On the Effect of Tether Composition on cis/trans Selectivity in Intramolecular Diels–Alder Reactions |
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| Authors: | Michael N. Paddon‐Row Prof. Alistair I. Longshaw Dr. Anthony C. Willis Dr. Michael S. Sherburn Prof. |
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| Affiliation: | 1. School of Chemistry, University of New South Wales, Sydney, NSW 2052 (Australia), (computational);2. Research School of Chemistry, Australian National University, Canberra, ACT 0200 (Australia), Fax: (+61) 2‐6125‐8114 (synthetic);3. Correspondence author for X‐ray crystallography |
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| Abstract: | Intramolecular Diels–Alder (IMDA) transition structures (TSs) and energies have been computed at the B3LYP/6‐31+G(d) and CBS‐QB3 levels of theory for a series of 1,3,8‐nonatrienes, H2C?CH? CH?CH? CH2? X? Z? CH?CH2 [? X? Z? =? CH2? CH2? ( 1 ); ? O? C(?O)? ( 2 ); ? CH2? C(?O)? ( 3 ); ? O? CH2? ( 4 ); ? NH? C(?O)? ( 5 ); ? S? C(?O)? ( 6 ); ? O? C(?S)? ( 7 ); ? NH? C(?S)? ( 8 ); ? S? C(?S)? ( 9 )]. For each system studied ( 1 – 9 ), cis‐ and trans‐TS isomers, corresponding, respectively, to endo‐ and exo‐positioning of the ? C? X? Z? tether with respect to the diene, have been located and their relative energies (ErelTS) employed to predict the cis/trans IMDA product ratio. Although the ErelTS values are modest (typically <3 kJ mol?1), they follow a clear and systematic trend. Specifically, as the electronegativity of the tether group X is reduced (X?O→NH or S), the IMDA cis stereoselectivity diminishes. The predicted stereochemical reaction preferences are explained in terms of two opposing effects operating in the cis‐TS, namely (1) unfavorable torsional (eclipsing) strain about the C4? C5 bond, that is caused by the ? C? X? C(?Y)? group’s strong tendency to maintain local planarity; and (2) attractive electrostatic and secondary orbital interactions between the endo‐(thio)carbonyl group, C?Y, and the diene. The former interaction predominates when X is weakly electronegative (X?N, S), while the latter is dominant when X is more strongly electronegative (X?O), or a methylene group (X?CH2) which increases tether flexibility. These predictions hold up to experimental scrutiny, with synthetic IMDA reactions of 1 , 2 , 3 , and 4 (published work) and 5 , 6 , and 8 (this work) delivering ratios close to those calculated. The reactions of thiolacrylate 5 and thioamide 8 represent the first examples of IMDA reactions with tethers of these types. Our results point to strategies for designing tethers, which lead to improved cis/trans‐selectivities in IMDAs that are normally only weakly selective. Experimental verification of the validity of this claim comes in the form of fumaramide 14 , which undergoes a more trans‐selective IMDA reaction than the corresponding ester tethered precursor 13 . |
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| Keywords: | cycloaddition density functional calculations diastereoselectivity tether groups transition structures |
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