Letter pubs.acs.org/OrgLett
Selective Synthesis of Spirooxindoles by an Intramolecular Heck−Mizoroki Reaction Tamal Roy,† Peter Brandt,† Alexander Wetzel,‡ Joakim Bergman,‡ Jonas Brånalt,‡ Jonas Sav̈ marker,# and Mats Larhed*,¤ †
Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden Department of Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden # The Beijer Laboratory, Department of Medicinal Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden ¤ Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden ‡
S Supporting Information *
ABSTRACT: We report a highly diastereoselective synthesis of cyclopentene−spirooxindole derivatives via an intramolecular Heck−Mizoroki reaction using aryl bromides as precursors. The reactions were performed under dry conditions or in a DMF− water system. This protocol can be useful to introduce several functionalities to the aromatic nucleus of the spirooxindoles. DFT calculations were performed to rationalize the high antiselectivity. A functionalized spiroproduct was transformed into a cyclic amino acid derivative.
A
accomplished through the remote protected amino substituent. To achieve high antidiastereoselectivity, it was essential to employ a diprotected nitrogen to control the conformation of the cyclopentene ring. The 2,5-dimethylpyrrole and phthalimide protecting groups were identified to be highly effective. Unnatural, rigid, cyclopentene-based amino acids are valuable building blocks used for chemical biology and drug discovery as they may render peptides more stable toward enzymatic hydrolysis.6 They may also be used to induce unique conformations of peptides and peptidomimetics.7 Although unnatural five-membered cyclic amino acids exhibit the potential for important biological and pharmaceutical applications, their synthesis with multiple stereocenters remains challenging. This is reflected in the rather limited diversity in substitution patterns, both among published pharmaceutical lead structures and drugs and in commercially available building blocks.8 Spirooxindoles are present in many natural products9,10 and are important synthetic targets due to their biological activity and applications for pharmaceutical lead discovery.11−16 These amino-functionalized, rigidified molecules provide scaffolds that should be useful in medicinal chemistry projects. Herein, we report a highly selective intramolecular 5-exo Heck−Mizoroki reaction with aryl bromides, providing cyclo-
valuable application of the palladium(0)-catalyzed HeckMizoroki reaction is the intramolecular version occurring between an aromatic halide in proximity to an alkene, leading to a ring-closing reaction.1,2 An advantage of the intramolecular Heck reaction is the commonly exclusive formation of only one ring size, the product resulting from exocyclization.1,2 This rule is valid even in the cases when strong electronic effects favor endoarylation such as in the ring closing of α,β-unsaturated carbonyl compounds. Furthermore, the reaction has been successfully tailored for the assembly of sterically congested quaternary carbon centers with high stereoselectivity.2−4 In our previous work, we focused on the intermolecular vinylation and arylation of cyclopentene acrylate derivatives of class A to provide rigid γ-amino acid derivatives and carbocylic nucleoside precursors (eq 1).5 High stereocontrol was
Received: April 11, 2017 Published: May 4, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b01094 Org. Lett. 2017, 19, 2738−2741
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Organic Letters pentene−spirooxindoles carrying a protected amino group (eq 1). Our investigation toward synthesis of spirooxindoles was initiated with the synthesis of the cyclization precursors 1a−l. We decided to block the amine as a 2,5-dimethylpyrrole since this protection group delivered high yields and selectivities in the intermolecular version of the reaction.5 Optically pure alkene 3 was first prepared from (+)-Vince lactam as previously reported.17,18 It was observed that the amide formation between 2-bromoanilines and the pyrrole-protected esters 1a−l proceeded very well using stoichiometric amounts of AlMe3, irrespective of the different nature of the aniline substituents (Scheme 1).19
Table 1. Optimization of Reaction Conditions for the Intramolecular Heck−Mizoroki Reactiona
entry
Pd (mol %)
ligand
temp (°C)
time (h)
1 2 3 4 5 6 7 8c 9c,d 10e 11 12 13 14 15 16 17f
10 10 10 10 10 10 10 10 10 10 5 2.5 1 5 5 5 10
A B C C D E F F F F F F F F F F F
80 80 80 120 80 80 80 80 80 80 80 80 80 120 60 25 80
6 6 16 16 6 6 6 6 6 8 8 16 16 6 14 20 6
Scheme 1. Synthesis of Substrates for the Intramolecular Heck−Mizoroki Reaction
conversion (product ratio 2a/4a)b 100 100 60 100 100 100 100 100 100 100 100 78 46 100 100 12 60
(53:47) (50:50) (99:1) (98:2) (66:34) (23:77) (99:1) (96:4) (96:4) (95:5) (99:1) (82:18) (66:34) (97:3) (99:1) (99:1) (30:70)
a
Reaction condition: substrate (0.2 mmol), base (0.36 mmol), DMF (1 mL), Pd(OAc)2 (1−10 mol %), ligand (2−20 mol %), Pd to ligand ratio 1:2. bConversion and the product ratio 2/4 was determined by 1 H NMR analysis of the crude reaction mixture. cK2CO3 was used as a base. d10 μL of water was added. eNaOAc was used as a base. f0.2 mmol of Ag2CO3 was added. A = triphenylphosphine, B = tri(otolyl)phosphine, C = tri-tert-butylphosphine tetrafluoroborate, D = Xphos (2-bicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), E = JohnPhos (2-(di-tert-butylphosphino)biphenyl), F = DPPF (1,1′bis(diphenylphosphino)ferrocene).
With starting material 1a in hand, the ring-closing Heck− Mizoroki reaction was evaluated under various reaction conditions. The results are summarized in Table 1. On the basis of the successful results when Pd(OAc)2 was used in the intermolecular Heck−Mizoroki reactions,5 this palladium source was selected together with DMF as the preferred solvent. To develop a protocol with broad scope, a phosphine ligand was included to facilitate use of the less reactive aryl bromides compared to aryl iodides.1,2 All of the phosphine ligands A−F tested under the present conditions were found to be effective in the intramolecular Heck−Mizoroki reaction, providing the desired 5-exo cyclization product 2a with good conversion (entries 1−7). However, with most of these phosphine ligands, an unexpected selective formation of one of two possible double-bond-migrated side products (4a) was detected together with the desired product (2a). Although the stereocenter at the 4-position of the cyclopentene is destroyed when 4a is formed, the stereochemical information was transferred to the spirocyclic center as evidenced by the observed optical rotation (see the Supporting Information). Both the preligand [P(t-Bu)3HBF4] and DPPF were found to strongly suppress the double-bond-migrated product (entries 3, 4, and 7). DPPF was selected as the ligand of choice based on the shorter reaction time required. Further, inorganic bases were also screened but with no added advantage over triethylamine (entries 8−10). A decrease in catalyst loading to 5 mol % from 10 mol % furnished similar conversion and product selectivity with a slight increase in reaction time (entry
11). However, a further decrease in catalyst loading showed adverse effects in terms of both conversion and product selectivity (entries 12 and 13). A variation of the reaction temperature showed that a higher temperature slightly increases the reaction rate with a minor decrease in product selectivity (entry 14). On the other hand, a decrease in reaction temperature leads to a very sluggish reaction with similarly high selectivity (entries 15 and 16). Silver salts have been reported to reduce double-bond isomerizations in a number of published Heck−Mizoroki reactions.5,20,21 However, addition of stoichiometric amounts of Ag2CO3 in the reaction conditions reported in entry 1 makes the reaction very sluggish, and product selectivity dropped (entry 17). Regardless of the selection of ligand and different reaction parameters, it is striking that 2a was obtained as a single diastereomer in all entries of Table 1.22 With the appropriate reaction conditions identified (entry 11, Table 1), the scope and limitations were studied with different functional groups attached to the aromatic ring of the aniline moiety. As depicted in Scheme 2, all of the 4-substituted 2bromoanilines (1a−g) were excellent substrates using the present reaction conditions, both in terms of the yield and the selectivity of the desired product (Scheme 2, 2a−g). The reactions were very robust, delivering the target spiro compounds with no obvious pattern regarding either product yield or selectivity. 2739
DOI: 10.1021/acs.orglett.7b01094 Org. Lett. 2017, 19, 2738−2741
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optimization was carried out for the intramolecular Heck− Mizoroki reaction with 1a, and the results are summarized in Table 2. As seen in Table 2, a further increase in water content increased the amount of dehalogenated product (1l).26 The catalyst loading was also varied, and it was found that 10 mol % catalyst loading was optimal for the reaction in the DMF/water mixture (Table 2, entries 4 and 6−8). The aqueous conditions were employed to screen the general applicability using the previous set of substrates, and the results are summarized in Scheme 3.
Scheme 2. Substrate Scope for Intramolecular Heck− Mizoroki Reaction with DPPF as Ligand
Scheme 3. Substrate Scope for Intramolecular Heck− Mizoroki Reaction Using DMF/Water Mixture and PPh3 as Ligand
In contrast, the presence of a strong electron-donating or -withdrawing group at the 5-position of the aniline reduces the product selectivity to some extent (2i and 2j). The reaction was also found to be somewhat more sluggish with the electrondonating methoxy group para to the bromine, suggesting that the oxidative addition step might be rate determining. This is also in line with the assumption that isomerization takes place after oxidative addition but before migratory insertion. With the more electron-neutral methyl (2h) or carboxylic acid groups in the 5-position, the selectivity remained excellent (2/4 = 99:1). We observed an increase in the reaction rate using microwave heating at 120 °C for 1 h without sacrificing the yield and selectivity of the products 2a and 2k (Scheme 2).23,24 In the isomerization experiments, it was observed that an increased amount of water was beneficial both for the reaction rate and for the product selectivity (Table 2, entries 1−4).25 Thus, in contrast to the results achieved employing a water-free method in Table 1, addition of water allowed the reaction to be carried out using the less expensive PPh3 as ligand. An
In parallel with the outcomes under water-free conditions using DPPF (Table 1), the alkene−spirooxindoles 2b and 2f obtained from 4-substituted anilines displayed higher selectivity toward the desired product as compared to their counterparts obtained from 5-substituted anilines. The applicability of the Heck−Mizoroki ring-closing reaction was shown in the conversion of the spiro product (2k) obtained from a larger scale (1.5 mmol) reaction of substrate (1k) to the aminoester (6) with moderate yield and high diastereoselectivity (Scheme 4).27
Table 2. Optimization of Reaction Condition for Intramolecular Heck−Mizoroki Reaction Using DMF/Water Mixturesa
Scheme 4. Synthesis of Aminoester from Spiro Product by Removal of the Protection Group Pd entry (mol %) 1 2 3 4 5 6 7 8
10 10 10 10 10 5 2.5 1
ligand (mol %)
DMF/ water (v/v)
time (h)
conversion (product ratio 2a/4a/1l)b
20 20 20 20 20 10 5 2
100:0 15:1 10:1 5:1 1:1 5:1 5:1 5:1
6 5 4 2 2 3 4 4
100 (53:47:0) 100 (80:1:19) 100 (84:1:15) 100 (97:1:2) 80 (67:1:32) 100 (89:1:10) 100 (86:6:14) 100(55:29:16)
Despite this Heck−Mizoroki reaction having the opposite regioselectivity in the migratory insertion step to the intermolecular version reported previously,5 the stereoselective control of the cyclization shares the same conformational preferences. In Figure 1 are shown two transition states leading to diastereomeric spirooxindole products. The anti selectivity furnishing the observed product 2a is governed by hyperconjugative interactions between the two axial allylic protons and the forming Pd−C and C−Caryl bonds in the transition
a
Reaction condition: substrate (0.2 mmol), NEt3 (0.36 mmol), DMF/ water (1 mL), Pd(OAc)2 (1−10 mol %), ligand (2−20 mol %). b Conversion and the product ratio was determined by 1H NMR analysis of the reaction mixture. 2740
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(10) Rosenberg, S.; Leino, R. Synthesis 2009, 2009, 2651. (11) Kumari, G.; Nutan; Modi, M.; Gupta, S. K.; Singh, R. K. Eur. J. Med. Chem. 2011, 46, 1181. (12) Lo, M. M. C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077. (13) Vintonyak, V. V.; Warburg, K.; Kruse, H.; Grimme, S.; Hübel, K.; Rauh, D.; Waldmann, H. Angew. Chem., Int. Ed. 2010, 49, 5902. (14) Kornet, M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892. (15) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104. (16) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F. ACS Catal. 2014, 4, 743. (17) Bray, B. L.; Dolan, S. C.; Halter, B.; Lackey, J. W.; Schilling, M. B.; Tapolczay, D. J. Tetrahedron Lett. 1995, 36, 4483. (18) Smith, M. E. B.; Derrien, N.; Lloyd, M. C.; Taylor, S. J. C.; Chaplin, D. A.; McCague, R. Tetrahedron Lett. 2001, 42, 1347. (19) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18, 4171. Other amide bond forming methods, such as carbidiimide couplings, were ineffective. (20) Karabelas, K.; Hallberg, A. J. Org. Chem. 1988, 53, 4909. (21) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250. (22) The relative stereochemistry of 2, anti selectivity, was confirmed in compound 2a by NOE experiments; see the Supporting Information for details. (23) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (24) Nilsson, P.; Gold, H.; Larhed, M.; Hallberg, A. Synthesis 2002, 1611. (25) We performed a number of control experiments to pinpoint a plausible mechanism for formation of isomerized product 4; see the Supporting Information for details. (26) Vallin, K. S. A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66, 4340. (27) Walia, A.; Kang, S.; Silverman, R. B. J. Org. Chem. 2013, 78, 10931. (28) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104.
Figure 1. Transition states for migratory insertion leading to the diastereomeric products. The selectivity for providing 2a was calculated to 4.0 kcal mol−1 by DFT (B3LYP-D3).28
state. These interactions are lost in the syn transition state as the dimethylpyrrole cannot adopt an axial orientation.22 In conclusion, we have developed a new intramolecular stereoselective Heck−Mizoroki reaction affording spirooxindoles of importance as building blocks in medicinal chemistry projects.
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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.7b01094. Experimental details and copies of 1H and 13C NMR spectra for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Peter Brandt: 0000-0002-2885-2016 Mats Larhed: 0000-0001-6258-0635 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS T.R., P.B., J.S., and M.L. thank Uppsala University for support and Professor Adolf Gogoll (Department of Chemistry-BMC, Uppsala University) for valuable NMR discussions.
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REFERENCES
(1) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (2) Larhed, M.; Odell, L. Science of Synthesis: Cross Coupling and Heck-Type Reactions 3, Metal-Catalyzed Heck-Type Reactions, and C−C Cross-Coupling via C−H Activation; Larhed, M., Ed.; Thieme: Stuttgart, 2013. (3) The Mizoroki−Heck Reaction; Oestreich, M., Ed.; John Wiley & Sons, Ltd.: Chichester, 2009. (4) Metal-Catalyzed Cross-Coupling Reactions and More; Meijere, A., de Brase, S., Oestreich, M., Eds.; Wiley-VCH: Weinheim, 2014. (5) Wetzel, A.; Bergman, J.; Brandt, P.; Larhed, M.; Brånalt, J. Org. Lett. 2017, 19, 1602. (6) Baeza, J. L.; de la Torre, B. G.; Santiveri, C. M.; Almeida, R. D.; García-López, M. T.; Gerona-Navarro, G.; Jaffrey, S. R.; Jiménez, M. Á .; Andreu, D.; González-Muñiz, R.; Martín-Martínez, M. Bioorg. Med. Chem. Lett. 2012, 22, 444. (7) Park, K.-H.; Kurth, M. J. Tetrahedron 2002, 58, 8629. (8) Singh, R.; Vince, R. Chem. Rev. 2012, 112, 4642. (9) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. 2741
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