Alkylierung und Alkenylierung von α,β-Diketoestern – Beiträge zur Totalsynthese von Chrolactomycin

Zu Beginn der Arbeit wurde versucht ein mehrfach funktionalisiertes Cyclohexenon-Derivat in Anlehnung an J. BAUMEISTER[34] durch Alkylierung darzustellen. Als erstes Testsystem für diese Alkylierung wurde dazu das literaturbekannte Cyclohexenon-Derivat 84 über drei Stufen mit einer Ausbeute von 2...

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Main Author: Selter, Lars Jörn
Contributors: Koert, Ulrich (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Published: Philipps-Universität Marburg 2017
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Table of Contents: At the beginning of the present work, syntheses of highly functionalized cyclohexenon derivatives by alkylation were examined, following procedures of J. BAUMEISTER[34]. The first test system for this alkylation reaction was cyclohexenon derivative 84, familiar from the literature, which was prepared in three steps with an overall yield of 24% (Scheme 1). Scheme 1: Preparation of cyclohexenon derivative 84. Furthermore the silylenol ether 95 was synthesised by a solvent-free DIELS-ALDER-reaction in a very good yield of 95% (Scheme 2). Proceeding from the precursor 95 preparation of cyclohexenon derivatives 85 was achieved in 96% yield, 86 in 46% over three steps and 87 in 43% over three steps respectively. With those four cyclohexenon derivatives in hand the regioselective α-alkylation was investigated (Scheme 3). Various reaction conditions (bases, temperature, solvents and additives) were tested; however the desired product could not be isolated. The corresponding double alkylated side product was sometimes obtained in moderate yields. Scheme 3: Desired reaction of the cyclohexenon derivatives to the corresponding α-alkylated products 82. Since no suitable alkylation method could be found, a synthesis following SCHEIDT’s ocilactomycin synthesis[15] for the preparation of the highly functionalized cylohexenon derivative by DIELS-ALDER-reaction as the key step was envisioned. (R)-Citronellal (78) was chosen as starting material for the preparation of the diene, and the isolated stereogenic centre is therefore derived from the chiral pool (Scheme 5). In a four-step sequence starting from 78 (25 g), mesitylate 110 was obtained in 67% overall yield by addition of MeMgBr, benzoyl protection, ozonolysis (with reductive work-up) and by transforming the primary alcohol into the desired mesitylate (Scheme 4). By reductive benzoyl deprotection, PCC oxidation and TEBBE-reaction, the mesitylate 114 was obtained in three steps with 48% overall yield (Scheme 5). Up to this step all reactions were performed in a multi-gram scale. SN2-Reaction with sodium cyanide and subsequent reduction of the nitrile gave access to the aldehyde 116 in 88% yield. HORNER-WADSWORTH-EMMONS-Reaction under PATERSON-conditions followed by WITTIG-reaction finally led to diene 102 in 78% yield over two steps and starting from (R)-Citronellal (78) in 22% over eleven steps. Diene 102 was used in a Me2AlCl-mediated DIELS-ALDER-reaction together with the dienophile EVANS-auxilary 55 and the desired product 101 was obtained in 75% yield and high diastereoselectivity (Scheme 6). The auxiliary was cleaved reductively by LiBH4, and, after DMP-oxidation, aldehyde 124 was obtained in nearly quantitative yield. Starting from commercially available carboxylic acids 228, the methyl β-ketoesters 230 were prepared first. Via REGITZ diazotransfer and oxidation with tert-BuOCl the hydrates 278 could be obtained (Scheme 7). The corresponding cyclohexyl β-ketoesters 264 were prepared from 230 by transesterification. By diazotransfer and oxidation the hydrates 279 were accessible. These three or four steps respectively could be executed in a multi-gram scale with good overall yields, and storage of the hydrates was possible. The hydrates 278 or 279 were dehydrated to the corresponding α,β-diketoesters 282 and 283 by bulb-to-bulb distillation or by molecular sieves (Scheme 8). These vicinal tricarbonyl compounds (VTC) were freshly prepared prior to use in alkylation/ arylation reactions with ZnMe2, ZnEt2 or ZnPh2. A selection of prepared substances is shown together with the yields obtained. On the whole good yields were obtained for those alkylation/ arylation reactions, whereby substituents in γ-position have a great impact on the reaction. It becomes clear that good yields could be obtained in the case of electronic neutral or electron-rich α,β-diketoesters, whereas low yields were obtained for electron-poor derivatives. Sterical influences appear to have a minor impact on the yields and no significant differences were observed between methyl esters and the corresponding cyclohexyl esters. The alkenylation of VTC proved to be difficult, and many conditions had to be tested before this reaction was successfully accomplished using zincates. Alkenyl-dimethyl-zincates enabled the desired reaction, however methyl transfer was also observed. In order to force back the side reaction as much as possible, sterically demanding neopentyl rests were used instead of methyl groups. As shown in Scheme 9 and starting from different vinyl iodides (307, 309 or 311), lithiated species were prepared first by iodine lithium exchange. Mixed alkenyl-dineopentyl-zincates 328 were obtained next and by addition of the VTC 282 or 283 respectively their alkenylation could be achieved. Selected examples of substances prepared via this way are shown together with the corresponding yields in Scheme 10. Substituents in γ-position once again have a great impact on the reaction, and the best yields were obtained for α,β-diketoesters without enolizable protons adjacent to the outer carbonyl group. Good yields were obtained for electronic neutral or electron-rich VTCs, whereas reactions with electron-poor derivatives did not yield the desired products. No significant differences were observed between methyl esters and the corresponding cyclohexylesters. For the vinyl iodides good yields were obtained in the case of the 2,2-disubsitituted derivative 307, whereby E-vinyliodide 309 gave moderate to good yields, while reactions with Z-vinyl iodide 311 gave low yields only. In the case of vinyliodide 307, products with two stereogenic centres were obtained. Interestingly, the diastereomeric ratio is unequal 1:1. Depending on the substituents separation of both diastereomers via column chromatography was possible; nevertheless elucidation of the relative orientation of the stereo centres was not possible by NMR. It did, however, succeed in one case using X-ray analysis (Abbildung 8/ Figure 7). Reactions with 309 and 311 respectively showed that this reaction is stereospecific in regard to doublebond geometry. For broader applicability this reaction should be transferred to trisubstituted vinyliodides, for example. Vinyliodides with functional groups might as well be of interest as a transfer of alkyn anions. It might be accomplished by lithiation and subsequent transformation into the respective zincate. In future the alkylation/arylation as well as alkenylation reactions should be designed enantioselectively, in order to utilise them for the synthesis of complex target molecules. One possibility could be the use of chiral ligands (Scheme 11). The starting point for the development of suitable ligands might be chiral amino-alcohols, which are shown in Schema 77. These ligands are used for enantioselective addition reactions of dialkylzinc reagents to aldehydes, and a transfer to VTC appears possible.