Spirodiepoxides are prepared by allene epoxidation, and they in turn are transformed in same-flask procedures to a range of oxygenated stereotriads, heterocycles, and other polyfunctionalized moieties for synthetic applications. The two epoxide rings of SDE’s open in a single cooperative step in the presence of a variety of nucleophilic reagents.
Spirodiepoxide transformations have been used as the key step in a total synthesis of the proteasome inhibitor epoxomicin, and in the formal total synthesis of the potent antitumor agent psymberin, as well as key portions of pectenotoxin and erythronolide A. In each case, a densely functionalized motif was created rapidly and selectively from the three carbons of a precursor allene.
The Thioacid/Azide amidation is the spontaneous reaction of a thiocarboxylate with an azide to afford a peptide linkage. The reaction proceeds in water solution and is effective in non-polar organic solvents and on solid support. Electron-rich azides react by an oxido-accelerated [3+2] cycloaddition, whereas electron poor azides reach the same thiatriazoline intermediate by a stepwise process. This mild coupling procedure has been used to assemble peptides, glycopeptides, N-acylsulfonamides, and other amide conjugates.
Other projects include mechanistic studies, new methods and for the synthesis of carbinolamides and allenes, the use of macrocyclic, silyl substitution, and reagent control for the stereoselective formation of SDEs, and natural product total synthesis.
Brief Overview of Published Work
Spirodiepoxides and Natural Product Synthesis
Spirodiepoxides in Total Synthesis: Epoxomicin [J. Am. Chem. Soc. 2004, 126, 15348-15349.]
This report constitutes the first use of the spirodiepoxide functional group in total synthesis, specifically a study that culminated in an efficient synthesis of the potent proteasome inhibitor epoxomicin. Spirodiepoxides are shown to give as the major product of nucleophilic opening syn disubstituted ketones and their derivatives, including orthoester, oxazoline, azido epoxide, as well as sulfonamide-, amide-, and azide-containing hydroxy ketones.
Spirodiepoxide Reaction with Cuprates [J. Am. Chem. Soc. 2007, 129, 2438-2429.]
This report describes the first examples of transition metal-mediated transformations of spirodiepoxides and the first general method for carbon-carbon bond formation using the spirodiepoxide functional group. Organocopper-mediated addition to spirodiepoxides gives direct access to densely functionalized hydroxy ketones. The process establishes two noncontiguous stereocenters, installs two oxygen atoms, and a new carbon substituent. The utility of the methodology was demonstrated by preparing the stereotetrad of erythromycin in a short, efficient, and stereoselective route.
A Spirodiepoxide-Based Strategy to the A-B Ring System of Pectenotoxin 4 [Org. Lett. 2007, 9, 869-873.]
This report describes the synthesis of the pectenotoxin 4 C1-C15 segment. Suitable C1-C7 and C8-C15 segments were prepared, coupled, converted to I and the C3-hydroxy variant, and then cyclized. Key findings include the stereoselective conversion of the allene to the corresponding spirodiepoxide, oxidative cleavage of the p-methoxybenzyl ether, and cyclization of the spirodiepoxide to spiroketal II in a one-flask transformation.
Synthesis of the C21-C28 Segment of Pectenotoxin 4 [Tetrahedron Lett. 2007, 48, 4761-4764. ]
This report describes part of our synthetic studies towards the pectenotoxins, specifically the synthesis of the C21-C28 segment of pectenotoxin-4 as the C21 Weinreb amide. Feasibility studies for the union of a related Weinreb amide and a functionalized alkyne are also reported.
Configuration of the Psymberin Amide Side-Chain [Org. Lett. 2005, 7, 2905-2908.]
This report proposed the first full structural assignment of psymberin, a potent and selective cytotoxin. Syn and anti models of the amide side chain were prepared. The structures were confirmed by x-ray crystallographic analysis of the anti isomer. Comparison of 1H and 13C NMR data established homology between the natural product and the synthetic model compound of anti configuration and not the corresponding syn isomer.
A Formal Synthesis of Psymberin [Org. Lett. 2007, 9, 1093-1096.]
This report describes a formal synthesis of psymberin. Key findings include the chemo, regio, and stereoselective oxidation of a 1,3-disubstituted allene, a configuration-dependent spirodiepoxide opening, the efficient syntheses of functionalized trans-2,6-disubstituted pyrans, and the union of a highly functionalized aldehyde with a pentasubstituted aryl homoenolate to give a dihydroisocumarin.
Spirodiepoxides: Heterocycle Synthesis and Mechanistic Insight [Angew. Chem. Int. Ed. Engl. 2007, 46, 15]
This disclosure describes the formation of heterocycles from the reaction of spirodiepoxides with amide, amidine, and thioamide, the first crystal structure of a spirodiepoxide, and a new mechanistic framework for spirodiepoxide opening. Nucleophilic spirodiepoxide opening is rationalized in terms of a reactivity continuum that involves the concerted, asynchronous opening of both epoxides. This process is facilitated by coordination to the oxygen destined to become the hydroxyl.
Thio Acid/Azide Amidation
The reaction of Thio Acids with Azides: A New Mechanism and New Synthetic Applications [J. Am. Chem. Soc. 2003, 125, 7754-7755.]
Disclosed in this report is a new amide synthesis strategy based on a fundamental mechanistic revision of the reaction of thio acids and organic azides. The data demonstrate that amines are not formed as intermediates in this reaction. Alternative mechanisms proceeding through a thiatriazoline intermediate are suggested. The reaction has been applied to the preparation of simple and architecturally complex amides that are difficult to access using conventional methods. The reaction is chemoselective, effective for unprotected substrates, and compatible with aprotic and protic solvents, including water.
Thioamides via Thiatriazolines [Tetrahedron Lett. 2006, 47, 1163-1166.]
This report describes a method for thioamide formation from dithioacids and azides. A remarkable base-dependence of the reaction is described. A mechanistic framework that involves the step-wise formation of a thiatriazoline intermediate is presented to account for the reported observations.
Thio Acid/Azide Amidation: An Improved Route to N-Acyl Sulfonamides [Org. Lett. 2006, 8, 823-826.]
This report describes a one-pot procedure for the conversion of carboxylic acids to N-acyl sulfonamides, via thio acid/azide amidation. The method is compatible with acid and base sensitive amino acid protection. Also demonstrated was N-acyl sulfonamide synthesis on solid support, peptide thio acid/sulfonazide coupling, and N-alkyl amide synthesis via selective cleavage of sulfonyl from an N-alkyl-N-acyl sulfonamide.
Mechanism of Thioacid/Azide Amidation [J. Am. Chem. Soc. 2006, 128, 5695-5702.]
This paper describes a combined experimental and computational mechanistic study of amide formation from thio acids and azides. The data support two distinct mechanistic pathways dependent on the electronic character of the azide component. Relatively electron-rich azides undergo bimolecular coupling with thiocarboxylates via an anion-accelerated [3+2] cycloaddition to give a thiatriazoline. Highly electron-poor azides couple via bimolecular union of the terminal nitrogen of the azide with sulfur of the thiocarboxylate to give a linear adduct. Cyclization of this intermediate gives a thiatriazoline. Decomposition to amide is found to proceed via retro-[3+2] cycloaddition of the neutral thiatriazoline intermediates. Computational analysis (DFT, 6-31+G(d)) identified pathways by which both classes of azide undergo [3+2] cycloaddition with thio acid to give thiatriazoline intermediates, although these paths are higher in energy than the thiocarboxylate amidations. These studies also establish that the reaction profile of electron-poor azides is attributable to a prior capture mechanism followed by intramolecular acylation