Thomas N. Snaddon

Bio: Thomas N. Snaddon is an academic researcher from Indiana University. The author has contributed to research in topics: Enantioselective synthesis & Lewis acids and bases. The author has an hindex of 15, co-authored 31 publications receiving 582 citations. Previous affiliations of Thomas N. Snaddon include Merck & Co. & Max Planck Society.

Uniting C1-Ammonium Enolates and Transition Metal Electrophiles via Cooperative Catalysis: The Direct Asymmetric α-Allylation of Aryl Acetic Acid Esters

Abstract: The direct, catalytic, asymmetric α-functionalization of acyclic esters constitutes a significant challenge in the area of asymmetric catalysis, particularly where the configurational integrity of the products is problematic. Through the unprecedented merger of two independent, yet complementary, catalysis events it has been possible to facilitate the direct asymmetric α-allylation of readily available aryl acetic acid esters. Since enantioselection is determined by the nucleophile, this conceptual approach to cooperative catalysis constitutes a potentially general solution to the direct catalytic asymmetric α-functionalization of acyclic esters.

Enantioselective α-Benzylation of Acyclic Esters Using π-Extended Electrophiles.

Abstract: The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1-ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX-9065a.

A Regio- and Stereodivergent Synthesis of Homoallylic Amines by a One-Pot Cooperative-Catalysis-Based Allylic Alkylation/Hofmann Rearrangement Strategy.

Abstract: Herein, we report a modular synthetic route to linear and branched homoallylic amines that operates through a sequential one-pot Lewis base/transition-metal catalyzed allylic alkylation/Hofmann rearrangement strategy. This protocol is operationally trivial, proceeds from simple and easily prepared substrates and catalysts, and enables all aspects of regio- and stereoselectivity to be controlled through a conserved experimental protocol. Overall, the high levels of enantio-, regio-, and diastereoselectivity obtained, in concert with the ability to access orthogonally protected or free amines, render this a straightforward and effective approach for the preparation of useful enantioenriched homoallylic amines. We have also demonstrated the utility of the products in the context of pharmaceutical synthesis.

A Synthesis-Driven Structure Revision of Berkelic Acid Methyl Ester†

Abstract: Matrix metalloproteinases (MMPs) are a family of zinccontaining endopeptidases involved in homeostasis of the extracellular matrix. Abnormal activity of such enzymes is implicated in pathological processes that result in osteoarthritis, rheumathoid arthritis, and multiple sclerosis, and also plays a decisive role in tumor metastasis. Small-molecule inhibitors of the individual MMPs are therefore highly interesting as prospective complements to the current chemotherapeutic regimens used in clinical settings. A promising lead in this context is berkelic acid, which was isolated from a Penicillium species collected in the very hostile environment of Berkeley Pit Lake, a flooded former copper mine in Butte, Montana. This particular extremophile has adapted to the waters of this lake, which are highly acidic (pH 2.5) and contain a cocktail of heavy-metal salts in remarkably high concentrations. Bioassay-guided fractionation of the CHCl3 extracts of the fungus showed berkelic acid to be the major metabolite responsible for the pronounced inhibition of MMP-3 (GI50 = 1.87 mm). [3] Moreover, the compound exhibits selective and potent activity against the ovarian cancer cell line OVCAR-3 (GI50 = 91 nm). [3] As MMP-3 is upregulated in OVCAR-3 but not in other ovarian cancer cell lines, these preliminary activity and selectivity data are highly encouraging and suggest that berkelic acid and derivatives thereof deserve more intense scrutiny. 4] The remarkable structural attributes of berkelic acid add further to the appeal of this compound. It was assigned the constitution and relative configuration 1 (Scheme 1) mainly on the basis of NMR experiments. Recent model studies directed towards synthesizing berkelic acid appear to corroborate this proposed structure, even though they reached contradictory conclusions as to whether the acetalization that produces the conspicuous chromane spiroketal core is thermodynamically or kinetically controlled. We now report our own investigations on berkelic acid methyl ester (2) which not only resolve this open question but also suggest that the original structure assignment needs to be revised. Since the configuration at the lateral quaternary stereocenter C22 of berkelic acid is unknown, a convergent approach was adopted that should allow both possible isomers to be prepared by incorporating either enantiomer of synthon A at a late stage (Scheme 1). This route utilizes a Michael addition/spiroacetalization cascade intended to convert a linear precursor of type C into the tetracyclic core B of the target in one step. Compound C, in turn, should arise from an aldol condensation between the aromatic nucleus D and the polyketide segment E. The preparation of the required building block D (Scheme 2) commenced with the copper-catalyzed opening of (R)-(+)-2-pentyloxirane (> 99% ee) by the Grignard reagent derived from 3,5-bis(benzyloxy)-1-bromobenzene to give 3. Hydrogenolysis of the benzyl ethers followed by a regioselective Kolbe–Schmitt carboxylation of the resulting phenol 4 furnished acid 5, which was esterified by treatment with diazomethane prior to conversion into bis-TBS ether 8 by exhaustive silylation and selective mono-desilylation. Since the attempted direct formylation of this product was unrewarding, we chose to introduce the required formyl Scheme 1. Retrosynthetic analysis of the structure 1 attributed to berkelic acid.

Gold-catalyzed carbon-heteroatom bond-forming reactions.

Abstract: A.L.-P. thanks CSIC for a contract under the JAE-doctor program. Financial support by PLE2009 project from MCIINN and Consolider-Ingenio 2010 (proyecto MULTICAT) are also acknowledged.

Allenes in Catalytic Asymmetric Synthesis and Natural Product Syntheses

Abstract: Allenes are the simplest class of cumulenes, with two contiguous CC bonds, and show unique physical and chemical properties. These features make allenes particularly attractive in modern organic chemistry. In this Review, attention is paid to the advances made in catalytic asymmetric synthesis and natural product syntheses based on well-established reactions of allenes, such as propargylation, addition, cycloaddition, cycloisomerization, cyclization, etc., with or without catalysts. Their versatile reactivity, substituent-loading ability, axial to center chirality transfer, and controllable selectivity allow access to target molecules by unique and efficient approaches. The main topics in this Review are presented with selected examples from 2003 to 2011.

Iridium-Catalyzed Asymmetric Allylic Substitution Reactions

Abstract: In this review, we summarize the origin and advancements of iridium-catalyzed asymmetric allylic substitution reactions during the past two decades. Since the first report in 1997, Ir-catalyzed asymmetric allylic substitution reactions have attracted intense attention due to their exceptionally high regio- and enantioselectivities. Ir-catalyzed asymmetric allylic substitution reactions have been significantly developed in recent years in many respects, including ligand development, mechanistic understanding, substrate scope, and application in the synthesis of complex functional molecules. In this review, an explicit outline of ligands, mechanism, scope of nucleophiles, and applications is presented.