Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

William Sommer

The enyne cycloisomerization is one of the most important reaction for the synthesis of functionalized cyclic structures.1 The structural complexity resulting from the cyclization of relatively simple acyclic subunits explains the enthusiasm surrounding this method. Among the catalyst used for this reaction, gold stands out as one of the most potent, yielding a wide array of cyclic products under mild conditions with high efficiency.

In 2004, Toste and coworkers reported the cycloisomerization of 1,5-enynes to bicyclo[3.1.0]hexenes in a high yielding stereocontrolled fashion, using a variety of gold catalysts.2Terminal and internal alkynyl substrates were screened showing equal reactivity. The catalyst system utilizes (Ph3P)AuCl in combination with AgBF4, AgPF6 or AgSbF6 activators. In a typical reaction 1 to 3 mol % of gold catalyst is needed in dichloromethane at room temperature (Scheme 1).

Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

Scheme 1.Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

This work was then followed by the report in 2005, by the Toste group, of the cycloisomerization of 1,4-enynes through the Rautenstrauch rearrangement. This new method provides an expeditious route to a diverse portfolio of functionalized cyclopentanones.3 Chiral 1-ethynyl-2-propenyl pivalates efficiently rearrange enantioselectively under mild conditions. Either (PPh3)AuSbF6 or (PPh3)AuOTf (generated in situ) can be used, depending on the substrates (Scheme 2). In a typical reaction, 5 mol% of Au(I) in acetonitrile at –20 °C for 12 hours is combined with the enyne to yield the desired product.

Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

Scheme 2.Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

In 2006, Echavarren and coworkers reported the intramolecular cycloaddition of 1,6-enynes with substituted alkenes.4 This new method gives access to tricyclic skeletons in one step. This motif is an essential pattern in numerous natural products. Using a bulky-biphenylbased phosphine gold complex as catalyst, various enynes yielded the desired tricyclic products with good selectivity (Scheme 3).

Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

Scheme 3.Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

More recently, Zou et al. reported the cycloisomerization of various cyclopropyl alkynyl acetates to synthesize a series of 5-, 6-, and 7-membered carbocycles.5 In the following example, an homopropargyl acetate underwent cyclization to afford a cycloheptenone in 72% yield (Scheme 4). The authors demonstrated that the chirality of the molecules was transferred during the transformation with the final products having up to 89% ee.

Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

Scheme 4.Cycloisomerization of 1,4-, 1,5-,1,6-, and 1,7-Enynes

Hashmi ASK. 2007. Gold-Catalyzed Organic Reactions. Chem. Rev.. 107(7):3180-3211.
Jiménez-Núñez E, Echavarren AM. Molecular diversity through gold catalysis with alkynes. Chem. Commun..(4):333-346.
Hashmi ASK, Hutchings GJ. 2006. Gold Catalysis. Angew. Chem. Int. Ed.. 45(47):7896-7936.
Luzung MR, Markham JP, Toste FD. 2004. Catalaytic Isomerization of 1,5-Enynes to Bicyclo[3.1.0]hexenes. J. Am. Chem. Soc.. 126(35):10858-10859.
Shi X, Gorin DJ, Toste FD. 2005. Synthesis of 2-Cyclopentenones by Gold(I)-Catalyzed Rautenstrauch Rearrangement. J. Am. Chem. Soc.. 127(16):5802-5803.
Jiménez-Núñez E, Claverie CK, Nieto-Oberhuber C, Echavarren AM. 2006. Prins Cyclizations in Au-Catalyzed Reactions of Enynes. Angew. Chem. Int. Ed.. 45(33):5452-5455.
Zou Y, Garayalde D, Wang Q, Nevado C, Goeke A. 2008. Gold-Catalyzed Cycloisomerization of Cyclopropyl Alkynyl Acetates: A Versatile Approach to 5-, 6-, and 7-Membered Carbocycles. Angew. Chem. Int. Ed.. 47(52):10110-10113.

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