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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Chemoselective Deprotection of the 2,2,2Trichloroethoxycarbonyl (Troc) Protecting Group Barry M. Trost,* Christopher A. Kalnmals,† Jacob S. Tracy,† and Wen-Ju Bai Department of Chemistry, Stanford University, Stanford, California 94305, United States
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S Supporting Information *
ABSTRACT: Nonreducing, pH-neutral conditions for the selective cleavage of the 2,2,2-trichloroethoxycarbonyl (Troc) protecting group are reported. Using trimethyltin hydroxide in 1,2-dichloroethane, Troc-protected alcohols, thiols, and amines can be selectively unmasked in the presence of various functionalities that are incompatible with the reducing conditions traditionally used to remove the Troc group. This mild deprotection protocol tolerates a variety of other hydrolytically sensitive and acid/base-sensitive moieties as well.
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Scheme 1. Troc Deprotection Methods
he 2,2,2-trichloroethoxycarbonyl (Troc) group was developed for protecting alcohols and amines by Windholz and Johnston based on Woodward’s use of 2,2,2trichloroethyl esters as masked carboxylic acids.1,2 The Troc group is easily installed by acylating the substrate with the corresponding chloroformate and is typically removed using zinc dust in a protic solvent, such as acetic acid or methanol. This useful protecting group resists acidic hydrolysis and is typically unaffected by fluoride, hydrogenolysis, and singleelectron oxidation, making it orthogonal to common alcohol and amine protecting groups.3 In a testament to its utility, the Troc protecting group has been used extensively in the synthesis of biologically important natural products.4 While the reducing conditions usually employed to remove the Troc group make it orthogonal to many other protecting groups, they also limit the scope of functionality that can be present elsewhere in the molecule. For example, the standard zinc acetic acid deprotection conditions can also reduce carbon−halogen bonds, heteroatom−heteroatom bonds, activated carbonyls, and heterocycles.5 Furthermore, the use of Zn/AcOH to remove Troc groups has occurred with the concomitant deprotection of silyl ethers,4i acetals,6 and acetonides.7 Milder deprotections can be achieved using alternative reducing conditions, such as cadmium−lead couple,8 indium,9 or zinc in the presence of N-methylimidazole,10 but the functional group compatibility of these methods is still limited with regards to reductively sensitive groups (Scheme 1). While Troc removal via hydrolysis seems attractive, literature conditions rely on the use of strongly acidic 11 or strongly basic 12 conditions that may be incompatible with other hydrolizable groups, such as esters. Additionally, epimerizable stereocenters can also be problematic under these conditions. Given these limitations, a general nonreductive method for the selective removal of Troc groups under neutral conditions would significantly expand the utility of this useful protecting group. © XXXX American Chemical Society
Recently, we happened upon a remarkably mild set of conditions for the selective hydrolysis of Troc protected alcohols with trimethyltin hydroxide, a reagent which was previously reported by Nicolaou to selectively hydrolyze methyl esters with exquisite specificity.13 When we applied these conditions to a substrate containing a Troc-protected alcohol and a methyl ester, we were surprised to see complete hydrolysis of the Troc group before observing any reactivity at the ester. Intrigued by this selective deprotection, we investigated this reaction more carefully. Treatment of 1a with 5 equiv of trimethyltin hydroxide in DCE at 60 °C for 2.5 h resulted in isolation of alcohol 2a in 93% yield with no evidence of any ester hydrolysis (Table 1, entry 1). Using 2 equiv of trimethyltin hydroxide resulted in a similar yield, but required a 24-h reaction time to achieve full conversion (entry 2). Fortunately, the reaction time could be significantly shortened by increasing the reaction concentration Received: November 14, 2018
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DOI: 10.1021/acs.orglett.8b03642 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 2. Reaction Scopea
Table 1. Optimization of Reaction Conditions
entry
X (equiv)
time (h)
conc (M)
yield of 2a (%)
1 2 3 4 5 6 7 8
5 2 2 2 1.1 1.5 1.5 1.5
2.5 24 10.5 7 17 19 34 20
0.1 0.1 0.2 0.4 0.4 0.4 0.4 0.6
93 90 90 92 66 70 56 60
a
Yields are isolated yields.
(entries 3 and 4). In general, decreasing the amount of trimethyltin hydroxide led to slower reactions and lower isolated yields due to competitive formation of polycaprolactone (entries 5, 6, and 8). When the conditions in entry 6 were repeated with a longer 34-h reaction time, the isolated yield of 2a dropped from 70% to 56%, indicating that free alcohol 2a is serving as a source of monomer for the formation of polycaprolactone (entry 7). The use of trimethyltin hydroxide was critical; no conversion was observed with trimethylsilanol, while potassium trimethylsilanolate gave partial conversion to 2a with concurrent formation of symmetrical carbonate 3. With optimized conditions (Table 1, entry 4) in hand, we set out to explore the scope of this mild deprotection method (Scheme 2). The affinity of trimethyltin hydroxide for Troc carbonates in the presence of esters is retained even when the protected alcohol is more hindered than the ester, as demonstrated by the selective deprotection of ethyl lactate derivative 1b and steroidal alcohol 1c. It was also possible to remove the Troc group from a thiol in the presence of an nbutyl ester (1d). Common hydrolytically labile ester-based protecting groups, including benzoate (1e) and especially acetate (1f), are also compatible with our conditions, and complete selectivity for the Troc group was observed in both cases. To push the limits of our deprotection method, we evaluated a substrate bearing both a Troc and a similarly electron-deficient Alloc group (1g). Remarkably, although the 13 C NMR shifts of the two carbonyl groups in 1g differ by only 1 ppm, trimethyltin hydroxide was completely selective for the hydrolysis of the Troc carbonate. A trialkyl phosphate (1h) was unaffected, and acid-sensitive blocking groups, including a TBS ether (1i) and a THP acetal (1j), were also retained. Notably, the deprotection of 1i could be performed on 1.0 mmol scale with 1.2 equiv of Me3SnOH without any ill effects, and 2i was obtained in 89% yield. In addition to being highly selective for Troc carbonates in the presence of other hydrolizable groups, our nonreducing deprotection conditions are compatible with a variety of other redox-sensitive functionality, including both alkyl (1k) and aryl (1l) bromides. Aryl iodides are also compatible, as exemplified by the deprotection of iodoaniline 1m, a noteworthy result given the lower reactivity of carbamates toward hydrolysis relative to carbonates. Chalcones such as 1n are rapidly reduced by zinc14 but are unharmed by trimethyltin hydroxide. Notably, our conditions are also compatible with a variety of
a
Yields are isolated yields. b80% 1H NMR yield relative to internal standard; 56% isolated yield due to volatility of 2b. c3.0 equiv of Me3SnOH. d89% isolated yield on 1.0 mmol scale. e4.0 equiv of Me3SnOH. B
DOI: 10.1021/acs.orglett.8b03642 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
broad range of functionality, including halide, disulfide, oxime, diazo, and nitro groups that would react under the reductive conditions historically used to cleave Troc groups. Our procedure is scalable and can be used to perform selective deprotections on polyfunctional molecules without affecting epimerizable stereocenters. This alternative deprotection method significantly expands the scope of functional groups that were previously incompatible with the Troc group, greatly enhancing its utility in organic synthesis.
heteroatom−heteroatom bonds, which are particularly sensitive to reduction. With disulfide 1o, the use of 4 equiv of Me3SnOH allowed us to remove both Troc groups. For substrate 1p, deprotection occurred without hydrolysis or isomerization of the oxime. Lastly, we were pleased to find that a tertiary Troc carbonate (1q) could also be hydrolyzed, and while the reaction was noticeably slower, 2q was obtained in good yield. To further highlight the selectivity and mildness of our Troc hydrolysis protocol, we performed several deprotections on some challenging polyfunctional substrates (Scheme 3).
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ASSOCIATED CONTENT
S Supporting Information *
Scheme 3. Reaction Scope with Polyfunctional Substratesa
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03642. Experimental details and spectroscopic data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Barry M. Trost: 0000-0001-7369-9121 Christopher A. Kalnmals: 0000-0003-3233-290X Jacob S. Tracy: 0000-0001-9261-7865 Wen-Ju Bai: 0000-0003-1412-8673 Author Contributions †
C.A.K. and J.S.T. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS J.S.T. acknowledges support from the Franklin Veatch Memorial Award Fellowship.
a
Yields are isolated yields. b2.5 equiv of Me3SnOH. c3.0 equiv of Me3SnOH at rt.
REFERENCES
(1) (a) Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbrüggen, H. The Total Synthesis of Cephalosporin C. J. Am. Chem. Soc. 1966, 88, 852− 853. (b) Woodward, R. B. Recent Advances in the Chemistry of Natural Products. Science 1966, 153, 487−493. (2) Windholz, T. B.; Johnston, D. B. R. Trichloroethoxycarbonyl: A Generally Applicable Proecting Group. Tetrahedron Lett. 1967, 8, 2555−2557. (3) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons: Hoboken, NJ, 2007. (4) For select references utilizing Troc protected alcohols in the synthesis of natural products: (a) Imoto, M.; Yoshimura, H.; Sakaguchi, N.; Kusumoto, S.; Shiba, T. Total Synthesis of Escherichia Coli Lipid A. Tetrahedron Lett. 1985, 26, 1545−1548. (b) Wakamatsu, K.; Kigoshi, H.; Niiyama, K.; Niwa, H.; Yamada, K. Stereocontrolled Total Synthesis of (+)-Tutin and (+)-Asteromurin, a Toxic Picrotoxane Sesquiterpenes. Tetrahedron 1986, 42, 5551−5558. (c) Meyers, A. I.; Dupre, B. An Asymmetric Total Synthesis of Unnatural (+)-Anisomycin. Heterocycles 1987, 25, 113−116. (d) Wanner, M. J.; Willard, N. P.; Koomen, G.-J.; Pandit, U. K. Stereospecific Synthesis of (+)- and (−)-Sesbanimide A. Tetrahedron 1987, 43, 2549−2556. (e) Sasaki, M.; Murae, T.; Takahashi, T. Synthesis of (±)-15-Deoxybruceolide and Conversion of (−)-15Deoxybruceolide into (−)-Bruceantin: Total Synthesis of Bruceantin. J. Org. Chem. 1990, 55, 528−540. (f) Fariña, F.; Noheda, P.; Paredes, M. C. Total Synthesis of (±)-5-Iminodaunomycinone and (±)-4Demethoxy-5-iminodaunomycine. Tetrahedron Lett. 1991, 32, 1109−
Because of the reduction-sensitive aryl halides and acidsensitive aminal present in alkaloid intermediate 1r, selective removal of the Troc group under standard Zn/AcOH conditions would be challenging, but proceeded uneventfully with trimethyltin hydroxide. Amino acid derived substrates were particularly reactive, and it was necessary to run the deprotection reactions at room temperature instead of 60 °C. Under these modified conditions, selective removal of the Troc carbonate from triply protected serine 1s was achieved without disturbing the methyl ester or the base-sensitive Fmoc carbamate. Notably, the epimerizable α-stereocenter was untouched, in good accordance with Nicolaou’s observations. Similar results were obtained with another triply protected amino acid, Trt-Ser(Troc)-OMe (1t). Lastly, Troc-protected dye 1u, which contains reduction-sensitive diazo, nitro, and chloro moieties, was successfully unmasked without any complications. In closing, we demonstrate that the Troc protecting group can be selectively removed from alcohols, thiols, and amines under mild, nonreducing, pH-neutral15 conditions using trimethyltin hydroxide. This protocol tolerates hydrolytically sensitive esters, including acetates and benzoates, as well as other common alcohol protecting groups, such as TBS, THP, and Alloc. Furthermore, our method is compatible with a C
DOI: 10.1021/acs.orglett.8b03642 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters 1112. (g) Matsuura, F.; Hamada, Y.; Shioiri, T. Total Synthesis of 2’Deoxymugineic Acid and Nicotianamine. Tetrahedron 1994, 50, 9457−9470. (h) Trost, B. M.; Patterson, D. E.; Hembre, E. J. Dynamic Kinetic Asymmetric Transformations of Conduritol B Tetracarboxylates: An Asymmetric Synthesis of D-myo-Inositol 1,4,5-Trisphosphate. J. Am. Chem. Soc. 1999, 121, 10834−10835. (i) Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima, I. Enantioselective Total Synthesis of (−)-Taxol. J. Am. Chem. Soc. 2000, 122, 3811−3820. (j) Trost, B. M.; Patterson, D. E.; Hembre, E. J. AAA in KAT/ DYKAT Processes: First and Second-Generation Asymmetric Synthesis of (+)- and (−)-Cyclophellitol. Chem. - Eur. J. 2001, 7, 3768− 3775. (k) Tanada, Y.; Mori, K. Eur. J. Org. Chem. 2001, 2001, 4313− 4319. (l) Bode, J. W.; Carreira, E. M. Stereoselective Synthesis of Epothilones A and B via Nitrile Oxide Cycloadditions and Related Studies. J. Org. Chem. 2001, 66, 6410−6424. (m) Valluri, M.; Hindupur, R. M.; Bijoy, P.; Labadie, G.; Jung, J.-C.; Avery, M. A. Total Synthesis of Epothilone B. Org. Lett. 2001, 3, 3607−3609. (n) Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell, M. D.; Chou, T.C.; Guan, Y.; Tong, W. P.; He, L.; Horwitz, S. B.; Danishefsky, S. J. Highly Concise Routes to Epothilones: The Total Synthesis and Evaluation of Epothilone 490. J. Am. Chem. Soc. 2002, 124, 9825− 9832. (o) Njardarson, J. T.; Biswas, K.; Danishefsky, S. J. Application of Hitherto Unexplored Macrocyclization Strategies in the Epothilone Series: Novel Epothilone Analogs by Total Synthesis. Chem. Commun. 2002, 2759−2761. (p) Jung, J.-C.; Kache, R.; Vines, K. K.; Zheng, Y.S.; Bijoy, P.; Valluri, M.; Avery, M. A. Total Synthesis of Epothilones B and D. J. Org. Chem. 2004, 69, 9269−9284. (q) Doi, T.; Numajiri, Y.; Munakata, A.; Takahashi, T. Total Synthesis of Apratoxin A. Org. Lett. 2006, 8, 531−534. (r) Chen, J.; Chen, X.; Willot, M.; Zhu, J. Asymmetric Total Synthesis of Ecteinascidin 597 and Ecteinascidin 583. Angew. Chem., Int. Ed. 2006, 45, 8028−8032. (s) Bader, B.; von Bonin, A.; Buchmann, B.; Gay, J.; Gruendemann, S.; Guenther, J.; Schaefer, M.; Spellig, T.; Zollner, T. M.; Zorn, L. Synthesis of 3HLabeled Efomycine M. Tetrahedron Lett. 2007, 48, 5984−5986. (t) Shirai, A.; Miyata, O.; Tohnai, N.; Miyata, M.; Procter, D. J.; Sucunza, D.; Naito, T. Total Synthesis of (−)-Mertinellic Acid via Radical Addition-Cyclization-Elimination Reaction. J. Org. Chem. 2008, 73, 4464−4475. (u) Numajiri, Y.; Takahashi, T.; Doi, T. Total Synthesis of (−)-Apratoxin A, 34-Epimer, and Its Oxazoline Analogue. Chem. - Asian J. 2009, 4, 111−125. (v) Imamura, A.; Ando, H.; Ishida, H.; Kiso, M. Ganglioside GQ1b: Efficient Total Synthesis and the Expansion to Synthetic Derivatives to Elucidate its Biological Roles. J. Org. Chem. 2009, 74, 3009−3023. (w) Doi, T.; Numajiri, Y.; Takahashi, T.; Takagi, M.; Shin-ya, K. Solid-Phase Total Synthesis of (−)-Apratoxin A and its Analogues and Their Biological Evaluation. Chem. - Asian J. 2011, 6, 180−188. (x) Nakashima, S.; Ando, H.; Saito, R.; Tamai, H.; Ishida, H.; Kiso, M. Efficiently Synthesizing Lacto-Ganglio-Series Gangliosides by Using a Glucosyl Ceramide Cassette Approach: The Total Synthesis of Ganglioside X2. Chem. - Asian J. 2012, 7, 1041−1051. (y) Robertson, B. D.; Wengryniuk, S. E.; Coltart, D. M. Asymmetric Total Synthesis of Apratoxin D. Org. Lett. 2012, 14, 5192−5195. (z) Masuda, Y.; Suzuki, J.; Onda, Y.; Fujino, Y.; Yoshida, M.; Doi, T. Total Synthesis and Conformational Analysis of Apratoxin C. J. Org. Chem. 2014, 79, 8000−8009. (aa) Ahlers, A.; de Haro, T.; Gabor, B.; Fürstner, A. Concise Total Synthesis of Enigmazole A. Angew. Chem., Int. Ed. 2016, 55, 1406−1411. (ab) Wu, P.; Cai, W.; Chen, Q.-Y.; Xu, S.; Yin, R.; Li, Y.; Zhang, W.; Luesch, H. Total Synthesis and Biological Evaluation of Apratoxin E and Its C30 Epimer: Configurational Reassignment of the Natural Product. Org. Lett. 2016, 18, 5400− 5403. (5) Ham, P.; Pilgrim, B. S.; Simon, R. J. G. Zinc-Acetic Acid. eEncyclopedia of Reagents for Organic Synthesis; John Wiley & Sons: 2017. (6) Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. A Highly Efficient Route to Taxotere by the β-Lactam Synthon Method. Tetrahedron Lett. 1993, 34, 4149−4152.
(7) Wiegerinck, P. H. G.; Sperling, D.; Braamer, L.; Damen, E. W. P.; Scheeren, J. W. Water Soluble Analogs and Prodrugs of Paclitaxel. PCT WO 00/10988, March 2, 2000. (8) Dong, Q.; Anderson, E.; Ciufolini, M. A. Reductive Cleavage of Troc Groups Under Neutral Conditions with Cadmium-Lead Couple. Tetrahedron Lett. 1995, 36, 5681−5682. (9) Valluri, M.; Mineno, T.; Hindupur, R. M.; Avery, M. A. IndiumMediated Chemoselective Deprotection of Trichloroethoxycarbonyl and Trichloroacetate Groups. Tetrahedron Lett. 2001, 42, 7153−7164. (10) Somsák, L.; Czifrák, K.; Veres, E. Selective Removal of 2,2,2Trichloroethyl- and 2,2,2-Trichloroethoxycarbonyl Protecting Groups With Zn-N Methylimidazole in the Presence of Reducible and AcidSensitive Functionalities. Tetrahedron Lett. 2004, 45, 9095−9097. (11) (a) Nikolaides, N.; Ganem, B. Design and Synthesis of Substrate Analogs for the Inhibition of Dehydroquinate Synthase. Tetrahedron Lett. 1989, 30, 1461−1464. (b) Jones, R. C. F.; Tankard, M. Enantiospecific Synthesis of the Hexahydrofuran Unit of Erythroskrine, a Pentaenoyltetramic Acid Metabolite. J. Chem. Soc., Chem. Commun. 1990, 765−767. (12) (a) Hashimura, K.; Tomita, S.; Hiroya, K.; Ogasawara, K. A Stereocontrolled Route to Both Enantiomers of the Necine Base Dihydroxyheliotridane via Intramolecular 1,3-Dipolar Addition Using the Same Chiral Precursor. J. Chem. Soc., Chem. Commun. 1995, 2291−2292. (b) Lee, C. B.; Chou, T.-C.; Zhang, X.-G.; Wang, Z.-G.; Kuduk, S. D.; Chappell, M. D.; Stachel, S. J.; Danishefsky, S. J. Total Synthesis and Antitumor Activity of 12,13-Desoxyepothilone F: An Unexpected Solvolysis Problem at C15, Mediated by Remove Substitution at C21. J. Org. Chem. 2000, 65, 6525−6533. (c) See 4j. (d) See 4t. (13) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. A Mild and Selective Method for the Hydrolysis of Esters with Trimethyltin Hydroxide. Angew. Chem., Int. Ed. 2005, 44, 1378−1382. (14) For a representative example, see: Srinivasan, B.; Johnson, T. E.; Lad, R.; Xing, C. Structure-Activity Relationship Studies of Chalcone Leading to 3-Hydroxy-4,3′,4’,5′-Tetramethoxychalcone and Its Analogues as Potent Nuclear Factor kB Inhibitors and Their Anticancer Activities. J. Med. Chem. 2009, 52, 7228−7235. (15) Furlán, R. L. E.; Mata, E. G.; Mascaretti, O. A. Efficient, NonAcidolytic Method for the Selective Cleavage of N-Boc Amino Acid and Peptide Phenacyl Esters Linked to a Polystyrene Resin. J. Chem. Soc., Perkin Trans. 1 1998, 355−358.
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DOI: 10.1021/acs.orglett.8b03642 Org. Lett. XXXX, XXX, XXX−XXX
