Andrew M. Harned

Palladium-catalyzed reactions of cyclohexadienones: regioselective cyclizations triggered by alkyne acetoxylation.

Regioselective cyclizations of alkyne-tethered cyclohexadienones can be accomplished under palladium catalysis. The cyclization involves an initial Pd-mediated acetoxylation of the alkyne, followed by migratory insertion and protonolysis of the resulting palladium enolate. The predictable regioselectivity of these atom-economical and stereoselective reactions is influenced by developing steric interactions during migratory insertion of a vinyl palladium intermediate.

A dual metathesis route to oligomeric sulfonamides

Abstract A strategy employing both ring-closing metathesis (RCM) and ring-opening metathesis polymerization (ROMP) as routes to synthesizing oligomeric sulfonamides is described. Amino acid-derived α,β-unsaturated γ-sultams, containing either exo-cyclic or γ-endo-cyclic stereogenic centers, are generated via RCM. These sultams undergo stereoselective Diels–Alder reactions to yield endo-norbornenyl sulfonamides as the major diastereomers. Subsequent ROMP rapidly produces sulfonamide-based oligomers.

Allene Carboxylates as Dipolarophiles in Rh‐Catalyzed Carbonyl Ylide Cycloadditions

have recently begun a program aimed at utilizing the unique structural features of axially chiral allenes to predictably control the stereochemical outcome of cycloaddition reactions as the key step in the synthesis of various natural products. We are particularly interested in cycloaddition reactions for which catalyst control of stereochemistry would be difficult, either from a mechanistic standpoint or due to substrate instability. Upon scanning the literature we were surprised to find a dearth of examples in which the axial chirality of allenes was employed to control the stereochemical outcome of dipolar cycloadditions (e.g. 1!3). There were also rather limited examples of allenes being used in carbonyl ylide cycloadditions. Herein we report that carboxylate-functionalized allenes can serve as dipolarophiles for carbonyl ylides and that excellent levels of allene facial selectivity can be achieved. Our first task was to determine the feasibility of using electron-deficient allenes as dipolarophiles. To test this we examined the Rh-catalyzed cycloaddition between diazocarbonyl compound 1 a and the achiral allene 2 a (Table 1). Attempting the reaction in CH2Cl2 or 1,2-dichloroethane (DCE) did not result in product formation, even at elevated temperatures (Table 1, entries 1–3). However, running the reaction in refluxing toluene formed 3 and 4 in a 2.5:1 diastereomeric ratio (Table 1, entry 4). Gratifyingly, the two diastereomers could be separated and their identity was determined by the magnitude of the allylic coupling constants. Running the reaction in benzene resulted in a slightly diminished yield with no dramatic improvement on

A concise synthetic approach to the sorbicillactones: total synthesis of sorbicillactone A and 9-epi-sorbicillactone A.

A concise (12 step) total synthesis of sorbicillactone A and 9-epi-sorbicillactone A is reported. Unlike typical routes to the sorbicillinoids, this strategy does not start from sorbicillin and allows for the production of the bicyclic core on a multigram scale. The intramolecular conjugate addition of a tethered malonate serves as an effective means of introducing the lactone ring and provides a synthetic handle for installing the amide nitrogen.

A Concise Synthetic Route to the Stereotetrad Core of the Briarane Diterpenoids

A concise synthesis (under 10 steps) of the stereotetrad core of the briarane diterpenoids is reported. This approach harnesses the unique reactivity of salicylate ester derived 2,5-cyclohexadienones to quickly build complexity. In particular, a highly diastereoselective acetylide conjugate addition/β-ketoester alkylation sequence was used to set the relative configuration of the C1 (quaternary) and C10 (tertiary) vicinal stereocenters. The sterochemical outcome of the β-ketoester alkylation appears to be governed by torsional steering in the transition state.

Origin of Stereoselectivity of the Alkylation of Cyclohexadienone-Derived Bicyclic Malonates

The diastereoselectivity of the alkylation of bicyclic malonates has been studied experimentally and computationally. In accordance with previous observations during a total synthesis of sorbicillactone A, alkylations involving methyl iodide proceed from the concave (endo) face of the bicyclo[4.3.0]nonene ring system. In contrast, carbon-based electrophiles larger than methyl iodide approach from the convex (exo) face. Computational studies using M06-2X and B3LYP methods have revealed that the observed stereoselectivity is explained by subtle energetic differences between a staggered transition state with less torsional strain and unfavorable steric interactions with the cyclohexenone ring. Using this model as a guide, hydrogenation of the C-C double bond was used to alter the steric environment of the substrate. As expected, this led to a reversal in the diastereoselectivity during the alkylation with methyl iodide.

Total Synthesis of Sorbicillactone A

Abstract This account describes the development of a synthetic route to sorbicillactone A. This natural product is a member of the sorbicillinoid family but is unusual in that an amino acid, in this case alanine, has been incorporated into its structure. This feature, along with a desire to use the bicyclic core of sorbicillactone A as a scaffold for library synthesis, required a synthetic approach that is atypical of those generally used for accessing other members of the sorbicillinoid family. The core structure was constructed using a regioselective conjugate addition of a malonate-tethered cyclohexadienone. Alkylation of the resulting bicyclic lactone involved approach of the electrophile from an unexpected direction relative to the bicyclic ring. Subsequent DFT calculations revealed that minimization of torsional strain was responsible for the observed stereoselectivity. Despite the strong substrate control observed during this alkylation, an efficient synthesis of the target molecule could be achieved.

Ring-Opening Metathesis Polymerization Approach to Phosphorus-Containing Biooligomers

Naturally occurring biopolymers (peptides, oligonucleotides, and proteins) are, in theory, excellent drug candidates. However, their poor bioavailability profiles limit their use as potential therapeutic agents. In order to address this problem, the synthesis of diverse polymers consisting of unnatural subunits has emerged as a powerful means of constructing new scaffolds with potentially useful pharmaceutical properties. This approach has recently been applied in the synthesis of peptidosulfonamides,1 cyclic urea scaffolds,2 peptide nucleic acid-based (PNA) pseudopeptides,3,4 ethoxyformacetal oligomers,5 pyrrolin-4-onebased motifs as mimics of peptidal β-strands,6 and peptidomimetic oligomers with a phosphodiester backbone.7 Ring-opening metathesis polymerization (ROMP) strategies using the Grubbs benzylidene catalyst to an array of functionalized biopolymers containing phosphorus and sulfur are discussed. The synthesis of phosphorus and sulfur containing biooligomers utilizing maleimidebased monomers has been developed. Subsequent polymerizations were carried out with various monomer:catalyst ratios and the obtained biooligomers were characterized by MALDI-TOF analysis. A strategy employing both ring-closing metathesis (RCM) reactions and ROMP reactions to derive oligomeric sulfonamides as novel peptidomimetics has also been developed. In addition, our efforts toward the synthesis of cationic, amphiphilic polymers will be presented. These phosphonium contaning polymers show an intriguing reactivity difference between the first generation and second generation Grubbs metathesis catalysts.