Giovanni Casiraghi

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress†

Rephrasing Fusons original formulation, the principle of vinylogy explains how the influence of a functional group may be relayed to a distant point in the molecule when these two sites are connected to by conjugated unsaturated linkages, such as double and triple bonds or aromatic moieties. This principle has been applied, over the years, to the majority of polar carbon-carbon bond-forming reactions of various repute, including the venerable Michael addition reaction, where the electrophilic -CdX site (1,2-addition) is “usurped” by a remote conjugated -RCdCR-CdX position (1,4-addition). The aldol addition reaction and the related Mannich process, both fundamental pillars of organic synthesis, have not escaped this fate, and both of their vinylogous extensions have emerged as extremely valuable synthetic methodologies.

The Synthetic utility of furan-, pyrrole- and thiophene-based 2-silyloxy dienes

The aim of this review is to highlight the utility of a remarkable triad of 2-silyloxy diene synthons derived from furan, pyrrole and thiophene in organic synthesis. These heterocycles, in reacting with a number of carbonyl-related compounds (aldehydes, imines, heteroatom-stabilized carbenium ions), act as vinylogous nucleophile modules giving rise to a myriad of functionality-rich aldol-type constructs. These, in turn, represent invaluable synthetic platforms onto which a limitless number of functional elements and chosen chirality may be introduced. Eleven syntheses, amongst the most appealing of 1991–1999, have been chosen to illustrate the potentiality of silyloxy diene chemistry.

Bifunctional Cinchona Alkaloid/Thiourea Catalyzes Direct and Enantioselective Vinylogous Michael Addition of 3‐Alkylidene Oxindoles to Nitroolefins

3-Alkylidene oxindoles (methyleneindolinones), be they natural or man-made substances, occupy a preeminent position among the various classes of chemically and medicinally relevant small-molecule scaffolds. Their plural functional architecture featuring a lactam carbonyl flanked by a highly substituted exocyclic double bond renders them enabling intermediates to be elaborated into a myriad of useful nitrogen heterocycles of varied complexity. For example, 3-alkylidene oxindoles can be viewed as electrophilic Michael acceptors, which react with carbon-centered anions to give bsubstituted oxindoles of type A (Scheme 1a). In addition, they can act as electron-poor components in synchronous (Scheme 1b) or stepwise (Scheme 1c) cycloadditive functionalizations, thus opening the way to a wide range of highly valuable 3,3-spirocyclic structures of type B or C. Whereas these protocols have been largely pursued and formed the basis of many synthetic achievements, an “umpolung” option could also be envisaged (Scheme 1d), and capitalizes on the vinylogous pro-nucleophilic character of the alkyl group attached at the b-position of the ylidene. By reacting with the proper acceptors, these nucleophiles furnish olefinic oxindoles of type D, which are functionalized at the most distant point of the molecule (Cγ).

Total syntheses of N-boc-protected 3′-deoxy-4′-azathymidine and 4′-azauridine

Abstract Novel modified nucleosides 4, 11, ent-11, and 17, wherein the furanose ring oxygen is replaced by nitrogen, have been synthesized by reacting azasugars 3, 10, ent-10, and 15 with silylated uracil or thymine bases.

The four-carbon elongation of three-carbon chiral synthons using 2-(trimethylsiloxy)furan: highly stereocontrolled entry to enantiomerically pure seven-carbon α,β-unsaturated 2,3-dideoxy-aldonolactones

Abstract The BF3-promoted addition of 2-(trimethylsiloxy)furan to three carbon synthons derived from D- and L-glyceraldehyde, D- and L-serinal, and imines thereof furnishes C7 α,β-unsaturated 2,3-dideoxy-aldonolactone derivatives in high yield, with very high level of diastereoselection. In all the cases, compounds having 4,5-threo:5,6-erythro relative stereodisposition preferentially emerge from the reactions, accompanied by only marginal amounts of 4,5-erythro:5,6-erythro epimers. An empirical rule for the rapid assigment of the configuration at C-4 (γ-carbon) of γ- substituted unsaturated and saturated γ-butyrolactones is given, based upon the sign of the optical rotation values.

Total synthesis of 1,5-dideoxy-1,5-iminoalditols

Abstract Enantiomerically pure 1,5-dideoxy-1,5-imino-D-glycero-D-allo-heptitol (10) has been synthesized in ca. 9% overall yield by utilizing 2,3-O-isopropylidene-D-glyceraldehyde-N-benzylimine (1) as a chiral source and 2-(trimethylsiloxy)furan (2) as a homologative reactant. The opening move was the preparation of properly protected seven-carbon butenolide 4, followed by diastereoselective anti, cis-dihydroxylation of the lactone double bond and furanose-to-azapyranose ring expansion. This generated a piperidine intermediate 7, the stereochemistry of which was secured by a single crystal X-ray analysis of its diacetate 9.

Total synthesis of both enentiomers of trans-β-hydroxyppecolic acid

Abstract trans-β-Hydroxypipecolic acids of both l - and d -series, l -1 and d -1, have been straightforwardly prepared in 14% and 15% yields, respectively, starting from glyceraldehyde imines d -7 and l -7 as useful three-carbon chirons. The key feature of these parallel syntheses lies on the highly diastereoselective character of the initial coupling manoeuver between silyloxy furan TBSOF and imines 7, which ultimately accounts for the relative, and hence absolute configuration of the target pipecolic acids.

Template catalysis via non-transition metal complexes. New highly selective syntheses on phenol systems

A methodological approach to conventional phenol chemistry based on the concepts and achievements of modern coordination chemistry allowed to find specific conditions for improving classical reactions and discovering new selective processes. Substrates, reagents, and ligands could be organized around non transition metal cations in suitable complexes, which were able to control the reactions and to determine highly selective ortho—attack on phenol systems. Template reactions of phenol substrates with carbonyl compounds in the presence of suitable ligands led to new general processes of ortho—formylation, ortho—acylation, ortho—alkylation and allylation. A rational route to all—ortho regular novolac resins was also disclosed. By using the basic strategy of Ziegler—Natta catalysis, the first synthesis of isotactic and syndiotactic all—ortho ethylidene—linked polyphenols was performed. Other synthetically useful Friedel—Crafts processes were performed according to an intramolecular template mechanism leading to new syntheses of important classes of oxygen heterocycles such as flavenes, chromanes, benzofuran derivatives, benzodioxins, and benzopyrylium salts. STRATEGY Activation of phenols, enols and indoles, which are typical ambident nucleophilic systems, is traditionally achieved by using strong bases which convert the substrates into the corresponding anions (phenolate, enolate, etc.), along with the use of dipolar aprotic solvents of high donicity (1) or phase transfer catalysis (2). In these conditions, the negative influence of the cation on reactivity is strongly reduced and, as a consequence, high activation of the substrate is usually observed. Moreover, predominant or exclusive functionalization at the more negative center (0, N) of the ambident system occurs (3). Reversing this general synthetic strategy, some years ago we focused our attention on the possible positive role of the cation and looked at these reactions in terms of coordinated processes in self—organized systems rather than of anion activation only (4). As far as phenol chemistry is concerned, we studied the possibility to exploit the complex structures of phenol salts as self—catalyzing systems, thereby systematically changing their organization in order to control and diversify their reactivity. In this systems the cation can play a fundamental role in coordinating both the phenolic substrate and the reagent, inducing intramolecular irreversible reactions within the phenolate—reagent complex. In order to achieve this goal the following rules are strictly required: i) the structure of the salt has to be designed according to the reagent or, viceversa, the reagent has to be selected in order to chelate the cation; ii) solvent and any species present in the reaction medium must not exclude the reagent from complexation in the reactive structure of the salt. On these bases a systematic research on phenol salts of highly coordinating non—transition metals was undertaken, utilizing mainly salts of lithium, magnesium, zinc, titanium, etc., in aprotic non polar media. Initially we selected as reagents carbonyl compounds and their oxygen derivatives according to their known complexing ability towards the aforementioned hard cations.

Selective reactions between phenols and formaldehyde. A novel route to salicylaldehydes

Treatment of phenols (1) with 2 mol equiv. of paraformaldehyde in aprotic and poorly electron-donating solvents in the presence of selected metal halides coupled with suitable bases produces salicylaldehydes (3) in high yields. The route is highly selective for ortho-formylation and also specific towards monoformylation. The crucial role of added bases is emphasized.

anti -selective, catalytic asymmetric vinylogous Mukaiyama Mannich reactions of pyrrole-based silyl dienolates with n-aryl aldimines

Pyrrole-based silyl dienolates undergo asymmetric vinylogous Mukaiyama Mannich reactions with a series of N-aryl aldimines in the presence of the Hoveyda-Snapper amino acid-derived silver(I) catalysts. The Mannich products-α,β-unsaturated δ-amino-γ-butyrolactams-are typically obtained in high yields, excellent γ-site selectivities and anti-diastereoselectivities, and up to 80% enantioselectivity.