The direct oxidative diene cyclization and related reactions in natural product synthesis

The direct oxidative diene cyclization and related reactions in natural product synthesis Juliane Adrian‡, Leona J. Gross‡ and Christian B. W. Stark* Review Open Access Address: Fachbereich Chemie, Institut für Organische Chemie, Universität Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany Email: Christian B. W. Stark* - * Corresponding author ‡ Equal contributors Keywords: asymmetric synthesis; natural products; oxidation catalysis; tetrahydrofurans; total synthesis Beilstein J. Org. Chem. 2016, 12, 2104–2123. doi:10.3762/bjoc.12.200 Received: 04 June 2016 Accepted: 07 September 2016 Published: 30 September 2016 This article is part of the Thematic Series "Natural products in synthesis and biosynthesis II". Guest Editor: J. S. Dickschat © 2016 Adrian et al.; licensee Beilstein-Institut. License and terms: see end of document. Abstract The direct oxidative cyclization of 1,5-dienes is a valuable synthetic method for the (dia)stereoselective preparation of substituted tetrahydrofurans. Closely related reactions start from 5,6-dihydroxy or 5-hydroxyalkenes to generate similar products in a mechanistically analogous manner. After a brief overview on the history of this group of transformations and a survey on mechanistic and stereochemical aspects, this review article provides a summary on applications in natural product synthesis. Moreover, current limitations and future directions in this area of chemistry are discussed. Introduction Scope of this article After a concise introduction on the history and mechanistic aspects of the title reaction, the primary aim of the present review article is to summarize all relevant applications in natural product synthesis. The main text of this article is ordered by compound classes, so that tactics can easily be analysed and compared and similar applications can be condensed (both in the text and in the corresponding schemes). Methodology driven investigations as well as mechanistic studies are not the main focus of this review but may be mentioned in the introductory section. Likewise, syntheses of fragments of natural products applying an oxidative cyclization protocol [1,2] and sequential epoxidation/cyclization procedures [3] are not in the scope of this article and are therefore not covered. Previous review articles concerning oxidative diene cyclization chemistry can be considered in complement [4-6]. Oxidative cyclization – Historical background In 1924 Kötz and Steche reported on an investigation of the constitution of the monoterpene geraniol (1, R = H) [7]. Though the overall structure was known at that time, the position of one 2104 Beilstein J. Org. Chem. 2016, 12, 2104–2123. of the two C–C-double bonds within that natural product was in dispute (Scheme 1). Thus, the authors subjected a derivative (geranyl acetate (1, R = Ac), Scheme 1) to an aqueous solution of permanganate to dihydroxylate both double bonds in order to elucidate the structure. Elemental analysis of the crystalline reaction product (“Der reine Stoff bildet prächtige Krystalle …“ [7]) revealed that not one of the expected tetrols 2a or 2b (Scheme 1) but rather a cyclic anhydro compound seemed to be the result. Though a set of further reactions were carried out on this oxidation product, it proved not possible to establish its structure. It was not until 1965 when Klein and Rojahn at the flavours and fragrance company DRAGOCO (now Symrise AG) in Holzminden, northern Germany, reinvestigated the conversion of geranyl acetate (1b, R = Ac) with permanganate and were able to determine that the actual product is a 2,5bis(hydroxymethyl) THF (3 in Scheme 1, the general structure of which is today often as a simplification referred to as “THF diol”) [8]. In addition, they found that this reaction proceeds with high stereoselectivity (vide infra) and demonstrated that the reaction is not only limited to terpenes such as geranyl- (1b, R = Ac) or neryl acetate but seemed to be fairly general to other 1,5-diene substrates. Finally, they speculated on possible intermediates which may account for the outcome and the overall stereoselectivity of this unusual reaction. A mechanism, however, was not provided (vide infra). To date it is firmly established that in addition to the permanganate-mediated reaction, both ruthenium- as well as osmium tetroxide mediate the same transformation (cf. Scheme 3) and that these reactions can, contrary to the original permanganatepromoted process, be run in a catalytic fashion. All published protocols using the three different d0-metals are highly diastereoselective (vide infra) and have been shown over the past decades to be applicable to a broad range of starting materials. Scheme 1: Putative structures of geraniol 1a (R = H) or 1b (R = H) (in 1924), their expected dihydroxylation products 2a or 2b and the true structure 3 as determined by Klein and Rojahn in 1965 [8]. a fact that has recently been corroborated through density functional theory calculations both by Strassner and co-workers (Mn(VII) and Os(VIII)) [12,13] and by Kirchner and co-workers (Ru(VIII)) [14]. Reasonable fractions of the transTHF isomer can be produced using ruthenium tetroxide in specifically optimized solvent compositions [15] (for other means to obtain the trans-isomer from cis-THFs see the examples section below). Mechanistic aspects, stereochemistry and substrate scope of the direct oxidative diene cyclization Intrigued by the unique chemistry reported by Klein and Rojahn [8], several research groups initiated programs in order to shed light on the stereochemical course and mechanism of what appeared to be a direct oxidative diene cyclization. After a controversial debate from the early years of the discovery until the 1980s, it was finally broadly accepted that the overall reaction is a result of two consecutive syn-stereospecific [3 + 2]-oxidative cycloadditions (cf. type A mechanism; Scheme 3) [9-11]. Therefore, the double bond geometry of each of the two reacting double bonds translates directly to the relative stereochemistry of the vicinal hydroxy ether motif of the product (Scheme 2). The stereochemistry across the THF ring is set in the cyclization event. As a result of geometrical constraints it is usually predominantly or even exclusively cis (Scheme 2) – Scheme 2: Correlation between the substrate double bond geometry and relative stereochemistry of the corresponding THF diol products. 2105 Beilstein J. Org. Chem. 2016, 12, 2104–2123. Scheme 3: Mechanisms and classification for the metal-mediated oxidative cyclizations to form 2,5-disubstituted THFs. For all three procedures (using Mn(VII), Ru(VIII) and Os(VIII)) the scope of the reaction is very broad and a large number of 1,5-dienes with any kind of substitution pattern and double bond geometry have been used as substrates [4-6,16,17]. In addition, for Ru(VIII) [17-19] and Mn(VII) [21] it has been shown that also 1,6-dienes serve as substrates and can thus be (...truncated)