Studies toward the Synthesis of Palhinine Lycopodium Alkaloids: A Morita–Baylis–Hillman/Intramolecular Diels–Alder Approach

A synthetic route to the isotwistane core of palhinine lycopodium alkaloids is described. A Morita–Baylis–Hillman/intramolecular Diels–Alder (IMDA) strategy sets the vicinal all-carbon quaternary centers present in this family of natural products. The regioselectivity of the IMDA reaction is dictated by the conditions employed for silyl enol ether formation, with one set of conditions providing the core of cardionine and alternate conditions generating the desired isotwistane core of isopalhinine

Determination of the Absolute Configuration of Cyclic Amines with Bode’s Chiral Hydroxamic Esters Using the Competing Enantioselective Conversion Method

The competing enantioselective conversion (CEC) strategy has been extended to cyclic amines. The basis for the CEC approach is the use of two complementary, enantioselective reactions to determine the configuration of the enantiopure substrate. Bode’s chiral acylated hydroxamic acids are very effective enantioselective acylating agents for a variety of amines. Pseudoenantiomers of these acyl-transfer reagents were prepared and demonstrated to react with enantiopure cyclic amines with modest to high selectivity. The products were analyzed by ESI-MS to determine selectivity, and the results were used to assign the configuration of the amine substrate. The method was applicable to a variety of cyclic amines as well as primary amines and acyclic secondary amines. The method is limited to amines that are unhindered enough to react with the reagents, and not all amine substitution patters lead to high selectivity

Generation, Stability, and Utility of Lithium 4,4′-Di-<i>tert</i>-butyl­biphenylide (LiDBB)

Several procedures were evaluated for the preparation of lithium 4,4′-di-<i>tert</i>-butyl­biphenylide (LiDBB, Freeman’s reagent) from lithium metal and 4,4′-di-<i>tert</i>-butyl­biphenyl (DBB) in THF. Solutions with nominal concentration of 0.4 and 1.0 M were formed. The stability of LiDBB solutions was evaluated over time, and the gradual uptake of lithium metal was observed. At 0 °C the LiDBB solutions were stable for over a week in THF. At 20 °C the LiDBB solution underwent various decomposition pathways, which led to uptake of more lithium metal and the accumulation of side products. These decomposition pathways were studied, and the importance of ethene in the destruction of THF by LiDBB was observed. On a practical note, LiDBB solutions in THF were stable and effective for over a week at 0 °C or for more than 37 weeks when stored under argon at −25 °C. These observations will extend the utility of LiDBB as a reagent in organic synthesis

Stereoselection in Intramolecular Diels–Alder Reactions of 2‑Cyano-1-azadienes: Indolizidine and Quinolizidine Synthesis

Progress toward understanding the scope and diastereoselectivity of intramolecular Diels–Alder reactions using 2-cyano-1-azadienes is described herein. The resulting cyanoenamine products are underutilized intermediates in organic synthesis. Assembly of the Diels–Alder precursors was achieved using an improved imine condensation/oxidative cyanation protocol. By this method, several highly substituted indolizidine and quinolizidine architectures were constructed. Quantum mechanical DFT calculations at the B3LYP/6-31+G­(d) level of theory were performed for these cyclizations and provide insights into the origins of the observed diastereoselectivities

Absolute Configuration of Lactams and Oxazolidinones Using Kinetic Resolution Catalysts

A simple method for determining the absolute configuration of oxazolidinones, lactams, and their derivatives using kinetic resolution catalysts is described. The optically pure substrates were acylated using the (<i>S</i>)-HBTM and the (<i>R</i>)-HBTM catalyst, and the faster reaction was determined. An empirical mnemonic was developed for the assignment of the absolute configuration based on the fast-reacting catalyst

Trianion Synthon Approach to Spirocyclic Heterocycles

A variety of spirocyclic heterocycles have been constructed by a double-alkylation and reductive cyclization approach utilizing α-heteroatom nitriles as trianion synthons. The method provides access to heteroatom-substituted spirocycles in a variety of ring sizes that are found in natural products and are important in pharmaceutical lead development and optimization

Route to Highly Substituted Pyridines

Pyridine rings are common structural motifs found in a number of biologically active compounds, including some top-selling pharmaceuticals. We have developed a new approach to access substituted pyridines. The method aims to provide a reliable synthesis of a diverse range of substituted pyridines through a three-step procedure. Readily available enones are first converted into 1,5-dicarbonyls through a two-step Hosomi–Sakurai allylation/oxidative cleavage sequence, which is followed by subsequent cyclization to the corresponding pyridine using hydroxylamine hydrochloride. A variety of substituted pyridines have been synthesized using this method

Heteroatom-Directed Acylation of Secondary Alcohols To Assign Absolute Configuration

Birman’s HBTM catalyst is effective for the enantioselective acylation and kinetic resolution of benzylic secondary alcohols. The enantioselective acylation has now been extended to secondary alcohols bearing electron-withdrawing groups such as halides and other heteroatoms. The level of selectivity is modest to good and is sufficient for determining configuration using the competing enantioselective conversion method. A mathematical analysis identifies conditions for achieving maximum differences in conversion and, consequently, assigning configuration with greater confidence. The new method is effective for halohydrins and secondary–tertiary 1,2-diols and was used to confirm the configuration of two inoterpene natural products

Formation of Highly Substituted Tetrahydropyranones: Application to the Total Synthesis of Cyanolide A

A new tetrahydropyranone synthesis has been developed that leads to cis-2,6-disubstituted 3,3-dimethyltetrahydropyran-4-one rings by condensation of an aldehyde and a hydroxy silyl enol ether. The reaction works with a variety of aldehydes to produce the tetrahydropyranone products in moderate to high yields. This new method was applied to the enantioselective synthesis of cyanolide A and its aglycone

Nanomole-Scale Assignment of Configuration for Primary Amines Using a Kinetic Resolution Strategy

The absolute configurations of primary amines were assigned using a kinetic resolution strategy with Mioskowski’s enantioselective <b>1</b>-(<i>R</i>,<i>R</i>) and <b>2</b>-(<i>S</i>,<i>S</i>) acylating agents. A simple mnemonic was developed to determine the configuration. A pseudoenantiomeric pair of reagents, <b>1</b>-(<i>R</i>,<i>R</i>) and <b>2</b>-(<i>S</i>,<i>S</i>)-<i>d</i>₃, was prepared and used to assay primary amines on a micromolar scale. The ESI-MS readout of the resulting acetamide products reproduced the selectivity factors from kinetic experiments. The method can be used on mixtures of amines and was validated with amine samples as small as 50 nmol