From Hydrindane to Decalin: A Mild Transformation through a

Letter pubs.acs.org/OrgLett

From Hydrindane to Decalin: A Mild Transformation through a Dyotropic Ring Expansion Hugo Santalla,† Olalla Nieto Faza,† Generosa Gómez,‡ Yagamare Fall,*,‡ and Carlos Silva López*,† †

Departamento de Química Orgánica, Campus Lagoas-Marcosende, 36310 Vigo, Spain Departamento de Química Orgánica and Instituto de Investigación Sanitaria Galicia Sur (IISGS), Campus Lagoas-Marcosende, 36310 Vigo, Spain

‡

S Supporting Information *

ABSTRACT: An unexpected ring expansion converting hydrindane cores into decalins has been observed. The process occurs under very mild conditions and with exquisite transfer of chiral information. The ring expansion provides access to decorated decalins with complete stereocontrol. The reaction mechanism is studied in order to gain insight into the underlying causes for the low thermal requirements in this reaction and the nature of the chirality transfer process. Interestingly, both result from an unprecedented dyotropic reaction involving a mesylate group.

Dyotropic rearrangements are a relatively late addition to the pericyclic set of reactions. They were defined by Reetz in 1972 as pericyclic processes in which two σ bonds migrate simultaneously. In type-I dyotropic reactions, the migrating groups interchange their relative positions, whereas in type-II reactions the migrating groups interchange positions with an insaturation (see Figure 1).1 According to the Woodward−Hoffmann rules, type-I dyotropic reactions are symmetry forbidden when they involve hydrocarbons since they imply the participation of four electrons in a [σ2S + σ2S] fashion (see Figure 1). In dyotropic reactions that have been observed experimentally, at least one heteroatom is usually migrating.1,2 This heteroatom provides a lone pair to the reacting system,3 transforming the pericyclic reaction into a pseudopericyclic one and circumventing the WH rules.4−6 This kind of reaction has been described late with respect to the other pericyclic processes because, even when the symmetry rules are out of the way through the participation of heteroatoms, the activation energies are high due to ring strain (notice the two opposed threemembered rings for the type-I dyotropic transition state depicted in Figure 1).2 For instance, activation barriers for the dyotropic rearrangement of various dichloroalkanes have been reported and cluster inside a 35−60 kcal/mol range. Only a few exceptional cases, like that of 5,6-dichlorocyclohexa-1,3-diene, show lower barriers (25.1 kcal/mol in this case).7 Dibromo derivatives also show reduced barriers.7,8 It is not surprising, therefore, that those type I dyotropic rearrangements that operate at room temperature use an additional driving force, normally in the form of pre-existing ring strain.9 A common strategy is to mate the dyotropic rearrangements with the ring expansion of a β-lactone ring.10−24 With these precedents at hand we were very surprised when we observed that the attempts to mesylate 1 and 1epi at −78 °C yielded different results and that in the case of 1 the transformation seemed to be compatible with a type-I dyotropic rearrangement (see Figure 2). © 2017 American Chemical Society

Figure 1. Models for type-I and type-II dyotropic reactions.

Figure 2. Products observed when 1 and 1epi were subjected to mesylation conditions.

Due to the very common structural motifs that this process connects (hydrindane and decalin cores) and the very mild reaction conditions required, this reaction could be exploited in the laboratory for numerous synthetic targets. Decalins are actually bicyclic frameworks that are often found in numerous polyterpenoid and steroid natural products with interesting biological activity (antifungal, antibacterial, etc.).25−27 The Received: June 1, 2017 Published: June 22, 2017 3648

DOI: 10.1021/acs.orglett.7b01621 Org. Lett. 2017, 19, 3648−3651

Letter

Organic Letters

Figure 3. Mechanistic hypothesis for the results shown in Figure 2.

synthesis of chiral and functionalized decalins is indeed a challenging task for organic chemists, and efforts are being currently made to develop versatile methods for their preparation.28−32 Our present findings could certainly pave the way to an easy access to polyfunctionalized chiral decalins in a stereocontrolled manner. For this reason, we performed a thorough characterization of the transformation, including a detailed description of its mechanism. The reaction of 1 under mesylation conditions to afford the ring expansion was completed in 2.5 h and provided the decalin derivative 3 in 74% yield. When 1epi was subjected to the same reaction conditions, only the mesylation product was obtained even when the temperature was raised to 0 °C. We hypothesized that upon mesylation 1 would undergo subsequent ring expansion via a dyotropic process that requires an anti disposition of the migrating bonds, hence the final stereochemistry obtained at the expanded ring. In the case of 1epi, for some reason only the mesylation step was operative (Figure 3). If this hypothesis were correct, the only difference at the transition state would be a methyl group switching from equatorial (in 3 and the corresponding transition state) to axial (in the epimeric substrates). Therefore, not only the low energetic requirement for the formal dyotropic rearrangement of 1 deserves rationalization but also the dramatic effect imparted by the spatial orientation of a single methyl group to the reactivity of the substrate. In order to bring these mechanistic problems to light, we resorted to density functional theory (DFT) simulations.33,34 Calculations were performed with the dispersion-corrected metahybrid density functional wB97XD35 and the extended double-ζ quality and strongly polarized def2-SVPP basis set. All of the calculations were performed with the Gaussian 09 program (further details in the SI).36 In our simulations, we used the complete structure of hydrindanes 1 and 1epi with the only exception of the OTBS group which was removed for computational efficiency. This group, however, does not participate in the ring-expansion process and does not even affect the preferred conformation since trans hydrindanes and decalins are quite rigid. We successfully located the transition states for the ring expansion of both epimers through a dyotropic rearrangement which showed surprising features. Most type I dyotropic reactions reported to date involve 1,2 migrations on both sides of the σ bond (hence the transition states with two opposed three-membered rings, high strain and consequentially high barriers).1 The location of the structures, however, suggested that the dyotropic rearrangement in this case occurred via a 1,2-migration on the alkyl side and a 3,2migration on the mesylate side (with opposing three- and fivemembered rings at the transition state; see Figure 4). These results opened the door for an explanation of the facile ring expansion of hydrindane 1. Significant ring strain is alleviated at least in one region of the transition state with respect to the usual

Figure 4. Typical dyotropic transition state for the 2 to 3 transformation versus one with a 3,2-migrating fragment.

type I dyotropic transition states. The activation barriers thus calculated for the ring expansion of 1 and 1epi were 38.8 and 45.7 kcal/mol. These values are not compatible with reactions occurring at low temperatures, but they are comparable with those obtained for dichloroalkanes, where two heteroatoms facilitate the migration through participation of their lone pairs.3 The 7 kcal/mol difference does, however, provide some evidence on the energetic impact associated with switching the relative position of the methyl group and is in agreement with one epimer suffering the ring expansion, whereas the other one is seemingly inert to this chemistry. Analysis of the structures at the transition state confirmed that a syn-pentane interaction is responsible for the higher barrier of 1epi. The change in the migration mode for the mesylate group (from 1,2 to 3,2) not only alleviates strain but also brings an additional electron pair to the cyclic arrangement of overlapping orbitals which should make the dyotropic process either symmetry allowed or pseudopericyclic.37 To analyze this, we decided to model dyotropic rearrangements for very simple substrates in which one of the migrating groups operates in this fashion (see Figure 5). In order to characterize the pericyclic or pseudopericyclic nature of the corresponding transition states ACID calculations were performed.38,39 From these results, it is clear that the dyotropic process in hexene, 5, is too costly to be ever observed, but the transition state is aromatic, and therefore, the reaction can be

Figure 5. Simple and degenerate dyotropic transformations featuring a 3,2-migrating group. The anisotropy of the current induced density (ACID) at the transition states is shown on the right (0.015 au isosurface and current vectors). 3649


Letter

Organic Letters clasified as symmetry allowed. Substitution of the allyl group with the isoelectronic ester 6 breaks the delocalization at the transition state, strongly suggesting that the dyotropic rearrangement becomes pseudopericyclic via the participation of the lone pairs. As a consequence, the activation barrier is considerably reduced (by almost 40 kcal/mol). Inclusion of lone pairs in the other migrating end, as in 7, does not affect significantly the delocalization of electron density, but it does further reduce the energy requirements of the reaction (by another 10 kcal/mol). All these computational results help to explain why hydrindane 1 undergoes an unexpected dyotropic rearrangement and provides structural arguments for its epimer not reacting under the same conditions. However, the computed activation barrier of 38.8 kcal/ mol for this transformation is not compatible with a reaction being performed at −78 °C. In order to find a plausible explanation for this, we focused on the environment. Our calculations take into account solvation only as a dielectric surrounding the molecule (see computational details in the SI), but the migration of the mesylate creates incipient charges that are excellent candidates for explicit solvent stabilization. Dichloromethane is not among the best solvents to form hydrogen bonds, but during the mesylation process triethylamonium is formed. We therefore computed the activation barriers for the dyotropic rearrangement of 1 in the presence of one unit of triethylamonium, and for the sake of comparison, we also considered two molecules of water. In both cases, the solvent molecules are located near the oxygen atoms of the mesylate group, hence improving its salient group ability. In both cases, the activation barrier was reduced significantly (by 7 and 10 kcal/mol, respectively). The overal barriers when one triethylamonium molecule or two water molecules were considered are 32.1 and 29.9 kcal/mol, respectively. These values are still high when considering that the dyotropic rearrangement of 1 occurs at −78 °C, but this experiment illustrates well the impact of taking into account explicit solvation interactions in some reactions. Systematically adding more explicit solvation molecules may require expensive simulations, and the overall correction is not expected to be much higher than the 10 kcal/mol obtained for the addition of one unit of triethylamonium. However, the extreme effect of very strong solvation interactions on this reaction can be simulated at a moderate computational cost. To do this, we assumed that the solvent induces dissociation of the mesylate in 2, producing a carbocation. Interestingly, we were not able to locate such a carbocation on the potential energy surface of this system, finding instead a number of barrierless steps during the optimization process (see Figure 6). The hydrindane structure smoothly converts into the trans-decalin, but under these dissociative conditions, the rearrangement does not stop at 3 and an additional barrierless migration produces a cis-decahydroazulene structure (4cat) that locates the positive charge on a tertiary carbon.These simulations suggest that if the solvent effect is strong enough to promote dissociation of the mesylate group the ring expansion is actually very facile (and compatible with the very mild thermal conditions employed in the experiment) but does not stop in the decalin due to the intrinsic instability of a secondary carbocation. Cascade processes like these and unconventional potential energy surgaces are not uncommon in secondary carbocations.40 Actually, they have been proposed to occur even in metabolic processes.41,42 In this particular case, the predicted cisdecahydroazulene is actually consistent with the trans-decalin to cis-hydrofluorene rearrangements used in pseudoguaianolide sesquiterpenes.43,44 Our experimental results also conflict with a mechanism implying complete dissciation and featuring a naked carbocation. For instance, if 2 can easily dissociate, then 2epi should

Figure 6. Geometry optimization initiated at the hydrindane minimum after removal of the mesylate group. Structures of the hydrindane, decalin, and decahydroazulene carbocations are shown in solid colors. Structures associated with bond migrations are shown in semitransparent colors.

Figure 7. Mechanistic hypothesis involving the fleeting protonated intermediate formed upon mesylation.

not be configurationally stable under the same (−78 °C) or harsher conditions (0 °C). However, our results confirm that 2epi is configurationally stable under these conditions. The mechanism behind this chemistry must therefore lie in between the chemically correct but too slow reactivity of the mesylate 2 and the kinetically correct but rendering the wrong transformation of the carbocation 2cat (Figure 7). In this sense, the solvolysis of the mesylate group would be intimately conected to the subsequent pericyclic process, very much like in the ring opening reactions of cyclopropyl cations.45−47 Following this connection, we realized that, during the mesylation process, the alcohol that displaces mesyl chloride may remain protonated for some short time and that this could activate the internal migration. Gratifyingly, when we computed the reaction profile for this process we obtained a small activation energy, fully compatible with the mild experimental conditions (5.6 kcal/mol). For this reaction, a singular transition structure could not be located due to the topology of the potential energy surface. A nudged elastic band method employed to explore how the reaction proceeds from 2H+ to 3H+ shows that the energy profile involves a small activation to reach a plateau48 (also referred to as calderas,49 mesas,50 or twixtyls51) in which the mesylate is very weakly bonded to the hydrindane structure and undergoes the migration with concomitant ring expansion to form the final decalin (see Figure 8). The exquisite chirality transfer observed in this reaction was experimentally supported by the careful interpretation of the NMR spectra obtained for 3. A more robust proof for the integrity and configuration of each chiral center was however very much desired. We managed to obtain a crystal of the reaction product which was submitted to X-ray diffraction. The resulting geometry confirmed the structural data anticipated through NMR (see SI). In summary, we present an unexpected but very promising transformation that converts a hydrindane into a decalin scaffold under very mild conditions. The rearrangament is based on a rare 3650


Letter

Organic Letters

(6) López, C. S.; Faza, O. N.; Freindorf, M.; Kraka, E.; Cremer, D. J. Org. Chem. 2016, 81, 404. (7) Zou, J.-W.; Yu, C.-H. J. Phys. Chem. A 2004, 108, 5649. (8) Christopher Braddock, D.; Roy, D.; Lenoir, D.; Moore, E.; Rzepa, H. S.; Wu, J. I.-C.; von Rague Schleyer, P. Chem. Commun. 2012, 48, 8943. (9) Davis, R. L.; Tantillo, D. J. J. Org. Chem. 2010, 75, 1693. (10) Mulzer, J.; Brüntrup, G. Angew. Chem., Int. Ed. Engl. 1979, 18, 793. (11) Zenk, P.; Wiley, R. Synthesis 1984, 695. (12) Cargill, R.; Jackson, T.; Peet, N.; Pond, D. Acc. Chem. Res. 1974, 7, 106. (13) Olah, G. Acc. Chem. Res. 1976, 9, 41. (14) Hogeveen, H.; van Kruchten, E. Top. Curr. Chem. 1979, 80, 89. (15) Miyashita, M.; Yamaguchi, R.; Yoshikoshi, A. J. Org. Chem. 1984, 49, 2857. (16) Podraza, K.; Sneden, A. J. Nat. Prod. 1985, 48, 792. (17) Black, T.; DuBay, W., III Tetrahedron Lett. 1987, 28, 4787. (18) Black, T.; Hall, J.; Sheu, R. J. Org. Chem. 1988, 53, 2371. (19) Black, T.; DuBay, W. J., III Tetrahedron Lett. 1988, 29, 1747. (20) Black, T.; DuBay, W., III; Tully, P. J. Org. Chem. 1988, 53, 5922. (21) Arrastia, I.; Lecea, B.; Cossio, F. Tetrahedron Lett. 1996, 37, 245. (22) Purohit, V.; Matla, A.; Romo, D. J. Am. Chem. Soc. 2008, 130, 10478. (23) Davis, R. L.; Leverett, C. A.; Romo, D.; Tantillo, D. J. J. Org. Chem. 2011, 76, 7167. (24) Leverett, C. A.; Purohit, V. C.; Johnson, A. G.; Davis, R. L.; Tantillo, D. J.; Romo, D. J. Am. Chem. Soc. 2012, 134, 13348. (25) Li, G.; Kusari, S.; Spiteller, M. Nat. Prod. Rep. 2014, 31, 1175. (26) Jadulco, R. C.; Koch, M.; Kakule, T. B.; Schmidt, E. W.; Orendt, A.; He, H.; Janso, J. E.; Carter, G. T.; Larson, E. C.; Pond, C.; Matainaho, T. K.; Barrows, L. R. J. Nat. Prod. 2014, 77, 2537. (27) Okamoto, S.; Hosoe, T.; Itabashi, T.; Nozawa, K.; Okada, K.; Takaki, G. M. d. C.; Chikamori, M.; Yaguchi, T.; Fukushima, K.; Miyaji, M.; Kawai, K.-i. J. Nat. Prod. 2004, 67, 1580. (28) Minami, A.; Oikawa, H. J. Antibiot. 2016, 69, 500. (29) Mizoguchi, H.; Micalizio, G. C. J. Am. Chem. Soc. 2015, 137, 6624. (30) Dhambri, S.; Mohammad, S.; vanBuu, O. N.;Galvani, G.; Meyer, Y.; Lannou, M.-I.; Sorin, G.; Ardisson, J. Nat. Prod. Rep. 2015, 32, 841. (31) Slutskyy, Y.; Jamison, C. R.; Lackner, G. L.;Müller, D. S.;Dieskau, A. P.; Untiedt, N. L.; Overman, L. E. J. Org. Chem. 2016, 81, 7029. (32) Singh, V.; Iyer, S. R.; Pal, S. Tetrahedron 2005, 61, 9197. (33) Hohenberg, P.; Kohn, W. Phys. Rev. 1964, 136, B864. (34) Kohn, W.; Sham, L. Phys. Rev. 1965, 140, A1133. (35) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615. (36) Frisch, M. J. et al. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2013. (37) Birney, D. M.; Xu, X.; Ham, S. Angew. Chem., Int. Ed. 1999, 38, 189. (38) Geuenich, D.; Hess, K.; Kohler, F.; Herges, R. Chem. Rev. 2005, 105, 3758. (39) Herges, R.; Geuenich, D. J. Phys. Chem. A 2001, 105, 3214. (40) Tantillo, D. J. Chem. Soc. Rev. 2010, 39, 2847. (41) Hong, Y. J.; Tantillo, D. J. Nat. Chem. 2014, 6, 104. (42) Hong, Y. J.; Tantillo, D. J. Nat. Chem. 2009, 1, 384. (43) Hendrickson, J.; Ganter, C.; Dorman, D.; Link, H. Tetrahedron Lett. 1968, 9, 2235. (44) Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907. (45) Alabugin, I. V. Stereoelectronic Effects; John Wiley & Sons, 2016; p 236. (46) Faza, O. N.; Lopez, C. S.; Alvarez, R.; de Lera, A. R. Org. Lett. 2004, 6, 905. (47) Faza, O. N.; Lopez, C. S.; Alvarez, R.; de Lera, A. R. J. Org. Chem. 2004, 69, 9002. (48) Tantillo, D. J. J. Phys. Org. Chem. 2008, 21, 561. (49) Doering, W. v. E.; Cheng, X.; Lee, K.; Lin, Z. J. Am. Chem. Soc. 2002, 124, 11642. (50) Carpenter, B. K. Chem. Rev. 2013, 113, 7265. (51) Hoffmann, R.; Swaminathan, S.; Odell, B. G.; Gleiter, R. J. Am. Chem. Soc. 1970, 92, 7091.

Figure 8. Nudged elastic band optimization between 2H+ and 3H+ showing a small activationn energy followed by plateau before reaching the decalin product.

dyotropic process that needs to start inmediately after mesylation, since the protonated system is the only one featuring the low activation energies compatible with a reaction occurring at −78 °C in a few hours. Additionally, we were able to identify the cause for the observed difference in reactivity for 1 and 1epi, which arises from strong syn-pentane steric contacts at the transition state.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01621. Experimental procedures and characterization data, including crystallographic data of compound 3, SCF energies, Cartesian coordinates, and number of imaginary frequencies for all computed structures (PDF) X-ray crystallographic data for compound 3 (CIF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: +34 986812320. *E-mail: [email protected]. Tel: +34 986813268. ORCID

Olalla Nieto Faza: 0000-0001-8754-1341 Carlos Silva López: 0000-0003-4955-9844 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the Centro de Supercomputación de Galicia (CESGA) for time on HPC infrastructures. Ministerio de Economiá y Competitividad (MINECO, CTQ2016-75023-C2-2P) and Xunta de Galicia (EM2014/040) are also acknowledged for financial support.

■

REFERENCES

(1) Fernández, I.; Cossío, F. P.; Sierra, M. A. Chem. Rev. 2009, 109, 6687. (2) Gutierrez, O.; Tantillo, D. J. J. Org. Chem. 2012, 77, 8845. (3) Fernández, I.; Bickelhaupt, F. M.; Cossio, F. P. Chem. - Eur. J. 2012, 18, 12395. (4) Ross, J. A.; Seiders, R. P.; Lemal, D. M. J. Am. Chem. Soc. 1976, 98, 4325. (5) Birney, D. M.; Ham, S.; Unruh, G. R. J. Am. Chem. Soc. 1997, 119, 4509. 3651


From Hydrindane to Decalin: A Mild Transformation through a

Recommend Documents