Catalytic Deracemization of α-Branched Aldehydes via Visible Light Promoted E/Z Isomerization of Enamine Intermediate

Catalytic deracemization of α-branched aldehydes represents an unmet challenge with fundamental importance in carbonyl chemistry. In this work, we report a photochemical E/Z isomerization strategy for the deracemization of α-branched aldehydes by using simple aminocatalysts and readily available photosensitizers. Various racemic α-branched aldehydes could be directly transformed into their corresponding single enantiomers in high enantioselectivity. Rapid photodynamic E/Z isomerization and highly stereospecific iminium/enamine tautomerization are two key factors that underlie the highly effective enantio-enrichment. This study presents a distinctive photochemical E/Z isomerizing strategy for externally tuning enamine catalysis.

A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules

<p></p><p> Development of a rapid synthesis of complex molecules from simple building blocks under a metal-and organocatalyst-free condition is both conceptually and chemically challenging. Here, we developed a hidden catalysis that allow the straightforward assembly of enantiopure aza-tricyclic molecules containing six contiguous stereocenters from <a>aminophenols, α,β-unsaturated aldehydes </a>and α-amino acids. <a>Without using a metal or an organocatalyst, our approach relies on a temporary formation of a spiroimidazolidinone intermediate and its participation in a sequential aza-Michael/Michael reaction as both a substrate and a catalyst</a> under an iminium/enamine catalysis. The formation of the putative iminium intermediate was supported by spectroscopic data and its interruptive reduction derivative was isolated and fully characterized. Whereas a conventional catalyst is always present and does not undergo a permanent chemical change in a classic catalysis, the spiroimidazolidinone intermediate is conceptualized as a sub-catalyst as it is only temporary produced from precursors and catalyzes its own consumption. This unique substrate-catalyst (sub-catalyst) dual role of the spiroimidazolidinone induces a substantial steric discrimination in the transition state and an excellent overall diastereoselectivity (>20:1 dr). It allows the use of an amino acid precursor as the sole chirality genesis and avoids the use of transition metals or organocatalysts. An enantiomer of an aza-tricyclic imidazolidinone can be prepared from a commercially available amino acid precursor. The aqueous-based reaction is practical and scalable for multi-gram synthesis. The success of implementing this sub-catalysis concept in the synthesis will pave the way for many efficient chiral catalyst-free preparations of chiral complex molecules.<br></p><br><p></p>

Downstream Paradigm in Enamine Catalysis: Comment on “On Stereocontrol in Organocatalytic α-Chlorinations of Aldehydes”

<p>We present kinetic modeling results in order to evaluate different mechanistic proposals that have been presented concerning the role of “downstream intermediates” in enamine catalysis. The focus of the debate is the identity and role of aminal intermediates. Are the aminals <i>syn</i> or are they <i>anti</i>, or are both observed? Do they lie on the catalytic cycle, as we suggest, or are they off-cycle species?</p>

Downstream Paradigm in Enamine Catalysis: Comment on “On Stereocontrol in Organocatalytic α-Chlorinations of Aldehydes”

<p>We present kinetic modeling results in order to evaluate different mechanistic proposals that have been presented concerning the role of “downstream intermediates” in enamine catalysis. The focus of the debate is the identity and role of aminal intermediates. Are the aminals <i>syn</i> or are they <i>anti</i>, or are both observed? Do they lie on the catalytic cycle, as we suggest, or are they off-cycle species?</p>

A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules containing six contiguous stereocenters

<p></p><p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.¹ In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an </a>α,β-unsaturated aldehyde under an iminium/enamine catalysis. <a>The enhanced co-ordinational proximity of the chiral substrate and catalyst</a> in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from <i>N</i>-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules.</p><br><p></p>

A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules containing six contiguous stereocenters

<p></p><p>Chiral molecules with their defined 3-D structures are of paramount importance for the study of chemical biology and drug discovery. Having rich structural diversity and unique stereoisomerism, chiral molecules offer a large chemical space that can be explored for the design of new therapeutic agents.¹ In practice, chiral architectures are usually prepared from organometallic and organocatalytic processes where a transition metal or an organocatalyst is tailor-made for a desired reaction. As a result, developing a method that enables rapid assembly of chiral complex molecules under a metal- and organocatalyst-free condition represents a daunting challenge. Here we developed a straightforward one-pot procedure to create a chiral 3-D structure from 2-D structures and an amino acid without any chiral catalyst. The center of this research is the design of a <a>special chiral spiroimidazolidinone cyclohexadienone intermediate</a>, a merger of a chiral reactive substrate with multiple nucleophillic/electrophillic sites and a transient organocatalyst. <a>This unique substrate-catalyst (“sub-catalyst”) dual role of the intermediate was displayed in its aza-Michael/Michael cascade reaction with an </a>α,β-unsaturated aldehyde under an iminium/enamine catalysis. <a>The enhanced co-ordinational proximity of the chiral substrate and catalyst</a> in the transition state resulted in a substantial steric discrimination and an excellent overall diastereoselectivity. Aza-tricylic molecules with six contiguous stereocenters were assembled from <i>N</i>-alkylated aminophenols, α,β-unsaturated aldehydes and chiral α-amino acids under a hidden “sub-catalysis” where the strategically produced “sub-catalyst” does not present in initial components of the reaction. The success of this methodology will pave the way for many efficient preparations of chiral complex molecules.</p><br><p></p>

Hierarchically assembled helicates as reaction platform – from stoichiometric Diels–Alder reactions to enamine catalysis

The stereoselectivity of a Diels–Alder reaction within the periphery of hierarchically assembled titanium(IV) helicates formed from mixtures of achiral, reactive and chiral, unreactive ligands was investigated in detail. Following the pathway of the chiral induction, the chiral ligands, solvents as well as substituents at the dienophile were carefully varied. Based on the results of the stoichiometric reaction, a secondary amine-catalyzed nitro-Michael reaction is performed as well which afforded reasonable diastereoselectivities.

Hierarchically assembled helicates as reaction platform – From stoichiometric Diels-Alder reactions to enamine catalysis

The stereoselectivity of a Diels-Alder reaction within the periphery of hierarchically assembled titanium(IV) helicates formed from mixtures of achiral, reactive and chiral, unreactive ligands is investigated in detail. Following the pathway of the chiral induction, the chiral ligands, solvents as well as substituents at the dienophile are carefully varied. Based on the results of the stoichiometric reaction a secondary amine catalyzed nitro-Michael reaction is performed as well which affords reasonable diastereoselectivities.