secoagroclavine from one of the adducts. DFT calculations suggest that the outcome of the reaction stems from the preferential evolution of a key nitronic acid intermediate through a nucleophilic addition pathway, rather than to the expected "quenching" through protonation.

12.
Molecules ; 20(7): 11733-64, 2015 Jun 25.
Article in English | MEDLINE | ID: mdl-26121398

ABSTRACT

Quinone methides (QMs) are highly reactive compounds that have been defined as "elusive" intermediates, or even as a "synthetic enigma" in organic chemistry. Indeed, there were just a handful of examples of their utilization in catalytic asymmetric settings until some years ago. This review collects organocatalytic asymmetric reactions that employ QMs as substrates and intermediates, from the early examples, mostly based on stabilized QMs bearing specific substitution patterns, to more recent contributions, which have dramatically expanded the scope of QM chemistry. In fact, it was only very recently that the generation of QMs in situ through strategies compatible with organocatalytic methodologies has been realized. This tactic has finally opened the gate to the full exploitation of these unstable intermediates, leading to a series of remarkable disclosures. Several types of synthetically powerful asymmetric addition and cycloaddition reactions, applicable to a broad range of QMs, are now available.


Subject(s)
Indolequinones/chemistry , Organic Chemicals/chemistry , Catalysis
13.
Chemistry ; 21(16): 6037-41, 2015 Apr 13.
Article in English | MEDLINE | ID: mdl-25766504

ABSTRACT

A new approach to the utilization of highly reactive and unstable ortho-quinone methides (o-QMs) in catalytic asymmetric settings is presented. The enantioselective reactions are catalysed by bifunctional organocatalysts, and the o-QM intermediates are formed in situ from 2-sulfonylalkyl phenols through base-promoted elimination of sulfinic acid. The use of mild Brønsted basic conditions for transiently generating o-QMs in catalytic asymmetric processes is unprecedented, and allows engaging productively in the reactions nucleophiles such as Meldrum's acid, malononitrile and 1,3-dicarbonyls. The catalytic transformations give new and general entries to 3,4-dihydrocoumarins, 4H-chromenes and xanthenones. These frameworks are recurring structures in natural product and medicinal chemistry, as testified by the formal syntheses of (R)-tolterodine and (S)-4-methoxydalbergione from the catalytic adducts.

14.
Chem Commun (Camb) ; 51(4): 658-60, 2015 Jan 14.
Article in English | MEDLINE | ID: mdl-25415618

ABSTRACT

In the presence of a thiourea catalyst, ß-CF3 nitroalkenes react with Hantzsch esters in a highly enantioselective fashion, giving a broad range of ß-CF3 amine precursors with a tertiary stereocentre at the ß-position. This reaction represents the first general catalytic enantioselective approach to this important class of ß-CF3 amines.

15.
Chem Commun (Camb) ; 50(4): 445-7, 2014 Jan 14.
Article in English | MEDLINE | ID: mdl-24252947

ABSTRACT

Indoles bearing Michael acceptors at the 4-position were engaged in organocatalytic enantioselective cascade reactions with enals. Careful optimisation of the reaction parameters overcame the inherent low reactivity of these substrates, rendering 3,4-ring fused indoles in good yields, excellent enantioselectivities and as single diastereoisomers.

16.
Chem Commun (Camb) ; 49(9): 880-2, 2013 Jan 30.
Article in English | MEDLINE | ID: mdl-23238127

ABSTRACT

The first example of a catalytic asymmetric vinylogous Povarov reaction is presented. 1-N-Acylamino-1,3-butadienes react selectively at their terminal double bond in the presence of a chiral phosphoric acid catalyst, delivering highly enantioenriched 1,2,3,4-tetrahydroquinolines bearing a synthetically versatile enecarbamate group at the 4-position.


Subject(s)
Butadienes/chemistry , Phosphoric Acids/chemistry , Quinolines/chemical synthesis , Catalysis , Stereoisomerism
17.
Org Biomol Chem ; 10(15): 2911-22, 2012 Apr 21.
Article in English | MEDLINE | ID: mdl-22378196

ABSTRACT

Several small organic molecule catalysts are reminiscent of natural enzymes in their mode of action and substrate interaction/activation. This striking similarity has been a great source of inspiration for the development of new organocatalytic asymmetric processes. A few representative examples, mostly dealing with catalysts interacting through multiple hydrogen-bonds (synthetic oxyanion holes), are highlighted in this perspective.


Subject(s)
Biomimetic Materials/chemistry , Amination , Catalysis , Catalytic Domain , Cyclization , Esterases/chemistry , Hydrogen Bonding , Protein Binding , Serine Proteases/chemistry , Stereoisomerism , Thiourea/analogs & derivatives , Thiourea/chemical synthesis , Thiourea/chemistry , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/chemistry
18.
Chem Commun (Camb) ; 46(2): 327-9, 2010 Jan 14.
Article in English | MEDLINE | ID: mdl-20024367

ABSTRACT

The asymmetric Povarov reaction of N-arylimines with 2- and 3-vinylindoles has been developed using a chiral phosphoric acid ((S)-TRIP) as catalyst. The peculiar reactivity of vinylindoles allowed also the disclosure of a Povarov Friedel-Crafts sequence, and the trapping of the reaction intermediate with nucleophilic species, thus providing a versatile platform for the preparation of highly enantioenriched indole derivatives.

19.
Chem Commun (Camb) ; (36): 4345-7, 2008 Sep 28.
Article in English | MEDLINE | ID: mdl-18802565

ABSTRACT

The unprecedented use of phase-transfer catalysis (PTC) in an asymmetric hydrophosphonylation reaction allows the obtainment of a range of optically active alpha-amino phosphonic acid derivatives directly from alpha-amido sulfones.


Subject(s)
Organophosphonates/chemical synthesis , Sulfones/chemistry , Catalysis , Imines/chemistry , Molecular Structure , Organophosphonates/chemistry , Phase Transition , Stereoisomerism
20.
Chemistry ; 13(29): 8338-51, 2007.
Article in English | MEDLINE | ID: mdl-17705329

ABSTRACT

Different malonates and beta-ketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected alpha-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained phase-transfer catalyst and proceeds under very mild and user-friendly conditions. The optimised protocol avoids the preparation and the isolation of the relatively unstable N-Boc and N-Cbz imines that are generated in situ from the bench-stable alpha-amido sulfones. The corresponding Mannich bases are generally obtained in good yields and enantioselectivities, and can be readily transformed into key compounds, such as optically active beta3-amino acids in one easy step. Enantioenriched N-Boc and N-Cbz protected beta-amino acids that are suitable for peptide synthesis are also available from the Mannich adducts through simple manipulations. Control experiments showed the dual role of the enolate-catalyst ion pair in this reaction, as well as the crucial role of the presence of water to achieve high enantioselectivities.

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