Design and Synthesis of Angularly Annulated Spirocyclics via Enyne Metathesis and the Diels–Alder Reaction as Key Steps

Abstract

We have developed a simple and an efficient route to a range of angularly fused spirocycles by the application of enyne metathesis and the Diels-Alder reaction as key steps. The enyne metathesis protocol has been further extended to the dibenzylation of indane-1,3-dione by using cross-enyne metathesis in the presence of hexa-1,5-diene with the aid of Grubbs' 1st generation catalyst followed by an aromatization sequence with DDQ.Since the development of ruthenium catalysts, 1 several metathesis protocols have opened up new and useful retrosynthetic strategies. 2 These advances have elevated organic synthesis to a higher level. The ring-closing enyne metathesis 3 (RCEM) protocol discovered by Katz in 1985 generate inner-outer 1,3-dienes, which are suitable for the Diels-Alder reaction. Generally, in the enyne metathesis sequence the alkylidene part migrates from the alkene to the alkyne carbon to deliver a conjugated diene and this skeletal reorganization is known as alkylidene migration reaction. Although ring-closing metathesis (RCM) is a useful route for the construction of carbon-carbon bonds, ring-closing enyne metathesis is unique and it is useful for the construction of conjugated 1,3-dienes containing polar functional groups in a single step. Over the last two decades, the metathesis sequence has been applied to generate challenging ring systems in natural products, 3k,4 in particular macrocyclic compounds and other biologically relevant substances. A number of selected bioactive natural products prepared by the enyne metathesis sequence are shown in Figure 1. 5 A simple access to dienes helps to expand the scope of the Diels-Alder reaction in preparative organic chemistry. It is worth noting that the DielsAlder reaction is a powerful tool that enhances molecular diversity immensely in a single step. Spirocyclics 2b,6 have attracted the attention of synthetic organic chemists because they constitute core structural units in several biologically important targets. 7 Molecules containing angularly fused aromatic systems with an extended π-framework are useful in designing electronic organic materials. These systems can create intricate molecular frameworks due to their unusual packing arrangement, which is difficult in linearly annulated structures. Although, a number of synthetic methods 8 are reported for the construction of linearly fused spirocyclics, only a limited number of strategies are available for the synthesis of angularly annulated spirocyclics. In our preliminary report, 9 we reported a simple synthetic strategy for the angularly annulation of indane-based spirocyclics starting with indane-1,3-dione (5) (Scheme 1, Figure 3). 10 Here, we report the full details of our preliminary work and also its extension to the generation of a library of angularly fused spirocyclics. We have assembled diverse spirocyclics by the sequential use of enyne metathesis and the Diels-Alder reaction which are atomeconomic. We have also expanded the metathesis sequence to a dibenzylated product by employing a crosseny...

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