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. Nat. Prod. Rep. 2011, 28, 1035-1053: "Biosynthesis via Carbocations: Theoretical Studies on Terpene Formation"

[a summary of quantum chemical calculations published through 2010]

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. Chem. Soc. Rev. 2010, 39, 2847-2854: "The Carbocation Continuum in Terpene Biosynthesis - Where are the Secondary Cations?"

[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]

Hong, Y. J.; Tantillo, D. J. Chem. Sci. 2013, 4, 2512-2518: "C-H---pi Interactions as Modulators of Carbocation Structure - Implications for Terpene Biosynthesis"

[the means by which C-H---pi interactions can affect carbocation reactivity]

Gutierrez, O.; Tantillo, D. J. J. Org. Chem. 2012, 77, 8845-8850: "Analogies Between Synthetic and Biosynthetic Reactions in which [1,2]-Alkyl Shifts are Combined with Other Events - Dyotropic, Schmidt and Carbocation Rearrangements," invited JOCSynopsis.

[analogies between terpene-forming carbocation rearrangements and synthetically relevant rearrangements]

Hong, Y. J.; Tantillo, D. J. Chem. Soc. Rev. 2014, 43, 5042-5050: "How Cyclobutanes are Assembled in Nature – Insights from Quantum Chemistry"

[general principles of cyclobutane formation mechanisms]

Wedler, H. B.; Pemberton, R. P.; Tantillo, D. J. Molecules 2015, 20, 10781-10792 : "Carbocations and the Complex Flavor and Bouquet of Wine: Mechanistic Aspects of Terpene Biosynthesis in Wine Grapes," invited contribution to special issue on wine chemistry.

[overview of terpenes in wine]

 

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. 2010, 51, 170-173: "Synthesis of (Sulfonyl)methylphosphonate Analogs of Prenyl Diphosphates"

Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2010, 132, 5375-5386: "Formation of Beyerene, Kaurene, Trachylobane and Atiserene Diterpenes by Rearrangements that Avoid Secondary Carbocations"

Tantillo, D. J. Org. Lett. 2010, 12, 1164-1167: "How an Enzyme Might Accelerate an Intramolecular Diels-Alder Reaction - Theozymes for the Formation of Salvileucalin B"

Hong, Y. J.; Tantillo, D. J. Org. Biomol. Chem. 2010, 8, 4589-4600: "Quantum Chemical Dissection of The Classic Terpinyl/Pinyl/Bornyl/Camphyl Cation Conundrum - The Role of Pyrophosphate in Manipulating Pathways to Monoterpenes"

Hong, Y. J.; Tantillo, D. J. Chem. Sci. 2010, 1, 609-614: "A Tangled Web - Interconnecting Pathways to Amorphadiene and the Amorphene Sesquiterpenes"

Hong, Y. J.; Tantillo, D. J. Org. Lett. 2011, 13, 1294-1297: "How Many Secondary Carbocations are Involved in the Biosynthesis of Avermitilol?"

Siebert, M. R.; Zhang, J.; Addepalli, S. V.; Tantillo, D. J.; Hase, W. L. J. Am. Chem. Soc. 2011, 133, 8335-8343: "The Need for Enzymatic Steering in Abietic Acid Biosynthesis: Gas-Phase Chemical Dynamics Simulation of Carbocation Rearrangements on a Bifurcating Potential Energy Surface"

Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2011, 133, 18249-18256: "The Taxadiene-Forming Carbocation Cascade"

Hong, Y. J.; Tantillo, D. J. Chem. Commun. 2012, 48, 1571-1573: "Theoretical Calculations on Carbocations Involved in the Biosynthesis of Bergamotenes and Related Terpenes - The Same and Not the Same." Part of the 2012 Emerging Investigators issue.

Siebert, M. R.; Paranjothy, M.; Sun, R.; Tantillo, D. J.; Hase, W. L. J. Chem. Theor. Comput. 2012, 8, 1212-1222: "Gas-Phase Chemical Dynamics Simulations on the Bifurcating Pathway of the Pimaradienyl Cation Rearrangement. Role of Enzymatic Steering in Abietic Acid Biosynthesis"

Hong, Y. J.; Ponec, R.; Tantillo, D. J. J. Phys. Chem. A 2012, 116, 8902-8909: "Changes in Charge Distribution, Molecular Volume, Accessible Surface Area and Electronic Structure Along the Reaction Coordinate for a Carbocationic Triple Shift Rearrangement of Relevance to Diterpene Biosynthesis"

Nguyen, Q. N. N.; Tantillo, D. J. Beistein J. Org. Chem. 2013, 9, 323-331: "Caryolene-forming Carbocation Rearrangements," part of thematic issue on "new reactive intermediates in organic chemistry."

Hong, Y. J.; Giner, J.-L.; Tantillo, D. J. J. Org. Chem. 2013, 78, 935-941: "Triple-Shifts and Thioether Assistance in Rearrangements Associated with an Unusual Biomethylation of the Sterol Side Chain"

Vaughan, M. M.; Webster, F. X.; Kiemle, D.; Hong, Y. J.; Tantillo, D. J.; Wang, Q.; Coates, R. M.; Wray, A. T.; Askew, W.; O'Donnell, C.; Tokuhisa, J. G.; Boland, W.; Tholl, D. Plant Cell, 2013, 25, 1108-1125: "Formation of the Unusual Semivolatile Diterpene Rhizathalene by the Arabidopsis Class I Terpene Synthase TPS08 in the Root Stele is Involved in Defense Against Belowground Herbivory"

Hong, Y. J.; Irmisch, S.; Wang, S. C.; Garms, S.; Gershenzon, J.; Zu, L.; Kollber, T. G.; Tantillo, D. J. Chem. Eur. J. 2013, 19, 13590-13600: "Theoretical and Experimental Analysis of the Reaction Mechanism of MrTPS2, a Triquinane-forming Sesquiterpene Synthase from Chamomile"

Chooi, Y.-H.; Hong, Y. J.; Cacho, R. A.; Tantillo, D. J.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 16805-16808: "A Cytochrome P450 Serves as an Unexpected Terpene Cyclase during Fungal Meroterpenoid Biosynthesis"

Lodewyk, M. W.; Willenbring, D.; Tantillo, D. J. Org. Biomol. Chem. 2014, 12, 887-894: "Pentalenene Formation Mechanisms Redux," featured on the inside cover.

Hong, Y. J.; Tantillo, D. J. Nature Chem. 2014, 6, 104-111: "Biosynthetic Consequences of Multiple Sequential Post-Transition State Bifurcations," highlighted in a News & Views article (Hornsby, C. E.; Paton, R. S. Nature Chem. 2014, 6, 88-89).

Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2014, 136, 2450-2463: "Branching Out from the Bisabolyl Cation. Unifying Mechanistic Pathways to Barbatene, Bazzanene, Chamigrene, Chamipinene, Cumacrene, Cuprenene, Dunniene, Isobazzanene, Iso-γ-bisabolene, Isochamigrene, Laurene, Microbiotene, Sesquithujene, Sesquisabinene, Thujopsene, Trichodiene and Widdradiene Sesquiterpenes"

Isegawa, M.; Maeda, S.; Tantillo, D. J.; Morokuma, K. Chem. Sci. 2014, 5, 1555-1560: "Predicting Pathways for Terpene Formation from First Principles - Routes to Known and New Sesquiterpenes"

Pemberton, R. P.; Tantillo, D. J. Chem. Sci. 2014, 5, 3301-3308: "Lifetimes of Carbocations Encountered along Reaction Coordinates for Terpene Formation"

Painter, P. P.; Wong, B. M.; Tantillo, D. J. Org. Lett. 2014, 16, 4818-4821: "Facilitating the Cope Rearrangement by Partial Protonation - Implications for Synthesis and Biosynthesis"

Hong, Y. J.; Tantillo, D. J. Helv. Chim. Acta 2014, 97, 1475-1480: "The Viability of Nonclassical Carbocations Proposed as Intermediates in the Biosynthesis of Atiserene, Beyerene, Kaurene and Trachylobane Diterpenes"

Zi, J.; Matsuba, Y.; Hong, Y. J.; Jackson, A. J.; Tantillo, D. J.; Pichersky, E.; Peters, R. J. J. Am. Chem. Soc. 2014, 136, 16951-16953: "Biosynthesis of Lycosantalonol, a cis-Prenyl Derived Diterpenoid"

Hong, Y. J.; Giner, J. L.; Tantillo, D. J. J. Am. Chem. Soc. 2015, 137, 2085-2088 : "Bicyclobutonium Ions in Biosynthesis - Interconversion of Cyclopropyl-Containing Sterols from Orchids"

Pemberton, R. P.; Ho, K. C.; Tantillo, D. J. Chem. Sci. 2015, 6, 2347-2353: "Modulation of Inherent Dynamical Tendencies of the Bisabolyl Cation via Preorganization in epi-Isozizaene Synthase"

Hamlin, T. A.; Hamann, C. S.; Tantillo, D. J. J. Org. Chem. 2015, 80, 4046-4053: "Delocalization of Charge and Electron Density in the Humulyl Cation - Implications for Terpene Biosynthesis"

Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2015, 137, 4134-4140: "Feasibility of Intramolecular Proton Transfers in Terpene Biosynthesis - Guiding Principles"

Wedler, H. B.; Pemberton, R. P.; Lounnas, V.; Vriend, G.; Tantillo, D. J.; Wang, S. C. J. Molec. Model. 2015, 21, 111: "Quantum Chemical Study of the Isomerization of 24-Methylenecycloartanol, A Potential Marker of Olive Oil Refining"

 

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.

Young J. Hong and Dean J. Tantillo: "Quantum Chemical Study on the Formation of Beyerene, Kaurene, Trachylobane and Atiserene Diterpenes." Lecture presented by Young Hong at the 239th ACS National Meeting, San Francisco, CA, March 21-25, 2010; paper ORGN 46.

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." Lecture presented by Trevor Hamlin at the 239th ACS National Meeting, San Francisco, CA, March 21-25, 2010; paper ORGN 107.

 

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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