Archive for the ‘organic synthesis’ Category

December 9, 2007

ts2.pngI have carried out simplified analysis of some recent papers on organocatalysis. The first example comes from a paper from the Jacobsen group (Raheem et al. J. Am. Chem. Soc. 2007, 13404, 10.1021/ja076179w) which describes a “H-bond donor” catalyst that effects an enantioselective Pictect-Spengler type reaction. Jacobsen attributes the selectivity to the substrate-halide-catalyst complex shown on the left. However, leaving the halide out of the complex yields an ion pair or perhaps a covalently bound intermediate as shown on the right. This brings the catalyst and substrate into closer contact than the halide-containing complex.

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A ground-state model of the des-halide intermediate appears to work in explaining the enantioselectivity of the reaction as shown in the pictures below. In intermediate I, which leads to the minor enantiomer, the indole ring is not able to cyclize onto the acyliminium ion since it is being blocked by an appendage projecting from the catalyst. In contrast when the catalyst is bound to the other face of the acyliminium ion, as in intermediate II, the indole is free to cyclize which leads to the observed dominant enantiomer. Although Jacobsen indicates that some of their experimental work on the mechanism of catalysis makes the direct interaction of the catalyst with the acyliminium less likely, this intermediate is consistent, at least qualitatively, with the stereoselectivity reported for the paper. I am eager to see more details concerning the mechanism to see if this my interpretation holds up.

Intermediate I

intermediatei.png

Intermediate II

intermediateii.png

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August 13, 2007

August 13, 2007

The summer will be winding down soon and I am hoping to get back on track with posting.

There is an interesting paper from David Milstein (Weizmann Institute of Science) in the August 10th issue of Science describing the synthesis of amides from alcohols and amines. The method employs a special Ruthenium catalyst that effects the removal of two equivalents of H2, as shown below, in order to form the amide group. What makes this method attractive is that it requires only a small amount of catalyst, 0.1 mol%, and is stoichiometric for both the alcohol and amine starting materials. Nonetheless, it might be hampered by the fact that the catalyst must be handled under strictly controlled Argon-atmosperic conditions (Glove box) and so far has only been demonstrated on millimolar scale reactions.

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New Coupling Reaction???

June 1, 2007

I realize I am not the first to highlight this paper….

An interesting reaction was reported in the May 25th issue of Science.  The method is touted as a new coupling method and involves an apparent Pd-catalyzed aryl cross-coupling reaction between two different “non-activated” aromatic substrates without the formation of homo-coupled products.  This could potentially be a useful and expedient method for the synthesis of biaryl-compounds since it avoids the necessicity of using aryl-halide, -stannane, -borate, etc…  starting materials according to the traditional transition metal coupling methods.

While I think this is interesting I am not sure this method provides a general solution to the issue of transition metal catalyzed cross-coupling of “non-activated” aromatic substrates.  Setting aside the the fact that the method requires a large excess of the phenyl component, the use of indole, which is the only example inlcuded in the paper as the other component of the reaction, suggests that there is a serious limitation in scope (I must assume that other heterocyles were tried but failed to deliver the desired product) Reactions at the C3-position of indole are well known and therefore the deck seems to be stacked in the author’s favor. In addition, the authors ignore the possiblity that Pd(II) might be acting as a Lewis acid.  As I show below, Tajima and Nakatsuku have shown the same transformation is possible using AlCl3 and MnO2. Granted this is not catalytic but it shows a parallel mechanism without the

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Synthesis of indolizines, pyrrolones and indolizinones

March 22, 2007

Simple heterocycles are the work-horse of modern medicinal chemistry, but unfortunately they don’t get as much attention, at least in academia, as more sterochemically complex molecules. I have had many instances where I needed to make a certain heterocyclic target but found that there was very little, if any, literature precedent concerning the heterocycle I was interested in. It is refreshing to find academic types developing new methods for the synthesis of heterocylic systems.

An interesting paper in Org. Lett. from the Sarpong group at UC Berkeley involves a simple method for the synthesis of pyridine fused heterocycles starting from readily available starting materials. The key step in the method involves a Pt(II) catalyzed ring closure which subsequently undergoes proton transfer and/or rearrangement to provide 5 or 8, depending on the subtituent attached to the carbinol center.

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