Organic & Biomolecular Chemistry

Organic & Biomolecular Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/obc Page 1 of 7 OrganicPlease & Biomoleculardo not adjust margins Chemistry Journal Name ARTICLE Enantioselective organocatalyzed aza-Morita −Baylis−Hillman reaction of isatin-derived ketimines with acrolein a a a a b Received 00th January 20xx, Yasushi Yoshida, Makoto Sako, Kenta Kishi, Hiroaki Sasai, Susumi Hatakeyama and Shinobu Manuscript Accepted 00th January 20xx Takizawa* a DOI: 10.1039/x0xx00000x A highly enantioselective aza-Morita−Baylis−Hillman (aza-MBH) reaction of isatin-derived ketimines with acrolein was established using β-isocupreidine (β-ICD) or α-isocupreine (α-ICPN) as a chiral acid-base organocatalyst. The present www.rsc.org/ protocol readily furnished (S) or (R)-aza-MBH adducts with a chiral tetrasubstituted carbon stereogenic center in up to 98% ee. reaction of isatin-derived ketimine 1a with 2 (Table 1). Introduction Chiral 3-amino-2-oxindoles are important structural motifs found in Accepted various biologically active compounds such as nelivaptan (SSR- 149,415), an orally active non-peptide vasopressin receptor antagonist, and AG-041R, a gastrin/cholecystokinin-B receptor 1 antagonist (Figure 1). To date, considerable efforts have been devoted to the development of efficient strategies to synthesize chiral 3-amino-2-oxindoles. 2 Among them, the enantioselective aza- 3 Morita−Baylis−Hillman (aza-MBH) reaction of isatin-derived ketimines gives highly functionalized 3-amino-2-oxindoles having a 4-7 chiral tetrasubstituted carbon stereogenic center. In 2013, Shi and Li reported the aza-MBH reaction of N-tert -butoxycarbonyl (Boc) protected ketimines 1 with methyl vinyl ketone using chiral 4 Fig. 1 Bioactive products with a 3-amino-2-oxindole skeleton. Chemistry acid-base organocatalysts. Sha and Wu also discovered that chiral phosphine-squaramide promoted the aza-MBH reaction of acrylates 5 with 1-Me protected isatin-derived ketimines. In 2015, Chimni Scheme 1 Enantioselective organocatalyzed aza-MBH reaction of found that maleimides were appropriate nucleophilic partners for 6 isatin-derived ketimines 1 with 2. the aza-MBH process. However the efficient enantioselective construction of 3-amino-2-oxindoles possessing a tetrasubstituted carbon stereogenic center via the aza-MBH reaction has been a challenge in catalytic asymmetric synthesis. Herein, we report enantiodiscriminating aza-MBH processes of isatin-derived ketimines 1 with acrolein (2) using β-isocupreidine (β-ICD)8a-c or α- 8d isocupreine ( α-ICPN) as natural alkaloid-derived chiral acid-base organocatalysts (Scheme 1). The present protocol with β-ICD or α- ICPN selectively gave (S) or (R)-adduct 3 in up to 98% ee. Biomolecular Results and discussion First, we studied the effect of solvent and temperature on the & Organic This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins OrganicPlease & Biomoleculardo not adjust margins Chemistry Page 2 of 7 ARTICLE Journal Name Table 1 Optimization of the reaction conditions.a Entry Solvent Chiral organocatalyst Temp. ( oC) Yield (%) b ee (%) c 1 toluene β-ICD -15 54 89 2 CH 2Cl 2 β-ICD -15 51 64 3 THF β-ICD -15 62 80 4 CPME d β-ICD -15 58 87 5 toluene β-ICD 10 e 27 93 6 toluene β-ICD -10 65 88 Manuscript 7 toluene β-ICD -20 53 90 8 toluene β-ICD -40 46 94 9 toluene β-ICD -60 19 97 10 toluene /CPME = 1/1 β-ICD -40 60 94 11 toluene /CPME = 1/1 4 -40 Trace - 12 toluene /CPME = 1/1 5 -40 16 90 13 toluene /CPME = 1/1 6 -40 35 80 a 1a (0.06 mmol) in the stated solvent (0.05 M for 1a ), chiral organocat alyst (0.012 mmol) and 2 (0 .18 mmol) were stirred for 48 h . b1 H-NMR yield of product 3a using 1,3,5-trimethoxybenzene as an internal standard. cDetermined by HPLC (Daicel Chiralpak IE). d Cyclopentyl methyl ether (CPME). Accepted eOver reaction of 3a with 2 was observed. N PPh N PPh2 2 OH OH OH OH OH 4 5 6 During the initial solvent screening (-15 oC, 20 mol % β-ICD), we 2). 5 The aza-MBH product 3a was also able to be converted into allyl found that the reaction proceeded better in toluene or cyclopentyl alcohol derivatives 7b and 9 (Scheme 3). Chemistry methyl ether (CPME) than in other solvents such as CH 2Cl 2 and THF (entries 1−4). Next we investigated the effect of the reaction temperature. Decreasing the reaction temperature to -40 oC gave 3a in an acceptable yield (46%) with 94% ee (entry 8). When the reaction was performed at 10 oC or -60 oC, 3a was obtained in low yields because of either over reaction of 3a with 2 (involving polymerization of 2)9 (entry 5) or low conversion (entry 9), respectively. Finally, we discovered that the use of mixed-solvent system toluene/CPME (1/1) for the aza-MBH reaction of 1a with 2 at -40 oC gave 3a in 60% yield with 94% ee (entry 10). Chiral acid- base organocatalysts 4−6, which are known to mediate enantioselective aza-MBH processes,10 were virtually ineffective at improving the chemical yields and ee values for 3a (entries 11−13). The optimal result ( 3a : 81% yield, 97% ee) was obtained when the reaction of 1a and 2 (2.0 eq.) was performed with β-ICD (15 mol %) Biomolecular in toluene/CPME (1/1; 0.05 M with respect to 1) at -40 °C in the presence of 3Å molecular sieves (MS3A) as an additive (Table 2, & entry 1). N-Substituted ketimines 1b −1d (R 1 = allyl, Ph, prenyl) were transformed to 3b −3d in 48−70% yields with excellent enantioselectivities (95−98% ee) (entries 3−5). Ketimines 1e−1j bearing an electron-withdrawing or electron-donating substituent on the aromatic ring also afforded the corresponding aza-MBH adducts 3e−3j in 68−83% yields with excellent enantioselectivities (95−98% ee) (entries 6−11). The absolute configuration of 3k was assigned as S by comparison with the optical rotation and HPLC data of allyl alcohol 7a derived from known compound 3l (Scheme Fig. 2 Plausible model of enantioselection. Organic 2 | J. Name ., 2012, 00 , 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 7 OrganicPlease & Biomoleculardo not adjust margins Chemistry Journal Name ARTICLE Table 2 Substrate scope in the aza-MBH reaction catalyzed by β-ICD or α-ICPN.a Entry β-ICD or α-ICPN 1 Yield (%) b ee (%) c 1 2 1 β-ICD 1a , R = H , R = Bn 3a , 81 97 ( S) 2d β-ICD 1a 3a , 76 97 ( S) 1 2 3 β-ICD 1b, R = H , R = allyl 3b, 70 96 ( S) 1 2 4 β-ICD 1c, R = H, R = Ph 3c, 52 98 (S) 1 2 Manuscript 5 β-ICD 1d, R = H, R = prenyl 3d, 48 95 (S) 1 2 6 β-ICD 1e, R = 5 -Cl , R = Bn 3e, 68 98 ( S) 1 2 7 β-ICD 1f, R = 6 -Cl , R = Bn 3f, 83 98 ( S) 1 2 8 β-ICD 1g, R = 7 -Cl , R = Bn 3g, 81 97 ( S) 1 2 9 β-ICD 1h, R = 5 -Br , R = Bn 3h, 73 96 ( S) 1 2 10 β-ICD 1i, R = 5 -F, R = Bn 3i, 78 98 ( S) e 1 2 11 β-ICD 1j, R = 5 -Me , R = Bn 3j, 77 95 ( S) 1 2 12 α-ICPN 1a , R = H , R = Bn 3a , 78 95 ( R) 1 2 13 α-ICPN 1b, R = H , R = allyl 3b, 59 90 ( R) 1 2 14 α-ICPN 1c, R = H, R = Ph 3c, 37 87 ( R) 1 2 15 α-ICPN 1d, R = H, R = prenyl 3d, 44 89 (R) 1 2 Accepted 16 α-ICPN 1e, R = 5 -Cl , R = Bn 3e, 74 87 ( R) 1 2 17 α-ICPN 1g, R = 7 -Cl , R = Bn 3g, 44 94 (R) 1 2 18 α-ICPN 1h, R = 5 -Br , R = Bn 3h, 79 88 ( R) f 1 2 19 α-ICPN 1j, R = 5 -Me , R = Bn 3j, 58 96 ( R) 1 2 20 α-ICPN 1k, R = H, R = Me 3k, 45 83 (R) 21 β-ICD or α-ICPN 1m, R1 = 4 -Cl, R 2 = Bn 3m , T race - 22 β-ICD or α-ICPN 1n , R1 = R 2 = H 3n , T race - a o 1 (0.06 mmol) in toluene/CPME (1/1, 0.05 M for 1), β-ICD or α-ICPN (0.009 mmol) and 2 (0.12 mmol) were stirred for 96 h at -40 C, unless otherwise noted. bIsolated product yield.

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