Figure - available from: Nature
This content is subject to copyright. Terms and conditions apply.
Synthesis of (−)-bilobalide a, Reagents and conditions: (1) 6a, 6b (1.2 equiv.), (−)-A (10 mol%), Et2Zn (3.0 equiv.), tetrahydrofuran (THF), −78 °C; (2) Bu3SnH (1.5 equiv.), azobisisobutyronitrile (AIBN; 0.1 equiv.), toluene, 85 °C; (3) tris(dipivaloylmethanato)manganese (Mn(dpm)3; 10 mol%), Ph(i-PrO)SiH2 (3.0 equiv.), PPh3 (1.5 equiv.), methylcyclohexane (C7H14), O2 (1 atm), 50 °C; (4) (−)-B (10 mol%), THF/H2O (2:1), 23 °C; (5) IBX (3.0 equiv.), dimethyl sulfoxide, 23 °C; (6) TMS-EBX (3.0 equiv.), TBAF (3.0 equiv.), THF, −78 °C to −20 °C; (7) SmI2 (8.4 equiv.), THF/H2O (5:1), 0 °C; (8) LiHMDS (3.0 equiv.), THF, −78 °C; B(OMe)3 (5.0 equiv.), 23 °C; m-CPBA (5.0 equiv.), 0 °C; (9) H2, Pd/C (10 wt%), MeOH, 23 °C; 3 M HCl (aq.), 80 °C; (10) benzoic anhydride (Bz2O; 1.5 equiv.), 4-dimethylaminopyridine (DMAP; 1.5 equiv.), THF, 23 °C; KHMDS (3.0 equiv.), −78 °C, (±)-(C) (3 equiv.), −78 °C; 3 M HCl (aq.), 80 °C. b, Solvent screen (enabled by Ph(ⁱPrOSiH2). c, Acid-catalysed oxetane acetal formation. a10, 39:61 e.r.; 11, 69:31 e.r.
Source publication
The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood1–4. Antagonism of gamma-aminobutyric acid A receptors (GABAARs) by bilobalide has been tied to rescue of cognitive deficits in mouse models of Down syndrome⁵. A lack of convulsant activity coupled with...
Similar publications
Despite advances in diabetes care, impaired diabetic wound healing remains a significant clinical problem. The present study was aimed at developing a novel cream based on Ginkgo biloba extract and investigating its wound healing effect on full-thickness wounds in diabetic rats. The topical formulated oil-in-water emulsion-based cream contains Gink...
Citations
... Furthermore, the intrinsic strain associated with the oxetane ring imparts distinctive reactivity patterns 10 , which can be harnessed to advance synthetic applications (Fig. 1a). These includes their use as versatile precursors for the synthesis of an array of organic compounds 16,17 , their role as pivotal intermediates in the total synthesis of natural products 18, 19 , their value as monomers in polymer construction 20,21 , and their function as potential scaffolds for protein modi cation 22,23 . Undoubtedly, the exploration of synthetic methodologies for the synthesis and transformation of oxetane-related compounds has consistently represented a vibrant area of research 10,24 . ...
The remarkable selectivity, sustainability, and efficiency afforded by biocatalytic strategies position them as complements or alternatives to traditional synthetic methods. Nevertheless, the currently narrow spectrum of enzymatic reactions available imposes limitations on synthesizing diverse desired compounds. Consequently, there continues to be a high demand for developing novel biocatalytic processes to access reactions that were previously unattainable. Herein, we report the discovery and subsequent protein engineering of a unique halohydrin dehalogenase to develop a biocatalytic platform for enantioselective formation and ring-opening of oxetanes. This biocatalytic platform, exhibiting high efficiency, excellent enantioselectivity, and broad scopes, facilitates the preparative-scale synthesis of not only both enantiomers of chiral oxetanes (up to 49% yield, >99 e.e.) but also a variety of chiral γ-substituted alcohols (up to 53% yield, >99 e.e.). Additionally, both the enantioselective oxetane formation and ring-opening processes have been proven scalable for large-scale transformations (20 mmol) at high substrate concentrations (200 mM), and can be integrated efficiently in a one-pot, one-catalyst cascade system. Moreover, useful derivatizations highlight the potential synthetic applications of the biocatalytic platform. This work expands the enzymatic toolbox for non-natural reactions and will promote further exploration of the catalytic repertoire of halohydrin dehalogenases in synthetic and pharmaceutical chemistry.
... Instead, we considered Reformatsky variants recently shown to couple ketone-aldehyde pairs that were unreactive under basic or Lewis acidic conditions. 41 Despite the low reactivity of 7, Niodosuccinimide effected high-yielding and diastereoselective α-halogenation on gram-scale (95%, >20:1 dr, 1 g per batch; see 11 X-ray); iodide 11 proved stable to thiosulfate workup, 28% 5% 20 not 10 mol% dppbenz O chromatography and crystallization (Et2O, -20 °C). Nevertheless, 11 underwent efficient Reformatsky reaction with malondialdehyde dimethylacetal (12) under the action of diethylzinc (Et2Zn) to yield the syn-aldol diastereomer in an axial orientation (77%, 9:1 dr; see 13 X-ray). ...
The salvinorins serve as templates for next generation analgesics, antipruritics and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we describe a short asymmetric synthesis that relies on a sterically-confined organocatalyst to dissociate acidity from reactivity and effect Robinson annulation of an unactivated nucleophile / unstable electrophile pair. Combined with a cobalt-catalyzed polarized diene-alkyne cycloaddition, the route allows divergent access to a focused library of salvinorins. We appraise the synthesis by its generation of multiple analogs that exceed the potency, selectivity, stability and functional bias of salvinorin A itself.
... Since their first applications in electrophilic alkynylation of enolates, 50,51 hypervalent iodine reagents have been widely used to install alkynes on the a-position of carbonyls, especially in total synthesis. [52][53][54][55][56][57][58] In addition, the Bisai group recently reported a transition-metal free alkynylation of 2-oxindoles using EBX reagents. 59 Using thiourea phosphonium salt catalysts, Wu and coworkers could develop an asymmetric alkynylation of azlactones and thiazolones leading to precursors of quaternary a-amino acids (Scheme 9). ...
Although alkynes are one of the smallest functional groups, they are among the most versatile building blocks for organic chemistry, with applications ranging from biochemistry to material sciences. Alkynylation reactions have traditionally relied on the use of acetylenes as nucleophiles. The discovery and development of ethynyl hypervalent iodine reagents have allowed to greatly expand the transfer of alkynes as electrophilic synthons. In this feature article the progress in the field since 2018 will be presented. After a short introduction on alkynylation reactions and hypervalent iodine reagents, the developments in the synthesis of alkynyl hypervalent iodine reagents will be discussed. Their recent use in base-mediated and transition-metal catalyzed alkynylations will be described. Progress in radical-based alkynylations and atom-economical transformations will then be presented.
... Endophytic P. uvicola was further isolated and identified from the medicinal tree Ginkgo biloba. Both the fungus and the tree produce bilobalide (140) [177,197]. Baker et al. [197] described a concise asymmetric synthesis of (-)-bilobalide; however, the production pathway in the endophytic fungus P. uvicola is unknown. Bilobalide (140) from the leaves of Ginkgo biloba exhibits various functions [198]. ...
... Both the fungus and the tree produce bilobalide (140) [177,197]. Baker et al. [197] described a concise asymmetric synthesis of (-)-bilobalide; however, the production pathway in the endophytic fungus P. uvicola is unknown. Bilobalide (140) from the leaves of Ginkgo biloba exhibits various functions [198]. ...
... [151]. Bioactivity compounds showed that (1) pestalol B (195) and pestalol C (196) exhibite tive effects at a range of 23.4-42.5 μM against 10 human tumor cell lines, 7, BT474, A549, DU145, H1975, SK-BR-3, K562, MOLT-4, U937, and BGC A-D (194)(195)(196)(197) showed significant effects on the influenza viruses H3N2 IC50 values of 18.9-48.0 μM [151]. ...
Pestalotiopsis species have gained attention thanks to their structurally complex and biologically active secondary metabolites. In past decades, several new secondary metabolites were isolated and identified. Their bioactivities were tested, including anticancer, antifungal, antibacterial, and nematicidal activity. Since the previous review published in 2014, new secondary metabolites were isolated and identified from Pestalotiopsis species and unidentified strains. This review gathered published articles from 2014 to 2021 and focused on 239 new secondary metabolites and their bioactivities. To date, 384 Pestalotiopsis species have been discovered in diverse ecological habitats, with the majority of them unstudied. Some may contain secondary metabolites with unique bioactivities that might benefit pharmacology.
... The preference for 3 over 1 contrasts the reactivity of other sesquiterpenes like bilobalide where benzoylation promotes a kinetically favorable but contrathermodynamic rearrangement to an isomeric scaffold. 17 Synthesis of the collybolide scaffold, therefore, cannot rely on lactone rearrangement of 2 to favor the desired scaffold; the preference for 2 would prove detrimental to our first-, second-, and third-generation routes and dictate our ultimately successful approach to 1. ...
The fungal metabolite collybolide has attracted attention as a non-nitrogenous, potent, and biased agonist of the kappa-opioid receptor (KOR). Here, we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, indicating that collybolide has been mischaracterized as a KOR agonist. Given the pharmaceutical, medical, and societal interest in collybolide as a next-generation antipruritic and analgesic, this refutation of KOR activity has important ramifications for ongoing studies. Classification of collybolide as a new non-nitrogenous, KOR-selective, potent agonist with the same clinical potential as salvinorin A seems to have been premature.
... Protection and deprotection of the 15-hydroxyl group with DHP under acidic conditions were screened for compatibility with hydroxylation at the C-2 position. The obtained 15 a and 15 b (85 %, dr 1 : 1) were then subjected to stereoselective hydroxylation (LDA/Davis reagent [20] ), furnishing 16 a and 16 b in 64 % yield, which were then subjected to selective deprotection and acetylation. Singlecrystal X-ray diffraction of 18 with a fine Flack parameter (0.008) [16] confirmed the β-orientation of C-2 and configuration of C-10. ...
Natural products possessing unique scaffolds may have antiviral activity but their complex structures hinder facile synthesis. A pharmacophore‐oriented semisynthesis approach was applied to (−)‐maoelactone A (1) and oridonin (2) for the discovery of anti‐SARS‐CoV‐2 agents. The Wolff rearrangement/lactonization cascade (WRLC) reaction was developed to construct the unprecedented maoelactone‐type scaffold during semisynthesis of 1. Further mechanistic study suggested a concerted mechanism for Wolff rearrangement and a water‐assisted stepwise process for lactonization. The WRLC reaction then enabled the creation of a novel family by assembly of the maoelactone‐type scaffold and the pharmacophore of 2, whereby one derivative inhibited SARS‐CoV‐2 replication in HPA EpiC cells with a low EC50 value (19±1 nM) and a high TI value (>1000), both values better than those of remdesivir.
... The nucleophilic oxygen (O5) of 1 is positioned 3.1 Å from C15 and the isomer, neocollybolide (3), is calculated (MM2) to be 1.2 kcal/mol more stable than 1, resulting in kinetic and thermodynamic preference for the formation of 2 and 3. 9 other sesquiterpenes like bilobalide where benzoylation of a hindered alcohol promotes scaffold rearrangement (e.g. 2 to 1). 10 Synthesis of the collybolide scaffold, therefore, cannot rely on lactone rearrangement of 2 to favor the desired scaffold; the preference for 2 would prove detrimental to our first-, second-and third-generation routes and dictate our ultimately successful approach to synthesize 1. ...
... Existing X-ray crystal structures of 1 and 9-epi-1 reported inconclusive Flack parameters 8 that prevent confidence in the assignment. 9 In contrast, the structure parameters of (+)-9 (X-ray) and others (see SI) allowed conclusive assignment of absolute stereochemistry in the series from (R)-(-)- 10. ...
The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, indicating that collybolide has been mischaracterized as a KOR agonist and leaving open the basis for antipruritic effects in mice.
... The preference for 3 over 1 stands in contrast to reactivity of other sesquiterpenes like bilobalide where benzoylation of a hindered alcohol promotes scaffold rearrangement. 10 Synthesis of the collybolide scaffold, therefore, cannot rely on rearrangement in favor of the desired scaffold; the preference for 2 would prove detrimental to our first-, second- and third-generation routes and dictate our ultimately successful approach to synthesize 1. ...
The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, indicating that collybolide has been mischaracterized as a KOR agonist and leaving open the basis for antipruritic effects in mice.
... The preference for 3 over 1 stands in contrast to reactivity of other sesquiterpenes like bilobalide where benzoylation of a hindered alcohol promotes scaffold rearrangement. 10 Synthesis of the collybolide scaffold, therefore, cannot rely on rearrangement in favor of the desired scaffold; the preference for 2 would prove detrimental to our first-, second- and third-generation routes and dictate our ultimately successful approach to synthesize 1. ...
The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, raising the specter of a yet-unidentified contaminant responsible for the reported activity.
... [1] The hydration of alkenes in the presence of at ransition metal catalyst, oxygen and ar eductant has been intensively investigated in the past with the first studies being published already in the 1980s (Scheme 1a). [2][3][4][5][6][7][8][9][10][11][12][13][14] In these cascades, mainly first row transition metals (Fe/Co/Mn) have been applied. [15] Moreover,O 2 is generally used as the C-radical oxygenation reagent in ar eaction that proceeds either near the diffusion limit or diffusion-controlled and accordingly is difficult to run with high stereoselectivity in non-rigid systems. ...
Hydration of alkenes using first row transition metals (Fe, Co, Mn) under oxygen atmosphere (Mukaiyama‐type hydration) is highly practical for alkene functionalization in complex synthesis. Different hydration protocols have been developed, however, control of the stereoselectivity remains a challenge. Herein, highly diastereoselective Fe‐catalyzed anaerobic Markovnikov‐selective hydration of alkenes using nitroarenes as oxygenation reagents is reported. The nitro moiety is not well explored in radical chemistry and nitroarenes are known to suppress free radical processes. Our findings show the potential of cheap nitroarenes as oxygen donors in radical transformations. Secondary and tertiary alcohols were prepared with excellent Markovnikov‐selectivity. The method features large functional group tolerance and is also applicable for late‐stage chemical functionalization. The anaerobic protocol outperforms existing hydration methodology in terms of reaction efficiency and selectivity.
