Synthesis of the Indolizidine Core of Virosinine A via a Microwave-Promoted Cascade Cyclization Involving Iminyl Radicals.

The indolizidine core of virosinine A was synthesized by means of a microwave-promoted cascade reaction featuring 5-- iminyl radical cyclization, thiyl radical elimination, and intramolecular imine alkylation. The resulting bicyclic iminium ion underwent stereoselective reduction by Red-Al to deliver the target compound. DFT calculations suggested that both the radical cyclization and thiyl radical elimination steps are reversible at high reaction temperatures.

Formal γ-C(sp)-H Activation of Ketones via Microwave-Promoted and Iminyl-Radical-Mediated 1,5-Hydrogen Atom Transfer.

Microwave irradiation of -phenyloximes triggers N-O homolysis and 1,5-hydrogen atom transfer (HAT), resulting in formal γ-C-H functionalization of ketones after trapping of the radical intermediate and imine hydrolysis. The Lewis acid InCl·HO facilitated HAT, enabling functionalization of benzylic and nonbenzylic secondary carbon atoms. Functionalization of primary carbons was feasible but afforded low yields, requiring ClCHCOH instead of InCl·HO as an additive.

Microwave- and Thermally Promoted Iminyl Radical Cyclizations: A Versatile Method for the Synthesis of Functionalized Pyrrolines.

A detailed study of iminyl radical cyclizations of -aryloximes tethered to alkenes is reported. The reactions can be triggered by either microwave irradiation or conventional heating in an oil bath. A variety of radical traps can be employed, enabling C-C, C-N, C-O, C-S, or C-X bond formation and producing a diverse array of functionalized pyrrolines.

Synthesis and Studies of Bulky Cycloalkyl α,β-Dehydroamino Acids that Enhance Proteolytic Stability.

Three new bulky cycloalkyl α,β-dehydroamino acids (ΔAAs) have been designed and synthesized. Each residue enhances the rigidity of model peptides and their stability to proteolysis, with larger ring sizes exhibiting greater effects. Peptides containing bulky cycloalkyl ΔAAs are inert to conjugate addition by a nucleophilic thiol.

Synthesis and evaluation of potent yaku'amide A analogs.

Two full-length analogs of the anticancer peptide yaku'amide A (1a) and four partial structures have been synthesized. These analogs were identified by computational studies in which the three - and -ΔIle residues of the natural product were replaced by the more accessible dehydroamino acids ΔVal and ΔEnv. Of the eight possible analogs, modeling showed that the targeted structures 2a and 2b most closely resembled the three-dimensional structure of 1a.

Towards a streamlined synthesis of peptides containing α,β-dehydroamino acids.

Investigation of a strategy to streamline the synthesis of peptides containing α,β-dehydroamino acids (ΔAAs) is reported. The key step involves generating the alkene moiety elimination of a suitable precursor after it has been inserted into a peptide chain. This process obviates the need to prepare ΔAA-containing azlactone dipeptides to facilitate coupling of these residues.

Synthesis of Functionalized Pyrrolines via Microwave-Promoted Iminyl Radical Cyclizations.

-Phenyloximes tethered to alkenes undergo 5-- iminyl radical cyclizations upon microwave irradiation. Trapping of the resulting cyclic radicals results in C-C, C-N, C-O, C-S, or C-X bond formation. Allylic sulfides undergo a tandem cyclization-thiyl radical β-elimination, affording terminal alkenes.

Convergent Total Synthesis of Yaku'amide A.

Total synthesis of the anticancer peptide natural product yaku'amide A is reported. Its β-tert-hydroxy amino acids were prepared by regioselective aminohydroxylation involving a chiral mesyloxycarbamate reagent. Stereospecific construction of the E- and Z-ΔIle residues was accomplished through a one-pot reaction featuring anti dehydration, azide reduction, and O→N acyl transfer.

Impact of Dehydroamino Acids on the Structure and Stability of Incipient 3-Helical Peptides.

A comparative study of the impact of small, medium-sized, and bulky α,β-dehydroamino acids (ΔAAs) on the structure and stability of Balaram's incipient 3-helical peptide () is reported. Replacement of the -terminal Aib residue of with a ΔAA afforded peptides - that maintained the 3-helical shape of . In contrast, installation of a ΔAA in place of Aib-3 yielded peptides - that preferred a β-sheet-like conformation.

Insights into base-free OsO-catalyzed aminohydroxylations employing chiral ligands.

Attempts to perform the OsO-catalyzed enantioselective base-free aminohydroxylation of β,β-disubstituted enoates are described. Low yields and racemic products were obtained in the presence of standard chiral ligands, suggesting the occurrence of a "Second Cycle" process due to slow hydrolysis of the amino alcohol product from the Os metal center. Support for this hypothesis was provided by the slightly improved enantioselectivity (60:40 er) obtained with an amino alcohol ligand.

Continuous flow synthesis of diaryl ketones by coupling of aryl Grignard reagents with acyl chlorides under mild conditions in the ecofriendly solvent 2-methyltetrahydrofuran.

An efficient continuous flow sequential synthesis of diaryl ketones was achieved by coupling of aryl Grignard reagents with acyl chlorides in the bio-derived "green" solvent 2-methyltetrahydrofuran (2-MeTHF) under mild reaction conditions (ambient temperature, 1 hour), allowing a safe and on-demand generation of 2-(3-benzoylphenyl)propionitrile with a productivity of 3.16 g hour.

Synthesis of Functionalized Nitriles by Microwave-Promoted Fragmentations of Cyclic Iminyl Radicals.

The synthesis of functionalized nitriles via microwave-promoted radical fragmentations of cyclic O-phenyl oxime ethers is reported. A variety of radical traps can be employed, permitting the generation of diverse adducts via C-O, C-C, C-N, or C-X bond formation. Other salient features include a simple and practical protocol, very short reaction times, and the avoidance of metal catalysts and toxic cyanide reagents.

Bulky Dehydroamino Acids Enhance Proteolytic Stability and Folding in β-Hairpin Peptides.

The bulky dehydroamino acids dehydrovaline (ΔVal) and dehydroethylnorvaline (ΔEnv) can be inserted into the turn regions of β-hairpin peptides without altering their secondary structures. These residues increase proteolytic stability, with ΔVal at the (i + 1) position having the most substantial impact. Additionally, a bulky dehydroamino acid can be paired with a d-amino acid (i.

The antioxidant properties of salicylate derivatives: A possible new mechanism of anti-inflammatory activity.

The synthesis and antioxidant evaluation by DPPH scavenging of a series of salicylic acid derivatives is described. Gentisic acid and its ester, amide, and amino analogs possess more radical scavenging capacity than salicylic acid and other salicylate derivatives. This property can possibly provide an additional pathway for anti-inflammatory activity through either single electron or hydrogen atom transfer, leading to a new strategy for the design of anti-inflammatory agents.

Microwave-promoted tin-free iminyl radical cyclization with TEMPO trapping: a practical synthesis of 2-acylpyrroles.

Microwave-promoted iminyl radical cyclizations can be terminated by trapping with TEMPO, affording functionalized adducts. The use of alkynes as radical acceptors delivers a range of 2-acylpyrroles in good yields. Toxic and hazardous reagents, which are frequently employed in radical reactions, are not required.

Selective access to E- and Z-ΔIle-containing peptides via a stereospecific E2 dehydration and an O → N acyl transfer.

A concise synthesis of peptides that contain E- or Z-dehydroisoleucine (ΔIle) residues is reported. The key reaction is an unusual anti dehydration of β-tert-hydroxy amino acid derivatives that is mediated by the Martin sulfurane. A subsequent tandem Staudinger reduction-O → N acyl transfer process forges an amide bond to the ΔIle residue with minimal E/Z alkene isomerization.

Total synthesis of the congested propellane alkaloid (-)-acutumine.

The enantioselective total synthesis of (-)-acutumine is described. The synthetic strategy was inspired by the premise that the cyclohexenone ring could be derived from an aromatic precursor. After successful construction of a propellane model system, an initial attempt to prepare the spirocyclic subunit was thwarted by incorrect regioselectivity in a radical cyclization.

Exploration of an epoxidation-ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement.

In the context of synthetic efforts targeting the alkaloid lyconadin A, scalemic epoxide 25 was prepared by a highly stereoselective sequence involving a Myers alkylation and a Shi epoxidation. Ring-opening of this epoxide with a vinylcopper complex afforded alcohol 26 instead of the expected product 27. An unusual Lewis acid promoted Payne rearrangement of an α-trityloxy epoxide is proposed to account for this outcome.

Diastereoselective synthesis of vicinal tertiary diols.

A strategy for the synthesis of differentiated vicinal tertiary diols is described. The key step is a high-yielding, diastereoselective LaCl3·2LiCl-mediated addition of a Grignard or organolithium reagent to ketone 2a. The reaction is believed to proceed via a 1,3-chelated intermediate.

Regioselective base-free intermolecular aminohydroxylations of hindered and functionalized alkenes.

Regioselective base-free intermolecular aminohydroxylations of functionalized trisubstituted and 1,1-disubstituted alkenes employing benzoyloxycarbamate 3a and catalytic OsO(4) are described. In all cases, the more substituted alcohol isomer is favored. Sluggish reactions could be promoted by gentle heating, the use of amine ligands, or increased catalyst loadings.

Experimental and theoretical investigation of the scope of enantioselective ketone allylations employing Nakamura's allylzinc-bisoxazoline reagent.

The scope of enantioselective allylations employing Nakamura's allylzinc-bisoxazoline reagent was examined by performing allylations of a selection of readily available ketones. Low-to-moderate ee's were observed, and a computational study was conducted to rationalize the results. Examination of transition structures of previously performed allylations that proceeded with high ee revealed the importance of both local and global control elements in these successful reactions.

Stereoselective additions of thiyl radicals to terminal ynamides.

Two complementary sets of conditions for radical additions of thiols to terminal ynamides are described. The use of 1 equiv of thiol affords the cis-beta-thioenamide adducts in rapid fashion (10 min) and good dr, whereas employing excess thiol and longer reaction times favors the trans products.