Valence Tautomerism in Titanium Enolates: Catalytic Radical Haloalkylation and Application in the Total Synthesis of Neodysidenin

Abstract

A direct ruthenium-catalyzed radical chloroalkylation of N-acyl oxazolidinones capitalizing on valence tautomerism of titanium enolates has been developed. The chloroalkylation method served as the centerpiece in the enantioselective total synthesis of trichloroleucine-derived marine natural product neodysidenin.Among more than four thousand halogenated natural products identified to date, 1 neodysidenin and other trichloroleucine-derived marine metabolites comprise a unique group. 2 For the majority of chlorinated natural products, a reasonable biosynthetic pathway involving an electrophilic chlorination can be proposed. 3 On the other hand, the trichloromethyl group in neodysidenin and related compounds arises from a remarkable direct chlorination of the pro-R methyl group of L-leucine carried out by nonheme Fe II halogenases requiring oxygen, chloride, and α-ketoglutarate for their activity. 4 In contrast, availability of synthetic methods for stereoselective trichloromethylation is highly limited, 5 whereas chlorinated natural products are attracting increasing attention as targets for chemical synthesis. 6 In this communication we describe a practical, efficient method for highly stereoselective direct chloroalkylation of titanium enolates and its application in the total synthesis of neodysidenin zakarian@chem.ucsb.edu. Supporting Information Available:Experimental procedures and copies of 1 H and 13 C NMR spectra. This information is available free of charge via the Internet at http://pubs.acs.org. that can be readily adopted for the synthesis of other bioactive natural products in this class. 7 Guided by an extension of the classic Kharasch reaction8 described by Eguchi and coworkers, 9 our early efforts involved Ru(II)-catalyzed 10 redox trichloromethylation of trimethylsilyl enol ethers generated from chiral N-acyl oxazolidinones such as 1 (Scheme 1). 11 Although encouraging results were obtained with silyl ketene acetals (~50% yields, ds 3:1), the recent characterization of valence tautomerism in titanium enolates provided a conceptual foundation for the development of a direct radical chloroalkylation of N-acyl oxazolidinones. NIH Public Access 12,13The unconventional biradical character of titanium enolates described by Moreira and coworkers suggests that these intermediates should be efficient radical acceptors. 7 Indeed, when the Ti enolate derived from 1 14 was treated with BrCCl 3 in the presence of [Ph 3 P] 3 RuCl 2 as a readily available redox catalyst (7 mol%), product 2 was obtained in an essentially quantitative yield with exquisite stereocontrol (Scheme 1). The the mechanistic hypothesis in Scheme 1 is based on well-established redox activity of [Ph 3 P] 3 RuCl 2 widely used in atom-transfer radical polymerization (ATRP) 15 and is similar to that proposed by Eguchi for a related process with silyl enol ethers.9 A major advantage, however, is that the radical addition product should be stabilized by electron delocalization onto titanium, not feasible with silyl enol ethers. Th...

Highly Stereoselective and Practical Synthesis of α‐Trichloromethyl Amines and 2,2‐Dichloroaziridines from Chloroform

“…The reaction mixtures were stirred for 0.5 h. Then half-saturated NH 4 Cl/H 2 O solution (2 mL) was added at a lower temperature and the quenched reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO 4 . Evaporation of the solvent afforded the crude product, which was subject to flash chromatography to give the corresponding a-trichloromethyl amine 3.…”

“…[2,3] While chlorinated natural products are attracting increasing attention as targets for chemical synthesis, the availability of synthetic methods for stereoselective trichloromethylation is highly limited. [4] Very recently, Zakarian and co-workers developed an elegant diastereoselective ruthenium-catalyzed chloroalkylation of titanium enolates, which represents a viable approach to incorporate trichloromethyl group(s) into target compounds based on radical trichloromethylation strategy. [4a] Compounds that contain the a-trichloromethyl amine substructure are of great pharmacological interest due to their biological activities.…”

Dual Ti–Ru Catalysis in the Direct Radical Haloalkylation of N‐Acyl Oxazolidinones

“…The utility of this method in the synthesis of a range of chloroleucinederived natural products has been illustrated. [4, 6] One intriguing aspect of the reaction that emerged during our investigations is the possibility of the catalytic generation and alkylation of the titanium enolate species. Herein, we describe the development of a haloalkylation process that is catalytic in both ruthenium and titanium and thus constitutes the first example of a catalytic enolate alkylation involving titanium enolates.…”

“…[4, 6] One intriguing aspect of the reaction that emerged during our investigations is the possibility of the catalytic generation and alkylation of the titanium enolate species. Herein, we describe the development of a haloalkylation process that is catalytic in both ruthenium and titanium and thus constitutes the first example of a catalytic enolate alkylation involving titanium enolates.During an examination of the putative mechanism of the trichloromethylation process outlined in Scheme 1, [4, 5] we directed our attention toward the function of titanium tetrachloride. This mechanism suggests that TiCl 4 should be regenerated at the completion of the reaction, which creates potential for the development of a catalytic process.…”

“…[3] Recently, we described a different mode of alkylation of titanium enolates in which they serve as efficient radical acceptors for haloalkyl radicals generated by a rutheniumcatalyzed redox process. [4] It has been postulated that the enolate serves as an electroactive ligand for the titanium center, [5] whereby it facilitates the radical addition process and participates in the ruthenium catalytic cycle. The utility of this method in the synthesis of a range of chloroleucinederived natural products has been illustrated.…”