Conjugate Addition Of Nitromethane Research Articles

Decoration of A-Ring of a Lupane-Type Triterpenoid with Different Oxygen and Nitrogen Heterocycles.

Betulinic acid (BA) was used as starting building block to create a library of novel BA-derived compounds containing O- and N-heterocycles. Firstly, BA was converted into methyl betulonate (BoOMe), which was used as intermediate in the developed methodologies. 1,2-Oxazine-fused BoOMe compounds were obtained in 12–25% global yields through a Michael addition of nitromethane to methyl (E)-2-benzylidenebetulonate derivatives, followed by nitro group reduction and intramolecular cyclization. Remarkably, the triterpene acts as a diastereoselective inducer in the conjugate addition of nitromethane, originating only one diastereomer out of four possible ones. Furthermore, other oxygen and nitrogen-containing heterocycles were installed at the A-ring of BoOMe, affording 2-amino-3-cyano-4H-pyran-fused BoOMe, diarylpyridine-fused BoOMe and 1,2,3-triazole–BoOMe compounds, using simple and straightforward synthetic methodologies. Finally, BA was revealed to be a versatile starting material, allowing the creation of a molecular diversification of compounds containing a triterpenic scaffold and O- and N-heterocycles.

Organocatalytic Enantioselective Conjugate Addition of Nitromethane to Benzylidene-2-Benzoyl Acetate: Asymmetric Synthesis of ABT - 627, an Endothelin Receptor Antagonist.

First catalytic and enantioselective conjugate addition of nitromethane to benzylidene-2-benzoyl acetate has been developed using dihydroquinine derived squaramide catalyst with moderate to high selectivities. Asymmetric total synthesis of ABT-627, a potent ETA receptor antagonist is accomplished utilizing the developed method in overall 15.7% yield.

Isoprenoid Amide Bisphosphonates As a Novel Class of Geranylgeranyl Diphosphate Synthase Inhibitors

Abstract Multiple myeloma is characterized by the production of monoclonal protein by clonal plasma cells and is a malignancy inherently susceptible to agents that disrupt protein homeostasis. We have previously demonstrated that targeting the geranylgeranylation of Rab GTPases is a novel mechanism by which to induce myeloma cell apoptosis via disruption of intracellular monoclonal protein trafficking and induction of the unfolded protein response pathway. Our previous efforts have focused on the development of novel triazole isoprenoid bisphosphonates as inhibitors of the enzyme geranylgeranyl diphosphate synthase (GGDPS). GGDPS is responsible for the synthesis of the 20-carbon isoprenoid (GGDP) that is utilized in protein geranylgeranylation reactions. Extensive structure-function analysis of the triazole-based inhibitors has revealed that both chain length and olefin stereochemistry have significant impact on inhibitor potency. Previous reports have utilized triazoles as bioisoteres of amides and we hypothesized that the converse might be true as well; namely that amides analogous to the triazoles would have efficacy as GGDPS inhibitors. To this end, we have prepared a number of novel isoprenoid amide bisphosphonates as potential GGDPS inhibitors. These new compounds were prepared from bisphosphonate 1 through a short reaction sequence including chain extension by conjugate addition of nitromethane, reduction to the amine 2, amide formation through reaction with a variety of carboxylic acids, and final hydrolysis of the phosphonate esters to obtain the salts 3. These analogues differed with respect to chain length (ranging from bishomoprenyl- to bishomogeranyl-length), olefin stereochemistry (E vs Z), absence of the proximal olefin (i.e., citronellyl) as well as the stereochemistry of the citronellyl derivatives (R vs S). All of the novel compounds were subjected to in vitro enzyme assays with GGDPS as well as for the related enzymes farnesyl diphosphate synthase, farnesyl transferase and geranylgeranyl transferase I, and IC50's were determined. Cellular activity in human myeloma cell lines (RPMI-8226, MM.1S) was assessed via immunoblot analysis of representative prenylated proteins. In addition, ELISA of intracellular levels of lambda light chain (a marker of disruption of Rab geranylgeranylation) was performed. These studies reveal that similar to the previously reported triazoles, both chain length and olefin stereochemistry have significant effects on GGDPS inhibitory activity. Extending the chain length from the bishomoprenyl length to the bishomogeranyl length increased cellular activity 50-fold: the lowest effective concentration (LEC) is 50 μM for the bishomoprenyl compound and 1 μM for the bishomogeranyl compound. Furthermore, changing the olefin stereochemistry to the bishomoneryl form (i.e., the Z-configuration), further enhanced the potency to an LEC of 0.5 μM. Interestingly, the stereochemistry of the citronellyl derivatives were found to have a significant impact on activity with the R-enantiomer being 10-fold more potent than the S-enantiomer (LEC of 5 μM vs 50 μM respectively). Enzyme assay studies confirmed the specificity of these agents as GGDPS inhibitors. In conclusion, these studies establish a novel family of amide isoprenoid bisphosphonates as GGDPS inhibitors with activity against myeloma cells. Further structure-function analysis will better define the optimal chain length and stereochemistry to maximize potency and enable future in vivo studies assessing efficacy as anti-myeloma therapy. Figure. Figure. Disclosures Wiemer: Terpenoid Therapeutics, Inc: Other: Founder. Holstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Enantioselective synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles from 2-iminochromenes

ABSTRACTA series of medicinally important 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles were synthesized using enantioselective conjugate addition of nitromethane to 2-iminochromenes. The reactions were performed using L8-Cu (II) catalytic system and moderate to good enantioselectivities (62–88%) and yields (66–96%) were obtained.

From Paracetamol to Rolipram and Derivatives: Application of Deacetylation-Diazotation Sequences and Palladium-Catalyzed Matsuda-Heck Reaction

A six-step synthesis of the antidepressant rolipram from the popular analgetic 4-acetamidophenol (paracetamol) is described. The steps include oxidative functionalization of the aromatic core, diazonium salt formation via deacetylation-diazotation, Matsuda–Heck reaction, conjugate addition of nitromethane, and hydrogenative cyclization.

ChemInform Abstract: Organocatalytic 1,4‐Addition Reaction of α,.beta±gamma.,δ‐Diunsaturated Aldehydes versus 1,6‐Addition Reaction.

AbstractThe conjugate addition of nitromethane (II), cyclopentadiene (IV) or nitroethanol (VIII) towards α,β,γ,δ‐unsaturated aldehydes in the presence of a prolinol‐derived organocatalyst proceeds chemoselectively in a 1,4‐addition mode.

ChemInform Abstract: Catalytic Enantioselective Synthesis of β‐Trifluoromethyl Pyrrolines.

AbstractThe first enantioselective synthesis of title compounds (III) and (V) is achieved via conjugate addition of nitromethane (II) to β‐trifluoromethylated enones (I) and (IV), resp., catalyzed by a bifunctional cinchona alkaloid—thiourea derivative, followed by a nitro reduction—cyclization—dehydration sequence in a one‐pot procedure.

ChemInform Abstract: Highly Diastereoselective Michael Addition to 2-Arylidene-1-tetralones Complexed with Cr(CO)3.

Abstract Conjugate addition of nitromethane to 2-arylidene-1-tetralones anchored on Cr(CO) 3 was found to be about 100% stereoselective.

Highly Enantioselective and Regioselective Conjugate Addition of Nitromethane to 1,5-Diarylpenta-2,4-dien-1-ones Using Bifunctional Cinchona Organocatalysts

A general and efficient asymmetric organocatalytic 1,4-Michael addition of nitromethane to 1,5-diarylpenta-2,4-dien-1-ones (cinnamylideneacetophenones) catalyzed by 9-thiourea-9-(deoxy)-epi-hydroquinine has been developed. The reactions afforded excellent enantioselectivities (up to 99%), high yields (up to 97%), and exclusive regioselectivity.

New Nitrilotriacetic Acid and Ethylenediaminetetraacetic Acid Nitro Derivatives for the Synthesis of Bifunctional and Trifunctional Chelating Agents

Dehydration of serine derivatives into didehydroamino acids and subsequent conjugate addition of nitromethane led to novel nitro derivatives of nitrilotriacetic acid and ethylenediaminetetraacetic acid. Straightforward transformations of these compounds allowed the synthesis of bifunctional and trifunctional metal‐chelating agents via an Henry reaction.