Construction of Tertiary Chiral Centers by Pd-catalyzed Asymmetric Allylic Alkylation of Prochiral Enolate Equivalents

The palladium-catalyzed decarboxylative allylic alkylation of enol carbonates derived from lactams and ketones is described. Employing these substrates with an electronically tuned Pd catalyst system trisubstituted chiral centers are produced. These stereocenters have been previously challenging to achieve using Pd complex/chiral P–N ligand systems

Enantioselective Pd-Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2-a]indolone Substrates: Efficient Syntheses of (−)-Goniomitine, (+)-Aspidospermidine, and (−)-Quebrachamine

The successful application of dihydropyrido[1,2-a]indolone (DHPI) substrates in Pd-catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross-coupling downstream. The first catalytic enantioselective total synthesis of (−)-goniomitine, along with divergent formal syntheses of (+)-aspidospermidine and (−)-quebrachamine, are reported herein

Enantioselective Synthesis of α‑Quaternary Mannich Adducts by Palladium-Catalyzed Allylic Alkylation: Total Synthesis of (+)-Sibirinine

A catalytic enantioselective method for the synthesis of α-quaternary Mannich-type products is reported. The two-step sequence of (1) Mannich reaction followed by (2) decarboxylative enantioselective allylic alkylation serves as a novel strategy to in effect access asymmetric Mannich-type products of “thermodynamic” enolates of substrates possessing additional enolizable positions and acidic protons. Palladium-catalyzed decarboxylative allylic alkylation enables the enantioselective synthesis of five-, six-, and seven-membered ketone, lactam, and other heterocyclic systems. The mild reaction conditions are notable given the acidic free N–H groups and high functional group tolerance in each of the substrates. The utility of this method is highlighted in the first total synthesis of (+)-sibirinine

Enantioselective Synthesis of Dialkylated N-Heterocycles by Palladium-Catalyzed Allylic Alkylation

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds

Selective syntheses of leuconolam, leuconoxine, and mersicarpine alkaloids from a common intermediate through regiocontrolled cyclizations by Staudinger reactions

Selective syntheses of leuconolam, leuconoxine, and mersicarpine alkaloids bearing distinctive core structures were achieved through Staudinger reactions using a common intermediate. In the key cyclization step, water functioned like a switch to control which core structure to produce. The chemistry allowed for selective syntheses of the group of alkaloids from a simple intermediate through straightforward chemical operations

An Efficient Protocol for the Palladium-Catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero-valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol% and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion

Novel quantitative immunohistochemical analysis for evaluating PD-L1 expression with phosphor-integrated dots for predicting the efficacy of patients with cancer treated with immune checkpoint inhibitors

IntroductionProgrammed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method.MethodsIn total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression.ResultsPD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group.ConclusionQuantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method

A Fischer Indolization Strategy toward the Total Synthesis of (–)-Goniomitine

A Fischer indolization strategy toward the core of (–)-goniomitine is reported. Initial investigations into the Pd-catalyzed asymmetric allylic alkylation of dihydropyrido[1,2-a]indolone (DHPI) substrates are also discussed