Stephen Chamberland

UCI Research Summary

Using Nucleophilic Substitution Reactions to Understand How a Remote Alkyl or Alkoxy Substituent Influences the Conformation of Eight-Membered Ring Oxocarbenium Ions

We have experimentally shown^1,2 that tetrahydropyran oxocarbenium ions with remote electronegative substituents (e.g. 1b) react with carbon nucleophiles through pseudoaxial conformers in accord with recent computational studies.^3,4 The nucleophilic addition product (3b) exhibits a 1,4–trans relationship with high diastereoselectivity (eq 1). My efforts to develop this phenomenon using synthetically challenging and interesting eight-membered ring systems have revealed the codependence of experimental data and theoretical analysis.⁵ Effective melding of these two approaches permits one to rationalize the sense and degree of selectivity observed upon nucleophilic addition to eight-membered ring oxocarbenium ions.⁶

Perhaps the most powerful application of this paradigm will be in the realm of medium-ring ether natural product synthesis,⁷ especially for oxocanes with an array of substituents. Professor Clark Still’s work with substituted eight-membered ring enolate alkylation codified the idea that even a single substituent can confer sufficient conformational bias to an unsaturated medium ring to make electrophilic attack selective.⁸ To examine the effects of remote substitution upon nucleophilic attack of an eight-membered ring oxocarbenium ion, I synthesized six lactol acetates to act as oxocarbenium ion precursors. Substrates containing methyl and benzyloxy substituents at the three, four, and five positions were chosen to probe the steric and electronic effects of the remote substituent on product diastereoselectivity.^9,10 Since no general approach could be used to prepare all six substrates, I researched, developed, and optimized synthetic routes featuring one of the following methodologies for ring closure: lactonization,¹¹ 8-endo radical cyclization,¹² radical atom transfer cyclizations,¹³ and ring closing metathesis.¹⁴ The C4-benzyloxy substituted lactol acetate 9 was the first substrate examined because it most closely resembled the structure of tetrahydropyran lactol acetate 1b and because nucleophilic substitution was expected to proceed with high selectivity.

From the outset, it was thought that peripheral nucleophilic attack¹⁵ on the lowest energy conformer¹⁶ (5 or 6) of an eight-membered ring oxocarbenium ion bearing a benzyloxy substituent at C-4 would give the 1,4–trans product 4 with high diastereoselectivity (eq 2). This result is counterintuitive using a conventional steric argument, because the C-4 position in conformers 5 and 6 is especially sensitive to substituent size. Any substituent at this position should reside outside the ring; however, the electrostatic attraction between the C4-alkoxy substituent and the positive charge at C-1 is the dominant factor controlling conformation as we observed for tetrahydropyran oxocarbenium ions.^1,2 After screening several experimental parameters (nucleophile, Lewis acid, temperature, quenching method), the desired product of nucleophilic substitution with Me₃SiCN¹⁷ was formed in excellent yield and in a 96 : 4 trans : cis diastereomeric ratio (Scheme 1).^18,19,20 Isolation of the major (1,4-trans) diastereomer (10) by chromatography, hydrolysis to the crystalline amide 12, and X-ray analysis firmly established the 1,4–trans relationship in the major diastereomer. Furthermore, I proved that this high selectivity results from kinetic addition of the cyanide by resubjecting 1,4–cis isomer 11 (also isolated by chromatography) to the reaction conditions. No racemization was observed, and 11 was recovered in near quantitative yield.

A methyl group at the C-4 was initially predicted to confer a high degree of conformational bias²¹ and exclusively provide the 1,4-cis product upon nucleophilic addition to the oxocarbenium ion intermediate. Surprisingly, Lewis acid-mediated addition of Me₃SiCN to acetate 14 was unselective (eq 3). This experimental outcome demonstrated that intuition alone is insufficient to predict the ground-state structures of these intermediates. To gain additional insight into the plethora of conformational possibilities present for these systems,⁸ I developed a computational model²² to predict the low-energy structures of C3-, C4-, and C5-alkyl and alkoxy substituted oxocarbenium ions. Agreement between the theoretical predictions and experimental results would serve to validate the model. A sound computational model will enable future practitioners of the art of medium ring ether remote stereocontrol to predict the sense and magnitude of the experimental outcome before performing any experiments.

Armed with this computational model, the C3- and C5-methyl and benzyloxy lactol acetates (17, 23, 20, and 26) were prepared and subjected to Lewis acid-mediated nucleophilic substitution by Me₃SiCN to give the corresponding carbonitriles (18, 24, 21, and 27) as shown in Scheme 2. The relevant low-energy conformers (28-33) for each substrate, the product that would result from nucleophilic addition to those conformers, the computationally predicted selectivity, and experimentally determined product ratios derived from the computational model appear in Table 1. General agreement between theory and experiment was observed in all cases.

Using the model I developed, one can reliably predict the lowest energy conformation of any substituted medium ring oxocarbenium ion. Nucleophilic addition to that intermediate should afford an approximate product ratio in favor of the predicted stereoisomer. One could envision using this model to predict the diastereoselectivity upon nucleophilic addition to an advanced intermediate (34) of the oxocane core of the marine natural product (+)-laurefucin (40) (Scheme 3). Lewis-acid mediated nucleophilic addition of trimethylsilyl cyanide to intermediate 35 should afford cyanohydrin ether 36, containing the desired a,a’-cis and 1,4-trans substitution patterns. The synthetic route to laurefucin should proceed through acetate 34 instead of acetate 37 because inclusion of the bromide at C-6 will lead to the incorrect diastereomer (39) upon Me₃SiCN addition. Using known chemistry,²³ the protected C-6 hydroxy group in 36 can be converted to the bromide at a later stage in the synthesis.

Concerning the Ground State Structure of Oxocarbenium Intermediates Involved in Highly Selective C-Glycosylation Reactions of 4-Alkyl- and 4-Alkoxy-substituted Tetrahydropyran Acetals

Nucleophilic substitution reactions of six-membered-ring oxocarbenium ions are known to proceed through chair-like transition structures with nucleophilic attack occurring along an axial trajectory.^24,25 We propose that the structures of the intermediates are also chair-like in the ground state (eq 4), but this assertion is only feasible through analysis of product stereochemistry (eq 1) and by invoking the Hammond Postulate. In an effort to prove that a C4- alkoxy and C4-alkyl substituent will reside in a pseudoaxial and pseudoequatorial orientation, respectively, in the ground state, I prepared the dialkoxycarbenium ion salts 45 and 47 as stable analogues of 41 and 42 (Scheme 4).^26-28 Obtaining proof of the unusual pseudoaxial orientation of a remote alkoxy substituent would contribute to the general understanding of charged intermediates, and would demonstrate that direct comparison to the structures of neutral species is insufficient.

The lower-energy structure predicted by theory is the major conformation in solution and in the solid state. Spectroscopic evidence²⁹ suggests that the methyl substituent in 45 adopts a pseudoequatorial orientation and the alkoxy substituent in 47 is pseudoaxial. Even more powerful than the spectroscopic data is the X-ray crystal structure of tetrahydropyrylium ion 47, which proves the pseudoaxial orientation of the C4-alkoxy substituent (Figure 1). These results are in agreement with gas-phase calculations (MP2/6-31G*) that favor the respective half-chair conformers by 1.0 kcal/mol for 45 and 5.3 kcal/mol for a C-4 methoxy analogue of 47.³⁰

References

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(2) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168-169.

(3) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992, 114, 859-864.

(4) Miljkovic, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L. J. Org. Chem. 1997, 62, 7597-7604.

(5) Chamberland, S.; Woerpel, K. A. Org. Lett. 2004, 6, 4739-4741.

(6) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915-7916.

(7) Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron 2002, 58, 1817.

(8) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981-3996.

(9) The methyl group was chosen to represent alkyl substitution in favor of the isosteric phenethyl group to simplify synthetic routes and because both groups had nearly identical effects upon product selectivities in the six-membered ring case (ref. 1).

(10) The numbering used considers the carbocationic carbon as C-1: Dudley, T. J.; Smoliakova, I. P.; Hoffmann, M. R. J. Org. Chem. 1999, 64, 1247-1253.

(11) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993.

(12) Lee, E.; Yoo, C. H.; Lee, T. H.; Kim, S. Y.; Ha, T. J.; Sung, Y.; Park, S.-H.; Lee, S. J. Am. Chem. Soc. 1998, 120, 7469-7478.

(13) Wang, J.; Li, C. J. Org. Chem. 2002, 67, 1271-1276.

(14) Crimmins, M. T.; Cleary, P. A. Heterocycles 2003, 61, 87-92.

(15) Still, W. C. J. Am. Chem. Soc. 1979, 101, 2493.

(16) Meyer, W. L.; Taylor, P. W.; Reed, S. A.; Leister, M. C.; Schneider, H.-J.; Schmidt, G.; Evans, F. E.; Levine, R. A. J. Org. Chem. 1992, 57, 291-298.

(17) For these reactions a small nucleophile, trimethylsilyl cyanide (Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J. Org. Chem. 1974, 39, 914-917), was chosen to minimize steric effects in the transition state that might perturb the inherent conformational preferences of the charged intermediates. Lewis acid mediated nucleophilic substitution of 17 and 23 with diethyl-2-phenylethynylalane gave selectivities comparable to those reactions using trimethylsilyl cyanide as the nucleophile.

(18) Mixtures of diastereomeric acetates were used in these reactions. Control experiments indicate that both anomers give the same product with largely the same degree of selectivity.

(19) In all cases, diastereoselectivities were determined by GC or single-scan ¹H NMR spectra of unpurified reaction mixtures. The relative stereochemistry for unselective reactions was not proven.

(20) Control experiments indicate that this reaction is under kinetic control and that Lewis acid is required for reaction to occur. The selectivity is also independent of the solvent (CH₂Cl₂, toluene, or Et₂O) and the Lewis acid (EtAlCl₂, TiCl₄, or SnCl₄) employed.

(21) Still used MM2 to calculate a pseudo A-value of >4.5 for an alkyl substituent at this position on an eight-membered ring (ref 7). This value was confirmed using Spartan '02 at the AM1 level of theory.

(22) Conformational Model: Using Spartan '02, a systematic conformer distribution was performed using molecular mechanics (MMFF). The resulting conformers were then optimized at the semiempirical PM3 level of theory. Conformations >3 kcal/mol above the minimum were deleted. Equilibrium geometries of the remaining conformers were determined at the density functional B3LYP/6-31G* level of theory. Based upon the relative energies and the expected products (cis or trans), the selectivity for formation of the major diastereomer was predicted.

(23) Bendall, J. G.; Payne, A. N.; Screen, T. E. O.; Holmes, A. B. Chem. Commun. 1997, 1067.

(24) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon: New York, 1983.

(25) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032.

(26) Childs, R. F.; Kostyk, M. D.; Lock, C. J. L.; Mahendran, M. Can. J. Chem. 1991, 69, 2024-2032.

(27) Deslongchamps, P.; Chênevert, R.; Taillefer, R. J.; Moreau, C.; Saunders, J. K. Can. J. Chem. 1975, 53, 1601-1615.

(28) Wiberg, K. B.; Waldron, R. F. J. Am. Chem. Soc. 1991, 113, 7705-7709.

(29) The C4-methine proton in 45 exhibits two large vicinal coupling constants (14.1 and 11.2 Hz) consistent with a pseudoaxial orientation of this proton. Furthermore, an nOe was observed between this proton and the pseudoaxial proton on C-2. Data collected for the C4-methine proton of compound 47 (sextet, J = 2.0 Hz) is consistent with a pseudoequatorial orientation of the proton; furthermore, no nOe was observed between this proton and the pseudoaxial proton at C-2. The sextet arises from coupling to four vicinal protons and remote coupling to the equatorial proton at C-2. All spectroscopic data was obtained at 500 MHz in CD₂Cl₂.

(30) Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 5322–5323.