A Biomimetic Approach to Okilactomycin and Chrolactomycin and The Hexadehydro-Diels-Alder (HDDA) Reaction

University of Minnesota Ph.D. dissertation. December 2013. Major: Chemistry. Advisor: Thomas Hoye. 1 computer file (PDF); xxii, 337 pages.We hypothesized that spirotetronate (+)-okilactomycin (1) and (-)-chrolactomycin (2) are biogenetically derived from a common intermediate, (-)-okilactomycin D (3), which in turn arises via an intramolecular Diels-Alder (IMDA) reaction from the linear precursor 4. Guided by this hypothesis, we have achieved an efficient synthesis of okilactomycin D by a route featuring a substrate-controlled, diastereoselective intramolecular Diels-Alder (IMDA) reaction of an analogue of polyene 4. The assigned absolute configuration of (-)-3 was confirmed. Conversion of (-)-3 toward 1 and 2 has also been explored. ortho-Benzyne (1,2-didehydrobenzene, 7 or 7') is one of the oldest, most interesting, most useful and most well-studied of all reactive intermediates in chemistry. The multifaceted and efficient reactions of benzynes with suitable trapping reagents have long been employed in the service of synthetic chemistry to give products that are used as pharmaceuticals, agrochemicals, dyes, polymers, and other fine chemicals. An accidental observation made in this laboratory led us to establish an unorthodox yet general aryne-generating strategy--the hexadehydro-Diels-Alder (HDDA) reaction. This enabling transformation, which produces the highly reactive benzyne intermediate from the thermal [4+2] cycloisomerization of a 1,3-diyne (like 6) with a 'diynophile' (like 5) in the absence of any metals or reagents, has allowed us to uncover some unprecedented aryne reactivities

Use of a catalytic co-solvent, N,N-dimethyl octanamide, allows the flow synthesis of Gleevec with no solvent switch

A general, efficient method for C−N cross‐coupling has been developed using N,N‐dimethyloctanamide as a catalytic cosolvent for biphasic continuous‐flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two‐step sequence which converted phenols into biarylamines via either triflates or tosylates. Additionally, the method was applied to a three‐step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches

50° Post-Eocene clockwise rotation of Mangkang and its implications for the oroclinal bending of the southeastern Tibetan Plateau

The extrusion and clockwise rotation of the southeastern Tibetan Plateau around the Eastern Himalaya Syntaxis has been playing an important role in accommodating the Tibetan Plateau lithosphere shortening. Establishing the extrusion and rotation processes has great significance in understanding the still hotly debated deformation of the Tibetan Plateau. Here we conduct a new paleomagnetic study of the Upper Eocene (∼33.4–36.4 Ma) volcanogenic rocks from Mangkang (29.7°N, 98.6°E), which is located in the eastern Qiangtang Terrane that bent around the Eastern Himalaya Syntaxis. A total of 184 characteristic remnant magnetizations of 20 sites were identified and have a tilt-corrected site-mean direction of Ds = 62.2 ± 5.5°, Is = 47.6 ± 5.7°, K = 46.7, A95 = 4.8°. The statistical properties of the obtained paleomagnetic directions can be straightforwardly explained by paleosecular variation, together with a positive fold test, yielding likely Late Eocene primary magnetizations. Integrated with other available paleomagnetic results and geological evidence in the adjacent areas, we speculate that there existed a ∼ 50° clockwise rotation of the Mangkang area with respect to the Eurasian Plate after the Late Eocene, due to the oroclinal bending around the Eastern Himalaya Syntaxis. The paleolatitudes estimated from paleomagnetic results indicate that the area between Eurasian and eastern Qiangtang has experienced significant latitudinal crustal shortening during the Eocene, which is consistent with geological evidence

Use of a Generalized Additive Model to Investigate Key Abiotic Factors Affecting Microcystin Cellular Quotas in Heavy Bloom Areas of Lake Taihu

Lake Taihu is the third largest freshwater lake in China and is suffering from serious cyanobacterial blooms with the associated drinking water contamination by microcystin (MC) for millions of citizens. So far, most studies on MCs have been limited to two small bays, while systematic research on the whole lake is lacking. To explain the variations in MC concentrations during cyanobacterial bloom, a large-scale survey at 30 sites across the lake was conducted monthly in 2008. The health risks of MC exposure were high, especially in the northern area. Both Microcystis abundance and MC cellular quotas presented positive correlations with MC concentration in the bloom seasons, suggesting that the toxic risks during Microcystis proliferations were affected by variations in both Microcystis density and MC production per Microcystis cell. Use of a powerful predictive modeling tool named generalized additive model (GAM) helped visualize significant effects of abiotic factors related to carbon fixation and proliferation of Microcystis (conductivity, dissolved inorganic carbon (DIC), water temperature and pH) on MC cellular quotas from recruitment period of Microcystis to the bloom seasons, suggesting the possible use of these factors, in addition to Microcystis abundance, as warning signs to predict toxic events in the future. The interesting relationship between macrophytes and MC cellular quotas of Microcystis (i.e., high MC cellular quotas in the presence of macrophytes) needs further investigation

Protecting group-free and 1,2-trans selective glycosylation of carboxylic acids

Here we report a simple and general method to achieve fully unprotected, 1,2-trans- (-) selective glycosylation of carboxylic acids employing allyl glycosyl sulfones as donors. This reaction occurs under ambient temperature and basic conditions under visible light irradiation. The method is stereoconvergent, as allyl glycosyl sulfone donors pass through glycosyl radical intermediates, en route to glycosyl electrophiles. Thanks to the unique radical-based donor activation mechanism, fully unprotected glycosyl donors can be used directly. This transformation displays remarkable substrate scope with respect to both reaction partners. To illustrate its generality and potential utility, a number of commercial drugs and an acid derived from anticancer agent paclitaxel were efficiently glycosylated. Experimental and theoretical studies provide insights into the origin of the stereochemical outcome of this reaction

A Concise Total Synthesis of (±)- and (−)-Okilactomycin D

The spirotetronate okilactomycin D (<b>7</b>) has been efficiently synthesized by a route featuring a substrate-controlled, diastereoselective (8:1) intramolecular Diels–Alder (IMDA) reaction of <b>11</b>. The assigned absolute configuration of (−)-<b>7</b> was confirmed

A Concise Total Synthesis of (±)- and (−)-Okilactomycin D

The spirotetronate okilactomycin D (<b>7</b>) has been efficiently synthesized by a route featuring a substrate-controlled, diastereoselective (8:1) intramolecular Diels–Alder (IMDA) reaction of <b>11</b>. The assigned absolute configuration of (−)-<b>7</b> was confirmed

Alkyl Sulfoxides as Radical Precursors and Their Use in the Synthesis of Pyridine Derivatives

We report here the use of simple and readily available alkyl sulfoxides as precursors to radicals and their application in the preparation of pyridine derivatives. We show that alkyl sulfoxides form EDA complexes with N-methoxy pyridinium salts, which upon visible light irradiation, undergo a cascade of radical processes to afford pyridine derivatives smoothly. This method displays broad scope with respect to both reactants. The synthetic versatility of sulfoxides as a handle in chemistry adds to the power of this transformation. The method is further applied in the synthesis of various pyridyl C–glycosides that are previously difficult to access

The Hexadehydro-Diels–Alder Cycloisomerization Reaction Proceeds by a Stepwise Mechanism

We report here experiments showing that the hexadehydro-Diels–Alder (HDDA) cycloisomerization reaction proceeds in a stepwise manneri.e., via a diradical intermediate. Judicious use of substituent effects was decisive. We prepared (i) a series of triyne HDDA substrates that differed only in the R group present on the remote terminus of the diynophilic alkyne and (ii) an analogous series of dienophilic alkynes (<i>n</i>-C₇H₁₅COCCR) for use in classical Diels–Alder (DA) reactions (with 1,3-cyclopentadiene). The R groups were CF₃, CHO, COMe/Et, CO₂Me, CONMe₂/Et₂, H, and 1-propynyl. The relative rates of both the HDDA cyclization reactions and the simple DA cycloadditions were measured. The reactivity trends revealed a dramatic difference in the behaviors of the CF₃ (slowest HDDA and nearly fastest DA) and 1-propynyl (fastest HDDA and slowest DA) containing members of each series. These differences can be explained by invoking radical-stabilizing energies rather than electron-withdrawing effects as the dominating feature of the HDDA reaction

Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines

Available in PMC 2016 July 03.Catalytic assembly of enantiopure aliphatic amines from abundant and readily available precursors has long been recognized as a paramount challenge in synthetic chemistry. Here, we describe a mild and general copper-catalyzed hydroamination that effectively converts unactivated internal olefins-an important yet unexploited class of abundant feedstock chemicals-into highly enantioenriched α-branched amines (≥96% enantiomeric excess) featuring two minimally differentiated aliphatic substituents. This method provides a powerful means to access a broad range of advanced, highly functionalized enantioenriched amines of interest in pharmaceutical research and other areas.National Institutes of Health (U.S.) (Grant GM58160)University of Pittsburg