Selectivity in formation of ∆ 1 -pyrazolines. 

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... gauche effect is a conformational phenomenon where two strongly electronegative 1,2-substituents, such as halogen-, oxygen-, and nitrogen-based functional groups, favor to assume the gauche over the corresponding anti conformation ( Figure 1) [1–6]. One most representative example is the conformational behavior of 1,2-difluoroethane where the gauche conformation has a lower energy than the anti by 2.4 ́ 3.4 kJ/mol [7–12]. The gauche effect was also identified as a key factor in certain biological systems such as collagen [13–16]. Hyperconjugation and bent bonds-based explanations are proposed for the gauche effect, and the former is considered to be the principal cause of the preferred gauche conformation of 1,2-difluoro-ethane. In the hyperconjugation model, the maximum delocalization of the C–H electron density to the σ * orbital of the C–F bond will be achieved in the gauche conformation. This is because the C–H bond is a better electron donor than the C–F bond due to the greater electronegativity of fluorine, while the σ * orbital of the C–F bond is a better electron acceptor than that of the C–H bond. In our recent study of the tandem addition of trimethylsilyldiazomethane (TMSD) to the carbonyl group of 4-alkenyl carbonyl compounds, followed by intramolecular [3+2] cycloaddition (32CA) of the diazoalkane intermediate with the tethered alkene to generate bi- and tricyclic ∆ 1 -pyrazolines, an unusual stereochemical outcome trend was observed [17]. In this report, Lewis bases, such as potassium tert -butoxide ( t -BuOK) or tetrabutylammonium triphenyldifluorosilicate (TBAT) catalyzed the tandem 1,2-addition, 1,3-Brook rearrangement followed by intramolecular 32CA of 4-alkenyl carbonyl compounds. For cyclic 4-alkenyl ketones, complete diastereoselectivity was observed in the reaction in favor of the syn adducts, as verified by X-ray crystallographic studies. When 4-alkenyl aldehydes were tested as substrates under the reaction conditions, the reaction was also selective, but favoring the anti -cycloadducts (2:1 to 1:0 dr). Finally, in the cases of 4-alkenyl ketones, the newly formed ∆ 1 -pyrazolines were formed with low diastereoselectivity. To probe the origin of selectivity and either prove or refute the gauche effect hypothesis, DFT calculations were thus performed. In the case of cyclic alkene-tethered α -silyloxydiazoalkanes, the seemingly less favorable diastereomer with syn- relationship of adjacent silyloxy group and C–N bond of the newly formed pyrazoline ring became more favorable over the corresponding anti -diastereomer. At a first glance, this seems to be the manifestation of the gauche effect of the vicinal C–O and C–N bonds. In the case of acyclic systems, steric effect overrides the gauche effect (Figure 2). To further elucidate the origin of the observed selectivity, the transition state structure (TSs) and product energies of representative systems containing different structural features were calculated. It was recognized that pyrazolines 1a – e formed as a single isomer upon treatment of α -allyl cyclic ketones with trimethylsilyldiazomethane (10 mol % t -BuOK, THF, 0 ̋ C) (Figure 3) [17]. The structural confirmation, including X-ray crystallographic analysis of pyrazolines 1a , 1b , and 1e , revealed that the newly formed pyrazoline ring is disposed syn to the trimethylsilyloxy group [18]. Intuitively, these C–O and C–N syn -disposed products are considered to be less favorable than the corresponding anti -diastereomers because of the lone-pair electrons on the oxygen and nitrogen moieties in close proximity. Careful examination of these structures indicates that the C–O bond of the silyloxy group and the C–N bond of the pyrazoline ring has a gauche relationship with dihedral angles about 54 ̋ . In the anti -diastereomers if they had been formed, these dihedral angles would be roughly 180 ̋ . At this juncture, we suspected that the well-known gauche effect of the vicinal polar bonds such as C–O and C–N bonds could be a strong driving force in this system such that the 32CA are to occur favorably generating the observed syn- diastereomers over the anti ones. To explore the gauche effect and steric factors that cause the observed high syn -selectivity of 32CA, we carried out density functional theory calculations (B3LYP/6-31+G(d) level) in solution phase. In general, the energy ...