Letter pubs.acs.org/OrgLett
Enantio- and Diastereoselective Betti/aza-Michael Sequence: Single Operated Preparation of Chiral 1,3-Disubstituted Isoindolines Shinobu Takizawa,*,† Makoto Sako,† Mohamed Ahmed Abozeid,† Kenta Kishi,† H. D. P. Wathsala,† Shuichi Hirata,† Kenichi Murai,‡ Hiromichi Fujioka,‡ and Hiroaki Sasai† †
The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita-shi, Osaka 565-0871, Japan
‡
S Supporting Information *
ABSTRACT: The first enantio- and diastereoselective Betti/ intramolecular aza-Michael sequence carried out using a C3symmetric chiral trisimidazoline organocatalyst is reported. The reaction of phenols and N-tosylimines bearing a Michael acceptor moiety afforded densely functionalized 1,3-disubstituted isoindolines bearing two stereogenic centers as single diastereomers in high yields (≤93%) and excellent enantioselectivities (≤99.9%). ince the first definition of the domino process by Tietze,1a,b development of enantioselective domino reactions using chiral catalysts (i.e., organocatalysts) has drawn much attention in organic synthesis because of their ability to easily construct complicated organic compounds from readily available starting materials under identical reaction conditions in a single operation.1c−e Organocatalyzed domino processes are currently utilized in the synthesis of a range of natural products, agrochemicals, and pharmaceuticals.2 Isoindolines are common structural motifs in a variety of natural products and pharmaceuticals, such as pagoclone,3a nuevamine,3b and their functionalized derivatives (see Figure 1),4
S
Enantioselective Betti reaction (a Friedel−Crafts-type reaction between imines and phenols) is an important approach in the preparation of optically active α-aminomethylphenols,9,10 which are commonly found in a range of biologically active compounds11 and are employed in various asymmetric transformations.12 The first reported enantioselective Betti reaction was presented by Hui,9a who employed a stoichiometric amount of a chiral zinc complex as a catalyst. Further contributions have since been made by Wang,9b Chimni,9c,d Qu,9e SohtomeNagasawa,9f Feng,9g and some of the present authors.9h,i In addition, Khan9j,k demonstrated preparation of recyclable chiral dinuclear Cu(II) catalysts from chiral diethyl tartrate. Recently, Pedro9l,m and the Wang and Xie group9n independently reported the elegant and highly enantioselective cinchona alkaloid-derived organocatalyzed Betti reaction of ketimine. However, to the best of our knowledge, no examples of a domino reaction initiated by a Betti process have been reported to date. To explore enantioselective domino processes,13 we were interested in designing a Betti cascade reaction to access important structural motifs. We envisioned that N-tosylimine 1 (incorporating a Michael acceptor moiety at the o-position) and phenol 2 would produce the Betti intermediate 3 in the presence of an appropriate organocatalyst, which would then undergo an aza-Michael reaction to yield the chiral 1,3-disubstituted isoindoline 4 (Scheme 1). Thus, we report the first catalytic and highly enantioselective Betti/intramolecular aza-Michael domino reaction promoted by a multifunctional organocatalyst. Initially, we investigated the reaction of N-tosylimine 1a with sesamol (2a) as prototypical substrates in the presence of various chiral catalysts (5−8), which are known to mediate the enantioselective Betti process (Table 1).9 Use of O-benzoylcupreine (5)9c promoted the reaction in both an enantio- and a
Figure 1. Examples of biologically active and natural compounds containing the isoindoline moiety.
and as such, these compounds exhibit a range of biological activities, including anxiolytic, antileukemic, antitumoral, and potent endothelin A receptor antagonist activities.3,4 Due to the potential application of isoindolines, development of novel new and efficient synthetic protocols for this heterocyclic system has received particular attention.5,6 However, to date, only a few reports have described the catalytic synthesis of 1,3-disubstituted isoindolines in racemic7 or optically active forms.8 © 2017 American Chemical Society
Received: August 30, 2017 Published: September 28, 2017 5426
DOI: 10.1021/acs.orglett.7b02693 Org. Lett. 2017, 19, 5426−5429
Letter
Organic Letters
(R = tBu), 8c (R = 2,3-Me2-C6H3),15c and 8d (R = 2-MeO-C6H4) suppressed the intramolecular aza-Michael process, giving acyclic 3a as the major product (entries 5−7). When catalysts 6 and 8b were employed, lower enantioselectivities of 3a were observed compared to those of 4a. These results indicate that the kinetic resolution of 3a8d,16 occurred during the aza-Michael step. Tuning the steric bulkiness and basicity of the trisimidazoline organocatalysts confirmed that 8e (R = 4-MeO-C6H4)9i efficiently promoted the Betti/intramolecular aza-Michael sequence to produce the desired 4a in 92% yield and 99.9% ee as a single diastereomer (entry 8). In contrast, use of the less basic trisimidazoline organocatalyst 8f resulted in a significantly reduced yield and enantioselectivity of the desired product 4a. With the optimized reaction conditions in hand, we evaluated the substrate scope and limitations of this transformation (Scheme 2). Excellent enantioselectivities of 4b−4g (86−99.9%
Scheme 1. Catalytic and Enantioselective Synthesis of 1,3Disubstituted Isoindolines Using a Betti/aza-Michael Domino Reaction (PG: Protecting Group)
Table 1. Catalyst Screeninga
Scheme 2. Scope of the Betti/Aza-Michael Sequence*
entry catalyst 1 2 3 4 5 6 7 8 9
5 6 7 8a 8b 8c 8d 8e 8f
ratio of 3a/4ab
total isolated yield (%)
ee of 3a and 4a (%)b
1:2.3 1:2.2 99 1:2.4 1.6:1 1.1:1 >99:1:>99 >1:>99
39 51 66 67 46 44 27 92 63
90(S), 90(S,S) rac, 99.0(R,R)14 −, 62(S,S)c 94(R), 97(S,S) 19(R), 91(S,S) 97(R), 98(S,S) 72(R), − −, 99.9(S,S) −, 67(S,S)
a
Reaction conditions: 1a (0.05 mmol), 2a (0.1 mmol), and catalyst (10 mol %) in dry toluene (0.2 mL). bDetermined by HPLC (Daicel Chiralpak ID). ccis/trans = 85.5:14.5. rac = racemic.
*
Reaction conditions: 1 (0.05 mmol), 2a (0.1 mmol), catalyst 8e (10 mol %) in dry toluene (0.2 mL). a1.0 mmol scale for 2a. bAt −15 °C for 96 h cIn dry DCM/toluene (1:1) (0.2 mL) at 35 °C for 72 h.
ee) were achieved upon variation of the ester R1 group [i.e., Et (1b) and Bn (1c)] and the N-sulfonyl R2 group [i.e., Ph (1d), 4NO2-C6H4 (1e), PMP (1f), and 4-Cl-C6H4 (1g)] in the substrates. In addition, C3-symmetric chiral trisimidazoline 8e promoted reaction of 2a with various substituted aromatic imines [R3 = 3,4-(−CH−)4 (1h), 5-Cl (1i), 5-F (1j), 5-Me (1k), and 4MeO (1l)] to afford the corresponding isoindolines 4h−4l in high enantioselectivities (71−98% ee). However, the use of Ntosylimine 1m containing a β,β-disubstituted α,β-unsaturated ester completely suppressed the aza-Michael reaction, likely due to the steric bulk of this substrate, and thus, the desired product 4m was not formed. We then shifted our attention to the substrate scope of phenolic substrate 2. As shown in Scheme 3, various substituted 1- and 2-naphthols were employed to give products 4n−4v in good yields (69−93%) and ≤99.3% ee, regardless of the electronic nature of the substrate. 3-Dimethylaminophenol was successfully converted to 4w under the optimized reaction conditions, although the yield was slightly reduced. As a lower enantioselectivity and catalytic activity were observed using bisimidazoline 9 and monoimidazoline 10 as catalysts (Scheme
diastereoselective manner (90% ee and a single diastereomer, entry 1); however, isoindoline 4a and the precursor 3a were obtained in only 39% total yield. The Michael addition of 2a to the α,β-unsaturated carbonyl group was not observed. Although thiourea-based organocatalysts 69l and 79e gave superior results to catalyst 5 (entries 2 and 3), yields of 4a remained unsatisfactory. During the screening of the various chiral catalysts,14 the C3symmetric chiral trisimidazoline 8a (R = Ph) gave promising results (entry 4),15 yielding a mixture of 3a and 4a in 67% total yield and 94 and 97% ee, respectively. To improve the yield of 4a, various substituted derivatives of 8 were also tested. Catalysts 8b 5427
DOI: 10.1021/acs.orglett.7b02693 Org. Lett. 2017, 19, 5426−5429
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Organic Letters Scheme 3. Scope of the Betti/Aza-Michael Sequence*
Scheme 5. Plausible Reaction Mechanism
highly functionalized Betti/aza-Michael product 4a, a variety of transformations were performed (Scheme 6). For example, Scheme 6. Synthetic Transformations of (S,S)-4a
* Reaction conditions: 1a (0.05 mmol), 2 (0.1 mmol), and catalyst 8e (10 mol %) in dry toluene (0.2 mL). aAt 25 °C for 48 h.
4), it became apparent that the three chiral imidazoline units on 8a constructed an optimal chiral environment,15e with the presence Scheme 4. Domino Reaction Catalyzed by 9 and 10
alcohol 11 was formed by LiAlH4 reduction of 4a, and subsequent treatment of this alcohol with lithium naphthalenide19 resulted in cleavage of the N-Ts group to provide the unstable amino alcohol 12. Nuevamine analogue20 13 was then obtained by cyclization of 12 with paraformaldehyde. Finally, 4a was easily hydrolyzed to the cyclic β-amino acid derivative 14 in the presence of LiOH in aq THF at 0 °C, and the high enantiopurity of the starting material 4a was maintained in the product. In summary, we developed a highly atom-economical, chemo-, diastereo-, and enantioselective approach to medicinally important 1,3-disubstituted isoindolines via an organocatalytic Betti/intramolecular aza-Michael reaction. We also demonstrated the potential of the obtained product for transformation into a variety of derivatives, thereby indicating the potential synthetic utility of our reported transformation. Further studies to extend the scope of this reaction and clearly determine the exact reaction mechanism are underway and will be reported in due course.
of three equally aligned reaction sites, to ultimately enhance the catalytic activity and promote asymmetric induction in the Betti and intramolecular aza-Michael processes. The relative and absolute configurations of 4a were then determined by NMR spectroscopic and X-ray crystallographic analysis (CCDC No. 1556651). The results indicated that the Betti/intramolecular aza-Michael domino reaction was cis-selective, resulting in the formation of S,S-configured 4.17 Based on the obtained results (1H NMR experiments; see Supporting Information), a plausible mechanism for the chiral trisimidazoline 8e-catalyzed domino reaction was then proposed (Scheme 5). Initially, an imidazoline nitrogen atom of 8e is protonated by 2a, allowing the other imidazoline group to interact with the oxygen atom of the hydroxy group in another molecule of 2a, thereby leading to tight ion-pair aggregation.15a,b,f,18 Subsequent attack of the generated chiral nucleophile to 1a would form Betti adduct 3a via an intermediate exhibiting the least steric hindrance between the 4-methoxyphenyl moiety of the catalyst and the fused aromatic ring of the substrate. Reaction using (S)-8e favors the generation of (S)-3a. Finally, 4a is produced via the chiral trisimidazoline-mediated intramolecular aza-Michael reaction. To demonstrate the synthetic utility of the
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02693. Experimental procedures, characterization data, NMR spectra, and HPLC traces for all new compounds (PDF) X-ray data for (S,S)-4a (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. 5428
DOI: 10.1021/acs.orglett.7b02693 Org. Lett. 2017, 19, 5426−5429
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Organic Letters ORCID
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Shinobu Takizawa: 0000-0002-9668-1888 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Nos. JP16K08163 (C), JP16H01152 (Middle Molecular Strategy), and JP17H05373 (Coordination Asymmetry), and to the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the JSPS, the CREST project of the Japan Science and Technology Corporation (JST), and the JST Advanced Catalytic Transformation Program for Carbon Utilization (ACT-C) Grant No. JPMJCR12YK. K.K. thanks the Grant-in-Aid for JSPS Research Fellow. We acknowledge the technical staff of the Comprehensive Analysis Center of ISIR, at Osaka University (Japan).
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DOI: 10.1021/acs.orglett.7b02693 Org. Lett. 2017, 19, 5426−5429
