Herein, Nature’s flavin-mediated activation of complex (poly)enes has been translated to a small molecule paradigm culminating in a highly (Z)-selective, catalytic isomerization of activated olefins ...using (−)-riboflavin (up to 99:1 Z/E). In contrast to the prominent Z → E isomerization of the natural system, it was possible to invert the directionality of the isomerization (E → Z) by simultaneously truncating the retinal scaffold, and introducing a third olefin substituent to augment A1,3-strain upon isomerization. Consequently, conjugation is reduced in the product chromophore leading to a substrate/product combination with discrete photophysical signatures. The operationally simple isomerization protocol has been applied to a variety of enone-derived substrates and showcased in the preparation of the medically relevant 4-substituted coumarin scaffold. A correlation of sensitizer triplet energy (E T) and reaction efficiency, together with the study of additive effects and mechanistic probes, is consistent with a triplet energy transfer mechanism.
Strategies to achieve spatiotemporal regulation of pre‐existing alkenes via external stimuli are essential given the ubiquity of feedstock olefins in chemistry and their downstream applications. ...Mirroring the 1‐0 switch that underpins mammalian vision through selective geometric isomerisation in retinal, strategies to manipulate 2D space by both geometric and positional isomerisation of alkenes via chemical, thermal and light‐driven processes are being intensively pursued. This minireview highlights the current state of the art in activating and achieving directionality in these fundamental chemical transformations.
Pinnacles: Reactions that emulate the remarkable efficiency of natural isomerases are academically stimulating and constitute the pinnacle of atom economy. This Minireview surveys strategies to achieve spatiotemporal regulation of pre‐existing alkenes by selective geometric and/or positional isomerisation.
A bioinspired, intermolecular radical Stetter reaction of α‐keto acids and aldehydes is disclosed that is contingent on a formal “radical umpolung” concept. Enabled by secondary amine activation, ...electrostatic recognition ensures that the α‐ketocarboxylic acids, which function as latent acyl radicals, are proximal to the in situ generated iminium salts. This photoactive contact ion pair is an electron donor–acceptor (EDA) complex, and undergoes facile single electron transfer (SET) and rapid decarboxylation prior to radical–radical recombination. Importantly, decarbonylation is mitigated by this strategy. The initial computational validation on which the process is predicated matches closely with experiment. Synergising organo‐ and photocatalysis activation principles finally expands the mechanistic and synthetic scope of the classic Stetter reaction to include α,β‐unsaturated aldehydes as acceptors.
A bioinspired radical Stetter reaction of α‐keto acids and aldehydes is contingent on a formal “radical umpolung”. Electrostatic recognition ensures that the α‐keto carboxylates, which function as latent acyl radicals, are proximal to the iminium ions generated in situ. Synergising organo‐ and photocatalysis activation principles finally expand the mechanistic and synthetic scope of the classic Stetter reaction to include α,β‐unsaturated aldehyde acceptors.
Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena. Delineating their biological origins ...and significance have resulted in landmark developments in synthetic organic chemistry: Arigoni's venerable synthesis of the chiral methyl group is a personal favourite. Whilst radioisotopes allow the steric footprint of the native group to be preserved, this strategy was never intended for therapeutic chemotype development. In contrast, leveraging H → F bioisosterism provides scope to complement the chiral, radioactive bioisostere portfolio and to reach unexplored areas of chiral chemical space for small molecule drug discovery. Accelerated by advances in I(
i
)/I(
iii
) catalysis, the current arsenal of achiral 2D and 3D drug discovery modules is rapidly expanding to include chiral units with unprecedented topologies and van der Waals volumes. This
Perspective
surveys key developments in the design and synthesis of short multi
vicinal
fluoroalkanes under the auspices of main group catalysis paradigms.
Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena.
Deconstructing Covalent Organocatalysis Holland, Mareike C.; Gilmour, Ryan
Angewandte Chemie (International ed.),
March 23, 2015, Volume:
54, Issue:
13
Journal Article
Peer reviewed
Modern organocatalysis has rapidly evolved into an essential component of contemporary organic synthesis. One of the most distinctive aspects of organocatalytic processes is the biomimetic nature in ...which the catalyst engages the substrate, often forming covalently bound intermediates in a manner reminiscent of enzyme catalysis. Indeed, the process of intramolecularization is often accompanied by a conformational change of the catalyst scaffold, further accentuating this analogy with biological systems. The isolation and study of these catalytic intermediates facilitate the rapid generation of conformation and reactivity profiles to assist in organocatalytic reaction development and/or clarify reaction outcomes. Emulating the formative advances that have derived from studying reaction intermediates in mechanistic organometallic and enzymatic catalysis, the deconstruction of covalently bound organocatalysis intermediates is gaining momentum as a design strategy.
In recent years, interest in organocatalytic intermediates has intensified. Through their study, various mechanistic anomalies have been illuminated, new reaction manifolds have been identified, and the intermediates themselves have proven to be valuable platforms for the study of many noncovalent interactions more commonly found in complex biomolecules. Cat=catalyst, P=product, S=substrate.
An E-Z boron swivel
Compounds with carbon-carbon double bonds can form two distinct isomers, depending on whether the heaviest substituents on both carbons lie on the same side (labeled Z) or ...diagonally across from each other (labeled E). Molloy
et al.
present a convenient method to reorient double bonds that bear boron and carbonyl substituents. When they are diagonally opposed, both substituents stay in plane, and the double bond is easily swiveled by photosensitization. However, once on the same side as the carbonyl, the boron rotates out of plane and further sensitization is inhibited.
Science
this issue p.
302
Rotation of a boron substituent biases photosensitized isomerization of a carbon-carbon double bond in just one direction.
Isomerization-based strategies to enable the stereodivergent construction of complex polyenes from geometrically defined alkene linchpins remain conspicuously underdeveloped. Mitigating the thermodynamic constraints inherent to isomerization is further frustrated by the considerations of atom efficiency in idealized low–molecular weight precursors. In this work, we report a general ambiphilic C
3
scaffold that can be isomerized and bidirectionally extended. Predicated on highly efficient triplet energy transfer, the selective isomerization of β-borylacrylates is contingent on the participation of the boron p orbital in the substrate chromophore. Rotation of the C(sp
2
)–B bond by 90° in the product renders re-excitation inefficient and endows directionality. This subtle stereoelectronic gating mechanism enables the stereocontrolled syntheses of well-defined retinoic acid derivatives.
Molecular design strategies that profit from the intrinsic stereoelectronic and electrostatic effects of fluorinated organic molecules have mainly been restricted to bio‐organic chemistry. Indeed, ...many fluorine conformational effects remain academic curiosities with no immediate application. However, the renaissance of organocatalysis offers the possibility to exploit many of these well‐described phenomena for molecular preorganization. In this minireview, we highlight examples of catalyst refinement by introduction of an aliphatic CF bond which functions as a chemically inert steering group for conformational control.
F in control: Conformational effects of fluorinated molecules have hitherto mainly been restricted to bio‐organic chemistry. The renaissance of organocatalysis, however, offers the possibility to exploit many of the stereoelectronic and electrostatic effects of fluorinated organic molecules for molecular preorganization. In this Minireview, we highlight examples of catalyst refinement by the introduction of an aliphatic CF bond which functions as a chemically inert steering group for conformational control.
Abstract The prominence and versatility of propargylic fluorides in medicinal chemistry, coupled with the potency of F/H and F/OH bioisosterism, has created a powerful impetus to develop efficient ...methods to facilitate their construction. Motivated by the well-established conversion of propargylic alcohols to allenes, an operationally simple, organocatalysis-based strategy to process these abundant unsaturated precursors to propargylic fluorides would be highly enabling: this would consolidate the bioisosteric relationship that connects propargylic alcohols and fluorides. Herein, we describe a highly regioselective fluorination of unactivated allenes based on I(I)/I(III) catalysis in the presence of an inexpensive HF source that serves a dual role as both nucleophile and Brønsted acid activator. This strategy enables a variety of secondary and tertiary propargylic fluorides to be prepared: these motifs are prevalent across the bioactive small molecule spectrum. Facile product derivatisation, concise synthesis of multi-vicinal fluorinated products together with preliminary validation of enantioselective catalysis are disclosed. The expansive potential of this platform is also demonstrated through the highly regioselective organocatalytic oxidation, chlorination and arylation of allenes. It is envisaged that the transformation will find application in molecular design and accelerate the exploration of organofluorine chemical space.
Trick the iminium! The concept of cyclopropyl iminium activation for the organocatalytic desymmetrization of meso‐cyclopropylcarbaldehydes is presented. A combination of nucleophilic and ...electrophilic chlorinating reagents leads to a formal addition of Cl2 across one of the cyclopropyl bonds giving access to 1,3‐dichlorides in an enantioselective, catalytic fashion.
An operationally simple protocol is disclosed to facilitate entry to benzo-3,4-coumarins directly from biaryl carboxylic acids without the need for substrate prefunctionalization. Complementary to ...classic lactonization strategies, this disconnection relies on the oxidation competence of photoactivated (−)-riboflavin (vitamin B2) to generate the heterocyclic core via photoinduced single electron transfer. Collectively, the inexpensive nature of the catalyst, ease of execution, and absence of external metal additives are a convincing endorsement for the incorporation of simple vitamins in contemporary catalysis.
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