Highly Enantioselective Rh-Catalyzed Intramolecular Alder–Ene Reactions for the Syntheses of Chiral Tetrahydrofurans

Abstract

Over 99 % ee was obtained for all the tested substrates in a Rh-catalyzed Alder–ene reaction. Simply mixing air-stable, commercially available [{Rh(cod)Cl}2] (cod=1,5-cyclooctadiene) and 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl (binap) at room temperature afforded functionalized and chiral tetrahydrofurans in high yields with high efficiency (turnover frequency: 1500 h−1). The catalyst loading was as low as 0.8 mol %. Alder–ene reactions are a powerful way to construct carbon–carbon bonds. The intramolecular version of these reactions can provide efficient routes to produce a variety of heterocyclic and carbocyclic compounds.1 Since the thermal Alder–ene reaction requires high temperature, it has found limited applications in organic syntheses. In contrast, transition-metal-catalyzed Alder–ene reactions can be performed under mild conditions and therefore are widely applied to organic syntheses.2 However, the enantioselective processes of metal-catalyzed Alder–ene reactions are relatively unexplored and the development of highly efficient catalysts still remains a great challenge.3 Recently, we have developed Rh-catalyzed intramolecular Alder–ene reactions of enynes using a [{Rh(diphos)Cl}2] precursor.4 Enantioselectivities between 65–98 % ee were obtained by using 1,2-bis(phospholano)benzene (Duphos), (2R,2′R)-bis(diphenylphosphanyl)-(1R,1′R)-dicyclopentane (BICP), or the related (2R,2′R)-bis(diphenylphosphinite)-(1R,1′R)-dicyclopentane (BICPO) as chiral ligands.4a Herein, we report a significant improvement of the catalytic system for these reactions. The new catalysts are prepared in situ by simply mixing a commercially available metal precursor and a ligand. Over 99 % ee has been achieved for a number of substrates. To achieve high enantioselectivities for Rh-catalyzed Alder–ene reactions, we have screened a number of chiral phosphane ligands. The enyne 1 a was chosen as a standard substrate to optimize the reaction conditions and the results are given in Table 1 Entry RhI T Additive Conversion [%][b] 1 [{Rh(cod)Cl}2] RT AgSbF6 <5 2 [{Rh(cod)Cl}2] 65 °C AgSbF6 <5 3 [Rh(cod)2]SbF6 RT none <5 4 [Rh(cod)2]SbF6 65 °C none <5 5 [Rh(nbd)Cl]2 RT AgSbF6 <5 6 [Rh(nbd)Cl]2 65 °C AgSbF6 100(65) 7 [Rh(nbd)2]SbF6 RT none <5 8 [Rh(nbd)2]SbF6 65 °C none 100(60) 9 [{Rh(cod)Cl}2]/rac-C4-Tunaphos RT AgSbF6 100(98) 10 [{Rh(cod)Cl}2]/rac-BINAP RT AgSbF6 100(99) 11 [{Rh(cod)Cl}2]/PPh3 RT AgSbF6 <5 12 [RhCl(PPh3)3] RT AgSbF6 <5 13 [{Rh(cod)Cl}2]/dppb RT AgSbF6 <5 14 [{Rh(cod)Cl}2]/dppbO RT AgSbF6 <5 15 [{Rh(cod)Cl}2]/rac-BICPO RT AgSbF6 <5 . In the absence of phosphane ligand, [{Rh(cod)Cl}2] was an ineffective catalytic precursor at either room temperature or 65 °C (Table 1, entries 1 and 2). However, [{Rh(nbd)Cl}2] (nbd=norbornadiene) can be used as a catalyst precursor at 65 °C (Table 1, entry 6). Using the Cn-Tunaphos ligands developed by our group,5 high efficiency was observed. When rac-C4-Tunaphos was used as the ligand in the presence of [{Rh(cod)Cl}2] and AgSbF6, high conversion (100 %) and a high yield (98 %) were obtained at room temperature within 20 min (Table 1, entry 9). Control experiments indicated that there were big differences between this new catalytic system and the earlier protocol developed by us using [{Rh(diphosphane)Cl}2] as catalytic precursor. We previously reported that [{Rh(BINAP)Cl}2] (BINAP= 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl) was inactive towards the Alder–ene reaction. In contrast to our earlier report, rac-BINAP was found to be an efficient ligand in this new catalytic system for Rh-catalyzed Alder–ene reactions; 100 % conversion and 99 % yield were obtained within 5 min at room temperature by simply mixing [{Rh(cod)Cl}2] and rac-BINAP (Table 1, entry 10).6 Further changes in catalysts and ligands showed that some systems did not work (Table 1, entries 11–15).7 Encouraged by these results, we focused our studies on the asymmetric Rh-catalyzed Alder–ene reaction. All Cn-Tunaphos5 (n=1–6) were effective ligands, and highly enantioselective products (>99 % ee) were obtained (Table 2 Entry L* Conversion[b] ee [%][c] 1 3 100 99.2 2 4 80 99.3 3 5 100 >99.9 4 6 100 >99.9 5 7 100 99.2 6 8 100 99.3 7 9 100 98.3 8 10 100 >99.9 , entries 1–6). It is noteworthy that extremely high enantioselectivities were achieved when (S)-C3-, (S)-C4-Tunaphos, and (S)-BINAP were used as ligands (Table 2, entries 3,4, and 8). With the optimized conditions in hand, we screened the reaction with a variety of enyne substrates (Table 3 Entry 1 R R1 2 Yield [%][b] ee [%][c] 1 1 a Ph Et (−)-2 a 96 >99.5 2 1 b Ph H (−)-2 b 96 >99.5 3 1 c C6H4(o-Cl) H (−)-2 c 95 99.0 4 1 d C6H4(m-Cl) H (−)-2 d 92 99.5 5 1 e C6H4(p-Cl) H (−)-2 e 95 >99.9 6 1 f C6H4(p-Me) H (−)-2 f 94 99.9 7 1 g C6H4(p-CF3) H (−)-2 g 93 99.1 8 1 h Me Me (−)-2 h 82 >99.9 9 1 i nBu H (−)-2 i 89 >99.9 ). Using enantiomerically pure BINAP as the ligand, high enantioselectivities were achieved with most tested substrates (Table 3, entries 1–6). Reactions of an enyne bearing an aryl terminal group were completed within 20 min at room temperature; high yields and over 99 % ee were achieved. Enyne substrates with an alkyl group were more reactive than enyne substrates with an aryl terminus (Table 3, entries 8 and 9); these reactions were completed less than 5 min. To broaden the substrate scope, we introduced ketone (Table 4 Entry 11 R 12 Yield [%][b] ee [%][c] 1 11 a Me (+)-12 a 86 99.5 2 11 b Ph (+)-12 b 99 >99.9 3 11 c EtO (+)-12 c 82 >99.9 Highly enantioselective Alder–ene reactions of enynes substituted at the allylic terminus. To test the catalytic efficiency of the reaction, a low catalyst loading was employed: In the presence of 1 mol % [{Rh(cod)Cl}2] and 2 mol % (S)-BINAP, the cycloisomerization of 1 h was complete at room temperature within 2 min in 99 % conversion (turnover frequency (TOF): 1500 h−1). The product (+)-2 h was obtained in over 99.9 % ee. Further experimentation showed that the reaction could be done with lower catalyst loading. In the presence of 0.4 mol % [{Rh(cod)Cl}2] and 0.8 mol % (S)-BINAP, this reaction was complete within 35 min with no decrease in enantioselectivity. In conclusion, we have developed a highly efficient Rh-catalyzed Alder–ene reaction for preparing a variety of chiral tetrahydrofurans using an air-stable [{Rh(cod)Cl}2] precursor with commercially available BINAP or the Cn-Tunaphos ligands. Functionalized tetrahydrofurans were obtained in high yields and over 99 % ee for all the substrates we tested. Syntheses of other functionalized carbocycles and heterocycles such as lactams and pyrrolidines are in progress and will be reported in due course. The procedure for the asymmetric alder–ene reaction of 1 b catalyzed by rhodium (2 b):4 In a dried Schlenk tube, [{Rh(cod)Cl}2] (4.9 mg, 0.01 mmol) and (S)-BINAP (13.8 mg, 0.022 mmol) were dissolved in freshly distilled 1,2-dichloroethane (2 mL), then freshly prepared 1 b (37.2 mg, 0.2 mmol) was added to the solution at room temperature under nitrogen. After the mixture had been stirred for 1 min, AgSbF6 (0.04 mmol) was added, and the reaction was complete within 5 min. The reaction mixture was directly subjected to column chromatography. Compound 2 b (35.8 mg, 96 % yield, >99.9 % ee) was obtained. The ee value was determined by GC with chiral select 1000 at 150 °C. [α]D=23.85 (c=0.5, CHCl3); 1H NMR (400 MHz, CDCl3): δ=7.33–7.29 (m, 2 H), 7.22–7.18 (m, 1 H), 7.12–7.10 (m, 2 H), 6.24( s, 1 H), 5.70–5.65 (m, 1 H), 5.2–5.16 (m, 2 H), 4.77 (d, J=14.0 Hz, 1 H), 4.64 (d, J=14.0 Hz, 1 H), 4.15 (t, J=7.7 Hz, 1 H), 3.60–3.48 ppm (m, 2 H); 13C NMR (90 MHz, CDCl3): δ=144.1, 137.6, 137.1, 128.9, 128.3, 127.1, 122.5, 118.1, 72.8, 70.7, 51.1 ppm. Dedicated to Professor Robert H. Grubbs on the occasion of his 60th birthday