Divergent Synthesis Research Articles

Base-Promoted Cascade 5-exo-dig Annulation/Carboxylation of o-(1-Alkynyl)benzenesulfonamides with CO2: Divergent Synthesis of Mono- or Gem-dicarboxylic Esters

A base-promoted cascade 5-exo-dig cyclization/carboxylation of o-alkynylsulfamides with CO2 has been accomplished, furnishing a variety of benzosultams-containing acrylates in good yields by using CO2 as the carboxylic source. Notably, in...

Divergent synthesis of polythioindoles using elemental sulfur as the polysulfur source under metal-free conditions

A novel protocol for the divergent synthesis of polythioindoles through a HI-catalyzed polysulfidation/annulation reaction between indoles and elemental sulfur has been described.

Diversified synthesis of poly(sulfonyl isourea)s by multicomponent polymerizations of isocyanides, sulfonyl azides, and alcohols/phenols

Multicomponent polymerization (MCP) has become a powerful tool for the preparation of polymers with complex or well-defined structures. The development of MCPs that can take full advantage of the great...

Recent advances in catalytic enantioselective carbometallation of cyclopropenes and cyclobutenes.

Enantioenriched small carbocycles are key structures in numerous natural products and pharmaceutically important molecules as well as vital intermediates in organic synthesis. Although various catalytic approaches for the construction of such molecules from acyclic precursors have been developed, direct enantioselective functionalization of preformed three-membered and four-membered rings represents the most straightforward and modular strategy, enabling rapid and diversified synthesis of enantioenriched cyclopropanes and cyclobutanes from a single set of starting materials without the need for the incorporation of specific functional groups. In this Feature Article, we have summarized the recent advances in catalytic enantioselective functionalization of cyclopropenes and cyclobutenes through carbometallation. The plausible mechanisms of such reactions and future of this field are also discussed.

Expedient and divergent synthesis of unnatural peptides through cobalt-catalyzed diastereoselective umpolung hydrogenation.

The development of a reliable method for asymmetric synthesis of unnatural peptides is highly desirable and particularly challenging. In this study, we present a versatile and efficient approach that uses cobalt-catalyzed diastereoselective umpolung hydrogenation to access noncanonical aryl alanine peptides. This protocol demonstrates good tolerance toward various functional groups, amino acid sequences, and peptide lengths. Moreover, the versatility of this reaction is illustrated by its successful application in the late-stage functionalization and formal synthesis of various representative chiral natural products and pharmaceutical scaffolds. This strategy eliminates the need for synthesizing chiral noncanonical aryl alanines before peptide formation, and the hydrogenation reaction does not result in racemization or epimerization. The underlying mechanism was extensively explored through deuterium labeling, control experiments, HRMS identification, and UV-Vis spectroscopy, which supported a reasonable CoI/CoIII catalytic cycle. Notably, acetic acid and methanol serve as safe and cost-effective hydrogen sources, while indium powder acts as the terminal electron source.

Divergent Chemo- and Biocatalytic Route to 16β-Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate.

16β-Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16β-methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability-oriented strategy toward the unified stereoselective synthesis of 16β-methylcorticoids in 12.6-14.0 % overall yield from commercially available 9α-hydroxyandrost-4-ene-3,17-dione (9α-OH-AD). In this approach, the chiral C16β-Me and C17α-OH groups of the corticosteroid D ring were installed via a substrate-controlled diastereo- and enantioselective Mn-catalyzed oxidation-reduction hydration of Δ4,9(11),16 -triene-3,20-dione. The C1-C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3-ketosteroid-Δ1 -dehydrogenase (MK4-KstD)-catalyzed regioselective Δ1 -dehydrogenation of Δ4,9(11) -diene-3,21-dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.

Divergent syntheses of (−)-carvone-derived dimers

A series of diterpene-type compounds were synthesized starting from commercially available (−)-carvone. The Michael reaction of (−)-carvone itself delivered four diastereomeric dimers divergently. Following in parallel transformations of reduction, condensation and reductive amination, the corresponding alcohol, oxime and amine were obtained respectively. Particularly, several cage-like structures were obtained via late-stage olefin functionalization. The absolute configurations of the aforementioned compounds were unambiguously determined by NMR spectral, X-ray crystallographic and conformational analysis. Finally, the in-vitro anti-cancer and anti-inflammatory activities of these dimers were tested preliminarily.

Divergent Chemo‐ and Biocatalytic Route to 16β‐Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate

Abstract16β‐Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16β‐methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability‐oriented strategy toward the unified stereoselective synthesis of 16β‐methylcorticoids in 12.6–14.0 % overall yield from commercially available 9α‐hydroxyandrost‐4‐ene‐3,17‐dione (9α‐OH‐AD). In this approach, the chiral C16β‐Me and C17α‐OH groups of the corticosteroid D ring were installed via a substrate‐controlled diastereo‐ and enantioselective Mn‐catalyzed oxidation‐reduction hydration of Δ4,9(11),16‐triene‐3,20‐dione. The C1−C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3‐ketosteroid‐Δ1‐dehydrogenase (MK4‐KstD)‐catalyzed regioselective Δ1‐dehydrogenation of Δ4,9(11)‐diene‐3,21‐dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.

Divergent Synthesis of Quinolines: Exploiting the Duality of Free Radicals.

Herein, we present a green scheme for the divergent synthesis of two polysubstituted quinolines from a singular substrate via exploiting free-radical duality. Photocatalytically generated imine radicals produce 3,4-disubstituted quinolines via a novel rearrangement in the presence of an inorganic base. Alternatively, they react in the presence of an organic base to furnish 2,3-disubstituted quinolines. Mechanism studies support the hypothesis that the electrophilic/nucleophilic bias of free radicals can be adjusted by altering the reaction conditions.

Divergent Synthesis of (Benzo[b][1,4]diazepin‐2‐yl)phosphonates and (Quinoxalin‐2‐yl)methylphosphonates from Phosphoryl‐Substituted Conjugated Ynones

AbstractIt is shown that the reaction of conjugated ynones containing a phosphoryl group with o‐phenylenediamines can, depending on the conditions, lead to the selective formation of phosphorylated 1,5‐benzodiazepines and quinoxalines. Phosphorylated quinoxalines can be used for synthesis of substituted vinyl quinoxalines.

Divergent synthesis of fractionated Cannabis sativa extract led to multiple cannabinoids C-&O-glycosides with anti-proliferative/anti-metastatic properties

Here, we present an interesting, previously unreported method for fractionating a particular class of cannabinoids from the crude leaf extract of Cannabis sativa using HP-20 resins. In this study, we report a novel method of divergent synthesis of fractionated Cannabis sativa extract, which allows the generation of multiple cannabinoids C- and O-glycosides which react with the glycosyl donor 2,3,4,6-tetra-O-acetyl-d-mannosyl trichloroacetimidate (TAMTA) to create eight C- and O-β-d-cannabinoids glycosides (COCG), which are separated by HPLC and whose structures are characterized by 1D, 2D NMR, and mass spectrometry. These glycosides exhibit improved anti-proliferative and anti-metastatic effects against numerous cancer cell lines in vitro and are more water-soluble and stable than their parent cannabinoids. The in vitro testing of the pure cannabinoids (1–4) and their C- & O-glycosides (1a-4a) and 1b-4b exhibited anti-proliferative and anti-metastatic activities against a panel of eight human cancer cell lines in contrast to their respective parent molecules. Different cancer cell lines' IC50 values varied significantly when their cell viability was compared. In addition to the others, compounds 2a, 3a, 4a, and 2b, 3b were highly potent, with IC50values ranging from 0.74 µM (3a) to 51.40 µM (4a).Although2a(1.42 µM) and3a(0.74 µM) exhibited lower IC50values in the MiaPaca-2 cell line than4a(2.58 µM). But, in addition to the comparable anti-clonogenic activity of4ain MiaPaca-2 and Panc-1 cells, it manifested remarkable anti-invasive activity than either 2a or 3a.In contrast to 2a, 2b, 3a, and 3b and their respective parent compounds,4ahad substantial anti-invasive/anti-metastatic capabilities and possessed anti-proliferative activity.The effects of 4a treatment on MiaPaca-2 and Panc-1 cells include a dose-dependent increase in the expression of E-cadherin and a significant decrease in the expression of Zeb-1, Vimentin, and Snail1. Our results demonstrate that divergent synthesis of fractionated Cannabis sativa extract is a feasible and efficient strategy to produce a library of novel cannabinoid glycosides with improved pharmacological properties and potential anticancer benefits.

Catalytic stereodivergent allylic alkylation of 2-acylimidazoles for natural product synthesis

The stereocontrolled allylic alkylation of carbonyl compounds with the goal of producing the full range of stereoisomers presents an effective approach for increasing the productivity of collective natural product synthesis and the creation of chiral molecule libraries for drug exploration. The simultaneous control of regio-, diastereo-, and enantioselectivity poses a significant synthetic challenge in contemporary organic synthesis. Herein, we describe a catalytic stereodivergent α-allylation protocol applicable to both aliphatic and aromatic 2-acylimidazoles, thereby providing a practical blueprint for the divergent synthesis of important chiral building blocks. Each of the six isomeric α-allylated compounds can be readily obtained with remarkable yields and exceptional stereoselectivities, by judiciously selecting the appropriate leaving group and permutations of enantiomers adapted from nickel and iridium catalysts. The versatility of this asymmetric allylic alkylation has been successfully utilized in the enantioselective synthesis of (R)-arundic acid and (S,S)-cinamomumolide, as well as in the stereodivergent total synthesis of tapentadol.

Mask and Release Strategy-Enabled Diversity-Oriented Synthesis for DNA-Encoded Library.

An ideal DNA-encoded library (DEL) selection requires the library to consist of diverse core skeletons and cover chemical space as much as possible. However, the lack of efficient on-DNA synthetic approaches toward core skeletons has greatly restricted the diversity of DEL. To mitigate this issue, this work disclosed a "Mask & Release" strategy to streamline the challenging on-DNA core skeleton synthesis. N-phenoxyacetamide is used as a masked phenol and versatile directing group to mediate diversified DNA-compatible C-H functionalization, introducing the 1st-dimensional diversity at a defined site, and simultaneously releasing the phenol functionality, which can facilitate the introduction of the 2nd diversity. This work not only provides a set of efficient syntheses toward DNA-conjugated drug-like core skeletons such as ortho-alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran but also provides a paradigm for on-DNA core skeleton synthetic method development.

Cover Picture

In nature, differences in temperature create completely distinguishable landscapes in winter and spring. Similarly, by controlling the reaction temperature, efficient regioselective control of nickel‐catalyzed hydrosilylation of conjugated dienes with primary silanes can be achieved, facilitating the divergent synthesis of various homoallylic silanes and allylic silanes under mild conditions. More details are discussed in the article by Zhang et al. on page 13—19.image

Methylene C(sp3 )-H Arylation Enables the Stereoselective Synthesis and Structure Revision of Indidene Natural Products.

The divergent synthesis of two indane polyketides of the indidene family, namely (±)-indidene A (11 steps, 1.7 %) and (+)-indidene C (13 steps, 1.3 %), is reported. The synthesis of the trans-configured common indane intermediate was enabled by palladium(0)-catalyzed methylene C(sp3 )-H arylation, which was performed in both racemic and enantioselective (e.r. 99 : 1) modes. Further elaboration of this common intermediate by nickel-catalyzed dehydrogenative coupling allowed the rapid installation of the aroyl moiety of (±)-indidene A. In parallel, the biphenyl system of (±)- and (+)-indidene C was constructed by Suzuki-Miyaura coupling. These investigations led us to revise the structures of indidenes B and C.

Methylene C(sp3)−H Arylation Enables the Stereoselective Synthesis and Structure Revision of Indidene Natural Products

AbstractThe divergent synthesis of two indane polyketides of the indidene family, namely (±)‐indidene A (11 steps, 1.7 %) and (+)‐indidene C (13 steps, 1.3 %), is reported. The synthesis of the trans‐configured common indane intermediate was enabled by palladium(0)‐catalyzed methylene C(sp3)−H arylation, which was performed in both racemic and enantioselective (e.r. 99 : 1) modes. Further elaboration of this common intermediate by nickel‐catalyzed dehydrogenative coupling allowed the rapid installation of the aroyl moiety of (±)‐indidene A. In parallel, the biphenyl system of (±)‐ and (+)‐indidene C was constructed by Suzuki–Miyaura coupling. These investigations led us to revise the structures of indidenes B and C.

Cavity-Shape-Dependent Divergent Chemical Reaction inside Aqueous Pd6L4 Cages.

Chemical reactions inside the confined pockets of enzyme-mimicking hosts, such as cages and macrocycles, have been an emerging field of interest over the past decade. Although many such reactions are known, the use of such cages toward the divergent synthesis of nonisomeric products has not been well explored. Divergent synthesis is a technique of forming two or more distinct products from the same reagents by changing the catalyst or reaction conditions. Changing the shape of the cage can also change the nature and magnitude of the host-guest interactions. Thus, is it possible for such changes to cause differences in the reaction pathways leading to formation of nonisomeric products? Herein, we report a divergent chemical transformation of anthrone [anthracen-9(10H)-one] inside different water-soluble M6L4 cages. When anthrone was encapsulated inside a newly synthesized M6L4 octahedral cage 1, it dimerized to form dianthrone [9,9'-bianthracen-10,10'(9H,9'H)-dione]. In contrast, when the same chemical reaction was performed inside a M6L4 double-square shaped cage 2, it was oxidized to form anthraquinone [anthracene-9,10-dione]. Similar results were obtained with a different set of isomeric aqueous Pd6 cages 3a (octahedral cage) and 3b (double-square cage), indicating the dependence of the shape of cavity on the divergent synthesis. The present report demonstrates a unique example of different outcomes/results of a reaction depending on the shape of the molecular container, which was driven by the host-guest interactions and the preorganization of the substrates.

Enantioselective Palladium(II)-Catalyzed Desymmetrizative Coupling of 7-Azabenzonorbornadienes with Alkynylanilines.

A PdII -catalyzed, domino enantioselective desymmetrizative coupling of 7-azabenzonorbornadienes with alkynylanilines is disclosed herein. This operationally simple transformation generates three covalent bonds and two contiguous stereocenters with excellent enantio- and diastereo-selectivity. The resulting functionalized indole-dihydronaphthalene-amine conjugates served as an appealing platform to streamline the diversity-oriented synthesis (DOS) of other valuable enantioenriched compounds. DFT calculations revealed that the two stabilizing non-covalent interactions contributed to the observed enantioselectivity.

Enantioselective Palladium(II)‐Catalyzed Desymmetrizative Coupling of 7‐Azabenzonorbornadienes with Alkynylanilines

AbstractA PdII‐catalyzed, domino enantioselective desymmetrizative coupling of 7‐azabenzonorbornadienes with alkynylanilines is disclosed herein. This operationally simple transformation generates three covalent bonds and two contiguous stereocenters with excellent enantio‐ and diastereo‐selectivity. The resulting functionalized indole‐dihydronaphthalene‐amine conjugates served as an appealing platform to streamline the diversity‐oriented synthesis (DOS) of other valuable enantioenriched compounds. DFT calculations revealed that the two stabilizing non‐covalent interactions contributed to the observed enantioselectivity.

A Chiral Titanocene Complex as Regiodivergent Photoredox Catalyst: Synthetic Scope and Mechanism of Catalyst Generation.

We describe a combined synthetic, spectroscopic, and computational study of a chiral titanocene complex as a regiodivergent photoredox catalyst (PRC). With Kagan's complex catCl2 either monoprotected 1,3-diols or 1,4-diols can be obtained in high selectivity from a common epoxide substrate in a regiodivergent epoxide opening depending on which enantiomer of the catalyst is employed. Due to the catalyst-controlled regioselectivity of ring opening and the broader substrate scope, the PRC with catCl2 is also a highly attractive branching point for diversity-oriented synthesis. The photochemical processes of cat(NCS)2, a suitable model for catCl2, were probed by time-correlated single-photon counting. The photoexcited complex displays a thermally activated delayed fluorescence as a result of a singlet-triplet equilibration, S1 ⇄ T1, via intersystem crossing and recrossing. Its triplet state is quenched by electron transfer to the T1 state. Computational and cyclic voltammetry studies highlight the importance of our sulfonamide additive. By bonding to sulfonamide additives, chloride abstraction from [catCl2]- is facilitated, and catalyst deactivation by coordination of the sulfonamide group is circumvented.