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How cyclobutanes are assembled in nature – insights from quantum chemistry Young J. Hong and Dean J. Tantillo*
Received 9th December 2013
Biosynthetic production of cyclobutanes leads to many complex natural products. Recently, theoretical
DOI: 10.1039/c3cs60452g
work employing quantum chemical calculations has shed light on many of the details of cyclobutaneformation, in particular, for terpene natural products. Specific insights and general principles derived
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from these theoretical studies are described herein.
Introduction
Carbocation cyclizations
Although cyclobutane is the second most strained monocyclic alkane, both in terms of total strain and strain per carbon atom,1 cyclobutane rings are found in many complex natural products.2–5 Herein we examine the means by which Nature overcomes strain to form cyclobutane-containing natural products. We focus on mechanisms for formation of cyclobutane substructures that have been subjected to scrutiny using modern quantum chemistry methods, but we also discuss mechanisms that can be predicted by analogy and those that cannot readily be predicted by analogy, the latter constituting opportunities for future theoretical work.
Many of the cyclobutanes present in natural products are formed through carbocation cyclization reactions. These reactions generally involve (2+2) cycloadditions between alkenes and allyl cations (Scheme 1), the latter of which can be viewed as an alkene bearing a carbocation substituent. Such cycloadditions can be stepwise or concerted, as described below, and are driven forward by the exchange of p-bonds for stronger s-bonds (e.g., structure D in Scheme 2 is predicted to be B20 kcal mol1 lower in energy than structure B6). While formation of cyclopentyl cations could compete with formation of cyclobutylcarbinyl cations, the latter usually dominates, due both to hyperconjugation between the cyclobutane ring and the attached carbocation and to substituent patterns present in terpene precursors. Variations on the (2+2) cycloaddition theme are described below. Note that
Department of Chemistry, University of California–Davis, Davis, CA 95616, USA. E-mail: [email protected]
Young J. Hong received BS and MS degrees from Seoul National University, South Korea and a PhD from UC Davis. She carried out postdoctoral research in the field of theoretical and computational organic chemistry at UC Davis. She is currently a staff scientist at UC Davis, where she continues to study terpene biosynthesis. Young J. Hong
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Dean J. Tantillo was born and raised in Quincy, Massachusetts, USA. He received an AB degree in Chemistry in 1995 from Harvard University and a PhD in 2000 from UCLA (with Kendall Houk). After receiving his PhD, he moved to Cornell University, where he carried out postdoctoral research with Roald Hoffmann. He joined the faculty at UC Davis in 2003, where he is now a Professor of Chemistry. Professor Tantillo can Dean J. Tantillo often be found walking through the woods touching terpenes and contemplating puzzling mechanistic questions in the areas of biosynthesis, reactive intermediate chemistry, catalysis, organometallic chemistry, and stereoselective synthetic reactions.
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Scheme 1
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Routes to cyclobutanes via carbocations.
Scheme 3
Scheme 2 Proposed pathway (previous proposal in black and revised proposal based on the results of quantum chemical calculations in blue) to protoilludene.
the carbocation calculations described herein address inherent (i.e., gas phase) reactivity, which has been shown to reflect the reactivity of many terpene synthase-promoted reactions.7
Simple cyclizations – not so simple The simplest route to a cyclobutane from a carbocation is ringclosure via nucleophilic attack on the formally positively charged carbon of the carbocation by a p-bond that resides three carbons away, i.e., three of the bonds of the incipient cyclobutane are present in the precursor to the carbocation (Scheme 1, step b). Protoilludene (Scheme 2) can form from direct deprotonation of the protoilludyl cation (Scheme 2, D) which is invoked in a variety of mechanistic proposals for sesquiterpene-forming carbocationic rearrangements.8 The generally proposed mechanism for formation of protoilludene is similar to the pathway in black in Scheme 2 (A-B-C-D). This mechanism was examined computationally by Gutta, Lodewyk, Willenbring and Tantillo.6,9 Quantum chemical calculations (mPW1PW91/6-31+G(d,p)//B3LYP/ 6-31+G(d,p)) suggest that tricyclic structure D results from a concerted but asynchronous combination of two cation-alkene
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Proposed pathways leading to chamipinene.
cyclization events, the second of which forms the cyclobutane ring (Scheme 2, blue, B-D). Possible pathways to the sesquiterpene chamipinene are shown in Scheme 3. Hong and Tantillo showed that chamigryl cation D can be formed not only by direct B 0 -D cyclization, but also by B0 -C cyclization followed by a 1,2-alkyl shift (C-D).10 On the basis of additional computations on the C-D conversion,11 it seems that once cation D adopts a conformation productive for cyclization, attack of the cyclohexene p-bond onto the carbocation center (C7) of D is barrierless (mPW1PW91/6-31+G(d,p)//B3LYP/ 6-31+G(d,p)). Thus, the barrier that is responsible for making formation of E a stepwise process is that for a conformational change, not that for the final cyclization. In carbocation E, the C2–C7 bond is elongated due to strong hyperconjugation. These examples highlight general principles at play in cyclobutane-forming carbocation reactions: (1) A strained ring can be formed if a p-bond is exchanged for a new s-bond (many additional examples are discussed below). (2) The final cyclization can be combined with other bond forming/breaking events into concerted, but often asynchronous,12 processes (e.g., see protoilludene above). Stepwise (2+2) cycloadditions Many cyclobutanes appear to be formed via the stepwise (2+2) cycloaddition of allyl cations and alkenes, i.e., reactions involving separate steps a and b in Scheme 1. A variety of examples are described below, highlighting how widespread this mechanistic manifold is in the world of terpene biosynthesis. The monoterpenes a-pinene and b-pinene (the former is shown in Scheme 4) are generally thought to be formed via mechanisms similar to that shown in Scheme 4.5,13 Cationalkene cyclization of the terpinyl cation (C) is proposed to lead to the pinyl cation (D). Two theoretical studies on the conversion of the terpinyl cation to the pinyl cation have been described in
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Fig. 1 Computed structures (B3LYP/6-31+G(d,p), distances in Å) of carbocation preceding pinene and the complex of this carbocation and a model diphosphate group.
Scheme 4 Possible carbocation rearrangements leading to pinenes (R = methyl) and bergamotenes (R = homoisoprenyl).
recent years, one by Weitman and Major14 and the other by Hong and Tantillo.15 These studies agree that, at least in the absence of an enzyme, pathways predicted using quantum chemical calculations are largely consistent with previously proposed mechanisms. Both studies involved surveys of a variety of different methods for computing geometries and energies of the carbocations involved in pinene formation. On the basis of the results reported by Hong and Tantillo (who optimized structures from Scheme 4 with various methods), the predicted barrier for the conversion of C to D does not vary much with the level of theory used (B3LYP, mPW1PW91, PBE, BB1K, MPWB1K and MP2 were examined). However, the predicted energy of D relative to that of C varies significantly. All levels of theory examined predicted very similar geometries for the pinyl cation, which has an extremely long C2–C7 bond (1.94 Å at the B3LYP/6-31+G(d,p) level, Fig. 1; this bond elongation is frequently found for cyclobutylcarbinyl cations). Hong and Tantillo also examined the susceptibility of the geometry of D to change upon participation in intermolecular interactions with electron rich groups, and the C2–C7 distance was shown to dramatically decrease (to 1.64 Å at the B3LYP/6-31+G(d,p) level) upon complexation via C–H O interactions with a pyrophosphate model (Fig. 1). Deprotonation of the pinyl cation using the diphosphate model shown to form the pinenes was also predicted to be facile. A sesquiterpene analogue of pinene is bergamotene (Scheme 4). Quantum chemical calculations were performed by Hong and Tantillo to compare and contrast the mechanism for formation of bergamotene with that of pinene.16 The mechanism for
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bergamotene formation was found to be similar to but not the same as that for pinene formation. The depth of the energy well associated with cation D was shown to vary with the nature of the R group (Scheme 4) and the theoretical method employed (the B3LYP, mPW1PW91 and MPWB1K methods were examined). Particular intramolecular interactions in certain conformers were shown to influence whether or not carbocation D is a discrete intermediate or instead exists along the slope of a pathway for conversion of carbocation C into an alternative carbocation (the camphyl cation). A more complex pinene analogue is ylangene, which has an additional ring fused to the pinene bicyclic core (Scheme 5). The mechanism for formation of ylangene was examined by Lodewyk, Gutta and Tantillo using mPW1PW91/6-31+G(d,p)// B3LYP/6-31+G(d,p) calculations.17 In analogy to the cases described above, one C–C distance of the cyclobutane ring is predicted to be very long due to hyperconjugation (1.95 Å), can be decreased to 1.76 Å upon complexation with ammonia, and can be decreased to a ‘‘normal’’ length after low barrier deprotonation. An analogous mechanistic scenario is expected for copaene (10-epi-ylangene) formation.18 The generally proposed mechanism for formation of caryophyllene (various isomers) includes 1,11-cyclization of the farnesyl cation resulting from loss of pyrophosphate from farnesyl diphosphate (FPP) and ring closure of the resulting secondary carbocation B to form the caryophyllyl cation C (Scheme 6, FPP-A-B-C).19 Wang and Tantillo examined ring closure of both E and Z isomers of B (Scheme 6, B and B 0 , respectively) to form cation C using quantum chemical calculations (mPW1PW91/6-31+G(d,p)//B3LYP/6-31+G(d,p)).20 Both B and B 0 were predicted to undergo ring closure with a small barrier (r5 kcal mol1) to form different conformers of carbocation C. The conformer formed directly from B 0 was productive for subsequent reactions leading to the sesquiterpene alcohol presilphiperfolanol. Carbocations A and A 0 were not located
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Scheme 7 Possible carbocation rearrangement pathways leading to plumisclerin A.
Scheme 5 Possible carbocation rearrangement pathways leading to ylangenes.
open the possibility that 1,11-cyclization may occur in concert with diphosphate loss. The possibility that the diterpenoid plumisclerin A21 could be formed via a stepwise cationic (2+2) reaction (Scheme 7) was examined by Sio et al. using a variety of quantum chemical methods.22 On the basis of the results of these calculations, the authors concluded that such a carbocation cascade is energetically viable if the aldehyde in the reactant is protonated (perhaps by an enzyme active site residue) to produce an activated allyl cation. In this case, the attacking alkene is also activated by an attached electron-releasing OAc group. Concerted [2+2] cycloadditions
Scheme 6 Possible carbocation rearrangement pathways leading to caryophyllenes.
as minima (for appropriate conformations, the absence of significant strain leads to barrierless carbocation/alkene collapse), leaving
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In some cases, putative intermediates in stepwise (2+2) cycloaddition pathways were found not to be discrete minima. Instead, these structures were found to reside on slopes of reaction coordinates for concerted processes in which the two bond-forming events are combined asynchronously (Scheme 1, where a and b are not separate elementary reactions, but rather are events occurring during a single reaction step).12,23 A concerted [p2S+p2S] cycloaddition that converts the farnesyl cation directly to the caryophyllyl cation (Scheme 6, A-C), is forbidden on orbital symmetry grounds.24 Nonetheless, two computational studies, one by Nguyen and Tantillo25 and the other by Hong et al.26 described concerted [2+2] cycloaddition pathways for the conversion of cation A to C (both cis and trans isomers). This reaction is predicted to have a low barrier (o5 kcal mol1 with mPW1PW91/6-31+G(d,p)//B3LYP/6-31+G(d,p)). How does one rationalize the ease of this reaction in light of the constraints of orbital symmetry? The answer comes from a close examination of the reaction coordinate. Although this reaction is concerted, the two bond-forming events occur very
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Fig. 2 Sesquiterpene natural products derived from caryophyllyl cations whose formation has been examined with quantum chemical calculations.
asynchronously, so much so that at no point along the reaction coordinate for cycloaddition is there strong cyclic orbital overlap. The orbital symmetry rules only apply to reactions where such cyclic overlap occurs along a reaction coordinate.27 In addition, a post-transition state bifurcation28 was also implicated for the conversion of A to C via the pathway just described, but also to B (Scheme 6) via another pathway connected to the same transition state structure. A selection of sesquiterpenes derived from isomers of C whose formation has so far been examined using quantum chemical calculations is shown in Fig. 2.25,26 Other terpenes/terpenoids are likely to be derived from (2+2) cycloadditions of allyl cations with alkenes, be they concerted or stepwise. A selection of natural products whose origins likely involve such reactions are shown in Scheme 8.29 Whether the particular (2+2) cycloaddition reactions shown would be stepwise or concerted is not clear and will likely require future theoretical studies to tease out the influence of conformational factors and carbocation substitution patterns (note that some stepwise processes shown involve the generation of secondary carbocations).30 Synthetic approaches to cyclobutanes have also made use of cationic (2+2) reactions.31
Scheme 8 Additional terpene/terpenoid natural products that could be formed via concerted or stepwise (shown) (2+2) cycloadditions.
Other cyclobutane-forming carbocation rearrangements involving alkyl shifts are under investigation. The cyclobutane-containing dendrowardol A and B were isolated from Dendrobium wardianum Warner along with the cyclopropanecontaining dendronbilin H (Scheme 9).32 The pathways proposed for dendronwardol A and B formation involve generation of a primary cyclopropylcarbinyl cation by protonation/ dehydration of dendronbilin H or its epimer (not yet found in nature), followed by ring expansion and recapture of water.32
Other carbocation reactions Another possible route to the caryophyllyl cation (Scheme 6, C) involves 1,10-cyclization to form tertiary carbocation D followed by a 1,2-alkyl shift to produce B, which could then cyclize to C. The latter two of these events might also be merged into a concerted process that avoids secondary carbocation B as a discrete intermediate. Our preliminary calculations (M06-2X/ 6-31+G(d,p)) indicate that the A-D-C pathway is viable and the conversion of cation A to D is predicted to occur without a significant barrier for at least one conformation. Clearly, no single mechanism captures the subtleties associated with caryophyllyl cation formation—different conformers and geometric isomers display related but different behavior. Which pathway is followed in a given biological scenario is likely determined not only by the electronic structure of the precursors to C, but also the shape and charge distribution of the particular terpene synthase active site in which they are generated.
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Scheme 9 Proposed biosynthesis of dendrowardol A and B sesquiterpenoid epimers.
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Scheme 12 Possible mechanisms for formation of the original and revised aquatolide structures. Scheme 10 formation.
Proposed dyotropic rearrangement for dendrowardol A/B
Scheme 11 Proposed dyotropic rearrangement for dendrowardol C formation.
Although it is attached to a cyclopropane ring, a primary carbocation center seems unlikely to be present in a discrete intermediate. A concerted dyotropic rearrangement (Scheme 10)33 could replace the stepwise process, although geometric constraints imposed by the polycylic system may discourage such a reaction. An analogous situation exists for dendrowardol C (Scheme 11), which is proposed to be derived from cyclosativene via oxidation.34 No doubt, future calculations on these systems will prove to be enlightening.
Photochemistry Many cyclobutanes in natural products are thought to arise from photochemical reactions.3 As shown above, viable alternatives to photochemistry exist, but photochemical reactions clearly do play a large role in enriching the pool of natural products with cyclobutane-containing structures. The biosynthesis of aquatolide provides a representative example. Aquatolide is a humulane-derived sesquiterpenoid lactone isolated from Asteriscus aquaticus.35 The structure of aquatolide was originally proposed to contain a rare [2]ladderane substructure (Scheme 12, 1).2,35 Recently, extensive quantum chemical NMR calculations, combined with experiments, by Lodewyk and co-workers led to the revision of the aquatolide structure (Scheme 12, 2).36 A biosynthetic pathway involving a [2+2] photocycloaddition of known natural product asteriscunolide C (3) was proposed (Scheme 12, blue), and this process is expected to occur more readily than photocycloaddition to form 1 (Scheme 12, red). These conjectures are currently being subjected to experimental scrutiny. A small selection of other natural products whose cyclobutane cores are thought to be produced via photochemical
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Fig. 3 Natural products whose cyclobutane cores are thought to arise from photochemical [2+2] cycloadditions.
[2+2] reactions is shown in Fig. 3;37 note that these compounds are members of several different natural product classes. To our knowledge, neither photochemical nor nonphotochemical mechanisms for formation of these natural products have yet been examined computationally. There is certainly much more to learn about biosynthetic cyclobutane formation!38 Photochemical rearrangements to form cyclobutane-containing natural products have also been proposed. One such example is shown in Scheme 13. Verbenone, a pinene-derived monoterpenoid was isolated along with filifolone (Scheme 13).39,40 The related monoterpenoid chrysanthenone (Scheme 13) has been isolated from a variety sources in Nature.40,41 Photochemical rearrangement of verbenone to chrysanthenone (a [1,3] sigmatropic shift; Scheme 13) has been reported in the literature, suggesting that this reaction might occur in Nature.39,42
Scheme 13
Photochemical rearrangement of verbenone to chrysanthenone.
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Scheme 16
Scheme 14
Example of a proposed diradical cyclization.
Other mechanisms Other mechanistic manifolds have been suggested for the formation of cyclobutanes in various natural products. One reaction type involves the cyclization of 1,4-diradicals (Scheme 14).43 Another involves a pericyclic cascade (sequential 8-electron and 6-electron electrocyclizations) (Scheme 15). The viability of these mechanistic pathways for specific natural products is ripe for theoretical scrutiny.44
Reactions of cyclobutanes In this section we briefly describe two computational studies on reactions of cyclobutane-containing natural products. These reactions are thought to correlate to important biological roles of the associated natural products. Houk, Baran and co-workers examined vinylcyclobutane-tocyclopentene rearrangements of sceptrin (Fig. 3).45 Heating of sceptrin was shown (through a combination of experiments and computations [UHF and UB3LYP with 6-31G*]) to produce ageliferin and nagelamide E (Fig. 4) through formal [1,3] sigmatropic shifts involving diradicals. This study provided a convincing argument that sceptrin may be the biosynthetic precursor to these natural products lacking cyclobutane rings.
Possible reactions of ladderane lipids.
The ladderane lipids (Scheme 16) are perhaps the most unusual cyclobutane-containing natural products.2 To date, no convincing evidence for the chemical mechanisms by which their fused oligocyclobutane polycycles are formed has been provided, although several mechanisms (both photochemical and nonphotochemical) have been considered.2,46,47 Recently, Nouri and Tantillo examined mechanisms by which ladderane lipids might react (using B3LYP, mPW1PW91 and CCSD(T) calculations).46 Protonation, hydrogen atom abstraction, and addition of radicals were all shown to break open the ladderane core, prompting speculation that ladderanes may play a role in trapping reactive species.
Conclusions Cyclobutanes are widespread in Nature. While photochemical [2+2] cycloadditions are likely responsible for formation of many cyclobutane-containing natural products, carbocation cyclization/ rearrangement processes, which provide routes to many cyclobutane-containing terpenes and terpenoids are likely just as prevalent. In both types of process, p-bonds are traded for s-bonds, providing a driving force for formation of strained cyclobutane rings.48 While many chemical mechanisms have been interrogated using quantum chemical methods, many have not—especially photochemical cyclobutane-forming reactions—leaving room for future theoretical work that will fill in additional details of the rich mechanistic framework associated with biosynthetic cyclobutane formation.
Acknowledgements Work on carbocation cyclizations in D.J.T.’s laboratory has been generously supported by the U.S. National Science Foundation.
Notes and references
Scheme 15 Example of a proposed pericyclic cascade.
Fig. 4 Natural products thought to be derived from sceptrin.
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U. S. A., 2004, 101, 9601; see also the seminal work of Poulter and colleagues, e.g., H. V. Thulasiram, H. K. Erickson and C. D. Poulter, Science, 2007, 316, 73; Hebelophyllenes: M. Wichlacz, W. A. Ayer, L. S. Trifonov, P. Chakravary and D. Khasa, J. Nat. Prod., 1999, 62, 484; Rhododaurichromanic acid A: A. V. Kurdyumov and R. P. Hsung, J. Am. Chem. Soc., 2006, 128, 6272; Artochamins: Y.-H. Wang, A.-J. Hou, D.-F. Chen, M. Weiller, A. Wendel and R. J. Staples, Eur. J. Org. Chem., 2006, 3457; K. C. Nicolaou, T. Lister, R. M. Denton and C. F. Gelin, Angew. Chem., Int. Ed., 2007, 46, 7501; K. C. Nicolaou, T. Lister, R. M. Denton and C. F. Gelin, Tetrahedron, 2008, 64, 4736. D. J. Tantillo, Chem. Soc. Rev., 2010, 39, 2847. Selected examples: H.-S. Yeom, H. Li, Y. Tang and R. P. Hsung, Org. Lett., 2013, 15, 3130; J. Deng, R. P. Hsung and C. Ko, Org. Lett., 2012, 14, 5562; C. Ko, J. B. Feltenberger, S. K. Ghosh and R. P. Hsung, Org. Lett., 2008, 10, 1971; R. Siedlecka, Tetrahedron, 2009, 65, 2351; P. G. Gassman, S. P. Chavan and L. B. Fertel, Tetrahedron Lett., 1990, 31, 6489; P. G. Gassman and A. C. Lottes, Tetrahedron Lett., 1992, 33, 157; Y.-J. Ko, S.-B. Shim and J.-H. Shin, Tetrahedron Lett., 2007, 48, 863. W. W. Fan, F. Q. Xu, F. W. Dong, X. N. Li, X. Y. Wei, J. Zhou and J. M. Hu, Tetrahedron Lett., 2013, 54, 1928. M. T. Reetz, Tetrahedron, 1973, 29, 2189; M. T. Reetz, Adv. Organomet. Chem., 1977, 16, 33; M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1972, 11, 130; M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1972, 11, 129; I. Fernndez, F. M. Bickelhaupt and F. P. Cossio, Chem. Rev., 2009, 109, 6687; for examples relevant to terpene biosynthesis: O. Gutierrez and D. J. Tantillo, J. Org. Chem., 2012, 77, 8845; Y. J. Hong and D. J. Tantillo, Nat. Chem., 2009, 1, 384. W. W. Fan, F. Q. Xu, F. W. Dong, X. N. Li, Y. Li, Y. Q. Liu, J. Zhou and J. M. Hu, Nat. Prod. Bioprospect., 2013, 3, 89. A. San Feliciano, M. Medarde, J. M. Miguel del Corral, A. Aramburu, M. Gordaliza and A. F. Barrero, Tetrahedron Lett., 1989, 30, 2851. M. W. Lodewyk, C. Soldi, P. B. Jones, M. M. Olmstead, J. Rita, J. T. Shaw and D. J. Tantillo, J. Am. Chem. Soc., 2012, 134, 18550. B. X. Zhao, Y. Wang, C. Li, G. C. Wang, X. J. Huang, C. L. Fan, Q. M. Li, H. J. Zhu, W. M. Chen and W. C. Ye, Tetrahedron Lett., 2013, 54, 4708; S. P. Kureel, R. S. Kapil and S. P. Popli, Tetrahedron Lett., 1969, 10, 3857; S. J. Piao, Y. L. Song, W. H. Jiao, F. Yang, X. F. Liu, W. S. Chen, B. N. Han and H. W. Lin, Org. Lett., 2013, 15, 3526; M. Zhou, H. B. Zhang, W. G. Wang, N. B. Gong, R. Zhan, X. N. Li, X. Du, L. M. Li, Y. Li, Y. Lu, J. X. Pu and H. D. Sun, Org. Lett., 2013, 15, 4446; R. P. Walker, D. J. Faulkner, D. Van Engen and J. Clardy, J. Am. Chem. Soc., 1981, 103, 6772; cyclobutane-containing pyrimidine dimers formed in DNA arise from photochemical [2+2] reactions—see, for example: R. B. Setlow, Science, 1966, 1153, 1379. For examples of computational studies on photochemical [2+2] reactions: E. Garcia-Exposito, M. J. Bearpark, R. M. Ortuno, M. A. Robb and V. Branchadell, J. Org. Chem.,
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39 40 41
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2002, 67, 6070; J. R. Cucarull-Gonzalez, J. Hernando, R. Alibes, M. Figueredo, J. Font, L. Rodriguez-Santiago and M. Sodupe, J. Org. Chem., 2010, 75, 4392; E. Garcia-Exposito, A. Alvarez-Larena, V. Branchadell and R. M. Ortuno, J. Org. Chem., 2004, 69, 1120. S. J. Torrance and C. Steelink, J. Org. Chem., 1974, 39, 1068. S. Cozzani, A. Muselli, J.-M. Desjobert, A.-F. Bernardini, F. Tomi and J. Casanova, Flavour Fragrance J., 2005, 20, 436–441. R. G. Buttery, D. M. Light, Y. Nam, G. B. Merrill and J. N. Roitman, J. Agric. Food Chem., 2000, 48, 2858; S. Gallori, G. Flamini, A. R. Bilia, I. Morelli, A. Landini and F. F. Vincieri, J. Agric. Food Chem., 2001, 49, 5907. J. J. Hurst and G. H. Whitham, J. Chem. Soc., 1960, 2864; W. F. Erman, J. Am. Chem. Soc., 1967, 89, 3828. P. A. Roethle and D. Trauner, Nat. Prod. Rep., 2008, 25, 298. C. M. Beaudry, J. P. Malerich and D. Trauner, Chem. Rev., 2005, 105, 4757.
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45 B. H. Northrop, D. P. O’Malley, A. L. Zografos, P. S. Baran and K. N. Houk, Angew. Chem., Int. Ed., 2006, 45, 4126. 46 D. H. Nouri and D. J. Tantillo, Org. Biomol. Chem., 2012, 10, 5514. ´, M. Strous, W. I. C. Rijpstra, E. C. Hopmans, 47 J. S. S. Damste J. A. J. Geenevasen, A. C. T. van Duin, L. A. van Niftrik and M. S. M. Jetten, Nature, 2002, 419, 708; H. Hopf, Angew. Chem., Int. Ed., 2003, 42, 2822; H. Hopf, J. F. Liebman and H. M. Perks, in The Chemistry of Cyclobutanes, ed. Z. Rappoport and J. F. Liebman, John Wiley & Sons, 2005, ch. 23. 48 The cyclobutenedione moniliformin is another unusual natural product containing a 4-membered ring, but with all four carbon atoms sp2 hybridized. Although the details of ring formation for moniliformin are not known, a polyketide pathway has been invoked. See: B. Franck and G. Breipohl, Angew. Chem., Int. Ed. Engl., 1984, 1923, 1996.
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REVIEW ARTICLE
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How cyclobutanes are assembled in nature – insights from quantum chemistry Young J. Hong and Dean J. Tantillo*
Received 9th December 2013
Biosynthetic production of cyclobutanes leads to many complex natural products. Recently, theoretical
DOI: 10.1039/c3cs60452g
work employing quantum chemical calculations has shed light on many of the details of cyclobutaneformation, in particular, for terpene natural products. Specific insights and general principles derived
www.rsc.org/csr
from these theoretical studies are described herein.
Introduction
Carbocation cyclizations
Although cyclobutane is the second most strained monocyclic alkane, both in terms of total strain and strain per carbon atom,1 cyclobutane rings are found in many complex natural products.2–5 Herein we examine the means by which Nature overcomes strain to form cyclobutane-containing natural products. We focus on mechanisms for formation of cyclobutane substructures that have been subjected to scrutiny using modern quantum chemistry methods, but we also discuss mechanisms that can be predicted by analogy and those that cannot readily be predicted by analogy, the latter constituting opportunities for future theoretical work.
Many of the cyclobutanes present in natural products are formed through carbocation cyclization reactions. These reactions generally involve (2+2) cycloadditions between alkenes and allyl cations (Scheme 1), the latter of which can be viewed as an alkene bearing a carbocation substituent. Such cycloadditions can be stepwise or concerted, as described below, and are driven forward by the exchange of p-bonds for stronger s-bonds (e.g., structure D in Scheme 2 is predicted to be B20 kcal mol1 lower in energy than structure B6). While formation of cyclopentyl cations could compete with formation of cyclobutylcarbinyl cations, the latter usually dominates, due both to hyperconjugation between the cyclobutane ring and the attached carbocation and to substituent patterns present in terpene precursors. Variations on the (2+2) cycloaddition theme are described below. Note that
Department of Chemistry, University of California–Davis, Davis, CA 95616, USA. E-mail: [email protected]
Young J. Hong received BS and MS degrees from Seoul National University, South Korea and a PhD from UC Davis. She carried out postdoctoral research in the field of theoretical and computational organic chemistry at UC Davis. She is currently a staff scientist at UC Davis, where she continues to study terpene biosynthesis. Young J. Hong
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Dean J. Tantillo was born and raised in Quincy, Massachusetts, USA. He received an AB degree in Chemistry in 1995 from Harvard University and a PhD in 2000 from UCLA (with Kendall Houk). After receiving his PhD, he moved to Cornell University, where he carried out postdoctoral research with Roald Hoffmann. He joined the faculty at UC Davis in 2003, where he is now a Professor of Chemistry. Professor Tantillo can Dean J. Tantillo often be found walking through the woods touching terpenes and contemplating puzzling mechanistic questions in the areas of biosynthesis, reactive intermediate chemistry, catalysis, organometallic chemistry, and stereoselective synthetic reactions.
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Scheme 1
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Routes to cyclobutanes via carbocations.
Scheme 3
Scheme 2 Proposed pathway (previous proposal in black and revised proposal based on the results of quantum chemical calculations in blue) to protoilludene.
the carbocation calculations described herein address inherent (i.e., gas phase) reactivity, which has been shown to reflect the reactivity of many terpene synthase-promoted reactions.7
Simple cyclizations – not so simple The simplest route to a cyclobutane from a carbocation is ringclosure via nucleophilic attack on the formally positively charged carbon of the carbocation by a p-bond that resides three carbons away, i.e., three of the bonds of the incipient cyclobutane are present in the precursor to the carbocation (Scheme 1, step b). Protoilludene (Scheme 2) can form from direct deprotonation of the protoilludyl cation (Scheme 2, D) which is invoked in a variety of mechanistic proposals for sesquiterpene-forming carbocationic rearrangements.8 The generally proposed mechanism for formation of protoilludene is similar to the pathway in black in Scheme 2 (A-B-C-D). This mechanism was examined computationally by Gutta, Lodewyk, Willenbring and Tantillo.6,9 Quantum chemical calculations (mPW1PW91/6-31+G(d,p)//B3LYP/ 6-31+G(d,p)) suggest that tricyclic structure D results from a concerted but asynchronous combination of two cation-alkene
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Proposed pathways leading to chamipinene.
cyclization events, the second of which forms the cyclobutane ring (Scheme 2, blue, B-D). Possible pathways to the sesquiterpene chamipinene are shown in Scheme 3. Hong and Tantillo showed that chamigryl cation D can be formed not only by direct B 0 -D cyclization, but also by B0 -C cyclization followed by a 1,2-alkyl shift (C-D).10 On the basis of additional computations on the C-D conversion,11 it seems that once cation D adopts a conformation productive for cyclization, attack of the cyclohexene p-bond onto the carbocation center (C7) of D is barrierless (mPW1PW91/6-31+G(d,p)//B3LYP/ 6-31+G(d,p)). Thus, the barrier that is responsible for making formation of E a stepwise process is that for a conformational change, not that for the final cyclization. In carbocation E, the C2–C7 bond is elongated due to strong hyperconjugation. These examples highlight general principles at play in cyclobutane-forming carbocation reactions: (1) A strained ring can be formed if a p-bond is exchanged for a new s-bond (many additional examples are discussed below). (2) The final cyclization can be combined with other bond forming/breaking events into concerted, but often asynchronous,12 processes (e.g., see protoilludene above). Stepwise (2+2) cycloadditions Many cyclobutanes appear to be formed via the stepwise (2+2) cycloaddition of allyl cations and alkenes, i.e., reactions involving separate steps a and b in Scheme 1. A variety of examples are described below, highlighting how widespread this mechanistic manifold is in the world of terpene biosynthesis. The monoterpenes a-pinene and b-pinene (the former is shown in Scheme 4) are generally thought to be formed via mechanisms similar to that shown in Scheme 4.5,13 Cationalkene cyclization of the terpinyl cation (C) is proposed to lead to the pinyl cation (D). Two theoretical studies on the conversion of the terpinyl cation to the pinyl cation have been described in
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Fig. 1 Computed structures (B3LYP/6-31+G(d,p), distances in Å) of carbocation preceding pinene and the complex of this carbocation and a model diphosphate group.
Scheme 4 Possible carbocation rearrangements leading to pinenes (R = methyl) and bergamotenes (R = homoisoprenyl).
recent years, one by Weitman and Major14 and the other by Hong and Tantillo.15 These studies agree that, at least in the absence of an enzyme, pathways predicted using quantum chemical calculations are largely consistent with previously proposed mechanisms. Both studies involved surveys of a variety of different methods for computing geometries and energies of the carbocations involved in pinene formation. On the basis of the results reported by Hong and Tantillo (who optimized structures from Scheme 4 with various methods), the predicted barrier for the conversion of C to D does not vary much with the level of theory used (B3LYP, mPW1PW91, PBE, BB1K, MPWB1K and MP2 were examined). However, the predicted energy of D relative to that of C varies significantly. All levels of theory examined predicted very similar geometries for the pinyl cation, which has an extremely long C2–C7 bond (1.94 Å at the B3LYP/6-31+G(d,p) level, Fig. 1; this bond elongation is frequently found for cyclobutylcarbinyl cations). Hong and Tantillo also examined the susceptibility of the geometry of D to change upon participation in intermolecular interactions with electron rich groups, and the C2–C7 distance was shown to dramatically decrease (to 1.64 Å at the B3LYP/6-31+G(d,p) level) upon complexation via C–H O interactions with a pyrophosphate model (Fig. 1). Deprotonation of the pinyl cation using the diphosphate model shown to form the pinenes was also predicted to be facile. A sesquiterpene analogue of pinene is bergamotene (Scheme 4). Quantum chemical calculations were performed by Hong and Tantillo to compare and contrast the mechanism for formation of bergamotene with that of pinene.16 The mechanism for
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bergamotene formation was found to be similar to but not the same as that for pinene formation. The depth of the energy well associated with cation D was shown to vary with the nature of the R group (Scheme 4) and the theoretical method employed (the B3LYP, mPW1PW91 and MPWB1K methods were examined). Particular intramolecular interactions in certain conformers were shown to influence whether or not carbocation D is a discrete intermediate or instead exists along the slope of a pathway for conversion of carbocation C into an alternative carbocation (the camphyl cation). A more complex pinene analogue is ylangene, which has an additional ring fused to the pinene bicyclic core (Scheme 5). The mechanism for formation of ylangene was examined by Lodewyk, Gutta and Tantillo using mPW1PW91/6-31+G(d,p)// B3LYP/6-31+G(d,p) calculations.17 In analogy to the cases described above, one C–C distance of the cyclobutane ring is predicted to be very long due to hyperconjugation (1.95 Å), can be decreased to 1.76 Å upon complexation with ammonia, and can be decreased to a ‘‘normal’’ length after low barrier deprotonation. An analogous mechanistic scenario is expected for copaene (10-epi-ylangene) formation.18 The generally proposed mechanism for formation of caryophyllene (various isomers) includes 1,11-cyclization of the farnesyl cation resulting from loss of pyrophosphate from farnesyl diphosphate (FPP) and ring closure of the resulting secondary carbocation B to form the caryophyllyl cation C (Scheme 6, FPP-A-B-C).19 Wang and Tantillo examined ring closure of both E and Z isomers of B (Scheme 6, B and B 0 , respectively) to form cation C using quantum chemical calculations (mPW1PW91/6-31+G(d,p)//B3LYP/6-31+G(d,p)).20 Both B and B 0 were predicted to undergo ring closure with a small barrier (r5 kcal mol1) to form different conformers of carbocation C. The conformer formed directly from B 0 was productive for subsequent reactions leading to the sesquiterpene alcohol presilphiperfolanol. Carbocations A and A 0 were not located
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Scheme 7 Possible carbocation rearrangement pathways leading to plumisclerin A.
Scheme 5 Possible carbocation rearrangement pathways leading to ylangenes.
open the possibility that 1,11-cyclization may occur in concert with diphosphate loss. The possibility that the diterpenoid plumisclerin A21 could be formed via a stepwise cationic (2+2) reaction (Scheme 7) was examined by Sio et al. using a variety of quantum chemical methods.22 On the basis of the results of these calculations, the authors concluded that such a carbocation cascade is energetically viable if the aldehyde in the reactant is protonated (perhaps by an enzyme active site residue) to produce an activated allyl cation. In this case, the attacking alkene is also activated by an attached electron-releasing OAc group. Concerted [2+2] cycloadditions
Scheme 6 Possible carbocation rearrangement pathways leading to caryophyllenes.
as minima (for appropriate conformations, the absence of significant strain leads to barrierless carbocation/alkene collapse), leaving
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In some cases, putative intermediates in stepwise (2+2) cycloaddition pathways were found not to be discrete minima. Instead, these structures were found to reside on slopes of reaction coordinates for concerted processes in which the two bond-forming events are combined asynchronously (Scheme 1, where a and b are not separate elementary reactions, but rather are events occurring during a single reaction step).12,23 A concerted [p2S+p2S] cycloaddition that converts the farnesyl cation directly to the caryophyllyl cation (Scheme 6, A-C), is forbidden on orbital symmetry grounds.24 Nonetheless, two computational studies, one by Nguyen and Tantillo25 and the other by Hong et al.26 described concerted [2+2] cycloaddition pathways for the conversion of cation A to C (both cis and trans isomers). This reaction is predicted to have a low barrier (o5 kcal mol1 with mPW1PW91/6-31+G(d,p)//B3LYP/6-31+G(d,p)). How does one rationalize the ease of this reaction in light of the constraints of orbital symmetry? The answer comes from a close examination of the reaction coordinate. Although this reaction is concerted, the two bond-forming events occur very
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Fig. 2 Sesquiterpene natural products derived from caryophyllyl cations whose formation has been examined with quantum chemical calculations.
asynchronously, so much so that at no point along the reaction coordinate for cycloaddition is there strong cyclic orbital overlap. The orbital symmetry rules only apply to reactions where such cyclic overlap occurs along a reaction coordinate.27 In addition, a post-transition state bifurcation28 was also implicated for the conversion of A to C via the pathway just described, but also to B (Scheme 6) via another pathway connected to the same transition state structure. A selection of sesquiterpenes derived from isomers of C whose formation has so far been examined using quantum chemical calculations is shown in Fig. 2.25,26 Other terpenes/terpenoids are likely to be derived from (2+2) cycloadditions of allyl cations with alkenes, be they concerted or stepwise. A selection of natural products whose origins likely involve such reactions are shown in Scheme 8.29 Whether the particular (2+2) cycloaddition reactions shown would be stepwise or concerted is not clear and will likely require future theoretical studies to tease out the influence of conformational factors and carbocation substitution patterns (note that some stepwise processes shown involve the generation of secondary carbocations).30 Synthetic approaches to cyclobutanes have also made use of cationic (2+2) reactions.31
Scheme 8 Additional terpene/terpenoid natural products that could be formed via concerted or stepwise (shown) (2+2) cycloadditions.
Other cyclobutane-forming carbocation rearrangements involving alkyl shifts are under investigation. The cyclobutane-containing dendrowardol A and B were isolated from Dendrobium wardianum Warner along with the cyclopropanecontaining dendronbilin H (Scheme 9).32 The pathways proposed for dendronwardol A and B formation involve generation of a primary cyclopropylcarbinyl cation by protonation/ dehydration of dendronbilin H or its epimer (not yet found in nature), followed by ring expansion and recapture of water.32
Other carbocation reactions Another possible route to the caryophyllyl cation (Scheme 6, C) involves 1,10-cyclization to form tertiary carbocation D followed by a 1,2-alkyl shift to produce B, which could then cyclize to C. The latter two of these events might also be merged into a concerted process that avoids secondary carbocation B as a discrete intermediate. Our preliminary calculations (M06-2X/ 6-31+G(d,p)) indicate that the A-D-C pathway is viable and the conversion of cation A to D is predicted to occur without a significant barrier for at least one conformation. Clearly, no single mechanism captures the subtleties associated with caryophyllyl cation formation—different conformers and geometric isomers display related but different behavior. Which pathway is followed in a given biological scenario is likely determined not only by the electronic structure of the precursors to C, but also the shape and charge distribution of the particular terpene synthase active site in which they are generated.
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Scheme 9 Proposed biosynthesis of dendrowardol A and B sesquiterpenoid epimers.
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Scheme 12 Possible mechanisms for formation of the original and revised aquatolide structures. Scheme 10 formation.
Proposed dyotropic rearrangement for dendrowardol A/B
Scheme 11 Proposed dyotropic rearrangement for dendrowardol C formation.
Although it is attached to a cyclopropane ring, a primary carbocation center seems unlikely to be present in a discrete intermediate. A concerted dyotropic rearrangement (Scheme 10)33 could replace the stepwise process, although geometric constraints imposed by the polycylic system may discourage such a reaction. An analogous situation exists for dendrowardol C (Scheme 11), which is proposed to be derived from cyclosativene via oxidation.34 No doubt, future calculations on these systems will prove to be enlightening.
Photochemistry Many cyclobutanes in natural products are thought to arise from photochemical reactions.3 As shown above, viable alternatives to photochemistry exist, but photochemical reactions clearly do play a large role in enriching the pool of natural products with cyclobutane-containing structures. The biosynthesis of aquatolide provides a representative example. Aquatolide is a humulane-derived sesquiterpenoid lactone isolated from Asteriscus aquaticus.35 The structure of aquatolide was originally proposed to contain a rare [2]ladderane substructure (Scheme 12, 1).2,35 Recently, extensive quantum chemical NMR calculations, combined with experiments, by Lodewyk and co-workers led to the revision of the aquatolide structure (Scheme 12, 2).36 A biosynthetic pathway involving a [2+2] photocycloaddition of known natural product asteriscunolide C (3) was proposed (Scheme 12, blue), and this process is expected to occur more readily than photocycloaddition to form 1 (Scheme 12, red). These conjectures are currently being subjected to experimental scrutiny. A small selection of other natural products whose cyclobutane cores are thought to be produced via photochemical
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Fig. 3 Natural products whose cyclobutane cores are thought to arise from photochemical [2+2] cycloadditions.
[2+2] reactions is shown in Fig. 3;37 note that these compounds are members of several different natural product classes. To our knowledge, neither photochemical nor nonphotochemical mechanisms for formation of these natural products have yet been examined computationally. There is certainly much more to learn about biosynthetic cyclobutane formation!38 Photochemical rearrangements to form cyclobutane-containing natural products have also been proposed. One such example is shown in Scheme 13. Verbenone, a pinene-derived monoterpenoid was isolated along with filifolone (Scheme 13).39,40 The related monoterpenoid chrysanthenone (Scheme 13) has been isolated from a variety sources in Nature.40,41 Photochemical rearrangement of verbenone to chrysanthenone (a [1,3] sigmatropic shift; Scheme 13) has been reported in the literature, suggesting that this reaction might occur in Nature.39,42
Scheme 13
Photochemical rearrangement of verbenone to chrysanthenone.
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Scheme 16
Scheme 14
Example of a proposed diradical cyclization.
Other mechanisms Other mechanistic manifolds have been suggested for the formation of cyclobutanes in various natural products. One reaction type involves the cyclization of 1,4-diradicals (Scheme 14).43 Another involves a pericyclic cascade (sequential 8-electron and 6-electron electrocyclizations) (Scheme 15). The viability of these mechanistic pathways for specific natural products is ripe for theoretical scrutiny.44
Reactions of cyclobutanes In this section we briefly describe two computational studies on reactions of cyclobutane-containing natural products. These reactions are thought to correlate to important biological roles of the associated natural products. Houk, Baran and co-workers examined vinylcyclobutane-tocyclopentene rearrangements of sceptrin (Fig. 3).45 Heating of sceptrin was shown (through a combination of experiments and computations [UHF and UB3LYP with 6-31G*]) to produce ageliferin and nagelamide E (Fig. 4) through formal [1,3] sigmatropic shifts involving diradicals. This study provided a convincing argument that sceptrin may be the biosynthetic precursor to these natural products lacking cyclobutane rings.
Possible reactions of ladderane lipids.
The ladderane lipids (Scheme 16) are perhaps the most unusual cyclobutane-containing natural products.2 To date, no convincing evidence for the chemical mechanisms by which their fused oligocyclobutane polycycles are formed has been provided, although several mechanisms (both photochemical and nonphotochemical) have been considered.2,46,47 Recently, Nouri and Tantillo examined mechanisms by which ladderane lipids might react (using B3LYP, mPW1PW91 and CCSD(T) calculations).46 Protonation, hydrogen atom abstraction, and addition of radicals were all shown to break open the ladderane core, prompting speculation that ladderanes may play a role in trapping reactive species.
Conclusions Cyclobutanes are widespread in Nature. While photochemical [2+2] cycloadditions are likely responsible for formation of many cyclobutane-containing natural products, carbocation cyclization/ rearrangement processes, which provide routes to many cyclobutane-containing terpenes and terpenoids are likely just as prevalent. In both types of process, p-bonds are traded for s-bonds, providing a driving force for formation of strained cyclobutane rings.48 While many chemical mechanisms have been interrogated using quantum chemical methods, many have not—especially photochemical cyclobutane-forming reactions—leaving room for future theoretical work that will fill in additional details of the rich mechanistic framework associated with biosynthetic cyclobutane formation.
Acknowledgements Work on carbocation cyclizations in D.J.T.’s laboratory has been generously supported by the U.S. National Science Foundation.
Notes and references
Scheme 15 Example of a proposed pericyclic cascade.
Fig. 4 Natural products thought to be derived from sceptrin.
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1 E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York, 1994, 756; N. L. Allinger, M. T. Tribble, M. A. Miller and D. H. Wertz, J. Am. Chem. Soc., 1971, 93, 1637; K. B. Wiberg, in The Chemistry of Cyclobutanes, ed. Z. Rappoport and J. F. Liebman, John Wiley & Sons, 2005, ch. 1. 2 D. H. Nouri and D. J. Tantillo, Curr. Org. Chem., 2006, 10, 2055. 3 T. Bach and J. P. Hehn, Angew. Chem., Int. Ed., 2011, 50, 1000. 4 T. Seiser, T. Saget, D. N. Tran and N. Cramer, Angew. Chem., Int. Ed., 2011, 50, 7740; J. Iriondo-Alberdi and M. F. Greaney, Eur. J. Org. Chem., 2007, 4801; J. C. Namyslo and D. E. Kaufmann, Chem. Rev., 2003, 103, 1485; B. M. Fraga,
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