Letter pubs.acs.org/OrgLett
Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki−Heck Reactions Alexander Wetzel,† Joakim Bergman,† Peter Brandt,‡ Mats Larhed,*,§ and Jonas Brånalt*,† †
Department of Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, SE-431 83, Mölndal, Sweden ‡ Department of Medicinal Chemistry, Division of Organic Pharmaceutical 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: Pd(0)-catalyzed Mizoroki−Heck alkenylations and arylations of protected aminocyclopentenes, prepared in a few steps from Vince lactam, afforded functionalized cyclopentenes in high yields and stereoselectivities. DFT calculations were performed to rationalize the high diastereoselectivities. Functionalized cyclopentene products were transformed into valuable chiral building blocks, such as cyclic γ-amino acids and carbocyclic nucleoside precursors. first synthetic approach relied on known hydroarylation and hydroalkenylation of bicyclic olefins.5 However, such olefin addition reactions of Vince lactam resulted in difficult to separate mixtures of regioisomers.6 Instead, we envisioned that an α,β-unsaturated cyclopentene ester of class B,7 which is readily available from (+)-Vince lactam, should allow regioselective conjugate addition of carbon nucleophiles. We also hoped to retain the high facial selectivity observed with Vince lactam by adorning the remote amino functionality of B with bulky protecting groups. Unfortunately, attempts at reacting B with various types of organometallic reagents were met with problems of either low reactivity or low chemoselectivity (1,2 vs 1,4 addition). Thus, we were pleased to find that Mizoroki−Heck8 vinylations and arylations of B proceed with full regioselectivity and with very high stereoselectivity, providing functionalized cyclopentene derivatives in good yields. Herein we report the results of this study as well as subsequent transformations, including highly chemo- and stereoselective hydrogenations to provide valuable rigid γ-amino acids of type A.9 To evaluate the role of the N-protecting group(s) of B on the stereoselectivity of Mizoroki−Heck vinylation reactions, a series of such derivatives were prepared from (+)-Vince lactam, via ring opening to give 1a. Next, a series of sequential N-protection/
N
ature contains a wide array of structurally diverse cyclopentane derivatives with important biological properties.1 The emergence of an increasing number of approved drugs (i.e., Ticagrelor and Peramivir) containing highly substituted cyclopentane moieties also demonstrate the importance of this class of carbocycles within small molecule drug discovery. Yet, exploration of the full potential of the cyclopentane core within medicinal chemistry has been hampered by challenges associated with de novo synthesis of functionalized cyclopentanes in a regio-, stereo-, and enantioselective manner. An alternative synthetic approach utilizes preformed chiral cyclopentane templates as starting materials, i.e. Vince lactam, which is commercially available in both enantiomeric forms and used in large scale production of a number of marketed drugs.2 As such, this latter strategy represents an attractive concept for preparation of novel chiral cyclopentanes, directly applicable for scale up into multigram quantities.3 As part of a drug discovery program,4 we were interested in the preparation of conformationally constrained γ-amino acids of type A (R = aryl, alkyl) and derivatives thereof (eq 1). Our
Received: February 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00325 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
tosyl or trityl showed little improvement (entries 2−3). Unprotected amine 2d (entry 4) gave a complex mixture, probably caused by intermolecular aza-Michael additions. To our delight, bis-protected amino derivatives yielded 4e−g as single stereoisomers (>98:2 dr) (entries 5−7). In addition, derivatives with cyclic protecting groups, such as phthalimide 2h and 2,5-dimethylpyrrole 2i, performed very well (entries 8− 9). The 2,5-dimethylpyrrole protecting group has the advantage of being introduced in a single step and can be removed under conditions orthogonal to other N-protecting groups. Thus, the alkenylation substrate scope was further investigated with 2i (Scheme 2).
olefin isomerization reactions were carried out to deliver cyclopentenes 2a−i (Scheme 1). Scheme 1. Synthesis of N-Protected Cyclopentenes 2a−ia
Scheme 2. Mizoroki−Heck Alkenylations with 2ia,b
a
Yields refer to isolated total yields from (+)-Vince lactam with >95% purity as judged by 1H NMR analysis.
a
Isolated yields with >95% purity as judged by 1H NMR analysis. Diastereomeric ratios were >98:2 for all examples by 1H NMR analysis. bVinyl bromide generated in situ from the corresponding 2,3dibromocarboxylic acid.
With cyclopentenes 2a−i in hand, the yields and diastereoselectivities in Mizoroki−Heck test reactions with vinyl bromide 3a were investigated under so-called Jeffery conditions,10 employing NaHCO3 and TBACl without addition of phosphine ligands11 (Table 1). Mono-Boc-protected amino cyclopentene 2a afforded 4a in good yield, however, as a 1:1 mixture of diastereomers. Changing the N-protecting group to
Good results were obtained in Mizoroki−Heck couplings with both cyclic and acyclic vinyl bromides substituted in the 2position providing 4i−p in 64−85% isolated yields as single stereoisomers (>98:2 dr).12 On the other hand, vinyl bromides with substituents in the 1-position turned out to be unsuitable substrates for the reaction. When applying Jeffery conditions in the Mizoroki−Heck arylation of cyclopentene 2i with phenyl iodide (5a) as an electrophile, the formation of cyclopentene 6a was accompanied by undesired double bond migration resulting in a mixture of arylated products. Efforts to suppress isomerization by using phenyl triflate as an arylpalladium precursor in the absence of TBACl shut down reactivity with unreacted 2i recovered.13 However, use of phenyl iodide and addition of stoichiometric amounts of Ag3PO4 completely suppressed13 undesired olefin isomerization and gave 6a with high selectivity (>98:2 dr) in 64% yield (Scheme 3).12 A variety of different functional groups on the aryl iodide coupling partner were accepted, and cyclopentenes 6b−l were isolated in moderate to good yields as single isomers (>98:2 dr). 1,3Benzodioxole 5i representing an ortho-substituted aryl iodide provided 6i in 63% yield. Notably, under these conditions bromide and chloride substituents (6f−g) were well tolerated. The high diastereoselectivity in the Mizoroki−Heck reactions of bis-protected derivatives of 2, e.g. 2i, might be expected to originate in a steric shielding of the si face by the bulky Nprotecting group and attack of the arylpalladium species from the re face of the cyclopentene (eq 2).
Table 1. Mizoroki−Heck Reaction with Cyclopentenes 2a−i
entry
4
R1
R2
yield (%)a
drb
1 2 3 4 5 6 7 8 9
4a 4b 4c 4d 4e 4f 4g 4h 4i
Boc Tos trityl H Boc Boc Bn phthalimide 2,5-dimethyl-pyrrole
H H H H Boc Bn Bn − −
68 75c 88c −d 66 87 19 84 85
1:1 2:3 1:1 − >98:2 >98:2 >98:2 >98:2 >98:2
a
Isolated yields with >95% purity as judged by 1H NMR analysis. Diastereomeric ratios determined by 1H NMR analysis. cYield estimated from 1H NMR analysis of crude mixture. dComplex mixture.
b
B
DOI: 10.1021/acs.orglett.7b00325 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 3. Mizoroki−Heck Arylations of 2ia
energy difference of 3.4 kcal mol−1 was found in favor of the conformation preferred for the anti-addition. Thus, what eventually gives the selectivity is the difference in conformational strain in the reacting cyclopentene ring. In contrast, for monoprotected derivatives such as Bocprotected 2a, insufficient shielding of the si face results in a 1:1 mixture of diastereomers. The calculated energy difference for this substrate was found to be as low as 0.2 kcal mol−1, in line with the low selectivity reported in Table 1. In this case, both diastereomers are formed via the same conformation of the cyclopentene in the migratory insertion (see Supporting Information). Please note that structurally related substrate 2j has been reported to react with aryl iodides under Jeffery conditions with predominantly si face attack.14 The observed selectivity was explained by coordination of the arylpalladium complex to the carbamate moiety.15,16 Using DFT calculations we have shown that, as for 2a, the monoprotected amine is facing the metal in the migratory insertion (energy difference: −4.7 kcal mol−1). Attempts to hydrogenate the double bonds of 4l with Pd/C in methanol resulted in an unselective reaction and low isolated yield, mainly due to competitive reduction of the pyrrole to the corresponding pyrrolidine (Table 2, entry 1). Changing the
a
Yields refer to isolated yields with >95% purity by 1H NMR analysis. Diastereomeric ratios were >98:2 for all examples by 1H NMR analysis.
Table 2. Stereoselective Hydrogenation of 4l However, the conformational flexibility of a cyclopentene ring allows the protected amine to adopt a position distant from the four-membered migratory insertion reaction center. To better understand the origin of the observed diastereoselectivity, we performed DFT calculations with the oxidative addition complex phenylpalladium acetate and 2i (see Supporting Information). For the initial π-complexes, coordination of Pd(II) syn to the 2,5-dimethylpyrrole group is preferred by 3.8 kcal mol−1. For the migratory insertion to occur, the aryl group on the metal center needs to rotate 90° relative to the double bond of the substrate. This also implies a change in coordination geometry placing the aryl group and the alkene of the substrate together with both oxygens of the acetate in the square plane resulting in a less favorable apical interaction with the methyl group. In Figure 1 are illustrated
a b
entry
additive
solvent
yield (%)a
drb
1 2 3 4 5 6 7
− − − Ph3P PhSH Et3N pyridine
MeOH THF THF/EtOH THF/EtOH THF/EtOH THF/EtOH THF/EtOH
14 n.r. 54 n.r. n.r. 66 85
50:50 − 50:50 − − >98:2 >98:2
Isolated yields with >95% purity as judged by 1H NMR analysis. Diastereomeric ratios determined by 1H NMR analysis.
solvent to THF annulated completely the reactivity of the catalyst (entry 2). By using a mixture of THF and ethanol (1:1), the chemoselectivity was improved; however, the product was still obtained as a mixture of diastereomers. To increase the selectivity, various catalyst poisons17 were added to the reaction mixture (entries 4−7). While triphenylphosphine and benzenethiol gave no reaction at all, nitrogen based catalyst poisons gave excellent stereoselectivities (>98:2 dr). Best results were obtained with pyridine as an additive, giving the desired cyclopentane 7a as a single diastereomer in good yield. The facial selectivity was confirmed by intramolecular NOE correlations from NMR analysis of 7a,12 indicating that the hydrogenation is controlled by steric shielding of the 2,5dimethylpyrrole substituent. These conditions were also applicable for the stereoselective hydrogenation of aryl substituted cyclopentenes, i.e. 6a, with equally good results (Scheme 4). Ester hydrolysis with LiOH followed by Ndeprotection18 with hydroxylamine in MeOH/water delivered γ-amino acids 8a and 8b as single stereoisomers in 58% and 57% yield, respectively, over three steps. Another useful
Figure 1. DFT structures of diastereomeric transition states for the migratory insertion of alkene 2i into the phenylpalladium bond illustrating the preferred conformation of the cyclopentene ring.
two diastereomeric transition states showing the preferred position of the 2,5-dimethylpyrrole group. The calculated energy difference is 3.4 kcal mol−1, which is in good agreement with experiments. To investigate what role the amine substituent plays in the selectivity, calculations on the unsubstituted cyclopentene carboxylic ester were also performed using the two conformations in Figure 1. Again an C
DOI: 10.1021/acs.orglett.7b00325 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 4. Post-Mizoroki−Heck Transformationsa
(4) Bengtsson, C.; Wetzel, A.; Bergman, J.; Brånalt, J. J. Org. Chem. 2016, 81, 708. (5) (a) Larock, R. C.; Gong, W. H.; Baker, B. E. Tetrahedron Lett. 1989, 30, 2603. (b) Ozawa, F.; Kobatake, Y.; Kubo, A.; Hayashi, T. J. Chem. Soc., Chem. Commun. 1994, 1323. (6) For hydroarylation of Vince lactam, see: (a) Abe, T.; Takeda, H.; Takahashi, Y.; Miwa, Y.; Yamada, K.; Ishikura, M. Eur. J. Org. Chem. 2010, 2010, 3281. (b) Piotrowski, D. W.; Polivkova, J. Tetrahedron Lett. 2010, 51, 17. (c) Kamlet, A. S.; Préville, C.; Farley, K. A.; Piotrowski, D. W. Angew. Chem., Int. Ed. 2013, 52, 10607. (7) (a) Bray, B. L.; Dolan, S. C.; Halter, B.; Lackey, J. W.; Schilling, M. B.; Tapolczay, D. J. Tetrahedron Lett. 1995, 36, 4483. (b) Migliore, M. D.; Zonta, N.; McGuigan, C.; Henson, G.; Andrei, G.; Snoeck, R.; Balzarini, J. J. Med. Chem. 2007, 50, 6485. (c) Cai, C.; Kang, F.-A.; Beauchamp, D. A.; Sui, Z.; Russell, R. K.; Teleha, C. A. Tetrahedron: Asymmetry 2013, 24, 651 and references cited therein. (8) Cross-Coupling and Heck-Type Reactions 3. Metal-Catalyzed HeckType Reactions and C−H Coupling; Larhed, M., Odell, L. R., Eds.; Science of Synthesis Reference Library Series: Thieme, 2013. (9) For a review, see: Vagner, J.; Qu, H.; Hruby, V. Curr. Opin. Chem. Biol. 2008, 12, 292. (10) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287. (b) Jeffery, T. Tetrahedron 1996, 52, 10113. (11) Other Heck conditions gave slower reactions and lower yields. (12) Relative stereochemistry determined by NOE correlation studies; see Supporting Information for details. (13) Sonesson, C.; Larhed, M.; Nyqvist, C.; Hallberg, A. J. Org. Chem. 1996, 61, 4756. (14) Ung, A. T.; Pyne, S. G.; Batenburg-Nguyen, U.; Davis, A. S.; Sherif, A.; Bischoff, F.; Lesage, A. S. J. Tetrahedron 2005, 61, 1803. (15) Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66, 544. (16) de Oliveira Silva, J.; Angnes, R. A.; da Silva, V. H. M.; Servilha, B. M.; Adeel, M.; Braga, A. A. C.; Aponick, A.; Correia, C. R. D. J. Org. Chem. 2016, 81, 2010. (17) (a) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465. (b) Augusto, C. C. C.; Zotin, J. L.; da Costa Faro, A., Jr. Catal. Lett. 2001, 75, 37. (18) It is essential to first hydrolyze the ester to avoid epimerization during N-deprotection. (19) For a review, see: Boutureira, O.; Matheu, M. I.; Diaz, Y.; Castillón, S. Chem. Soc. Rev. 2013, 42, 5056.
a
Yields refer to isolated total yields from 4l and 6a with >95% purity by 1H NMR analysis. Diastereomeric ratios by 1H NMR analysis.
transformation involves reduction of 4l and 6a with DIBAl-H and subsequent N-deprotection to furnish allylic alcohols, and carbocyclic nucleoside precursors,19 9a and 9b in 87% and 69% yield, respectively, over two steps. We have developed a new methodology for stereoselective synthesis of cyclopentene derivatives through a substrate controlled Mizoroki−Heck reaction. DFT calculations show that the selectivity is given by control of the cyclopentene conformation. Further, a new method for the chemo- and stereoselective hydrogenation was developed. This route enables stereoselective synthesis of carbocyclic nucleoside precursors and important cyclic γ-amino acids.
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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.7b00325. Experimental details, 1H and 13C NMR spectra for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *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 We thank Magnus Polla, Maria Halvarsson, Staffan Karlsson, Christoffer Bengtsson, Tomas Leek, Lena von Sydow, and Gunnar Grönberg at AstraZeneca.
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REFERENCES
(1) (a) Heasley, B. Eur. J. Org. Chem. 2009, 2009, 1477. (b) Heasley, B. Curr. Org. Chem. 2014, 18, 641. (2) Singh, R.; Vince, R. Chem. Rev. 2012, 112, 4642. (3) Teleha, C. A.; Branum, S.; Zhang, Y.; Reuman, M. E.; Van Der Steen, L.; Verbeek, M.; Fawzy, N.; Leo, G. C.; Kang, F.-A.; Cai, C.; Kolpak, M.; Beauchamp, D. A.; Wall, M. J.; Russell, R. K.; Sui, Z.; Vanbaelen, H. Org. Process Res. Dev. 2014, 18, 1622. D
DOI: 10.1021/acs.orglett.7b00325 Org. Lett. XXXX, XXX, XXX−XXX
