Interdisciplinary PhD in Molecular Biosciences

Dr. Scott T. Handy - Research Interests

Project 1: The Regioselective Polycoupling Reaction (existing support by NIH)

Heteroaromatic systems are the heart of the majority of drugs and drug candidates, certainly in the pharmaceutical industry. Interestingly, the synthetic approaches to these compounds almost invariably follow the same classic condensation pathways. In part this is due to two main advantages: 1. Good predictability as to when they will and will not work and 2. Convergence. At the same time, the condensation reactions do have limitations, most notably, a limited range of substitution patterns that are accessible. For example, substituted pyrroles can be synthesized using the Knorr, Paal-Knorr, and Hantzsch syntheses, but both the Knorr and Hantzsch syntheses result in products with one or two ester moieties at the 2 and 4 positions while the Paal-Knorr synthesis affords only products substituted at the 2 and 4 positions.

A alternative to the condensation approach is the use of transition-metal catalyzed cross-couplings. The cross-coupling reaction (Stille, Suzuki, Negishi, etc.) is a phenomenally important and versatile reaction, particularly for the construction of carbon-carbon bonds between two sp 2-hybridized centers. Unfortunately, a major limitation is the greater linearity mandated by a cross-coupling approach. Thus, if one wishes to create a trisubstituted heteroaromatic compound using cross-coupling reactions, then three separate halogenation/coupling sequences will be required, resulting in a synthesis that will be at least 6 steps long. We have encountered such a situation in our first-generation synthesis of the lamellarin family of natural products in which over half of the synthesis is either a halogenation or a coupling step (6 out of 10 steps). 1 Clearly, if such an approach is to be rendered shorter, but maintain flexibility and convergence, then a new coupling paradigm is required.

The solution we have been developing is based on regioselective couplings of polyhaloheteroaromatics. Thus, all of the necessary halogens are installed in one step, followed by regioselective cross-coupling reactions in the second step. Now, a 6-step sequence (three halogenations and three couplings) can be reduced to 2 steps (one halogenation and one coupling) and very closely resembles the condensation pathways with respect to convergence, but with the flexibility of a cross-coupling reaction for the installation of a wide range of substituents.

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One of the two main questions that such an approach raises is whether regioselectivity in the coupling reactions can be achieved and, equally importantly, is predictable. A number of regioselective couplings of polyhalogenated heteroaromatics have been reported 2 and we have developed a method that accurately predicts the outcome of these reactions as well as others done in our group. This guide is based on the 1H NMR chemical shift data for the non-halogenated parent system upon which the halogenated substrate is based. 3 The more electron-deficient (more deshielded) site undergoes coupling first, followed by the less electron-deficient site.

The other critical question is whether multiple couplings can be performed in a one-pot fashion. We have published some successful double Suzuki couplings on pyridines, thiophenes, and pyrroles. (Scheme 1) Further, as yet unpublished work has also determined conditions for double Suzuki couplings of other thiophenes, thiazoles, quinolines, and pyrimidines. In general, all of these reactions work quite well and afford reasonable yields (40-90%) of the dicoupled products, which are easy to isolate. Although no uniform set of coupling conditions have been developed, a recent discovery using boronates in place of boronic acids has given hope that this can be achieved. 4 Further investigation of these boronate couplings on a wider range of heteroaromatics is a clear priority and readily achievable by undergraduate researchers in a finite period of time.

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The next significant step for this research is to move beyond just double Suzuki couplings. In particular, the ability to sequence different types of cross-couplings (mixed couplings) would be of great value. In a preliminary study, it has been shown that a one-pot Sonogashira/Suzuki tandem can be performed on dibromothiophenes and pyridines. The resultant products have great potential for future applications as the alkyne can be readily converted into an alkene, an alkyl group, or even a carbonyl group. Indeed, Scheme 2 illustrates some of the biologically oriented targets of interest: indolocarbazoles, the proximicins, and neolamellarins. In each of these cases, the brevity of the synthetic route will make it highly amenable for biochemical studies of these species. There are numerous other potential applications as well, so this project is expected to have a significant impact on synthetic chemistry and open the door to numerous interesting collaborations with other groups.

Project 2: Benzannulations

Building upon the Sonogashira/Suzuki coupling reactions, this opens the door to a very simple method for benzannulation. In one case, an initial mixed double cross-coupling of a 1,2-dihaloaromatic compound affords an arene/yne product 1. (Scheme 3) Compounds of this type have then been cyclized to afford tricyclic aromatics using various electrophiles (such as NIS or Au catalysis). 5 In the case of a halogen-induced cyclization, a new aryl halide 2 is produced, which can be the subject of further reactions, including an iterative route to highly benzannulated species.. Such compounds are graphene-like and are of interest in a number of areas, including the development of new acceptors for bulk heterojunction organic solar cells and various optical devices.

A second option for benzannulation is similar, but far less well precedented. In this case, a mixed double cross-coupling of a 1,2-dihaloaromatic will afford an ene/yne 4. (Scheme 3) Cyclization of this compound could be expected to occur thermally. Recently, there have been several examples of diene systems undergoing thermal electrocyclization, followed by in situ oxidation to afford benzannulated products. 6 With the ene/yne, an electrocyclization should directly afford a product at the correct oxidation state, but the reaction must proceed via a diradical intermediate. Although possible, this is likely to be a much less thermodynamically favored pathway. A second option involves electrophilic induction of the cyclization event. One isolated example of this reaction has recently been reported, and does lead directly to a benzannulated product 5, which would also contain a new halogen for further functionalization. As a result, there is much to be gained from such a reaction.

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There are many possible applications of this second type of benzannulation. One is the synthesis of highly substituted benzannulated heteroaromatics such as indoles and quinolines, which serve as the core of a large number of pharmaceutical agents. Still, the explored substitution patterns are limited due to the difficulty in readily preparing derivatives substituted in the benzene ring of the heteroaromatic. By using a benzannulation on a 1,2-dibromopyridine or pyrrole (both of which are readily available), though, now mono-, di-, or trisubstituted compounds could be prepared in a controlled fashion, thus enabling the exploration of this space for biological applications. Another application bridges both the biological and materials areas � the synthesis of benzannulated porphyrins. Such compounds are of interest as potential dyes for solar cells or in vivo optical imaging, and even as agents for photodynamic therapy. 7 The advantage in any of these areas is the fact that the benzannulated porphyrins should exhibit absorption into the far-red and infrared regions. For imaging and photodynamic therapy, this feature will enable deep penetration into soft tissue.


  1. Handy, S.T.; Zhang, Y.; Bregman, H.? J. Org. Chem.? 2004, 69, 2362-2366.
  2. Schroeter, S.; Stock, C.; Bach, T.? Tetrahedron? 2005, 61, 2245-2267.
  3. Handy, S.T.; Zhang, Y.? Chem. Commun.? 2006, 299-301.
  4. Handy, S.T.; Varallo, S.? Synthesis? 2009, 138-142.
  5. Yao, T.; Campo, M.A.; Larock, R.C.? J. Org. Chem.? 2005, 70, 3511-3517.? Furstner, A.; Mamane, V.? J. Org. Chem.? 2002, 67, 6264-6267.
  6. Toguem, S.M.T.; Hussain, M.;? Malik, I.; Villinger, A.;? Langer, P.? Tetrahedron Lett.? 2009, 50, 4962-4964.
  7. Ruzie, C.; Krayer, M.; Lindsey, J.S.? Org. Lett.? 2009, 11, 1761-1764.