The Passerini three-component (P-3CR) and the Ugi four-component (U-4CR) are two of the most prominent isocyanide-based multicomponent reactions (IMCRs). The P-3CR transforms isocyanides, aldehydes (ketones), and carboxylic acids to α-acyloxy carboxamides, while the U-4CR converts isocyanides, aldehydes (ketones), amines, and carboxylic acids to α-acetamido carboxamides. Conversion of the high energy formal divalent isocyano carbon into a tetravalent amide carbonyl carbon provides the driving force for these reactions. While the prototypical P-3CR and U-4CR provide linear adducts, many heterocycles and macrocycles are now readily synthesized by modifying these truly versatile reactions. As one stereocenter is generated by the nucleophilic addition of the isocyanide to the carbonyl and imine functions, the search for enantioselective versions of these reactions has become a much sought after goal among synthetic chemists. This seemingly trivial endeavor turns out to be extremely difficult to achieve, in sharp contrast to the remarkable progress documented in the field of asymmetric synthesis in general and catalytic enantioselective nucleophilic addition to C═X bond in particular. Since Denmark's first report in 2003 on the catalytic enantioselective Passerini two-component reaction of isocyanides with aldehydes, several Lewis acid (LA) and Brønsted acid-catalyzed enantioselective protocols have been developed. However, it is fair to say that truly catalytic enantioselective P-3CR and U-4CR with wide application scope remain elusive. In this Account, we summarize the progress recorded in this field over the past 15 years. We entered the field by investigating the enantioselective reaction of α-isocyanoacetamides with aldehydes and imines, which was previously developed in our lab for the synthesis of functionalized 5-aminooxazoles. Our initial experimental results, in conjunction with Dömling's and Schreiber's earlier findings, prompted us to assume that the low turnover number in LA-catalyzed asymmetric IMCRs is a main hurdle for enantioselectivity. We speculated that the LA incapable of forming chelates would be the catalyst of choice for enantioselectivity, the rational being that the P-3CR and the U-4CR afforded bidentate intermediates (α-hydroxy imidates, α-amino imidates) and products (α-acyloxy carboxamides, α-acetamido carboxamides) from nonchelating inputs. Therefore, the transfer of catalyst from these chelating intermediates or products to the monocoordinating starting materials would be difficult, hence the problem with catalyst turnover. This working hypothesis turned out to be a valuable guide that allowed us to develop Al-salen and Al-phosphate-catalyzed enantioselective P-3CR and enantioselective construction of chiral heterocycles such as oxazoles and tetrazoles. Nevertheless, all our attempts to apply these LA catalysts to the Ugi reaction failed. Indeed, to date, no reports on the successful LA-catalyzed asymmetric Ugi-type reactions exist in the literature. However, significant progress has bee...
The enantioselective synthesis of molecules containing quaternary stereocenters is a field of intense research interest and development. Among the known organic transformations, carbopalladation-initiated domino transformations constitutes a general method for the construction of compounds containing cyclic or spiro quaternary stereocenters. In this Minireview, recent achievements in palladium-catalyzed domino Heck/C-H functionalizations and developments in enantioselective carbopalladation-initiated domino processes are summarized.
The generation of heteroatom-centred radicals followed by intramolecular 1,5-HAT and functionalisation of the translocated carbon-centred radical is an efficient way to functionalize chemo- and regio-selectively the remote unactivated C(sp3)–H bond.
Under mild dual photoredox/copper catalysis,t he reaction of N-alkoxypyridinium salts with readily available silyl reagents (TMSN 3 ,TMSCN,TMSNCS) afforded d-azido, d-cyano,a nd d-thiocyanato alcohols in high yields.T he reaction went through ad omino process involving alkoxy radical generation, 1,5-hydrogen atom transfer (1,5-HAT) and copper-catalyzed functionalization of the resulting C-centered radical. Conditions for catalytic enantioselective d-C(sp 3 )ÀH cyanation were also documented.
Pd-catalyzed intramolecular asymmetric carbopalladation of N-aryl acrylamides followed by reduction of C(sp )-Pd intermediate using diboron-water as a hydride source afforded enantioenriched 3,3-disubstituted oxindoles in high yields and enantioselectivities. When heavy water was used as a deuterium donor in combination with bis(catecholato)diboron (Cat B ), deuterium was incorporated into the products with high synthetic efficiency. The ligand determined both the enantioselectivity of the reaction and the reaction pathways, thereby affording either hydroarylation (reductive Heck) or carboborylation products.
We report herein the first examples of ap alladiumcatalyzede nantioselective Cacchir eaction for the synthesis of indoles bearing ac hiral C2-aryl axis.I nt he presence of ac atalytic amount of Pd(OAc) 2 and (R,R)-QuinoxP* ligand, reaction of N-aryl(alkyl)sulfonyl-2-alkynylanilides with arylboronic acids under oxygen atmosphere afforded enantioenriched 2,3-disubstituted indoles in high yields and enantioselectivity.The indole ring is constructed de novo in this process and ac omplexation-induced chirality transfer is proposed to account for the observed enantioselectivity. Scheme 1. Axially chiral indoles:occurrence and synthesis.Scheme 3. Synthesis and X-ray structural characterization of (L6)PdArX complexes 7a (X = OAc) and 8a (X = I). Scheme 4. Results of control experiments using QuinoxP*(=O) and QuinoxP*(=O) 2 as ligands. Angewandte Chemie Communications 2107
We report herein a strategy to construct enantiopure inherently chiral macrocycles, ABCD-type heteracalix[4]aromatics, through a catalytic enantioselective intramolecular C−N bond forming reaction. A chiral ligand-palladium complex was found to efficiently induce the inherent chirality of molecules during the macrocyclization process with ee values up to >99%. The resulting ABCD-type heteracalix[4]aromatics displayed excellent and pH-triggered switchable electronic circular dichroism and circularly polarized luminescence properties.
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