Direct Coupling of Indoles and Pyrroles

Countless natural products and biologically active compounds incorporate indole and pyrrole heterocycles. Any method that makes it easy to introduce these moieties into complex structures would be a boon to total synthesis and medicinal chemistry. Now, chemists at Scripps Research Institute have taken a step in that direction with a method to couple indoles and pyrroles with carbonyl compounds directly, without prior modification of either coupling partner. The chemists, led by Phil S. Baran, have shown that this approach can dramatically shorten routes to commercially relevant compounds.

In oxidative carbon-carbon heterocouplings, usually the coupling partners are primed to react by functionalization. In a Suzuki coupling to form a biaryl, for example, one reagent must be in the form of an aryl halide and the other, an arylboronic acid. In a sense, the partners are preprogrammed to seek each other and react. Preprogramming, however, incurs a cost in time, materials, and resources and does not always guarantee high yields. Eliminating preprogramming has been the focus of Baran and coworkers in considering how to install nitrogen heterocycles in complex structures.

IN THE SYNTHESIS of the alkaloid hapalindole Q, for example, Baran and graduate student Jeremy M. Richter used exactly the coupling partners indicated by retrosynthetic analysis without additional modification for the key carbon-carbon bond construction. They formed the bond simply by reacting carvone and indole in an oxidizing system containing a substoichiometric amount of copper(II) 2-ethylhexanoate as oxidant [J. Am. Chem. Soc., 126, 7450 (2004)].

In organic reactions, replacing the hydrogen in a carbon-hydrogen bond with anything else is equivalent to changing the oxidation state of the carbon atom in that bond, Baran says. By using unmodified indole and carvone, he and Richter accomplish an oxidative coupling using only the innate oxidation states of the reagents.

The effectiveness of the Scripps system can be appreciated by comparing it with previous syntheses of hapalindole Q. The most recent proceeds in about 1% overall yield [J. Am. Chem. Soc., 125, 14120 (2003)], compared with 22% for the Scripps route. In that earlier work, however, the structure was built upon an alkylated indole scaffold through an asymmetric Diels-Alder reaction.

A better apple-to-apple comparison would be with the first synthesis of hapalindole Q, in which a carbonyl compound also was coupled with an indole [J. Am. Chem. Soc., 115, 3499 (1993)]. In this work, the bond was formed by palladium-mediated coupling between a brominated and nitrogen-protected indole and the enol ester of the carbonyl compound in a reaction requiring tin-containing reagents.

The Scripps route is efficient, does not require protecting groups, and is so simple that "one graduate student can make large quantities of this rare marine-derived natural product in less than a week," Baran points out.

The Scripps approach boils down to discovering the appropriate oxidizing system that would work with just the native reactivity of the reagents. "We were aiming for as simple and as practical a route as possible," Baran says. As further demonstration of the method's usefulness, Baran and Richter have used the carvone-indole coupling product as the means to achieve the first total synthesis and absolute configuration assignment of a member of the class of alkaloids known as fischerindoles.

It appears that oxidative coupling exemplified by the direct copper-mediated coupling of an indole to a carbonyl compound might be more widely applicable. Recently, Baran, Richter, and graduate student David W. Lin reported direct coupling of pyrrole to carbonyl compounds, also mediated by a copper(II) oxidant. Furthermore, they have fashioned an intramolecular version in which the oxidant is an iron(III) species and used this reaction, in conjunction with a chiral auxiliary, in a three-step enantioselective synthesis of (S)-ketorolac, a pain reliever [Angew. Chem. Int. Ed., 44, 609 (2005)].

The Scripps route to (S)-ketorolac "won't revolutionize access" to the drug, Baran points out. "Industry has a wonderful way to make the racemic version and to resolve it enzymatically. The purpose is to show how rapidly you can make this type of compound without using halogens, disposable functionality, or protecting groups. Medicinal chemists needing to make that bond can make it in an afternoon instead of a week with a multistep synthesis," he adds.

In an accompanying paper [Angew. Chem. Int. Ed., 44, 606 (2005)], Baran, graduate students Carlos A. Guerrero and Benjamin D. Hafensteiner, and postdoctoral associate Narendra B. Ambhaikar demonstrate the versatility of the iron-mediated intramolecular oxidative coupling by applying it to the synthesis of the alkaloid stephacidin A. In this case, instead of a pyrrole, an amide is oxidatively coupled to an ester to forge a new ring and simultaneously set two of the stereogenic centers of the structurally complex natural product with complete stereo control. Neither of the coupling partners is prefunctionalized, Baran explains. "They just snap together with the correct stereochemistry."