Stereoselective Diels Research Articles

Highly Stereoselective Diels–Alder Reactions Catalyzed by Diboronate Complexes**

AbstractA highly enantioselective catalytic system for exo‐Diels–Alder reactions was developed based on the newly discovered bispyrrolidine diboronates (BPDB). Activated by various Lewis or Brønsted acids, BPDB can catalyze highly stereoselective asymmetric exo‐Diels–Alder reactions of monocarbonyl‐based dienophiles. When 1,2‐dicarbonyl‐based dienophiles are used, the catalyst can sterically distinguish between the two binding sites, which leads to highly regioselective asymmetric Diels–Alder reactions. BPDB can be prepared as crystalline solids on a large scale and are stable under ambient condition. Single‐crystal X‐ray analysis of the structure for acid‐activated BPDB indicated that its activation involves cleavage of a labile B←N bond.

Highly Stereoselective Diels-Alder Reactions Catalyzed by Diboronate Complexes.

A highly enantioselective catalytic system for exo-Diels-Alder reactions was developed based on the newly discovered bispyrrolidine diboronates (BPDBs). When activated various Lewis or Brønsted acids, BPDBs could catalyze highly stereoselective asymmetric exo-Diels-Alder reactions of monocarbonyl-based dienophiles. When 1,2-dicarbonyl-based dienophiles are used, the catalyst can sterically distinguish between the two binding sites, which leads to highly regioselective asymmetric Diels-Alder reactions. BPDBs can be prepared as crystalline solids on a large scale and are stable under ambient conditions. Single-crystal X-ray analysis of the structure for acid-activated BPDB indicated that activation involves breakage of a labile N→B bond.

Enantioselective fullerene functionalization through stereochemical information transfer from a self-assembled cage.

The regioselective functionalization of C60 remains challenging, while the enantioselective functionalization of C60 is difficult to explore due to the need for complex chiral tethers or arduous chromatography. Metal-organic cages have served as masks to effect the regioselective functionalization of C60. However, it is difficult to control the stereochemistry of the resulting fullerene adducts through this method. Here we report a means of defining up to six stereocentres on C60, achieving enantioselective fullerene functionalization. This method involves the use of a metal-organic cage built from a chiral formylpyridine. Fullerenes hosted within the cavity of the cage can be converted into a series of C60 adducts through chemo-, regio- and stereo-selective Diels-Alder reactions with the edges of the cage. The chiral formylpyridine ultimately dictates the stereochemistry of these chiral fullerene adducts without being incorporated into them. Such chiral fullerene adducts may become useful in devices requiring circularly polarized light manipulation.

Concise Synthesis of (S)-7-Hydroxy-5-aza-8a-epi-d-swainsonine from a d-Erythrose Derivative

AbstractA five-step synthesis of (S)-7-hydroxy-5-aza-8a-epi-d-swainsonine [(3S,4S,4aS,5S,6R)-octahydropyrrolo[1,2-b]pyridazine-3,4,5,6-tetraol] was accessed in good overall yield from readily available d-erythrosyl benzylidene acetal buta-1,3-diene. The key step of the reaction sequence is a full stereoselective Diels–Alder cycloaddition between­ the diene and dienophile: diethyl azodicarboxylate (DEAD) or di-tert-butyl azodicarboxylate (DBAD). The cycloadducts were further transformed into the title 5-aza-indolizidine. Optimized procedures were obtained for the synthesis of intermediates and products.

Catalytic mechanism and endo-to-exo selectivity reversion of an octalin-forming natural Diels-Alderase.

We have previously reported the identification of CghA, a proposed Diels-Alderase responsible for the formation of the bicyclic octalin core of the fungal secondary metabolite Sch210972. Here we show the crystal structure of the CghA-product complex at a resolution of 2.0 Å. Our result provides the second structural determination of eukaryotic Diels-Alderases and adds yet another fold to the family of proteins reported to catalyse [4 + 2] cycloaddition reactions. Site-directed mutagenesis-coupled kinetic characterization and computational analyses allowed us to identify key catalytic residues and propose a possible catalytic mechanism. Most interestingly, we were able to rationally engineer CghA such that the mutant was able to catalyse preferentially the formation of the energetically disfavoured exo adduct. This work expands our knowledge and understanding of the emerging and potentially widespread class of natural enzymes capable of catalysing stereoselective Diels-Alder reactions and paves the way towards developing enzymes potentially useful in various bio/synthetic applications.

Total Synthesis of (−)‐Lepadin F based on a Stereoselective Diels–Alder Reaction Controlled by a Ketolactone‐type Dienophile

An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels-Alder reaction, in which a novel ketolactone-type dienophile with chiral diol unit is employed to generate the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by SN 2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (-)-lepadin F is synthesized from ethyl l-lactate for the first time.

Highly selective Diels-Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole.

A highly regio-, chemo- and stereoselective divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles is herein described, starting from 2-formylpyrrole and employing Diels–Alder and Heck arylation reactions. 3-(N-Benzyl-2-pyrrolyl)acrylates and 4-(pyrrol-2-yl)butenones underwent a highly endo-Diels–Alder cycloaddition with maleimides to furnish octahydropyrrolo[3,4-e]indoles, which served as precursors in the regioselective synthesis of aza-polycyclic skeletons via an intramolecular Heck arylation reaction. Through the latter reaction, the 3-(N-benzyl-2-pyrrolyl)acrylates give rise to 3-(pyrrolo[2,1-a]isoindol-3-yl)acrylates. A further oxidative aromatization of the polycyclic intermediates provides the corresponding polycyclic pyrrolo-isoindoles and isoindolo-pyrrolo-indoles. A theoretical study on the stereoselective Diels–Alder reactions, carried out by calculating the endo/exo transition states, revealed the assistance of non-covalent interactions in governing the endo stereocontrol.

Highly Diastereoselective Palladium-Catalyzed Oxidative Cascade Carbonylative Carbocyclization of Enallenols.

A palladium-catalyzed oxidative cascade carbonylative carbocyclization of enallenols was developed. Under mild reaction conditions, a range of cis-fused [5,5] bicyclic γ-lactones and γ-lactams with a 1,3-diene motif were obtained in good yields with high diastereoselectivity. The obtained lactone/lactam products are viable substrates for a stereoselective Diels-Alder reaction with N-phenylmaleimide, providing polycyclic compounds with increased molecular complexity.

Insight into Stereo-Induction by Minor Modification in the Ligand in DNA-Based Hybrid Catalysis

A pair of bisbenzimidazole derivatives as catalytic ligand was evaluated in DNA-based hybrid asymmetric reaction. Similar structure of both ligands induced entirely different stereoselectivity in Diels–Alder reaction and Friedel–Crafts alkylation. The binding mode of the two Cu2+ complexes to st-DNA was elaborated by circular dichroism, UV–vis, IR, Raman spectroscopy, and singular value decomposition analysis. The coordination mode of ligand to Cu2+ substantially impacted on dominant conformation of complex. The major binding mode depended on the steric chemistry of complex, directly regulating chiral microenvironment in hybrid catalytic system. Although the title ligand did not present considerable enantioselectivity in catalysis, the current research provided a feasible approach to insight into catalytic microenvironment of chiral scaffold. It will help to reveal the mechanism of stereo-induction in DNA-based hybrid asymmetric reaction.

Highly regio- and Stereoselective Diels–Alder Cycloadditions of α-Alkoxyvinyl(ethoxy)carbene complexes with exo-heterocyclic dienes

A comparative study of reactivity and selectivity was carried out between the α-alkoxyvinyl(ethoxy)carbene complexes of group 6 metals (CO)5M = C[C(=CH2)(OR)]OEt [1a–c: M = Cr; 6a–c: M = Mo; 7a–c: M = W; a, R = Et; b, R = n–Pr; c, R = n–Bu] and exo-heterocyclic dienes 5a–e in Diels–Alder reactions. The cycloadditions of complexes 1, 6 and 7 with the unsubstituted diene 5a (R1 = H) were performed at 25 °C, proving to be highly regioselective in favor of the para pentacarbonyl cycloadducts 8, 10 and 12. On the other hand, the cycloadditions of complexes 1a–c and 6a–c with the substituted dienes 5b–e (R1 = Me or Et) took place at a higher temperature (50 °C) to afford the novel para-endo C,O-chelated tetracarbonyl cycloadducts 15a–f and 17a–d, respectively, in high regio- and stereoselectivity. DFT calculations of the transition states rationalized their selectivity. Under the same reaction conditions, the W(0) carbene complexes 7a–c produced the para-endo non-chelated pentacarbonyl complex adducts 19a–e. The stereochemical assignment of the cycloadducts was supported by NOE measurements. The C,O-chelated tetracarbonyl cycloadduct 15b and non-chelated cycloadduct 19d were further characterized by single-crystal X-ray diffraction.

Towards Storage of Solar Energy in Photochromic Molecules: Benzannulation of the Dihydroazulene/Vinylheptafulvene Couple

AbstractOne challenge in the development of molecular photoswitches for solar energy storage is to increase the energy of the isomer formed upon irradiation. This work focuses on how to affect the relative stabilities of the isomers of the dihydroazulene/ vinylheptafulvene (DHA/VHF) couple by combining the light‐induced DHA to VHF conversion with the loss of aromaticity. We present a synthetic procedure for benzannulation of DHA at the C7−C8 bond, with the key steps being a stereoselective Diels–Alder cycloaddition followed by an oxidation. The optical properties and switching abilities of this compound are described in a combined theoretical and experimental study. Calculations support that benzannulation serves to increase the overall energy capacity of the photoswitch by stabilizing the DHA and destabilizing the VHF.

Enantioselective Organocatalytic Diels-Alder Trapping of Photochemically Generated Hydroxy-o-Quinodimethanes.

The photoenolization/Diels–Alder strategy offers straightforward access to synthetically valuable benzannulated carbocyclic products. This historical light‐triggered process has never before succumbed to efforts to develop an enantioselective catalytic approach. Herein, we demonstrate how asymmetric organocatalysis provides simple yet effective catalytic tools to intercept photochemically generated hydroxy‐o‐quinodimethanes with high stereoselectivity. We used a chiral organic catalyst, derived from natural cinchona alkaloids, to activate maleimides toward highly stereoselective Diels–Alder reactions. An unconventional mechanism of stereocontrol is operative, wherein the organocatalyst is actively involved in both the photochemical pathway, by leveraging the formation of the reactive photoenol, and the stereoselectivity‐defining event.

Enantioselective Organocatalytic Diels–Alder Trapping of Photochemically Generated Hydroxy‐o‐Quinodimethanes

AbstractThe photoenolization/Diels–Alder strategy offers straightforward access to synthetically valuable benzannulated carbocyclic products. This historical light‐triggered process has never before succumbed to efforts to develop an enantioselective catalytic approach. Herein, we demonstrate how asymmetric organocatalysis provides simple yet effective catalytic tools to intercept photochemically generated hydroxy‐o‐quinodimethanes with high stereoselectivity. We used a chiral organic catalyst, derived from natural cinchona alkaloids, to activate maleimides toward highly stereoselective Diels–Alder reactions. An unconventional mechanism of stereocontrol is operative, wherein the organocatalyst is actively involved in both the photochemical pathway, by leveraging the formation of the reactive photoenol, and the stereoselectivity‐defining event.

ChemInform Abstract: A Ring‐Closing Enyne Metathesis Approach to Functionalized Semicyclic Dienes: The Total Synthesis of (‐)‐Tetrangomycin.

The angucycline antibiotic (–)-tetrangomycin was synthesized in 13 steps (11 % overall yield) by using a stereoselective Diels–Alder reaction between a naphthoquinone and a semicyclic diene to construct the benz[a]anthraquinone ring system. The diene intermediates were synthesized through a ring-closing enyne metathesis reaction. The tertiary alcohol at C-3 was installed by an asymmetric dihydroxylation reaction. The relative stereochemistry of the dienes was verified by the NMR analyses of the cycloadducts that were obtained from their reaction with N-phenylmaleimide. Selective aromatization of the B ring was achieved under oxidative conditions.

Synthetic studies on azadirachtin: construction of the ABC ring system via the Diels–Alder reaction of a vinyl allenylsilane derivative

Studies toward the asymmetric total synthesis of azadirachtin are explored. The ABC ring system was constructed through the stereoselective Diels–Alder reaction of an optically active vinyl allenylsilane derivative followed by an intramolecular aldol reaction. The highly hindered C8–C14 bond was formed by an intermolecular addition reaction of an aldehyde and the allylborane moiety in the B ring. Cyclization of the E ring moiety by the Pd-catalyzed Nazarov reaction afforded a compound having the highly functionalized ABCE ring system of azadirachtin.

ChemInform Abstract: Stereoselective Diels—Alder Reactions Promoted under Continuous‐Flow Conditions by Silica‐Supported Chiral Organocatalysts

AbstractA simple HPLC column filled with silica‐supported MacMillian catalyst works as a catalytic reactor for the Diels—Alder reaction between cyclopentadiene and cinnamic aldehyde affording the cycloadducts in high yields and enantioselectivities.

Catalytically Active Cu(II)-Pybox Complexes: Insights by EPR Spectroscopy and DFT Computations

This paper addresses the geometry of the catalytic Cu(II) complexes formed in the course of stereoselective Diels–Alder reaction. The parent catalyst is [Cu(II)-isopropyl-pybox](OTf)2. Ethyl glyoxylate serves as dienophile and it reacts with 1,3-cyclohexadiene. The reaction is followed by CW EPR, HYSCORE, and (pulsed) ENDOR spectroscopy and the experimental results are supported by DFT computations. It is shown that during the catalytic process, the Cu(II) complex is pentacoordinated and one of the triflate counterions is coordinated to the Cu(II) center in axial position.

Stereoselective DielsAlder Reactions Promoted under Continuous‐Flow Conditions by Silica‐Supported Chiral Organocatalysts

AbstractSilica nanoparticles of different morphological properties were functionalized with enantiomerically pure imidazolidinones, through different immobilization techniques; stainless‐steel columns were then loaded with silica bearing chiral organocatalysts to realize chiral “homemade” reactors. The influence of the material properties and immobilization procedures on the chemical and stereochemical activities of the chiral HPLC columns was studied by performing organocatalyzed DielsAlder reactions between cyclopentadiene and α,β‐unsaturated aldehydes under continuous‐flow conditions. In some cases, excellent enantioselectivities were obtained, thus showing that a catalytic reactor may work efficiently to continuously produce enantiomerically enriched cycloadducts for more than 200 h. Regeneration of the organocatalytic column was also partially accomplished, although associated with a slightly lower enantioselectivity, thus prolonging the “life” of the reactor to more than 300 h.

ChemInform Abstract: A Highly Stereoselective Diels—Alder Cycloaddition of Enones with Chiral Cyclic 2‐Amidodienes Derived from Allenamides.

AbstractThe Lewis acid promotes highly regioselective and diastereoselective Diels‐Alder reaction giving access to optically enriched [2.2.2]‐bicyclic manifolds.

A Ring‐Closing Enyne Metathesis Approach to Functionalized Semicyclic Dienes: The Total Synthesis of (–)‐Tetrangomycin

AbstractThe angucycline antibiotic (–)‐tetrangomycin was synthesized in 13 steps (11 % overall yield) by using a stereoselective Diels–Alder reaction between a naphthoquinone and a semicyclic diene to construct the benz[a]anthraquinone ring system. The diene intermediates were synthesized through a ring‐closing enyne metathesis reaction. The tertiary alcohol at C‐3 was installed by an asymmetric dihydroxylation reaction. The relative stereochemistry of the dienes was verified by the NMR analyses of the cycloadducts that were obtained from their reaction with N‐phenylmaleimide. Selective aromatization of the B ring was achieved under oxidative conditions.