Article Cite This: J. Am. Chem. Soc. 2018, 140, 9291−9298
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Rearrangement of Hydroxylated Pinene Derivatives to FenchoneType Frameworks: Computational Evidence for DynamicallyControlled Selectivity Marcus Blümel,† Shota Nagasawa,† Katherine Blackford,† Stephanie R. Hare,‡ Dean J. Tantillo,*,‡ and Richmond Sarpong*,† †
Department of Chemistry, University of California, Berkeley, California 94720, United States Department of Chemistry, University of California, Davis, California 95616, United States
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‡
S Supporting Information *
ABSTRACT: An acid-catalyzed Prins/semipinacol rearrangement cascade reaction of hydroxylated pinene derivatives that leads to tricyclic fenchone-type scaffolds in very high yields and diastereoselectivity has been developed. Quantum chemical analysis of the selectivity-determining step provides support for the existence of an extremely flat potential energy surface around the transition state structure. This transition state structure appears to be ambimodal, i.e., the fenchonetype tricyclic scaffolds are formed in preference to the competing formation of a bornyl (camphor-type) skeleton under dynamic control via a post-transition state bifurcation (PTSB).
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INTRODUCTION α- and β-Pinene (6 and 7, Scheme 1A) are abundant terpenes that are employed as starting materials for the preparation of fragrances,1 bioactive natural products,2 agrochemicals, and pharmaceuticals,3 as well as organic polymers.4 In line with the established biosynthesis of many terpenoid secondary metabolites,5 it has been shown that 6 and 7 arise from geranyl or neryl pyrophosphate (1).6 In each case, the corresponding geranyl or neryl cation (2) is converted to the pinyl cation (3) via an enzyme-catalyzed process involving a “polyene” cascade. A terminating deprotonation then leads to either 6 or 7. Alternatively, at the stage of the pinyl cation (3), a Wagner− Meerwein-type rearrangement7 can lead to either the bornyl (10) or fenchyl cation (8) depending on the bridging carbon atom (i.e., C6 or C7 in 3) that undergoes migration. On the basis of the established migratory aptitudes of alkyl substituents adjacent to carbocations,8 it would be expected that migration of the more substituted carbon (i.e., C6), thereby forming the camphor-type framework (11), would be favored should a rearrangement ensue from the pinyl cation. In line with this expectation, Shoolery and co-workers have shown that subjecting pinene to AcOD and B2O3 leads to its conversion to borneol in 45% yield accompanied by a 30% yield of fenchol.9 We have previously shown that subjecting dihydroxlyated α-pinene derivative 12 (Scheme 1B) to Brønsted acids such as PPTS results in the formation of the camphor derivative 13 as the major product and fenchone derivative 14 as the minor product.10 Furthermore, subjecting 12 to mCPBA effects epoxidation followed by epoxide-opening rearrangement to give dihydroxylated camphor derivative 15 as the major product. Despite the preference for the camphor© 2018 American Chemical Society
type framework in these acid-mediated rearrangements under laboratory conditions, the occurrence of the fenchone-type framework in Nature suggests that, under certain circumstances, rearrangement of the pinyl cation to the fenchane-type scaffold may be favored over rearrangement to the camphortype framework. Given that many polyene cationic cyclization events occur in an enzyme pocket where molecular dynamics constraints can dictate reaction outcome,11 it may be the case that, under enzymatic catalysis, the pinyl cation adopts a specific conformation that is optimal for the formation of either the camphor or fenchane framework by better aligning one of the bridging carbons for migration during the requisite Wagner-Meerwein rearrangement. As a part of an ongoing program in one of our laboratories aimed at the total synthesis of terpenoid natural products,10,12 we sought to protect the diol of dihydroxylated pinene derivative 16a as a benzylidene acetonide. To our surprise, we observed conversion of 16a exclusively to the caged fenchonetype structure 19, along with its elimination product 20 (Scheme 1C). As illustrated in Scheme 2, we envisioned 19 and 20 arising from an initially formed oxocarbenium ion (21) resulting from acid-mediated condensation of 16a and dimethyl acetal 17. An ensuing Prins-type cyclization of 21 to yield 22 followed by semipinacol rearrangement would then give 23.13 In this case, as opposed to the previously observed protic acid-mediated rearrangement of 16b (where R = Ac),10 we hypothesized that the conformation of 22, likely dictated by the bridging ether, led to a more facile migration of the Received: June 2, 2018 Published: July 3, 2018 9291
DOI: 10.1021/jacs.8b05804 J. Am. Chem. Soc. 2018, 140, 9291−9298
Article
Journal of the American Chemical Society
that the outcome of the pinyl cation rearrangement, and consequently whether the bornane or fenchane framework is formed, may be dictated by the conformation of the pinyl cation intermediate and the molecular dynamics of this facile rearrangement. Importantly, the molecular dynamics and conformational effects that we have uncovered may also explain the observed selectivity for the formation of the fenchane or bornyl scaffold from the pinyl cation in Nature.
Scheme 1. (A) Proposed Biosynthetic Pathway to Pinenes, Camphor, and Fenchone; (B) Previous Reports of Rearrangement Reactions of Dihydroxylated Pinene Derivative 12 (Red Bond); (C) Prins/Semipinacol Sequence to Access Tri- and Bicyclic Fenchone Derivatives (Blue Bond)
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RESULTS AND DISCUSSION Scope of Acetal Condensation Partners. We commenced our studies by seeking to optimize the reaction of dihydroxylated pinene derivative 16a10,14 with benzaldehyde dimethyl acetal in the presence of Brønsted or Lewis acids. As illustrated in Table 1, while various protic acids (pKa, −6.5 to Table 1. Optimization of the Prins Reaction/Semipinacol Rearrangement Cascade Employing Acetalsa
Scheme 2. Initially Proposed Prins/Semipinacol Reaction Sequence
entry
cat (mol %)
solvent
time [h]
yieldb [%]
1 2 3 4 5 6 7 8 9 10 11 12
PPTS (2) pTSA (2) TFA (2) HCl (2) O3ReOSiPh3 (2) pTSA (2) pTSA (2) pTSA (2) pTSA (2) pTSA (2) pTSA (5) pTSA (1)
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 1,2-DCE toluene EtOAc MeNO2 CH2Cl2 CH2Cl2
43 16 67 17 22 2 2 43 96 2 2 17
60 82 68 66 79 74 74 69 73 88 (4:1)c 76 86
a
Reactions were carried out with hydroxylated pinene derivative 16a (0.125 mmol), benzaldehyde dimethyl acetal (17a) (0.150 mmol, 1.2 equiv), and catalyst (2.5 μmol, 2 mol %) in solvent (c = 0.125 M) at ambient temperature. bYield of the isolated product. cTricyclic compound 19a ((6R)-epimer) was obtained as a 4:1-mixture with the epimer (6S)-19a.
4.76)15,16 gave good yields of the desired product (19a, entries 1−4), p-toluenesulfonic acid (pTSA) proved to be the most effective, cleanly leading to 19a in 82% yield (entry 2). The use of Lewis acid catalysts, for example, O3ReOSiPh3 (entry 5), which has been employed to great effect in other Prins-type processes,17 also led to full conversion and high yields of up to 79%. However, due to ease of handling, as well as considerations regarding expense and sustainability, we opted to continue our investigations with pTSA. We next investigated the influence of solvent on the cascade reaction (entries 6− 10). Most chlorinated solvents were effective and led to good yields in the range of 74−79% (entries 6, 7), except for CCl4, in which 19a was only sparingly soluble. Solvents such as toluene and EtOAc required longer reaction times but also gave good yields of the desired product (entries 8, 9). Interestingly, the use of nitromethane had an accelerating effect but also led to the competing formation of epimeric adduct (6S)-19a (entry 10). Highly coordinating polar aprotic solvents such as THF, Et2O, MeCN, or DMF effectively shut
methylene bridge (C7) rather than the migration of the tetrasubstituted carbon (C6). Acid-mediated ionization of the tertiary ether in 19, followed by E1 elimination, would ultimately afford 20. In this article, we report the scope of this Prins reaction/ semipinacol rearrangement, which affords a broad range of compounds bearing the fenchone core structure. Furthermore, we provide insight into the mechanism of the overall process using quantum chemical calculations, particularly regarding the factors that determine which of the two bridging carbons (i.e., C6 or C7 in 22) migrate. Our findings (vide infra) indicate 9292
DOI: 10.1021/jacs.8b05804 J. Am. Chem. Soc. 2018, 140, 9291−9298
Article
Journal of the American Chemical Society down the reaction, presumably by slowing down protonation events that led to the formation of the mixed acetal (e.g., 34, Scheme 4) and oxocarbenium (e.g., 21) intermediates. As anticipated, the conversion of the dimethyl acetal (17a) to the mixed acetal intermediate (e.g., 34, Scheme 4) is not favored in MeOH; consequently, no reaction was observed in MeOH. A lower catalyst loading of only 1 mol % of pTSA proved to be ideal, resulting in 86% of the desired tricycle (19a, entry 12). Varying the equivalents of acetal 17a or the temperature did not result in further improvements in reaction efficiency. The optimal conditions that we identified were to carry out the reaction in CH2Cl2 with 1 mol % pTSA at ambient temperature (entry 12) over 17 h. The corresponding benzylidene diethyl and cyclic acetals (e.g., dioxolanes) were also effective condensation partners in the Prins/semipinacol cascade reaction to give 19a, albeit requiring longer reaction times.18 The scope of the Prins/semipinacol rearrangement cascade reaction is illustrated in Table 2. A broad range of electron-deficient and electron-rich benzylidene dimethyl acetals 17 were smoothly converted into the corresponding fenchone-type derivatives in excellent yields of up to 99% and with high diastereoselectivities (see 19a−q). Fenchone-type derivative 19i provided a suitable single crystal for X-ray crystallographic analysis, which unambiguously supports the unusual strained tricyclic framework of the product, as well as the (R)-configuration of the stereocenter bearing the aryl group (i.e., C6 in 19) that presumably avoids interactions with the vinyl Me group at C2 of the [3.1.1] bicycle in the transition state leading to the Prins adduct. In addition, the parent aldehydes (i.e., 18) of the benzylidene acetal condensation partners could also be employed in the cascade reaction as condensation partners with 16, although slightly lower yields were obtained in these cases. Benzylidene acetals bearing highly electron-withdrawing groups or their corresponding aldehydes were poor condensation partners, likely due to destabilization of the incipient oxocarbenium ion related to 22. Substitution on the methylene bridge of precursor 16a had only a marginal impact on reactivity and selectivity (see 19r). In contrast, a sterically demanding pivalate group proximal to the primary hydroxyl19 led to lower yields (see 19s). While alkyl acetals also give the desired adducts (see 19t and 19u), these reactions proceed in lower yield, pointing to the crucial role of the aromatic system of the benzylidene acetal or aldehyde condensation partners in stabilizing the intermediate oxocarbenium ion. In the cases employing π-excessive or highly electron-rich benzylidene acetals or their corresponding aldehydes as condensation partners, ionization of the bridging cyclic ether oxygen followed by deprotonation led to substituted [2.2.1] bicycles (i.e., 20a−h). Scope of Ketal Condensation Partners. We then explored the Prins/semipinacol cascade of hydroxylated pinene derivatives such as ent-16a with dimethyl ketal condensation partners such as 2,2-dimethoxy propane 25a. Under the optimized conditions for acetals and aldehydes, the reactions with the ketal condensation partners only proceeded to give moderate yields of the anticipated products (e.g., 48% for 25a; Table 3, entry 1). Furthermore, competing formation of cyclic ether 27 in almost equimolar amounts was observed, along with some remaining starting material (i.e., ent-16a).10 To suppress the formation of 27, which likely arises via acidcatalyzed intramolecular etherification of ent-16a, we explored the use of oxophilic Lewis acid catalysts (entries 2−6), which would bind the oxygen nucleophile more tightly and prevent
Table 2. Scope of Different Acetal and Aldehyde Substrates 17 and 18 for the Prins Reaction/Semipinacol Rearrangement Sequence
a
Yields for the reaction with the aldehyde (18) are given in parentheses. bThe acetal (17) was used for this reaction. cThe yield of the reaction employing SnCl2 (10 mol %) in 1,2-DCE is given in parentheses. dThe respective aldehyde 18 was used. e8% of the tricyclic product was obtained as a side product.
etherification.16 While ZnCl2 did not catalyze the reaction, iron, titanium, and silicon-based Lewis acids typically led to a complete but unselective reaction. Overall, SnCl4 and SnCl2, despite lower conversions at room temperature, gave the cleanest transformation of ent-16a to 26a without the competing formation of 27 (entries 5 and 6). We elected to proceed with SnCl2 as catalyst given the ease in handling this relatively nonhygroscopic reagent. A solvent and temperature screen (entries 7−12) revealed that using 1,2-dichlorethane as the solvent, as well as heating the reaction mixture to 60 °C, was optimal. The best yields were obtained by using two equivalents of the dimethyl ketal (entry 11). As shown in Table 4, a broad range of dimethylketals derived from aliphatic and aromatic ketones, participate as condensation partners with ent-16a in the Prins/semipinacol reaction. Both acyclic and 9293
DOI: 10.1021/jacs.8b05804 J. Am. Chem. Soc. 2018, 140, 9291−9298
Article
Journal of the American Chemical Society Table 3. Optimization of the Prins Reaction/Semipinacol Rearrangement Cascade Employing Ketalsa
entry
acid (mol %)
conv [%]
26ab [%]
27b [%]
1 2 3 4 5 6 7c 8c 9c 10c,d 11d,e 12d,e
pTSA (1) FeCl3 (5) TiCl4 (5) TMSCl (5) SnCl4 (5) SnCl2 (5) SnCl2 (10) SnCl2 (20) SnCl2 (50) SnCl2 (10) SnCl2 (10) SnCl2 (5)
97 75 >99 >99 74 44 82 85 >99 >99 >99 >99
48 44 32 8 73 26 65 73 78 81 (61) 78 (77) 78 (71)
31
Table 4. Scope of Ketals 25 in the Prins Reaction/ Semipinacol Rearrangement Sequence
trace 81
a
Reactions were carried out with hydroxylated pinene derivative ent16a (0.125 mmol), 2,2-dimethoxypropane (25a) (0.150 mmol, 1.2 equiv), and catalyst (6.3 μmol, 5 mol %) in CH2Cl2 (c = 0.125 M) at ambient temperature bYield determined by 1H NMR with 1,3,5trimethoxybenzene as internal standard. Yield of the isolated products are given in parentheses. c25a (0.375 mmol, 3.0 equiv) was used. d The reaction was carried out in 1,2-DCE at 60 °C. e25a (0.250 mmol, 2.0 equiv) was used. a SnCl2 (20 mol %) was used. bAlkene resulting from cleavage of the ether-bridge was obtained as side product in 20% yield. cSnCl2 (15 mol %) was used. dThe reaction was carried out at 65 °C with SnCl2 (50 mol %) and 25a (3.0 equiv).
cyclic aliphatic ketals were transformed to the anticipated products in yields ranging from 11 to 83% (see 26a−i). In contrast to our observations with acetal condensation partners (Table 2), the use of unsymmetrical ketals usually led to the formation of both epimers at C6 (see 26c and 26j−r). However, pronounced steric differences between the two substituents on the ketal, (e.g., in 25c) led to excellent diastereoselectivity (>19:1). Analogous to our observations with the acetal condensation partners (i.e., R′ = H in 26), the larger substituent ultimately resides in a position that presumably avoids interactions with the vinyl Me group at C2 in ent-16. Acetophenone-derived ketals furnished the corresponding tricyclic fenchone-type structures (26j−r), whereas π-excessive and highly electron-rich ketals (e.g., 25q) underwent spontaneous C−O cleavage of the bridging ether oxygen following the Prins/semipinacol sequence.18 If desired, C−O cleavage of the ether bridge in the caged products can be subsequently achieved by treating the cyclic ether adducts with phosphoric acid (see Scheme 3A). Substituents on the cyclobutanol portion of the dihydroxylated pinene derivative precursor are also tolerated, as illustrated by the formation of 26s and 26t, albeit requiring increased catalyst loadings. As shown in Scheme 3B for 26a, one-pot ether cleavage/esterification to alkenes 28 and 29, α-oxidation to lactone 30, and diastereoselective carbonyl reduction (to give 31)18 highlight the potential for further derivatization of these fenchone-type polycyclic structures. Detailed Mechanistic Considerations and Quantum Chemical Studies. While our initially proposed mechanism (Scheme 2) is consistent with most of our observations, it became apparent as we continued to explore the scope of the Prins/semipinacol reaction that a more complete mechanistic picture was necessary (Scheme 4). For example, following the
Scheme 3. (A) Conversion of Tricyclic Fenchone-Type Structure 19a into the Corresponding Bicyclo[2.2.1] Framework 20i; (B) Derivatization of Tricyclic Compound 26a
initial condensation of pinene derivative 16a with dimethyl acetal 17 under acidic conditions, oxocarbenium ion 35, which results from elimination of MeOH from cation 34, might benefit from stabilizing cation−π interactions with the alkene 9294
DOI: 10.1021/jacs.8b05804 J. Am. Chem. Soc. 2018, 140, 9291−9298
Article
Journal of the American Chemical Society Scheme 4. Proposed Mechanism for the Prins/Semipinacol Rearrangement Cascade Reaction
growing, with various examples having been discovered in the realms of synthetic organic chemistry, organometallic chemistry, and natural products biosynthesis.20 To further probe the validity of our hypothesis that such nonstatistical dynamic effects are important for the reactions described herein, dynamics trajectory simulations starting from ambimodal transition state structure 36 were carried out (using ωB97X-D/6-31G(d)).18 Out of a total of 232 trajectories, 66% connected the primary alkyl shift product (38) with oxocarbenium ion reactant 35, 33% were recrossing trajectories, 0.4% (1 trajectory) remained at 36 after 1000 fs and connected to 35, and 0.9% (2 trajectories) generated the product of the tertiary alkyl shift (39) with connection to 35. The large proportion of recrossing trajectories (74 trajectories) is consistent with the region of cyclization TSS 36 on the potential energy surface (PES) being quite flat (Scheme 5, bottom). This result is not unexpected, as the optimized TSS is very early with respect to C−C bond formation (and this TSS could not be located at some levels of theory). Thus, nearly complete (∼99:1) selectivity was predicted, which is consistent with our experimental observations.24 We believe that this preference arises from the dynamical tendency for less massive groups to move more rapidly (see Figure 1), leading to a higher migratory aptitude, as precedented by Singleton’s studies of newtonian kinetic isotope effects.25,26 This new example of a reaction that is subject to nonstatistical dynamic effects bridges the worlds of synthetic and biosynthetic organic chemistry, highlighting the importance of such effects in both realms and their potential for rationally controlling selectivity in the former. Why does our synthetic system display a different selectivity than that of the hydrocarbon system found in Nature? The inherent reactivity11e of the pinyl carbocation was examined previously by Weitman and Major,11a who showed that neither bornyl nor fenchyl cations, both secondary carbocations arising from 1,2-alkyl shifts,27 are PES minima. Instead, TSSs
group in 35. Furthermore, in the transition state that leads to 38, the larger substituent on the oxocarbenium moiety likely avoids interactions with the vinyl methyl group on the [3.1.1] bicycle, which would explain the exclusive formation of the (R)-epimer in the subsequent Prins reaction. Quantum Chemical Studies. Still intriguing to us was the observed selectivity for the migrating bridging carbon. Selectivity for the migration of the more- or less-substituted bridging carbon ultimately leads to formation of the fenchonetype or bornyl (camphor-type) framework, respectively (see 3 → 8 or 10, Scheme 1). We hypothesize that, in the Prins/ semipinacol reaction cascade, there exists a post-transition state bifurcation (PTSB) following the Prins transition state (36), making this transition state structure (TSS) “ambimodal”.20 Thus, the selectivity for the formation of the fenchonetype products is most probably kinetically controlled but determined by nonstatistical dynamic effects rather than by the energies of competing transition state structures. Using density functional theory (DFT) computations at the ωB97X-D21/631+G(d,p)22 level,18 structures of carbocation 37, the TSS for the initial ring closure (i.e., Prins reaction; 36), and TSSs for the two possible rearrangements leading to products 38 and 39, were located. Carbocation 37 resides in a shallow potential energy surface (PES) minimum with predicted free energy barriers for the migration of the primary and tertiary alkyl groups of only 1.2 and 3.3 kcal/mol, respectively. If these barriers were zero, as they likely are at some levels of theory,23 this system would have a post-transition state bifurcation (PTSB) following the ring-closure TSS 36. Given the shallowness of the minimum, we postulate that the (kinetic) selectivity for this cyclization/rearrangement reaction is dynamically determined regardless of whether there is an explicit PTSB or a very shallow minimum with two exit channels. Appreciation for the role of nonstatistical dynamic effects in controlling product distributions for organic reactions is 9295
DOI: 10.1021/jacs.8b05804 J. Am. Chem. Soc. 2018, 140, 9291−9298
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Journal of the American Chemical Society
associated with this level of selectivity is small (
