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The Studies on the Synthesis of Endocyclic Enol Lactones via a RCM of Selected Vinyl Esters. Anna Brodzka, Filip Borys, Dominik Koszelewski, and Ryszard Ostaszewski J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00807 • Publication Date (Web): 12 Jun 2018 Downloaded from http://pubs.acs.org on June 12, 2018
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The Journal of Organic Chemistry
The Studies on the Synthesis of Endocyclic Enol Lactones via a RCM of Selected Vinyl Esters. Anna Brodzka, Filip Borys, Dominik Koszelewski, Ryszard Ostaszewski* Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warszawa, Poland KEYWORDS: Grubbs catalysts, ring-closing metathesis, endocyclic enol lactones
ABSTRACT: The novel and efficient approach toward the synthesis of endocyclic enol lactones was devised based on ring-closing metathesis of unsaturated carboxylic acids vinyl esters. Systematic studies revealed that vinyl esters are suitable substrates for RCM reaction. The developed methodology offers the easy route for synthetically challenging target molecules with different functional groups and substitution. We have also demonstrated that vinyl esters of cyclic carboxylic acids can be successfully applied for domino ring-opening ring-closing metathesis sequences.
Small ring unsaturated lactones are important intermediates in medicine, natural product chemistry or pharmacy.1 Among others, endocyclic enol lactones are of particular interest due to their biological activity2 and synthetic potential.3 Despite many literature routes for the synthesis of these compounds, only few are efficient. The most common method for the preparation of enol lactones is the alkynoic acids cyclization reaction catalyzed by acid4 or transition metal complexes.5 The main drawback of such procedures is low selectivity as both exo- and endocyclic enol lactones are formed. Another approach for obtaining endocyclic enol lactones is a BayerVilliger oxidation of α,β-unsaturated ketones.6 Despite the high efficiency, this methodology suffers from the lack of selectivity. Recently, much attention has been paid to the design of new synthetic routes for the synthesis of 3,4-dihydropyran-2-ones as they are valuable synthons7 in organic chemistry and possess interesting biological activities.8 Recent report published by Feringa et. al described an asymmetric conjugate addition of Grignard reagents to 2H-pyran-2-one and 5,6-dihydro-2Hpyran-2-one obtaining 3,4-dihydropyran-2-ones with good yield.9 Despite the high efficiency, this methodology suffers from harsh reaction conditions and limited scope because only 6-membered enol lactones were obtained. To overcome this inconvenience, ring-closing metathesis (RCM) reaction can be applied. RCM is one of the most powerful tools for a ring formation. Various rings –small, medium or large, carbocyclic or heterocyclic can be constructed from acyclic compounds using this strategy. To the best of our knowledge, no successful RCM of vinyl esters derivatives has
ever been reported. It has been reported that vinyl esters, comparably to vinyl ethers, are not suitable substrates for metathesis reaction as they deactivate the ruthenium-based metathesis catalysts by forming the unreactive Fischer-type ruthenium carbene.10 To circumvent this limitation, the molybdenumbased metathesis catalyst (Schrock-type) was successfully applied for metathesis of vinyl ethers derivatives.11 However, further studies proved that vinyl ethers are inactive only in ruthenium-based cross metathesis (CM), not ring-closing metathesis.12 According to the literature, the ring-closing metathesis of vinyl esters seems to be a problematic task, as such transformation has not been reported in literature. After many trials we have found that easily accessible vinyl esters of unsaturated carboxylic acids are suitable substrates for the synthesis of endocyclic enol lactones within the ring-closing metathesis methodology (Scheme 1). We anticipated that the application of vinyl esters as substrates may increase the entropic effect that can enhance the RCM product formation. Scheme 1. Ring-closing metathesis of vinyl esters.
The initial study was carried out using vinyl 3-phenyl-4-pentenoate (1a) as a model substrate to validate our approach. Several commercially available ruthenium metathesis catalysts – Grubbs 1st (C-1), Grubbs 2nd (C-2), Hov-
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eyda-Grubbs 2nd (C-3) and one molybdenum - Schrock catalyst (C-4) were tested as well as various solvents (Figure 1). The results are shown in Table 1.
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ducted in the presence of the Grubbs 2nd catalyst (C-2) as it demonstrated the highest activity towards a model substrate. When the reaction was performed in anhydrous dichloromethane (DCM) at 45oC, the desired product 2a was obtained with 56% yield (Table 1, entry 5). The change of DCM on higher-boiling dichloroethane (DCE) resulted in better efficiency (72%, Table 1, entry 6). The obtained results show that the best result was achieved in toluene at 80oC, using 5mol% of Grubbs 2nd catalyst (Table 1, entry 2). The application of 10 mol% of catalyst C-2 did not significantly affected the reaction yield. However, when lower amount of catalyst was used (3 and 1 mol%), the formation of product decreased drastically (Table 1, entries 7-8). It is worth to note that in all cases only RCM product was formed under optimal reaction conditions, and products of cross-metathesis (CM) were not observed. This result indicates that the mentioned above entropic effect indeed strongly affects the reaction course. Table 2. Screening of the RCM reaction parametersa
Figure 1. Metathesis catalysts.
Table 1. Screening of the RCM reaction parametersa
Entry
Substrate
Product
95 (95)
1 1b Yield [%]b
Entry
Catalyst
Solvent
Temp. [oC]
2a
Dimer
1
C-1
PhMe
80
28
