Synlett 2018; 29(06): 769-772
DOI: 10.1055/s-0037-1609150
letter
© Georg Thieme Verlag Stuttgart · New York

Synthetic Studies of Haliclonin A: Construction of the 3-Azabicyclo[3.3.1]nonane Skeleton with a Bridge that Forms the 17-Membered Ring

Kensuke Orihara
a   Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan   Email: yokosima@ps.nagoya-u.ac.jp   Email: fukuyama@ps.nagoya-u.ac.jp
,
Fumiki Kawagishi
a   Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan   Email: yokosima@ps.nagoya-u.ac.jp   Email: fukuyama@ps.nagoya-u.ac.jp
b   Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
,
a   Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan   Email: yokosima@ps.nagoya-u.ac.jp   Email: fukuyama@ps.nagoya-u.ac.jp
,
Tohru Fukuyama*
a   Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan   Email: yokosima@ps.nagoya-u.ac.jp   Email: fukuyama@ps.nagoya-u.ac.jp
› Author Affiliations
This work was financially supported by JSPS KAKENHI (Grant ­Numbers 25221301 and 16H01141) and by the Platform Project for Supporting Drug Discovery and Life Science Research from the Japan Agency for Medical Research and Development (AMED).
Further Information

Publication History

Received: 24 November 2017

Accepted after revision: 17 December 2017

Publication Date:
29 January 2018 (online)


Abstract

The core structure of haliclonin A, a 3-azabicyclo[3.3.1]­nonane with a bridge that forms a 17-membered ring, was constructed. The synthesis features a ring-closing metathesis that constructs the macrocyclic ring, the stereoselective introduction of carbon units via the intra­molecular cyclopropanation of a diazoester, the conjugate addition of an organocopper reagent, and the formation of 3-azabi­cyclo­[3.3.1]­nonane skeleton via an unexpected 1,5-hydride shift.

Supporting Information

 
  • References and Notes

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  • 10 (1R,15R,22R,Z)-4-Tosyl-22-vinyl-17-oxa-4-azatricyclo[13.6.2.015,20]tricos-18-en-21-one To a solution of 15 (25.9 mg, 53.4 μmol) and CuI (7.5 mg, 53.4 μmol) in THF (1.5 mL) was added vinylmagnesium chloride in THF (1.45 M, 73.6 μL, 0.107 mmol) at 0 °C. After stirring for 1 h at 0 °C, aq NH3 was added, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (30% EtOAc/hexane) to afford 16 (20.0 mg, 39.0 μmol, 73%) as a colorless foam. IR (neat): 2930, 2856, 1700, 1645, 1540, 1456, 1339, 1157, 913. 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.2 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 2 H), 6.37 (dd, J = 6.0, 2.8 Hz, 1 H), 5.65 (ddd, J = 16.6, 10.1, 9.1 Hz, 1 H), 5.16 (d, J = 16.6 Hz, 1 H), 5.13 (d, J = 9.1 Hz, 1 H), 4.42 (dd, J = 6.0, 2.3 Hz, 1 H), 3.65 (d, J = 11.0 Hz, 1 H), 3.51 (d, J = 11.0 Hz, 1 H), 3.34 (t, J = 6.4 Hz, 2 H), 3.20 (ddd, J = 16.0, 11.0, 5.5 Hz, 1 H), 3.09 (ddd, J = 16.0, 11.0, 4.6 Hz, 1 H), 2.98 (m, 1 H), 2.43 (m, 1 H), 2.41 (s, 3 H), 2.27 (ddd, J = 11.5, 5.5, 2.8 Hz, 1 H), 2.07 (dd, J = 13.3, 13.3 Hz, 1 H), 1.94 (m, 1 H), 1.64 (m, 1 H), 1.55 (m, 2 H), 1.26–1.37 (m, 17 H). 13C NMR (100 MHz, CDCl3): δ = 213.0 (C), 143.8 (CH), 142.7 (CH), 140.7 (C), 138.1 (C), 129.4 (CH), 127.1 (CH), 115.9 (CH2), 98.7 (CH), 72.2 (CH2), 50.6 (CH), 47.0 (CH2), 46.8 (CH), 44.3 (CH2), 40.8(CH), 36.4 (C), 35.5 (CH2), 34.1 (CH2), 28.1 (CH2), 27.8 (CH2), 27.5 (CH2), 27.4 (CH2), 27.3 (CH2), 26.5 (CH2), 24.8 (CH2), 24.6 (CH2), 21.5 (CH3), 20.8 (CH2). HRMS (ESI+): m/z calcd for C30H43N1O4SNa: 536.2811; found: 536.2803.
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  • 12 After acidic hydrolysis of the cyclic acetal moiety in 20 with aqueous acetic acid at 80 °C, the resulting hemiacetal was treated with O-methylhydroxylamine hydrochloride in pyridine with the goal of cleaving the hemiacetal. The reaction did not occur, even at 80 °C. When the reaction was carried out at 100 °C, the hemiacetal moiety was opened, forming an oxime ether, and lactone formation occurred between the liberated hydroxy group and the amide moiety.
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  • 14 Swern or PCC oxidation caused oxidation of the thioacetal moiety, giving the mono-S-oxide. TPAP oxidation yielded the desired aldehyde 21 in a moderate yield, accompanied by the production of a sizable amount of the corresponding S-oxide.
  • 15 (1R,15R,16S,20R,21R)-20-[(1,3-Dithian-2-ylidene)methyl]-18-[(Z)-octa-4,7-dien-1-yl]-17-oxo-12-tosyl-12,18-diazatricyclo[13.4.2.11,16]docosan-21-yl acetate To a solution of 21 (2.0 mg, 2.53 μmol) in toluene (0.5 mL) was added CSA (1.2 mg, 5.17 μmol) and quinoline (0.3 μL, 24.9 μmol) at room temperature. After stirring for 9.5 h at 80 °C, 1 N HCl was added, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. This material was used for the next step without further purification. To a solution of the crude material in 5% TFA/DCE (0.5 mL) was stirred at 50 °C. After stirring for 1 h at 50 °C, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc/hexane) to afford 24 (1.2 mg, 1.56 μmol, 62%, 2 steps) as a colorless oil. IR (neat): 2923, 2551, 1737, 1541, 1276, 1159, 1000, 990 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 5.80 (dddd, J = 17.4, 11.9, 6.4, 3.7 Hz, 1 H), 5.74 (d, J = 10.0 Hz, 1 H), 5.47 (ddd, J = 10.1, 6.4, 5.5 Hz, 1 H), 5.42 (ddd, J = 10.1, 6.4, 6.4 Hz, 1 H), 5.03 (dd, J = 17.4, 1.8 Hz, 1 H), 4.97 (m, 1 H), 4.97 (m, 1 H), 3.52 (ddd, J = 13.7, 10.1, 6.4 Hz, 1 H), 3.31–3.24 (m, 3 H), 3.19–3.00 (m, 3 H), 2.92–2.74 (m, 8 H), 2.50 (m, 1 H), 2.41 (s, 3 H), 2.29 (m, 1 H), 2.17–1.97 (m, 4 H), 1.97 (s, 3 H), 1.82 (m, 1 H), 1.74 (m, 1 H), 1.73 (m, 1 H), 1.68 (m, 1 H), 1.56–1.25 (m, 19 H), 0.96 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 170.6 (C), 169.7 (C), 143.1 (C), 136.9 (CH), 136.1 (C), 132.5 (C), 129.8 (CH), 129.7 (CH), 128.6 (CH), 127.6 (CH), 127.1 (CH), 114.7 (CH2), 70.9 (CH), 54.5 (CH2), 50.3 (CH2), 48.2 (CH2), 46.5 (CH2), 43.2 (CH), 41.6 (CH), 38.3 (CH2), 37.8 (CH), 31.5 (CH2), 30.4 (CH2), 30.0 (CH2), 29.7 (CH2), 29.6 (C), 29.4 (CH2), 29.0 (CH2), 28.6 (CH2), 28.1 (CH2), 27.7 (CH2), 27.1 (CH2), 26.9 (CH2), 26.5 (CH2), 25.8 (CH2), 25.0 (CH2), 24.7 (CH2), 23.1 (CH2), 21.5 (CH3), 21.1 (CH3). HRMS (ESI+): m/z calcd for C42H62N2O5S3Na 793.3718; found: 793.3699