N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by site-, diastereo- and enantioselective vinylogous Mannich reactions.

A readily accessible small-molecule phosphine, derived from commercially available starting materials such as an enantiomerically pure amino acid, serves as the precursor to a Ag-based chiral complex that can be prepared and used in situ to promote a variety of enantioselective vinylogous Mannich (EVM) reactions that involve siloxypyrroles as reaction partners. Transformations with unsubstituted nucleophilic components proceed efficiently and with exceptional site- (γ vs α-addition), diastereo- and enantioselectivity [up to 98% yield, generally >98:2 γ/α and diastereomeric ratio (dr) and up to 99:1 enantiomeric ratio (er)]. The first examples of efficient, diastereo- and enantioselective vinylogous Mannich additions with 5-methyl-substituted siloxyfuran, resulting in the formation of O-substituted quaternary carbon stereogenic centers are presented as well. Appreciable efficiency and diastereo- and enantioselectivity (up to >98:2 dr and >99:1 er) is accompanied by formation of α-addition products that can be oxidatively removed.

Enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts.

Catalytic enantioselective monosilylations of diols and polyols furnish valuable alcohol-containing molecules in high enantiomeric purity. These transformations, however, require high catalyst loadings (20-30 mol%) and long reaction times (2-5 days). Here, we report that a counterintuitive strategy involving the use of an achiral co-catalyst structurally similar to the chiral catalyst provides an effective solution to this problem. A combination of seemingly competitive Lewis basic molecules can function in concert such that one serves as an achiral nucleophilic promoter and the other performs as a chiral Brønsted base. On the addition of 7.5-20 mol% of a commercially available N-heterocycle (5-ethylthiotetrazole), reactions typically proceed within one hour, and deliver the desired products in high yields and enantiomeric ratios. In some instances, there is no reaction in the absence of the achiral base, yet the presence of the achiral co-catalyst gives rise to facile formation of products in high enantiomeric purity.

Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols.

The discovery of catalysts that can be used to synthesize complex organic compounds by enantioselective transformations is central to advances in the life sciences; for this reason, many chemists aim to discover catalysts that allow for preparation of chiral molecules as predominantly one mirror-image isomer. The ideal catalyst should not contain precious elements and should bring reactions to completion in a few hours through operationally simple procedures. Here we introduce a set of small organic molecules that can catalyse reactions of unsaturated organoboron reagents with imines and carbonyls; the products of the reactions are enantiomerically pure amines and alcohols, which might serve as intermediates in the preparation of biologically active molecules. A distinguishing feature of this catalyst class is the presence of a 'key' proton embedded within their structure. Catalysts are derived from the abundant amino acid valine and are prepared in large quantities in four steps with inexpensive reagents. Reactions are scalable, do not demand stringent conditions, and can be performed with as little as 0.25 mole per cent catalyst in less than six hours at room temperature to generate products in more than 85 per cent yield and ≥97:3 enantiomeric ratio. The efficiency, selectivity and operational simplicity of the transformations and the range of boron-based reagents are expected to render this advance important for future progress in syntheses of amines and alcohols, which are useful in chemistry, biology and medicine.

Development and evaluation of a solid-supported cyclobutadieneiron tricarbonyl complex for parallel synthesis applications.

Cycloadditions of cyclobutadiene can offer rapid access to rigid polycyclic ring systems. Further functionalization of these strained-ring cycloadducts can lead to unique scaffolds for probing unexplored regions of chemical space. Along these lines, opportunities for high-throughput syntheses of these novel systems could be facilitated with the introduction of an immobilized cyclobutadiene reagent. Reported herein are preliminary studies of an iron tricarbonyl cyclobutadiene complex attached to solid support. Oxidative unmasking of the immobilized cyclobutadiene in the presence of various dienophiles is shown to produce a small collection of substituted bicyclo[2.2.0]hexene derivatives. The solid support cycloaddition strategy is shown to be comparable, but lower in efficiency to solution phase methods for generating these cycloadducts.

Regiodivergent reactions through catalytic enantioselective silylation of chiral diols. Synthesis of sapinofuranone A.

Through the use of an amino acid based imidazole catalyst, a regiodivergent silylation of chiral diols in cases where there is not a significant steric and electronic difference between the regioisotopic hydroxyl groups has been developed. This transformation allows for the conversion of racemic diols into regioisomeric, enantiomerically enriched, monosilylated products. The utility of this process is highlighted in the efficient enantioselective preparation of a useful synthetic intermediate and the natural product, sapinofuranone A.

Formation of polycyclic lactones through a ruthenium-catalyzed ring-closing metathesis/hetero-Pauson-Khand reaction sequence.

Processes that form multiple carbon-carbon bonds in one operation can generate molecular complexity quickly and therefore be used to shorten syntheses of desirable molecules. We selected the hetero-Pauson-Khand (HPK) cycloaddition and ring-closing metathesis (RCM) as two unique carbon-carbon bond-forming reactions that could be united in a tandem ruthenium-catalyzed process. In doing so, complex polycyclic products can be obtained in one reaction vessel from acyclic precursors using a single ruthenium additive that can catalyze sequentially two mechanistically distinct transformations.

Enantioselective synthesis of homoallylic amines through reactions of (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkene-substituted aldimines catalyzed by chiral C1-symmetric NHC-Cu complexes.

A catalytic method for enantioselective synthesis of homoallylamides through Cu-catalyzed reactions of stable and easily accessible (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkenyl-substituted N-phosphinoylimines is disclosed. Transformations are promoted by 1-5 mol % of readily accessible NHC-Cu complexes, derived from C(1)-symmetric imidazolinium salts, which can be prepared in multigram quantities in four steps from commercially available materials. Allyl additions deliver the desired products in up to quantitative yield and 98.5:1.5 enantiomeric ratio and are amenable to gram-scale operations. A mechanistic model accounting for the observed selectivity levels and trends is proposed.

Ruthenium-catalyzed tandem enyne metathesis/hydrovinylation.

In situ modification of Grubbs' first-generation metathesis catalyst allows for a tandem enyne metathesis/hydrovinylation that is complementary to the regioselectivity of known ruthenium-catalyzed hydrovinylations.

A new structural class of S-adenosylhomocysteine hydrolase inhibitors.

Effective inhibitors of S-adenosylhomocysteine hydrolase hold promise towards becoming useful therapeutic agents. Since most efforts have focused on the development of nucleoside analog inhibitors, issues regarding bioavailability and selectivity have been major challenges. Considering the marine sponge metabolite ilimaquinone was found to be a competitive inhibitor of S-adenosylhomocysteine hydrolase, new opportunities for developing selective new inhibitors of this enzyme have become available. Based on the activities of various hybrid analogs, SAR studies, pharmacophore modeling, and computer docking studies have lead to a predictive understanding of ilimaquinone's S-adenosylhomocysteine hydrolase inhibitory activities. These studies have allowed for the design and preparation of simplified structural variants possessing new furanoside bioisosteres with 100-fold greater inhibitory activities than that of the natural product.

Ag-catalyzed diastereo- and enantioselective vinylogous Mannich reactions of alpha-ketoimine esters. Development of a method and investigation of its mechanism.

An efficient diastereo- and enantioselective Ag-catalyzed method for additions of a commercially available siloxyfuran to alpha-ketoimine esters is disclosed. Catalytic transformations require an inexpensive metal salt (AgOAc) and an air stable chiral ligand that is prepared in three steps from commercially available materials in 42% overall yield. Aryl- as well as heterocyclic substituted ketoimines can be used effectively in the Ag-catalyzed process. Additionally, two examples regarding reactions of alkyl-substituted ketoimines are presented. An electronically modified N-aryl group is introduced that is responsible for high reaction efficiency (>98% conversion, 72-95% yields after purification) as well as diastereo- (up to >98:2 dr) and enantioselectivity (up to 97:3 er or 94% ee). The new N-aryl unit is crucial for conversion of the asymmetric vinylogous Mannich (AVM) products to the unprotected amines in high yields. Spectroscopic and X-ray data are among the physical evidence provided that shed light on the identity of the Ag-based chiral catalysts and some of the mechanistic subtleties of this class of enantioselective C-C bond forming processes.

Three-component Ag-catalyzed enantioselective vinylogous mannich and Aza-Diels-Alder reactions with alkyl-substituted aldehydes.

Efficient protocols for three-component catalytic enantioselective vinylogous Mannich (VM) reactions of alkyl-substituted aldimines (including those bearing heteroatom-containing substituents) and readily available siloxyfurans are presented. High efficiency and stereoselectivity is achieved through the use of o-thiomethyl-p-methoxyaniline-derived aldimines. Reactions, performed under an atmosphere of air and in undistilled THF, can be promoted in the presence of as little as 1 mol % of easily accessible amino acid-based chiral ligands and commercially available AgOAc. The desired products are obtained in 44 to 92% yield, and in up to >98:<2 diastereomer and >99:<1 enantiomer ratio (>98% ee). Removal of the N-activating group is performed through a one-vessel oxidation/hydrolysis operation, which proceeds via a stable aza-quinone (characterized by X-ray crystallography). Evidence is presented indicating that reactions with chiral nonracemic aldehydes are subject to catalyst control: both substrate enantiomers react to afford the desired product diastereomers in high stereoselectivity. Aryl- and alkynyl-substituted o-thiomethyl-p-methoxyaniline-derived aldimines undergo Ag-catalyzed enantioselective VM reactions more efficiently and with higher selectivity than the corresponding o-anisidyl substrates. Additionally, Ag-catalyzed aza-Diels-Alder reactions of the alkyl-substituted aldimines bearing the structurally modified N-aryl unit afford enantiomerically enriched (up to 95% ee) products in up to 88% yield.

Aluminum-catalyzed asymmetric alkylations of pyridyl-substituted alkynyl ketones with dialkylzinc reagents.

Alkylations of pyridyl-substituted ynones with Et2Zn and Me2Zn, promoted by amino acid-based chiral ligands in the presence of Al-based alkoxides, afford tertiary propargyl alcohols efficiently in 57% to >98% ee. Two easily accessible chiral ligands are identified as optimal for reactions of the two dialkylzinc reagents. Catalytic alkylations with Et2Zn require a chiral ligand carrying two amino acid moieties (valine and phenylalanine) along with a p-trifluoromethylphenylamide C-terminus. In contrast, reactions with Me2Zn are most effectively promoted in the presence of a chiral ligand containing a single amino acid (benzyl cysteine), capped by an n-butylamide. Enantiomerically enriched tertiary alcohols bearing a pyridyl and an alkyne substituent can be functionalized in a variety of manners to furnish a wide range of difficult-to-access acyclic and heterocyclic structures; two noteworthy examples are Cu-catalyzed protocols for conversion of tertiary propargyl alcohols to enantiomerically enriched tetrasubstituted allenes and bicyclic amides that bear an N-substituted quaternary carbon stereogenic center. Mechanistic models that account for the trends and enantioselectivity levels are provided.

Catalytic asymmetric alkylations of ketoimines. Enantioselective synthesis of N-substituted quaternary carbon stereogenic centers by Zr-catalyzed additions of dialkylzinc reagents to aryl-, alkyl-, and trifluoroalkyl-substituted ketoimines.

Catalytic enantioselective alkylations of three classes of ketoimines are reported. Reactions are promoted in the presence 0.5-10 mol % of a Zr salt and a chiral ligand that contains two inexpensive amino acids (valine and phenylalanine) and involve Me2Zn or Et2Zn as alkylating agents. Requisite aryl- and alkyl-substituted alpha-ketoimine esters, accessed readily and in >80% yield on gram scale through a two-step sequence from the corresponding ketones, undergo alkylation to afford quaternary alpha-amino esters in 79-97% ee. Aryl-substituted trifluoroketoimines are converted to the corresponding amines by reactions with Me2Zn, catalyzed by a chiral complex that bears a modified N-terminus. The utility of the catalytic asymmetric protocols is illustrated through conversion of the enantiomerically enriched alkylation products to a range of cyclic and acyclic compounds bearing an N-substituted quaternary carbon stereogenic center.

A cross-metathesis route to the 5-F(2)-isoprostanes.

A library of eight 5-F(2)-isoprostanes was prepared through a ring-opening metathesis/cross-metathesis protocol between functionalized bicyclo[3.2.0]heptenes, ethylene, and alpha,beta-unsaturated ketones. This sequence provided racemic enones in a regio- and stereoselective fashion that could be converted to enantiomerically enriched allylic alcohols through a catalyst-controlled asymmetric reduction. Completion of the sidechains, followed by global deprotection, resulted in a stereodivergent route to eight enantiomerically enriched 5-F(2)-isoprostanes. Overall, the synthesis of this library of known and anticipated lipid oxidation metabolites was achieved in 10 steps from commercially available 4-hydroxy-2-cyclopentenone.

Ruthenium-catalyzed tandem cross-metathesis/Wittig olefination: generation of conjugated dienoic esters from terminal olefins.

[reaction: see text] In the presence of ruthenium-based olefin metathesis catalysts and triphenylphosphine, alpha,beta-unsaturated aldehydes can be olefinated with diazoacetates. This ruthenium-catalyzed transformation has been employed in tandem with olefin cross-metathesis to convert terminal olefins into 1,3-dienoic esters in a single operation.