Jeremy A. May

Biomimetic approach to communesin B (a.k.a. nomofungin)

The development of an approach to the alkaloid communesin B (2) is presented. The approach is based on considerations of a possible biosynthetic sequence involving an oxidative coupling of tryptamine with a derivative of the ergot alkaloid aurantioclavine. Structure revision is also suggested for the recently isolated microfilament disrupting alkaloid nomofungin.

Synthesis of Bridged Polycyclic Ring Systems via Carbene Cascades Terminating in C–H Bond Insertion

A carbene cascade reaction that constructs functionalized bridged bicyclic systems from alkynyl diazoesters is presented. The cascade proceeds through diazo decomposition, carbene/alkyne metathesis, and C-H bond insertion. The diazoesters are easily synthesized from cyclic ketones. Substrate ring size and substitution patterns control the connectivity and diastereomeric preference found in the products.

Biomimetic synthesis of the antimalarial flindersial alkaloids.

A biomimetic strategy for the synthesis of the antimalarial flindersial alkaloids is described. Flinderoles A, B, and C, desmethylflinderole C, isoborreverine, and dimethylisoborreverine were all synthesized in three steps from tryptamine. The key step is an acid-promoted dimerization of the natural product borrerine. This approach is thought to mirror the biosynthesis of these compounds.

A diastereodivergent synthetic strategy for the syntheses of communesin F and perophoramidine.

An efficient, unified, and stereodivergent approach toward communesin F and perophoramidine was examined. The C(3) all-carbon quaternary center of an oxindole was smoothly constructed by base-promoted indolone-malonate alkylation chemistry. The complementary relative stereochemistry of the crucial vicinal quaternary centers found in communesin F and perophoramidine was selectively installed by substrate-controlled decarboxylative allylic alkylations.

A General Method for the Enantioselective Synthesis of α-Chiral Heterocycles

The enantioselective formation of stereocenters proximal to unprotected heterocycles has been accomplished. Thus, vinyl boronic acids are added to heterocycle-appended enones via a modified-BINOL catalyst. Catalyst design was key to enable a general reaction. High yields and useful ers are observed for a host of common heteroaryls.

Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine

Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Additionally, several novel and interesting intermediates en route to the target natural products, such as an intriguing propellane hexacyclic oxindole encountered in the communesin F sequence, are disclosed. Indeed, such unanticipated structures may prove to be convenient strategic intermediates in future syntheses.

Molecular recognition of arginine in small peptides by supramolecular complexation with dibenzo-30-crown-10 ether

Abstract The protonated, alkyl-guanidinium side chain of arginine forms a stable noncovalently bound complex with dibenzo-30-crown-10 (DB30C10) in the gas phase. This gas phase adduct is detected through the use of electrospray ionization mass spectrometry (ESI-MS). The supramolecular complex is stabilized by extensive hydrogen bonding and ion–dipole interactions between the protonated guanidinium group and the 10 oxygen atoms present in DB30C10. Competitive collision induced dissociation (CID) experiments demonstrate that DB30C10 possesses a higher affinity for alkyl-guanidinium ions than the related compound 27-crown-9 (27C9). This is attributed to the smaller size of 27C9, which does not afford extra space to accommodate the alkyl portion of the side chain of arginine. Recent experiments in our laboratory have demonstrated the molecular recognition and quantification of lysine residues in small peptides through the formation of 18-crown-6 (18C6) adducts. The molecular recognition capabilities of 18C6 and DB30C10 are mutually compatible and can be utilized to determine whether a peptide contains arginine or lysine (or both) without any prior knowledge of the peptide sequence. Competitive CID experiments demonstrate that the DB30C10/arginine interaction is stronger than the 18C6/lysine interaction when they are attached to the same peptide. In contrast to the behavior observed for 18C6 interacting with lysine containing peptides, multiple adducts of DB30C10 with a peptide containing multiple arginine residues are not observed in great abundance, limiting the utility of DB30C10 for the quantification of arginine residues.

Biomimetic approaches to gas phase peptide chemistry: combining selective binding motifs with reactive carbene precursors to form molecular mousetraps

Abstract Biomimetic reagents capable of selectively forming non-covalent complexes and initiating intermolecular reactions with peptides in the gas phase are presented. In the present work, 18-crown-6 ether (18C6) is utilized to bind specifically to various protonated primary amines, including the protonated side chain of lysine. The use of multiple crown ethers is shown to be an efficient method for enhancing the binding energy, which is a critical factor influencing the success of these reagents. The binding energy must exceed any reaction barriers to the desired chemistry, otherwise simple dissociation of the complex occurs. Two reagents containing acidic and transition metal binding functionalities, respectively, designed to selectively cleave peptide bonds, are synthesized and tested experimentally. A third class of reagent designed to covalently attach to peptides utilizing carbene insertion chemistry is also presented. The results demonstrate that combining the recognition and binding powers of 18C6 with an easily activated diazo group allows for the efficient generation of a highly reactive carbene within a non-covalent complex. Intermolecular insertion reactions initiated by the carbene can transform these non-covalent complexes into covalently bound molecules. Electrospray ionization mass spectrometry and density functional theory (DFT) are utilized to evaluate these intermolecular insertion reactions. The results from experiments with several small molecules and peptides are presented. These diazo-based reagents prove to be highly versatile molecules capable of binding to, and with appropriate activation, becoming covalently attached to virtually any molecule that contains a primary amine. For this reason, we have dubbed them “molecular mousetraps.”

Hydrazone-initiated carbene/alkyne cascades to form polycyclic products: ring-fused cyclopropenes as mechanistic intermediates.

A hydrazone-based carbene/alkyne cascade produced a variety of bridged and fused polycyclic products. NaOSiMe3 is a superior base for conversion of hydrazones to diazoalkanes. A key mechanistic intermediate, a ring-fused cyclopropene, has been isolated and characterized.

Organocatalyzed Asymmetric Conjugate Addition of Heteroaryl and Aryl Trifluoroborates: a Synthetic Strategy for Discoipyrrole D†

Bis-heteroaryl or bis-aryl stereocenters were formed by an organocatalytic enantioselective conjugate addition using the respective trifluoroborate salts as nucleophiles. Control studies suggested that fluoride dissociation is necessary in the anhydrous conditions. This strategy is applicable to the synthesis of discoipyrrole D, an inhibitor of BR5 fibroblast migration.