Cu Dual Catalysis: Enantio- and Diastereodivergent Access to α,α

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Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent Access to α,αDisubstituted α‑Amino Acids Bearing Vicinal Stereocenters Xiaohong Huo,†,‡ Jiacheng Zhang,† Jingke Fu,† Rui He,† and Wanbin Zhang*,†,‡ †

Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering and ‡School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China S Supporting Information *

Compared to dual catalysis consisting of a metal and an organocatalyst,10 synergistic bimetallic catalysis has emerged as an efficient process to accomplish a series of unprecedented asymmetric transformations.9e,h,11 Recently, we developed stereodivergent α-allylations of α-hydroxyketones by the combination of iridium and zinc catalysts.9e,h Herein, we set out to demonstrate a new development in bimetallic catalysis, whereby a Cu-Phox complex-activated imine ester was combined with a metallacyclic iridium complex-catalyzed allylic allylation process,12,13 to afford an efficient methodology for the synthesis of enantiopure α,α-disubstituted α-AAs bearing vicinal stereocenters (Scheme 1). The direct use of readily available imine esters in Ir-catalyzed allylic substitution is attractive yet troublesome due to the steric hindrance of the bond-forming process and challenges associated with the control of stereoselectivity.14 We envisioned that the introduction of a copper complex to this process could activate the prochiral nucleophile to form an N-metalated azomethine ylide I, and help to improve both the activity and stereo recognition of the reaction.15 Additionally, the interception of the reactive allyliridium intermediate II by the ylide I with welldefined geometry, allows for the control of the configurations of both stereocenters. Compared to traditional methods involving multiple synthetic routes in accessing the desired stereoisomers of a target product, this Ir/Cu dual catalysis led to the enantio- and diastereodivergent synthesis of the desired product, that is, a simultaneous synthesis of the full matrix of stereoisomeric products from the same set of starting materials under identical conditions. The utility of this concept is showcased by the enantio- and diastereodivergent construction of both dipeptides and analogues of biologically active molecules. The allylic substitution was initiated using the aldimine ester (1a) and the allylic carbonate (2) (LG = OCO2Me) as model substrates (Table 1). In order to find a highly efficient catalyst for the asymmetric allylation, a bimetallic catalyst system consisting of a chiral Cu(OTf)2 complex modified with phosphino-oxazoline ligands16 and a chiral iridium complex derived from phosphoramidites,12 was generated. A brief ligand screen showed that the combination of Cu-L1 complex and IrL2 complex was the optimal catalyst system, giving the product (R,S)-3a in 88% yield with >20:1 dr and >99% ee (Table 1, entry 1).17 Subsequently, the influence of the leaving group (LG) of the allylic substrates was examined. A poor leaving

ABSTRACT: We describe a fully stereodivergent synthesis of a range of α,α-disubstituted α-amino acids via an Ir/Cu-catalyzed α-allylation of readily available imine esters. The introduction of a Cu-Phox complex-activated imine ester into the chiral iridium-catalyzed allylic allylation process is crucial for its high reactivity and excellent enantio- and diastereoselectivity (up to >99% ee and >20:1 dr). Importantly, the two chiral catalysts allow for full control over the configuration of the stereocenters, affording all stereoisomers of the desired products. The utility of this methodology was demonstrated by synthesizing dipeptides and analogues of bioactive molecules in a stereodivergent manner. on-proteinogenic α,α-disubstituted α-amino acids (αAAs) are valuable compounds in biochemical and pharmacological research.1 In particular, optically active α,αdisubstituted α-AAs containing vicinal stereocenters are important structural motifs in biologically active natural products and pharmaceuticals (e.g., lactacystin, sulfonamide altemicidin, and neooxazolomycin).1a,2 The biological activities of these α-AAs have proved to be closely dependent on their absolute and relative stereochemical configurations.3 As such, the development of reliable transformations that provide the full set of stereoisomers of a target α-amino acid would not only provide access to α-AAs with varied biological activities but also contribute to the exploration of structure−activity relationships, which is important in the drug discovery and development process.2,3 Despite this significance, the development of a facile and general method for the construction of α,α-disubstituted αAAs bearing vicinal stereocenters, with selective access to all their stereoisomers, remains an unmet synthetic challenge4,5 and is yet to be reported. Iridium-catalyzed allylic substitution is well-established as a powerful tool for enantioselective C−C bond formation and for the generation of branched products.6 The introduction of a second chiral catalyst to this process, i.e., dual catalysis, to simultaneously activate both the prochiral nucleophile and the allyl electrophile may provide an efficient and flexible methodology for the construction of target products containing two vicinal stereocenters.7 Furthermore, dual catalysis consisting of two distinct chiral catalysts, whereby each catalyst allows for full control over the configuration of each respective stereocenter, is expected to afford all possible stereoisomers of a desired product.8,9

N

© 2018 American Chemical Society

Received: January 6, 2018 Published: January 30, 2018 2080

DOI: 10.1021/jacs.8b00187 J. Am. Chem. Soc. 2018, 140, 2080−2084

Communication

Journal of the American Chemical Society Scheme 1. Stereodivergent Synthesis of Non-proteinogenic α,α-Disubstituted α-AAs Containing Vicinal Stereocenters

Scheme 2. Stereodivergent Access to All Stereoisomers of 3a and 4a

Table 1. Optimization of the α-Allylation of Aldimine Estersa a

Reaction conditions: please see Table 1, entry 1. Other reaction conditions: (a) AcCl, Et3N, THF, 0 °C. (b) RuCl3, NaIO4, CCl4/ CH3CN/H2O, 70 °C. (c) 6 N HCl, 80 °C. 3a′ is the N-protected 3a with p-NO2-C6H4CO (C black, H gray, O red, N blue).

Table 2. Substrate Scope of Allylic Carbonatesa

entry

L for Cu

L for Ir

LG

yield (%)b

drc

ee (%)d

1 2 3 4 5

(S,Sp)-L1 (S,Sp)-L1 (S,Sp)-L1 no Cu (S,Sp)-L1

(R,R,R)-L2 (R,R,R)-L2 (R,R,R)-L2 (R,R,R)-L2 no Ir

OCO2Me OAc OBoc OCO2Me OCO2Me

88 20:1 − 15:1 1.3:1 −

>99 − 94 99 −

a Reaction conditions: 1a (0.25 mmol, 1.0 equiv), 2 (0.35 mmol, 1.4 equiv), Cu(OTf)2 (4 mol%), (S,Sp)-L1 (4 mol%), [Ir(cod)Cl]2 (2 mol %), (R,R,R)-L2 (4 mol%), Cs2CO3 (1.0 equiv), rt, 12 h; hydrolysis with citric acid (10%, 4 mL). LG = leaving group. bIsolated yield of two diastereoisomers. nr = no reaction. cDetermined by 1H NMR integration of the crude reaction mixtures. dDetermined by HPLC analysis.

group, OAc, delivered only trace amounts of products, while good leaving groups such as OCO2Me and OBoc provided superior results (entries 1−3). It was reasoned that the leaving ability of the LG and the basicity of the resulting groups both affected the reactivity and stereoselectivity of the transformation. In order to explore the synergistic effect of the bimetallic catalysis, control experiments were conducted. The Ir-catalyzed allylic substitution reaction proceeded with substantially lower reactivity and diastereoselectivity (65% yield, 1.3:1 dr) in the absence of the Cu catalyst (entry 4). It was presumed that the low reactivity and the problematic diastereocontrol of this transformation could not be overcome without the participation of the Cu catalyst. Additionally, no reaction occurred using only the Cu catalyst (entry 5). These results demonstrated that the bimetallic catalysts played a synergistic and indispensable role in improving both the reactivity and stereoselectivity of the reaction. We then set out to establish the availability of the enantioand diastereodivergent access to the 3a. Under the optimized conditions, the reaction of 1a and 2a proceeded smoothly, affording all four stereoisomers of 3a in high yields with >99%

a Reaction conditions: please see Table 1, entry 1. bThe ee values of the products 3d−3f and 3p were measured after N-protecting with BzCl.

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DOI: 10.1021/jacs.8b00187 J. Am. Chem. Soc. 2018, 140, 2080−2084

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Journal of the American Chemical Society Table 3. Substrate Scope of Aldimine Estersa

Table 5. Stereodivergent α-Allylations of Dipeptidesa

a

gave products 3 with access to two diastereoisomers.19 It was found that allylic carbonates bearing substituents at the ortho-, meta-, or para-position of the phenyl ring were all tolerated in this transformation, affording their respective products (3b− 3m) in high yields and with high enantio- and diastereoselectivities. Notably, allylic carbonates containing naphthyl, indolyl, and even simple methyl groups were also tolerated (3n−3p). Next, the scope of aldimine esters as nucleophile components was investigated (Table 3). A series of αsubstituted aldimine esters derived from DL-alanine, DLmethionine, and other non-natural α-AAs (R1 = Et, allyl, and aryl) reacted with 2a smoothly, providing the non-coded α-AAs (3q-3w) in good yields and with high enantio- and diastereoselectivities. It was noteworthy that all these reactions furnished products in a stereodivergent manner, allowing for access to both diastereoisomers.19 To further explore the practicability of this bimetallic catalyst system, less reactive cyclic ketimine Schiff bases 5 were conducted under the optimal reaction conditions. To our delight, the reactions proceeded well to deliver products (R,S)6 and (S,S)-6 in high yields with 96% → 99% ee and 10:1 → 20:1 dr (Table 4).20 The incorporation of non-natural α-AAs bearing vicinal stereocenters into peptides provides a rational approach to the design and modification of AAs and peptides.1b Here, we demonstrate the practicality of the site-specific modification of dipeptides in a stereodivergent manner (Table 5).20 The reactions of 2a and dipeptide Gly-Gly derivatives 7a and 7b furnished both diastereoisomers of 8a and 8b in good yields and stereoselectivities. Importantly, reactions with dipeptide Gly-L-Ala and Gly-L-Leu derivatives bearing pre-existent chiral centers also proceeded well, affording stereodivergent products (8c and 8d) with similar results. In summary, we have documented the development of a synergistic Ir/Cu-catalyzed allylic alkylation process, which can be used for the construction of a range of α,α-disubstituted αAAs bearing two vicinal stereocenters in a single transformation with complete control over their absolute and relative configurations. Significantly, we established the practicality of the site-specific incorporation of non-natural α-AAs bearing vicinal stereocenter residues in dipeptides as well as the construction of analogues of a biologically active molecule,

a

Reaction conditions: please see Table 1, entry 1. The ligand for Cu(OTf)2 is (S,Sp)-L3 (Et-FerroPhox) instead of (S,Sp)-L1 (iPrRuthePhox).17

Table 4. Stereodivergent α-Allylation of Cyclic Ketimine Schiff Basea

a

Reaction conditions: please see Table 1, entry 1.

Reaction conditions: please see Table 1, entry 1.

ee and >20:1 dr from the same set of starting materials under otherwise identical reaction conditions (Scheme 2). The absolute configurations of both diastereoisomers were determined by X-ray crystallography. α,β-Disubstituted aspartate analogues are known as possible subtype-selective blockers of glutamate transporters, which play a key role in maintaining extracellular glutamate concentration in the mammalian central nervous system.1a,18 The obtained products 3a were then elaborated to provide full access to the stereoisomers of the α,β-disubstituted aspartate analogue 4 following the sequence of reactions shown in Scheme 2. Compared with the currently available route which necessitates the involvement of enantiopure allylic alcohols and the alteration of alkene geometry (E versus Z),4b this stereodivergent bimetallic catalysis dictates all configurations of 4 simply by the permutation of chiral catalyst combinations. The scope of allylic carbonates was explored in a stereodivergent manner under the optimal reaction conditions (Table 2). The reaction of 1a and a range of allylic carbonates 2 all 2082

DOI: 10.1021/jacs.8b00187 J. Am. Chem. Soc. 2018, 140, 2080−2084

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Journal of the American Chemical Society

An, Q.; Zhang, W. Org. Lett. 2015, 17, 5768. (g) Spoehrle, S. S. M.; West, T. H.; Taylor, J. E.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2017, 139, 11895. (h) Su, Y.-L.; Li, Y.-H.; Chen, Y.-G.; Han, Z.-Y. Chem. Commun. 2017, 53, 1985. (6) For selected reviews, see: (a) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641. (b) Helmchen, G.; Dahnz, A.; Dübon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675. (c) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461. (d) Liu, W.-B.; Xia, J.-B.; You, S.-L. Top. Organomet. Chem. 2011, 38, 155. (e) Tosatti, P.; Nelson, A.; Marsden, S. P. Org. Biomol. Chem. 2012, 10, 3147. (f) Oliver, S.; Evans, P. A. Synthesis 2013, 45, 3179. (g) Helmchen, G. In Molecular Catalysts; Gade, L. H., Hofmann, P., Eds.; Wiley-VCH: Weinheim, 2014. (h) Kazmaier, U. Org. Chem. Front. 2016, 3, 1541. (i) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. ACS Catal. 2016, 6, 6207. (j) Qu, J.; Helmchen, G. Acc. Chem. Res. 2017, 50, 2539. (7) For selected reviews concerning dual catalysis, see: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633. (c) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015, 13, 8116. (d) Pye, D. R.; Mankad, N. P. Chem. Sci. 2017, 8, 1705. (8) For perspectives on stereodivergent dual catalysis, see: (a) Schindler, C. S.; Jacobsen, E. N. Science 2013, 340, 1052. (b) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013, 52, 13149. (c) Lin, L.; Feng, X. Chem. - Eur. J. 2017, 23, 6464. (d) Bihani, M.; Zhao, J. C.-G. Adv. Synth. Catal. 2017, 359, 534. (e) Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 5627. (9) For examples of stereodivergent synthesis via dual catalysis, see: (a) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065. (b) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020. (c) Næsborg, L.; Halskov, K. S.; Tur, F.; Mønsted, S. M. N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2015, 54, 10193. (d) Sandmeier, T.; Krautwald, S.; Zipfel, H. F.; Carreira, E. M. Angew. Chem., Int. Ed. 2015, 54, 14363. (e) Huo, X.; He, R.; Zhang, X.; Zhang, W. J. Am. Chem. Soc. 2016, 138, 11093. (f) Jiang, X.; Beiger, J. J.; Hartwig, J. F. J. Am. Chem. Soc. 2017, 139, 87. (g) Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 1029. (h) He, R.; Liu, P.; Huo, X.; Zhang, W. Org. Lett. 2017, 19, 5513. (i) Kassem, S.; Lee, A. T. L.; Leigh, D. A.; Marcos, V.; Palmer, L. I.; Pisano, S. Nature 2017, 549, 374. (10) For selected reviews, see: (a) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2010, 2999. (b) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res. 2014, 47, 2365. (c) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun. 2014, 50, 4272. (d) Afewerki, S.; Córdova, A. Chem. Rev. 2016, 116, 13512. For our work, see: (e) Zhao, X.; Liu, D.; Xie, F.; Liu, Y.; Zhang, W. Org. Biomol. Chem. 2011, 9, 1871. (f) Zhao, X.; Liu, D.; Guo, H.; Liu, Y.; Zhang, W. J. Am. Chem. Soc. 2011, 133, 19354. (g) Huo, X.; Quan, M.; Yang, G.; Zhao, X.; Liu, D.; Liu, Y.; Zhang, W. Org. Lett. 2014, 16, 1570. (h) Huo, X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W. Angew. Chem., Int. Ed. 2014, 53, 6776. (11) (a) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309. (b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928. (c) Jia, T.; Cao, P.; Wang, B.; Lou, Y.; Yin, X.; Wang, M.; Liao, J. J. Am. Chem. Soc. 2015, 137, 13760. (d) Saito, A.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2017, 56, 5551. (e) Huo, X.; He, R.; Fu, J.; Zhang, J.; Yang, G.; Zhang, W. J. Am. Chem. Soc. 2017, 139, 9819. (f) Wei, L.; Xu, S.-M.; Zhu, Q.; Che, C.; Wang, C.-J. Angew. Chem., Int. Ed. 2017, 56, 12312. For selected recent reviews, see: (g) Pye, D. R.; Mankad, N. P. Chem. Sci. 2017, 8, 1705. (h) Fu, J.; Huo, X.; Li, B.; Zhang, W. Org. Biomol. Chem. 2017, 15, 9747. (12) For original discoveries, see: (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164. (b) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14272. For mechanistic studies, see: (c) Madrahimov, S. T.; Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7228. (d) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 8136. (e) Chen, M.; Hartwig, J. F. J. Am.

aspartate, in a stereodivergent manner. The construction of a set of enantioenriched building blocks will not only provide a versatile library for drug screening but also facilitate the exploration of structure−activity relationships, which may further simplify and accelerate the process of drug discovery.

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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/jacs.8b00187. Experimental procedures and characterization data for all reactions and products, including 1H and 13C NMR spectra, HPLC spectra, crystal data, and crystallographic data (PDF) X-ray crystallographic data for (R,S)-3a′ (CIF) X-ray crystallographic data for (S,S)-3a′ (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Wanbin Zhang: 0000-0002-4788-4195 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Dedicated to Professor Isao Ikeda on the occasion of his 80th birthday. We thank the National Natural Science Foundation of China (Nos. 21232004, 21472123, and 21620102003), Science and Technology Commission of Shanghai Municipality (No. 15JC1402200), and Shanghai Municipal Education Commission (No. 201701070002E00030) for financial support.

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REFERENCES

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DOI: 10.1021/jacs.8b00187 J. Am. Chem. Soc. 2018, 140, 2080−2084