Ti(Oi-Pr)4-promoted photoenolization Diels–Alder reaction to construct polycyclic rings and its synthetic applications

Stereoselective construction of polycyclic rings with all-carbon quaternary centers, and vicinal all-carbon quaternary stereocenters, remains a significant challenge in organic synthesis. These structures can be found in a wide range of polycyclic natural products and drug molecules. Here we report a Ti(Oi-Pr)4-promoted photoenolization/Diels–Alder (PEDA) reaction to construct hydroanthracenol and related polycyclic rings bearing all-carbon quaternary centers. This photolysis proceeds under mild conditions and generates a variety of photo-cycloaddition products in good reaction efficiency and stereoselectivity (48 examples), and has been successfully used in the construction of core skeleton of oncocalyxones, tetracycline and pleurotin. It also provides a reliable method for the late-stage modification of natural products bearing enone groups, such as steroids. The total synthesis of oncocalyxone B was successfully achieved using this PEDA approach.

found that 2-methylbenzaldehyde substrates lacking a methoxy group ortho to the aldehyde showed no reactivity in this photoenolization/Diels-Alder reaction, such as the substrates C1-4 in Supplementary  Figure 84. This identifies the ortho methoxy group as crucial for the reaction, consistent with observations by Nicolaou and coworkers. We considered that the photoenolized hydroxy-o-quinodimethane and ortho methoxy group may be chelated by Ti(Oi-Pr) 4 , forming a relatively stable complex. The ortho methoxy may serve as a key neighboring group that helps to stabilize the short-lived photoenolized hydroxy-oquinodimethane diene.

Supplementary Figure 84.
Substrates lacking a methoxy group ortho to the aldehyde.
To gain further insights into the reaction mechanism, we carefully investigated the effects of dienophile and Ti(Oi-Pr) 4 dosage on the reaction yield using the model reaction between 7 and 8 (Supplementary Table 5 and 6). We found that increasing the dosage and concentration of dienophile 8 had little effect on the reaction rate or yield (left curve, Supplementary Figure 85). In contrast, the reaction yield depended strongly on the dosage of Ti(Oi-Pr) 4 . Photolysis using Ti(Oi-Pr) 4 dosages >2.0 equiv. gave stable and comparable yield (right curve, Supplementary Figure 85), while decreasing the dosage dramatically reduced the reaction yield. Using 50 mol % Ti(Oi-Pr) 4 produced the cycloaddition product 9 in only 5.7% yield. These findings suggest that the reaction intermediates of diene and dienophile may interact with twice amounts of Ti(Oi-Pr) 4 during the photoreaction. Figure 85. Effects of dienophile and Ti(Oi-Pr) 4 dosage on the reaction yield.

Supplementary
We also tried to study the process of this PEDA reaction using NMR spectrum (Supplementary Figure 86). A mixture of 7,   4 in toluene-d 8 was irradiated with UV light under the optimized conditions. We monitored the reaction using NMR every 5 minutes without quenching the reaction by saturated sodium bicarbonate. We found that the cycloaddition product 9 formed quickly during photolysis, and that it existed mainly as a Ti-chelated complex based on comparison with the NMR spectrum of purified 9. This Ti-chelated complex could be transformed to product 9 by treatment with sat. NaHCO 3 . This clearly indicates that Ti(Oi-Pr) 4 plays a key role in this photoreaction, and that a chelation between Ti(Oi-Pr) 4 and diene/dienophile occurs during this process.

Supplementary Figure 86.
Monitor the PEDA reaction with NMR spectrum.
Given these results and structural data on PEDA products, we propose plausible transition states for the reaction as shown in Supplementary Figure 87, which presents the formation of 9 as an example. We consider that the hydroxy-o-quinodimethane species is effectively generated via photoenolization, after which the Z-dienol and ortho methoxy group may be chelated by Ti(Oi-Pr) 4 , forming a relatively stable complex. This complex may exist as a monomeric (C5) or dimeric titanium complex (C6). Although we cannot rule out the possibility of a monomeric form, we think the dimeric form C6 is more likely, given the observed relationships between Ti dosage and reaction yield. The ortho methoxy may serve as a key neighboring group that helps to stabilize the short-lived photoenolized hydroxy-o-quinodimethane diene, which then interacts with a cyclic dienophile such as 8 to give a chelated intermediate C7. Then the activated enone reacts with the diene component from the endo direction, forming the Ti-chelated complex of 9, which can be detected by NMR (Shown in Supplementary Figure 86). After dissociation, cycloaddition product 9 with three consecutive stereogenic centers is generated stereospecifically.

Supplementary Methods
General Experimental Procedures: All reactions were carried out under nitrogen unless noted. Anhydrous 1,4-dioxane, dichloromethane, acetonitrile, N,N-dimethylformamide, 1,2-dichloroethane were distilled from calcium hydride. Tetrahydrofuran was distilled from sodium-benzophenone ketyl, anhydrous toluene was distilled from sodium. All degassed solvents were obtained by bubbling N 2 over 40 min. Flash column chromatography was performed as described by Still 1 ,. TLC analyses were performed on EMD 250 m Silica Gel HSGF 254 plates and visualized by quenching of UV fluorescence (λ max =254 nm), or by staining ceric ammonium molybdate, ammonium molybdate, phosphomolybdic acid, or potassium permanganate. The [α] D was recorded using PolAAr 3005 High Accuracy Polarimeter. Infrared (IR) spectra were obtained using a Bruker tensor 27 infrared spectrometer. 1 H and 13 C NMR spectra were recorded on a Bruker-500, 400 spectrometer. Chemical shifts for 1 H and 13 C NMR spectra are reported in ppm (δ) relative to residue protium and carbon resonance in the solvent (CDCl 3 : δ 7.26, 77.0 ppm) and the multiplicities are presented as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. We found that the 13 C NMR spectrum of some pure compounds have splitting carbon peaks. This may be caused by the NMR equipment or their special chemical structures. High-resolution mass spectra (HRMS) were acquired on Waters Micromass GCT Premier, and Mass spectra at Agilent 5975C. The photo reactor used for this photolysis is Rayonet . The emission spectra of the 16 lamps for 366 nm in the Rayonet chamber reactor range from 300 to 400 nm with maximum emission wavelength at 366 nm. We use "λ max = 366 nm" as a brief substitute.
(Notice: The size of quartz tube we chose for our photoreactions is as follows: 15 centimeters for length, 1.3 centimeters for inside diameter, 1.5 centimeters for outside diameter. As to quartz tube of larger size, the result of this photolysis is not very good.)

General procedure A for Titanium(IV)-promoted photoenolization/Diels-Alder reaction:
To a solution of aromatic aldehyde (0.3 mmol, 1.0 equiv.) in anhydrous and degassed 1,4-dioxane (15 mL, 0.02 M) in quartz tube sealed with rubber plug was added dienophile (1.8 mmol, 6.0 equiv.) (if the dienophile was solid, it was added before the solvent) under N 2 , then titanium(IV) isopropoxide (0.9 mmol, 3.0 equiv.) was added, after homogeneous mixing, the solution was photolyzed at rt in a Rayonet chamber reactor (16 lamps) at λ max = 366 nm for certain time described below. Then the reaction mixture was poured into saturated sodium bicarbonate and stirred over 30 min, the above mixture was extracted three times with ethyl acetate, the combined organic phases were washed twice with brine and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the corresponding product.

General procedure B for Titanium(IV)-promoted photoenolization/Diels-Alder reaction:
To a solution of aromatic aldehyde (0.3 mmol, 1.0 equiv.) in anhydrous and degassed toluene (15 mL, 0.02 M) in quartz tube sealed with rubber plug was added dienophile (0.45 mmol, 1.5 equiv.) (if the dienophile was solid, it was added before the solvent) under N 2 , then titanium(IV) isopropoxide (0.36 mmol, 1.2 equiv.) was added, after homogeneous mixing, the solution was photolyzed at rt in a Rayonet chamber reactor (16 lamps) at λ max = 366 nm for certain time described below. Then the reaction mixture was poured into saturated sodium bicarbonate and stirred over 30 min, the above mixture was extracted three times with ethyl acetate, the combined organic phases were washed twice with brine and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the corresponding product.

General procedure C for Titanium(IV)-promoted photoenolization/Diels-Alder reaction:
To a solution of dienophile (0.3 mmol, 1.0 equiv.) and aromatic aldehyde (1.2 mmol, 4.0 equiv.) in anhydrous and degassed toluene (60 mL, concentration for aromatic aldehyde is 0.02 M) in quartz tube sealed with rubber plug was added titanium(IV) isopropoxide (0.9 mmol, 3.0 equiv.) under N 2 , after homogeneous mixing, the solution was photolyzed at rt in a Rayonet chamber reactor (16 lamps) at λ max = 366 nm for certain time described below. Then the reaction mixture was poured into saturated sodium bicarbonate and stirred over 30 min, the above mixture was extracted three times with ethyl acetate, the combined organic phases were washed twice with brine and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the corresponding product. (Due to need for much solvent, four parallel reactions were conducted with four quartz tubes, 15 ml toluene for each quartz tube, then combined for workup.)

General procedure D for Titanium(IV)-promoted photoenolization/Diels-Alder reaction:
To a solution of dienophile (0.4 mmol, 1.0 equiv.) and aromatic aldehyde (1.6 mmol, 4.0 equiv.) in anhydrous and degassed dioxane (40 mL, concentration for dienophile is 0.01 M) in quartz tube sealed with rubber plug was added titanium(IV) isopropoxide (1.2 mmol, 3.0 equiv.) under N 2 , after homogeneous mixing, the solution was photolyzed at rt in a Rayonet chamber reactor (16 lamps) at λ max = 366 nm for certain time described below. Then the reaction mixture was poured into saturated sodium bicarbonate and stirred over 30 min, the above mixture was extracted three times with ethyl acetate, the combined organic phases were washed twice with brine and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the corresponding product. (Due to need for much solvent, four parallel reactions were conducted with four quartz tubes, 10 ml dioxane for each quartz tube, then combined for workup. The gas inside was replaced into N 2 with oil pump under the low temperature (liquid nitrogen), because of the dienophile used here can be easily taken away by oil pump at rt.) Compound 7 was prepared according to the following procedure. To a stirred solution of 7-1 (10.1 g, 45.04 mmol, 1.0 equiv.) in anhydrous toluene/hexane(1:3) (200 mL) was added n-BuLi (2.5 M solution in hexane, 36 mL, 90.08 mmol, 2.0 equiv.) dropwise at -25 o C under N 2 , the resulting mixture was vigorously stirred at -25 o C for 11.5 h, then MeI (11.2 mL, 180.16 mmol, 4.0 equiv.) in anhydrous tetrahydrofuran (80 mL) was was added to the above mixture, after the addition, the reaction mixture was stirred over 5 h. Then the mixture was quenched with saturated sodium bicarbonate (100 mL), the solvent was removed under vacuum and the residue was extracted with ethyl acetate (3×100 mL), the combined organic layer was washed with brine (2×150 mL) and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (2% to 5% ethyl acetatepetroleum ether) to give 7-2 as a colorless oil (4.86 g, 45%).
To a stirred solution of S2 (205 mg, 1.33 mmol, 1.0 qeuiv.) in anhydrous tetrahydrofuran (10 mL) was added methyllithium (1.3 M solution in diethyl ether, 1.53 mL, 2.0 mmol, 1.5 equiv.) dropwise at -78 o C under N 2 , the resulting mixture was stirred at -78 o C until TLC showed S2 was consumed completely. Then the reaction was quenched with saturated ammonium chloride (10 mL), the mixture was extracted with ethyl acetate (3×10 mL), the combined organic layer was washed with brine (2×15 mL) and dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated under vacuum. The residue was drained completely with oil pump and dissolved in dichloromethane (10 mL), then pyridinium chlorochromate (1.14 g, 5.3 mmol, 4.0 equiv.) was added to the above mixture, the resulting mixture was stirred at rt until TLC showed no material was remaining. The reaction mixture was filtered through a short pad of column chromatography and rinsed with ethyl acetate, the filtrate was concentrated under vacuum.