Making use of crystallization-induced asymmetric transformations in solid state organic photochemistry: application to the enantioselective Yang photocyclization of endo-bicyclo[2.1.1]hexyl aryl ketones

Abstract

Achiral endo-bicyclo[2.1.1]hexyl aryl keto-acid 1a exists in solution as a rapidly equilibrating 1∶1 mixture of enantiomers. When a solution of this compound is treated with an optically pure amine, a crystallization-induced asymmetric transformation of the second kind takes place, and crystals of only one of the two possible diastereomeric salts are deposited. Irradiation of the crystals leads to a diastereoselective Yang photocyclization reaction of the carboxylate anion portion of the salt, and following diazomethane workup to form the corresponding methyl ester, high yields of novel cyclobutanols of structure 2 are formed in enantiomeric excesses as high as 90%.

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The IUPAC Compendium of Chemical Terminology defines a crystallization-induced asymmetric transformation as follows: “If the two enantiomers of a chiral substrate A are freely interconvertible and if an equal amount or excess of a non-racemizing second enantiomerically pure chemical species, say (R)-B, is added to a solution of racemic A, then the resulting equilibrium mixture of adducts A·B will, in general, contain unequal amounts of the diastereomers (R)-A·(R)-B and (S)-A·(R)-B. The result of this equilibration is called asymmetric transformation of the first kind. If, in such a system, the two diastereomeric adducts differ considerably in solubility so that only one of them, say (R)-A·(R)-B, crystallizes from the solution, then the equilibration of diastereomers in solution and concurrent crystallization will continue so that all (or most) of the substrate A can be isolated as the crystalline diastereomer (R)-A·(R)-B. Such a ‘crystallization-induced asymmetric transformation’ is called an asymmetric transformation of the second kind.”¹

Crystallization-induced asymmetric transformations have attracted increasing attention in recent years,² and in the present communication we show how such a process can be used to isolate a single conformational diastereomer in the solid state and how this conformational chirality can then be transformed into permanent molecular chirality through a solid state photochemical transformation. As an added bonus, the solid state photoreaction was found to be of the single crystal-to-single crystal type,³ which permitted its absolute stereochemical course to be mapped out in detail by X-ray crystallography.

The compounds chosen for study were those possessing the general endo-bicyclo[2.1.1]hexyl aryl ketone structure 1 (Scheme 1).⁴ Although achiral, such compounds have enantiomeric minimum energy conformations (1 and ent-1) that are in rapid equilibrium with one another in solution as a result of rotation of the aroyl group away from the average plane of symmetry bisecting the molecule.⁵ When the aryl group bears a carboxylic acid substituent (1a), addition of optically pure (S)-(−)-1-phenylethylamine caused deposition of one of the diastereomerically pure salts in a crystallization-induced asymmetric transformation of the second kind.

Scheme 1

Fig. 1 shows the X-ray crystal structure of the (S)-(−)-1-phenylethylamine salt of keto-acid 1a, which corresponds in configuration to structure 1 in Scheme 1.⁶ As can be seen, this situates the ketone oxygen atom closer to γ-hydrogen atom H_X (2.47 Å) than to H_Y (3.41 Å). Based on extensive research from our group on the geometric requirements for photo-induced γ-hydrogen atom abstraction,⁷ this indicated that when this salt is irradiated in the crystalline state, H_X should be abstracted selectively and the resulting 1,4-hydroxybiradical should undergo Yang cyclization⁸ to form more of the corresponding cyclobutanol 2 than its enantiomer ent-2.⁹ Diazomethane workup of the solid state reaction mixture would then afford the photoproduct as the corresponding methyl ester 2b. In the event, when crystals of the (S)-(−)-1-phenylethylamine salt of keto-acid 1a were photolyzed at 0 °C to 87% conversion followed by esterification using diazomethane, the ratio of 2b to ent-2b was found to be 82.5 ∶ 17.5, i.e., 65% enantiomeric excess (ee). Even higher enantiomeric excesses could be obtained by using other amine chiral auxiliaries. The best of those tried was (R)-(−)-1-cyclohexylethylamine, which afforded photoproduct 2b in 90% ee at 92% conversion. The results are summarized in Table 1. Solution phase photolysis of the salts (acetonitrile) also afforded photoproduct 2b as the sole product following diazomethane workup. In these cases, however, the ee was 0%, i.e., photoproduct 2b was formed as a racemate.

Fig. 1 ORTEP view of the molecular structure of the (S)-(−)-1-phenylethylamine salt of keto-acid 1a drawn at the 50% probability level. The ammonium ion has been omitted for clarity. Click /ej/ce/2005/b514952e/1.htm to access a 3-D rotatable image of Fig. 1.

Table 1 Solid state photolysis of salts of carboxylic acid 1a with optically pure amines¹⁰

Amine	Temp (°C)	Conv (%)	ee (%)	α
(R)-(−)-1-Cyclohexylethylamine	−40	92	90	−
	0	100	82
	20	72	73
(R)-(−)-1-Aminoindan	−20	10	89	+
	0	92	62
	20	67	63
(1S,2S)-(+)-Pseudoephedrine	−40	64	80	−
	0	92	68
	20	67	77
(S)-(−)-1-Phenylethylamine	−40	51	66	+
	0	87	65
	20	66	62
(1R,2R)-(−)-2-Amino-1-phenyl-1,3-propanediol	−20	53	59	+
	0	98	45
	20	77	27
(1S,2R)-(−)-cis-1-Aminoindanol	−40	41	78	+
	−20	71	24
	20	56	13

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The lack of ee in solution is not surprising, because even if there is an unequal distribution of diastereomeric salts present (asymmetric transformation of the first kind), the rate of equilibration between them is undoubtedly much greater than the rate-determining photochemical step (hydrogen atom abstraction). Furthermore, owing to the loose coordination between anion and cation in solution, the rate of hydrogen atom abstraction is the same for 1 and ent-1. According to the Curtin–Hammett principle, therefore, one would expect formation of equal amounts of photoproducts 2 and ent-2.¹¹ In the solid state, on the other hand, only one diastereomeric salt is present (asymmetric transformation of the second kind) and conformational equilibration is prevented by the restraints imposed by the crystal lattice. In a perfect crystal in which reaction occurs randomly throughout the bulk of the crystal, the ee should be 100%. While some salts do approach this value, particularly at low temperature, the fact that reaction undoubtedly occurs more near the crystal surface and at defect sites than in the ideal bulk means that this upper limit is seldom met. Another factor contributing to lowered ee's in the crystalline state is disruption of the ideal reactant lattice as the product accumulates. For this reason, ee generally declines with increasing conversion (Table 1).

In the case of the 1-phenylethylamine salt of keto-acid 1a, the solid state photoreaction was found to be single crystal-to-single crystal in nature. This allowed the structure of a partially (50%) and fully reacted crystal to be obtained.¹²Fig. 2a shows an ORTEP representation of the anionic portion of the fully reacted crystal with the chiral auxiliary omitted for clarity. The structure of the 50% reacted crystal is shown in Fig. 2b; the gray lines belong to the reactant and the black lines to the cyclobutanol photoproduct. As can be seen, there is a close correspondence in size and shape between reactant and product, a common feature of nearly all single crystal-to-single crystal transformations. The structure of the 50% mixed crystal establishes the absolute configuration of the photoproduct and also confirms the prediction that abstraction of the closer γ-hydrogen (H_X) should be favored over abstraction of H_Y. This follows from the fact that the γ-carbon atom involved in formation of the four-membered ring of the photoproduct is the one to which H_X was originally attached.

Fig. 2 ORTEP view at the 50% probability level of the carboxylate anion portion of the (S)-(−)-1-phenylethylamine salt of keto-acid 1a following irradiation to (a) complete conversion and (b) 50% conversion (hydrogen atoms omitted for clarity). Click /ej/ce/2005/b514952e/2a.htm to access a 3-D rotatable image of Fig. 2a. Click /ej/ce/2005/b514952e/2b.htm to access a 3-D rotatable image of Fig. 2b.

To conclude, the reactions described above add to the growing list of solid state photorearrangements that afford high yields of unusual and highly strained products in excellent enantiomeric excess. The protocol employed, which we term the solid state ionic chiral auxiliary method, appears to be quite general provided that the reactant crystallizes in a conformation suitable for reaction.¹³ The purpose of the present communication is, therefore, not so much to provide yet another example of a well established method of asymmetric synthesis, but rather to analyze it as an example of the practical application of a crystallization-induced asymmetric transformation of the second kind. The ease with which such transformations can be carried out on ammonium carboxylate salts opens the door for studying asymmetric induction in a wide variety of solid state reactions, both photochemical and ground state.

CCDC reference numbers 287133–287135. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b514952e

Acknowledgements

Financial support by the Natural Sciences and Engineering Research Council of Canada is gratefully acknowledged.

Notes and references

1. IUPAC Compendium of Chemical Terminology, 2nd Edition, ed. A. D. McNaught and A. Wilkinson, Blackwell Science, 1997.
2. A comprehensive list is beyond the scope of this communication. For some recent examples, see the following articles and the references cited therein. (a) E. Vedejs, R. W. Chapman, S. Lin, M. Müller and D. R. Powell, J. Am. Chem. Soc., 2000, 122, 3047; (b) E. Vedejs and Y. Donde, J. Org. Chem., 2000, 65, 2337; (c) W. H. J. Boesten, J-P. G. Seerden, B. de Lange, H. J. A. Dielemans, H. L. M. Elsenberg, B. Kaptein, H. M. Moody, R. M. Kellogg and Q. B. Broxterman, Org. Lett., 2001, 3, 1121; (d) H. Komatsu and H. Awano, J. Org. Chem., 2002, 67, 5419; (e) K. M. Brands, J. F. Payack, J. D. Rosen, T. D. Nelson, A. Candelario, M. A. Huffman, M. M. Zhao, J. Li, B. Craig, Z. J. Song, D. M. Tschaen, K. Hansen, P. N. Devine, P. J. Pye, K. Rossen, P. G. Dormer, R. A. Reamer, C. J. Welch, D. J. Mathre, N. N. Tsou, J. M. McNamara and P. J. Reider, J. Am. Chem. Soc., 2003, 125, 2129; (f) J. M. Keane, F. Ding, M. Sabat and W. D. Harman, J. Am. Chem. Soc., 2004, 126, 785.
3. For a discussion of the different types of solid state chemical reactions, including those of the single crystal-to-single crystal variety, see A. E. Keating and M. A. Garcia-Garibay, in Molecular and Supramolecular Photochemistry, ed. V. Ramamurthy and K. S. Schanze, Marcel Dekker, New York, NY, 1998, vol. 2, ch. 5.
4. For studies of the solution phase photochemistry of endo-5-benzoylbicyclo[2.1.1]hexane, see A. Padwa and W. Eisenberg, J. Am. Chem. Soc., 1972, 94, 5859.
5. Molecular mechanics calculations (HyperChem/ChemPlus version 5.11/2.0) confirm 1/ent-1 as the minimum energy conformation (Ar = Ph). The extent of rotation of the aroyl group from the average plane of symmetry bisecting the molecule was calculated to be 95°, which is very close to the X-ray angle of 93°.
6. Crystal data for 1-phenylethylamine salt of keto-acid 1a: C₂₃H₂₇N₁O₃, M = 365.46, orthorhombic, a = 6.1272(8), b = 7.2620(10), c = 45.252(6) Å, V = 2013.5(5) ų, T = 173 K, space group P2₁2₁2₁ (no. 19), Z = 4, μ(Mo Kα) = 0.079 mm⁻¹, 24878 reflections measured, 3540 unique (R_int = 0.050) which were used in all calculations. The final wR(F²) was 0.109 (all data).
7. J. R. Scheffer and C. Scott, in CRC Handbook of Organic Photochemistry and Photobiology, ed. W. M. Horspool and F. Lenci, CRC Press, Boca Raton, FL, 2004, 2nd edn, ch. 54.
8. Yang cyclization refers to cyclobutanol formation in the Norrish type II reaction and was first reported by N. C. Yang and D. H. Yang, J. Am. Chem. Soc., 1958, 80, 2913 . For a recent review, see P. J. Wagner, in CRC Handbook of Organic Photochemistry and Photobiology, ed. W. M. Horspool and F. Lenci, CRC Press, Boca Raton, FL, 2004, 2nd edn, ch. 58.
9. In addition to a closer approach of H_X to the carbonyl carbon, formation of photoproduct 2 is also favored by better values of the angular parameters ω (the angle by which H_X or H_Y lies outside the mean plane of the carbonyl group), Δ (the C=O⋯H angle) and θ (the C–H⋯O angle). For H_X, ω = 63°, Δ = 82° and θ = 114°. For H_Y, ω = 86°, Δ = 44° and θ = 92°. For a discussion of these parameters, see ref. 6.
10. For a description of the solid state photolysis technique, see M. Leibovitch, G. Olovsson, J. R. Scheffer and J. Trotter, J. Am. Chem. Soc., 1998, 120, 12755.
11. For an analysis of the Curtin–Hammett principle as applied to photochemical reactions, see F. D. Lewis, R. W. Johnson and D. E. Johnson, J. Am. Chem. Soc., 1974, 96, 6090.
12. Crystal data for 1-phenylethylamine salt of keto-acid 1a irradiated to 50% conversion: C₂₃H₂₇N₁O₃, M = 365.46, orthorhombic, a = 6.1739(8), b = 7.1907(9), c = 44.763(7) Å, V = 1987.2(5) ų, T = 173 K, space group P2₁2₁2₁ (no. 19), Z = 4, μ(Mo Kα) = 0.080 mm⁻¹, 9447 reflections measured, 2570 unique (R_int = 0.126) which were used in all calculations. The final wR(F²) was 0.248 (all data). Crystal data for same salt irradiated to 100% conversion: C₂₃H₂₇N₁O₃, M = 365.46, orthorhombic, a = 6.2120(10), b = 7.213(2), c = 44.481(9) Å, V = 1993.1(8) ų, T = 173 K, space group P2₁2₁2₁ (no. 19), Z = 4, μ(Mo Kα) = 0.080 mm⁻¹, 22894 reflections measured, 3527 unique (R_int = 0.117) which were used in all calculations. The final wR(F²) was 0.225 (all data).
13. For reviews of the solid state ionic chiral auxiliary approach to asymmetric synthesis, see ref. 6 as well as (a) J. R. Scheffer, Can. J. Chem., 2001, 79, 349 andJ. R. Scheffer, in Molecular and Supramolecular Photochemistry, Vol. 11: Chiral Photochemistry, ed. Y. Inoue and V. Ramamurthy, Marcel Dekker, New York, NY, 2004, ch. 12.

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