Development of a Formal [4 + 1] Cycloaddition: Pd(OAc)2-Catalyzed Intramolecular Cyclopropanation and MgI2-Promoted VCP-CP rearrangement

Development of a Formal [4 + 1] Cycloaddition:

Pd(OAc)2-Catalyzed Intramolecular Cyclopropanation of 1,3-Dienyl-Keto Esters and MgI2-Promoted Vinylcyclopropane – Cyclopentene Rearrangement

Rockford W. Coscia, and Tristan H. Lambert

DOI: http://dx.doi.org/10.1021/ja809226x

About half a year ago this interesting paper was published and is still in the list of the most viewed papers of the JACS so I decided to put in my two cents and give you a short overview. The overall reaction looks like this:

Scheme 1

060409_11

As mentioned above the first step is a palladium catalysed cyclopropanation, which is the main investigation in this paper, followed by a vinylcyclopropane/cyclopentene rearrangement (VCP-CP) to give the cis-fused 5/6 ring system.

The first step involves a Mg(ClO4)2 induced enolisation with a simultaneously Pd(II) coordination to the 1,3-diene unit. The formed enol attacks the palladium complex to give the 6-membered ring. After another enolisation a fused cyclopropane is formed with concomitant reduction of the Pd(II) to Pd(0) which is reoxidised with the copper additive. While using Cu(OAc)2 as the oxidant a reductive elimination and a Saegusa type oxidation is observed due to a ligand exchange on the Pd(II) source, which can be overcome by changing the anion from acetate to iPrCO2. The reaction cycle is shown below:

Scheme 2

060409_21

Some compounds which were produced during the investigation are given in the next scheme:

Scheme 3

060409_31

The main drawback with this methodology is the need for a double substituted α-C to increase the yield and to prevent the above mentioned oxidation. Without these substituents the yield dropped to 52% (compound 3) but with complex starting materials the yield is still moderate (compound 4).

With these vinylcyclopropanes in hand a MgI2 induced ring opening/ring closure reaction was used to convert the cyclopropane to a cyclopentene.

The proposed mechanism is shown here:

Scheme 4

060409_41

The Lewis acidic MgI2 attacks the acetyl acetate moiety and releases an iodide. This opens the cyclopropane on reaction with the terminal alkene in a concerted or stepwise manner to give the allyl iodide. A SN2 reaction of the enolate closes the ring again to give this time the thermodynamically favoured cyclopentene. This process gives generally good yields in contrast to the varying yield of the first step.

Some examples were produced to test again the scope of the methodology.

Currently the authors are working on a more general route to 1) extend the strategy to other nucleophilic moieties, 2) remove the need for gem-dimethyl blocking group, and 3) running the two reactions in one pot.

Maybe by using a chiral Lewis acid it should be possible to increase the diastereomeric ratio? In conclusion I think that this methodology has a great potential and I am interested to see its first application in a total synthesis.

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