Glycocinnasperimicin D Synthetic Studies: Synthesis of Cinnamoyl Glycosides via Iodination-Heck Reaction Sequence Starting from Phenyl Glycosides

Abstract

A new approach for the synthesis of cinnamoyl glycoside has been developed via iodination-Heck reaction sequence starting from phenyl glycoside. Successful application of this procedure accomplished the construction of the right core structure of amino­sugar antibiotic, glycocinnasperimicin D.

Key words

antibiotics - cinnamoyl glycoside - glycosylation - Heck reaction - palladium

References

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• For the synthetic studies of LL-BM123β, see the references:
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• 4a Oyama K. Kondo T. Synlett  1999,  1627 ; and references therein
• 4b

  See also ref. [3c]

• 5 We avoid glycosylation with iodophenol, because our preliminary experiments showed that catalytic hydrogenolysis of 6-iodo-glycopyranose is the most simple and high-yielding method for multigram synthesis of 6-deoxy glycopyranose. For recent examples of C6-deoxygenation: Medgyes A. Farkas E. Liptak A. Pozsgay V. Tetrahedron  1997,  53:  4159 
• 7 Sugiyama T. Bull. Chem. Soc. Jpn.  1981,  54:  2847 
• 8a Bromination of β-phenyl glucoside 9 (Br₂, CH₂Cl₂, -5 °C) and the Heck reaction of the resultant brominated glycosylated aromatic with alkenes has been reported by Lepoittevin et al.: Mabic S. Lepoittevin J.-P. Tetrahedron Lett.  1995,  36:  1705 
• 8b

  In our case, bromophenyl glycosides, prepared (NBS, DMF, r.t.) in good yields, were found to be poor substrates for the Heck reaction.

• 9 Although cinnamoyl glycosides are known as important natural products, their synthesis suffer from the low nucleophilicity of p-hydroxycinnamic acid derivatives. For example: Takada N. Kato E. Ueda K. Yamamura S. Ueda M. Tetrahedron Lett.  2002,  43:  7655 
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6

This acid-catalyzed glycosylation initially led to the formation of an anomeric mixture of phenyl galactosides. Prolonged reaction time (4 d) resulted in a gradual decrease of the β-isomer proportion and concomitant increase in the formation of α-anomer.

10

We have found the reversal of selectivity in this glycosylation using TMSOTf and Et₂O (Scheme [5] ).

11

Spectroscopic data of 19; [α]_D ²⁶ = +98.9 (c 1.09, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ = 1.17 (d, J = 6.5 Hz, 3 H), 1.40-1.90 (m, 6 H), 1.44 (s, 9 H), 1.48 (s, 9 H), 2.05 (s, 3 H), 2.07 (s, 3 H), 3.08-3.25 (br s, 4 H), 3.25-3.40 (br s, 4 H), 3.64 (s, 3 H), 3.93 (dq, J = 10.5, 6.5 Hz, 1 H), 4.18 (td, J = 10.5, 3.5 Hz), 4.50-4.70 (br s, 1 H), 4.94 (dd, J = 10.5, 9.5 Hz, 1 H), 5.11 (d, J = 10.0 Hz, 1 H), 5.37 (dd, J = 10.5, 9.5 Hz, 1 H), 5.54 (d, J = 3.5 Hz, 1 H), 6.37 (d, J = 15.5 Hz, 1 H), 7.04-7.10 (3 H), 7.44-7.52 (2 H), 7.57 (d, J = 15.5 Hz, 1 H). ¹³C NMR (CDCl₃, 75 MHz): δ = 17.1, 20.47, 20.53, 25.5, 27.2, 27.5, 28.19, 28.23, 35.6, 39.9, 43.2, 46.5, 52.3, 53.9, 66.3, 70.7, 73.1, 79.0, 79.7, 95.6, 116.4, 120.2, 129.2, 129.8, 139.4, 156.0, 156.5, 157.0, 166.1, 169.7, 171.2.