Stereodivergent synthesis of vicinal quaternary-quaternary stereocenters and bioactive hyperolactones

Although great success has been achieved in asymmetric Claisen rearrangement for the synthesis of chiral γ,δ-unsaturated carbonyl compounds bearing vicinal tertiary-quaternary stereocenters, the development of asymmetric versions for stereodivergent construction of adjacent quaternary-quaternary stereocenters remains a formidable challenge because of the high steric hindrance. Here we report a catalytic enantioselective dearomatization Claisen rearrangement of allyl furyl ethers catalyzed by chiral N,N′-dioxide-NiII complex catalysts. A variety of chiral γ,δ-unsaturated carbonyl compounds bearing vicinal quaternary-quaternary stereocenters were obtained with excellent outcomes under mild conditions. Furthermore, we disclosed that by matching the configuration of the catalysts and the alkene unit of the substrates, four stereoisomers of the products could be prepared in excellent yields and stereoselectivities. Finally, the fascination of this strategy was demonstrated by stereodivergent synthesis of bioactive natural products hyperolactones B, C, and their epimers. A possible catalytic model was proposed to explain the origin of the asymmetric induction.

T he Claisen rearrangement of allyl vinyl ethers is one of the most reliable and useful methods for synthesizing γ,δunsaturated carbonyl compounds, valuable intermediates in natural product construction [1][2][3][4] . On the basis of chiral Lewis acids 5-10 , Jacobsen's guanidinium salts 11 , N-heterocyclic carbenes 12 , or transition metals [13][14][15] catalysts, various of linear and cyclic vinyl units have been transformed via catalytic asymmetric Claisen rearrangement to afford chiral γ,δ-unsaturated carbonyl compounds bearing vicinal tertiary-quaternary stereocenters (Fig. 1a). However, the direct and catalytic stereoselective assembly of these compounds with two adjacent quaternaryquaternary stereocenters remains scarce, because of the inherent steric congestion in the formation of C-C bond. To obtain vicinal quaternary-quaternary arrays and accomplish the total synthesis of several natural products, chiral starting materials were usually conducted through this type of reaction. Zhai and co-workers reported the total synthesis of (−)-Jiadifenin, in which the key intermediate was acquired on the basis of Ireland-Claisen rearrangement of chiral acetal precursor 16 . Nakamura developed a stereoselective Ireland-Claisen Rearrangement for the synthesis of the CDE ring system of antitumor and chiral building blocks for oxygenated Terpenoids 17,18 . In regard of catalytic asymmetric methodology, in 2010, the Jacobsen group reported the only catalytic example to produce the vicinal quaternary-quaternary array 19 . However, limited substrates were evaluated though good results were obtained, which restricted further application in the total synthesis of natural products. Although great achievement has been made in asymmetric Claisen rearrangement, the direct catalytic stereodivergent accessing to optically pure γ,δ-unsaturated carbonyl compounds bearing two adjacent quaternary stereocenters is yet to be described and would be of great value for the natural product-oriented asymmetric synthesis.
The hyperolactones A-C 20,21 and (−)-biyouyanagin A 22 are a family of spirolactone natural products isolated from Hypericum chinese L, which possess significant activity against HIV replication (Fig. 1b). These compounds contain a mutual spirolactone fragment with two chiral vicinal quaternary carbon centers. Besides, the configuration of hyperolactones A, C, and (−)-biyouyanagin A is (S,S), while the configuration of hyperolactone B is (R,S), which varies from the spirocyclic center. Because of their anti-HIV biological activities and unique structures, synthetic chemists have developed many methodologies for their total syntheses [22][23][24][25][26][27][28][29][30][31][32] . Particularly, Kraus utilized a tandem Claisen rearrangement to realize the synthesis of racemic hyperolactones C 33 . Though, the yield was only 25% even heating the reaction mixture in a sealed tube at 130°C for 15 h, which indicated the challenge of the construction of adjacent quaternary stereocenters. Motivated by these initial results, we try to establish a general and efficient asymmetric Claisen rearrangement methodology for the synthesis of the family compounds of hyperolactone. Besides, we envision that by matching the configuration of the chiral catalysts and the substrates, all of the four stereoisomers might be accessible (Fig. 1c).

Results
Optimization of reaction conditions. Initially, we selected compound 1a with E-configuration as the model substrate to optimize the reaction conditions. The classical catalysts of Cu (OTf) 2 (Table 1, entry 9). Furthermore, we discovered that the reaction temperature even could be reduced to 35°C by prolonging the reaction time to 4 days and the desired product 2b could be obtained in 96% yield, 10:1 dr and 99% ee (Table 1, entry  10). But further decreasing the reaction temperature led to low conversion. Variation of ester group on furyl unit of the substrate was also explored in the reaction. However, the yield and enantioselectivity were excellent but the dr was moderate (Table 1, entries 11 and 12).
Substrate scope. With the optimized reaction conditions identified, a wide range of substrates with varied substituents on furan unit were investigated. In all cases, the reaction proceeded smoothly with excellent yields and stereoselectivities (Fig. 2). Either electron-withdrawing (1g-1i) or electron-donating (1f and 1j) substituents on the 5-phenyl ring of the furan unit were tolerated in the reaction, furnishing the corresponding products (2f-2j) in excellent yields, diastereo-and enantioselectivities (up to 99% yield, 12:1 dr and 99% ee). 1-Naphthyl (1k) and heteroaromatic (1l and 1m) substituted furan substrates performed the reaction well, giving the related products (2k-2m) in 94-96% yields, 8:1-9:1 dr and 99% ee. Besides, when the 5-alkyl substituted furan substrates (1n-1p) were conducted in the reaction, the products (2n-2p) could also be obtained in excellent results (up to 96% yield, 9:1 dr and 99% ee) after prolonging the reaction time. To demonstrate the utility of this Claisen rearrangement, preparative-scale synthesis of the products 2b and 2k was carried out. Delightedly, the reactivity and stereoselectivity were maintained, which indicated that this method could tolerate the gramscale chemical production. Furthermore, the absolute configuration of 2g was determined to be (S,S) by the X-ray diffraction of the related spirolactone derivative 3g (See Supplementary Fig. 76) (CCDC 1554368 (3g)). The compounds 2b and 2n exhibited a similar Cotton effect in their circular dichroism (CD) spectra (See Supplementary Figs. 64-75). The substrates with variation at the alkene unit were also examined (Fig. 3). Under the optimized reaction conditions, Eethyl substituted substrate 1q and E-isobutyl substituted substrate 1r were transformed into the desired products 2q and 2r in excellent yields and enantioselectivities (Fig. 3a, up to 85% yield and 99% ee). The latter showed relatively lower diastereoselectivity (2q/2r,13:1/5:1dr), which is probably due to the larger steric congestion that affects the stereoselective formation of C-C bond 16,19 . When E-phenyl substituted alkene substrate (E-1s) was treated in the reaction, no reaction was detected even raising the reaction temperature to 80°C, which might be caused by the disfavored 1,3-repulsion interaction between aryl group and furan group in the reaction model (See Supplementary Fig. 80). Inversely, Z-aryl substituted alkene substrates could afford the corresponding diastereo-isomers 2′ as the major ones. We found the ligand L-PiMe 3 was superior to L-PiMe 2 in terms of reactivity and stereoselectivity, and the use of Ni(BF 4 ) 2 /ent-L-PiMe 3 catalyst for the reaction of Z-1s′ resulted in better formation of the related isomer 2s′ compared with Ni(BF 4 ) 2 /L-PiMe 2 catalyst (89% yield, 19:1 dr, 83% ee vs. 75% yield, 9:1 dr, 80% ee). With Ni (BF 4 ) 2 /ent-L-PiMe 3 catalyst, the substrates Z-1s′ to Z-1x′ could participate in the Claisen rearrangement to afford the desired products 2s′-2x′ in excellent yields, stereoselectivities (Fig. 3b,  62% ee. In addition, the 2-naphthyl substituent alkene E-1x′ was found suitable for this reaction, delivering the product 2x′ in 82% yield with 8:1 dr and 83% ee. Furthermore, terminal monophenyl substituted alkene substrate E-1y could afford the desired product 2y in 97% yield with 95% ee and 12:1 dr in the presence of Ni(BF 4 ) 2 /L-PiMe 2 catalyst. Both E-1z and Z-1z′ with terminal disubstituent were suitable in this reaction to afford the corresponding products 2z and 2z′ in excellent results (Fig. 3c, up to 96% yield, 99% ee and 9:1 dr).
Asymmetric synthesis of four stereoisomers. To examine our initial stereodivergent assumption and the purpose of synthesizing natural products hyperolactones B and C, we prepared the E-1b, 1n and Z-1b′, 1n′ and treated them under the optimal reaction conditions (Fig. 4). As expected, the E-substrates preferably afforded (S,S)-configuration products 2b and 2n, while, the Z-substrates yielded the (S,R)-configuration products 2b′ and 2n′ (The configuration of the products were confirmed by CD spectra and NOE spectra analysis of hyperolactones, see   Proposed stereochemical model. On the basis of our previous works [49][50][51] and the absolute configuration of the product 2g, a possible stereocontrol model was proposed in Fig. 6. The chiral N, N′-dioxide coordinates to the nickel(II) center to form octahedral metal complex in which the chiral ligand occupies four sites. The substrate 1g displays the ancillary solvents or anion and could coordinate to the Lewis acid catalyst via a bidentate manner with the oxygen of ether and carbonyl group of the auxiliary ester group. Due to the steric hindrance between alkene unit and the bulky aniline moiety of ligand, the alkene preferentially approaches α position of furan unit from the Re face. Therefore, the E-alkene substrate 1g affords (S,S)-2g and the Z-alkene substrate 1g′ affords (S,R)-2g′.

Discussion
In summary, we have developed a catalytic asymmetric dearomatization Claisen rearrangement of allyl furyl ethers for the synthesis of chiral γ,δ-unsaturated carbonyl compounds with two adjacent quaternary-quaternary carbon centers. By adjusting the configuration of the catalysts and alkene units, all four possible product stereoisomers could be prepared in excellent yields and stereoselectivities. In addition, the reaction has a broad substrate scope, which may lead to the discovery of new bioactive molecules. Furthermore, the bioactive natural products hyperolactones B, C, and their epimers could be readily acquired in high efficiency, which are also the key intermediates for the synthesis of natural product (−)-biyouyanagin A and its epimer.
After the reaction completed (monitored by TLC), flash column chromatography was carried out to provide the desired product (Petroleum ether/EtOAc = 20:1 to 10:1).