Prototropic Shift in the Biosynthesis of

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Coupled Electrocyclization/Prototropic Shift in the Biosynthesis of Crotinsulidane Diterpenoids Renan B. Campos† and Dean J. Tantillo*,‡ †

Departamento Acadêmico de Química e Biologia, Universidade Tecnológica Federal do Paraná, Rua Deputado Heitor de Alencar Furtado, 5000, 81280-340, Curitiba, Brazil ‡ Department of Chemistry, University of CaliforniaDavis, 1 Shields Avenue, Davis, California 95616, United States S Supporting Information *

ABSTRACT: The energetic viability of proposed mechanisms for the formation of the fivemembered ring in crotinsulidane diterpenes is assessed using density functional theory calculations. A protonation-assisted coupled four-electron electrocyclization/prototropic shift mechanism is predicted to have a low (biologically relevant) barrier.

T

display transition state aromaticity, was examined using nucleus independent chemical shifts (NICS) calculations.6 Geometry optimizations and frequency calculations were performed with B3LYP,7,8 using the 6-31+G(d,p) basis set for all systems presented in Figure 1. Single point energy calculations were also carried out on stationary points using the M06-2X9,10 and ωB97X-D11 functionals. In order to assess solvent effects, single point calculations were performed with B3LYP using the SMD continuum model for water.12 Optimized geometries for transition state structures (TSSs) and predicted energy barriers for each cyclization are presented in Figure 1. For TSS(1), we performed conformational searching using Spartan;13 however, the π-bonds present limit the accessible conformers. While we managed to locate two conformers of 1 (by changing the C−C9−C10−C dihedral angle, Figure 2), one conformer was predicted to be 5.9 kcal/ mol lower in energy than the other. The higher energy conformer is also not preorganized for cyclization. Preorganized reactant conformers were used in determining barriers for all other systems. Several low energy conformers of 2 were described previously.2b The predicted barrier for the uncatalyzed cyclization of 1 ranged from 21 to 27 kcal mol−1, depending on the DFT method used (Figure 1). Although a barrier of this magnitude can be overcome in a biological setting, it is near the limit of feasibility for a biological reaction.14 As presented in Figure 3, intrinsic reaction coordinate (IRC) calculations indicate that C−C bond formation and proton transfer occur asynchronously;15−17 on the basis of bond distances, the prototropic shift is 98% complete in TSS(1), while the new C−C bond is only 36% formed. The NICS(0) value of approximately −7 (calculated at the center of mass of the five carbon atoms involved in cyclization) suggests significant transition state

he isolation and characterization of three new crotinsulidane diterpenes featuring bicyclo[10.2.1]alkane frameworksEBC-318 (2, Scheme 1); EBC-219 which differs only Scheme 1. Proposed Mechanism for the Formation of Diterpene 21

by the presence of a hydroxyl group at C5; and EBC-339, possessing a carbonyl at C5were recently described.1 On the basis of computed olefin strain energy, 2 was predicted to be isolable, despite possessing a bridgehead CC π-bond.2 The mechanism proposed for formation of the cyclopentenone ring in 2 involved a vinylogous aldol cyclization (coupled to an intramolecular proton transfer; Scheme 1, 1 → 2), analogous to the mechanism suggested previously for formation of euphoperfolianes from jatrophanes.1,3 The cyclization shown in Scheme 1 can also be viewed as a four-electron electrocyclization (consider a resonance structure of the carbonyl with a positive charge on its carbon atom), related to the Nazarov cyclization reaction.4 Here, we use density functional theory (DFT) calculations to assess the energetic viability of the 1 → 2 transformationfrom a neutral reactant (1, Scheme 1), from a reactant with a protonated carbonyl (4a,b), from a reactant with a deprotonated alcohol (3) and in the presence of hydrogen bonding groups (5a−c),5 which could be provided by aqueous solvent or an enzyme active site (Figure 1). Whether or not these reactions more closely resemble aldol reactions or electrocyclizations, the latter of which would be expected to © 2017 American Chemical Society

Received: November 15, 2017 Published: December 22, 2017 1073

DOI: 10.1021/acs.joc.7b02904 J. Org. Chem. 2018, 83, 1073−1076

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The Journal of Organic Chemistry

Figure 1. Drawings of reactants, ball-and-stick images of optimized TSS geometries, predicted barriers (kcal mol−1), relevant bond distances (Å), and NICS(0) values (in parentheses) obtained with (top to bottom) B3LYP/6-31+G(d,p), M06-2X/6-31+G(d,p)//B3LYP/6-31+G(d,p), ωB97X-D/631+G(d,p)//B3LYP/6-31+G(d,p), and SMD(water)-B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p).

aromaticity, consistent with a pericyclic reaction.4,6 In fact, this value is close to that computed for the TSS for cyclization of unsubstituted pentadienyl cation (TSS(PD), Figure 4, approximately −9), the prototype of a four-electron electrocyclization. The predicted barrier for cyclization is lowered by both deprotonation (3) and protonation (4). Deprotonation lowers the barrier to 14−17 kcal mol−1 (Figure 1) but abolishes the aromaticity of the TSS (based on the computed NICS(0) value), consistent with this reaction resembling an aldol reaction under basic conditions (the slightly longer C(O)− C(O) bond in TSS(2) compared to that in other TSSs is also consistent with this characterization). The predicted barrier is

even lower when the carbonyl of 1 is protonated (4a and 4b, Figure 1). Previous studies have shown that pentadienyl cations with OH groups at the 1-position cyclize with higher barriers than unsubstituted pentadienyl cations, while those with OH groups at the 2-position cyclize with lower barriers.4b Again, these TSSs appear to be cyclically delocalized on the basis of their computed NICS(0) values, although once again they are predicted to be not as aromatic as analogous systems lacking an attached macrocycle (Figure 4). Note that the hydrogen bonding pattern of 4a leads to a lower barrier than that predicted for 4b, consistent with donating groups at the 1position retarding cyclizationthe donor ability is decreased by the hydrogen bond in 4aand donating groups at the 21074

DOI: 10.1021/acs.joc.7b02904 J. Org. Chem. 2018, 83, 1073−1076

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The Journal of Organic Chemistry

Figure 2. Optimized geometries of the two conformers found for 1 (Scheme 1, B3LYP/6-31+G(d,p)). The lefthand conformer is predicted to be 5.9 kcal mol−1 lower in energy than the righthand conformer.

bond formation was also the most advanced in system 5c (Figure 1), consistent with a later TSS expected for a less favorable reaction (in both kinetic and thermodynamic senses). System 5a is predicted to have the lowest barrier of 5a−c, likely a result of its ideal hydrogen bonding pattern, which mimics the protonation state of 4a In summary, the cyclization proposed to lead to 2 is predicted to be energetically feasible on its own in a biological setting, although the rate for such a process is not expected to be high. Protonation of the carbonyl oxygen (or strong hydrogen bonding to it) is predicted to increase the rate dramatically. TSS geometries and NICS(0) values are consistent with the 1-to-2 reaction (on its own, protonated, or in the presence of hydrogen-bond donors) being best described as an electrocyclization coupled, in a concerted but asynchronous manner, to a prototropic shift.

Figure 3. IRC plot for TSS(1) (B3LYP/6-31+G(d,p)). Energies along the reaction coordinate are shown as blue circles. The solid lines represent the C−C(carbonyl) (dark gray) and (carbonyl)O···H (red).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02904. Coordinates and energies for all computed structures, IRC data, and full Gaussian 09 reference (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Figure 4. Optimized TSS of the pentadienyl cation cyclizations. The predicted barriers (kcal mol−1), relevant bond distances (Å), and NICS(0) values (in parentheses) were obtained with B3LYP/631+G(d,p).

ORCID

Dean J. Tantillo: 0000-0002-2992-8844 Notes

The authors declare no competing financial interest.

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position assisting cyclizationthe donor ability is increased by the hydrogen bond in 4a. Considering that full deprotonation or protonation is unlikely in a biological system, we examined how much of the barrier lowering described above could be captured by simple hydrogen bonding. As shown in Figure 1, three possible orientations of a water molecule interacting with 1 were evaluated: the water donating a hydrogen bond to the carbonyl oxygen (5a), the water donating a hydrogen bond to the OH group (5b), and the water simultaneously donating a hydrogen bond to the carbonyl oxygen and receiving a hydrogen bond from the OH group (5c). The highest barrier was observed for system 5c (ΔG⧧ = 37.0 kcal mol−1), which has the least aromatic TSS of 5a−c according to NICS(0) values. C−C

ACKNOWLEDGMENTS Support from the US National Science Foundation (CHE1565933 and computing support from CHE030089 [XSEDE]) is gratefully acknowledged.

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REFERENCES

(1) (a) Maslovskaya, L. A.; Savchenko, A. I.; Gordon, V. A.; Reddell, P. W.; Pierce, C. J.; Parsons, P. G.; Williams, C. M. RSC Adv. 2016, 6, 25110. (b) Maslovskaya, L. A.; Savchenko, A. I.; Krenske, E. H.; Pierce, C. J.; Gordon, V. A.; Reddell, P. W.; Parsons, P. G.; Williams, C. M. Angew. Chem., Int. Ed. 2014, 53, 7006. (2) (a) Krenske, E. H.; Williams, C. M. Angew. Chem., Int. Ed. 2015, 54, 10608. (b) Mak, J. Y.; Pouwer, R. H.; Williams, C. M. Angew. Chem., Int. Ed. 2014, 53, 13664. 1075

DOI: 10.1021/acs.joc.7b02904 J. Org. Chem. 2018, 83, 1073−1076

Note

The Journal of Organic Chemistry (3) Appendino, G.; Jakupovic, S.; Tron, G. C.; Jakupovic, J.; Milon, V.; Ballero, M. J. Nat. Prod. 1998, 61, 749. (4) (a) Rieder, C. J.; Winberg, K. J.; West, F. J. Am. Chem. Soc. 2009, 131, 7504. (b) Davis, R. L.; Tantillo, D. J. Curr. Org. Chem. 2010, 14, 1561. (5) Tantillo, D. J.; Chen, J.; Houk, K. N. Curr. Opin. Chem. Biol. 1998, 2, 743−750. (6) (a) Jiao, H.; Schleyer, P. v. R. J. Phys. Org. Chem. 1998, 11, 655. (b) Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. v. R. Chem. Rev. 2005, 105, 3842. (7) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (8) Gaussian 09 was used for all DFT calculations; please see the Supporting Information for the full reference. (9) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. (10) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157. (11) Sengupta, A.; Raghavachari, K. Org. Lett. 2017, 19, 2576. (12) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378. (13) Spartan’10; Wavefunction, Inc.: Irvine, CA, 2010. (14) Wang, S. C.; Tantillo, D. J. J. Org. Chem. 2008, 73, 1516. (15) Maeda, S.; Harabuchi, Y.; Ono, Y.; Taketsugu, T.; Morokuma, K. Int. J. Quantum Chem. 2015, 115, 258. (16) Williams, A. Concerted organic and bio-organic mechanisms; CRC Press: Boca Raton, Fl, 1999; Vol. 12. (17) (a) Tantillo, D. J. J. Phys. Org. Chem. 2008, 21, 561. (b) Hess, B. A. J. Am. Chem. Soc. 2002, 124, 10286.

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DOI: 10.1021/acs.joc.7b02904 J. Org. Chem. 2018, 83, 1073−1076