Reinhold Zimmer

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.

Synthesis of 5‐Acetyloxazoles and 1,2‐Diketones from β‐Alkoxy‐β‐ketoenamides and Their Subsequent Transformations

Lithiated alkoxyallenes, nitriles, and carboxylic acids have been employed as precursors in a three-component reaction leading to highly substituted β-alkoxy-β-ketoenamides. Upon treatment with trifluoroacetic acid, these enamides could be easily cyclized to 5-acetyloxazole derivatives. The synthesis is very flexible with respect to the substitution pattern at C-2 and C-4 of the oxazole core. A mechanistic suggestion for the oxazole formation is presented on the basis of (18)O-labeled compounds and their mass spectrometric analysis. In several cases, 1,2-diketones are formed as side products or even as major components. The acetyl moiety at C-5 of the oxazole derivatives can efficiently be converted into alkenyl or alkynyl moieties, which allows a multitude of subsequent reactions. Condensation reactions of the acetyl group provided the expected oxime or hydrazone. By applying a Fischer reaction, the phenylhydrazone could be transferred into an indole, which emphasizes the potential of 5-acetyloxazoles for the preparation of highly substituted (poly)heterocyclic systems. The alkynyl group at C-2 is prone to addition reactions, providing an enamine with interesting photophysical properties. Sonogashira couplings were performed with 5-alkynyl-substituted oxazoles, furnishing the expected aryl-substituted products. This alkynyl unit was employed for the preparation of a new, star-shaped trisoxazole derivative. The ability of this multivalent compound to form self-assembled monolayers between the basal plane of highly oriented pyrolytic graphite and 1-phenyloctane was demonstrated by scanning tunneling microscopy (STM). The star-shaped compound seems to prefer the C(3)-symmetric arrangement in this two-dimensional crystal. Two 1,2-diketones were smoothly converted into functionalized quinoxaline derivatives.

Thrilling Strain! Donor–Acceptor‐Substituted Cyclobutanes for the Synthesis of (Hetero)Cyclic Compounds

The analogy goes further: Following the often-studied donor-acceptor-substituted cyclopropanes, the corresponding cyclobutane derivatives were employed for the ring-strain-driven stereoselective syntheses of carbo- and heterocycles.

Optimisation, Scope and Limitations of Enantioselective Aldol Reactions of an S‐Ketene Silyl Acetal with Aliphatic Aldehydes under (R)‐BINOL‐Titanium(IV) Catalysis Conditions

The Mukaiyama aldol reaction between the functionalised aldehydes 5 and the S-ketene silyl acetal 2 catalysed by 1,1′-binaphthyl-derived chiral titanium(IV) complex 4 afforded the corresponding aldol products 6 in good yields and with good to excellent enantioselectivities. The chemical yield could further be enhanced, without loss of stereoselection, by addition of phenol and/or molecular sieves. The presented aldol reactions with aluminium, boron and ytterbium-BINOL catalysts demonstrate that only low chiral induction can be achieved. Aldol product 6a was converted into an α-lipoic acid precursor 8, thus providing a formal synthesis of this biologically active compound. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Enantioselective synthesis of (S)- and (R)-6-hydroxy-8-nonene-carboxylates by asymmetric catalysis: a formal synthesis of (R)-α-lipoic acid and its (S)-antipode

Abstract A short and efficient enantioselective synthesis of (S)- and (R)-configured 6-hydroxy-8-nonene-carboxylates — precursors to (R)-α-lipoic acid and its (S)-enantiomer — by allylation of alkoxycarbonyl substituted aldehydes with allyltrimethylstannane and BINOL/Ti(OiPr)4 catalyst is described. The best results in terms of enantiomeric purity and yield are obtained employing 10 mol% of the titanium-species without molecular sieves.

SYNTHETIC MODIFICATIONS OF ASCOMYCIN. I: A CHEMOSELECTIVE REMOVAL OF THE CYCLOHEXYL RESIDUE OF ASCOMYCIN

Abstract An efficient semisynthetic preparation of des-28-(cyclohexyl)methylene-28-oxo-ascomycin derivatives starting from 24,33- O -bis( tert -butyldimethylsilyl)-ascomycin ( 1 ) is described. The strategy for preparing 28-oxo-ascomycin derivatives involves the reduction of C-22 carbonyl group, followed by 5-endo-cyclization of the resulting C-22 alcohol with the C-19/C-20 double bond using an oxymercuration reaction; ozonolysis of the C-28/C-29 double bond and regeneration of the C-19/C-20 double bond. Further, the 20-mercury-substituted ascomycin derivatives could be reduced to the corresponding metal free cyclic ethers using n -Bu 3 SnH.

Synthesis of (+)-Greek Tobacco Lactone via a Diastereoablative Epoxidation and a Selenium-Catalyzed Oxidative Cyclization

An asymmetric synthesis of the C11-homoterpenoid (+)-Greek tobacco lactone is developed starting from readily available (R)-linalool. The synthesis is comprised of four operations and features a diastereoablative epoxidation and an oxidative tetrahydropyran formation using vanadium-, palladium-, and selenium-catalyzed cyclizations.

Synthesis of Poly(Ethylene Glycol)–Supported (R)-BINOL Derivatives and Their First Application in Enantioselective Mukaiyama Aldol Reactions

Abstract The Mukaiyama aldol reaction of 2-styryl-oxazole-4-carbaldehyde (1) as model substrate with S-ketene silyl acetal 2 catalyzed by poly(ethylene glycol)-supported binaphthyl-derived chiral titanium(IV) complexes afforded the corresponding aldol product in good to excellent yields and enantioselectivities up to 94% ee. The chemical yields and/or the enantioselectivities are enhanced by generating the active catalyst from Ti(OiPr)4, polymer-supported ligands (R)-6 or (R)-8, and chiral or achiral promoters. Pyrrolidine derivative (S)-13 and trifluoromethyl-substituted phenol 12 are the most efficient additives found.

Lithiated 3-trifluoromethyl-substituted 1,2-oxazines and their reactions

Abstract 3-Trifluoromethyl-substituted 1,2-oxazine 1 was smoothly deprotonated with lithiumdiisopropylamine and subsequently treated with various electrophiles. Reactions with alkyl halides furnished the 4-alkylated 1,2-oxazines 4–7 in good yield and with excellent cis -diastereoselectivity, whereas carbonyl compounds could not be employed successfully as electrophiles. Deuteration of lithiated 1 afforded the 4-deuterated product 2 as a single diastereomer. Transfer of a nitro group was achieved with isoamyl nitrate as electrophile. A structure for lithiated 1 is proposed to explain the high diastereoselectivities. Treatment of 1,2-oxazines 5–7 with HClO 4 provided the trifluoromethyl-substituted oximes 11–13 in good yield, whereas reduction of 4 with LiAlH 4 furnished 3,4,5,6-tetrahydro-2 H -1,2-oxazine 14 with excellent diastereoselectivity.