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.e., d-Pro) to synergistically enhance resistance to proteolysis. A link between proteolytic stability and peptide structure is established by the finding that a stabilized ΔVal-containing β-hairpin is more highly folded than its Asn-containing congener.

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. The O-phenyl oxime ether substrates are constructed in a single step from readily available ketones.

A method of incorporating bulky α,β-dehydroamino acids such as dehydrovaline and dehydroethylnorvaline into peptides via solid-phase peptide synthesis is reported. The key step involves ring opening of an azlactone (i.e., oxazolone) containing the dehydroamino acid by the amino group of a resin-bound peptide. The use of Alloc-protected azlactones was key to the success of the process.

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.

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. Density functional calculations attribute the stereospecific dehydration to a highly asynchronous E2 anti process.

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. One of the adducts has been transformed into a functionalized cyclopentenone resembling the core structure of pactamycin.

Regioselective base-free intermolecular aminohydroxylations of functionalized trisubstituted and 1,1-disubstituted alkenes employing benzoyloxycarbamate 3a and catalytic OsO4 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. A competitive rearrangement was observed with a secondary allylic alcohol substrate. The adducts serve as useful precursors to dehydroamino acids.

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. The ability of density functional theory methods to estimate the enantioselectivity of these asymmetric ketone allylations was established. All allylations that were studied computationally exhibited low (<5 kcal/mol) activation barriers, a result that is consistent with the highly reactive nature of Nakamura’s reagent.An investigation of the scope of enantioselective ketone allylations employing Nakamura’s chiral allylzinc–bisoxazoline reagent is described, along with the development of a theoretical model to explain the results.

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-β-thioenamide adducts in rapid fashion (10 min) and good dr, whereas employing excess thiol and longer reaction times favors the trans products.

The first total synthesis of the tetracyclic alkaloid (−)-acutumine is described. Key reactions include an asymmetric ketone allylation mediated by Nakamura’s chiral allylzinc reagent, an anionic oxy-Cope rearrangement, and the Lewis acid-promoted cyclization of an amine onto an α,β-unsaturated dimethyl ketal.