Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Catalytic Enantio- and Diastereoselective Cyclopropanation of 2‑Azadienes for the Synthesis of Aminocyclopropanes Bearing Quaternary Carbon Stereogenic Centers Xinxin Shao and Steven J. Malcolmson* Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
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S Supporting Information *
ABSTRACT: We report the catalytic enantio- and diastereoselective preparation of aminocyclopropanes by the cyclopropanation of terminal and (Z)-internal 2-azadienes with donor/acceptor carbenes derived from α-diazoesters. The resulting cyclopropanes bear quaternary carbon stereogenic centers vicinal to the amino-substituted carbon and are formed as a single diastereomer in up to 99:1 er and 97% yield with 0.5 mol % of Rh2(DOSP)4 and only 1.5 equiv of the diazo reagent. Transformations with internal azadienes afford cyclopropanes with three contiguous stereogenic centers.
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Scheme 1. Catalytic Enantioselective Methods toward Aminocyclopropanes with Quaternary Stereogenic Centers
evelopment of new strategies for the catalytic enantioselective synthesis of amino-substituted stereogenic centers is critical as these chiral amines are found in numerous natural products, pharmaceuticals, and fine chemicals. The stereoselective construction of enantioenriched amines comprised of multiple contiguous stereogenic centers is particularly challenging, especially as these carbons become more substituted. One attractive class of chiral amines for preparing bioactive compounds are aminocyclopropanes1 due to the geometric constraint imposed by the carbocycle and the resulting precise orientation of the functional groups that decorate it. However, the enantioselective synthesis of aminocyclopropanes with a quaternary stereogenic center vicinal to the amino group is challenging, and lack of accessibility has perhaps diminished the exploration of molecules within this chemical space in drug discovery. Adding further complexity to these structures are aminocyclopropanes with a third stereogenic center. One enantioselective approach that has emerged for synthesizing aminocyclopropanes with quaternary carbon stereogenic centers involves the desymmetrization of highly strained cyclopropenes (Scheme 1). Both hydroamination2 and carboamination3 strategies, including annulation reactions,4 have recently been disclosed. While enabling the preparation of cyclopropanes with 2−3 stereogenic carbons, this approach relies upon preassembly of the three-membered ring. A second tactic utilizes nitroalkenes5 in a number of related annulations with enolate nucleophiles (Scheme 1).6 Access to the amine would require reduction of the nitro group; furthermore, epimerization may occur at the nitro-substituted carbon.5b A straightforward way to prepare aminocyclopropanes is the enantio- and diastereoselective cyclopropanation of N-substituted olefins with disubstituted carbene precursors;7,8 however, this strategy has seen limited success, being restricted to just a handful of examples.9,10 Most cyclopropanations of N© XXXX American Chemical Society
alkenyl substrates have entailed reactions with ethyl diazoacetate or related α-diazoesters while also being constrained to terminal Received: July 31, 2019
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DOI: 10.1021/acs.orglett.9b02692 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
olefins, leading to products lacking quaternary carbons or more than two stereogenic centers.11 The expansion of this disconnection to encompass disubstituted olefins and/or donor/acceptor carbene12 precursors would provide access to more highly substituted cyclopropanes, including those bearing quaternary stereogenic centers. In 2012, Gu, Li, and co-workers reported the enantioselective cyclopropanation of 1,1-disubstituted alkenyl azides with donor/acceptor carbenes (Scheme 1).13,14 The products contain vicinal fully-substituted carbons, however, reduction of the azide is necessary for preparing the aminocyclopropane. Compounds with a third stereogenic carbon were not reported. In this work, we have developed enantioselective cyclopropanations of terminal and (Z)-internal 2-azadienes15 with donor/acceptor carbenes. The reactions proceed efficiently with 0.5 mol % Rh2(DOSP)4 catalyst and a slight excess of the diazoester (Scheme 1). The cyclopropane products, comprised
Scheme 2. Catalyst Performance in Azadiene Cyclopropanation
Scheme 3. Scope of Diazoesters for Cyclopropanation of Azadiene 1
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DOI: 10.1021/acs.orglett.9b02692 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 4. Azadiene Cyclopropanation with Diazoesters Derived from Natural Products and Drug Molecules
Scheme 5. Cyclopropanation of (Z)-4-Alkyl-2-azadienes
Scheme 6. Alternative Annulations with 3-Substituted Azadienes or α-Styrenyl Diazoesters of two to three stereogenic centers, one of which is quaternary, are formed with excellent diastereo- and enantiocontrol with the benzophenone imine serving as a protecting and stabilizing group for the amine within this donor/acceptor cyclopropane.16 We initiated our studies by examining the cyclopropanation of terminal 2-azadiene 1 with phenyl-substituted diazoester 2a (Scheme 2).17 With several chiral Rh(II)-based catalysts in nonpolar solvent, cyclopropane 3a is obtained in ≥80% yield as a single diastereomer with the imino and ester groups in a trans relationship. The highest enantioselectivity and yield of 3a is obtained with Rh2(R-DOSP)4 (Rh-1) at −45 °C in hexanes. With the feasibility of our approach to aminocyclopropanes established, we next set out to investigate the range of donor/ acceptor diazo reagents that would participate in Rh-1-catalyzed cyclopropanation of 2-azadiene 1. While the conditions shown in Scheme 2 proved optimal for the transformation of diazo reagent 2a, diazoesters bearing other aryl groups often require elevated temperatures and/or alternative nonpolar solvents for reaction efficiency (Scheme 3). In some instances, this is due to the electronic character of the Rh−carbene and in others because of poor solubility of the diazo reagent in hexanes or at low temperature. A range of electronically modified arenes within the diazo reagent are tolerated, including electron-donating methoxy (3b), siloxymethyl (3i), naphthyl (3q), and dioxalato (3r) groups and electron-withdrawing ester (3j), ketone (3k), nitrile
(3l), trifluoromethyl (3m), boronic ester (3n), and nitro (3o) functionality. Several halides and pseudohalides at the paraposition afford cyclopropanes 3c−h in 88−97% yield. Halogens at the meta- (3s, 3u) and ortho-positions (3t)18 also allow for efficient preparation of the protected aminocyclopropanes. Heteroarene-substituted cyclopropanes, such as indolyl 3v and thiophenyl 3w, can be isolated from cyclopropanation of terminal azadiene 1. In all cases, the cyclopropanes are formed as the trans-imino ester isomer in 72−97% yield and 90:10 to 99:1 er. We have also investigated the cyclopropanation of azadiene 1 with diazoesters prepared from natural products and drugs C
DOI: 10.1021/acs.orglett.9b02692 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 7. Functionalization of Cyclopropane Productsa
attempted reactions of the imine, with the ester still intact, lead to complex mixtures.17 Reduction of the ester of 3a to alcohol 9 allows for hydrolysis to the free amine, which may be acylated to deliver 10 (Scheme 7). This pathway to the free amine, easily obtained under mildly acidic conditions, will enable elaboration of the aminocyclopropane building blocks to downstream synthesis, including providing a pathway for incorporation of this unit into peptides.24,25 Additionally, the methyl ester of 3a may be hydrolyzed under mild conditions to furnish carboxylic acid 11 in 62−83% yield (Scheme 7). The somewhat unstable carboxylic acid, if used immediately, may serve as an acyl donor: conversion to the activated N-hydroxysuccinimide ester and subsequent transformation to the carboxamide enables 12 to be obtained in 86% yield over two steps. 2-Azadienes continue to emerge as useful chemical building blocks for constructing chiral amines.15 Whereas we have previously shown their utility as enamine umpolung reagents,15 here we illustrate that they may serve as a highly useful protected form of an amino-substituted olefin. Cyclopropanations of Ncontaining alkenes are an attractive strategy for accessing aminocyclopropanes but these transformations are uncommon, especially those that afford compounds with quaternary stereogenic centers (donor/acceptor carbenes) or wherein each carbon of the cyclopropane is stereogenic. In this study, we have demonstrated that Rh2(DOSP)4-catalyzed cyclopropanations of 2-azadienes with donor/acceptor carbenes proceed with exceptional levels of efficiency, diastereo-, and enantioselectivity to afford myriad protected aminocyclopropanes bearing quaternary stereogenic centers.
a
DIC = diisopropylcarbodiimide; Suc = succinyl.
(Scheme 4). Both clofibrate- (3x) and fenofibrate-derived (3y) diazoesters deliver iminocyclopropanes in ca. 97:3 er. Additionally, connection of chiral molecules to the diazo reagents through an ester (menthol, 3z) or benzyl ether (vitamin E, 3ab) linkage enables formation of N-substituted cyclopropanes in ca. 88% yield and 94.5:5.5 dr. For the estrone-derived diazoester that affords cyclopropane 3aa, the Rh2(R-DOSP)4 catalyst (Rh1) is efficient but only modestly diastereoselective (86% yield, 91.5:8.5 dr). Contrastingly, the catalyst enantiomer is “matched” and furnishes the diastereomer of 3aa (97:3 dr) in 87% yield. Achiral Rh2(esp)2 is significantly less stereoselective (29:71 dr), delivering only 65% yield of product. We next turned our attention to reactions of 4-alkyl-2azadienes (Scheme 5). Whereas the (E)-olefin isomers fail to undergo cyclopropanation with Rh-1-derived donor/acceptor carbenes, instead undergoing allylic C−H insertion,12,17 the (Z)-internal azadienes 4 deliver multisubstituted cyclopropanes 5 comprised of three contiguous stereogenic centers in good yield as a single diastereomer. Several diazoesters participate in cyclopropanation of phenethyl-substituted azadiene 4a, furnishing imino esters 5a−d in 89:11 to 92.5:7.5 er. Variation of the azadiene’s aryl group is permissible with cyclopropanes 5e−g formed with good enantioselectivity. Ethereal functionality within the azadiene alkyl chain is tolerated but leads to modest enantioselectivity (5h−i). We attempted a number of additional azadiene/diazoester couplings to prepare aminocyclopropanes with other substitution patterns or bearing alternative functional groups; however, rather than the anticipated cyclopropane, different annulation products were formed (Scheme 6). 3-Methyl-2-azadiene 6 leads to unsaturated pyrrolidine 7 in 75% yield and 91.5:8.5 er. The enantioselectivity suggests that the transformation proceeds through Rh-1-catalyzed cyclopropanation of the azadiene and subsequent transition-metal-mediated ring expansion19,20 of the donor/acceptor cyclopropane, similar to vinylcyclopropane to cyclopentene rearrangements.21 Furthermore, the reaction of terminal azadiene 1 with the styrenyl-substituted diazoester 2ad affords unsaturated pyrrolidine 8 (96:4 er) via formal [3 + 2]cycloaddition. Likely the reaction proceeds through initial attack of the azadiene nitrogen upon the donor/acceptor carbene followed by cyclization from the resulting ammonium ylide.22,23 Once more, the high enantioselectivity indicates that Rh-1 is intimately associated with the cyclization event that leads to 8. The imine-protected form of the nitrogen atom within the cyclopropane products is sufficiently deactivating to suppress ring-opening of the donor/acceptor cyclopropane;24 however, hydrolysis of the imine leads to ring-opening, and other
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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.9b02692. Experimental procedures, analytical data for new compounds, and spectral data (PDF) Accession Codes
CCDC 1920043 contains 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 data_
[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 Author
*E-mail:
[email protected]. ORCID
Steven J. Malcolmson: 0000-0003-3229-0949 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the NIH (GM124286) and Duke University for financial support of this research. We thank Dr. Roger Sommer (NC State) for assistance with X-ray crystallography. D
DOI: 10.1021/acs.orglett.9b02692 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Tseng, L.; Malcolmson, S. J. 2-Azadienes as Reagents for Preparing Chiral Amines: Synthesis of 1,2-Amino Tertiary Alcohols by CuCatalyzed Enantioselective Reductive Couplings with Ketones. J. Am. Chem. Soc. 2018, 140, 598. (16) Reissig, H.-U.; Zimmer, R. Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis. Chem. Rev. 2003, 103, 1151. (17) For additional data, see the Supporting Information. (18) The stereochemistry of the major isomer of 3t was established by single-crystal X-ray diffraction. The absolute stereochemistry of all other products is assigned by analogy. (19) For a related example with a carbodiene, see: Schnaubelt, J.; Marks, E.; Reiβig, H.-U. [4 + 1] Cycloadditions of the Rhodium Di(methoxycarbonyl) Carbenoid to 2-Silyloxy-1,3-Dienes. Chem. Ber. 1996, 129, 73. (20) (a) Rodriguez, K. X.; Kaltwasser, N.; Toni, T. A.; Ashfeld, B. A. Rearrangement of an Intermediate Cyclopropyl Ketene in a RhIICatalyzed Formal [4 + 1]-Cycloaddition Employing Vinyl Ketenes as 1,4-Dipoles and Donor−Acceptor Metallocarbenes. Org. Lett. 2017, 19, 2482. (b) de Nanteuil, F.; Serrano, E.; Perrotta, D.; Waser, J. Dynamic Kinetic Asymmetric [3 + 2] Annulation Reactions of Aminocyclopropanes. J. Am. Chem. Soc. 2014, 136, 6239. (c) de Nanteuil, F.; Waser, J. Catalytic [3 + 2] Annulations of Aminocyclopropanes for the Enantiospecific Synthesis of Cyclopenylamines. Angew. Chem., Int. Ed. 2011, 50, 12075. (21) (a) Hudlicky, T.; Koszyk, F. J.; Kutchan, T. M.; Sheth, J. P. Cyclopentene Annulation via Intramolecular Addition of Diazoketones to 1,3-Dienes. Applications to the Synthesis of Cyclopentanoid Terpenes. J. Org. Chem. 1980, 45, 5020. (b) Aris, V.; Brown, J. M.; Conneely, J. A.; Golding, B. T.; Williamson, D. H. Synthesis and Thermolysis of Rhodium and Iridium Complexes of endo-6vinylbicyclo[3.1.0]hex-2-ene. A Metal-Promoted Vinylcyclopropane to Cyclopentene Rearrangement. J. Chem. Soc., Perkin Trans. 2 1975, 2, 4. (22) For a closely related non-enantioselective example, see: Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg, L. S. Highly Selective CatalystDirected Pathways to Dihydropyrroles from Vinyldiazosacetates and Imines. J. Am. Chem. Soc. 2003, 125, 4692. (23) For reactions with carbodienes, resulting in a different reaction pathway, see: (a) Guzmán, P. E.; Lian, Y.; Davies, H. M. L. Reveral of the Regiochemistry in the Rhodium-Catalyzed [4 + 3] Cycloaddition between Vinyldiazoacetates and Dienes. Angew. Chem., Int. Ed. 2014, 53, 13083. (b) Parr, B. T.; Davies, H. M. L. Rhodium-Catalyzed Tandem Cyclopropanation/Cope Rearrangement of 4-Alkenyl-1sulfonyl-1,2,3-triazoles with Dienes. Angew. Chem., Int. Ed. 2013, 52, 10044. (24) Boddaert, T.; Taylor, J. E.; Bull, S. D.; Aitken, D. J. A Selective Deprotection Strategy for the Construction of trans-2-Aminocyclopropanecarboxylic Acid Derived Peptides. Org. Lett. 2019, 21, 100. (25) (a) Kiss, L.; Mándity, I. M.; Fülöp, F. Highly Functionalized Cyclic β-Amino Acid Moieties as Promising Scaffolds in Peptide Research and Drug Design. Amino Acids 2017, 49, 1441. (b) Werner, H. M.; Horne, W. S. Folding and Function in α/β-Peptides: Targets and Therapeutic Applications. Curr. Opin. Chem. Biol. 2015, 28, 75. (c) Cabrele, C.; Martinek, T. A.; Reiser, O.; Berlicki, L. Peptides Containing β-Amino Acid Patterns: Challenges and Successes in Medicinal Chemistry. J. Med. Chem. 2014, 57, 9718. (d) Urman, S.; Gaus, K.; Yang, Y.; Strijowski, U.; Sewald, N.; De Pol, S.; Reiser, O. The Constrained Amino Acid β-Acc Confers Potency and Selectivity to Integrin Ligands. Angew. Chem., Int. Ed. 2007, 46, 3976. (e) Gnad, F.; Reiser, O. Synthesis and Applications of β-Aminocarboxylic Acids Containing a Cyclopropane Ring. Chem. Rev. 2003, 103, 1603.
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