Nature makes a wide range of complex, stereodense molecules starting with only a few acyclic terpenes (molecules constructed from isoprene units) such as farnesyl pyrophosphate (shown above). Many details of the complicated mechanisms that Nature uses to convert farnesyl pyrophosphate into complex terpenoid natural products such as pentalenene (above) remain to be uncovered. We are using computational quantum chemistry to study the mechanisms of these reactions, both in the presence and absence of enzyme catalysts.
For example, we find two distinct pathways for pentalenene formation (above), each differing from previous mechanistic proposals, and each involving unusual and unexpected intermediates. Diversions from these pathways lead readily to caryophyllene, humulene, africanene, protoilludene, and asteriscadiene via deprotonation, indicating that a key function of pentalenene synthase is to regulate the timing and location of proton removal.
The following papers describe some of the overall themes we have uncovered...
Tantillo, D. J. J. Phys. Org. Chem. 2008, 21, 561-570: "Recent Excursions to the Lands between Concerted and Stepwise: From Natural Products Biosynthesis to Reaction Design"
[concerted rearrangements with asynchronous events]
Tantillo, D. J., submitted: "The Carbocation Continuum in Terpene Biosynthesis - Where are the Secondary Cations?" invited tutorial review.
[survey of different sorts of delocalization, avoidance of secondary carbocations]
Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2009, 131, 7999-8015: "Consequences of Conformational Preorganization in Sesquiterpene Biosynthesis. Theoretical Studies on the Formation of the Bisabolene, Curcumene, Acoradiene, Zizaene, Cedrene, Duprezianene, and Sesquithuriferol Sesquiterpenes"
[concerted rearrangements with asynchronous events, avoidance of secondary carbocations, conformational preorganization, C-H•••X interactions that affect carbocation structures]
The papers below provide more specific details...
Gutta, P.; Tantillo, D. J. Angew. Chem. Int. Ed. 2005, 44, 2719-2723: "Proton Sandwiches: Nonclassical Carbocations with 4-Coordinate Protons." This article was highlighted in the "Science Concentrates" section of the May 2, 2005 issue of C&EN.
Bojin, M. D.; Tantillo, D. J. J. Phys. Chem. A 2006, 110, 4810-481: "Nonclassical Carbocations as C-H Hydrogen Bond Donors"
Gutta, P.; Tantillo, D. J. J. Am. Chem. Soc. 2006, 128, 6172-6179: "Theoretical Studies of Farnesyl Cation Cyclization: Pathways to Pentalenene"
Hong, Y. J.; Tantillo, D. J. Org. Lett. 2006, 8, 4601-4604: "Which is More Likely in Trichodiene Biosynthesis: Hydride or Proton Transfer?"
Gutta, P.; Tantillo, D. J. Org. Lett. 2007, 9, 1069-1071: "A Promiscuous Proton in Taxadiene Biosynthesis?"
Willenbring, D.; Tantillo, D. J. Russ. J. Gen. Chem. 2008, 78, 723-731 (Rossiiskii Khimicheskii Zhurnal 2007, 51, 49-55): "Mechanistic Possibilities for Oxetane Formation in the Biosynthesis of Taxol's D Ring"
Lodewyk, M. W.; Gutta, P.; Tantillo, D. J. J. Org. Chem. 2008, 73, 6570-6579: “Computational Studies on Biosynthetic Carbocation Rearrangements Leading to Sativene, Cyclosativene, alpha-Ylangene, and beta-Ylangene"
Wang, S. C.; Tantillo, D. J. Org. Lett. 2008, 10, 4827-4830: "Prediction of a New Pathway to Presilphiperfolanol"
Ho, G. A.; Nouri, D. H.; Tantillo, D. J. Tetrahedron Lett. 2009, 50, 1578-1581: "Carbocation Rearrangements in Aspernomine Biosynthesis"
Hong, Y. J.; Tantillo, D. J. Nature Chem. 2009, 1, 384-389: "A Potential Energy Surface Bifurcation in Terpene Biosynthesis"
Hong, Y. J.; Tantillo, D. J. Org. Biomol. Chem. 2009, 7, 4101-4109: "Modes of Inactivation of Trichodiene Synthase by a Cyclopropane-Containing Farnesyldiphosphate Analog"
Lodewyk, M. W.; Lui, V. G.; Tantillo, D. J. Tetrahedron Lett., 2009, in press: "Synthesis of (Sulfonyl)methylphosphonate Analogs of Prenyl Diphosphates"
Hong, Y. J.; Tantillo, D. J., submitted: "Formation of Beyerene, Kaurene, Trachylobane and Atiserene Diterpenes by Rearrangements that Avoid Secondary Carbocations"
Tantillo, D. J., submitted: "How an Enzyme Might Accelerate an Intramolecular Diels-Alder Reaction - Theozymes for the Formation of Salvileucalin B"
Pradeep Gutta and Dean J. Tantillo: "Theoretical Studies on Farnesyl Cation Cyclization: Pathways to Pentalenene and Diversions to Other Natural Products." Lecture presented by Pradeep Gutta at the 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006.
Pradeep Gutta, Yong J. Hong, and Dean J. Tantillo: "Sesquiterpene-Forming Carbocation Rearrangements." Short lecture by Dean Tantillo invited based on poster presented at the 31st Reaction Mechanisms Conference, University of Maryland, College Park, MD, June 27-30, 2006.
Young J. Hong and Dean J. Tantillo: "Quantum Chemical Studies on Trichodiene Biosynthesis." Poster presented by Young Hong atthe 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006; paper ORGN 831.
Young J. Hong and Dean J. Tantillo: "Quantum Chemical Studies on Trichodiene Biosynthesis." Poster presented by Young Hong at the SYLICCO.07 Symposium, Davis, CA, July 26, 2007.
Dan Willenbring and Dean J. Tantillo: "Histidine and Cations: Probing the Perfect Pairing on the Pathway to Pentalenene." Poster presented by Dan Willenbring at the R. Bryan Miller Symposium, UC Davis, Davis, CA, March 6-7, 2008.
Christian S. Hamann and Dean J. Tantillo: "Calculating the Conformational Hops of the Humulyl Cation." Poster and lecture presented by Chris Hamann at the 32nd Reaction Mechanisms Conference, University of North Carolina, Chapel Hill, NC, June 25-28, 2008.
Michael W. Lodewyk, Pradeep Gutta, and Dean J. Tantillo: "Computational Studies on Biosynthetic Carbocation Rearrangements Leading Sativene, alpha-Ylangene, and beta-Ylangene." Poster presented by Mike Lodewyk at Department of Chemistry Recruiting Weekend Poster Session, University of California, Davis, CA, March 19-20, 2009.
Michael W. Lodewyk, Pradeep Gutta, and Dean J. Tantillo: "Computational Studies on Biosynthetic Carbocation Rearrangements Leading Sativene, alpha-Ylangene, and beta-Ylangene." Poster presented by Mike lodewyk at the R. Bryan Miller Symposium, UC Davis, Davis, CA, April 2-3, 2009.
Victor Liu, Michael W. Lodewyk, and Dean J. Tantillo: "Progress Towards a Geranyl Pyrophosphate Mimic." Lecture presented by Victor Liu at the 2009 Richard Larock Undergraduate Research Conference, University of California, Davis, CA, May 16, 2009.
Trevor A. Hamlin, Dean J. Tantillo, and Christian S. Hamann: "Using Borane, Ammonium and Methylene Substitution to Characterize the Stabilizing Features of a Macrocyclic Sesquiterpene Cation." Poster presented by Chris Hamann at the National Organic Symposium, Boulder, CO, June 7-11, 2009; paper C33.
Here are some of the terpenes that we have examined so far...
...africanene...
...astersicadiene (J. Am. Chem. Soc. 2006, 128, 6172)...
...caryophyllene... (J. Phys. Org. Chem. 2008, 21, 561)...
...cyclosativene (J. Org. Chem. 2008, in press)...
...humulene (J. Am. Chem. Soc. 2006, 128, 6172)...
...isobisabolene (Org. Lett. 2006, 8, 4601)...
...longifolene (J. Org. Chem. 2005, 70, 5139)...
...pentalenene (J. Am. Chem. Soc. 2006, 128, 6172)...
...protoilludene (J. Am. Chem. Soc. 2006, 128, 6172)...
...sativene (J. Org. Chem. 2008, in press)...
...taxadiene (Org. Lett. 2007, 9, 1069)...
...trichodiene (Org. Lett. 2006, 8, 4601)...
...ylangene (J. Org. Chem. 2008, in press)...
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