Fischer Carbene Catalysis of Alkynol Cycloisomerization: Application to the Synthesis of the Altromycin B Disaccharide

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol070435s.html

From Prof. Frank E. McDonald's group at Emory University, Atlanta, GA.

This article appeared in Org Lett ASAP demonstrates the utility of Fischer carbene and its novel non-photochemical method of activation for use in catalytic alkynyl alcohol cycloisomerization.

The general concept of this catalyst is shown in the following figure.

As seen in the figure, in the presence of catalytic amount of tungsten complex, alkynyl alcohol 1 is expected to cycloisomerize to give dihydropyran derivative 2. As for the tungsten complex, the conventional method of generating this catalyst involves photolysis of W(CO)6 in presence of Et3N. However, the tungsten Fischer carbene 3 could also be activated by Et3N to generating the reactive catalyst. Thus a stable and easily-prepared tungsten Fischer carbene 3 served a the pre-catalyst for the reaction.

Upon obtaining the optimal conditions for generating the catalyst, a number of substrates were screen in cycloisomerization and the results are summarized in the table below.

As seen in the table, a variety of cyclic enol ether products could be prepared using this method in good to excellent yields. However, further optimizations were needed for substrates possessing C3- and C4-oxygen substituents (such as 20, vide infra) as this substrate, under the current conditions, cycloisomerized to give a mixture of endo and exo cyclic products, 21 and 22, respectively. This is in contrast to using DABCO under photochemical conditions which gave better results with this substrate. The optimizations are shown in the table below.

The selectivity between endo and exo cyclization was found to depend on the steric bulk of C3-OSiR3 group. According to the proposed mechanism below, by having small SiR3 group on C3, coordination of tungsten to alkyne functioned as Lewis acid activation for the substrate to cyclize in the endo fashion. However, by increasing steric bulk of OSiR3, this pathway became less favored (see steric interaction in 25) while the eta-2 cooridnation of tungsten became more prominent. This action led to formation of the desired tungsten vinylidene, intermediate which further led to the desired endo cyclization product (ie. 23 -> 24 -> 26 -> 21). (Compare entries 3 and 6 in Table 2).

Finally, the utility of this method was shown in the successful synthesis of altromycin disaccharide as shown in the scheme below.