Direct Catalytic Asymmetric 1,6-Conjugate Addition of Amides to p

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Direct Catalytic Asymmetric 1,6-Conjugate Addition of Amides to p‑Quinone Methides Zhongdong Sun, Bo Sun, Naoya Kumagai,* and Masakatsu Shibasaki* Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan S Supporting Information *

ABSTRACT: Amide pronucleophiles were successfully incorporated into a 1,6-conjugate addition reaction manifold using p-quinone methides (p-QMs) as electrophiles. Four different types of functionalities were tolerated as αsubstituents of the amides, allowing for expeditious access to a range of enantiomerically enriched diarylmethine products. The 7-azaindoline unit is critically important for in situ catalytic enolization of the amide pronucleophile, engaging in 1,6conjugate addition to p-QMs with readily available catalyst components.

p-Quinone methides (p-QMs) are characterized by their sixmembered cyclic bisvinylogous enone framework, which is not only shared by a myriad of biologically active natural products but is also recognized as a transient reactive intermediate.1 Despite the omnipresence of p-QMs in the field of organic chemistry and recognition for a century, their utility in catalytic asymmetric transformations was not unveiled until quite recently. The extended enone framework of p-QMs and their propensity for aromatization led to the rapid emergence of their privileged utility as reactive electrophiles in 1,6-conjugate addition over the last 5 years.2,3 p-QMs possessing an aromatic substituent are privileged substrates that accept a range of nucleophiles, furnishing enantiomerically enriched diverse diarylmethine units, which are found in a number of biologically active compounds, including therapeutics.4 Carbon-based nucleophiles, including active methylene compounds,5 aldehydes,6 oxindoles,7 and azlactones,8 are generally tolerated to afford diarylmethine units with carbon-based structural extensions. The Rauhut−Currier reaction (vinylogous Morita−Baylis−Hillman reaction),9 formal [3 + 2] reaction,10 and integrated domino reactions involving oxaMichael reaction/1,6-conjugate addition reactions11 expand the scope of structural variants of these useful reactions. Of note, in situ generation of p-QMs from p-hydroxybenzyl alcohols via Brønsted acid catalysis offers operationally simple protocols by eliminating the preformation process of p-QMs, where pyrroles, indoles, and naphthols serve as nucleophiles to give enantioenriched triarylmethanes.12 In addition to the abovementioned carbon-based nucleophiles, enantioselective introduction of boron13 and sulfur14 nucleophiles expands the accessible molecular space of this useful conjugate addition manifold. In our continuing program of catalytic enolization chemistry, we reasoned that the stereoselective addition of amide pronucleophiles would further leverage the potential of p-QMs in synthetic chemistry (Scheme 1). Herein, we report a direct catalytic asymmetric 1,6-conjugate addition of 7-azaindoline amides 1 to p-QMs. The catalysis was driven by specific © XXXX American Chemical Society

recognition/activation of 7-azaindoline amides by a cooperative catalytic system, incorporating amides with different αsubstituents (i.e., Me, CF3, N3, and OBn) as competent pronucleophiles. We began our study by probing the reactivity of p-QM 2a under standard catalytic settings for the enolization of 1-CF3.15 The readily prepared catalyst comprising commercially available mesitylcopper16 and a chiral bisphosphine ligand quickly emerged as a competent catalyst to afford the conjugate addition product 3a in decent yields and stereoselectivities at ambient temperature (Table 1). Initially, oligomeric mesitylcopper reacted with 1-CF3 to generate the corresponding Cu(I)−enolate I decorated with the chiral ligand. Subsequent 1,6-conjugate addition to 2a led to intermediary Cu(I)−aryl oxide II, which rendered the following catalytic cycle as a soft Lewis acid/Brønsted base cooperative catalyst (Figure 1). Among the bisphosphine ligands screened, biaryl-type ligands bearing 3,5-xylyl groups on the phosphorus atom exhibited excellent enantioselectivity (entries 3 and 5), while ferroceneembedded ligands afforded lower enantioselectivity (entries 6 and 7). The general propensity for formation of the antidiastereomer could be attributed to the acyclic approach of incoming 2a to Cu(I)-enolate I in the arrangement minimizing steric and dipole repulsions. (R)-Xyl-Segphos L5 was optimal in terms of yield and stereoselectivity (entry 5), and the catalyst loading could be reduced to 5 mol % without any loss of stereoselectivity (entry 8). The substrate generality is summarized in Scheme 2 using a range of p-QMs 2.17 This operationally simple, roomtemperature protocol furnished the desired conjugate adducts with generally high stereoselectivity. The scalability was validated by a 6 mmol scale reaction between 1-CF3 and 2a. All ortho-, meta-, para-substitution patterns were tolerated, Received: April 9, 2018

A

DOI: 10.1021/acs.orglett.8b01109 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. (a) Prior Art and (b) This Work on Catalytic Asymmetric 1,6-Conjugate Addition to p-QMs

Figure 1. Plausible catalytic cycles starting from the catalytic settings of mesitylcopper/L5.

Scheme 2. Direct Catalytic Asymmetric 1,6-Conjugate Addition of 1-CF3 to p-QMs 2a

Table 1. Screening of Chiral Ligandsa

entry

ligand

x (mol %)

yieldb (%)

anti/sync

ee (%)

1 2 3 4 5 6 7 8

L1 L2 L3 L4 L5 L6 L7 L5

10 10 10 10 10 10 10 5

93 90 98 95 98 94 90 97d

8.6/1 7.3/1 >20/l 6.9/1 >20/l 8.3/1 6.6/1 >20/l

76 76 91 89 97 31 70 97

a

1-CF3: 0.2 mmol. 2: 0.24 mmol. dr denotes diastereomeric ratio (anti major); isolated yield is reported. b1-CF3: 6.0 mmol. 2: 7.2 mmol. c10 mol % of catalyst was used.

irrespective of the substituent’s electronic nature, including carbon substituents (3b,c), halogen substituents (F: 3d-f, Cl: 3g-i, Br: 3j-l), and methoxy groups (3m-o), exemplifying the broad coverage of accessible diarylmethine units. p-QMs bearing other electron-withdrawing substituents (3p−s), as

a

1-CF3: 0.1 mmol. 2a: 0.12 mmol. bDetermined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. cDetermined by 1H NMR of the crude reaction mixture. dIsolated yield. B

DOI: 10.1021/acs.orglett.8b01109 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters well as those having an electron-rich methylenedioxy unit (3t), were applicable with consistently high yield and stereoselectivity. A marginal loss in the yield and diastereomeric ratio was detected in the reaction of a p-QM with a heteroaromatic 2-furyl group, even with 10 mol % of catalyst loading, although the enantioselectivity was excellent (3u). It is worth noting that the present conjugate addition protocol accommodates 7-azaindoline amides possessing other α-substituents, e.g., α-Me (1-Me),18 α-N3 (1-N3),19 and α-OBn (1-OBn).20 The reaction profile using p-QM 2a under identical reaction conditions is traced in Figure 2. Due to the low

Scheme 3. Optimized Conditions for 1-Me, 1-N3, and 1-OBn

Scheme 4. Transformation of the Reaction Products

conversion to an ester was applicable to 1,6-adduct 5 derived from 1-N3, and ester 9 was obtained under simple acidic conditions for prospective use as a precursor of unnatural amino acids. In conclusion, we developed a protocol for a catalytic asymmetric 1,6-conjugate addition of 7-azaindoline amides to p-QMs. Four different α-substituents were successfully exploited in the amide pronucleophiles, expanding the variety of accessible enantioenriched products with a diarylmethine unit.

Figure 2. Reaction profile of 7-azaindoline amides bearing a different α-substituent. Combined yield of anti and syn isomers is plotted. Mixed solvent of THF/CH2Cl2 = 9/1 was used for 1-OBn.

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solubility of 1-OBn in THF at 0 °C, a mixed solvent of THF/ CH2Cl2 = 9/1 (0.1 M) was used for 1-Bn. The difference in the reaction rates (1-N3 > 1-CF3 > 1-Me > 1-OBn) largely supports the electron-withdrawing nature of the α-substituents, suggesting that the enolization efficiency was a primary determinant of the reaction rate. Although the optimal reaction temperature depended upon the nature of the α-substituents on the basis of the reaction rate profile, the identical catalyst settings proved effective to achieve a high level of conversion and stereoselectivity (Scheme 3). The flexible accessibility of the enantioenriched products having α-fluoroalkyl (RF), -alkyl (C), -azido (N), and -benzyloxy (O) groups highlights the potential synthetic utility of the present 1,6-conjugate addition protocol. Functional group transformations were demonstrated without compromising the stereochemical integrity (Scheme 4). Two tert-butyl groups on the phenol unit of 1,6-adduct 3a were removed by AlCl3 to give 7.21 A reduction/oxidation sequence, followed by methylation with diazomethane was applied to achieve the conversion to ester 8. A more facile direct

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01109. Experimental procedures; spectroscopic data of new compounds; NMR spectra (PDF) Accession Codes

CCDC 1834945−1834949 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 emailing [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

*E-mail: [email protected]. *E-mail: [email protected]. C

DOI: 10.1021/acs.orglett.8b01109 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters ORCID

(14) Dong, N.; Zhang, Z.-P.; Xue, X.-S.; Li, X.; Cheng, J.-P. Angew. Chem., Int. Ed. 2016, 55, 1460. (15) (a) Yin, L.; Brewitz, L.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2014, 136, 17958. (b) Brewitz, L.; Arteaga, F. A.; Yin, L.; Alagiri, K.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2015, 137, 15929. (c) Matsuzawa, A.; Noda, H.; Kumagai, N.; Shibasaki, M. J. Org. Chem. 2017, 82, 8304. (d) Saito, A.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2017, 56, 5551. (16) (a) Tsuda, T.; Yazawa, T.; Watanabe, K.; Fujii, T.; Saegusa, T. J. Org. Chem. 1981, 46, 192. (b) Meyer, E. M.; Gambarotta, S.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. Organometallics 1989, 8, 1067. (c) Stollenz, M.; Meyer, F. Organometallics 2012, 31, 7708. (17) The absolute configuration was determined by X-ray crystallographic analysis. See Supporting Information for details. (18) (a) Arteaga, F. A.; Liu, Z.; Brewitz, L.; Chen, J.; Sun, B.; Kumagai, N.; Shibasaki, M. Org. Lett. 2016, 18, 2391. (b) Liu, Z.; Takeuchi, T.; Pluta, R.; Arteaga, A. F.; Kumagai, N.; Shibasaki, M. Org. Lett. 2017, 19, 710. (19) (a) Sun, Z.; Weidner, K.; Kumagai, N.; Shibasaki, M. Chem. Eur. J. 2015, 21, 17574. (b) Weidner, K.; Sun, Z.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2015, 54, 6236. (20) Sun, B.; Pluta, R.; Kumagai, N.; Shibasaki, M. Org. Lett. 2018, 20, 526. (21) Saleh, S. A.; Tashtoush, H. I. Tetrahedron 1998, 54, 14157.

Naoya Kumagai: 0000-0003-1843-2592 Masakatsu Shibasaki: 0000-0001-8862-582X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by ACT-C (JPMJCR12YO) from JST and KAKENHI (17H03025 and JP16H01043 in Precisely Designed Catalysts with Customized Scaffolding) from JSPS. N.K. thanks the Naito Foundation for financial support. We thank Dr. Tomoyuki Kimura at the Institute of Microbial Chemistry for assistance with the X-ray crystallography.

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DOI: 10.1021/acs.orglett.8b01109 Org. Lett. XXXX, XXX, XXX−XXX