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.

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.

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.

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.

Total synthesis of the Lycopodium alkaloid serratezomine A using free radical-mediated vinyl amination to prepare a ß-stannyl enamine linchpin.

Serratezomine A is a member of the structurally diverse class of compounds known as the Lycopodium alkaloids. The key supporting studies and successful total synthesis of serratezomine A are described in this account. Significant features of the synthesis include the first application of free radical mediated vinyl amination and Hwu's oxidative allylation in a total synthesis and an intramolecular lactonization via a transannular S(N)i reaction. Minimal use of protecting groups and the highly diastereoselective formation of a hindered, quaternary stereocenter using an umpolung allylation are also highlights from a strategy perspective. Observation of quaternary carbon epimerization via a retro-Mannich/Mannich sequence highlights the additional challenge presented by the axial alcohol at C8 in serratezomine A.

A sulfone-based strategy for the preparation of 2,4-disubstituted furan derivatives.

2,4-Disubstituted furans are prepared by treating 2,3-dibromo-1-phenylsulfonyl-1-propene (DBP, 2) with 1,3-diketones under basic conditions. The furan-forming step involves a deacetylation, and the selectivity of this process depends upon the steric demand of the R group. The substituent in position 4 is elaborated by reaction of sulfonyl carbanions with alkyl halides, acyl halides, and aldehydes. Oxidative or reductive desulfonylation produces the 2,4-disubstituted furans in 60-92% yield. This strategy has been used to prepare rabdoketone A (12) and the naturally occurring nematotoxic furoic acid 13.

Diastereoselective allylstannane additions to (S)-5,6-dihydro-2H-5-phenyloxazin-2-one. A concise synthesis of (S)-beta-methylisoleucine.

The addition of allyl stannanes to (S)-4,5-dihydro-5-phenyl-2H-oxazinone (3) was achieved under Brønsted acid catalysis to give 2-allylmorpholinones with high diastereoselectivity (up to dr 14.2:1). The product of dimethylallyltributylstannane addition to 3 was converted to l-beta-methylisoleucine, an alpha-amino acid residue found in the complex, biologically active marine-derived peptides polytheonamides A and B, and polydiscamides A-C.

Oxazoline-oxazinone oxidative rearrangement. divergent syntheses of (2S,3S)-4,4,4-trifluorovaline and (2S,4S)-5,5,5-Trifluoroleucine.

Stereoselective syntheses of the valuable fluorinated amino acids (2S,3S)-4,4,4-trifluorovaline and (2S,4S)-5,5,5-trifluoroleucine have been achieved starting from 4,4,4-trifluoro-3-methylbutanoic acid by using a conceptually simple transformation: conversion to a chiral oxazoline, SeO2-promoted oxidative rearrangement to the dihydro-2H-oxazinone, and face-selective hydrogenation of the C=N bond, followed by hydrogenolysis-hydrolysis. The transformation is limited by the tendency of the intermediate beta-trifluoromethyldihydrooxazinone to undergo imine-enamine isomerization. Both amino acids were obtained as configurationally pure hydrochloride salts identical in all respects with those in literature reports.

Total synthesis of the lycopodium alkaloid (+)-serratezomine A.

The first total synthesis of (+)-serratezomine A is described. Key aspects of the synthesis include (a) the first deployment of free-radical-mediated vinyl amination (an intramolecular alkyne aminostannation) in a complex target synthesis, (b) the use of a beta-stannyl enamine as the lynchpin for convergent assembly of the natural product backbone, (c) the use of an oxidative allylation promoted by cerium(IV) (CAN) to establish the all-carbon quaternary chiral center with the proper configuration, and (d) an intramolecular substitution reaction to form the sensitive bridging lactone. Overall, 15 steps (longest linear sequence) are required to prepare the natural product from a commercially available aldehyde, and assembly of the contiguous array of six stereocenters is accomplished with high stereocontrol.