Facile Access to Sterically Hindered Aryl Ketones via Carbonylative Cross-Coupling: Application to the Total Synthesis of Luteolin

A general and mild protocol for achieving the carbonylative cross-coupling of sterically hindered, ortho-disubstituted aryl ketones is reported. The commercially available PEPPSI-IPr catalyst is shown to efficiently promote the carbonylative cross-coupling of hindered ortho-disubstituted aryl iodides to give diaryl ketones; traditional phosphine catalysts are less effective. Carbonylative Suzuki-Miyaura cross-couplings provide a diverse array of biaryl ketones in good to excellent yields. The same catalyst is also shown to catalyze a carbonylative Negishi cross-coupling reaction, utilizing a variety of alkynyl-zinc reagents to give the corresponding alkynyl aryl ketones. Application of this new methodology to the synthesis of the natural product luteolin is reported.     

Total synthesis of (+)-papulacandin D

A total synthesis of (+)-papulacandin D has been achieved in 31 steps, in a 9.2% overall yield from commercially available materials. The synthetic strategy divided the molecule into two nearly equal sized subunits, the spirocyclic C-arylglycopyranoside and the polyunsaturated fatty acid side-chain. The C-arylglycopyranoside was prepared in 11 steps in a 30% overall yield from triacetoxyglucal. The fatty acid side-chain was also prepared in 11 steps in a 30% overall yield from geraniol. The key strategic transformations in the synthesis are: (1) a palladium-catalyzed, organosilanolate-based cross-coupling reaction of a dimethylglucal-silanol with an electron-rich and sterically hindered aromatic iodide and (2) a Lewis-base catalyzed, enantioselective allylation reaction of a dienal and allyltrichlorosilane. A critical element in the successful execution of the synthesis was the development of a suitable protecting group strategy that satisfied a number of stringent criteria.     

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12′ together with the previously reported L0 and L0′ define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Easily applied enantioselective addition of aliphatic and aromatic Grignard reagents to ketones provides modular and universal access to challenging chiral tertiary alcohols, enabling the straightforward preparation of natural products and APIs.     

Short,enantioselective, gram-scale synthesis of (−)-zephyranthine

A reasonable synthesis design by strategically integrating functional group manipulation into the ring system construction resulted in a short, enantioselective, gram-scale total synthesis of (−)-zephyranthine. The concise route includes a catalytic Michael/Michael cascade for the asymmetric synthesis of a penta-substituted cyclohexane with three contiguous stereogenic centers, a remarkable 8-step one-pot operation to easily assemble the zephyranthine tetracyclic skeleton, the regioselective construction of a double bond in the C ring and an asymmetric dihydroxylation. This synthesis is also flexible and paves a potential path to a variety of cyclohexylamine-fused tricyclic or polycyclic alkaloids.

A reasonable synthesis design by strategically integrating functional group manipulation into the ring system construction resulted in a short, enantioselective, gram-scale total synthesis of (−)-zephyranthine.     

Cu(i) catalysis for selective condensation/bicycloaromatization of two different arylalkynes: direct and general construction of functionalized C–N axial biaryl compounds

Selective condensation/bicycloaromatization of two different arylalkynes is firstly developed under ligand-free copper(i)-catalysis, which allows the direct synthesis of C–N axial biaryl compounds in high yields with excellent selectivity and functional group tolerance. Due to the critical effects of Cu(i) catalyst and HFIP, many easily occurring undesired reactions are suppressed, and the coupled five–six aromatic rings are constructed via the selective formation of two C(sp²)–N(sp²) bonds and four C(sp²)–C(sp²) bonds. The achievement of moderate enantioselectivity verifies its potential for the simplest asymmetric synthesis of atropoisomeric biaryls. Western blotting demonstrated that the newly developed compounds are promising targets in biology and pharmaceuticals. This unique reaction can construct structurally diverse C–N axial biaryl compounds that have never been reported by other methods, and might be extended to various applications in materials, chemistry, biology, and pharmaceuticals.

Selective condensation/bicycloaromatization of two different arylalkynes is firstly developed under ligand-free copper(i)-catalysis, which allows the direct synthesis of C–N axial biaryl compounds in high yields with excellent selectivity and functional group tolerance.     

Efficient synthesis of optically active α-substituted glutamate analogs possessing α-hydroxymethyl and α-alkoxymethyl groups

Highly enantioselective synthesis of (2R)-α-(hydroxymethyl)glutamate (1), a selective agonist of mGluR2 and 3, was achieved in short steps using an asymmetric version of the Strecker synthesis. This was converted into its α-methoxymethyl- and α-benzyloxymethyl derivatives 2 and 3, possible ligands as tools to investigate glutamate receptors, via protection of the sterically hindered amino group by means of phase transfer catalyst.     

Silacyclization through palladium-catalyzed intermolecular silicon-based C(sp2)–C(sp3) cross-coupling

Silicon-based cross-coupling has been recognized as one of the most reliable alternatives for constructing carbon–carbon bonds. However, the employment of such reaction as an efficient ring expansion strategy for silacycle synthesis is comparatively little known. Herein, we develop the first intermolecular silacyclization strategy involving Pd-catalyzed silicon-based C(sp²)–C(sp³) cross-coupling. This method allows the modular assembly of a vast array of structurally novel and interesting sila-benzo[b]oxepines with good functional group tolerance. The key to success for this reaction is that silicon atoms have a stronger affinity for oxygen nucleophiles than carbon nucleophiles, and silacyclobutanes (SCBs) have inherent ring-strain-release Lewis acidity.

Herein, we develop the first silacyclization between 2-halophenols and SCBs, which allows the modular assembly of sila-benzo[b]oxepines with good functional group tolerance and can be applied for the late-stage modification of biologically active molecules.     

Alkaloids from alkaloids: total synthesis of (±)-7a-epi-hyacinthacine A1 from Z-protected tropenone via Baeyer-Villiger oxidation

Baeyer-Villiger oxidations of several tropane derivatives have been investigated. Whereas tropenones 15a-c underwent exclusive epoxidation to 21a-c, the corresponding 6-oxotropane derivative 28 yielded the desired lactone 29. Baeyer-Villiger oxidation was also possible for the O-isopropylidene-protected diols 32a,b. The resulting lactones 33a,b were employed in the total synthesis of (±)-7a-epi-hyacinthacine A₁ (7a-epi-7) via an intramolecular nucleophilic alkyllithium addition to a carbamate as the key lactamization step. The target compound was prepared from tropenone 15b in 10 steps and 14% overall yield. Enzymatic resolution of pyrrolidine (±)-36 provided a formal total synthesis to both enantiomers of 7.     

Copper-catalyzed radical cascade reaction of simple cyclobutanes: synthesis of highly functionalized cyclobutene derivatives

Cyclobutenes as versatile and highly valuable synthons have been widely applied in synthesis. Although various methods for their synthesis have been well established, new strategies for the construction of the cyclobutene skeleton from simple substrates are still highly desirable. Starting from simple cyclobutanes, the construction of the cyclobutene skeleton especially introducing multiple functional groups simultaneously had never been achieved. Here, we developed a novel radical cascade strategy for the synthesis of highly functionalized cyclobutenes directly from cyclobutanes involving rare cleavage of four or five C–H bonds and formation of two C–N/C–S or three C–Br bonds. With copper as catalyst and N-fluorobenzenesulfonimide (NFSI) as oxidant, a wide range of diaminated, disulfonylated and tribrominated cyclobutene derivatives were efficiently synthesized.

A novel radical cascade strategy for the synthesis of highly functionalized cyclobutenes directly from cyclobutanes involving rare four or five C–H bonds cleavage and two C–N/C–S or three C–Br bonds formation has been successfully developed.     

Flexible approach for the asymmetric synthesis of (−)-hyacinthacine A1 and its 7a-epimer

The diastereoselective nucleophilic addition of organic boronic ester to 3-hydroxy-2-substituted N-acyliminium ions 9 led to the formation of 2,5-cis-pyrrolidine 10, from which a convenient synthesis of (−)-7a-epi-1 was developed. In addition, an efficient asymmetric synthesis of (−)-hyacinthacine A1 1 was achieved through the reduction/ring-opening process.     

Visible-light-induced cross-coupling of aryl iodides with hydrazones via an EDA-complex

A visible-light-induced, transition-metal and photosensitizer-free cross-coupling of aryl iodides with hydrazones was developed. In this strategy, hydrazones were used as alternatives to organometallic reagents, in the absence of a transition metal or an external photosensitizer, making this cross-coupling mild and green. The protocol was compatible with a variety of functionalities, including methyl, methoxy, trifluoromethyl, halogen, and heteroaromatic rings. Mechanistic investigations showed that the association of the hydrazone anion with aryl halides formed an electron donor–acceptor complex, which when excited with visible light generated an aryl radical via single-electron transfer.

Visible-light-induced catalyst-free cross-coupling of aryl iodides with hydrazones via single-electron-transfer was reported. The mechanistic investigations showed that the association of hydrazone anion with aryl iodides formed an EDA complex.     

Rh2(ii)-catalyzed enantioselective intramolecular Büchner reaction and aromatic substitution of donor–donor carbenes

The chiral dirhodium(ii) tetracarboxylate-catalyzed enantioselective intramolecular Büchner reaction of donor/donor-carbenes was reported and a series of valuable chiral polycyclic products were synthesized. Both aryloxy enynones and diazo compounds were efficient carbene precursors for this reaction. Excellent yields (up to 99%) and outstanding enantioselectivities (up to >99% ee) were achieved under standard conditions. For furyl substituted chiral cyclohepta[b]benzofurans bearing a substituent at the C4 position on cycloheptatrienes, control reactions showed that the chiral Büchner products could slowly racemize either under dark or natural light conditions. A diradical-involved mechanism rather than a zwitterionic intermediate was proposed to explain the racemization. Furthermore, furyl substituted chiral fluorene derivatives were obtained via asymmetric aromatic substitution when biaryl enynones were employed as carbene precursors.

The chiral dirhodium(ii) tetracarboxylate-catalyzed enantioselective intramolecular Büchner reaction and aromatic substitution of donor/donor-carbenes were reported and a series of valuable chiral polycyclic products were synthesized.     

Aryl diazonium intermediates enable mild DNA-compatible C–C bond formation for medicinally relevant combinatorial library synthesis

Forging carbon–carbon (C–C) linkage in DNA-encoded combinatorial library synthesis represents a fundamental task for drug discovery, especially with broad substrate scope and exquisite functional group tolerance. Here we reported the palladium-catalyzed Suzuki–Miyaura, Heck and Hiyama type cross-coupling via DNA-conjugated aryl diazonium intermediates for DNA-encoded chemical library (DEL) synthesis. Starting from commodity arylamines, this synthetic route facilely delivers vast chemical diversity at a mild temperature and pH, thus circumventing damage to fragile functional groups. Given its orthogonality with traditional aryl halide-based cross-coupling, the aryl diazonium-centered strategy expands the compatible synthesis of complex C–C bond-connected scaffolds. In addition, DNA-tethered pharmaceutical compounds (e.g., HDAC inhibitor) are constructed without decomposition of susceptible bioactive warheads (e.g., hydroxamic acid), emphasizing the superiority of the aryl diazonium-based approach. Together with the convenient transformation into an aryl azide photo-crosslinker, aryl diazonium''s DNA-compatible diversification synergistically demonstrated its competence to create medicinally relevant combinatorial libraries and investigate protein–ligand interactions in pharmaceutical research.

Taking advantage of aryl diazonium intermediates, this work reported a DNA-compatible C–C bond formation strategy, achieving broad substrate scope, exquisite functional group tolerance, and orthogonality to aryl halide-based coupling reactions.     

Asymmetric synthesis of chromanone lactones via vinylogous conjugate addition of butenolide to 2-ester chromones

Chiral chromanone lactones are a class of natural products with important biological activity. We report a direct diastereo- and enantioselective vinylogous conjugate addition of butenolide to 2-ester substituted chromones. The transformation proceeded well in the presence of as low as 1 mol% of a chiral N,N′-dioxide/Sc^III complex, 3 Å MS and a catalytic amount of hexafluoroisopropanol (HFIP). The scope of Michael acceptors includes a variety of substituted chromones at different positions, and the desired chromanone lactones upon reduction are afforded in good yield and diastereoselectivity, and excellent enantioselectivity (up to 99% ee). The strategy could be used in the concise synthesis of blennolide C and gonytolide A, C and G.

We report a direct, diastero- and enantioselective vinylogous 1,4-addition of butanolide to 2-ester chromones. A chiral Sc^III complex enabled the reaction to proceed smoothly to give a variety of chraomanone lactones.     

Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (–)-psychotriasine and (+)-pestalazine B

We report a unified strategy for the total syntheses of (–)-psychotriasine and (+)-pestalazine B based on the advanced intermediates of 3α-amino-hexahydropyrrolo[2,3-b]indole. To construct these structural motifs, a cascade reaction involving a BINOL-derived phosphoric anion-paired catalyst for enantioselective or diastereoselective azo-coupling/iminium-cyclizations was developed. The remaining key steps of the synthesis involve a sterically hindered amination via hypervalent iodine reagents and the Larock annulation. These transformations enable a general approach to the syntheses of indole alkaloids containing a 3α-amino-hexahydropyrrolo[2,3-b]indole motif and could be further applied to build a natural product-based library.     

Solid-phase synthesis of aryl, heteroaryl, and sterically hindered alkyl amines using the Curtius rearrangement

An efficient method for the solid-phase synthesis of aryl amines, heteroaryl amines, and sterically hindered alkyl amines has been developed. The key step in this process was the formation of resin-bound carbamates (B) by the Curtius rearrangement of aryl carboxylic acids with Wang resin providing the trapping hydroxyl group. N-Alkylation reactions of B gave secondary amines in good yield. Some biaryl amines, which are found widely in biologically active substances, were also prepared by the Suzuki reaction of resin-bound carbamates of 2-iodoaniline (16) or 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (21). The developed methods can be applied to the preparation of libraries containing aryl, heteroaryl, and sterically hindered alkyl amine structures as the pharmacophores.     

A facile synthesis of 1,4-dideoxy-1,4-imino-l-ribitol (LRB) and (−)-8a-epi-swainsonine from d-glutamic acid

A facile synthesis of (−)-8a-epi-swainsonine 2 and 1,4-dideoxy-1,4-imino-l-ribitol (LRB) 4 has been achieved by using the versatile building block 3, which was available from cheap d-glutamic acid. The new forming stereogenic center in synthesis of 2 was constructed by highly selective reduction of the ketone 13 with Li(t-BuO)₃AlH in THF (dr=95:5).     

Total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and formal synthesis of pumiliotoxin-251D

A concise and efficient synthesis of (6R,7S,8R,8aS)-6,7,8-trihydroxyindolizidine (1-deoxy-7,8a-di-epi-castanospermine) 2 is described. The synthesis employs cross metathesis in building the key intermediate 9 and is used effectively in constructing indolizidine skeleton for the total synthesis of 1-deoxy-7,8a-di-epi-castanospermine and also for the bicyclic framework of pumiliotoxin 251D 12, 13. The indolizidine skeleton is achieved in one pot sequence of transformations such as deprotection of Cbz group, reduction of double bond, and cyclization. The configurational and conformational structures of compound 10 are unambiguously confirmed by X-ray analysis.     

Ligand-controlled regioselective and chemodivergent defluorinative functionalization of gem-difluorocyclopropanes with simple ketones

Modulating the reaction selectivity is highly attractive and pivotal to the rational design of synthetic regimes. The defluorinative functionalization of gem-difluorocyclopropanes constitutes a promising route to construct β-vinyl fluorine scaffolds, whereas chemo- and regioselective access to α-substitution patterns remains a formidable challenge. Presented herein is a robust Pd/NHC ligand synergistic strategy that could enable the C–F bond functionalization with exclusive α-regioselectivity with simple ketones. The key design adopted enolates as π-conjugated ambident nucleophiles that undergo inner-sphere 3,3′-reductive elimination warranted by the sterically hindered-yet-flexible Pd-PEPPSI complex. The excellent branched mono-defluorinative alkylation was achieved with a sterically highly demanding IHept ligand, while subtly less bulky SIPr acted as a bifunctional ligand that not only facilitated α-selective C(sp³)–F cleavage, but also rendered the newly-formed C(sp²)–F bond as the linchpin for subsequent C–O bond formation. These examples represented an unprecedented ligand-controlled regioselective and chemodivergent approach to various mono-fluorinated terminal alkenes and/or furans from the same readily available starting materials.

A robust Pd/NHC ligand synergistic strategy that enables the exquisite regioselective and chemodivergent C–F bond functionalization of gem-difluorocyclopropanes with simple ketones, is reported.     

Synthesis of bioactive fluoropyrrolidines via copper(i)-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides

Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, and the development of efficient methods for the synthesis of diverse structured pyrrolidine derivatives is of great importance. Meanwhile, incorporating fluorine containing groups into small molecules often changes their activities to a great extent due to the special physicochemical properties of fluorine atoms. Herein, we report an efficient route to obtain enantioenriched 3,3-difluoro- and 3,3,4-trifluoropyrrolidinyl derivatives by Cu(i)-catalysed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active 1,1-difluoro- and 1,1,2-trifluorostyrenes. A series of new fluorinated pyrrolidines have been prepared in high yields (up to 96%) and with excellent stereoselectivities (up to >20 : 1 dr and 97% ee), and these unique structural blocks could be readily introduced into some natural compounds and pharmaceuticals. Additionally, antifungal activity investigation against four common plant fungi showed that some products possess general and high biological activities; comparison with the low antifungal activities of corresponding nonfluorinated compounds revealed that the fluorine atoms at the pyrrolidinyl rings play a crucial role in the antifungal activity.

Chiral fluoropyrrolidines were synthesized by Cu(i)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active fluorinated styrenes, with broad substrate scope and high yield, stereoselectivity and biological activity.