2,6-Bis(trifluoromethyl)phenylboronic Esters as Protective Groups for

Letter Cite This: Org. Lett. 2018, 20, 6064−6068

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2,6-Bis(trifluoromethyl)phenylboronic Esters as Protective Groups for Diols: A Protection/Deprotection Protocol for Use under Mild Conditions Naoyuki Shimada,*,† Sari Urata,† Kenji Fukuhara,† Takao Tsuneda,‡ and Kazuishi Makino*,† †

Org. Lett. 2018.20:6064-6068. Downloaded from pubs.acs.org by UNIV OF NEW ENGLAND on 10/05/18. For personal use only.

Laboratory of Organic Chemistry for Drug Development and Medical Research Laboratories, Department of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan ‡ Fuel Cell Nanomaterials Center, University of Yamanashi, Kofu 400-0021, Japan S Supporting Information *

ABSTRACT: The application of 2,6-bis(trifluoromethyl)phenyl boronic acid (o-FXylB(OH) 2 ; o-FXyl = 2,6(CF3)2C6H3) as a recoverable and reusable protective agent for diols is described. The resulting cyclic boronic esters are water- and air-stable and tolerant to various organic transformations. Moreover, they can be deprotected under mild conditions. This methodology was applied to the synthesis of a highly conjugated enetriyne natural product with antiangiogenic activities.

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chromatography, and a wide range of organic transformations has led to the search for more-versatile protective agents that are based on boronic acid. Recently, research groups led by Marder and Jäkle10 reported air- and moisture-stable triarylboranes containing the 2,4,6-tris(trifluoromethyl)phenyl (FMes) group.11 The two ortho-trifluoromethyl substituents of the FMes group sterically protect the B atom of the triarylboranes, which can be further functionalized without decomposition. However, to the best of our knowledge, studies on the stabilities and reactivities of the corresponding boronic acids and esters have not reported. In the present study, we demonstrate the stability of 2,6bis(trifluoromethyl)phenylboronic esters in aqueous media and, thus, the application of 2,6-bis(trifluoromethyl)phenyl boronic acid (o-FXylB(OH)2; o-FXyl = 2,6-(CF3)2C6H3, 1a)12 as an effective diol-protecting agent (see Figure 1). We initially investigated the formation of cyclic boronic esters between 1a and different diols (Scheme 1). In the optimized procedure,13 a mixture of diol (1.0 equiv) and 1a (1.0 equiv) in dichloroethane was stirred under reflux for 24 h. After the reaction mixture was cooled to ambient temperature, the solvent was evaporated to give the cyclic boronic ester in quantitative yield at a satisfactory level of purity. Notably, all the 2,6-bis(trifluoromethyl)phenylboronic esters obtained were compatible with silica gel, allowing convenient reaction monitoring by TLC and facile purification by silica gel chromatography. Acyclic 1,2- and 1,3-diols furnished the corresponding boronic esters 3a−3e in high to excellent yields (80%−99%). The reaction of (±)-hydrobenzoin afforded the

espite remarkable recent advances in the strategies and methodologies available to synthetic organic chemists, protective groups still play an indispensable role in the synthesis of multifunctional organic compounds. Accordingly, the advent of a new protective group that offers selective protection, orthogonal deprotection, and tolerance against various chemical transformations provides new synthetic approaches to more complex and multifunctional organic compounds. Since the diol functional group is a ubiquitous structural motif in biomolecules such as carbohydrates, nucleosides, and many other biologically active natural products, the development of an effective diol-protecting group is highly desired. A large number of protective groups for 1,2- and 1,3-diols have been developed.1 As a result, cyclic acetals, ketals, carbonates, and siloxanes as protective groups for diols are most commonly used. However, the introduction and removal of these protective groups generally require acidic or basic conditions, presenting problems when substrates containing labile functional groups are employed. It is well-known that boronic acids form covalent bonds with 1,2- or 1,3-diols to generate five- or six-membered cyclic boronic esters under mild and neutral conditions.2,3 Therefore, boronic acids such as phenyl boronic acid and polymersupported boronic acids have been used as protective or transient masking agents for diols.1,4,5 However, cyclic arylboronic esters, except those derived from highly hindered substrates,6−9 are susceptible to hydrolysis, even under neutral conditions. Consequently, this poor stability limits the reaction conditions under which this protective strategy may be applied. Accordingly, the need for diol-protecting groups that form water- and air-stable adducts, regardless of substrate structure, and that are tolerant to aqueous workup, silica gel © 2018 American Chemical Society

Received: August 1, 2018 Published: September 18, 2018 6064

DOI: 10.1021/acs.orglett.8b02427 Org. Lett. 2018, 20, 6064−6068

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Organic Letters

Scheme 2. Stabilities of Arylboronic Esters in Aqueous Media

Figure 1. Diol protection using o-FXylB(OH)2.

Scheme 1. Formation of Cyclic Boronic Esters between oFXylB(OH)2 and Different Diols

hydrolysis of 2,6-bis(trifluoromethyl)phenylboronic ester 3e, which incorporates trifluoromethyl groups instead of methyl groups in both ortho positions, proceeded very slow to exhibit an exceptionally prolonged half-life of 27 days.14 To demonstrate the utility of 2,6-bis(trifluoromethyl)phenylboronic ester as a protective group for diols, we next explored several applicable chemical transformations (Scheme 3). The sequential protection and deprotection of the hydroxy group in 3k using acetyl,15 benzyl, and triethylsilyl groups Scheme 3. Transformation of 2,6Bis(trifluoromethyl)phenylboronic Esters

a

Reaction time: 60 h

trans-cyclicboronate 3f in 83% yield. The cyclic cis-1,2cyclohexanediol 2g was converted to the corresponding bicyclic boronic esters 3g, whereas trans-1,2-cyclohexanediol did not form a boronic esters 3g, whereas trans-1,2cyclohexanediol did not form a boronic ester under the conditions applied. The reaction of the five- and eightmembered cyclic cis-1,2-diols such as cyclopentanediol (2h) and cyclooctanediol (2i) provided the corresponding bicyclic boronic esters 3h and 3i in 90% yield, respectively. The reaction of 2-hydroxybenzyl alcohol 2j, which contains a phenolic hydroxy group, afforded the stable cyclic boronic ester 3j in 84% yield. Regioselective formation of a cyclic boronic ester was accomplished in the case of triol 2k, providing the six-membered cyclic boronic ester 3k in high yield. Thus, the selective protection of a 1,3-diol in the presence of a 1,4-diol moiety is possible using 1a. We next estimated the half-lives of boronic esters 3e, and 3l−3n in aqueous media by 1H NMR experiments to investigate the structure−stability relationship of cyclic arylboronic esters (Scheme 2). The solvolysis of phenylboronic ester 3e and 2-trifluoromethylphenylboronic ester 3l occurred in CD3OD/D2O (9:1) at room temperature within 5 min to afford diol 2e-d2 quantitatively. The sterically crowded 2,6dimethylphenylboronic ester 3n exhibited a certain degree of tolerance in aqueous media, but its half-life (t1/2) was still only 6 h, even under neutral conditions. In stark contrast, the

AcCl, collidine, CH2Cl2, rt, 99%. bDIBAL-H, CH2Cl2, −78 °C, 78%. BnBr, Ag2O, (CH2Cl)2, reflux, 81%. dH2, Pd/C, MeOH, rt, 97%. e TESOTf, 2,6-lutidine, CH2Cl2, rt, 91%. f1 M HCl/THF (1:1), rt, 74%. g(COCl)2, DMSO, Et3N, CH2Cl2, −78 °C to 0 °C, 89%. h Dess−Martin periodinane, CH2Cl2, rt, 75%. iNaBH4, MeOH, 0 °C, 90%. jPhMgBr, Et2O, rt, 70%. k(1) BnNH2, CH2Cl2, rt; (2) NaBH4, MeOH, 0 °C, 86%. lPh3PCH3Br, n-BuLi, THF, 0 °C, 99%. mPh3P = CHCO2Me, CH2Cl2, rt, 80%. nCrCl2, CHI3, 1,4-dioxane, 10 °C, 68% (E/Z = 93:7). oNaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, rt, 86%. pp-TsOH·H2O, MeOH, rt, 74%. qBnNH2, EDCI, HOBt, CH2Cl2, rt, 83%. rm-CPBA, CH2Cl2, 0 °C, 94%. sMethyl vinyl ketone, Grubbs second catalyst, CH2Cl2, rt, 81%. t(CH2CH)SnBu3, PdCl2(PPh3)2, THF, rt, 63% (E/Z = 93:7). a c

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Organic Letters proceeded in good to high yields, demonstrating that the 2,6bis(trifluoromethyl)phenylboronic ester group exhibits excellent orthogonality to these other protective groups. The 2,6-bis(trifluoromethyl)phenylboronic ester was also tolerant to Swern oxidation and Dess−Martin oxidation to provide aldehyde 5. Addition to 5 using a Grignard reagent afforded alcohol 6 in 70% yield. Reductive amination of 5 with benzylamine proceeded to give amine 7 in 86% yield. Carbonchain elongations via Wittig reactions with an unstable and a stable ylide were applicable to 5, affording alkene 3c and α,βunsaturated ester 8, respectively, in excellent yields. Aldehyde 5 was also converted to iodoolefin 9 in 68% yield by CrCl2promoted Takai olefination. Generally, boronic acid derivatives are unstable under oxidative conditions. However, 5 was converted to the carboxylic acid 10 by Pinnick−Kraus oxidation in high yield (86%) without any decomposition of the boronic ester. Moreover, carboxylic acid 10 was easily transformed to methyl ester 11 by acid-catalyzed esterification in methanol. Amide bond formation between carboxylic acid 11 and benzyl amine in the presence of EDCI/HOBt afforded amide 12 in 83% yield. It is also noteworthy that m-CPBA epoxidation conditions, which caused decomposition of the corresponding phenylboronic ester, can be applied to 2,6bis(trifluoromethyl)phenylboronic ester 3c, affording epoxide 13 in 94% yield. We also explored transition-metal-catalyzed reactions. Olefin cross-metathesis of alkene 3c with methyl vinyl ketone, using a second-generation Grubbs catalyst, provided enone 14 with exclusive E stereochemistry in 81% yield. Palladium-complexcatalyzed Stille coupling of iodolefin 9 proceeded smoothly to give diene 15 in 63% yield. Thus, these results demonstrate that the 2,6-bis(trifluoromethyl)phenyl boronic ester group can be used to protect diols and is tolerant against typical organic transformations such as oxidation, reduction, hydrogenolysis, C−C/C−N bond formation, amide condensation, organometallic addition, and transition-metal-catalyzed cross coupling. We then investigated the deprotection of the boronic ester. Transesterification with diols is widely used for the deprotection of boronic esters.1 Although this method allows deprotection under neutral conditions, the reverse reaction, which reproduces the starting material during workup, is often problematic. Moreover, an elaborate purification step is required to separate the deprotected product and the newly generated boronic ester. To overcome these limitations, we employed transesterification using 2-amino-2-methyl-1,3-propanediol (16) for the deprotection protocol (see Scheme 4A). After optimization of the reaction conditions, we found that the deprotection of boronic ester 3e proceeded smoothly to give diol 2e within 24 h in 93% yield by treatment with 16 in methanol at 50 °C.16 Since an excess of diol 16 and the boronic ester generated from 16 can be removed via simple aqueous workup, the desired diol 2e was obtained at a satisfactory level of purity without any other purification procedures. To the best of our knowledge, this is the first report of the use of 16 in the deprotection of boronic esters by transesterification. In terms of synthetic utility, the recovery of the protective agent is desirable. Accordingly, we focused on developing an alternative deprotection protocol by which 1a could be recovered (see Scheme 4B). The reaction of boronic ester 3e with aqueous potassium hydrogen fluoride17 produced diol 2e in 91% yield and the corresponding potassium trifluor-

Scheme 4. Deprotection of Boronic Ester 3e

oborate 17 as a highly crystalline solid in quantitative yield. Thus, the separation of diol 2e and potassium trifluoroborate 17 can be achieved by simple filtration. Subsequently, 17 can be converted to 1a in good yield by treatment with trimethylsilyl chloride18 in aqueous acetonitrile. Thus, we found that 1a can be used as a recoverable and reusable protective agent for diols. In order to demonstrate the synthetic utility of the 2,6bis(trifluoromethyl)phenylboronic ester group as a protective group for diols, 1,3-dihydroxy-6(E)-tetradecene-8,10,12-triyne (18),19 which exhibits significant anti-angiogenic activities and the ability to regulate the expression of cell cycle mediators, was synthesized using our protection−deprotection protocol. The Pd-catalyzed Stille coupling of iodoolefin 9 with 1tributylstanyl-1,3,5-heptatriyne 1920 proceeded smoothly to provide enetriyne 20 in 85% yield (E/Z = 93:7) (see Scheme 5). Deprotection of boronic ester 20 by transesterification Scheme 5. Synthesis of an Enetriyne Natural Product

using 16 under mild conditions completed the first synthesis of 18. It is noteworthy that our mild deprotection conditions were tolerant of the enetriyne framework without any decomposition. To investigate the factors responsible for the unique properties of 2,6-bis(trifluoromethyl)phenylboronic ester, we performed geometric optimization on boronic esters 3o−3r by long-range correction21a for Becke 1988 exchange22 and oneparameter progressive correlation21b functional (LC-BOP) with the cc-pVTZ basis set on the developmental version of the Gaussian 09 program (see Figure 2). The B atoms in the optimized structures of boronic esters 3o−3r adopt trigonal planar geometry, and the angle between the 1,3,2-dioxaborinane ring and the benzene ring is influenced by the presence of substituent(s) at the ortho position(s) of the benzene ring. 6066

DOI: 10.1021/acs.orglett.8b02427 Org. Lett. 2018, 20, 6064−6068

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Takao Tsuneda: 0000-0002-0249-5276 Kazuishi Makino: 0000-0001-8518-6593 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported, in part, by a Kitasato University Research Grant for Young Researchers. We thank Dr. K. Nagai and Ms. M. Sato (Kitasato University) for instrumental analyses.

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Figure 2. Optimized structures of boronic esters 3o−3r by density functional theory (DFT) calculation.

The optimized structure of phenylboronic ester 3p adopts a virtually coplanar conformation of the 1,3,2-dioxaborinane and benzene rings (dihedral angle of O1−B1−C1−C2: 0.1°). In contrast, the planes of the 1,3,2-dioxaborinane rings in 3o, 3q, and 3r, which have substituent(s) at the ortho position(s), are twisted out of the planes of the benzene rings (dihedral angles of O1−B1−C1−C2: 71.3° for 3o, 45.9° for 3q, and 114.4° for 3r). Because of this twisted angle of the 1,3,2-dioxaborinane ring from the plane of the benzene ring, the bulky substituents in both ortho positions effectively shield the B atom against attack by water, molecular oxygen, and other nucleophiles approaching the 1,3,2-dioxaborinane ring perpendicularly. Clearly, this effect is more pronounced for the more bulky trifluoromethyl groups.23 In summary, we have demonstrated 2,6-bis(trifluoromethyl)phenyl boronic ester as a protective group for 1,2and 1,3-diols. Our novel protocol exhibits the following characteristic features: (1) introduction of the protecting group can be performed without any additives under neutral conditions; (2) 2,6-bis(triflulromethyl)phenylboronic ester tolerates a wide range of organic transformations; (3) deprotection of the protective group can be performed under mild conditions; and (4) the protective agent, o-FXylB(OH)2 (1a), can be recovered and reused. Thus, this methodology serves as an alternative to the use of acetals, ketals, carbonates, and siloxanes for the protection of diols.

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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.8b02427. Full experimental procedures, spectroscopic characterizations computational data, and copies of NMR spectra (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (N. Shimada). *E-mail: [email protected] (K. Makino). ORCID

Naoyuki Shimada: 0000-0002-0143-7867 6067

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Organic Letters (10) (a) Yin, X.; Chen, J.; Lalancette, R. A.; Marder, T. B.; Jäkle, F. Angew. Chem., Int. Ed. 2014, 53, 9761−9765. (b) Zhang, Z.; Edkins, R. M.; Nitsch, J.; Fucke, K.; Steffen, A.; Longobardi, L. E.; Stephan, D. W.; Lambert, C.; Marder, T. B. Chem. Sci. 2015, 6, 308−321. (c) Zhang, Z.; Edkins, R. M.; Haehnel, M.; Wehner, M.; Eichhorn, A.; Mailänder, L.; Meier, M.; Brand, J.; Brede, F.; Müller-Buschbaum, K.; Braunschweig, H.; Marder, T. B. Chem. Sci. 2015, 6, 5922−5927. (d) Yin, X.; Guo, F.; Lalancette, R. A.; Jäkle, F. Macromolecules 2016, 49, 537−546. (e) Meng, B.; Ren, Y.; Liu, J.; Jäkle, F.; Wang, L. Angew. Chem., Int. Ed. 2018, 57, 2183−2187. (11) For a review on the effects of steric and electronic stabilization of 2,4,6-tris(trifluoromethyl)phenyl group for transition-metal complexes and typical element compounds based on the X-ray structures, see: Edelmann, F. T. Comments Inorg. Chem. 1992, 12, 259−284. (12) Dillon and Fox’s group reported the synthesis and characterization of o-FXylB(OH)2 (1a): Cornet, S. M.; Dillon, K. B.; Entwistle, C. D.; Fox, M. A.; Goeta, A. E.; Goodwin, H. P.; Marder, T. B.; Thompson, A. L. Dalton Trans 2003, 4395−4405. We prepared 1a from 1,3-bis(trifluoromethyl)benzene using the modified their method, which was documented in the Supporting Information. oFXylB(OH)2 (1a) is now commercially available (13) The optimization of reaction conditions for the formation of cyclic boronic esters was summarized in the Supporting Information. (14) In the 11B-NMR spectra of boronic ester 3e, the boron nucleus appears at δ 27.94 ppm in CDCl3 and δ 27.93 ppm in CD3OD/D2O (9:1), respectively. This result indicated that the boron atom in 3e adopt trigonal planar geometry even in aqueous media. (15) The selective deprotection of acetyl group in 3d using LiOH in THF−H2O was problematic, and gave the triol instead of 3k. In this context, Perrin reported protodeboronation of arylboronic acids with 2,6-electron-withdrawing groups under basic conditions. See: Lozada, J.; Liu, Z.; Perrin, D. M. J. Org. Chem. 2014, 79, 5365−5368. (16) The more sterically hindered 2,6-diisopropylphenyl boronic ester of diol 2e was also compatible with aqueous treatment and silica gel chromatography. However, the deprotection did not occur under this condition. Accordingly, the presence of both ortho trifluoromethyl groups of o-FXylB(OH)2 (1a) are crucial for the use of protective agent. (17) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020−3027. (b) Churches, Q. I.; Hooper, J. F.; Hutton, C. A. J. Org. Chem. 2015, 80, 5428−5435. (18) Yuen, A. K. L.; Hutton, C. A. Tetrahedron Lett. 2005, 46, 7899− 7903. (19) Rü cker, G.; Kehrbaum, S.; Sakulas, H.; Lawong, B.; Goeltenboth, F. Planta Med. 1992, 58, 266−269. (20) (a) Mukai, C.; Miyakoshi, N.; Hanaoka, M. J. Org. Chem. 2001, 66, 5875−5880. (b) Kumar, C. R.; Tsai, C.-H.; Chao, Y.-S.; Lee, J.-C. Chem. - Eur. J. 2011, 17, 8696−8703. (21) (a) Tsuneda, T.; Hirao, K. WIREs Comput. Mol. Sci. 2014, 4, 375−390. (b) Tsuneda, T.; Suzumura, T.; Hirao, K. J. Chem. Phys. 1999, 110, 10664−10678. (22) Becke, A. D. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098− 3100. (23) Additional discussions based on the DFT calculations of 3o−3r were documented in the Supporting Information.

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