28 research outputs found
Presentación
A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products
Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma
SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers
Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples
Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts
Stereocontrol in asymmetric γ-lactam syntheses from imines and cyanosuccinic anhydrides.
Computations (SCS-MP2//B3LYP) reveal that the asymmetric synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds through a Mannich reaction between the enol form of the anhydride and the E-imine, followed by a transannular acylation. This new mechanistic picture accounts for both the observed reactivity and stereoselectivity. CH-O and hydrogen bonding interactions in the Mannich step and torsional steering effects in the acylation step are responsible for stereocontrol. It is demonstrated that this new mechanistic picture applies to the related reactions of homophthalic anhydrides with imines and presents new vistas for the design of a new reaction to access complex molecular architectures
Stereoselective synthesis of γ-lactams from imines and cyanosuccinic anhydrides.
A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products
Stereoselective Synthesis of γ‑Lactams from Imines and Cyanosuccinic Anhydrides
A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products
Synthesis of a γ-Lactam Library via Formal Cycloaddition of Imines and Substituted Succinic Anhydrides
Formal cycloaddition reactions between imines and cyclic
anhydrides
serve as starting point for the synthesis of diverse libraries of
small molecules. The synthesis of succinic anhydrides substituted
with electron-withdrawing groups is facilitated by new mild conditions
for alkylation of aryl-substituted acetyl esters with ethyl bromoacetate.
These anhydrides are then used in formal cycloaddition reactions with
imines to produce γ-lactams. 2-Fluoro-5-nitrophenylsuccinic anhydride
reacts efficiently with imines to provide lactams that are
further diversified by conversion of the nitro group to either an
aniline and an azide for subsequent reactions with acylating agents
and alkynes, respectively. The synthesis of cyanosuccinic anhydride
is reported for the first time, and the use of this compound in reactions
with imines and subsequent functionalization of the resultant lactams
is demonstrated
Synthesis of a γ-Lactam Library via Formal Cycloaddition of Imines and Substituted Succinic Anhydrides
Formal cycloaddition reactions between imines and cyclic
anhydrides
serve as starting point for the synthesis of diverse libraries of
small molecules. The synthesis of succinic anhydrides substituted
with electron-withdrawing groups is facilitated by new mild conditions
for alkylation of aryl-substituted acetyl esters with ethyl bromoacetate.
These anhydrides are then used in formal cycloaddition reactions with
imines to produce γ-lactams. 2-Fluoro-5-nitrophenylsuccinic anhydride
reacts efficiently with imines to provide lactams that are
further diversified by conversion of the nitro group to either an
aniline and an azide for subsequent reactions with acylating agents
and alkynes, respectively. The synthesis of cyanosuccinic anhydride
is reported for the first time, and the use of this compound in reactions
with imines and subsequent functionalization of the resultant lactams
is demonstrated