A Total Synthesis of (+)-Ryanodol

Highly oxygenated, architecturally complex terpenoids constitute a biologically important class of natural products, yet their development into medicinally relevant analogs and effective biological probes are obstructed by their synthetic accessibility. Ryanodine is a unique diterpenoid that exhibits high affinity to a class of intracellular calcium ion channels bearing its name: ryanodine receptors. Structure-activity relationship studies have demonstrated how peripheral structural modifications affect binding affinity and selectivity among receptor isoforms, but to date have been limited to analogs prepared via chemical derivatization of natural material due to the intractability of total chemical synthesis. This thesis details synthetic efforts culminating in a total synthesis of ryanodol that proceeds in only 15-steps from commercially available (–)-pulegone. Early stage oxygen atom incorporation is strategically implemented to facilitate key, stereoselective carbon-carbon bond formation. In particular, a rhodium-catalyzed, intramolecular Pauson–Khand reaction is utilized to rapidly assemble the tetracyclic ABCD-ring system that constitutes the anhydroryanodol core. A novel, selenium-dioxide mediated oxidation to install three oxidation states and three oxygen atoms was discovered, enabling the rapid oxidative functionalization of the ryanodol A-ring. The modular route described herein allows for the preparation of synthetic structural analogs not readily accessible via chemical degradation, and is anticipated to enable rapid construction and evaluation of biologically active ryanodine analogs.</p

Benzoquinone-derived sulfinyl imines as versatile intermediates for alkaloid synthesis: Total synthesis of (–)-3-demethoxyerythratidinone

The preparation and synthetic applications of benzoquinone monoketal-derived N-tert-butanesulfinyl imines is described. These synthetically versatile intermediates undergo highly diastereoselective 1,2-addition reactions with organometallic reagents to provide 4-aminocyclohexadienones in good yields. The utility of this methodology is demonstrated in a six-step enantioselective synthesis of (–)-3-demethoxyerythratidinone

A Mild and General Larock Indolization Protocol for the Preparation of Unnatural Tryptophans

A mild and general protocol for the Pd(0)-catalyzed heteroannulation of o-bromoanilines and alkynes is described. Application of a Pd(0)/P(^tBu)_3 catalyst system enables the efficient coupling of o-bromoanilines at 60 °C, mitigating deleterious side reactions and enabling access to a broad range of useful unnatural tryptophans. The utility of this new protocol is demonstrated in the highly convergent total synthesis of the bisindole natural product (−)-aspergilazine A

Short, Enantioselective Total Syntheses of (—)-8-Demethoxyrunanine and (—)-Cepharatines A, C, and D

All together! A unified synthetic strategy has resulted in the first enantioselective total syntheses of the natural products 8-demethoxyrunanine and cepharatines A, C, and D

A copper-catalyzed arylation of tryptamines for the direct synthesis of aryl pyrroloindolines

An operationally simple, copper-catalyzed arylation of N-tosyltryptamines provides direct access to C3-aryl pyrroloindolines. A range of electron-donating and electron-withdrawing substituents is tolerated on both the indole backbone and the aryl electrophile. These reactions occur under ambient temperatures and with equimolar quantities of the coupling partners

Interpretable classification of Alzheimer's disease pathologies with a convolutional neural network pipeline.

Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline that identifies specific neuropathologies-amyloid plaques and cerebral amyloid angiopathy-in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotate &gt; 70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieve strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualize morphology distributions at high resolution. Resulting network-derived amyloid beta (Aβ)-burden scores correlate well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrates that networks learn patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist's ability suggests a route to neuropathologic deep phenotyping

Copper-Catalyzed Diastereoselective Arylation of Tryptophan Derivatives: Total Synthesis of (+)-Naseseazines A and B

A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site- and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B

A 3D-Shape Similarity-based Contrastive Approach to Molecular Representation Learning

Molecular shape and geometry dictate key biophysical recognition processes, yet many graph neural networks disregard 3D information for molecular property prediction. Here, we propose a new contrastive-learning procedure for graph neural networks, Molecular Contrastive Learning from Shape Similarity (MolCLaSS), that implicitly learns a three-dimensional representation. Rather than directly encoding or targeting three-dimensional poses, MolCLaSS matches a similarity objective based on Gaussian overlays to learn a meaningful representation of molecular shape. We demonstrate how this framework naturally captures key aspects of three-dimensionality that two-dimensional representations cannot and provides an inductive framework for scaffold hopping