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]

Hare, S. R.; Tantillo, D. J. Beilstein J. Org. Chem. 2016, 12, 377-390: "Dynamic Behavior of Rearranging Carbocations – Implications for Terpene Biosynthesis," invited review for thematic series on "Natural Products in Synthesis and Biosynthesis II"

[dynamic effects in terpene-forming carbocation cyclization/rearrangements]

 

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"

Hong, Y. J.; Tantillo, D. J. Org. Lett. 2015, 17, 5388-5391: "Tension between Internal and External Modes of Stabilization in Carbocations Relevant to Terpene Biosynthesis - Modulating Minima Depth via C–H---π Interactions"

Potter, K. C.; Zi, J.; Hong, Y. J.; Malchow, B. K.; Tantillo, D. J.; Peters, R. J. Angew. Chem. Int. Ed. 2016, 55, 634-638: "Blocking Deprotonation with Retention of Aromaticity in a Plant ent-Copalyl Diphosphate Synthase Leads to Product Rearrangement"

Potter, K. C.; Jia, M.; Hong, Y. J.; Tantillo, D. J.; Peters, R. J. Org. Lett. 2016, 18, 1060-1063: "Product Rearrangement from Altering a Single Residue in the Rice syn-Copalyl Diphosphate Synthase"

O'Brien, T. E.; Bertolani, S. J.; Tantillo, D. J.; Siegel, J. B. Chem. Sci. 2016, 7, 4009-4015: "Mechanistically Informed Predictions of Binding Modes for Carbocation Intermediates of a Sesquiterpene Synthase Reaction"

Ortega, D. E.; Nguyen, Q. N. N.; Tantillo, D. J.; Toro-Labbe, A. J. Comput. Chem. 2016, 37, 1068-1081: "The Catalytic Effect of the NH3 Base on the Chemical Events in the Caryolene-forming Carbocation Cascade"

Tantillo, D. J. Org. Lett. 2016, 18, 4482-4484: "Does Nature Know Best? Pericyclic Reactions in the Daphniphyllum Alkaloid-Forming Cation Cascade"

Wedler, H. B.; Newman, T.; Tantillo, D. J. J. Nat. Prod. 2016, 79, 2744-2748: "Decarboxylation Facilitated by Carbocation Formation and Rearrangement During Steam Distillation of Vetiver Oil"

Mafu, S.; Karunanithi, P. S.; Palazzo, T. A.; Harrod, B. L.; Rodriguez, S. M.; Mollhoff, I. N.; O'Brien, T. E.; Tong, S.; Fiehn, O.; Tantillo, D. J.; Bohlmann, J.; Zerbe, P. Proc. Natl. Acad. Sci. USA 2017, 114, 974-979: "Biosynthesis of the Microtubule-Destabilizing Diterpene Pseudolaric Acid B from Golden Larch Involves an Unusual Diterpene Synthase"

Hong, Y. J.; Tantillo, D. J. Aust. J. Chem. 2017, 70, 362-366: "The Variediene-Forming Carbocation Cyclization/Rearrangement Cascade"

Hong, Y. J.; Tantillo, D. J. J. Org. Chem. 2017, 82, 3957-3959: "Is a 1,4-Alkyl Shift Involved in the Biosynthesis of Ledol and Viridiflorol?"

 

Here are just 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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