Synthesis of Hydrophobically Modified Analogues of Adenophorine

Abstract

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

Key words

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

References and Notes

• For reviews, see:
• 2a Afarinkia K. Bahar A. Tetrahedron: Asymmetry  2005,  16:  1239 
• 2b Pearson MSM. Mathé-Allainmat M. Fargeas V. Leberton J. Eur. J. Org. Chem.  2005,  2159 
• 2c Compain P. Martin OR. Bioorg. Med. Chem.  2001,  9:  3077 
• 2d Watson AA. Fleet GWJ. Asano N. Molyneux RJ. Nash RJ. Phytochemistry  2001,  56:  265 
• 2e Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 
• 2f Picasso S. Chimia  1996,  50:  648 
• 3a Yoshikimi Y. Ezure Y. Seto T. Mori K. Watanabe M. Enomoto H. Chem. Pharm. Bull.  1989,  37:  106 
• 3b Kimura M. Chen F.-J. Nakamisha N. Kimura I. Asano N. Koya S. J. Trad. Med.  1995,  12:  214 
• 4a Greimel P. Spreitz J. Stütz AE. Wrondnigg TM. Curr. Top. Med. Chem.  2003,  3:  315 
• 4b Dwek RA. Butters TD. Platt FM. Zitmann N. Nat. Rev. Drug Discovery  2002,  1:  65 
• 5a Besra GD. Khoo K.-H. McNeil MR. Dell A. Morris HR. Brennan PJ. Biochemistry  1995,  34:  4257 
• 5b Shilvock JP. Wheatley JR. Davis B. Nash RJ. Griffiths RC. Jones MG. Müller M. Crook S. Watkin DJ. Smith C. Besra GS. Brennan PJ. Fleet GWJ. Tetrahedron Lett.  1996,  37:  8569 
• For example, see:
• 6a Pearson WH. Hembre EJ. J. Org. Chem.  1996,  61:  5546 
• 6b Pearson WH. Guo L. Tetrahedron Lett.  2001,  42:  8267 
• 6c Fleet GWJ. Smith PW. Nash RJ. Fellows LE. Parekh RJ. Rademacher TW. Chem. Lett.  1986,  1051 
• 7a Cox T. Lachmann R. Hollak C. Aerts J. van Weely S. Hrebicek M. Platt F. Butters T. Dwek R. Moyses C. Gow I. Elstein D. Zimran A. Lancet  2000,  355:  1481 
• 7b Kolter T. Angew. Chem., Int. Ed. Engl.  1997,  36:  1955 
• 8a Fleet GWJ. Namgoong SK. Barker C. Baines S. Jacob GS. Winchester B. Tetrahedron Lett.  1989,  30:  4439 
• 8b Platt FM. Neises GR. Karlsson GB. Dwek RA. Butters TD. J. Biol. Chem.  1994,  269:  27108 
• 8c Blériot Y. Veighey CR. Smelt KH. Cadefau J. Stalmans W. Biggadike K. Lane AL. Müller M. Watkin DJ. Fleet GWJ. Tetrahedron: Asymmetry  1996,  7:  2761 
• 8d Butters TD. van den Broek LAGM. Fleet GWJ. Krulle TM. Wormald MR. Dwek RA. Platt FM. Tetrahedron: Asymmetry  2000,  11:  113 
• 9 Khanna IK. Weier RM. Julien J. Mueller RA. Lankin DC. Swenton L. Tetrahedron Lett.  1996,  37:  1355 
• 10 Ikeda K. Takahashi M. Nishida M. Miyauchi M. Kizu H. Kameda Y. Arisawa M. Watson AA. Nash RJ. Fleet GWJ. Asano N. Carbohydr. Res.  2000,  323:  73 
• 11 Asano N. Nishida M. Miyauchi M. Ikeda K. Yamamoto M. Kizu H. Kameda Y. Watson AA. Nash RJ. Fleet GWJ. Phytochemistry  2000,  53:  379 
• 12 Maughan MAT. Davies IG. Claridge TDW. Courtney S. Hay P. Davis BG. Angew. Chem. Int. Ed.  2003,  42:  3788 
• 13 Felpin FX. Boubekeur K. Lebreton J. J. Org. Chem.  2004,  69:  1497 
• 14 Afarinkia K. Bahar A. Neuss J. Synlett  2003,  2341 
• 15 Afarinkia K. Bahar A. Neuss J. Vyas M. Tetrahedron Lett.  2004,  45:  7121 
• 16 Afarinkia K. Bahar A. Neuss J. Ruggerio A. Tetrahedron Lett.  2004,  45:  3995 
• 17 Meerpool L. Hoornaert GJ. Synthesis  1990,  905 
• 18 Corey EJ. Bass JD. LeMathieu R. Mitra RB. J. Am. Chem. Soc.  1964,  86:  5570 
• 19a Tomisawa H. Fujita R. Noguchi KJ. Hongo H. Chem. Pharm. Bull.  1970,  18:  941 
• 19b Afarinkia K. Nelson TD. Vinader MV. Posner GH. Tetrahedron  1992,  48:  9111 

1

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

20

Compound 17: IR (film): ν_max = 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-7^a), 2.24 (ddd, 1 H, J = 2.2, 9.7, 15.2 Hz, H-7^b), 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 (C_ipso), 171.4 (C-3).
Compound 18: mp 75-77 °C. IR (mull): ν_max = 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-7^b), 2.32 (dd, 1 H, J = 8.8, 14.9 Hz, H-7^a), 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 (C_ipso), 169.9 (C-3).

21

Compound 5: IR (CH₂Cl₂): ν_max = 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-4^a), 2.00-2.09 (m, 1 H, CHHCH₃), 2.19 (d, 1 H, J = 4.4, 12.4 Hz, H-4^b), 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): ν_max = 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-4^a), 2.02 (dd, 1 H, J = 3.3, 15.4 Hz, H-4^b), 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): ν_max = 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-4^a), 1.91 (dd, 1 H, J = 5.3, 13.4 Hz, H-4^b), 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): ν_max = 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-4^a), 2.00 (dd, 1 H, J = 3.4, 14.1 Hz, H-4^b), 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).