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. 2016 Dec 1;7(12):6919-6927.
doi: 10.1039/c6sc00940a. Epub 2016 Jul 4.

Non-bonding 1,5-S···O interactions govern chemo- and enantioselectivity in isothiourea-catalyzed annulations of benzazoles

Emily R T Robinson  1 , Daniel M Walden  2 , Charlene Fallan  1 , Mark D Greenhalgh  1 , Paul Ha-Yeon Cheong  2 , Andrew D Smith  1
Affiliations

Non-bonding 1,5-S···O interactions govern chemo- and enantioselectivity in isothiourea-catalyzed annulations of benzazoles

Emily R T Robinson et al. Chem Sci. .

Abstract

Isothiourea-catalyzed annulations between 2-acyl benzazoles and α,β-unsaturated acyl ammonium intermediates are selectively tuned to form either lactam or lactone heterocycles in good yields (up to 95%) and high ee (up to 99%) using benzothiazole or benzoxazole derivatives, respectively. Computation gives insight into the significant role of two 1,5-S···O interactions in controlling the structural preorganization and chemoselectivity observed within the lactam synthesis with benzothiazoles as nucleophiles. When using benzazoles the absence of a second stabilizing non-bonding 1,5-S···O interaction leads to a dominant C-H···O interaction in determining structural preorganization and lactone formation.

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Figures

Scheme 1
Scheme 1. Previous work using benzazoles in enantioselective catalysis. Eqn (1) nickel-catalyzed Michael addition to nitroalkenes; eqn (2) isothiourea-catalyzed enantioselective annulation with α,β-unsaturated acyl ammonium intermediates.
Scheme 2
Scheme 2. Chemo- and enantioselective isothiourea-catalyzed annulation of acylbenzazoles with α,β-unsaturated acyl ammonium intermediates.
Scheme 3
Scheme 3. Probing the effects of acyl and benzazole substituents on annulation chemo- and enantioselectivity. aRatio of constitutional isomers arising from either N- or O-cyclization calculated from 1H NMR spectra of crude reaction product. bee values obtained via chiral HPLC. cFollowing a single recrystallization ee could be enhanced to 97%.
Scheme 4
Scheme 4. Generation of all-carbon quaternary centres.a
Scheme 5
Scheme 5. Product derivatization through cross coupling. a Isolated yield. b ee values obtained via chiral HPLC.
Fig. 1
Fig. 1. Catalytic cycle of the isothiourea-catalyzed annulations between 2-acyl benzazoles and homoanhydrides to form the lactam (left) or the lactone (right) using benzothiazole (X = S) or benzoxazole (X = O) derivatives, respectively.
Fig. 2
Fig. 2. Conformational preferences of anionic benzoxazole and benzothiazole nucleophiles.
Fig. 3
Fig. 3. Model systems probing the relative energetic values (in kcal mol–1) between S···O and C–H···O nonbonding interactions.
Fig. 4
Fig. 4. Computed chemoselectivity determining cyclization transition structures for benzoxazole and thiazole nucleophiles. All transition structures are stepwise (tetrahedral intermediate formation followed by HBTM release) except for favored-lactamization-(X = S)-TS (see ESI for computed reaction coordinates). Forming bonds shown in grey. S···O interactions shown in orange, C–H···O highlighted in green, and van der Waals repulsion shown in red. Aromatic interaction shaded in purple. Relative energy values given in kcal mol–1. Structure images rendered using CYLview.
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