Mechanochemical Pd-Catalyzed Amino- and Oxycarbonylations using FeBr2(CO)4 as a CO Source.

Herein, we describe the development of mechanochemical amino- and oxycarbonylation employing FeBr2(CO)4 as a solid CO source. This Pd/XantPhos-catalyzed reaction affords a range of carboxamides and esters from aryl iodides and various amines or phenols. Both primary and secondary amines, including amino acids, can be employed as N-nucleophiles.

Synthetic Study of Natural Metabolites Containing a Benzo[c]oxepine Skeleton: Heterocornol C and D.

A versatile strategy for the enantioselective synthesis of a benzo[c]oxepine structural core containing natural secondary metabolites was developed. The key steps of the synthetic approach include ring-closing alkene metathesis for seven-member ring construction, the Suzuki-Miyaura cross-coupling reaction for the installation of the double bond and Katsuki-Sharpless asymmetric epoxidation for the introduction of chiral centers. The first total synthesis and absolute configuration assignment of heterocornol D (3a) were achieved. Four stereoisomers, 3a, ent-3a, 3b and ent-3b, of this natural polyketide were prepared, starting with 2,6-dihydroxy benzoic acid and divinyl carbinol. The absolute and relative configuration of heterocornol D was assigned via single-crystal X-ray analysis. The extension of the described synthetic approach is further presented with the synthesis of heterocornol C by applying the ether group reduction method to the lactone.

A Universal Strategy for Synthesis of Agropyrenol Family. Total Synthesis of Agropyrenol, Sordarial, and Heterocornol A and B.

A divergent strategy for natural polyketides synthesis has been designed. This synthetic route allowed chemical alterations leading to all stereoisomers of the natural agropyrenol 1, sordarial 2, and heterocornol B 4. Key steps involve desymmetrization of divinylcarbinol using asymmetric Sharpless epoxidation and Heck coupling of an easily available aromatic partner and prepared chiral alkene. The versatility of the synthetic method was demonstrated on the preparation of heterocornol A 3 and sordariol 5. The absolute and relative configurations of prepared natural compounds 2·1/3C6H12 and 4 were confirmed and assigned by single-crystal X-ray analysis.

Continuous Pd-Catalyzed Carbonylative Cyclization Using Iron Pentacarbonyl as a CO Source.

This work discloses a continuous flow carbonylation reaction using iron pentacarbonyl as source of CO. The described transformation using this surrogate was designed for use in commonly accessible flow equipment. Optimized conditions were applied to a scalable synthesis of the natural compound isolated from perianal glandular pheromone secretion of the African civet cat. In addition, a flow Pd-catalyzed carbonylation of aryl halides is successfully reported.

One-Step Synthesis of Isoindolo[2,1-a]indol-6-ones via Tandem Pd-Catalyzed Aminocarbonylation and C-H Activation.

A unified catalytic system for tandem Pd-catalyzed carbonylation and C-C cross-coupling via C-H activation was designed. The proposed cascade reaction allows a facile one-step construction of a tetracyclic isoindoloindole skeleton, in which three new C-C/C-N bonds are simultaneously formed. In detail, the carbonylation of aryl dibromides with indoles and C-H activation of in situ formed N-(2'-bromoaroyl)-indole provide biologically relevant 6H-isoindolo[2,1-a]indol-6-ones from commercially available substrates. The aminocarbonylation step in the proposed tandem reaction utilizes glyoxylic acid monohydrate as an environmentally friendly CO surrogate.

Total Synthesis, Configuration Assignment, and Cytotoxic Activity Evaluation of Protulactone A.

The first total synthesis and absolute configuration assignment of protulactone A (1) has been achieved. Four stereoisomers, 1a, ent-1a, 1b, and ent-1b, of this natural polyketide were prepared by chiral pool synthesis starting from l- and d-arabinose, respectively. The absolute and relative configurations of all isomers were assigned by single-crystal X-ray analysis. Target compounds were screened for their in vitro cytotoxicity toward certain human tumor cells (NCI60 cancer cell line panel).

Zn-Mediated Reduction of Oxalyl Chloride Forming CO and Its Application in Carbonylation Reactions.

An efficient protocol for the generation of carbon monoxide by Zn-mediated reduction of oxalyl chloride has been developed. Oxalyl chloride was applied as an extremely effective substitute for toxic gaseous CO in the palladium-catalyzed alkoxy-/amino-/hydrogen-/hydroxycarbonylation processes providing industrially interesting esters, amides, aldehydes, and carboxylic acids in good to excellent yields. This new procedure can be applied to various carbonylation reactions in the presence of a transition metal catalyst under mild conditions and with a stoichiometric amount of CO source.

Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds.

The study of Pd-catalysed cyclisation reactions of alkenols using different catalytic systems is reported. These transformations affect the stereoselective construction of mono- and/or bicyclic oxaheterocyclic derivatives depending on a starting alkenol. The substrate scope and proposed mechanism of Pd-catalysed cyclisation reactions are also discussed. Moreover, the diastereoselective Pd-catalysed cyclisation of appropriate alkenols to tetrahydrofurans and subsequent cyclisation provided properly substituted 2,5-dioxabicyclo[2.2.1]heptane and 2,6-dioxabicyclo[3.2.1]octane, respectively. Such bicyclic ring subunits are found in many natural products including ocellenynes and aurovertines.

Asymmetric approach to hyacinthacines B1 and B2.

Naturally occurring hyacinthacines B1 and B2 have been prepared from a common, easily available, advanced intermediate. The approach features several highly stereoselective transformations: inter alia, a dichloroketene-enol ether [2 + 2] cycloaddition, a Bruylants alkylation, and an amino-nitrile alkylation-reduction.

A prototype continuous-flow liquid-liquid extraction system using open-source technology.

A prototype continuous-flow liquid-liquid extraction system is reported. By harnessing several open-source software libraries, a computer control script was written using the Python programming language. Using a 'computer-vision' approach, this allowed the computer to monitor the interface level between the organic and aqueous phases using a simple webcam setup and (by dynamically controlling pump flow rate) to keep this interface within defined limits. The system enabled the efficient 'inline' extraction of excess reagent in hydrazone formations, dithiane formations and epoxidations. The initial results of dispersion measurement are also presented.

Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal-Knorr pyrrole formation and gas concentration measurement by inline flow titration.

Using a simple and accessible Teflon AF-2400 based tube-in-tube reactor, a series of pyrroles were synthesised in flow using the Paal-Knorr reaction of 1,4-diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature.

Teflon AF-2400 mediated gas-liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO concentration.

We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situ FTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.

Enantiopure aminopyrans by a Lewis acid promoted rearrangement of 1,2-oxazines: versatile building blocks for oligosaccharide and sugar amino acid mimetics.

1,3-Dioxolanyl-substituted 1,2-oxazines, such as syn-1 and anti-1, rearrange under Lewis acidic conditions to provide bicyclic products 2-5. Subsequent reductive transformations afforded enantiopure 3-aminopyran derivatives such as 7 and 9 or their protected diastereomers 16 and 18, which can be regarded as carbohydrate mimetics. An alternative sequence of transformations including selective oxidation of the primary hydroxyl groups in 21 and 24 led to two protected beta-amino acid derivatives with carbohydrate-like backbone (sugar amino acids). Treatment of bicyclic ester 23 with samarium diiodide cleaved the N--O bond and furnished the unusual beta-lactam 27 in excellent yield. Alternatively, gamma-amino acid derivative 29 was efficiently prepared in a few steps. Fairly simple transformations gave azides 32 and 35 or alkyne 30 which are suitable substrates for the construction of oligosaccharide mimetics such as 34 by copper iodide catalyzed cycloadditions. With this report we demonstrate that enantiopure rearrangement products 2-5 are protected precursors of a variety of polyfunctionalized pyran derivatives with great potential for chemical biology.

Approach to the hyacinthacines: first non-chiral pool synthesis of (+)-hyacinthacine A1.

The first non-chiral pool total synthesis of (+)-hyacinthacine A(1) is described. This synthesis is based on an effective [2 + 2] cycloaddition of dichloroketene to a Stericol-based enol ether, a diastereoselective dihydroxylation, and an efficient Tamao-Fleming oxidation.