Synlett 2015; 26(13): 1815-1818
© Georg Thieme Verlag Stuttgart · New York
Synthesis of Orthogonally Protected 2,6-Diazaspiro[3.5]nonane and 2,6-Diazaspiro[3.4]octane Analogues as Versatile Building Blocks in Medicinal Chemistry
Received: 25 March 2015
Received: 25 March 2015
Accepted after revision: 07 May 2015
25 June 2015 (online)
A novel and efficient synthesis of orthogonally protected spirocyclic amines is described for the first time.
Key wordsspirocyclic amine - 2,6-diazaspiro[3.5]nonane - 2,6-diazaspiro[3.4]octane - azetidine deprotection - orthogonal protecting groups
References and Notes
- 1 Carter RG, Kuiper DL. Asymmetric Synthesis of Spiroketals, Bisspiroketals, and Spiroaminals . In Stereoselective Synthesis 2: Stereoselective Reactions of Carbonyl and Imino Groups. Vol. 2. Molander GA. Thieme; Stuttgart: 2011: 863-914
- 2 Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TB, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rolemma H, Lu Y, Mansbach RS, Chambers CK, Rovetti CC, Schultz DW, Tingley D, O’Neill BT. J. Med. Chem. 2005; 48: 3474
- 3 Bemis GW, Murcko MA. J. Med. Chem. 1996; 39: 2887
- 4 Wuitschik G, Rogers-Evans M, Buckl A, Bernasconi M, Maerki M, Godel T, Fischer H, Wagner B, Parrilla I, Schuler F, Schneider J, Alker A, Schweizer WB, Mueller K, Carreira EM. Angew. Chem. Int. Ed. 2008; 47: 4512
- 5 Orr ST. M, Cabral S, Fernando DP, Makowski T. Tetrahedron Lett. 2011; 52: 3618
- 6 Sippy KB, Anderson DJ, Bunnelle WH, Hutchins CW, Schrimpf MR. Bioorg. Med. Chem. Lett. 2009; 19: 1682
- 7 Grygorenko OO, Radchenko DS, Volochnyuk DM, Tolmachev AA, Komarov IV. Chem. Rev. 2011; 111: 5506
- 8 McClure KF, Jackson M, Cameron KO, Kung DW, Perry DA, Orr ST. M, Zhang Y, Kohrt J, Tu M, Gao H, Fernando D, Jones R, Erasga N, Wang G, Polivkova J, Jiao W, Swartz R, Ueno H, Bhattacharya SK, Stock IA, Varma S, Bagdasarian V, Perez S, Kelly-Sullivan D, Wang R, Kong J, Cornelius P, Michael L, Lee E, Janssen A, Steyn SJ, Lapham K, Goosen T. Bioorg. Med. Chem. Lett. 2013; 23: 5410
- 9 Engel W, Eberlein W, Trummlitz G, Mihm G, Doods H, Mayer N, de Jonge A. EP 417631, 1991
- 10 The benzoyl group was chosen as protecting group for the nitrogen since protection with benzyl chloride or bromide proceeded with lower yield (69%).
- 11 Holl R, Jung B, Schepmann D, Humpf H.-U, Gruenert R, Bednarski PJ, Englberger W, Wuensch B. ChemMedChem 2009; 4: 2111
- 12 Fyfe MC. T, Gattrell W, Rasamison CM. WO 116230, 2007
- 13 Shiozaki M, Ishida N, Hiraoka T, Maruyama H. Tetrahedron 1984; 40: 1795
- 14 Fukuyama T, Jow C.-K, Cheung M. Tetrahedron Lett. 1995; 36: 6373
- 15 Typical Procedure for Nosyl Group Removal Cs2CO3 (22.64 g, 0.069 mol) and thiophenol (5.21 mL, 0.051 mol) were successively added to a solution of nosyl-protected spiro amine 10 (18.6 g, 0.046 mol) in MeCN (150 mL). The mixture was stirred at r.t. for 16 h. After this time the starting material was consumed as judged by TLC. The reaction mixture was filtered through a short layer of Celite. The cake was washed first with EtOAc (300 mL) and further with CH2Cl2–MeOH–NH3 (7 M in MeOH, 80:18:2, 3 × 100 mL), and the collected organic layer was concentrated to give in total 31.3 g of the crude oil, which was absorbed on the minimum of silica gel and poured into a chromatography column containing a 1 cm layer of silica gel. The elution was carried out with EtOAc to wash off unpolar impurities and then with the system CH2Cl2–MeOH–NH3 (7 M in MeOH, 80:18:2) to give the product 11 (8.8 g, 89% yield) as yellow oil. LCMS (214 nm): t R = 7.8 min (89.1% content), [M + H]+ = 217.0. TLC analysis: Rf = 0.07 in CH2Cl2–MeOH–NH3 (7 M in MeOH). 1H NMR (400 MHz, CD3OD): δ = 7.36–7.19 (m, 5 H), 3.51 (s, 2 H), 3.38–3.33 (m, 4 H), 2.53–2.28 (m, 4 H), 1.65 (s, 2 H), 1.60–1.51 (m, 2 H). 13C NMR (101 MHz, CD3OD): δ = 137.93, 128.91, 127.92, 126.84, 62.73, 61.32, 55.05, 53.12, 38.27, 33.82, 21.78.
- 16 Terao Y, Kotaki H, Imai N, Achiwa K. Chem. Pharm. Bull. 1985; 33: 2762
- 17 Intermediate 18 was also obtained from the dimesyl analogue of 17; however, the isolated yield was lower (51%).
- 18 The p-toluenesulfonamide derivative of intermediate 18 was obtained, and the deprotection to spirocyclic amine 19 was carried out with Red-Al® in toluene under reflux; however, the isolated yield of was lower.