Alexander J. Cresswell

Beyond the Balz–Schiemann Reaction: The Utility of Tetrafluoroborates and Boron Trifluoride as Nucleophilic Fluoride Sources

The Balz-Schiemann synthesis of aryl fluorides via the thermal decomposition of aryl diazonium tetrafluoroborate salts represents both the earliest and the most proverbial example of the BF4 ion as a nucleophilic fluoride source. Mechanistic studies of the Balz-Schiemann reaction have accrued strong experimental support for an SN1 mechanism via the intermediacy of an aryl cation, which is quenched by fluoride transfer directly from the BF4 ion. A notable advance in this area has been the development by Ohmori and co-workers of a fluorinative variant of the Mitsunobu reaction, involving the electrooxidative generation and subsequent thermal decomposition of alkoxytriphenylphosphonium tetrafluoroborates, allowing for the conversion of alcohols to the corresponding alkyl fluorides with inversion of configuration. Although stereoselectivity during C-F bond formation for reactions proceeding via (putative) carbocation intermediates can be highly variable, the ring-opening of strained rings or ?iranium intermediates via fluoride transfer from fluoroborate ions typically proceeds with high stereoselectivity.

Catalytic, stereospecific syn-dichlorination of alkenes

As some of the oldest organic chemical reactions known, the ionic additions of elemental halogens such as bromine and chlorine to alkenes are prototypical examples of stereospecific reactions, typically delivering vicinal dihalides resulting from anti-addition. Although the invention of enantioselective variants is an ongoing challenge, the ability to overturn the intrinsic anti-diastereospecificity of these transformations is also a largely unsolved problem. Here, we describe the first catalytic, syn-stereospecific dichlorination of alkenes, employing a group transfer catalyst based on a redox-active main group element (selenium). With diphenyl diselenide (PhSeSePh) (5 mol%) as the pre-catalyst, benzyltriethylammonium chloride (BnEt3NCl) as the chloride source and an N-fluoropyridinium salt as the oxidant, a wide variety of functionalized cyclic and acyclic 1,2-disubstituted alkenes, including simple allylic alcohols, deliver syn-dichlorides with exquisite stereocontrol. This methodology is expected to find applications in streamlining the synthesis of polychlorinated natural products such as the chlorosulfolipids. The synthetic challenge of constructing arrays of contiguous, chlorinated stereogenic centres in natural products, like the chlorosulfolipids, has sparked recent interest in new methods for stereocontrolled chlorination. Now the first catalytic, syn-stereospecific dichlorination of alkenes, employing a redox-active main group element as a group transfer catalyst is described.

Ammonium-Directed Oxidation of Cyclic Allylic and Homoallylic Amines

The ammonium-directed olefinic oxidation of a range of cyclic allylic and homoallylic amines has been investigated. Functionalization of a range of allylic 3-(N,N-dibenzylamino)cycloalk-1-enes with m-CPBA in the presence of Cl(3)CCO(2)H gives exclusively the corresponding syn-epoxide for the 5-membered ring (>99:1 dr), the anti-epoxide for the 8-membered ring (>99:1 dr), and predominantly the anti-epoxide for the 7-membered ring (94:6 dr). Oxidation of the homoallylic amines 3-(N-benzylamino)methylcyclohex-1-ene and 3-(N,N-dibenzylamino)methylcyclohex-1-ene gave, in both cases, the corresponding N-protected 1,2-anti-2,3-syn-3-aminomethylcyclohexane-1,2-diol with high levels of diastereoselectivity (>or=90:10 dr). The versatile synthetic intermediates resulting from these oxidation reactions are readily transformed into a range of amino diols.

β-Fluoroamphetamines via the Stereoselective Synthesis of Benzylic Fluorides

A range of substituted aryl epoxides undergo efficient ring-opening hydrofluorination upon treatment with 0.33 equiv of BF(3) x OEt(2) in CH(2)Cl(2) at -20 degrees C to give the corresponding syn-fluorohydrins, consistent with a mechanism involving a stereoselective S(N)1-type epoxide ring-opening process. The benzylic fluoride products of these reactions are valuable templates for further elaboration, as demonstrated by the preparation of a range of aryl-substituted beta-fluoroamphetamines.

Diastereodivergent Hydroxyfluorination of Cyclic and Acyclic Allylic Amines: Synthesis of 4-Deoxy-4-fluorophytosphingosines

A diastereodivergent hydroxyfluorination protocol enabling the direct conversion of some conformationally biased allylic amines to the corresponding diastereoisomeric amino fluorohydrins has been developed. Sequential treatment of a conformationally biased allylic amine with 2 equiv of HBF(4)·OEt(2) followed by m-CPBA promotes epoxidation of the olefin on the face proximal to the amino group under hydrogen-bonded direction from the in situ formed ammonium ion. Regioselective and stereospecific epoxide ring-opening by transfer of fluoride from a BF(4)(-) ion (an S(N)2-type process at the carbon atom distal to the ammonium moiety) then occurs in situ to give the corresponding amino fluorohydrin. Alternatively, an analogous reaction using 20 equiv of HBF(4)·OEt(2) results in preferential epoxidation of the opposite face of the olefin, which is followed by regioselective and stereospecific epoxide ring-opening by transfer of fluoride from a BF(4)(-) ion (an S(N)2-type process at the carbon atom distal to the ammonium moiety). The synthetic utility of this methodology is demonstrated via its application to a synthesis of 4-deoxy-4-fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-phytosphingosine, each in five steps from Garners aldehyde.

Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity

A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors.

Room-temperature gold-catalysed arylation of heteroarenes: complementarity to palladium catalysis

Tailoring of the pre-catalyst, the oxidant and the arylsilane enables the first room-temperature, gold-catalysed, innate C-H arylation of heteroarenes. Regioselectivity is consistently high and, in some cases, distinct from that reported with palladium catalysis. Tolerance to halides and boronic esters, in both the heteroarene and silane partners, provides orthogonality to Suzuki-Miyaura coupling.

Ring-Opening Hydrofluorination of 2,3- and 3,4-Epoxy Amines by HBF4·OEt2: Application to the Asymmetric Synthesis of (S,S)-3-Deoxy-3-fluorosafingol

Treatment of a range of 2,3- and 3,4-epoxy amines with HBF(4)·OEt(2) at room temperature results in fast and efficient S(N)2-type ring-opening hydrofluorination to give stereodefined amino fluorohydrins. Operational simplicity, scalability, and short reaction time at ambient temperature are notable features of this method. The utility of this methodology is exemplified in a concise asymmetric synthesis of (S,S)-3-deoxy-3-fluorosafingol.