Squaramide Organocatalyzed Addition of a Masked Acyl Cyanide to ß-Nitrostyrenes.

A method for the squaramide-organocatalyzed enantioselective addition of a silyl-protected masked acyl cyanide (MAC) reagent to various ß-nitrostyrenes is described. Reactions are carried out in a freezer and provide products cleanly and in high enantioselectivities at very low catalyst loadings. Adducts are then unmasked, providing various oxidation state 3 functional groups, thereby highlighting the utility of these MAC reagents and a new strategy for the preparation of ß-amino acids.

Synthesis of 2,3-Disubstituted Pyrroles by Lewis Acid Promoted Cyclization of N-Sulfonyl Vinylogous Carbamates and Amides.

A three-step sequence to construct pyrroles from three components including 2,2-dimethoxyethylamine, aryl/alkyl sulfonyl chlorides and alkynes bearing electron-withdrawing groups is presented. The pyrroles are proposed to arise via a 5-exo-trig cyclization proceeding through both oxocarbenium and N-sulfonyliminium ions. This modular route allows for the variability at the N-sulfonyl group, the C2 and C3 substituents for rational vectoring of the pyrrole nucleus for downstream processes.

Optimized binding of substituted quinoline ALLINIs within the HIV-1 integrase oligomer.

During the integration step, human immunodeficiency virus type 1 integrase (IN) interacts with viral DNA and the cellular cofactor LEDGF/p75 to effectively integrate the reverse transcript into the host chromatin. Allosteric human immunodeficiency virus type 1 integrase inhibitors (ALLINIs) are a new class of antiviral agents that bind at the dimer interface of the IN catalytic core domain and occupy the binding site of LEDGF/p75. While originally designed to block IN-LEDGF/p75 interactions during viral integration, several of these compounds have been shown to also severely impact viral maturation through an IN multimerization mechanism. In this study, we tested the hypothesis that these dual properties of ALLINIs could be decoupled toward late stage viral replication effects by generating additional contact points between the bound ALLINI and a third subunit of IN. By sequential derivatization at position 7 of a quinoline-based ALLINI scaffold, we show that IN multimerization properties are enhanced by optimizing hydrophobic interactions between the compound and the C-terminal domain of the third IN subunit. These features not only improve the overall antiviral potencies of these compounds but also significantly shift the ALLINIs selectivity toward the viral maturation stage. Thus, we demonstrate that to fully maximize the potency of ALLINIs, the interactions between the inhibitor and all three IN subunits need to be simultaneously optimized.

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives.

A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation-build-up strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.

(R)-(+)-3,5-Dinitro-N-(1-phenylethyl)benzothioamide.

(R)-(+)-3,5-dinitro-N-(1-phenylethyl)benzothioamide 1 is a potential chiral solvating agent (CSA) for the spectral resolution of enantiomers via 1H NMR spectroscopy. The single enantiomer of 1 was synthesized from commercially available (R)-(+)-a-methylbenzylamine 2 in two steps with 85% yield.

Multi-Substituted Quinolines as HIV-1 Integrase Allosteric Inhibitors.

Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.

Two approaches to diverting the course of a free-radical cyclization: application of cyclopropylcarbinyl radical fragmentations and allenes as radical acceptors.

Free radical cyclization of 4 and 7 gave the expected cyclization-reduction products (5 and 8) along with considerable amounts of products derived from a cyclization-atom transfer-secondary cyclization process (6 and 9). Two approaches to avoiding these unexpected products were explored. Use of a cyclopropylcarbinyl fragmentation avoided the secondary cyclization reaction (25 or 43 --> 26 or 44), whereas use of an allene as a radical acceptor avoided the atom-transfer reaction altogether (49 --> 52).

Use of comparative triazolinium triflate fragmentation rates as a tool to assay relative competency of Brønsted bases in N-->N proton transfer.

Brønsted acid-induced fragmentation of a triazoline is used as a tool to identify Brønsted base additives capable of playing the role of a proton shuttle. Relative to water, dimethyl formamide accelerates proton transfer substantially under these conditions. A series of alcohols and ethers were also used to demonstrate that the Brønsted basicity of additive functionality, not their Brønsted acidity, is responsible for their ability to accelerate proton transfer from triazoline N3 to N1. This knowledge was then used to develop a convenient two step protocol for the synthesis of oxazolidine diones from benzyl azide and an unsaturated imide that employs a substoichiometric additive for triazolinium fragmentation.

On the nature of rate acceleration in the synthesis and fragmentation of triazolines by Brønsted acid: secondary catalysis by water (hydronium triflate).

Rate acceleration of the addition of benzyl azide to an electron deficient olefin is characterized using in situ IR spectroscopy. Under strictly anhydrous conditions and at depressed temperature (-20 degrees C), a triazoline intermediate is selectively formed. The stability of this protonated triazoline intermediate at -20 degrees C is indefinite, but warming of the reaction mixture to 0 degrees C or above results in its conversion to the beta-amino oxazolidine dione observed under conditions used in our earlier report. As an alternative to warming, the same conversion can be effected by the addition of a single equivalent of water. Our experiments collectively demonstrate the metastability of the protonated triazoline intermediate and secondary catalysis of triazolinium ring fragmentation by water. This behavior is attributed to the ability of water to transfer a proton from N3 to N1 of the triazoline, thereby allowing ring fragmentation and nitrogen expulsion.

Synthesis and Evaluation of Aryl Quinolines as HIV-1 Integrase Multimerization Inhibitors.

HIV-1 integrase multimerization inhibitors have recently been established as an effective class of antiretroviral agents due to their potent ability to inhibit viral replication. Specifically, quinoline-based inhibitors have been shown to effectively impair HIV-1 replication, highlighting the importance of these heterocyclic scaffolds. Pursuant of our endeavors to further develop a library of quinoline-based candidates, we have implemented a structure-activity relationship study of trisubstituted 4-arylquinoline scaffolds that examined the integrase multimerization properties of substitution patterns at the 4-position of the quinoline. Compounds consisting of substituted phenyl rings, heteroaromatics, or polycyclic moieties were examined utilizing an integrase aberrant multimerization in vitro assay. para-Chloro-4-phenylquinoline 11b and 2,3-benzo[b][1,4]dioxine 15f showed noteworthy EC50 values of 0.10 and 0.08 µM, respectively.

Quassinoid support studies: fused carbocycle synthesis from benzoic acid derivatives via 5-hexynyl and 6-heptynyl radical cyclizations.

Eight bromoalkynes were prepared from substituted benzoic acids and treated with n-Bu3SnH to provide trans-fused perhydroindans or cis- and trans-fused perhydronaphthalenes. Atom-transfer reactions that accompany the free radical reactions resulted in several tandem radical cyclizations with formation of up to three carbon-carbon bonds in a single reaction. The relationship between these reactions and an approach to the quassinoid family of natural products is also described.

Preparation of a protected phosphoramidon precursor via an H-phosphonate coupling strategy.

The preparation of a phosphoramidon precursor is described using a phosphorus(III) coupling protocol.