ABSTRACT
The natural product FR901464 (1) was isolated by the Fujisawa Pharmaceutical Co. and shown to have intriguing biological properties including impressive antitumor activity. In this paper we describe the first total synthesis of 1 in full detail. A chiral building block synthetic strategy was used to assemble the target: optically active components were generated using asymmetric catalytic reactions, and these fragments were coupled together at a late stage in a convergent synthesis. In particular, a versatile, asymmetric hetero-Diels-Alder (HDA) reaction was developed in the context of this synthesis and used with great effectiveness for the preparation of the two densely functionalized pyran rings. The flexible nature of the synthetic route also allowed us to prepare a series of analogues of 1. These compounds were used to prove the relative stereochemistry of the natural product as well as to probe the importance of certain structural features of FR901464 with regard to biological activity.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Pyrans/chemical synthesis , Spiro Compounds/chemical synthesis , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Molecular Structure , Pyrans/chemistry , Pyrans/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of the metal salen-catalyzed asymmetric ring-opening (ARO) of epoxides is chronicled. A screening approach was adopted for the identification of catalysts for the addition of TMSN(3) to meso-epoxides, and the chiral (salen)CrN(3) complex was identified as optimal. Kinetic and structural studies served to elucidate the mechanism of catalysis, which involves cooperative activation of both epoxide and azide by two different metal centers. Covalently linked bimetallic complexes were constructed on the basis of this insight, and shown to catalyze the ARO with identical enantioselectivity but 1-2 orders of magnitude greater reactivity than the monomeric analogues. Extraordinarily high selectivity is observed in the kinetic resolution of terminal epoxides using the (salen)CrN(3)/TMSN(3) system. A search for a practical method for the kinetic resolution reaction led to the discovery of highly enantiomer-selective hydrolytic ring-opening using the corresponding (salen)Co(III) catalyst. This system displays extraordinary substrate generality, and allows practical access to enantiopure terminal epoxides on both laboratory and industrial scales.
Subject(s)
Epoxy Compounds/chemistry , Catalysis , Chelating Agents/chemistry , Ethylenediamines/chemistry , Kinetics , Metals, Heavy/chemistry , Models, Molecular , Molecular Structure , Organometallic Compounds/chemistryABSTRACT
The asymmetric ring opening of meso epoxides with TMSCN is catalyzed by (pybox)YbCl3 complexes, yielding the beta-trimethylsilyloxy nitrile ring-opened products with good enantioselectivities (83-92% ee). The reaction exhibits a second-order kinetic dependence on catalyst concentration and a first-order dependence on epoxide concentration, consistent with a bimetallic pathway involving simultaneous activation of epoxide and cyanide.
Subject(s)
Cyanides/chemical synthesis , Epoxy Compounds/chemical synthesis , Metals, Rare Earth/chemistry , Trimethylsilyl Compounds/chemical synthesis , Catalysis , Chromatography, GasABSTRACT
[formula: see text] Highly enantioselective addition of HCN to ketoimines has been achieved for the first time using readily accessible and recyclable Schiff base catalysts. Essentially quantitative isolated yield and enantioselectivity of up to 95% ee was obtained. Furthermore, some of the Strecker adducts could be recrystallized in high recovery, yielding optically pure materials. Conversion of the alpha-aminonitrile adducts to the corresponding alpha-quaternary alpha-amino acids was effected in high yield by a formylation/hydrolysis sequence.
Subject(s)
Amino Acids/chemical synthesis , Hydrogen Cyanide , Imines/chemistry , Amino Acids/chemistry , Indicators and Reagents , Schiff Bases , StereoisomerismABSTRACT
[formula: see text] A catalytic method for the enantioselective ring opening of meso aziridines by TMSN3 is described. Tridentate Schiff base chromium complexes derived from 1-amino-2-indanol were identified as the optimal catalysts.
Subject(s)
Aziridines/chemistry , Chromium/chemistry , Schiff Bases/chemistry , Catalysis , Indans/chemistry , StereoisomerismABSTRACT
[formula: see text] The kinetic resolution of epoxides with phenols catalyzed by a polymer-supported Co(salen) complex is applied to the first enantioselective catalytic synthesis of parallel libraries. The corresponding 1-aryloxy-2-alcohols are obtained in high yield, purity, and enantiomeric excess. Further elaboration with diversity elements provides highly efficient access to important classes of pharmacologically active compounds.
Subject(s)
Ethylenediamines/chemistry , Cobalt/chemistry , Polymers/chemistry , StereoisomerismABSTRACT
The design, synthesis and evaluation of transition metal containing combinatorial libraries has received much attention in the past few years. As a result, a variety of synthetic techniques have been developed, and rapid assays for metal ion binding have yielded new ligand classes displaying high affinity and selectivity. Research in catalysis has centered around lead optimization using much smaller parallel libraries because of the lack of a truly efficient reaction screening method. Materials science applications have also focused on spatially addressed libraries and have employed a variety of techniques to identify compounds with desired physical properties. Nonetheless, high-throughput characterization and reaction product detection methods must still be developed in order to realize the full potential of combinatorial chemistry for the discovery of novel metal-containing compounds.
Subject(s)
Catalysis , Chemistry, Organic/methods , Metals , Oligopeptides/chemistry , Peptide Library , Binding Sites , Drug Design , Ligands , Oligopeptides/chemical synthesisABSTRACT
Epoxides are versatile building blocks for organic synthesis. However, terminal epoxides are arguably the most important subclass of these compounds, and no general and practical method exists for their production in enantiomerically pure form. Terminal epoxides are available very inexpensively as racemic mixtures, and kinetic resolution is an attractive strategy for the production of optically active epoxides, given an economical and operationally simple method. Readily accessible synthetic catalysts (chiral cobalt-based salen complexes) have been used for the efficient asymmetric hydrolysis of terminal epoxides. This process uses water as the only reagent, no added solvent, and low loadings of a recyclable catalyst (<0.5 mole percent), and it affords highly valuable terminal epoxides and 1, 2-diols in high yield with high enantiomeric enrichment.
Subject(s)
Catalysis , Epoxy Compounds/chemistry , Water/chemistry , Epoxy Compounds/isolation & purification , Hydrolysis , Kinetics , StereoisomerismABSTRACT
Enzymes, synthetic catalysts, and catalytic antibodies can all be used to perform asymmetric reactions, but their practical utility is not always easy to evaluate. Criteria with which to compare such catalysts are proposed and illustrated for asymmetric epoxidation, a reaction to which all three approaches have been applied.
