David A. Vicic

Active trifluoromethylating agents from well-defined Copper(I)-CF3 complexes.

The first examples of isolable and structurally characterized Cu(I)-CF3 complexes are reported. N-Heterocyclic carbene (NHC)-supported copper tert-butoxide complexes reacted with Me3Si-CF3 to afford new (NHC)Cu-CF3 complexes whose structures were dependent on whether or not the C4-C5 positions of the five-membered NHC rings were saturated. In situ generated (SIiPr)Cu-CF3 cleanly transferred its trifluoromethyl group to a number of organic halides under mild conditions.

Nickel-Catalyzed Synthesis of Aryl Trifluoromethyl Sulfides at Room Temperature

Inexpensive nickel-bipyridine complexes were found to be active for the trifluoromethylthiolation of aryl iodides and aryl bromides at room temperature using the convenient [NMe(4)][SCF(3)] reagent.

Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops.

The HIV-1 envelope (Env) spike (gp1203/gp413) undergoes considerable structural rearrangements to mediate virus entry into cells and to evade the host immune response. Engagement of CD4, the primary human receptor, fixes a particular conformation and primes Env for entry. The CD4-bound state, however, is prone to spontaneous inactivation and susceptible to antibody neutralization. How does unliganded HIV-1 maintain CD4-binding capacity and regulate transitions to the CD4-bound state? To define this mechanistically, we determined crystal structures of unliganded core gp120 from HIV-1 clades B, C, and E. Notably, all of these unliganded HIV-1 structures resembled the CD4-bound state. Conformational fixation with ligand selection and thermodynamic analysis of full-length and core gp120 interactions revealed that the tendency of HIV-1 gp120 to adopt the CD4-bound conformation was restrained by the V1/V2- and V3-variable loops. In parallel, we determined the structure of core gp120 in complex with the small molecule, NBD-556, which specifically recognizes the CD4-bound conformation of gp120. Neutralization by NBD-556 indicated that Env spikes on primary isolates rarely assume the CD4-bound conformation spontaneously, although they could do so when quaternary restraints were loosened. Together, the results suggest that the CD4-bound conformation represents a “ground state” for the gp120 core, with variable loop and quaternary interactions restraining unliganded gp120 from “snapping” into this conformation. A mechanism of control involving deformations in unliganded structure from a functionally critical state (e.g., the CD4-bound state) provides advantages in terms of HIV-1 Env structural diversity and resistance to antibodies and inhibitors, while maintaining elements essential for entry.

Oxidative Trifluoromethylthiolations of Aryl Boronic Acids Using a Copper/O2‐Based Protocol

The development of new protocols to prepare perfluoroalkyl sulfides is of growing synthetic interest. Carbon– sulfur bonds are prevalent in medicinally and agriculturally relevant molecules, and fluorination provides additional functionality unique from the non-fluorinated forms. One motivation for the synthesis of perfluoroalkyl sulfides is the high lipophilicities of these derivatives. The SCF3 functional group, for instance, has one of the highest Hansch lipophilicity parameters for its size (p =1.44), which makes it an appealing functional group to incorporate into new library syntheses. Traditional methods to form perfluoroalkyl sulfides have involved, among other methods, substitution of perchloroalkyl sulfides with fluoride sources, UV irradiation of thiophenols or disulfides with perfluoroalkyl iodides in liquid ammonia, and perfluoroalkylation of thiols using hypervalent iodine sources. It has recently been shown that, in addition to the aforementioned classical methods, Group 10 metals can mediate trifluoromethylthiolations by cross-coupling aryl halides under quite mild conditions. c] Buchwald and co-workers found that a Brettphos-ligated palladium complex can convert aryl bromides and iodides into aryl trifluoromethyl sulfides at 80 8C using AgSCF3 as the nucleophilic partner [Eq. (1); Cy= cyclohexyl, cod =1,5-cyclooctadiene, TMS= trimethylsilyl]. Vicic and co-workers found that the same substrates undergo trifluoromethylthiolations at room temperature using the less expensive and more conveniently prepared [NMe4] ACHTUNGTRENNUNG[SCF3] nucleophile in combination with an earth-abundant nickel bipyridine catalyst [Eq. (2); dmbpy= 4,4’-dimethyl-2,2’-bipyridine]. Both of these protocols represent significant advances to earlier known methods used to prepare aryl trifluoromethyl sulfides. However, neither protocol was successful in the trifluoromethylthiolation of aryl chlorides. Since aryl chlorides can be catalytically converted to aryl boronic acids, we imagined that a coppercatalyzed oxidative trifluoromethylthiolation reaction might be an alternative approach to the formation of aryl trifluoromethyl sulfides from substrates that could ultimately originate from aryl chlorides. Indeed, in the course of preparing this manuscript, Qing and co-workers showed that CuSCN mediates such a reaction [Eq. (3)]. Qing s method allows for the coupling of a variety of aryl boronic acids bearing additional functionality on the aryl groups, and proceeds under relatively mild conditions. Although the protocol outlined in Equation (3) employs the use of a catalytic amount (10 %) of CuSCN, four mole equivalents of silver atoms are required relative to the boronic acid for high conversions. Additionally, a fivefold excess of the costly Me3SiCF3 was also employed. Here, we present our own efforts to develop copper-catalyzed oxidative trifluoromethylthiolations, and offer a complementary protocol to that shown in Equation (3) which does not require the use of silver salts or large excesses of Me3SiCF3 in the presence of the organic coupling substrate.

An organocatalytic asymmetric Nazarov cyclization.

An organocatalytic asymmetric Nazarov cyclization of diketoesters that proceeds by means of a dual activation mechanism has been developed. Screening of a number of catalysts led to a new thiourea that incorporates a primary amino group. The method gives rise to cyclic products with two adjacent quaternary asymmetric carbon atoms, one of which is an all-carbon stereocenter, with complete or nearly complete diastereoselectivity and in high or very high enantiomeric excess. A brief and very convenient synthesis of the acyclic diketoester starting materials through nucleophilic addition to a ketene is also described.

A Five-Coordinate Nickel(II) Fluoroalkyl Complex as a Precursor to a Spectroscopically Detectable Ni(III) Species

Mechanistic proposals for nickel-catalyzed coupling reactions often invoke five-coordinate alkyl- or aryl-bound Ni(II) and/or high-valent nickel(III) species, but because of their reactive nature, they have been difficult to study and fingerprint. In this work, we invoked the stabilizing properties of fluoroalkyl ligands to access such nickel species bearing ligands that are commonplace in organic coupling reactions. We show that five-coordinate Ni(II) complexes containing nickel-carbon bonds can readily be prepared given the appropriate precursor, and we also present evidence for the formation of Ni(III) species upon chemical and electrochemical oxidation of the five-coordinate complexes.

Enamine-Iminium Ion Nazarov Cyclization of α-Ketoenones

The mono-triflate salts of some chiral nonracemic 1,2-diamines react with alpha-ketoenones in a stoichiometric reaction to form products of the Nazarov cyclization in high enantiomeric ratios. The mechanism appears to involve rearrangement of an enamine-iminium ion.

Direct Difluoromethylation of Aryl Halides via Base Metal Catalysis at Room Temperature

A stable and isolable difluoromethyl zinc reagent has been prepared through the reaction of ICF2H with diethyl zinc and DMPU. This new zinc reagent is a free-flowing solid and can be used in combination with a nickel catalyst to difluoromethylate aryl iodides, bromides, and triflates at room temperature. Such mild conditions for the catalytic difluoromethylation of these substrates are unprecedented.

Transition-Metal-Catalyzed Difluoromethylation, Difluoromethylenation, and Polydifluoromethylenation Reactions

One way to introduce fluorine into a molecule is through fluoroalkylation reactions. Transition-metal catalysts play an increasing role in selectively incorporating fluoroalkyl groups into organic molecules, especially during the late stages of a synthesis. In this review, we highlight the development of methodologies to incorporate the (CF2H), (CF2R), and ((CF2)n) functionalities into organic substrates by transition-metal complexes. Also discussed are the structural changes that can arise when repeating arrays of (CF2) or (CH2CF2) units are introduced into a single molecule through polydifluoromethylenation reactions.

Rapid and Selective Catalytic Oxidation of Secondary Alcohols at Room Temperature by Using (N-Heterocyclic Carbene)-Ni0 Systems

The selective, anaerobic catalytic oxidation of secondary alcohols at room temperature by using an in situ (N-heterocyclic carbene)-Ni(0) system is presented. The use of non-anhydrous, non-degassed 2,4-dichlorotoluene as both the oxidant and the solvent allows for very short reaction times and very high yields. In addition, a well-defined (N-heterocyclic carbene)-Ni(0) complex was synthesized and applied to these oxidation reactions.