Synlett 2015; 26(08): 1063-1068
DOI: 10.1055/s-0034-1379900
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Cyclic Analogue of Tuv N-Methyl Tubulysin

Yunjeong Park
a  College of Pharmacy & Graduate School of Pharmaceutical Sciences, Global Top 5 Research Program, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemun-Gu, Seoul 120-750, Republic of Korea   Email: ryuj@ewha.ac.kr
,
Jae Kyun Lee
b  Center for Neuro-Medicine, Korea Institute of Science & Technology, Hwarangro 14-gil, Seongbuk-Gu, Seoul 136-791, Republic of Korea
,
Jae-Sang Ryu*
a  College of Pharmacy & Graduate School of Pharmaceutical Sciences, Global Top 5 Research Program, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemun-Gu, Seoul 120-750, Republic of Korea   Email: ryuj@ewha.ac.kr
› Author Affiliations
Further Information

Publication History

Received: 16 January 2015

Accepted after revision: 09 February 2015

Publication Date:
09 March 2015 (online)


Abstract

Tubulysins are the most potent antimitotic agents known so far. We are interested in the conformational effect of tubulysin and herein we report the design and synthesis of a conformationally rigid cyclic analogue of Tuv N-methyl tubulysin. A conformationally rigid tetrahydropyran moiety was incorporated into the Tuv fragment via enantioselective hetero Diels–Alder reaction to prevent the rotation of the Tuv chain. The following diastereoselective reductive amination yielded the (4-methylamino)tetrahydropyranyl Tuv fragment, which was coupled to d-Mep-l-Ile dipeptide fragment and Tup fragment sequentially.

Supporting Information

 
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  • 16 Synthesis of 1: To a solution of tetrapeptide methyl ester 15 (86.2 mg, 126 μmol) in 1,4-dioxane (1.2 mL) was added 1 M NaOH (252 μL, 252 μmol) dropwise at 0 °C. The reaction mixture was stirred at 4–8 °C for 29 h. After evaporating the volatiles under reduced pressure, the residue was dissolved in H2O (0.5 mL), acidified to pH 2 with 1 M HCl, and then concentrated by rotary evaporation. The residue was purified by column chromatography (CH2Cl2–MeOH, 10:1 → 5:1) to afford the conformationally rigid Tuv N-methyl tubulysin analogue 1 (65.4 mg, 78%) as a white solid. TLC: Rf 0.43 (CH2Cl2–MeOH, 7:1); mp 104–106 °C; [α]D 26.7 –25.6 (c = 0.75, MeOH). IR (KBr, film): 3388, 2961, 1640, 1548 cm–1. 1H NMR and 13C NMR data confirmed a 1.4:1 mixture of rotamers. Major and minor rotamers: 1H NMR (400 MHz, CD3OD): δ = 8.06 (s, 1 H), 8.04 (s, 1.4 H), 7.18–7.22 (m, 9.6 H), 7.12–7.16 (m, 2.4 H), 4.78–4.88 (m, 3.4 H), 4.82 (dd, J = 11.2, 2.4 Hz, 1.4 H), 4.70 (d, J = 8.4 Hz, 1.4 H), 4.62 (tm, J = 12.0 Hz, 1 H), 4.31–4.36 (m, 2.4 H), 4.20–4.28 (m, 2.4 H), 3.87 (td, J = 12.0, 1.6 Hz, 1 H), 3.78 (td, J = 12.0, 1.6 Hz, 1.4 H), 3.12 (s, 4.2 H), 2.86–3.10 (m, 4.4 H), 2.89 (d, J = 6.8 Hz, 1.4 H), 2.87 (s, 3 H), 2.79 (dd, J = 10.8, 2.8 Hz, 1.4 H), 2.47–2.52 (m, 2.4 H), 2.41 (d, J = 12.8 Hz, 1 H), 2.22–2.34 (m, 3.8 H), 2.29 (s, 7.2 H), 2.11 (m, 1 H), 1.78–2.01 (m, 15.8 H), 1.66–1.72 (m, 4.8 H), 1.57–1.65 (m, 9.6 H), 1.34–1.41 (m, 2.4 H), 1.18–1.25 (m, 2.4 H), 1.14 (d, J = 6.8 Hz, 7.2 H), 0.98 (d, J = 6.8 Hz, 7.2 H), 0.94 (t, J = 7.6 Hz, 3 H), 0.93 (t, J = 7.6 Hz, 4.2 H). 13C NMR (100 MHz, CD3OD): δ = 182.2, 182.0, 174.1, 173.8, 173.7, 173.6, 173.4, 173.1, 163.1, 163.0, 150.7 (2 × C), 139.7, 139.6, 130.6, 130.5, 129.3, 129.2, 127.4, 127.3, 124.8, 124.7, 77.7, 77.4, 69.8, 69.6, 68.5, 68.2, 56.6, 56.5, 55.2, 54.8, 54.7, 52.0, 51.1, 50.9, 44.3, 44.2, 42.1, 41.9, 39.6, 39.4, 39.2, 39.1, 38.3, 38.2, 37.6, 36.8, 31.2, 31.1, 31.0, 30.9, 29.7, 28.5, 25.8 (2 × C, identified from HSQC), 25.7, 25.5, 23.8, 23.7, 18.9, 18.8, 16.2, 15.9, 11.4, 11.3. HRMS (ESI): m/z calcd for C35H51N5O6S: 669.3560; found: 669.3569.