Contiguous Stereogenic Carbons Research Articles

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Simultaneous Construction of C-N Axial and Central Chirality via Silver-Catalyzed Desymmetrizative [3 + 2] Cycloaddition of Prochiral N-Aryl Maleimides with Activated Isocyanides.

Herein, we report an unprecedented strategy for the simultaneous construction of a remote C-N stereogenic axis and three contiguous stereogenic carbon centers via silver-catalyzed desymmetrizative [3 + 2] cycloaddition of prochiral N-aryl maleimides with activated isocyanides. This method features operational simplicity, wide substrate scope, high efficiency, and good to excellent stereoselectivity. Notably, it represents the first example of catalytic enantioselective synthesis of C-N atropisomers with the use of activated isocyanides.

Expeditious Access to Morphinans by Chemical Synthesis

AbstractMorphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven‐step, asymmetric chemical synthesis of (−)‐codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double‐Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo‐redox hydroamination protocol provides a novel, atom‐economical means for assembling the piperidine D‐ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N‐demethyl codeine. Our work highlights the capacity for contemporary, stand‐alone chemical synthesis regimes to diversify access to essential opiate medicines.

Expeditious Access to Morphinans by Chemical Synthesis.

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven-step, asymmetric chemical synthesis of (-)-codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double-Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo-redox hydroamination protocol provides a novel, atom-economical means for assembling the piperidine D-ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N-demethyl codeine. Our work highlights the capacity for contemporary, stand-alone chemical synthesis regimes to diversify access to essential opiate medicines.

Catalytic enantioselective synthesis of benzocyclobutenols and cyclobutanols via a sequential reduction/C-H functionalization.

We report here a sequential enantioselective reduction/C–H functionalization to install contiguous stereogenic carbon centers of benzocyclobutenols and cyclobutanols. This strategy features a practical enantioselective reduction of a ketone and a diastereospecific iridium-catalyzed C–H silylation. Further transformations have been explored, including controllable regioselective ring-opening reactions. In addition, this strategy has been utilized for the synthesis of three natural products, phyllostoxin (proposed structure), grandisol and fragranol.

Enantioselective Synthesis of Polycyclic γ-Lactams with Multiple Chiral Carbon Centers via Ni(0)-Catalyzed Asymmetric Carbonylative Cycloadditions without Stirring.

γ-Lactam derivatives with multiple contiguous stereogenic carbon centers are ubiquitous in physiologically active compounds. The development of straightforward and reliable synthetic routes to such chiral structural motifs in a stereocontrolled manner should thus be of importance. Herein, we report a strategy to construct polycyclic γ-lactam derivatives that contain more than two contiguous stereogenic centers in an enantioselective as well as atom-economic manner. Moreover, we have achieved the first enantioselective synthesis of strigolactam derivative GR-24, a racemic variant of which is a potential seed germination stimulator and plant-growth regulator. A key of the procedure presented here is a nickel(0)/chiral phosphoramidite-catalyzed asymmetric [2+2+1] carbonylative cycloaddition between readily accessible ene-imines and carbon monoxide, which proceeded enantioselectively to furnish up to 90% ee (>99% ee after recrystallization). The results of mechanistic studies, including the isolation of a chiral heteronickelacycle, support that the enantioselectivity on the two contiguous carbon atoms of the γ-lactams is determined during the oxidative cyclization on nickel(0).

SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis.

Pericyclic reactions are among the most powerful synthetic transformations to make multiple regioselective and stereoselective carbon-carbon bonds1. These reactions have been widely applied for the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centers2–6. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples, intramolecular Diels-Alder (IMDA) reaction7, Cope8 and Claisen rearrangements9, have been characterized. Here, we report the discovery of a S-adenosyl-L-methionine (SAM) dependent enzyme LepI that can catalyse stereoselective dehydration, bifurcating IMDA/hetero-DA (HDA) reactions via an ambimodal transition state, and a [3,3]-sigmatropic retro-Claisen rearrangement leading to the formation of dihydopyran core in the fungal natural product leporin10. Combined in vitro enzymatic characterization and computational studies provide evidence and mechanistic insight about how the O-methyltransferase-like protein LepI regulates the bifurcating biosynthetic reaction pathways (“direct” HDA and “byproduct recycle” IMDA/retro-Claisen reaction pathways) by utilizing SAM as the cofactor in order to converge to the desired biosynthetic end product. This work highlights that LepI is the first example of an enzyme catalysing a (SAM-dependent) retro-Claisen rearrangement. We suggest that more pericyclic biosynthetic enzymatic transformations are yet to be discovered in the intriguing enzyme toolboxes in Nature11, and propose an ever expanding role of the versatile cofactor SAM in enzyme catalysis.

Homodimericin A: A Complex Hexacyclic Fungal Metabolite

Microbes sense and respond to their environment with small molecules, and discovering these molecules and identifying their functions informs chemistry, biology, and medicine. As part of a study of molecular exchanges between termite-associated actinobacteria and pathogenic fungi, we uncovered a remarkable fungal metabolite, homodimericin A, which is strongly upregulated by the bacterial metabolite bafilomycin C1. Homodimericin A is a hexacyclic polyketide with a carbon backbone containing eight contiguous stereogenic carbons in a C20 hexacyclic core. Only half of its carbon atoms have an attached hydrogen, which presented a significant challenge for NMR-based structural analysis. In spite of its microbial production and rich stereochemistry, homodimericin A occurs naturally as a racemic mixture. A plausible nonenzymatic reaction cascade leading from two identical achiral monomers to homodimericin A is presented, and homodimericin A’s formation by this path, a six-electron oxidation, could be a response to oxidative stress triggered by bafilomycin C1.

Catalytic asymmetric detrifluoroacetylative aldol reactions of aliphatic aldehydes for construction of C-F quaternary stereogenic centers

We demonstrate, that the reactions of in situ generated fluoro-enolates with a range of aliphatic aldehydes can be successfully performed using asymmetric catalyst derived from chiral ligand and Cu(OTf)2. The enantioselectivity of the formation of two contiguous stereogenic carbons in these additions was excellent, rendering the developed approach as an important methodological advance in asymmetric catalytic reactions of detrifluoroacetylatively generated fluoro-enolates. This process allows preparation of structurally new pharmaceutically interesting class of 1,3-hydroxy ketones containing C-F quaternary stereogenic center adjacent to secondary hydroxy group.

Organocatalytic asymmetric one-pot sequential reaction: synthesis of highly substituted spirocyclohexanepyrazolones with six contiguous stereogenic carbons

An atom-economical synthesis of chiral polyfunctionalized spiropyrazolone derivatives based on the development of a new organocatalytic enantioselective one-pot sequential Michael/Michael/Aldol reaction of 1,3-dicarbonyl compounds with unsaturated pyrazolones and α,β-unsaturated aldehydes has been developed. The notable features of this one-pot sequential process include the generation of up to six consecutive stereogenic carbon centers including one quaternary stereocenter and five tertiary stereocenters with high enantioselectivities (up to 95% ee) and excellent diastereoselectivities (>99:1 d.r.).

Stereoselective synthesis of quaternary carbons via the dianionic Ireland-Claisen rearrangement.

A dianionic Ireland–Claisen rearrangement of chiral, nonracemic α-methyl-β-hydroxy allylic esters has been developed that proceeds with high diastereoselectivity and provides products containing three contiguous stereogenic carbons, including a quaternary center. The potential utility of the rearrangement for complex molecule synthesis is also demonstrated.

ChemInform Abstract: Three‐Component Reactions of Sulfonylimidates, Silyl Glyoxylates and N‐tert‐Butanesulfinyl Aldimines: An Efficient, Diastereoselective, and Enantioselective Synthesis of Cyclic N‐Sulfonylamidines.

Three-component coupling reactions of sulfonylimidates, silyl glyoxylates and N-tert-butanesulfinyl aldimines efficiently provide cyclic N-sulfonylamiclines containing free endocyclic N-H. The formation of two C-C bonds (contiguous stereogenic carbons), one O-Si bond, and one C-N bond, together with the cleavage of the chiral auxiliary (tert-butanesulfinyl group), occurs with excellent chemoselectivity, diastereoselectivity, and enantioselectivity in this one-pot cascade transformation.

Three-Component Reactions of Sulfonylimidates, Silyl Glyoxylates and N-tert-Butanesulfinyl Aldimines: An Efficient, Diastereoselective, and Enantioselective Synthesis of Cyclic N-Sulfonylamidines

Three-component coupling reactions of sulfonylimidates, silyl glyoxylates and N-tert-butanesulfinyl aldimines efficiently provide cyclic N-sulfonylamidines containing free endocyclic N-H. The formation of two C-C bonds (contiguous stereogenic carbons), one O-Si bond, and one C-N bond, together with the cleavage of the chiral auxiliary (tert-butanesulfinyl group), occurs with excellent chemoselectivity, diastereoselectivity, and enantioselectivity in this one-pot cascade transformation.

ChemInform Abstract: Stereocontrolled Solution and Solid Phase Enolate Alkylations and Hydroxylations — Generation of Three and Four Contiguous Stereogenic Carbon Atoms in Acyclic Systems.

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Stereocontrolled solution and solid phase enolate alkylations and hydroxylations — generation of three and four contiguous stereogenic carbon atoms in acyclic systems

Potassium enolates of γ-alkoxy-α-methyl pentanoates can be alkylated with allylic and benzylic halides in solution and on solid phase with high 2,3-syn selectivity. Polypropionate units can be constructed on solid phase by a series of stereocontrolled conjugate additions and enolate hydroxylations relying on 1,2-induction.