New synthetic strategies for the stereocontrolled synthesis of substituted ‘skipped’ diepoxides

This report describes a number of new synthetic approaches toward methyl-substituted mono- and diepoxy alcohols that serve as substrates for endo-selective epoxide-opening cascades. The key transformations involve the manipulation of alkynes. Highlighted are the directed methylmetalation of bishomopropargylic alcohols, the bromoallylation of alkynes, and Pd-catalyzed cross-coupling between an alkenyl boronate ester and allylic bromides.National Institute of General Medical Sciences (U.S.) (GM72566)Massachusetts Institute of Technology. Department of Chemistry (George Buchi Summer Graduate Fellowship

A reductive coupling strategy towards ripostatin A

Synthetic studies on the antibiotic natural product ripostatin A have been carried out with the aim to construct the C9−C10 bond by a nickel(0)-catalyzed coupling reaction of an enyne and an epoxide, followed by rearrangement of the resulting dienylcyclopropane intermediate to afford the skipped 1,4,7-triene. A cyclopropyl enyne fragment corresponding to C1−C9 has been synthesized in high yield and demonstrated to be a competent substrate for the nickel(0)-catalyzed coupling with a model epoxide. Several synthetic approaches toward the C10−C26 epoxide have been pursued. The C13 stereocenter can be set by allylation and reductive decyanation of a cyanohydrin acetonide. A mild, fluoride-promoted decarboxylation enables construction of the C15−C16 bond by an aldol reaction. The product of this transformation is of the correct oxidation state and potentially three steps removed from the targeted epoxide fragment.National Institute of General Medical Sciences (U.S.)Novartis (Firm

Safe and Efficient Tetrazole Synthesis in a Continuous Flow Microreactor

Safer flow: The synthesis of 5-substituted tetrazoles in flow (see scheme) is safe, efficient, scalable, requires no metal promoter, and uses a near-equimolar amount of NaN[subscript 3], yet nonetheless displays a broad substrate scope. The hazards associated with HN[subscript 3] are essentially eliminated, shock-sensitive metal azides such as Zn(N[subscript 3])[subscript 2] are avoided, and residual NaN[subscript 3] is quenched in-line with NaNO[subscript 2].Novartis Foundation (MIT Center for Continuous Manufacturing

Hydroxyl-Substituted Ladder Polyethers via Selective Tandem Epoxidation/Cyclization Sequence

A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) isopropoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endo-cyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity.National Institute of General Medical Sciences (U.S.) (GM72566)National Science Foundation (U.S.) (CHE-0234877)National Science Foundation (U.S.) (CHE-9808061

End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts

A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1 : 1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional solvent at high temperature gives the target compound directly as a molten salt (ionic liquid above 168 °C) in high yield. This represents the first example of continuous active pharmaceutical ingredient (API) production in this manner. Six of the twelve principles of green chemistry as defined by the American Chemical Society are achieved, most prominently waste minimization and atom economy.United States. Defense Advanced Research Projects Agency (DARPA N66001-11-C-4147

A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

Ladder polyether natural products are a class of natural products denoted by their high functional-group density and large number of well-defined stereocenters. They comprise the toxic component of harmful algal blooms (HABs), having significant negative economic and environmental ramifications. However, their mode of action, namely blocking various cellular ion channels, also denotes their promise as potential anticancer agents. Understanding their potential mode of biosynthesis will not only help with developing ways to limit the damage of HABs, but would also facilitate the synthesis of a range of analogs with interesting biological activity. 1,3-Dioxan-5-ol substrates display remarkable ‘enhanced template effects’ in water-promoted epoxide cyclization processes en route to the synthesis of these ladder polyether natural products. In many cases, they provide near complete endo-to-exo selectivity in the cyclization of epoxy alcohols, thereby strongly favoring the formation of tetrahydropyran (THP) over tetrahydrofuran (THF) rings. The effects of various Brønsted and Lewis acidic and basic conditions are explored to demonstrate the superior selectivity of the template over the previously reported THP-based epoxy alcohols. In addition, the consideration of other synthetic routes are also considered with the goal of gaining rapid access to a plethora of potential starting materials applicable towards the synthesis of ladder polyethers. Finally, cascade sequences with polyepoxides are investigated, further demonstrating the versatility of this new reaction template.National Institute of General Medical Sciences (U.S.) (Grant GM72566)Natural Sciences and Engineering Research Council of CanadaFonds québécois de la recherche sur la nature et les technologie

Rhodium-Catalyzed Endo -Selective Epoxide-Opening Cascades: Formal Synthesis of (−)-Brevisin

[Rh(CO)₂Cl]₂ is as an effective catalyst for endo-selective cyclizations and cascades of epoxy-(E)-enoate alcohols, thus enabling the synthesis of oxepanes and oxepane-containing polyethers from di- and trisubstituted epoxides. Syntheses of the ABC and EF ring systems of (−)-brevisin via all endo-diepoxide-opening cascades using this method constitute a formal total synthesis and demonstrate the utility of this methodology in the context of the synthesis of marine ladder polyether natural products.National Institute of General Medical Sciences (U.S.) (GM72566)National Institute of General Medical Sciences (U.S.) (F32GM095014

Highly Regioselective Indoline Synthesis under Nickel/Photoredox Dual Catalysis

Nickel/photoredox catalysis is used to synthesize indolines in one step from iodoacetanilides and alkenes. Very high regioselectivity for 3-substituted indoline products is obtained for both aliphatic and styrenyl olefins. Mechanistic investigations indicate that oxidation to Ni(III) is necessary to perform the difficult C–N bond-forming reductive elimination, producing a Ni(I) complex, which in turn is reduced to Ni(0). This process serves to further demonstrate the utility of photoredox catalysts as controlled single electron transfer agents in multioxidation state nickel catalysis.National Institute of General Medical Sciences (U.S.) (GM63755

One-Flow, Multi-Step Synthesis of Nucleosides via Brønsted Acid- Catalyzed Glycosylation

Nucleosides in flow: A general, scalable method of Brønsted acid-catalyzed nucleoside formation is described. Because of the high reaction temperatures readily available to the flow reaction format, mild Brønsted acids, particularly pyridinium triflates, can be used. A one-flow multistep synthesis of unprotected nucleosides is also reported (see scheme)