Diastereodivergent and Enantioselective [4+2] Annulations of γ-Butenolides with Cyclic 1-Azadienes

An asymmetric annulation reaction of γ-butenolides and cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif has been studied, proceeding in a tandem Michael addition-aza-Michael addition sequence. Endo-type cycloadducts bearing fused tetracyclic skeletons were isolated in fair yields and with high enantioselectivity (up to >99% ee) under the catalysis of modified cinchona alkaloid (DHQD)2PHAL. Besides, exo-type diastereomers could be produced using β-isocupreidine (β-ICD) as the catalyst, though with moderate enantioselectivity.


Introduction
γ-Butenolides represent an important class of heterocycles, which widely exist in a large number of natural products and pharmaceutically useful molecules [1,2]. In addition, the γ-butenolides act as competent direct vinylogous nucleophiles in addition reactions for the construction of an array of structurally diverse architectures [3][4][5][6], even for preparing more challenging molecules with quaternary carbon centers by using γ-substituted butenolides [7][8][9][10][11][12][13]. In contrast to abundant γ-regioselective OPEN ACCESS vinylogous addition reactions, to the best of our knowledge, no examples have been reported to utilize the γ-butenolides as the reactants towards tandem reactions in consideration of the potential reactivity of both γ-and β-positions [14]. Recently, our group reported a direct asymmetric allylic alkylation of γ-butenolides with MBH carbonates to access γ,γ-disubstituted butenolides that could allow sequential aza-Michael addition to deliver interesting bicyclic piperidine derivatives [15]. These results inspired us to explore domino or tandem Michael addition-aza-Michael addition to construct a variety of polycyclic skeletons.
On the other hand, our group recently developed a series of asymmetric reactions involving cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif [16][17][18][19]. They are stable materials, and readily available from diverse saccharins and aldehydes. Importantly, they exhibit high electrophilicity, and can perform as either 2π or 4π partners in Diels-Alder cycloaddition reactions with HOMO-activated enamine species. Therefore, the good reactivity of such 1-azadienes in cycloaddition reactions suggests that they could be applied as potential reactants in the [4+2] reaction with the in situ generated dienolates from the γ-butenolides, either in a concerted or stepwise manner [15]. Here, we would like to report the asymmetric assembly of 3-vinyl-1,2-benzoisothiazole-1,1-dioxides and γ-butenolides to furnish chiral tetracyclic molecules with high structural and functional complexity.

Studies on Endo-Cycloaddition Reaction Catalyzed by (DHQD)2PHAL 1g
In order to further improve the data of endo-cycloadduct 4a by the catalysis of (DHQD)2PHAL 1g, more reaction parameters were investigated. The results are summarized in Table 2. At first, a few solvents were explored at 20 °C (Table 2, entries 1-4), and better diastereoselectivity and excellent enantioselectivity could be obtained in PhCF3 (entry 4). The enantioselectivity was decreased at lower or higher reaction temperature (entries 5 and 6). In addition, the yield could not be improved by increasing the catalyst loadings (entry 7) or reaction concentration (entry 8), or by adding 1-azadiene 3a in portions (entry 9). It should be pointed out that significant amounts of α-regioselective Michael adduct 6 (about 20%) was observed in all the tested reactions, which might account for the fair yield of endo-cycloadduct 4a.  With the optimized conditions in hand, we then explored a variety of cyclic 1-azadienes 2 and γ-butenolides 3 under the catalysis of (DHQD)2PHAL 1g in PhCF3 at 20 °C. The results are summarized in Table 3. At first, a variety of cyclic 1-azadienes bearing electron-withdrawing or -donating groups on the aryl ring were tested in reactions with α-angelica lactone 3a (Table 3, entries 1-6). In general, the substrates could be effectively consumed, but the reactions were not clean since some side products were always observed. The desired endo-type [4+2] cycloadducts 4 could be smoothly isolated in fair to moderate yields, while high to excellent ee values were generally obtained. In addition, outstanding enantioselectivity was also attained for the cyclic 1-azadienes bearing heteroaryl groups, though the yields were still unsatisfactory (entries 7 and 8). In addition, substitutions on the isothiazole ring had marginal effect on the yields and ee values (entries 9 and 10). On the other hand, other γ-butenolides were further explored in reactions with 1-azadiene 2a. The similar excellent enantioselectivity along with a fair yield was gained for γ-phenyl-substituted butenolide (entry 11), while the simple 2-butenolide showed poor reactivity, and a moderate ee value was produced (entry 12). Moreover, 4-styryl-1,2,3-benzoxathiazine-2,2-dioxides 7 could also be assembled with α-angelica lactone 3a under the same catalytic conditions, and the corresponding cycloadducts 8 were isolated in excellent enantioselectivity and with modest yields (Scheme 1).
2.1.4. More Studies on the Exo-Type Cycloaddition Reaction Catalyzed by β-ICD 1b As mentioned above, β-ICD 1b-catalyzed reaction of 1-azadiene 2a and α-angelica lactone 3a dominantly gave exo-type cycloadduct 5a in DCM, thus we explored more reaction conditions with β-ICD 1b. The results are summarized in Table 4. The similar data were obtained in 1,2-dichloroethane (DCE, Table 4, entry 2), but both diastereo-and enantioselectivity were decreased when other solvents were used (entries 3-6). In addition, changing other types of parameters, such as reaction temperature (entry 7), catalyst loadings (entry 8), and substrate ratio (entry 9), failed to improve the yield and enantioselectivity. As the γ-regioselective vinylogous Michael addition intermediate also was detected in the reaction mixture, tetramethylguanidine (TMG) was added to facilitate the intramolecular aza-Michael addition after the disappearance of substrate 2a. Pleasingly, better yield for exo-5a could be obtained without diminishing the stereoselectivity (entry 10). Therefore, the exo-cycloadduct seems to be greatly favored by using less hindered Brønsted base as the promoter. Although moderate ee value was obtained, the optical purity of exo-cycloadduct 5a could be improved to 90% ee after a single recrystallization (entry 10, data in parentheses). Consequently, a few cyclic imine 2 were further tested in reactions with α-angelica lactone 3a under the above optimized conditions. As summarized in Table 5, all the reactions exhibited exclusive exo-diastereoselectivity, and the similar moderate enantioselectivity along with fair to modest yields was obtained ( Table 5, entries 1-6). Simple 2-butenolide showed good reactivity, delivering the product 5g in moderate yield and ee value (entry 7).

Absolute Configuration of Endo-4a and Exo-5a
In order to determine the absolute configuration of the cycloadducts, single crystals suitable for X-ray crystallographic analysis were obtained from product 4a and 5a, respectively. Over 99% ees could be obtained after recrystallization from 4a (95% ee) and 5a (55% ee) in a mixture of ethyl acetate, isopropanol and petroleum ether. Thus, the absolute configuration of 4a and 5a could be unambiguously assigned, as outlined in Figure 1 [24], and more crystal data and structures refinement for 4a and 5a could be found in the supplementary materials.

Derivation of the Cycloaddition Product
The unsaturated cyclic enamide group of 4a could be reduced by Et2O . BF3 and Et3SiH [25], delivering the corresponding product 9 in a good yield and with a moderate diastereoselectivity (Scheme 2).

Scheme 2.
Reduction of cycloaddition product.

General Methods
NMR data were obtained for 1 H at 600 MHz and for 13 C at 151 MHz. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in CDCl3 solution. ESI HRMS was recorded on a Waters SYNAPT G2. In each case, enantiomeric ratio was determined by HPLC analysis on a chiral column in comparison with authentic racemate, using a Daicel Chiralcel OD-H Column (250 × 4.6 mm), Chiralcel IA Column (250 × 4.6 mm), Chiralcel IC Column (250 × 4.6 mm), Chiralcel IE Column (250 × 4.6 mm), Chiralcel IF Column (250 × 4.6 mm), or Chiralcel AS-H Column (250 × 4.6 mm). UV detection was monitored at 210 nm or 285 nm. Optical rotation was examined in CH2Cl2 solution at 25 °C. Column chromatography was performed on silica gel (400 mesh) eluting with ethyl acetate and petroleum ether or DCM. TLC was performed on glass-backed silica plates. UV light and I2 were used to visualize products. All chemicals including α-angelica lactone 2a were used without purification as commercially available unless otherwise noted, and the other butenolides were prepared according to the literatures [15]. α,β-Unsaturated imines 2 and 7 were prepared according to the literature procedures [16]. The tertiary amines 1b and 1c were also synthesized according to the literature procedures [21,22], and others were commercial available.

General Procedure for the Preparation of Endo-Cycloadduct 4 or 8
The reaction was carried out with cyclic 1-azadiene 2 or 7 (0.3 mmol) and butenolide 3 (0.6 mmol) in benzotrifluoride (3.0 mL) in the presence of tertiary amine catalyst 1g (23.4 mg, 0.03 mmol) at 20 °C. After accomplishment, the solution was concentrated and the residue was purified by flash chromatography on silica gel (DCM/ethyl acetate = 150:1) to afford the chiral product 4 or 8.