Scanning the Potential Energy Surface of Furanosyl Oxocarbenium

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Scanning the Potential Energy Surface of Furanosyl Oxocarbenium Ions: Models for Reactive Intermediates in Glycosylation Reactions Jonathan S. Rhoad,* Brett A. Cagg,† and Patrick W. Carver‡ Department of Chemistry, Missouri Western State UniVersity, 4525 Downs DriVe, St. Joseph, Missouri 64507 ReceiVed: October 20, 2009; ReVised Manuscript ReceiVed: March 17, 2010

A new scanning method with complementary graph to describe the ring potential energy surface of furanoses is introduced. Density functional theory at the B3LYP level of theory with the 6-311G(d,p) basis set is used to calculate the energy of the partially minimized structures. The method is used to determine the correlation between the preferred conformation of oxocarbenium ions that are model intermediates for a glycosylation reaction and recent experimental results. Key disagreements between the predicted geometry and the minima based on the scans described herein indicate that the preferred oxocarbenium ion conformation is not a consistent predictor of preferred stereochemistry of the products. Introduction The relevance of carbohydrate conformations to the proper function of cellular processes is now firmly recognized. Interest in the biological function of carbohydrates, from use as pharmaceuticals1 to glycobiology,2 is vigorous.3 For example, the saccharide-based vaccine for Haemophilus influenzae type b is saving children from bacterial meningitis.1c Synthetic strategies for accessing tumor-associated carbohydrate antigens are drawing us closer to viable antitumor vaccines.1a Glycoconjugates, compounds consisting of a carbohydrate covalently bound to a noncarbohydrate moiety, and oligosaccharides have been used to probe interactions between cell surfaces and carbohydrate-specific receptors.2c To continue expanding our understanding of biologically important carbohydrates, it is necessary to be able to synthesize oligosaccharides, glycoconjugates, and oligosaccharide analogs, such as the HIV surface antigen.4 Efforts to automate this synthesis are ongoing.5 Control of the stereochemistry of the glycosylation reaction is crucial to these syntheses because poor stereoselectivity translates to poor yields of the desired product. The ability to control the stereochemistry of glycosylation reactions is in large part dependent on whether the carbohydrate is in the furanose (five-membered ring) or pyranose (sixmembered ring) form. The stereocontrol of glycoslations of pyranose has been studied extensively and is far better understood than that of furanoses. Generally, there is one well-defined conformation for a pyranose ring: that is, the favored chair conformation for a given carbohydrate. The furanose, in contrast, has greater flexibility, giving it less well-defined conformational preferences. Despite advances,6 there is much work to be done in controlling the stereoselectivity of glycosylation of furanoses. The greater flexibility of the five-membered ring led to the idea of pseudorotation. The concept of pseudorotation of five-membered rings was first introduced to explain the unexpectedly high entropy in cyclopentane.7 Unsubstituted cyclopentane has two possible * To whom correspondence should be addressed. Phone: 816-271-4389. Fax: 816-271-4217. E-mail: [email protected]. † Current address: The University of South Carolina, Department of Chemistry & Biochemistry, 631 Sumter Street, Columbia, SC 29208. ‡ Current address: Nestle Purina PetCare Company, 4502 Packers Avenue, St. Joseph, MO 64504.

conformations, the “twist” and “envelope”, which are each 10fold degenerate. The twist conformation has one carbon above and a neighboring carbon below the plane of the remaining three carbons, and the envelope conformation has four carbon atoms in a plane with the fifth perturbed out of the plane. Pseudorotation is the interconversion between these conformations, not by passing through the planar conformation, but by “rotating” around the pseudorotational wheel alternating from envelope to twist conformation. Consequently, there are infinite intermediary conformations between the “pure” twist and envelope conformations. This model was adapted to explain the conformational preferences of the furanoside sugar ring in DNA.8 In a furanose (five-membered carbohydrate) ring, the degeneracy is lost, and there are now 10 possible twist and 10 envelope conformations.8a The absolute conformation then is described by a pseudorotational phase angle (P) and the amplitude (τm). The definition of the phase angle and amplitude that will be used herein comes from Altona and Sundaralingam.8a The phase angle is a single number that gives the relative magnitude of the five intraring dihedrals, i.e. it gives the overall ring conformation. The idealized ring conformations (envelope and twist) alternate at intervals of 18°. When the phase angle is taken with the amplitude, it gives the absolute magnitude of the five intraring dihedrals. If three (twist) or four (envelope) atoms are used to define the plane, the amplitude describes how far out of plane the remaining atom(s) are. The graphical description of the concept has been called the “pseudorotational wheel” (Figure 1), and a shorthand for the idealized conformations was developed. For example, the 3T2 conformation is a twist in which carbon 3 is above the plane of the other three ring atoms, and carbon 2 is below the plane. The E4 conformation is an envelope conformation in which carbon 4 is below the plane. Since the phase angle of a ring is not limited to integer multiples of 18, there are an infinite number of conformations at each amplitude. It was proposed8a that for most furanose rings, equilibrium exists between a “north” conformer (phase angle between -90° and 90°) and a “south” conformer (phase angle between 90° and 270°), and this has been supported by many experimental9 and computational10 studies. The methods used in most of the computational studies allow scanning of the phase angle, but report only the minimum for amplitude at each phase angle.

10.1021/jp9100448  2010 American Chemical Society Published on Web 03/30/2010

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Figure 2. Depiction of attack on the “inside” or “outside” face of an envelope as described in ref 13.

Figure 3. Definition of ring dihedrals.

Figure 1. Pseudorotational phase angle with envelope and twist conformations.

Each of these studies restricted itself to a limited number of conformations because of the potential for a very large number of possible conformations (2430;10e 8919c), described by eq 1,

P ) S3 × C

(1)

where P is the number of potential conformations; S is the number of substituents that have minima at three staggered conformations; and C is the number of ring conformers chosen to explore, usually the 10 envelope conformations and the planar conformation. Even this is a conservative estimate because it is possible to have twist conformations and an infinite number of intermediary conformations (i.e., the phase angle is not restricted to integers). We propose herein a scanning method that approximates more closely the full potential energy surface (PES) of the furanose ring. A complementary graphing method is demonstrated that gives an at-a-glance understanding of the ring PES with respect to both P and τm. The system that we have chosen for examination with this scanning method is the furanosyl oxocarbenium ion, the putative intermediate in many glycosylation methods. We are interested in better understanding the factors that influence stereoselectivity in glycosylation with furanosyl donors. It has been demonstrated that the stereocontrol in a model glycosylation reaction is not dependent on the leaving group,11 so the leaving group can be excluded when trying to explain stereoselectivity. Previous studies by the Woerpel group have demonstrated that carbon nucleophiles tend to add syn to ether groups attached to carbon 2 or 3 of the furanose ring.12 Combined with their studies with locked conformations,13 Woerpel et al. developed a theory that nucleophiles preferred to add to the “inside face” (Figure 2) of the furanosyl oxocarbenium ion in the envolope conformation. This implies that the lowest energy conformation influences the stereochemistry of addition. It is possible, as stated

Figure 4. Models for ring PES scans.

in the Curtin-Hammet principle,14 that the product does not come from the lowest energy conformation. This inspired us to scan the ring PES of mono- and dioxygensubstituted furanosyl oxocarbenium ions to determine whether the minimum can be used to predict the major diastereomeric product. To do this, we will compare the relative energy of lowenergy conformations to stereoselectivities from experimental studies.12 If the conformation is key, we would expect those intermediates with a single deep well to have high selectivity. If the Woerpel model is accurate, we would expect the lowest energy conformation would lead to the preferred product through addition on the inside of the envelope. We will use simplified models of three major classes of hydroxyl protecting groups: ethers, silyl ethers, and esters. Our model compounds include both noninteracting (methyl, silyl) and interacting (formyl) protecting groups. Computational Methods To define the conformational subspace (puckering) of a ring, N-3 parameters are required,8b so two internal coordinates are required to define the furanose ring conformation. With pseudorotation at constant amplitude τm, the internal ring dihedrals (D0-D4, Figure 3) undulate from approximately -τm to τm at phase angle intervals of 72° (Figure 1).8a Therefore, one needs to assign only two nonconsecutive internal ring dihedrals to define a certain phase angle and amplitude. By scanning two dihedrals, C1-C2-C3-C4 (D0) and C2-C1-O-C4 (D3, see Figure 3) here, the puckering subspace, that is, the full range of phase angles at amplitudes under 40°, is examined. The maximum dihedral range that is convenient to scan is -45° to 45°, because larger angles tend to open the ring. The tightness of the mesh for the ring PES is then determined by the size of steps.

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Figure 5. Ring PES and minimum conformation of 1 (energy expressed in kcal/mol).


Dihedrals D0 and D3 of compounds 1-12 (Figure 4) were scanned from -40° to 40° in increments of 10°, which resulted in 81 conformations. All other internal coordinates were unconstrained. All calculations were performed using Gaussian03.15 Studies were performed with B3LYP16 density functional theory, as in previous studies10a,d,f–h,17 on similar structures, and the 6-311G(d,p)18 basis set. The data were then graphed as a polar contour plot19 using Origin20 graphing software. The phase angle (P) was graphed as θ; the amplitude (τm) was graphed as r; and the energy, in kcal/mol, was graphed on the vertical axis, similar to methods used by others.21 The origin has no real phase angle and amplitude equal to zero. The plot was then cropped to τm e 40°. Results and Discussion In most ring PES graphs of the oxocarbenium ions, there is a valley that runs from the 3E (18°) to the E3 (P ) 198°). This is to be expected because these are the two conformations that have a dihedral of 0° for D3 (Figure 3); that is, envelope

conformations where the carbenium ion and oxygen nonbonding electrons have the most favorable overlap. In the cases that there is a preference for the 3E or E3, the conformation that places the oxygen atom in the pseudoaxial position is a result of the attraction of the oxygen nonbonding electrons for the carbenium ion. Exceptions to this are when the oxygen of the interacting protecting group (formate) is rotated toward the carbenium ion. These structures tend to prefer the conformation that minimizes the distance between the carbonyl oxygen and the carbenium ion. The PES for 1 (3-methoxytetrahydrofuran-2-ylium ion, Figure 5) is, in general, flatter than for 2 (4-methoxytetrahydrofuran2-ylium ion, Figure 6). The PES for 5 (3-siloxytetrahydrofuran2-ylium ion, Figure 7) has two local minima that are both below 1 kcal/mol, whereas the PES for 6 (4-siloxytetrahydrofuran-2ylium ion, Figure 8) looks very similar to the PES for 2. This agrees well with the observation that a substituent on carbon 3 has more influence over the stereoselectivity of nucleophile addition.12 As stated above, the lowest energy pseudorotamer for each of these structures is an envelope conformation (3E or





E3) that places the oxygen in the pseudoaxial position, in agreement with experiment.22 However, both the 2-substituted and 3-substituted electrophile prefer to add the nucleophile syn to the oxygenated substituent.12 In the case of 1 and 5, the nucleophile would have to add to the outside of the envelope to give syn addition, contrary to the proposed theory.12,13 A simple analysis of the above observations would give rise to some basic predictions. When vicinal disubstituted structures are considered, the cis would have two competing minimal conformations, each with one of the substituents in the pseudoaxial orientation. This would give rise to two minima on the ring conformation PES that are close in energy. The trans structure, on the other hand, would be able to place both substituents in the pseudoaxial position simultaneously, which should give rise to one conformation that is much lower in energy than all others and lower in energy than the cis minima. The deepest minimum of the ring PES of 3 (trans-3,4dimethoxytetrahydrofuran-2-ylium ion, Figure 9) and 7 (trans3,4-disiloxytetrahydrofuran-2-ylium ion, Figure 10) are 1.55 and 0.32 kcal/mol lower in energy than that of 4 (cis-3,4-dimethoxytetrahydrofuran-2-ylium ion, Figure 11) and 8 (cis-3,4-disi-

loxytetrahydrofuran-2-ylium ion, Figure 12), respectively, matching the prediction above. However, the relative ring PESs of 3 as compared to 4 and 7 to 8 do not fit this simple analysis. The cis isomers (4 and 8) have deeper wells on the ring PES, and the ring PESs of the trans isomers (3 and 7) are flatter. There are two factors that can lead to this unexpected result. One is the general trend that substituents tend to prefer pseudoequatorial positions to lessen electronic repulsion to the ring. This trend would be counter to the attraction of the substituent oxygen lone pair for the carbenium ion, leading to a flatter ring PES. The other is the gauche effect.23 In the lowest energy conformation (3E) of the trans isomers, the oxygen substituents are anti to each other. As the conformation changes to the E3, the oxygen atoms would approach a gauche relationship, again counter in energy to the oxygen-cation attraction. In comparison, the gauche effect does not influence the cis isomers, as the oxygen substituents are gauche, regardless of the conformation. Another difference to be noted between the ring PES of 4 and 8 is that 4 has one large minimum, and 8 has two defined minima. The relative energy of the less favored conformer in each case is not that different. The methylated derivative, 4, is

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>2 kcal/mol higher than the ring minimum, whereas the disilyl derivative, 8, is >3 kcal/mol higher. In the ring PES of 8, there is a barrier between the two. This indicates that the planar conformation (amplitude of 0°) is more disfavored for 8 than for 4. For structures 1-8, only one exocyclic rotamer was considered with respect to the substituents,19 but this is not reasonable for the formate substituents. The carbonyl oxygen has a significant interaction with the carbenium ion. Therefore, scans were performed with the carbonyl rotated away from the anomeric center (exo rotamers) as well as rotated toward the anomeric center (endo rotamers). In the case of the disubstituted structures, three total calculations were performed (exo, 2-endo, and 3-endo rotamers) so that the interaction of the two carbonyl groups could be compared. The exo rotamers in general were very similar to the methoxyand siloxy-substituted analogs. The ring PES of 10 (4-formyloxytetrahydrofuran-2-ylium ion, Figure S1 in Supporting Information) has a well depth and shape like 2 and 4. The disubstituted isomers 11 (trans-2,3-diformyloxytetrahydrofuran, Figure S2 in Supporting Information) and 12 (cis-2,3-diformyl-

oxytetrahydrofuran, Figure S3 in Supporting Information) each have a deeper and a shallower minimum. The ring PES of 11 (trans) is flatter than that of 12 (cis), like the methoxy- (3,4) and siloxyl- (7, 8) analogs. The major difference is the ring PES of 9 (3-formyloxytetrahydrofuran-2-ylium ion, Figure S4 in Supporting Information), which is much flatter than the other analogs (1, 5). Although the ring PES of 2 has one large minimum well that encompasses the origin (planar ring) at less that 1 kcal/mol, it is primarily centered on the conformation with the methoxy group in the pseudoaxial position. The ring PES of 5 has two minima with a transition near the origin, but again, the minimum with the siloxy group in the pseudoaxial position slightly predominates. The ring PES of the exo rotamer of 9 has one large well below 1 kcal/mol that encompasses all of the conformations along the 3E-to-E3 axis. Therefore, this rotamer has no bias for any conformation and, therefore, could not lead to stereoselectivity. The endo rotamers of 9, 10, 11, and 12 (Figures S5-S10 in Supporting Information) are far more important energetically. The exo rotamer closest in energy to an endo rotamer of the same structure is 7.3 kcal/mol higher in energy (Tables 1 and





TABLE 1: Relative Energies of the Minima of Rotamers of 9 and 10 relative energy (kcal/mol) 9-endo 9-exo 10-endo 10-exo

0.0 11.2 2.4 7.3

TABLE 2: Relative Energies of the Minima of Rotamers of 11 and 12 relative energy (kcal/mol) 11-2-endo 11-3-endo 11-exo 12-2-endo 12-3-endo 12-exo

7.8 0.0 19.9 9.0 10.2 17.5

2). The 2-endo conformations are lower in energy than the 3-endo conformations by 3-4 kcal/mol. The conformational preferences of the endo rotamers are all the same in one respect: the lowest energy conformation places the carbonyl oxygen as

close as possible to the carbenium ion. The carbenium ion carbon is no longer planar for any of structures 9-12 in the lowest energy conformation. Nucleophilic attack on structures such as 9, 11, and 12 that have interacting groups neighboring the carbenium ion are known to have a strong preference for anti addition because the syn face is blocked. The endo rotamer of 10 is only 2.4 kcal/mol higher in energy than that of 9, indicating that anchimeric assistance from the protecting group on oxygen-3 should be possible. A literature search revealed no reported instances of anchimeric assistance from a structure similar to 10. Conclusions Potential energy surface subsets for the ring conformation have been shown for simplified analogs of three common classes of protecting groups in carbohydrate chemistry: ethers, silyl ethers, and esters. The esters have a predictable pattern in which the interaction of the carbonyl of the protecting group blocks the syn face of the carbenium ion, directing the nucleophile to add anti. The ethers and silyl ethers have a consistent pattern

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in which the lowest energy ring conformation has the oxygen atom in the pseudoaxial conformation. When comparing these results with the experimental addition of nucleophiles to analogous intermediates of compounds 1-8,12 there is a mixture of agreement and disagreement. The ring PESs of 2 and 6 show deeper wells than 1 and 5, indicating that the substituent on carbon 3 has a greater influence over conformation and therefore stereoselectivity of addition than carbon 2. The ring PES of the cis structures (4 and 8) are steeper than those of the trans structures, indicating that the cis should have greater selectivity, as reported.12 Nucleophile addition “inside” the envelope (see Figure 2) of the preferred conformation of 2 and 6, gives the syn addition product as seen.12 Nucleophile addition “inside” the envelope of the preferred conformation of 1 and 5, gives the anti addition product, contrary to the model proposed.12,13 Therefore, the preferred conformation of the ring is not a consistent predictor of the addition of a nucleophile. Acknowledgment. Support for this research came from Missouri Western State University in the form of start-up funds, and acceptance into Undergraduates Research Summer Institute and Summer Research Institute programs. Supporting Information Available: Eight ring PES graphs of the formate ester derivatives with both the endo and exo rotation. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) (a) Galonic´, S.; Gin, D. Y. Nature 2007, 446, 1000–1007. (b) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046–1051. (c) Alper, J. Science 2001, 291, 2338–2343. (2) (a) Hart, G. W.; Housley, M. P.; Slawson, C. Nature 2007, 446, 1017–1022. (b) Bishop, J. R.; Schuksz, M.; Esko, J. D. Nature 2007, 446, 1030–1037. (c) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357– 2364. (3) Hurtley, S.; Service, R.; Szuromi, P. Science 2001, 291, 2337. (4) Scanlan, C. N.; Offer, J.; Zitzmann, N.; Dwek, R. A. Nature 2007, 446, 1038–1045. (5) Seeberger, P. Carb. Res. 2008, 343, 1889–1896. (6) (a) Gadikota, R. R.; Callam, C. S.; Wagner, T.; Del Fraino, B.; Lowary, T. L. J. Am. Chem. Soc. 2003, 125, 4155–4165. (b) de Oliveria, M. T.; Hughes, D. L.; Nepogodiev, S. A.; Field, R. A. Carb. Res. 2008, 343, 211–220. (c) Hou, D.; Lowary, T. L. Org. Lett. 2007, 9, 4487–4490. (d) Boutureira, O.; Rodriguez, M. A.; Benito, D.; Matheu, M. I.; Diaz, Y.; Castillon, S. Eur. J. Org. Chem. 2007, 3564–3572. (e) Trost, B. M.; Dudash, J., Jr.; Dirat, O. Chem.sEur. J. 2002, 8, 259–268. (f) Karst, N.; Jacquinet, J.-C. J. Chem Soc., Perkin Trans. 1 2000, 2709–2717. (g) Xia, X.; Wang, J.; Hager, M. W.; Sisti, N.; Liotta, D. C. Tetrahedron Lett. 1997, 38, 1111– 1114. (h) Wilson, L. J.; Hager, M. W.; El-Kattan, Y. A.; Liotta, D. C. Synthesis 1995, 1465–1479. (i) Hanessian, S.; Conde, J. J.; Lou, B. Tetrahedron Lett. 1995, 36, 5865–5868. (7) Kilpatrick, J. E.; Pitzer, K. S.; Spitzer, R. J. Am. Chem. Soc. 1947, 69, 2483–2488. (8) (a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94, 8205–8212. (b) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354– 1358. (9) (a) D’Souza, F. W.; Ayers, J. D.; McCarren, P. R.; Lowary, T. L. J. Am. Chem. Soc. 2000, 122, 1251–1260. (b) Houseknecht, J. B.; Lowary, T. L. J. Org. Chem. 2002, 67, 4150–4164. (c) Church, T. J.; Carmichael, I.; Seriani, A. S. J. Am. Chem. Soc. 1997, 119, 8946–8964. (d) Bandyopadhyay, T.; Wu, J.; Stripe, W. A.; Carmichael, I.; Serianni, A. S. J. Am. Chem. Soc. 1997, 119, 1737–1744. (e) Martin-Pastor, M.; Bush, C. A. Biochemistry 1999, 38, 8045–8055. (f) Callam, C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J. Am. Chem. Soc. 2003, 125, 13112–13119.

Rhoad et al. (10) (a) Houseknecht, J. B.; Lowary, T. L.; Hadad, C. M. J. Phys. Chem. A 2003, 107, 5763–5777. (b) McCarren, P. R.; Gordon, M. T.; Lowary, T. L.; Hadad, C. M. J. Phys. Chem. A 2001, 105, 5911–5922. (c) Suzuki, T.; Kawashima, H.; Kotoku, H.; Takayuki Sota, T. J. Phys. Chem. B 2005, 109, 12997–13005. (d) Gordon, M. T.; Lowary, T. L.; Hadad, C. M. J. Org. Chem. 2000, 65, 4954–4963. (e) Evdokimov, A. G.; Martin, J. M. L.; Kalb, A. J. J. Phys. Chem. A 2000, 104, 5291–5297. (f) Cloran, F.; Zhu, Y.; Osborn, J.; Carmichael, I.; Serianni, A. S. J. Am. Chem. Soc. 2000, 122, 6435–6448. (g) Cloran, F.; Carmichael, I.; Serianni, A. S. J. Am. Chem. Soc. 2001, 123, 4781–4791. (h) Cloran, F.; Carmichael, I.; Serianni, A. S. J. Phys. Chem. A 1999, 103, 3783–3795. (i) Houseknecht, J. B.; McCarren, P. R.; Lowary, T. L.; Hadad, C. M. J. Am. Chem. Soc. 2001, 123, 8811– 8824. (j) Suzuki, T.; Kawashima, H.; Kotoku, H.; Sota, T. J. Phys. Chem. B 2005, 109, 12997–13005. (11) Shenoy, S. R.; Woerpel, K. A. Org. Lett. 2005, 7, 1157–1160. (12) (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879–10884. (b) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149– 14152. (c) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208–12209. (13) Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149–14152. (14) Hammett, L. P. Physical Organic Chemistry, 2nd ed.; McGrawHill: New York; pp 119-120. (15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, ReVision D.02, Gaussian, Inc.: Wallingford CT, 2004. (16) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789. (c) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200–1211. (d) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623–11627. (17) (a) Wong, K.-Y.; Richard, J. P.; Gao, J. J. Am. Chem. Soc. 2009, 131, 13963–13971. (b) Yang, M. T.; Woerpel, K. A. J. Org. Chem. 2009, 74, 545–553. (c) Beaver, M. G.; Billings, S. B.; Woerpel, K. A. J. Am. Chem. Soc. 2008, 130, 2082–2086. (18) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650–654. (19) The use of a smooth PES to describe the relationship between points in this type of graph is asserted to be valid on the basis of the Hammond postulate. The conformations of the structure correlated to two nearby points are very similar, and therefore, the energy surface between the two should be smooth. This graph represents the structure with a single rotational conformation with respect to the substituents. If the influence of rotation of a single substituent is of interest, three potential energy surfaces can be generated. As has been pointed out, the rotational degrees of freedom of substituents scales with 3n, so determining the full PES quickly becomes overwhelming. This method should be considered a method complementary to those in reference 10. (20) Origin, Origin 8; OriginLab Corp.: Northampton, MA, 2007. (21) (a) Cros, S.; du Penhoat, C. H.; Pe´rez, S.; Imberty, A. Carb. Res. 1993, 248, 81–93. (b) Wu, A.; Cremer, D. Int. J. Mol. Sci. 2003, 4, 158– 192. (c) Dowd, M. K.; French, A. D.; Reilly, P. J. J. Carb. Chem. 2000, 19, 1091–1114. (22) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528. (23) (a) Wolfe, S. Acc. Chem. Res. 1972, 5, 102–111. (b) Wolfe, S.; Tel, L. M.; Liang, J. H.; Csizmadia, I. G. J. Am. Chem. Soc. 1972, 94, 1361–1364.

JP9100448

Scanning the Potential Energy Surface of Furanosyl Oxocarbenium

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