Total Synthesis of Putative 11-epi-Lyngbouilloside Aglycon.

We report here the total synthesis of 11-epi-lyngbouilloside aglycon. Our strategy features a Boeckman-type esterification followed by a RCM to form the 14-membered ring macrolactone and a late-stage side chain introduction via a Wittig olefination. Overall, the final product was obtained in 20 steps and 2% overall yield starting from commercially available 3-methyl-but-3-enol. Most importantly, the strategy employed is versatile enough to eventually allow us to complete the synthesis of the natural product and irrevocably confirm its structure.

Total Synthesis of Δ(12) -Prostaglandin J3 : Evolution of Synthetic Strategies to a Streamlined Process.

The total synthesis of Δ(12) -prostaglandin J3 (Δ(12) -PGJ3 , 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji-Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C-H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ(12) -PGJ3 and designed analogues for further biological and pharmacological studies.

Synthesis and Biological Investigation of Δ(12)-Prostaglandin J3 (Δ(12)-PGJ3) Analogues and Related Compounds.

A series of Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure-activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.

Synthesis and biological evaluation of dimeric furanoid macroheterocycles: discovery of new anticancer agents.

A recently developed dimerization/macrocyclization was employed to synthesize a series of macroheterocycles which were biologically evaluated, leading to the discovery of a number of potent cytotoxic agents (e.g., 27: GI50 = 51 nM against leukemia CCRF-CEM cell line; 29: GI50 = 99 nM against melanoma MDA-MB-435 cell line). Further biological studies support an apoptosis mechanism of action for these compounds involving deregulation of the tricarboxylic acid cycle activity and suppression of mitochondrial function in cancer cells.

Total synthesis of viridicatumtoxin B and analogues thereof: strategy evolution, structural revision, and biological evaluation.

The details of the total synthesis of viridicatumtoxin B (1) are described. Initial synthetic strategies toward this intriguing tetracycline antibiotic resulted in the development of key alkylation and Lewis acid-mediated spirocyclization reactions to form the hindered EF spirojunction, as well as Michael-Dieckmann reactions to set the A and C rings. The use of an aromatic A-ring substrate, however, was found to be unsuitable for the introduction of the requisite hydroxyl groups at carbons 4a and 12a. Applying these previous tactics, we developed stepwise approaches to oxidize carbons 12a and 4a based on enol- and enolate-based oxidations, respectively, the latter of which was accomplished after systematic investigations that revealed critical reactivity patterns. The herein described synthetic strategy resulted in the total synthesis of viridicatumtoxin B (1), which, in turn, formed the basis for the revision of its originally assigned structure. The developed chemistry facilitated the synthesis of a series of viridicatumtoxin analogues, which were evaluated against Gram-positive and Gram-negative bacterial strains, including drug-resistant pathogens, revealing the first structure-activity relationships within this structural type.

Total synthesis of Δ¹²-prostaglandin J3, a highly potent and selective antileukemic agent.

A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, formed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.

Lyngbouilloside and related macrolides from marine cyanobacteria.

Lyngbouilloside and the related macrolides lyngbyaloside, lyngbyaloside B and lyngbyaloside C have attracted a lot of attention over the past decade due to their intriguing architecture, their natural scarcity and their potential biological activities. This review aims to showcase the various strategies that have been used to access these natural products.

Total synthesis of nominal lyngbouilloside aglycon.

The first enantioselective total synthesis of the originally assigned structure of lyngbouilloside aglycon has been achieved using a particularly flexible route featuring an acylketene macrolactonization of a tertiary methyl carbinol as the key step. Comparison of the C13 chemical shifts of our synthetic aglycon with the ones pertaining to natural lyngbouilloside and lyngbyaloside C resulted in a possible stereochemical reassignment of the C11 stereogenic center.

Coupling reaction between electron-rich pyrimidinones and α-amino acids promoted by phosphonium salts.

Coupling reaction between electron-rich 2-morpholino-4(3H)-pyrimidinone and nucleophilic side chains of several natural α-amino acids promoted by phosphonium salt has been developed to prepare new optically active pyrimidin-4-yl amino acids. The best results were obtained using a two-step method through the easily available benzotriazolyl-1-oxy intermediate. A detailed optimization study of this reaction is discussed.

Expedient synthesis of a stereoisomer of acremolide B.

A highly straightforward strategy for the synthesis of the acremolide class of lipodepsipeptides has been developed. Synthetic highlights include a cross-metathesis to couple the C1-C7 and the C8-C12 fragments, an esterification to introduce the dipeptide unit, a macrolactamization to build the macrolide core, and two stereoselective allylations/crotylations to control all four stereogenic centers of the C1-C12 polypropionate segment.

Two concise total syntheses of (-)-bitungolide F.

The enantioselective total synthesis of the dual-specificity phosphatase inhibitor (-)-bitungolide F has been achieved using two convergent routes. Both strategies feature an asymmetric boron-mediated pentenylation, a stereoselective aldol, and a hydroxyl-directed 1,3-anti-reduction in order to control the stereogenic centers at C4, C5, C9, and C11. Whereas the first total synthesis was achieved in 11 steps and 14.6% overall yield using an Evans-type asymmetric alkylation, the second was completed in 9 steps and 11.4% overall yield using a highly enantioselective organocatalytic Michael addition as a key step and a protecting group free strategy.