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1.
This study described palladium-catalyzed chemoselective direct α-arylation of carbonyl compounds with chloroaryl triflates in the Ar–Cl bond. The Pd/SelectPhos system showed excellent chemoselectivity toward the Ar–Cl bond in the presence of the Ar–OTf bond with a broad substrate scope and excellent product yields. The electronic and steric hindrance offered by the –PR2 group of the ligand with the C2-alkyl group was found to be the key factor affecting the reactivity and chemoselectivity of the α-arylation reaction. The chemodivergent approach was also successfully employed in the synthesis of flurbiprofen and its derivatives (e.g., –OMe and –F).Palladium-catalyzed chemoselective direct α-arylation of carbonyl compounds with chloroaryl triflates in the Ar–Cl bond is reported. The effects of –PR2 and C2-alkyl groups of the ligands are investigated using experimental and computational methods. 相似文献
2.
Pim J. de Vink Auke A. Koops Giulia D'Arrigo Gabriele Cruciani Francesca Spyrakis Luc Brunsveld 《Chemical science》2022,13(9):2744
Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR–ligands modulate Protein–Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor γ (PPARγ), which describes NR–ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR–coregulator binding (KID) and NR–ligand binding (KIID), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure–activity-relationships for NR–ligands and can steer NR modulator discovery and optimization via a completely novel approach.A cooperativity framework describes the formation of nuclear receptor ternary complexes and deconvolutes ligand and cofactor binding into intrinsic affinities and a cooperativity factor, providing a conceptually new understanding of NR modulation. 相似文献
3.
Polyesters are important plastics, elastomers and fibres; efficient and selective polymerizations making predictable, high molar mass polymers are required. Here, a new type of catalyst for the ring-opening polymerization (ROCOP) of epoxides and anhydrides combines unusually high chain end-group selectivity, fast rates, and good molar mass control. The organometallic heterodinuclear Al(iii)/K(i) complex, applied with a diol, is tolerant to a range of epoxides/phthalic anhydride and produces only α,ω-hydroxyl telechelic polyesters with molar masses from 6–91 kg mol−1, in all cases with monomodal distributions. As proof of its potential, high molar mass poly(vinyl cyclohexene oxide-alt-phthalic anhydride) (91 kg mol−1) shows 5× greater flexural strain at break (εb = 3.7%) and 9× higher maximum flexural stress (σf = 72.3 MPa) than the previously accessed medium molar mass samples (24 kg mol−1). It is also enchains phthalic anhydride, vinyl cyclohexene oxide and ε-decalactone, via switchable catalysis, to make high molar mass triblock polyesters (81 kg mol−1, Đ = 1.04). This selective catalyst should be used in the future to qualify the properties of these ROCOP polyesters and to tune (multi)block polymer structures.A heterodinuclear Al(iii)/K(i) organometallic ring-opening copolymerization catalyst shows exceptional rates, end-group selectivity and good loading tolerance to deliver monodisperse polyesters with molar masses up to 91 kg mol−1. 相似文献
4.
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.We report here a sequential enantioselective reduction/C–H functionalization to install contiguous stereogenic carbon centers of benzocyclobutenols and cyclobutanols.Molecules with inherent ring strain have gained considerable interest in the synthetic community.1 Among them, four-membered ring molecules have been recognized as powerful building blocks in organic synthesis.2 Driven by ring strain releasing, the reactions of carbon–carbon bond cleavage have been extensively studied in recent years.3 Meanwhile, cyclobutane motifs represent important structural units in natural product and bioactive molecules as well (Scheme 1).4 Therefore, a general and robust method to constitute four-membered ring derivatives is of great value, especially in an enantiomerically pure form.5Open in a separate windowScheme 1Representative cyclobutane-containing bioactive molecules.[2 + 2]-Cycloaddition6 and the skeleton rearrangement reaction7 are two primary methods to prepare chiral cyclobutane derivatives. Recently, the precision modification of four-membered ring skeletons to access enantioenriched cyclobutane derivatives has attracted emerging attention. Several strategies have been developed, including allylic alkylation,8 α-functionalization,9 conjugate addition10 and C–H functionalization11 of prochiral or racemic cyclobutane derivatives (Scheme 2a).12 However, the enantioselective synthesis of chiral benzocyclobutene derivatives is still underdeveloped.13 Although two efficient palladium-catalyzed C–H activation strategies have been developed by Baudoin14 and Martin15 groups via similar intermediate five-membered palladacycles, no enantioenriched benzocyclobutene derivative has been prepared by employing the above two methods. In 2017, Kawabata reported an elegant example of asymmetric intermolecular α-arylation of enantioenriched amino acid derivatives to afford benzocyclobutenones with tetrasubstituted carbon via memory of chirality (Scheme 2b).16 In 2018, Zhang reported an iridium-catalyzed asymmetric hydrogenation of α-alkylidene benzocyclobutenones in good enantioselectivities (3 examples, 83–88% ee).12c To the best of our knowledge, there is no report on enantioselective synthesis of benzocyclobutene derivatives with all-carbon quaternary centers.Open in a separate windowScheme 2Asymmetric synthesis of cyclobutanes and their derivatives. (a) Enantioselective functionalization of four-membered ring substrates. (b) Synthesis of chiral benzocyclobutenone via memory of chirality. (c) This work: sequential enantioselective reduction/C–H functionalization.In line with our continued interest in precision modification of four-membered ring skeletons,9d,10c,12a we initiated our studies on the synthesis of chiral benzocyclobutenes via enantioselective functionalization of highly strained benzocyclobutenones. It is well known that benzocyclobutene derivatives are labile to undergo a ring-opening reaction to release their inherent ring strains.17 Therefore, it is a challenging task to modify the benzocyclobutenone and preserve the four-membered ring skeleton at the same time. We envisioned that a carbonyl group directed C–H functionalization18 of the gem-dimethyl group could furnish enantioenriched α-quaternary benzocyclobutenones (Scheme 2c). This could be viewed as an alternative approach to achieve the alkylation of benzocyclobutenone, which was otherwise directly inaccessible using enolate chemistry through the unstable anti-aromatic intermediate.19 In addition, a highly regioselective C–H activation would be required to functionalize the methyl group instead of the aryl ring. Here we report our work on sequential enantioselective reduction and intramolecular C–H silylation to provide enantioenriched benzocyclobutenols and cyclobutanols with all-carbon quaternary centers. The excellent diastereoselectivity and regioselectivity of silylation were attributed to rigid structural organization of the 4/5 fused ring. Furthermore, this strategy has been utilized to accomplish the total synthesis of natural products phyllostoxin (proposed structure), grandisol and fragranol.We commenced our studies with enantioselective reduction of readily prepared dimethylbenzocyclobutenone 1a (Scheme 3).15,20 Surprisingly, enantioselective reduction of the carbonyl group of cyclobutanone derivatives received little attention. The first reduction of parent benzocyclobutenone was studied in 1996 by Kündig using chlorodiisopinocamphenylborane21 or chiral oxazaborolidines (CBS reduction),22 and only moderate enantioselectivity (44–68% ee) was obtained.23 Although copper-catalyzed asymmetric hydrosilylation of benzocyclobutenone 1a using CuCl/(R)-BINAP gave the benzocyclobutenol ent-2a in 88% ee, optimization of ligands gave no further improvement (Scheme 3a, see Tables S1–S4† for details).24 Gladly, excellent enantioselective reduction could be achieved in 94% yield and 97% ee under Noyori''s asymmetric transfer hydrogenation conditions (Scheme 3b, conditions A, RuCl[(S,S)-Tsdpen](p-cymene)).25 The product 2a showed remarkable stability and no ring-opening byproduct 2a′ was observed. The reduction of parent benzocyclobutenone was examined under conditions A, and benzocyclobutenol was obtained in 90% yield and 81% ee. Apparently, the steric influence imposed by the α-dimethyl group enhanced the enantioselectivity of the reduction. Similarly, the CBS reduction ((S)-B–Me) of benzocyclobutenone 1a gave better results compared with parent benzocyclobutenone, affording the product 2a in 86% yield and 92% ee (Scheme 3c).Open in a separate windowScheme 3Enantioselective reduction of benzocyclobutenone 1a. (a) Copper hydride reduction. (b) Ru-catalyzed asymmetric transfer hydrogenation. (c) CBS reduction.We then examined the substrate scope of the reduction reaction (26 was chosen to improve the yield and enantioselectivity. Besides, benzocyclobutenol 2g with nitro substitution could be obtained in 96% yield and 93% ee. Treatment of pyrrolidinyl substituted benzocycobutenone 1h with catalyst (S,S)-Ts-DENEB afforded desired product 2h in 49% yield and 89% ee, together with ring-opening product 2h′ (18%).Enantioselective reduction of benzocyclobutenonesa
Open in a separate windowaConditions A: 1a (0.5–2.0 mmol), RuCl[(S,S)-Tsdpen](p-cymene) (1–2 mol%), HCOOH/Et3N (5/2), rt. All results are corrected to the (S)-catalyst. The ee values were determined by HPLC analysis; see the ESI for more details.b(S,S)-Ts-DENEB (1–2 mol%) was used, rt or 60 °C.3,3-Disubstituted cyclobutanones were also explored (l-selectride gave cis-4i as a single product in 99% yield and 96% ee. The reaction of 3j gave similar results, and enantioenriched cyclobutanols cis-4j could be furnished in 78% yield and 97% ee from ent-trans-4j (98% ee) following the above oxidation–reduction procedure. The absolute configurations of 2a, ent-2j and trans-4i were unambiguously determined by single-crystal X-ray diffraction analysis of their corresponding nitrobenzoate derivative.27Enantioselective reduction of cyclobutanones 3a
Open in a separate windowaConditions B: 3a (1.0–5.0 mmol), (S)-B–Me (10 mol%), BH3·Me2S (0.6 equiv.), THF, rt.b(S)-B–Me (20 mol%), BH3·Me2S (1.0 equiv.).c(−)-Ipc2BCl (1.2 equiv.), THF, −20 °C. (−)-Ipc2BCl = (−)-diisopinocampheylchloroborane.Inspired by powerful and reliable directed C–H silylation chemistry pioneered by Hartwig,28 we envisioned that the transition-metal catalyzed intramolecular C–H silylations of the above alcohols would provide a single diastereomer owing to rigid structural organization. The challenges here are the control of regioselectivity in the cyclization step and inhibition of the ring-opening pathway. Benzocyclobutenol 2a was chosen as a model substrate to study this intramolecular C–H silylation. The transition-metal catalyst system and alkene acceptors were screened (Scheme 4, see Tables S5–S9† for details). Acceptor norbornene (nbe) derivative A gave the optimal yield in the cyclization step (63% NMR yield), and other phenanthroline ligands gave inferior results. The reaction showed remarkable regio- and diastereoselectivity; no silylation of the arene was detected.With optimal intramolecular silylation conditions in hand, sequential hydroxysilylation/C–H silylation/phenyllithium addition reaction of 2a provided desired product 5a in 56% overall yield without any obvious erosion of enantiomeric purity (