PD 173212

Pd-Catalyzed Regioselective 1,2-Dicarbofunctionalization of Unactivated Olefins by a Heck Reaction/Enolate Cyclization Cascade.[Pubmed:28383271]

Org Lett. 2017 Apr 21;19(8):2154-2157.

We disclose a Pd-catalyzed reaction protocol that regioselectively difunctionalizes unactivated olefins with aryl iodides and tethered enolates. The current method allows the rapid synthesis of a variety of 1,3,4-trisubstituted pyrrolidinones from simple and readily available amides. We further demonstrate this new method's application by postsynthetically modifying the arylacetic acid side chains of two commercial nonsteroidal anti-inflammatory drugs, indomethacin and tolmetin, to highly decorated 4-benzylpyrrolidinone frameworks. Mechanistic studies reveal that the reaction proceeds via a Heck reaction/enolate cyclization cascade, a process that exploits beta-H elimination in a constructive mode for regioselective 1,2-difunctionalization of unactivated olefins.

The PD-1 expressing immune phenotype of T cell exhaustion is prominent in the 'immunoreactive' microenvironment of colorectal carcinoma.[Pubmed:28383777]

Histopathology. 2017 Sep;71(3):366-374.

AIMS: This study was designed to test programmed cell death 1 (PD-1) expression of T cells, the hallmark of T cell exhaustion, in different 'immune-classes' of colorectal carcinoma microenvironments as delineated by unsupervised hierarchical cluster analysis. METHODS AND RESULTS: A tissue microarray was made with punches from the invasive margins of 40 microsatellite-unstable and 34 microsatellite-stable colorectal carcinomas. Immune cells were phenotyped by CD8, granzyme B, CD4, FoxP3, CD68, S-100, PD-1 and programmed cell death ligand 1 (PD-L1) immunohistochemistry; tumour area per tissue spot was quantified by cytokeratin (CK)18 immunohistochemistry. For each tissue spot, intra-epithelial immune cells were counted and densities of the various immune cells were calculated. Unsupervised hierarchical cluster analysis with these data yielded a group of 'anergic/immune-naive' microenvironments (47.3%), a group of 'intermediates' (27.0%) and a group of 'immunoreactives' (25.7%) in which PD-1 expressing T cells were prominent. Sixteen of 19 tissue spots representing immunoreactive microenvironments derived from microsatellite-unstable tumours and three were from microsatellite-stable tumours. Further phenotyping of intra-epithelial T cells by sequential immunohistochemistry showed frequent granzyme B/CD8 co-expression, whereas PD-1/CD8 co-expression was more variable. Using receiver operating curve (ROC) analysis, assignment to immune classes was seen to be feasible with good sensitivity and specificity by CD8 counts only. CONCLUSION: A subset of colorectal carcinoma microenvironments is distinguished from the rest by an immune cell composition suggestive of active host anti-tumour immune defence, but this appears to be antagonized by a brisk undercurrent of T cell exhaustion. This observation may have implications for selecting colorectal carcinoma patients for immune checkpoint therapy.

Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids.[Pubmed:28383026]

Nat Commun. 2017 Apr 6;8:14904.

alpha-amino acids bearing aromatic side chains are important synthetic units in the synthesis of peptides and natural products. Although various beta-C-H arylation methodologies for amino acid derivatives involving the assistance of directing groups have been extensively developed, syntheses that directly employ N-protected amino acids as starting materials remain rare. Herein, we report an N-acetylglycine-enabled Pd-catalysed carboxylate-directed beta-C(sp(3))-H arylation of aliphatic acids. In this way, various non-natural amino acids can be directly prepared from phthaloylalanine in one step in good to excellent yields. Furthermore, a series of aliphatic acids have been shown to be amenable to this transformation, affording beta-arylated propionic acid derivatives in moderate to good yields. More importantly, this ligand-enabled direct beta-C(sp(3))-H arylation could be easily scaled-up to 10 g under reflux conditions, highlighting the potential utility of this synthetic method.