Diagnosis and Management of Constitutional Mismatch Repair Deficiency Syndrome.

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive genetic disorder that has little more than 200 total cases reported as of 2020. Whereas a single mutation in genes responsible for mismatch repair causes the autosomal dominant Lynch syndrome (LS), CMMRD is caused by biallelic heterozygous defects: distinct deleterious mutations on each allele for a single gene. As the disease is exceedingly rare and may present via a wide variety of signs, including neurofibromatosis type 1- and Lynch Syndrome-associated malignancies, diagnosis and subsequent surveillance are complex with suggested methods published by the International Replication Repair Deficiency Consortium.

Decreasing Colectomy Rates in Advanced Adenomas.

Advanced colon adenomas are commonly treated with colectomy, which is associated with substantial morbidity and mortality. Novel endoscopic resection techniques have been described, including endoscopic mucosal resection (EMR) and endoscopic submucosal resection (ESR), which demonstrate promise in treating these neoplasms without colectomy. We performed a retrospective review of patients with advanced adenomas who were referred to a colorectal surgeon for evaluation for resection over 4 years.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

Evaluating Surgery Resident Technical Skills: Intestinal Anastomosis in a Porcine Model.

Because work hour restrictions and technological developments such as staplers change the surgical landscape, efficient resident training methods are necessary to ensure surgical quality. This study evaluates efficacy of a porcine skills laboratory for teaching surgery residents to perform handsewn intestinal anastomoses based on a validated subjective tool and novel objective measurements. We hypothesized that resident performance would improve postintervention; junior residents would improve more than the seniors would.

Robotic inguinal lymph node dissection for melanoma: a novel approach to a complicated problem.

Background: Indications for superficial inguinal lymph node (ILN) dissection in melanoma include fine needle aspiration or clinically positive ILN and sentinel lymph nodes (SLN). Open inguinal lymphadenectomy may be complicated by poor wound healing, deep vein thrombosis, and lymphedema. Technical considerations and case series of a novel surgical approach, robotic inguinal lymphadenectomy, are presented.

Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis.

Small-molecule dual hydrogen-bond (H-bond) donors such as ureas, thioureas, squaramides, and guanidinium ions enjoy widespread use as effective catalysts for promoting a variety of enantioselective reactions. However, these catalysts are only weakly acidic and therefore require highly reactive electrophilic substrates to be effective. We introduce here a mode of catalytic activity with chiral H-bond donors that enables enantioselective reactions of relatively unreactive electrophiles.

Chiral Thioureas Promote Enantioselective Pictet-Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction.

An investigation of the mechanism of benzoic acid/thiourea co-catalysis in the asymmetric Pictet-Spengler reaction is reported. Kinetic, computational, and structure-activity relationship studies provide evidence that rearomatization via deprotonation of the pentahydro-β-carbolinium ion intermediate by a chiral thiourea·carboxylate complex is both rate- and enantioselectivity-determining. The thiourea catalyst induces rate acceleration over the background reaction mediated by benzoic acid alone by stabilizing every intermediate and transition state leading up to and including the final selectivity-determining step.

Model for the Enantioselectivity of Asymmetric Intramolecular Alkylations by Bis-Quaternized Cinchona Alkaloid-Derived Catalysts.

A model for the stereoselectivity of intramolecular alkylations by N,N'-disubstituted cinchona alkaloids reported by Xiang et al. was established using density functional theory (DFT) calculations. The stereocontrol is based on the minimal distortion of the transition state (TS) and catalyst required to achieve favorable electrostatic interactions in the favored TS.

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions.

Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)/(,)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (,)-QuinoxP*·PdBr complex.

A multifunctional catalyst that stereoselectively assembles prodrugs.

The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer.

Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction.

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee.

Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C-N Coupling with Chiral Bisphosphine Mono-oxides.

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

Chiral sulfinamide/achiral sulfonic acid cocatalyzed enantioselective protonation of enol silanes.

The application of chiral sulfinamides and achiral sulfonic acids as a cocatalyst system for enantioselective protonation reactions is described. Structurally simple, easily accessible sulfinamides were found to induce moderate-to-high ee's in the formation of 2-aryl-substituted cycloalkanones from the corresponding trimethylsilyl enol ethers.

Palladium-catalyzed conversion of aryl and vinyl triflates to bromides and chlorides.

The palladium-catalyzed conversion of aryl and vinyl triflates to aryl and vinyl halides (bromides and chlorides) has been developed using dialkylbiaryl phosphine ligands. A variety of aryl, heteroaryl, and vinyl halides can be prepared via this method in good to excellent yields.

Copper-promoted coupling of vinyl boronates and alcohols: a mild synthesis of allyl vinyl ethers.

A copper-promoted coupling of vinyl pinacol boronate esters and alcohols for the synthesis of enol ethers is reported. The reaction occurs in 50-99% yield and is compatible with a variety of functional groups. Cupric acetate is the copper source, and triethylamine buffer is used to prevent protodeboration; the reaction occurs at room temperature.

Pd-catalyzed N-arylation of secondary acyclic amides: catalyst development, scope, and computational study.

We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation.

Synthesis of 5,5-disubstituted butenolides based on a Pd-catalyzed gamma-arylation strategy.

Methods for the construction of quaternary carbon centers are of great interest to synthetic chemists due to their presence in natural products. Development of the Pd-catalyzed arylation of butenolides with high selectivity for the gamma-position allows for a facile construction of quaternary centers. The preparation of a wide variety of gamma-aryl butenolides containing a number of functional groups is outlined.

Orthogonal Pd- and Cu-based catalyst systems for C- and N-arylation of oxindoles.

In the cross-coupling reactions of unprotected oxindoles with aryl halides, Pd- and Cu-based catalyst systems displayed orthogonal chemoselectivity. A Pd-dialkylbiarylphosphine-based catalyst system chemoselectively arylated oxindole at the 3 position, while arylation occurred exclusively at the nitrogen using a Cu-diamine-based catalyst system. Computational examination of the relevant L1Pd(Ar)(oxindolate) and diamine-Cu(oxindolate) species was performed to gain mechanistic insight into the controlling features of the observed chemoselectivity.