Letter Cite This: Org. Lett. 2018, 20, 248−251
pubs.acs.org/OrgLett
CuH-Catalyzed Asymmetric Intramolecular Reductive Coupling of Allenes to Enones Yun-Xuan Tan,†,∥ Xiao-Qi Tang,†,‡,∥ Ping Liu,† De-Shen Kong,†,§ Ya-Li Chen,*,‡ Ping Tian,*,†,§ and Guo-Qiang Lin*,†,§ †
Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China § Institute of Innovative Chinese Medicine (ICM), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China S Supporting Information *
ABSTRACT: The CuH-catalyzed asymmetric intramolecular reductive coupling of allenes to enones is successfully realized, providing cis-hydrobenzofurans with promising yields and excellent enantioselectivities. Such brilliant enantioselectivities are partially contributed by CuH-catalyzed favorable kinetic resolution of the cyclization products. This protocol tolerates a broad range of functional groups, allowing for further construction of tricyclic and bridged-ring structures. Moreover, the meta-chiral functionalization of 4-substituted phenol and asymmetric dearomatization modification of phenol-contained bioactive molecules are also described.
O
(enone-tethered allenes), enabled by in situ generated chiral ligand-bound CuH catalysts to furnish the optically pure cyclization products. As for enone-tethered allenes,10 the neighboring steric repulsion impedes the direct 1,4-reduction of CuH to enone; thus, the regioselective insertion of terminal allene to CuH consequently occurs in the first and places the Cu at the less hindered site of the allene to form α-substituted allylcopper intermediate T (Scheme 1, eq 3). One major concern for the following cyclization process is the potential β-oxygen elimination pathway.11 In our control experiment, the CuHcatalyzed hydrogenation of α-benzyloxymethyl allene only afforded semireduction product, suggesting that a β-oxygen elimination process would not take place easily.12 Subsequently, the α-substituted allylcopper undergoes preferential intramolecular α-addition rather than γ-addition to enone, simultaneously generating three consecutive stereogenic centers in cis-hydrobenzofuran products. However, the remote stereocontrol (1,8-asymmetric induction) of such addition process in a diastereo- and enantioselective manner remains quite challenging. Thus, successful implementation of this strategy requires a powerful catalyst capable of efficient hydrocupration of the allene and, more importantly, the effective enantiotopic facial discrimination of the enone moiety. With these considerations in mind, a set of privileged nonracemic ligands in asymmetric CuH chemistry were
ver the past two decades, asymmetric copper hydride (CuH) chemistry has blossomed and become an attractive alternative to related C−C bond formations. It delivers hydride asymmetrically at newly created sp3 centers with absolute stereocontrol, while early studies tended to focus on simple 1,2- and 1,4-reduction.1 Very recently, a significant breakthrough has been achieved, demonstrating that the transient nucleophilic alkylcopper species can be in situ generated via unactivated alkenes insertion to CuH and intercepted with a range of electrophiles (Scheme 1, eq 1).2−6 Currently, the asymmetric reductive coupling strategy has been extended to hydroallylation of alkynes.7 However, as for allenes, major efforts were devoted to the racemic reductive coupling reaction in the primary literature, and an asymmetric version is still unavailable to the best of our knowledge.8 Herein, we report the first asymmetric intramolecular reductive coupling of allenes to enones through a CuH-based strategy. The insertion of terminal allenes to CuH produces the nucleophilic α-substituted allylcopper complexes. A handful of their racemic post-transformations using different electrophiles, allyl halides for allylic substitution,8c CO2, and imines, for allylic addition has been reported (Scheme 1, eq 2).8a,b Among them, there are only two asymmetric entries, and promising levels of enantioselectivities (ee ≤85%) have been described. 8b Compared to the simple and β-substituted allylcopper nucleophiles,9 the absolute stereocontrol in the asymmetric conversion of α-substituted (β-nonsubstituted) allylcopper intermediates becomes more challenging.9c We hypothesized that such a challenge could be addressed through the intramolecular reductive coupling of allenes to enones © 2017 American Chemical Society
Received: November 21, 2017 Published: December 15, 2017 248
DOI: 10.1021/acs.orglett.7b03608 Org. Lett. 2018, 20, 248−251
Letter
Organic Letters Table 1. Selected Optimization Studiesa
Scheme 1. Strategic Design
evaluated for this catalytic asymmetric intramolecular reductive coupling using enone-tethered allene 1a, and selected results are summarized in Table 1.12 The use of (R)-Binap L1 as ligand afforded the desired product 3a in good yield but with poor enantioselectivity (Table 1, entry 1), and further reduction of 3a by the CuH catalyst was also observed to generate two side products, ketone 4a and alcohol 5a. Next, several bisphosphine ligands L8,3,5 L9, L16, L21,3a and L294,6 were subjected to this reaction, and only (R,R)-iPr-DuPhos L21 gave a promising yield and ee value (Table 1, entry 5 vs entries 2−4). Lowering the reaction temperature resulted in slight improvement of enantioselectivity (Table 1, entries 7 and 8), but increasing DEMS loading led to great enhancement of enantioselectivities (Table 1, entries 9−11). In particular, excellent enantioselectivity was achieved when 2.2 equiv of DEMS was used (Table 1, entry 11). The moderate yield was mainly caused by further reduction of 3a, which is considered as a favorable kinetic resolution process. With the optimal conditions identified, we next evaluated the scope of enone-tethered allenes 1. With the R1 substituent as an alkyl, cycloalkyl, vinyl, allyl, benzyl, or phenyl group, the reactions proceeded smoothly with moderate yields and high to perfect enantioselectivities (Scheme 2, 3a−j, ee up to 99%). The absolute configuration of the cyclization product 3j was unambiguously established as (3R,3aS,7aS) by X-ray crystallography. With a heteroatom O, N, Br, and I as part of the R1 substituent in substrates 1, the ee values remained at excellent levels (Scheme 2, 3k−r, ee = 97−99%). It was particularly noted that the highly reactive bromo- and iodoalkyl groups were comfortably tolerated without any observation of nucleophilic substitution product (Scheme 2, 3q and 3r).13 For α-methylenone-tethered allene 1s, the corresponding cyclization product 3s was obtained in much higher yield (95%) and with high enantioselectivity. To confirm that the further reduction of cyclization products was a favorable kinetic resolution process, i.e., the minor enantiomer of the cyclization product was consumed faster by
entry
L
X
temp (°C)
time (h)
convb (%)
yieldc (%)
eed (%)
1 2 3 4 5 6 7 8 9 10 11
L1 L8 L9 L16 L21 L29 L21 L21 L21 L21 L21
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.5 2.0 2.2
0 0 0 0 0 0 −20 −40 −40 −40 −40
12 12 12 12 12 12 24 48 48 48 48
97 90 85 100 88 75 84 81 98 100 100
78 30 51 81 60 31 55 67 65 51 43
39 7 −5 −35 52 −50 60 57 68 86 95
a
Reactions were performed under an Ar atmosphere. bDetermined by H NMR analysis of unpurified mixtures. cYield of isolated product 3a. d Determined by HPLC analysis. DEMS = diethoxymethylsilane. 1
excessive DEMS, racemic cyclization product 3a was subjected to these reaction conditions. In line with our expectations, the remaining 3a was recovered with good enantioselectivity (ee = 82%, Scheme 3). This study clearly demonstrated that the further reduction was a favorable kinetic resolution process, and this can be used to explain excellent enantioselectivity could be achieved by using excessive DEMS (Table 1, entry 11). As revealed in Scheme 2, this mild protocol tolerates a wide range of functional groups, providing a flexible platform for further conversion. When 3r was treated with t-BuLi, the resulting alkyllithium underwent an intramolecular Michael addition to deliver the tricyclic product 6r (Scheme 4). In addition, an intramolecular alkylation occurred equally well to give the bridged-ring structure 7r upon treatment of 3r with LiHMDS. Under acidic conditions, the rearomatization of 3a afforded the optically enriched meta-substituted phenol 8a (Scheme 4). On the other hand, 1a was easily prepared from oxidative dearomatization of p-cresol.10 Thus, such a stepwise dearomatization, asymmetric cyclization, and rearomatization process presents a novel strategy for meta-chiral functionalization of 4substituted phenols.14 The phenol structure widely exists in numerous bioactive molecules. As for salidroside tetraacetate 9, the phenol moiety was similarly dearomatized to afford the enone-tethered allene substructure (Scheme 5).12 Through CuH-catalyzed asymmet249
DOI: 10.1021/acs.orglett.7b03608 Org. Lett. 2018, 20, 248−251
Letter
Organic Letters Scheme 2. Scope of Enone-Tethered Allenesa
Scheme 5. Asymmetric Dearomatization Modifications of Bioactive Molecules
This combination of dearomatization and asymmetric cyclization provided an alternative to catalytic asymmetric dearomatization strategy.15 Using the same procedure as above, the asymmetric dearomatization modification of estrone 13 also proceeded uneventfully to afford optically pure and pharmaceutically potential cis-hydrobenzofuran 15 (Scheme 5), whose absolute configuration was confirmed by X-ray crystallography. In summary, the first CuH-catalyzed asymmetric intramolecular reductive coupling of allenes to enones has been established through regioselective insertion of allenes to CuH and subsequent enantioselective addition to enones. This tandem reaction proceeded smoothly to furnish cis-hydrobenzofurans with promising yields and excellent enantioselectivities (ee up to 99%). Such brilliant enantioselectivities proved to be partially caused by further favorable kinetic resolution of the cyclization products, i.e., the in situ reduction of enone functionality. The cyclization products could be converted to tricyclic and bridged-ring structures. Additionally, meta-chiral functionalization of 4-substituted phenols and asymmetric dearomatization modification of phenol-contained bioactive molecules were presented. Our next challenge is to develop the intermolecular asymmetric version.
a
Reactions were performed under an Ar atmosphere. bYield of isolated product 3. cDetermined by HPLC analysis. d1.0 mmol of 1e was used. Boc = tert-butoxycarbonyl, TBS = tert-butyldimethylsilyl, and Ac = acetyl.
Scheme 3. CuH-Catalyzed Kinetic Resolution of (±)-3a
Scheme 4. Synthetic Transformations
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03608. Experimental procedures, spectra for all new compounds, and X-ray crystallographic data for compounds 3j and 15 (PDF) Accession Codes
CCDC 1572373−1572374 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ric cyclization, the optically pure cis-hydrobenzofuran derivative 12 was achieved with excellent diastereoselectivity (dr = 97:3). 250
DOI: 10.1021/acs.orglett.7b03608 Org. Lett. 2018, 20, 248−251
Letter
Organic Letters
(6) For CuH-catalyzed asymmetric reductive coupling of alkenes to carboxylic anhydrides and unsaturated carboxylic acids, see: (a) Bandar, J. S.; Ascic, E.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138, 5821− 5824. (b) Zhou, Y.; Bandar, J. S.; Buchwald, S. L. J. Am. Chem. Soc. 2017, 139, 8126−8129. (7) For CuH-catalyzed asymmetric reductive coupling of alkynes, see: (a) Xu, G.; Zhao, H.; Fu, B.; Cang, A.; Zhang, G.; Zhang, Q.; Xiong, T.; Zhang, Q. Angew. Chem., Int. Ed. 2017, 56, 13130−13134. For selected CuH-catalyzed reductive coupling of alkynes, see: (b) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Angew. Chem., Int. Ed. 2011, 50, 523−527. (c) Uehling, M. R.; Rucker, R. P.; Lalic, G. J. Am. Chem. Soc. 2014, 136, 8799−8803. (d) Uehling, M. R.; Suess, A. M.; Lalic, G. J. Am. Chem. Soc. 2015, 137, 1424−1427. (e) Shi, S. L.; Buchwald, S. L. Nat. Chem. 2015, 7, 38−44. (f) Cheng, L. J.; Mankad, N. P. J. Am. Chem. Soc. 2017, 139, 10200−10203. (8) (a) Tani, Y.; Kuga, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Chem. Commun. 2015, 51, 13020−13023. (b) Liu, R. Y.; Yang, Y.; Buchwald, S. L. Angew. Chem., Int. Ed. 2016, 55, 14077−14080. (c) Fujihara, T.; Yokota, K.; Terao, J.; Tsuji, Y. Chem. Commun. 2017, 53, 7898−7900. (d) During preparation of this manuscript, Lalic reported CuHcatalyzed racemic hydroalkylation of allenes. Lee, M.; Nguyen, M.; Brandt, C.; Kaminsky, W.; Lalic, G. Angew. Chem., Int. Ed. 2017, 56, 15703−15707. (9) During the course of the Cu-catalyzed asymmetric allylation of Eor Z-crotylborons to aldimines, appreciable enantioselectivity (ee ≤ 80%) and low diastereoselectivity (dr = ∼60:40) were observed in ref 9c. (a) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687−7691. (b) Shi, S. L.; Xu, L. W.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 6638−6639. (c) Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 3332−3335. (d) Zhao, Y. S.; Liu, Q.; Tian, P.; Tao, J. C.; Lin, G. Q. Org. Biomol. Chem. 2015, 13, 4174−4178. (e) Meng, F.; Jang, H.; Jung, B.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2013, 52, 5046−5051. (f) Meng, F.; McGrath, K. P.; Hoveyda, A. H. Nature 2014, 513, 367−374. (10) He, Z. T.; Tang, X. Q.; Xie, L. B.; Cheng, M.; Tian, P.; Lin, G. Q. Angew. Chem., Int. Ed. 2015, 54, 14815−14818. (11) β-Oxygen elimination readily occurs in the Cu-catalyzed borylation of α-alkoxy allenes; see: Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Angew. Chem., Int. Ed. 2013, 52, 12400−12403. (12) For more details, see the Supporting Information. (13) In some cases of CuH-catalyzed cross-coupling reactions, the alkyl and alkenyl copper intermediates underwent nucleophilic substitution with the alkyl triflates and alkyl bromides. See refs 5a and 7d. (14) For selected meta-functionalization of phenols, see: (a) Dai, H. X.; Li, G.; Zhang, X. G.; Stepan, A. F.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135, 7567−7571. (b) Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P. X.; Ishoey, M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. D.; Yu, J. Q. J. Am. Chem. Soc. 2016, 138, 9269−9276. (15) For recent reviews, see: (a) Zhuo, C. X.; Zhang, W.; You, S. L. Angew. Chem., Int. Ed. 2012, 51, 12662−12686. (b) You, S. L. Asymmetric Dearomatization Reactions; Wiley-VCH: Weinheim, 2016.
ing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*Email: ylchen@staff.shu.edu.cn. *Email:
[email protected],
[email protected]. *Email:
[email protected]. ORCID
Ping Tian: 0000-0002-5612-0664 Author Contributions ∥
Y.-X.T. and X.-Q.T. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support was generously provided by the 973 Program (2015CB856600), NSFC (21372243, 21232009, 21572251, 21572253), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB 20020100), and the Collaborative Innovation Center of Chemical Science and Engineering (Tianjin). We thank Dr. Hanqing Dong (Arvinas, Inc.) for helpful discussions.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03608 Org. Lett. 2018, 20, 248−251
