Introducing Savie: A Biodegradable Surfactant Enabling Chemo- and Biocatalysis and Related Reactions in Recyclable Water.

Savie is a biodegradable surfactant derived from vitamin E and polysarcosine (PSar) developed for use in organic synthesis in recyclable water. This includes homogeneous catalysis (including examples employing only ppm levels of catalyst), heterogeneous catalysis, and biocatalytic transformations, including a multistep chemoenzymatic sequence. Use of Savie frequently leads to significantly higher yields than do conventional surfactants, while obviating the need for waste-generating organic solvents.

Lipase-catalyzed esterification in water enabled by nanomicelles. Applications to 1-pot multi-step sequences.

Esterification in an aqueous micellar medium is catalyzed by a commercially available lipase in the absence of any co-factors. The presence of only 2 wt% designer surfactant, TPGS-750-M, assists in a 100% selective enzymatic process in which only primary alcohols participate (in a 1 : 1 ratio with carboxylic acid). An unexpected finding is also disclosed where the simple additive, PhCF3 (1 equiv. vs. substrate), appears to significantly extend the scope of usable acid/alcohol combinations. Taken together, several chemo- and bio-catalyzed 1-pot, multi-step reactions can now be performed in water.

Nanomicelle-enhanced, asymmetric ERED-catalyzed reductions of activated olefins. Applications to 1-pot chemo- and bio-catalysis sequences in water.

Bio-catalytic reactions involving ene-reductases (EREDs) in tandem with chemo-catalysis in water can be greatly enhanced by the presence of nanomicelles derived from the surfactant TPGS-750-M. Transformations are provided that illustrate the variety of sequences now possible in 1-pot as representative examples of this environmentally attractive approach to organic synthesis.

One-Pot Synthesis of Indoles and Pyrazoles via Pd-Catalyzed Couplings/Cyclizations Enabled by Aqueous Micellar Catalysis.

An effective one-pot synthesis of either indoles or pyrazoles can be achieved via Pd-catalyzed aminations followed by subsequent cyclizations facilitated by aqueous micellar catalysis. This new technology includes efficient couplings with low loadings of palladium, a more stable source of the required hydrazine moiety, greater atom economy for the initial coupling, and reduced reaction temperatures, all leading to environmentally responsible processes.

N2Phos - an easily made, highly effective ligand designed for ppm level Pd-catalyzed Suzuki-Miyaura cross couplings in water.

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki-Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000-2500 ppm or 0.10-0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N2Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand-Pd(0) complex more for N2Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand-Pdo complex that is more reactive in oxidative addition to aryl chlorides.

Modular Synthesis of DOTA-Metal-Based PSMA-Targeted Imaging Agents for MRI and PET of Prostate Cancer.

A practical, convergent synthesis of prostate-specific membrane antigen (PSMA) targeted imaging agents for MRI, PET, and SPECT of prostate cancer has been developed. In this approach, metals chelated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were placed on the side chains of lysine early in the synthesis to form imaging modules. These are coupled to targeting modules, in this case consisting of the PSMA-binding urea DCL, bonded to an activated linker. The modular approach to targeted molecular imaging agents (TMIAs) offers distinct advantages. By chelating the MRI contrast metal Gd early, it doubles as a protecting group for DOTA. Standard coupling and deprotection steps may be utilized to assemble the modules into peptides, and the need for tri-tert-butyl protection of DOTA requiring removal by strong acid is averted. This enables mild conjugation of the imaging module to a wide variety of targeting agents in the final step. It was further discovered that two labile metals, La3+ or Ce3+ , can be used as placeholders in DOTA during the synthesis, then transmetalated in mild acid by Cu2+ , Ga3+ , In3+ , and Y3+ , metals used in PET/SPECT. This enables the efficient synthesis of nonradioactive analogues of targeted molecular imaging agents that may be transported or stored until needed. A simple and mild two-step transmetalation, involving de-metalation in dilute acid, followed by rapid chelation of the radioactive metal, may be conveniently performed later at the clinic to provide the TMIAs for PET or SPECT.

Bridging the gap between transition metal- and bio-catalysis via aqueous micellar catalysis.

Previous studies have shown that aqueous solutions of designer surfactants enable a wide variety of valuable transformations in synthetic organic chemistry. Since reactions take place within the inner hydrophobic cores of these tailor-made nanoreactors, and products made therein are in dynamic exchange between micelles through the water, opportunities exist to use enzymes to effect secondary processes. Herein we report that ketone-containing products, formed via initial transition metal-catalyzed reactions based on Pd, Cu, Rh, Fe and Au, can be followed in the same pot by enzymatic reductions mediated by alcohol dehydrogenases. Most noteworthy is the finding that nanomicelles present in the water appear to function not only as a medium for both chemo- and bio-catalysis, but as a reservoir for substrates, products, and catalysts, decreasing noncompetitive enzyme inhibition.