Total Synthesis, Stereochemical Assignment, and Divergent Enantioselective Enzymatic Recognition of Larreatricin.

A concise and efficient total synthesis of the lignan natural product larreatricin as well as an unambiguous assignment of configuration of its enantiomers are reported, resolving a long-held controversy. Enzyme kinetic studies revealed that different polyphenol oxidases show high and remarkably divergent enantioselective recognition of this secondary metabolite.

Influence of Hydrogen-Bonding Interactions on Nuclearity and Structure of Palladium Tiara-like Complexes.

The role of intramolecular hydrogen-bonding interactions upon the nuclearity of palladium tiara-like complexes is reported herein. The synthesis of three palladium tiaras is described with three related thiolate ligands that vary in their hydrogen-bonding capability, amide vs ester for N-acetylcysteamine (tiara 1) vs 2-mercaptoethyl acetate (tiara 2) or ethyl thioglycolate (tiara 3), and in the relative position of the ester group, 2-mercaptoethyl acetate (2) or ethyl thioglycolate (3). Mass spectrometry indicates that, in the absence of protic solvents, N-acetylcysteamine reacts to form exclusively a six-membered tiara, [Pd(SCH2CH2NHCOCH3)2]6, 1, whereas the ester containing analogues form both six- and eight-membered tiaras. Single-crystal X-ray diffraction studies indicate the significance of intramolecular N-H···O hydrogen bonds in determining the nuclearity of the amide-containing tiara 1. NMR studies indicate that 1 is not in equilibrium with larger tiaras in solution, and that the smaller size of the aggregate inhibits the fluxional behavior of the pendant thiolate ligands, typically observed for larger tiaras. Electrochemical investigations of 1 reveal reductive processes that exhibit an increase in current upon addition of acid, along with the formation of palladium nanoparticles.

In pursuit of a competitive target: total synthesis of the antibiotic kendomycin.

Kendomycin is a novel polyketide having a unique quinone methide ansa structure and an impressive biological profile. Herein we provide a chronological overview of the synthetic work towards the title compound. Thus far, over a period of about eight years, eight groups worldwide have published on their synthetic efforts resulting in five total syntheses, one formal synthesis, and a number of fragment syntheses. Most approaches roughly mimic the biogenetic pathway, starting with an aromatic polyphenol subunit to which a polyketide chain is attached. Subsequent key steps include macrocyclization and the formation of the densely substituted tetrahydropyran ring, and then a late-stage oxidation and lactol formation.

Ring-closing metathesis and photo-fries reaction for the construction of the ansamycin antibiotic kendomycin: development of a protecting group free oxidative endgame.

Two convergent total syntheses of the ansa-polyketide (-)-kendomycin (1) are described. The syntheses benefit from the use of readily available and cheap starting materials. Highly complex diastereoselective Claisen-Ireland rearrangements were used to introduce the (E)-double bond and the C16-Me group. The ring closure of the strained ansa macrocycle was achieved by ring-closing metathesis and a highly efficient combination of macrolactonization and photo-Fries reaction. A protecting group free endgame via an unstable o-quinone is presented. Additionally some unsuccessful synthetic efforts towards the total synthesis of 1 are described.

Synthesis of analogue structures of the p-quinone methide moiety of kendomycin.

[reaction: see text] The synthesis of two model p-quinone methide ring systems of the antibiotic and antiosteoporotic compound kendomycin is reported. Two approaches were examined in detail, and the two-step (i) demethylation and (ii) DMDO oxidation were found to be reliable and generally applicable. Additionally, it was found that oxidation of a benzofuran by NaIO(4) on silica produced a long-lived semiquinone radical.

Toward the synthesis of the carbacylic ansa antibiotic kendomycin.

The convergent synthesis of a benzofuran analog of the carbacyclic ansa compound kendomycin has been achieved by assembling three major fragments by means of epoxide opening and directed ortho lithiation. The crucial tetrahydropyran ring was formed by a highly stereoselective cationic cyclization. Analysis of all synthesized tetrahydropyran-arene compounds reveals a hindered sp(2)-sp(3) rotation, which results in rotational isomers or atropisomers affecting macrocyclization reactions. The latter could only be achieved by means of Horner-Wadsworth-Emmons olefination.

New mechanistic studies on the proline-catalyzed aldol reaction.

The mechanism of the proline-catalyzed aldol reaction has stimulated considerable debate, and despite limited experimental data, at least five different mechanisms have been proposed. Complementary to recent theoretical studies we have initiated an experimental program with the goal of clarifying some of the basic mechanistic questions concerning the proline-catalyzed aldol reaction. Here we summarize our discoveries in this area and provide further evidence for the involvement of enamine intermediates.

Lessons learned from macrolide synthesis.

The highlights of three macrolide syntheses recently completed in our laboratory are described. In the epothilone B synthesis we developed the "early epoxide approach," which resulted in the first completely stereocontrolled synthesis of this natural product. In the laulimalide synthesis our contribution was the auxiliary controlled ene-macrocyclization and Sharpless' kinetic resolution for achieving a regioselective epoxidation of two pseudo-enantiomorphic allylic alcohol subunits. The tartrolon B synthesis was the first to be completed. In this case, a substrate controlled aldol addition was used to assemble the entire carbon skeleton of the compound.

A novel approach toward the synthesis of kendomycin: selective synthesis of a C-aryl glycoside as a single atropisomer.

[reaction: see text] A convergent and concise route to an advanced precursor 2b of kendomycin (1) has been developed by applying a S(N)1 ring cyclization as a key step. The resulting C-aryl glycoside was initially isolated as a rotameric mixture, but after MOM protection of the o-hydroxyl of the phenol, the conformation was frozen to the desired kendomycin-like atropisomer.

Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolecular aldol reactions.

Quantum mechanical calculations were employed to predict the ratio of four stereoisomeric products expected from two complex reactions involving the aldol reactions of cyclohexanone with benzaldehyde or with isobutyraldehyde catalyzed by (S)-proline. Experimental tests of these predictions provide an assessment of the state-of-the-art in quantum mechanical prediction of products of complex organic reactions in solution.

The proline-catalyzed direct asymmetric three-component Mannich reaction: scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols.

We have developed proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines. Several of the studied reactions provide beta-amino carbonyl compounds (Mannich products) in excellent enantio-, diastereo-, regio-, and chemoselectivities. The scope of each of the three components and the influence of the catalyst structure on the reaction are described. Reaction conditions have been optimized, and the mechanism and source of asymmetric induction are discussed. We further present application of our reaction to the highly enantioselective synthesis of 1,2-amino alcohols.

Synthesis of the C1-C13 Fragment of Kendomycin: Atropisomerism around a C-Aryl Glycosidic Bond.

The left-hand fragment 2 of the novel antibiotic kendomycin (1) has been synthesized by an aldol addition and a Michael-type 1,4-addition of a C5 alcohol with a C9-C11 enone. Compound 2 shows an interesting atropisomerism around the C4a-C5-sp2 -sp3 bond. The atropisomers can be separated in pure forms by low-temperature high-pressure liquid chromatography.