Steven L. Castle

Total Synthesis of (−)-Acutumine

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

Enantioselective Total Synthesis of (−)-Acutumine

An account of the total synthesis of the tetracyclic alkaloid (-)-acutumine is presented. A first-generation approach to the spirocyclic subunit was unsuccessful as a result of incorrect regioselectivity in a radical cyclization. However, this work spawned a second-generation strategy in which the spirocycle was fashioned via a radical-polar crossover reaction. This process merged an intramolecular radical conjugate addition with an enolate hydroxylation and created two stereocenters with excellent diastereoselectivity. The reaction was promoted by irradiation with a sunlamp, and a ditin reagent was required for aryl radical formation. These facts suggest that the substrate may function as a sensitizer, thereby facilitating homolytic cleavage of the ditin reagent. The propellane motif of the target was then installed via annulation of a pyrrolidine ring onto the spirocycle. The sequence of reactions used included a phenolic oxidation, an asymmetric ketone allylation mediated by Nakamuras chiral allylzinc reagent, an anionic oxy-Cope rearrangement, a one-pot ozonolysis-reductive amination, and a Lewis acid promoted cyclization of an amine onto an alpha,beta-unsaturated dimethyl ketal. Further studies of the asymmetric ketone allylation demonstrated the ability of the Nakamura reagent to function well in a mismatched situation. A TiCl(4)-catalyzed regioselective methyl enol etherification of a 1,3-diketone completed the synthesis.

Total Synthesis of the Antimitotic Bicyclic Peptide Celogentin C

An account of the total synthesis of celogentin C is presented. A right-to-left synthetic approach to this bicyclic octapeptide was unsuccessful due to an inability to elaborate derivatives of the right-hand ring. In the course of these efforts, it was discovered that the mild Braslau modification of the McFadyen-Stevens reaction offers a useful method of reducing recalcitrant esters to aldehydes. A left-to-right synthetic strategy was then examined. The unusual Leu-Trp side-chain cross-link present in the left-hand macrocycle was fashioned via a three-step sequence comprised of an intermolecular Knoevenagel condensation, a radical conjugate addition, and a SmI(2)-mediated nitro reduction. A subsequent macrolactamization provided the desired ring system. The high yield and concise nature of the left-hand ring synthesis offset the modest diastereoselectivity of the radical conjugate addition. Formation of the Trp-His side-chain linkage characteristic of the right-hand ring was then accomplished by means of an indole-imidazole oxidative coupling. Notably, Pro-OBn was required as an additive in this reaction. Detailed mechanistic investigations indicated that Pro-OBn moderates the concentration of NCS in the reaction mixture, thereby minimizing the production of an undesired dichlorinated byproduct. The natural product was obtained after macrolactamization and deprotection. The chemical shifts of the imidazole hydrogen atoms exhibited significant dependence on temperature, concentration, and pH. Antitumor screening indicated that celogentin C inhibits the growth of some cancer cell lines.

Synthesis of isohasubanan alkaloids via enantioselective ketone allylation and discovery of an unexpected rearrangement.

A synthesis of the hasubanan alkaloids hasubanonine, runanine, and aknadinine via a unified route was attempted. Construction of key phenanthrene intermediates by a Suzuki coupling-Wittig olefination-ring-closing metathesis sequence allowed a convergent and flexible approach. Conversion of the phenanthrenes into the target structures was projected to involve six steps including phenolic oxidation, ketone allylation, anionic oxy-Cope rearrangement, and acid-promoted cyclization. The final step was thwarted by a pinacol-like rearrangement that delivered the unnatural isohasubanan alkaloid skeleton. The structures of the products were established by exhaustive NMR experiments and confirmed by GIAO (13)C NMR calculations of runanine, isorunanine, and three other isomers. These computations revealed some inconsistencies with the benzene solvent correction which suggest that caution should be used in employing this algorithm. The racemic synthesis of isohasubanonine was transformed into an enantioselective synthesis by the discovery that Nakamuras chiral bisoxazoline-ligated allylzinc reagent mediates the enantioselective allylation of ketone 19 in 93% ee. This method could be extended to three other structurally related ketones (92-96% ee), and the enantioselective syntheses of two other isohasubanan alkaloids, isorunanine and isoaknadinine, were accomplished. Racemic isohasubanonine was found to be an ineffective analgesic agent.

Total Synthesis of Celogentin C

The bicyclic octapeptide celogentin C (1, Figure 1) was isolated by Kobayashi and co-workers from the seeds of Celosia argentea.[1] Other structurally similar natural products include the bicyclic peptides moroidin,[2] celogentins A–H,[3] and celogentin J,[3] as well as the monocyclic peptides celogentin K[4] and stephanotic acid.[5] Some of these compounds inhibit tubulin polymerization,[6] with 1 ranking as the most potent antimitotic agent of this natural product family. The unusual structure of 1 is derived from two cross-links between amino acid side chains. A bond between the leucine β-carbon atom and the indole C6 of tryptophan forms the left-hand ring of 1, whereas the right-hand macrocycle contains a C–N linkage between the indole C2 and the imidazole N1. The resultant heterobiaryl axis introduces the potential of atropisomer stereochemistry. The combination of useful biological activity and intriguing architecture has prompted numerous synthetic efforts targeting 1 and related compounds.[7–10] However, a total synthesis of one of the bicyclic members of the celogentin family has not yet been reported.[11] Herein, we describe our efforts which have culminated in the synthesis of celogentin C.

Second-Generation DBFOX Ligands for the Synthesis of β-Substituted α-Amino Acids via Enantioselective Radical Conjugate Additions

A set of second-generation DBFOX ligands possessing extended aryl or benzyl-type groups was synthesized. The requisite amino alcohols were either commercially available (DBFOX/Bn) or constructed via Sharpless asymmetric aminohydroxylation (DBFOX/Nap, DBFOX/ t-BuPh, DBFOX/Pip) or phase-transfer-catalyzed asymmetric alkylation (DBFOX/MeNap). Complexes of the ligands with Mg(NTf2)2 were evaluated as promoters of enantioselective radical conjugate additions to alpha,beta-unsaturated alpha-nitro amides and esters. Reactions employing the DBFOX/Nap ligand exhibited improved enantioselectivity relative to previously published additions mediated by DBFOX/Ph. However, the relatively modest increase in diastereomeric ratio suggests that our substrate-Lewis acid binding model, which was formulated based on results from DBFOX/Ph-promoted radical conjugate additions, is in need of revision.

Regioselective Base-Free Intermolecular Aminohydroxylations of Hindered and Functionalized Alkenes

Regioselective base-free intermolecular aminohydroxylations of functionalized trisubstituted and 1,1-disubstituted alkenes employing benzoyloxycarbamate 3a and catalytic OsO(4) 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.

Stereoselective Additions of Thiyl Radicals to Terminal Ynamides

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

Thermal atropisomerism of fully functionalized vancomycin CD, DE, and CDE ring systems

Abstract A study of the thermal atropisomerism of fully functionalized vancomycin CD, DE and CDE ring systems is detailed. The studies suggested and resulted in the realization of a selective DE ring system atropisomerism of a fully functionalized vancomycin CDE ring system, offering a unique solution to the control of natural product atropisomer stereochemistry.

Microwave-Promoted Tin-Free Iminyl Radical Cyclization with TEMPO Trapping: A Practical Synthesis of 2-Acylpyrroles

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.