Reports: DNI149279-DNI1: Development of Intramolecular [4+1] Cycloadditions

Tristan H. Lambert, PhD , Columbia University

                  Theprimary aim of this research program was to develop new strategies to effect[4+1] cycloaddition reactions under mild conditions for the synthesis ofcomplex five-membered ring architectures. The research conducted with financial support from the PRF has lead notonly to the invention of a novel and broadly useful [4+1] strategy, but also tothe discovery of a number of unexpected research avenues with broad potentialimplications.

                  Ouroriginal proposal was based on the discovery of a new [4+1] strategy thatinvolved the direct palladium(II)-catalyzed intramolecular cyclopropanation of1,3-dienes by pendant beta-ketoesters, followed by a mildvinylcyclopropane-cyclopentene (VCP-CP) rearrangement mediated by magnesium(II)iodide.  Based on studies conductedwith PRF funding, we came to the conclusion that limitations of our oxidationstrategy would be best addressed by the identification of new oxidants thatwould effect the intramolecular cyclopropanation with broader substrate scopeand greater convenience.  As such,we identified a remarkably simple yet effective strategy for [4+1]cycloadditions involving molecular iodine and magnesium(II) iodide, in thepresence of triethylamine. This new [4+1] methodology substantially improves onour original approach, primarily in that it does not require a blockingfunctionality (e.g. gem-dimethyl group),works in a single flask, is highly efficient, and utilizes simple andinexpensive reagents rather than transition metals. 

                  Theutility of this [4+1] strategy is that it assembles rapidly and with highstereocontrol functionalized [6,5]-fused ring systems, a privileged motif inthe realm of complex molecules.  Tostress this point, we have been working to demonstrate the use of our [4+1]reaction for the rapid synthesis of a series of complex molecules.  The completion of these efforts, whichis expected shortly, will lead to a manuscript describing this new methodology,as well as further applications of this approach to complex moleculesynthesis. 

                  Oneof the major directions this research program has helped initiate is thedevelop of novel oxidation methods. For example, we have developed the Saegusa-type oxidation process weobserved in our original method development, which was in that case undesired,and have turned it into a convenient and selective aldehyde oxidation protocolto generate unsaturated aldehydes. The key aspect to this reactivity is the use of a Lewis acid salt,specifically magnesium(II) perchlorate or ytterbium(III) triflate.  This work is completed and a manuscriptis in preparation.

                  Asa continuation of our efforts to identify alternative oxidation protocols, wehave subsequently investigated the use of cyclopropenium ions as a new class ofhighly tunable organocatalysts for visible light photoredox chemistry.  Cyclopropenium ions are readilysynthesized in one or two steps from commercially available materials and offera tremendous range of structural and electronic tunability.  We have found that appropriatelysubstituted cyclopropenium ions catalyze the a-cyanation of amines, aswell as other reactions, under irradiation from simple fluorescent lightsources.  We expect these newphotocatalysts may provide an important new tool for chemists involved inphotoredox catalysis.

                  Ourexploration of novel oxidants has also led us to explore a previously unknownfunctional group in organic chemistry, namely the diaziridinium ion.  Although these structures have beenproposed as intermediates for certain processes, none have been isolated or characterized.  We were intrigued by the possibilitythat diaziridinium ions might display nitrogen transfer reactivity, analogousto the oxygen transfer reactivity of dioxiranes and oxaziridinium ions.  We have successfully synthesized andcharacterized a diaziridinium ion for the first time and have discovered anintriguing nitrogen insertion reaction that utilizes these intermediates.  We are now preparing a manuscriptdescribing these findings.

                  Finally,and perhaps most significantly, we became interested in strategies that wouldallow us to develop asymmetric variants of our [4+1] cycloaddition in order toaccess the valuable cycloadducts in enantioenriched form.  Among the numerous possibilities, wewere particularly interested in chiral Brznsted base catalysis as a potentiallyhighly effective strategy. Subsequently, we have found that cyclopropeneimines are an extremelypromising new class of chiral Brznsted base, with significantly higherbasicities, and hence reactivity, compared to established systems.  Although in its early developmentstages, this discovery is expected to lead to a major research programentailing numerous advances for the field of synthesis and catalysis. 

                  Thefunding provided by the PRF has had a major impact on the PI's earlycareer.  In a direct sense, it hasallowed us to advance our [4+1] program through the development of a highlyefficient and general new strategy, which should enable a range of applicationsinvolving complex molecule synthesis. In addition, the pursuit of this primaryresearch goal has allowed us to uncover a number of exciting new discoveries,several of which are expected to become major research endeavors.  In part due to the work supported bythis grant, our group was able to successfully compete for an NSF CAREERgrant.  Without question, this PRFgrant has been crucial to the successful launching of the PI's career.

                  Theimpact of PRF funding on the students who were supported has been significantas well.  Perhaps the greatestreflection of that impact is on where those students who have graduated havesecured further employment.  Inthis regard, two students are currently postdoctoral fellows in organicsynthesis, at Harvard with Eric Jacobsen (Dr. David Hardee) and at UC-Berkeleywith Richmond Sarpong (Dr. Ethan Fisher). A third student is a postdoctoral fellow at Rockefeller University inthe lab of Howard Hang (Dr. Lisa Ambrosini-Vadola).  A fourth student (Dr. Julia Allen) is now working in thechemical industry at Infineum, a company involved in the petroleumindustry.  Finally, two students(Dr. Rockford Coscia and Dr. Brendan Kelly) have secured employment asscientific consultants at major firms in the New York area.  It is without question that theseemployment successes were aided in no small part by the successful researchthese students conducted as part of our PRF funded program.

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