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Synlett 2007(9): 1375-1378  
DOI: 10.1055/s-2007-980359
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Hydrophobically Modified Analogues of Adenophorine

Kamyar Afarinkia*a, Akmal Bahara, Judi Neussb
a Institute of Cancer Therapeutics, University of Bradford, Bradford, BD1 7DP, UK
b Celltech R&D Ltd., 208 Bath Road, Slough, Berkshire, SL1 3WE, UK
Fax: +44(1274)233234; e-Mail: k.afarinkia@bradford.ac.uk;
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Publication History

Received 20 February 2007
Publication Date:
23 May 2007 (online)

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Abstract

The synthesis of 3-methyl-4-deoxyadenophorine and three related analogues is reported.

Key words

azasugars - Diels-Alder cycloaddition - Stille reaction - stereoselectivity - regioselectivity

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1

Previous address: Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK.

20

Compound 17: IR (film): νmax = 1772 (s, lactone) cm-1. MS (CI, NH3): m/z (%) = 306 (100) [MH+]. HRMS (ESI+): m/z calcd for C17H24NO4 [MH+]: 306.1700; found: 306.1702. 1H NMR (360 MHz, CDCl3): δ = 1.09 (t, 3 H, J = 7.5 Hz, CH2CH 3), 1.27 (s, 3 H, CH3), 1.42-1.57 (m, 1 H, CHHCH3), 1.59-1.70 (m, 1 H, CHHCH3), 1.90 (dd, 1 H, J = 2.5, 15.2 Hz, H-7a), 2.24 (ddd, 1 H, J = 2.2, 9.7, 15.2 Hz, H-7b), 3.03 (dt, 1 H, J = 2.2, 10.4 Hz, H-6), 3.56 (s, 3 H, OCH3), 3.80 (dd, 1 H, J = 2.5, 9.7 Hz, H-8), 4.62 (d, 1 H, J = 12.3 Hz, CHHPh), 4.84 (d, 1 H, J = 12.3 Hz, CHHPh), 7.25-7.37 (m, 5 H, Ph). 13C NMR (90 MHz, CDCl3): δ = 11.2 (CH2 CH3), 21.7 (CH3), 25.0 (CH2CH3), 37.3 (C-7), 52.1 (OCH3), 62.6 (C-6), 73.6 (CH2Ph), 74.3 (C-8), 82.7 (C-1/C-4), 87.4 (C-4/C-1), 127.5 (2 × CH, Ph), 127.7 (CH, Ph), 128.4 (2 × CH, Ph), 138.4 (Cipso), 171.4 (C-3).
Compound 18: mp 75-77 °C. IR (mull): νmax = 1760 (s, lactone) cm-1. MS (CI, NH3): m/z (%) = 323 (100) [MNH4 +]. HRMS (ESI+): m/z calcd for C17H24NO4 [MH+]: 306.1700; found: 306.1702. 1H NMR (360 MHz, CDCl3): δ = 1.01 (t, 3 H, J = 6.9 Hz, CH2CH 3), 1.35 (s, 3 H, CH3), 1.52-1.60 (m, 2 H, CH 2CH3), 1.86 (app. dt, 1 H, J = ca. 2.0 Hz, J d = 14.9 Hz, H-7b), 2.32 (dd, 1 H, J = 8.8, 14.9 Hz, H-7a), 2.93 (dt, 1 H, J = 1.7, 10.6 Hz, H-6), 3.55 (s, 3 H, OCH3), 3.76 (dd, 1 H, J = 2.5, 8.8 Hz, H-8), 4.63 (d, 1 H, J = 12.2 Hz, CHHPh), 4.77 (d, 1 H, J = 12.2 Hz, CHHPh), 7.27-7.38 (m, 5 H, Ph). 13C NMR (100 MHz, CDCl3): δ = 10.9 (CH2 CH3), 21.8 (CH3), 25.8 (CH2CH3), 36.7 (C-7), 51.3 (OCH3), 62.1 (C-6), 71.7 (CH2Ph), 74.7 (C-8), 82.5 (C-1/C-4), 87.0 (C-4/C-1), 127.7 (CH, Ph), 127.9 (2 × CH, Ph), 128.4 (2 × CH, Ph), 137.9 (Cipso), 169.9 (C-3).

21

Compound 5: IR (CH2Cl2): νmax = 3354 (br, OH) cm-1. MS (CI, NH3): m/z (%) = 190 (100) [MH+]. HRMS (ESI+): calcd for C9H20NO3 [MH+]: 190.1438; found: 190.1439. 1H NMR (400 MHz, CD3OD): δ = 1.17 (t, 3 H, J = 7.6 Hz, CH2CH 3), 1.27 (s, 3 H, CH3), 1.56-1.66 (m, 1 H, CHHCH3), 1.68-1.82 (m, 1 H, H-4a), 2.00-2.09 (m, 1 H, CHHCH3), 2.19 (d, 1 H, J = 4.4, 12.4 Hz, H-4b), 2.91-2.98 (m, 2 H, H-2, H-6), 3.80 (ddd, 1 H, J = 4.4, 10.5, 11.8 Hz, H-5), 3.96-3.99 (m, 2 H, CH 2 OH). 13C NMR (100 MHz, CD3OD): δ = 12.3 (CH2 CH3), 21.8 (CH3), 22.3 (CH2CH3), 49.4 (C-4), 58.9 (CH2OH), 64.8 (C-6), 65.9 (C-2), 67.1 (C-5), 70.7 (C-3).
Compound 6: IR (CH2Cl2): νmax = 3354 (br, OH) cm-1. MS (CI, NH3): m/z (%) = 190 (100) [MH+]. HRMS (ESI+): calcd for C9H20NO3 [MH+]: 190.1438; found: 190.1440. 1H NMR (400 MHz, CD3OD): δ = 1.14 (t, 3 H, J = 7.5 Hz, CH2CH 3), 1.25 (s, 3 H, CH3), 1.68-1.82 (m, 1 H, CHHCH3), 1.84-1.93 (m, 2 H, CHHCH3, H-4a), 2.02 (dd, 1 H, J = 3.3, 15.4 Hz, H-4b), 3.17-3.26 (m, 1 H, H-2), 3.33 (ddd, 1 H, J = 1.6, 3.3, 4.9 Hz, H-6), 3.86 (d, 2 H, J = 6.8 Hz, CH 2 OH) 4.02-4.07 (m, 1 H, H-5). 13C NMR (100 MHz, CD3OD): δ = 12.1 (CH2 CH3), 21.9 (CH2CH3), 26.7 (CH3), 38.2 (C-4), 60.8 (CH2OH), 63.9 (C-6), 57.3 (C-2), 66.8 (C-5), 72.4 (C-3).
Compound 7: IR (CH2Cl2): νmax = 3378 (br, OH) cm-1. MS (CI, NH3): m/z (%) = 190 (100) [MH+]. HRMS (ESI+): calcd for C9H20NO3 [MH+]: 190.1438; found: 190.1444. 1H NMR (500 MHz, CD3OD): δ = 1.01 (t, 3 H, J = 7.5 Hz, CH2CH 3), 1.18 (s, 3 H, CH3), 1.35-1.69 (m, 3 H, CH 2 CH3, H-4a), 1.91 (dd, 1 H, J = 5.3, 13.4 Hz, H-4b), 2.17-2.96 (m, 2 H, H-2, H-6), 3.19-3.25 (m, 1 H, H-5), 3.66 (dd, 1 H, J = 7.5, 11.6 Hz, CHHOH), 3.91 (dd, 1 H, J = 3.3, 11.6 Hz, CHHOH). 13C NMR (125 MHz, CD3OD): δ = 11.6 (CH2 CH3), 21.1 (CH2CH3), 26.4 (CH3), 41.5 (C-4), 57.9 (C-6), 59.4 (CH2OH), 63.6 (C-2), 65.5 (C-5), 71.5 (C-3).
Compound 8: IR (CH2Cl2): νmax = 3378 (br, OH) cm-1. MS (CI, NH3): m/z (%) = 190 (100) [MH+]. HRMS (ESI+): calcd for C9H20NO3 [MH+]: 190.1438; found: 190.1444. 1H NMR (500 MHz, CD3OD): δ = 1.06 (t, 3 H, J = 7.6 Hz, CH2CH 3), 1.19 (s, 3 H, CH3), 1.35-1.69 (m, 3 H, CH 2 CH3, H-4a), 2.00 (dd, 1 H, J = 3.4, 14.1 Hz, H-4b), 2.17-2.96 (m, 2 H, H-2, H-6), 3.19-3.25 (m, 1 H, H-5), 3.73 (d, 1 H, J = 6.6 Hz, CHHOH) 3.85 (dt, 1 H, J = 5.1, 10.8 Hz, CHHOH). 13C NMR (125 MHz, CD3OD): δ = 11.9 (CH2 CH3), 22.2 (CH2CH3), 23.4 (CH3), 46.4 (C-4), 60.4 (CH2OH), 62.9 (C-6), 64.5 (C-2), 67.4 (C-5), 70.1 (C-3).