Simultaneous Deprotection and Purification of BOC-amines Based on Ionic Resin Capture

Combinatorial chemistry and the synthesis of chemical libraries has resulted in a need to develop new strategies to rapidly and simply purify, isolate, and manipulate library members during each synthetic step. Two major strategies have been used. The first uses cross-linked polymers such as those used in Merrifield’s solid-phase peptide synthesis.1,2 The second strategy uses soluble polymer supports or biphasic syntheses.3,4 The recent development of polymer-supported quenching reagents as a rapid purification tool in solution-phase parallel synthesis is an outgrowth of the former strategy.5 This chemistry typically relies on molecular reactivity and/or molecular recognition (often acid-base chemistry) as the means by which excess reagents or byproducts are sequestered and isolated. On the other hand, the “resin capture” idea has also recently been introduced as an alternative solution-phase library methodology.6 This method uses functionalized resins to trap selectively (via a covalent bond linkage) the desired products away from solution-phase reagents or byproducts. The products are then released from the resin through an appropriate cleavage step. Herein, we disclose a new and simple ionic equivalent of this resin capture technique as demonstrated by the deprotection and purification of solutionphase BOC-protected amines through the use of a strongly acidic macroreticular ion-exchange resin, Amberlyst 15. The tert-butyloxycarbonyl (BOC) group is widely used in organic synthesis as an amine protecting group. Deprotection of BOC-protected amines is usually achieved by using an acid like CF3COOH or HCl.7 Recently, ionexchange chromatography was used to expedite purification of libraries of amines or amine derivatives.8 We reasoned that a strongly acidic ion-exchange resin should be able to both deprotect BOC-protected amines and to also isolate the resulting amine products. This expectation has been successfully realized. In a typical procedure, N-BOC-(R)-R-methylbenzylamine (1) was treated with cleaned Amberlyst 15 by gentle agitation at 25 °C in CH2Cl2. All the BOC-amine 1 was deprotected in 12 h (Scheme 1). The reaction was readily monitored by TLC or HPLC. Complete disappearance of the BOC derivative by these methods served to indicate when complete deprotection of the BOC-amine had occurred. The pure (R)-R-methylbenzylamine (3) was then isolated in 93% yield in a second step by gently shaking the amine bound resin 2 with excess ammonia in methanol for 50 min. No additional purification steps were required. Various other BOC-protected amines were also deprotected satisfactorily as shown in Table 1. The deprotection/immobilization process took place smoothly in dichloromethane, THF, or chloroform but was very slow in methanol. We found that both primary and secondary BOCprotected aliphatic amines can be deprotected efficiently * To whom correspondence should be addressed. (D.B.) Tel.: (409) 845-3437. Fax: (409) 845-4719. E-mail: Bergbreiter@chemvx.tamu.edu. (D.R.) Tel.: (409) 845-9571. Fax: (409) 845-4719. E-mail: Romo@ chemvx.tamu.edu. (1) For some recent reviews, see: (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449-472. (b) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555-600. (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144-154. (d) Curran, D. P. Chemtracts-Org. Chem. 1996, 9, 75-87. (e) Terret, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135-8173. (2) (a) Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17-42. (b) Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org. Chem. 1996, 61, 924-928. (3) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489-509. (4) (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823-826. (b) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531-2532. (c) Carell, T.; Wintner, E. A.; Bashir-Hashemi, A.; Rebek, J., Jr. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 2059-2061. (5) (a) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882-4886. (b) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; Woodard, S. J. Am Chem. Soc. 1997, 119, 4874-4881. (c) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. J. Tetrahedron Lett. 1996, 37, 7193-7196. (6) (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574-2583. (b) Brown, S. D.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 6331-6332. (7) Greene, T. W. In Protective Groups in Organic Synthesis; John Wiley & Sons: New York, 1981; Chapter 7, pp 232-233. (8) Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360. Scheme 1