Hans-Ulrich Reissig

Sugars, alkaloids, and heteroaromatics: exploring heterocyclic chemistry with alkoxyallenes.

As master craftsmen, modern synthetic chemists are challenged to achieve remarkable feats of efficiency and elegance toward molecular targets. The nature of this pursuit necessitates the collection of synthetic repertoires that are tried and true. With methodologies and pathways increasingly scrutinized, the adept chemist must seek out propitious tools to incorporate into the arsenal. With this in mind, this Account highlights the versatility of alkoxyallenes as precursors to valuable heterocyclic building blocks for such efforts as natural product synthesis. Accessed by the etherification of either propargyl alcohols or propargylic halides, alkoxyallenes are obtained after base-catalyzed isomerizations of the propargylic ethers. A host of umpolung synthons are available through this scheme after metalation, generating C(3) nucleophiles synthetically equivalent to vital anionic and zwitterionic synthons. Reactions with a diverse set of heteroatomic electrophiles yield carbohydrates, spiroketals, alkaloids, and heteroaromatics via [3 + 2] or [3 + 3] cyclizations. By employing lithiated alkoxyallenes into transformation routes, the natural product chemist can utilize this methodology as a viable resource in stereoselective synthesis. A survey of our own utilization of alkoxyallenes along synthetic pathways toward natural product targets reveals their suitability for generating advantageous precursors. A set of four stereoisomeric 2,6-dideoxyhexoses were stereoselectively obtained after an initial lithiated alkoxyallene and lactaldehyde cyclization, followed by the oxidative ring opening of the dihydrofurans. Through the addition of a lithiated alkoxyallene to a functionalized benzaldehyde, an essential spiroketal diastereomer was rapidly achieved in a few steps. We greatly benefitted from alkoxyallenes in the construction of complex nitrogen-containing synthetic targets, whether pyrrolidine alkaloids, substituted imidazole derivatives, or functionalized pyridines. A pinnacle example of their utility came from the coupling of alkoxyallenes to nitrones affording 1,2-oxazines, which served as a gateway to an array of novel polyfunctionalized compounds such as aminopolyols, hydroxylated pyrrolidines, or carbohydrate mimetics. Alkoxyallenes have proven themselves to be powerful C(3) building blocks toward complex molecular targets, revealing novel pathways to a variety of desirable highly functionalized heterocycles. In our view, the full extent of their synthetic utility has yet to be truly realized.

Three Carbons for Complexity! Recent Developments of Palladium-Catalyzed Reactions of Allenes

The three carbon atoms of allene moieties allow unique transformations and rapid generation of complexity. Not surprisingly, allenes became extremely versatile building blocks in organic synthesis. Transition‐metal‐catalyzed reactions of these cumulene π‐systems have been particularly successful, and many applications in the synthesis of complex products have been reported. This review summarizes the palladium‐catalyzed transformation of allenes published during the last decade. Many of the examples presented are impressive multicomponent processes or cascade reactions involving two or more steps leading to molecular complexity in simple one‐pot operations. Consequently, several reactions have been developed with the goal of delivering new synthetic routes to natural products.

A New Samarium Diiodide Induced Reaction: Intramolecular Attack of Ketyl Radical Anions on Aryl Substituents with Formation of 1,4-Cyclohexadiene Derivatives

Beware of samarium diiodide and aryl ketones! If the ketyl radical anion which is formed by electron transfer finds a properly placed aryl group, a highly diastereoselective cyclization may occur. After the transfer of a second electron and protonation bi- and polycyclic products with a common 1,4-cyclohexadiene moiety may be isolated [Eq. (a)]. X=CHCO2 R, NCH2 Ph; HMPA=(Me2 N)3 PO.

Lewis-acid-promoted additions of carbonyl compounds to donor-acceptor substituted cyclopropanes: a new synthesis of 2,3-dihydrofurane derivatives

Abstract Methyl 2,3-dihydrofurane-3-carboxylates are synthesized from siloxycyclopropaneesters and ketones in the presence of TiCl 4 with good yields.

A titanoxycyclopropane as intermediate in a highly stereoselective homoaldol type addition syntheses of cis-substituted tetrahydrofuran derivatives

Abstract Reaction of methyl 2-siloxycyclopropanecarboxylate 4 with TiCl4 provides the unique titanoxycyclpropane 10 whose structure could be elucidated by means of NMR-spectroscopy. Its additions to aldehydes and acetophenone occur with high stereoselectivity to afford homoaldol products like 6 . These intermediates can further be transformed to highly substituted tetrahydrofuran derivatives by activation with BF3-OEt2 and reaction with HSiEt3 or silylated carbon nucleophiles, respectively. This substitution involves an oxocarbenium ion and proceeds with excellent diastereoselectivity.

Three-component synthesis of perfluoroalkyl- or perfluoroaryl-substituted 4-hydroxypyridine derivatives and their palladium-catalyzed coupling reactions.

A three-component reaction with lithiated alkoxyallenes, nitriles, and perfluorinated carboxylic acids as precursors led to a series of perfluoroalkyl- or perfluoroaryl-substituted 4-hydroxypyridine derivatives. These compounds were converted into 4-pyridyl nonaflates which can be employed as versatile building blocks for the synthesis of pi-conjugated compounds with use of palladium-catalyzed couplings. Suzuki reactions at C-4 and C-3 of the pyridine ring proceeded with moderate to high yields. In addition, Suzuki-Miyaura, Stille, or Buchwald-Hartwig coupling reactions have also been studied and afforded the corresponding highly substituted pyridine derivatives. Starting from an arylated propargylic ether the three-component reaction led to a pentasubstituted 4-hydroxypyridine derivative that could also be employed in palladium-catalyzed processes at C-4 and at C-3 of the pyridine core. With this simple approach the sterically highly crowded 3,4,5-triphenyl-substituted pyridine derivative 37a could be prepared and studied by an X-ray analysis. With acetonitrile as precursor a different reaction pathway was found when this component was used in excess resulting in a pyridine derivative with a new substitution pattern. In summary, the methods described here allow a flexible and fairly efficient entry to a variety of highly substituted pyridine derivatives bearing perfluorinated alkyl or aryl groups.

Three-component synthesis of highly functionalized 5-acetyloxazoles.

By a flexible three-component synthesis, alkoxy-substituted enamides are easily available from lithiated alkoxyallenes, nitriles and carboxylic acids (see scheme). The treatment of these versatile intermediates with trifluoroacetic acid provided 5-acetyloxazoles in moderate to good yields. Different substituents are possible at C-2 and C-5 and the 5-acetyl group is a suitable handle for further synthetic transformations.

Stereoselective syntheses of heterocycles via metallated alkoxyallenes

n-Butyllithium smoothly deprotonates alkoxyallenes at C-1. The generated lithiated species reacts with a variety of electrophiles furnishing after cyclization functionalized furan, pyrrole, or 1,2-oxazine derivatives. The formation of new CC bonds often occurs with high stereoselectivities, which are exploited for efficient and selective syntheses of natural products or other compounds of interest.

Regioselective and stereoselective synthesis of vinylcyclopropane derivatives from 1,3-dienes and a Fischer carbene complex

Summary Reactions of acceptor-substituted 1,3-dienes with a carbene complex occur with high regioselectivity and stereoselectivity to provide trifunctional cyclopropane derivatives.

Stereocomplementary Routes to Hydroxylated Nitrogen Heterocycles: Total Syntheses of Casuarine, Australine, and 7‐epi‐Australine

Addition of lithiated 1-benzyloxyallene to a D-arabinose-derived cyclic nitrone occurred with perfect diastereoselectivity furnishing a bicyclic 1,2-oxazine derivative, which is an excellent precursor for pyrrolizidine alkaloids hydroxylated at C-7 with optional configuration at this stereogenic center. Depending on the stage of the N-O bond cleavage and ring re-closure, 7-hydroxypyrrolizidines with 7R or 7S configuration were obtained, as a result of completely selective addition reactions occurring complementarily at the bottom or top face of the endocyclic C-C double bond in six- and five-membered B rings, respectively. Applicability of these stereodivergent routes to obtain polyhydroxy pyrrolizidine alkaloids is demonstrated by the efficient syntheses of casuarine and australine as examples of the two classes of diversely configured 7-hydroxypyrrolizidine alkaloids. An alternative synthesis of australine and two strategies for the preparation of 7-epi-australine are also reported, which demonstrate that the stereoselectivity of hydride reduction of an exocyclic C-O double bond is independent of the ring size, occurring preferentially from the top face either in a six- or five-membered ring.