Total Synthesis of Sanctolide A and Formal Synthesis of (2S)-Sanctolide A.

Two synthetic strategies employing phosphate tether-mediated one-pot sequential protocols for the total synthesis of the polyketide nonribosomal peptide macrolide, sanctolide A, and the formal synthesis of the (2S)-epimer of sanctolide A are reported. In this work, a phosphate tether-mediated one-pot sequential ring-closing metathesis/cross metathesis/substrate-controlled "H2"/tether removal approach was developed to accomplish the total synthesis of the natural product sanctolide A.

Modular Synthesis of Novel Macrocycles Bearing α,ß-Unsaturated Chemotypes through a Series of One-Pot, Sequential Protocols.

A series of one-pot, sequential protocols was developed for the synthesis of novel macrocycles bearing α,ß-unsaturated chemotypes. The method highlights a phosphate tether-mediated approach to establish asymmetry, and consecutive one-pot, sequential processes to access the macrocycles with minimal purification procedures. This library amenable strategy provided diverse macrocycles containing α,ß-unsaturated carbon-, sulfur-, or phosphorus-based warheads.

Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of P-Stereogenic, Z-Configured Bicyclo[7.3.1]- and Bicyclo[8.3.1]phosphates.

A phosphate tether-mediated ring-closing metathesis (RCM) study to the synthesis of Z-configured, P-stereogenic bicyclo[7.3.1]- and bicyclo[8.3.1]phosphates is reported. Investigations suggest that C3-substitution, olefin substitution, and proximity of the forming olefin to the bridgehead carbon of the bicyclic affect the efficiency and stereochemical outcome of the RCM event. This study demonstrates the utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol-containing dienes in the generation of macrocyclic phosphates with potential synthetic and biological utility.

Phosphate tethers in natural product synthesis.

Recent advances in phosphate tether-mediated natural product synthesis are reviewed. Synthetic approaches toward dolabelide C, (-)-salicylihalimide A, (-)-tetrahydrolipstatin, and (+)-strictifolione are included. In addition, current efforts in method development are briefly reviewed, including a detailed study on the effect of stereochemical complexity on the phosphate-mediated, diastereoselective ring-closing metathesis reaction and recent advances in multi-reaction, one-pot sequential processes mediated by the phosphate tether. Overall, this review seeks to highlight the utility of phosphate triesters to serve as multifunctional tethers with protecting group and latent leaving group characteristics and the ability to orchestrate multiple, orthogonal reaction pathways to allow for the facile synthesis of complex, bioactive small molecules and their analogs.

Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si-OTP) Alkylating Reagents.

The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBP(n)) and triazole phosphates (Si-OTP(n)) using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBP(n) and Si-OTP(n), can be used to carry out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated products in good yield and high purity.

Modular, One-Pot, Sequential Aziridine Ring Opening-S(N)Ar Strategy to 7-, 10-, and 11-Membered Benzo-Fused Sultams.

The generation of common and stereochemically rich medium-sized benzo-fused sultams via complementary pairing of heretofore-unknown (o-fluoroaryl)sulfonyl aziridine building blocks with an array of amino alcohols/amines in a modular one-pot, sequential protocol using an aziridine ring opening and intramolecular nucleophilic aromatic substitution is reported. The strategy employs a variety of amino alcohols/amines and proceeds with 6 + 4/6 + 5 and 6 + 1 cycloetherification pathways in a highly chemo- and regioselective fashion to obtain skeletally and structurally diverse, polycyclic, 10- to 11- and 7-membered benzo-fused sultams for broad-scale screening.

Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of Medium to Large, P-Stereogenic Bicyclo[n.3.1]phosphates.

A phosphate tether-mediated ring-closing metathesis study towards the synthesis of P-stereogenic bicyclo[6.3.1]-, bicyclo[7.3.1]-, and bicyclo[8.3.1]phosphates is reported. This study demonstrates expanded utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol dienes in generating complex medium to large, P-stereogenic bicyclo[n.3.1]phosphates..

Synthetic Studies to Lyngbouilloside: A Phosphate Tether-Mediated Synthesis of the Macrolactone Core.

A concise synthetic pathway to the originally assigned structure of lyngbouilloside macrolactone (3) is reported. The core macrocycle 3 was synthesized via a phosphate tether-mediated, one-pot, sequential RCM/CM/chemoselective hydrogenation reaction, Roskamp homologation, and a high yielding Boeckman acylketene cyclization.

A modular phosphate tether-mediated divergent strategy to complex polyols.

An efficient and divergent synthesis of polyol subunits utilizing a phosphate tether-mediated, one-pot, sequential RCM/CM/reduction process is reported. A modular, 3-component coupling strategy has been developed, in which, simple "order of addition" of a pair of olefinic-alcohol components to a pseudo-C 2-symmetric phosphoryl chloride, coupled with the RCM/CM/reduction protocol, yields five polyol fragments. Each of the product polyols bears a central 1,3-anti-diol subunit with differential olefinic geometries at the periphery.

Phosphate-tether-mediated ring-closing metathesis for the preparation of complex 1,3-anti-diol-containing subunits.

An array of examples of diastereoselective, phosphate-tether-mediated ring-closing metathesis reactions, which highlight the importance of product ring size and substrate stereochemical compatibility, as well as complexity, is reported. Studies focus primarily on the formation of bicyclo[n.3.1]phosphates, involving the coupling of C2-symmetric dienediol subunits with a variety of simple, as well as complex, alcohol partners.

Synthesis of a Library of 1,5,2-Dithiazepine 1,1-Dioxides. Part 1: A One-Pot Sulfonylation/Thia-Michael Protocol.

A novel one-pot sulfonylation/intramolecular thia-Michael protocol is reported for the synthesis of 1,5,2-dithiazepine 1,1-dioxides. Sulfonylation between cysteine ethyl ester/cysteamine and 2-chloroethanesulfonyl chloride, followed by in situ intramolecular thia-Michael addition, was achieved and afforded the titled 1,5,2-dithiazepine-1,1-dioxide scaffolds. Diversification was demonstrated for future library synthesis.

Synthesis of a Library of 1,5,2-Dithiazepine 1,1-Dioxides. Part 2: Routes to Bicyclic Sultams.

The synthesis of a library of bicyclic sultams incorporating the 1,5,2-dithiazepine 1,1-dioxide moiety is reported. Following scaffold synthesis via a one-pot sulfonylation/intramolecular thia-Michael protocol, several additional cyclization strategies have been realized enabling access to new bicyclic sultams.

Exploring chemical diversity via a modular reaction pairing strategy.

The efficient synthesis of an 80-member library of unique benzoxathiazocine 1,1-dioxides by a microwave-assisted, intermolecular nucleophilic aromatic substitution (S(N)Ar) diversification pathway is reported. Eight benzofused sultam cores were generated by means of a sulfonylation/S(N)Ar/Mitsunobu reaction pairing protocol, and subsequently diversified by intermolecular S(N)Ar with ten chiral, non-racemic amine/amino alcohol building blocks. Computational analyses were employed to explore and evaluate the chemical diversity of the library.

An Iterative Phosphate Tether Mediated Approach for the Synthesis of Complex Polyol Subunits.

A pot-economical approach to advanced polyol subunits is reported. The key reactions involved are iterative use of a phosphate tether-mediated one-pot sequential RCM/CM/H2 with subsequent utilization of either a regio-/diasteroselective cuprate addition or a Pd-catalyzed reductive allylic transposition. This method highlights the asymmetric synthesis of 12 complex polyol subunits in 4-6 one-pot sequential operations with a total of 12-14 reactions, of which 4-5 are catalytic, with minimal workup and purification procedures.

Phosphate tether-mediated approach to the formal total synthesis of (-)-salicylihalamides A and B.

A concise formal synthesis of the cytotoxic macrolides (-)-salicylihalamides A and B is reported. Key features of the synthetic strategy include a chemoselective hydroboration, highly regio- and diastereoselective methyl cuprate addition, Pd-catalyzed formate reduction, and an E-selective ring-closing metathesis to construct the 12-membered macrocycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4 steps), a 13-step route and a more efficient 9-step sequence relying on regioselective esterification of a key diol.

Total synthesis of dolabelide C: a phosphate-mediated approach.

The first synthesis of dolabelide C (1), a cytotoxic marine macrolide, is reported utilizing a phosphate tether-mediated approach. Bicyclic phosphates (S,S,S(P))-5 and (R,R,R(P))-5 serve as the central building blocks for the construction of two major 1,3-anti-diol subunits in 1 through selective cleavage pathways, regioselective olefin reduction, and cross-metathesis. Overall, phosphate-mediated processes provided copious amounts of both major subunits allowing for a detailed RCM macrocyclization study to the 24-membered macrolactone 1.

Investigation on the Anticancer Activity of Symmetric and Unsymmetric Cyclic Sulfamides.

The sulfamide functional group has been extensively employed in organic synthesis to discover probes and drugs in various applications such as cancer, human immunodeficiency virus (HIV), virus, and diabetes. Herein, we describe the synthesis of 7-membered symmetric and unsymmetric sulfamide compounds and their biological evaluation through the National Cancer Institute (NCI) panel of 60 human tumor cell lines (NCI-60) and the mechanism of action study. The results of a study from the NCI-60 cell line exhibited that many synthesized cyclic sulfamide compounds inhibited breast cancer (MDA-MB-468). The mechanism of action study of a representative compound 18 showed the inhibition of proliferation and apoptosis in A549 lung cancer cells.

Immobilization on a Nanomagnetic Co/C Surface Using ROM Polymerization: Generation of a Hybrid Material as Support for a Recyclable Palladium Catalyst.

A novel hybrid material is reported as support for a recyclable palladium catalyst via surface immobilization of a ligand onto Co-based magnetic nanoparticles (NPs). A standard "click" reaction is utilized to covalently attach a norbornene tag (Nb-tag) to the surface of the carbon coated cobalt NPs. The hybrid magnetic nanoparticles are produced by initiating polymerization of a mixture containing both Nb-tagged ligand (Nb-tagged PPh (3)) and Nb-tagged carbon coated cobalt NPs. In turn, the norbornene units are suitably functionalized to serve as ligands for metal catalysts. A composite material is thus obtained which furnishes a loading that is one order of magnitude higher than the value obtained previously for the synthesis of functionalized Co/C-nanopowders. This allows for its application as a hybrid support with high local catalyst concentrations, as demonstrated for the immobilization of a highly active and recyclable palladium complex for Suzuki-Miyaura cross-coupling reactions. Due to the explicit magnetic moment of the cobalt- NPs, the overall magnetization of this organic/inorganic framework is significantly higher than of polymer coated iron oxide nanoparticles with comparable metal content, hence, its rapid separation from the reaction mixture and recycling via an external magnetic field is not hampered by the functionalized polymer shell.

Reagent based DOS: a "Click, Click, Cyclize" strategy to probe chemical space.

The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an important aspect of chemical-biology. Herein we report a reagent-based, diversity-oriented synthetic (DOS) strategy to probe chemical and biological space via a "Click, Click, Cyclize" protocol. In this DOS approach, three sulfonamide linchpins underwent cyclization protocols with a variety of reagents to yield a collection of structurally diverse S-heterocycles. In silico analysis is utilized to evaluate the diversity of the compound collection against chemical space (PC analysis), shape space (PMI) and polar surface area (PSA) calculations.

S(N)Ar-based, facile synthesis of a library of benzothiaoxazepine-1,1'-dioxides.

The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S(N)Ar diversification-ODCT(50) scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted for biological evaluation.