Cyclization Strategies for the Concurrent Installation of Multiple Quaternary Stereogenic Centers

In this review we highlight the general cyclization strategies currently available to organic chemists for the concurrent and stereoselective installation of multiple Quaternary Stereogenic Centers (QSC) atoms in cyclic or polycyclic architectures. QSCs embedded in rigid cyclic architectures are motifs found in many blockbuster drugs and important bioactive natural product classes, and yet, direct access to these structures stereoselectively from simple precursors remains a significant challenge. Underscoring the difficulty associated with their synthesis, such topologically three-dimensional molecules are underrepresented in existing small molecule compound libraries, which are instead dominated by linear or flat molecules. This review focuses on methods disclosed in both natural product synthesis and methodology studies since the turn of the 21st century. The cases to be examined successfully achieve these challenging transformations: (1) one-step assembly of the cyclized architecture; and (2) concurrent stereoselective installation of multiple (≥2) new QSCs. These cyclization strategies, which address the aforementioned fundamental challenges in complex molecule synthesis, have been categorized into five broad groups: i) Biomimetic Polyene Cyclization Cascades; ii) Cyclization Cascades of Prochiral Alkenes; iii) Cycloadditions; iv) Dearomatizations; v) Electrocyclizations

Assessing Doha's Street Network from the Perspective of 'Complete Streets' Concept

Streets are considered dynamic spaces in cities, and their design should be safe, comfortable and efficient for all users. Well-functioning streets can create a healthy lifestyle for a city and its users. Many cities are suffering from transportation issues because of their poorly designed street networks that do not integrate the different modes of transportation, or establish safe environments in which pedestrian and cyclists are treated as kings. In this manner, Doha as a city is experiencing the same kind of problem, creating corridors that do not take into consideration different travel modes, which causes severe congestion, delay and shortage in street capacity and, most importantly, users’ dissatisfaction. Therefore, there is a need to investigate and explore some methods that aim to improve cities’ street networks. “Complete Streets” is a roadway design concept initiated with the intention of integrating numerous modes of transportation and their variety of users. Complete Streets are also envisioned to provide traffic, safety and public health benefits, and integrate a healthy lifestyle into built environments worldwide. The newly-emerging concept can be adapted in contexts that fail to combine the different street elements that a street should have. Considering the low quality of the current street network, this thesis aims to evaluate the current streets in Doha city based on the degree of users’ satisfaction, and provide approaches to enhance them from the perspective of the ‘Complete Streets’ concept. The study analyzes two international case studies that have successfully implemented the concept and improved their current street network and enhanced users’ built environment. The analysis will help in extracting criteria that are used to assess the current performance of the street network and recommending ways to improve them. The methodological approach of this research will focus on the selection of two neighborhoods in Doha based on their contextual location and types of land use: a downtown area or urban center exemplified in Fereej bin Mahmoud, and a suburban area or residential district of Al Waab. Three nominated streets of the existing network within the two areas will be selected based on an evaluation matrix, and assessed according to the users’ perspectives and future preferences and aspirations. This approach is supported by two major data collection tools: a visual questionnaire survey and semi-structured interviews with local authorities. A total of 100 questionnaires were collected for the two selected areas from different types of users. Results showed that users are completely unsatisfied with the current conditions of the selected streets in the two areas, which lack the major components of Complete Street variables: pedestrian, bicycle, green and transit improvements, which has resulted in the absence of safety. The produced results along with the evaluation criteria have helped in improving the current streets’ designs and have created a new enhanced cross-section that meets the concept of Complete Streets

A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex

Dysregulated pre-mRNA splicing is an emerging Achilles heel of cancers and myelodysplasias. To expand the currently limited portfolio of small-molecule drug leads, we screened for chemical modulators of the U2AF complex, which nucleates spliceosome assembly and is mutated in myelodysplasias. A hit compound specifically enhances RNA binding by a U2AF2 subunit. Remarkably, the compound inhibits splicing of representative substrates and stalls spliceosome assembly at the stage of U2AF function. Computational docking, together with structure-guided mutagenesis, indicates that the compound bridges the tandem U2AF2 RNA recognition motifs via hydrophobic and electrostatic moieties. Cells expressing a cancer-associated U2AF1 mutant are preferentially killed by treatment with the compound. Altogether, our results highlight the potential of trapping early spliceosome assembly as an effective pharmacological means to manipulate pre-mRNA splicing. By extension, we suggest that stabilizing assembly intermediates may offer a useful approach for small-molecule inhibition of macromolecular machines

Advancing nursing practice : the emergence of the role of Advanced Practice Nurse in Saudi Arabia

Background: The roots of advanced practice nursing can be traced back to the 1890s, but the Nurse Practitioner (NP) emerged in Western countries during the 1960s in response to the unmet health care needs of populations in rural areas. These early NPs utilized the medical model of care to assess, diagnose and treat. Nursing has since grown as a profession, with its own unique and distinguishable, holistic, science-based knowledge, which is complementary within the multidisciplinary team. Today Advanced Practice Nurses (APNs) demonstrate nursing expertise in clinical practice, education, research and leadership, and are no longer perceived as “physician replacements” or assistants. Saudi Arabia has yet to define, legislate or regulate Advanced Practice Nursing. Aims: This article aims to disseminate information from a Saudi Advanced Practice Nurse thought leadership meeting, to chronicle the history of Advanced Practice Nursing within the Kingdom of Saudi Arabia, while identifying strategies for moving forward. Conclusion: It is important to build an APN model based on Saudi health care culture and patient population needs, while recognizing global historical underpinnings. Ensuring that nursing continues to distinguish itself from other health care professions, while securing a seat at the multidisciplinary health care table will be instrumental in advancing the practice of nursing

Progress towards the total synthesis of tetrapetalone A

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2009.An efficient and diastereoselective heterogeneous catalytic hydrogenation reaction of highly substituted pyrrole systems has been developed to synthesize pyrrolidine derivatives stereoselectively. The substituted pyrroles are limited to certain substitution patterns. The origin of the diastereoselectivity is believed to come from the stereocenters on the side chain. More evidence needs to be found to explain the stereoselectivity. With the diastereoselectivity in the heterogeneous catalytic hydrogenation and the known asymmetric reduction of ketones and imines, a convenient enantioselective protocol for the reduction of substituted pyrroles is promising. Tetrapetalone A, was targeted for synthesis due to its novel tetracyclic skeletal structure. The 5-6 fused bicyclic core could be accessed via a polarized Nazarov reaction, and this bicyclic core was converted into an aryl triflate in order to test transition metal-catalyzed coupling reactions to form the C-N bond. The intermolecular cross-coupling reactions between the bicyclic aryl triflate of tetrapetalone A and different nitrogen nucleophiles showed that the steric hindrance from both coupling partners had a strong impact on the efficiency of the C-N bond formation, and the cleavage of the triflate by attack of base decreased the yields of the reaction. The approach based on intramolecular coupling for C-N bond formation via tethered metathesis was not successful because the ester tethered metathesis reaction didn’t give the desired ring-closing product, an eight-member lactone. A new and promising approach based on intramolecular coupling for C-N bond formation via modification of nitrone is in progress. A new synthetic route to synthesize the corresponding bicyclic aryl bromide would address the problems during the intermolecular or intramolecular cross-coupling reactions of aryl triflates

Introduction to phomactin A II. The β-iodoallenolate cyclization III. Studies toward the synthesis of phomactin A

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2012.β-Iodoallenolate intermediates generated from alkynones can participate in intramolecular aldol reactions to generate either cyclohexenols or oxadecalins, both of which contain a β-iodoalkenone functionality. In most cases, the selective formation of either product is possible, depending on the Lewis acid. The versatility of this reaction is demonstrated by its use in our efforts towards the total synthesis of phomactin A. This new annulation method not only produces highly functionalized products with orthogonal reactive groups in high yield, but it has also shown applicability in complex natural product synthesis

The 1,6-conjugate addition initiated nazarov and 1,5-hydride transfer initiated cascade cyclization

Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2019.The iodoaldol reaction can generate densely functionalized iodoallylic alcohols which can be further functionalized under acidic conditions to affect cyclization reactions. This reaction can be conducted in both an intermolecular and intramolecular fashion. This process has the potential to rapidly introduce functionality and structural complexity into a system from simple starting materials. The 1,6-conjugate addition initiated Nazarov (1,6-CAIN) reaction allows us to rapidly generate highly stereodefined cyclopentenones, which are then able to undergo further transformations. The 1,6-CAIN sets up a 1,5-Hydride transfer / oxyallyl cation formation / Friedel-Crafts cyclization cascade sequence which allows for the formation of bridged N-heterocycles

Progress toward the total synthesis of roseophilin

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2009.[Could not render

Convenient cycloaromatization protocol for synthesis of polysubstituted phenol derivatives: method development and mechanistic studies

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2013.I. Oxidation-Initiated Nazarov Cyclization of Vinyl Alkoxyallenes. This chapter describes the development of an oxidation-triggered Nazarov cyclization of vinyl alkoxyallenes. First, we discuss how a successful use of this reaction in our laboratory’s first generation synthesis of (±)-Rocaglamide stimulated our interest in this transformation. An account of the biosynthetic pathways which proceed via rearrangement of an allene oxide to a cyclopentenone is given, followed by an analysis of earlier synthetic studies on the reaction. We then provide an overview of our efforts on the synthesis of substrates, the screening of conditions, and the eventual optimization of the oxidation-initiated Nazarov cyclization. Examination of substrate scope is rounded out by an analysis of experiments which give insight into the mechanism of the reaction. Finally, a mechanistic hypothesis based on these experiments and observed product diastereochemical outcomes is provided, offering an encouraging glimpse into the potential of the reaction to exhibit chirality memory. II. Efforts Toward an Improved Synthesis of Rocaglamide Amenable to Analog Synthesis. In this chapter, we describe studies conducted toward an improved synthesis of the insecticidal and antiproliferative cyclopenta[b]tetrahydrofuran natural product rocaglamide. First, an overview of the isolation and biosynthesis of the flavaglines, the class of natural products of which rocaglamide is a member, is provided. The insecticidal and anticancer activity of the flavaglines and of rocaglamide in particular are discussed, followed by an examination of the molecular mode of action of this class of natural products. Previous syntheses of rocaglamide are then covered. Efforts toward improving the synthesis of a key benzofuran aldehyde intermediate are presented, followed by discussion of the successful development of a versatile cyclopentenone scaffold formed through a tin-free oxidation-triggered Nazarov cyclization for the synthesis of rocaglamide derivatives. III. A Convenient Cycloaromatization Protocol for Synthesis of Polysubstituted Phenol Derivatives: Method Development and Mechanistic Studies In this chapter, a cycloaromatization method for the synthesis of polysubstituted phenols is described. We explain how this endeavor was sparked during our rocaglamide studies by a serendipitous discovery that benzyltrimethylammonium hydroxide catalyzes the cycloaromatization of a propargylic ether intermediate toward the synthesis of a rocaglamide analog. Then, after discussing existing methods for generating and cycloaromatizing allenyl diene systems, we give an overview on the synthesis of substrates, optimization of the reaction conditions, and screening of various substrates to test the scope of the reaction. Lastly, we analyze a series of mechanistic experiments that suggest the reaction proceeds through an electrocyclization followed by a combination of 1,3-proton transfer and sequential deprotonation-reprotonation