Stereoselective Synthesis of the C1-C12 Fragment of the Cytotoxic Macrolide FD-891

Juan Murga; Jorge García-Fortanet; Miguel Carda; J. Alberto Marco

doi:10.1055/s-2004-835653

LETTER

Stereoselective Synthesis of the C1-C12 Fragment of the Cytotoxic Macrolide FD-891

Juan Murga^a, Jorge García-Fortanet^a, Miguel Carda*^a, J. Alberto Marco*^b
^a Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Castellón, 12071 Castellón, Spain
^b Depart. de Q. Orgánica, Univ. de Valencia, 46100 Burjassot, Valencia, Spain
Fax: +34(96)3544328; e-Mail: alberto.marco@uv.es;

Abstract

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Abstract

A stereoselective synthesis of the C1-C12 fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. The initial chirality was created via an asymmetric Evans aldol reaction. Two other asymmetric reactions, a Sharpless epoxidation and an aldehyde Brown allylation were further key steps of the synthesis.

Key words

antitumor agents - aldol reactions - chiral auxiliaries - stereoselective synthesis - asymmetric allylations

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References

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Compound A: ¹H NMR (500 MHz, CDCl₃): δ = 7.10 (br s, 1 H), 5.83 (m, 1 H), 5.55 (d, J = 10.0 Hz, 1 H), 5.10-5.00 (m, 2 H), 4.20 (q, J = 7.0 Hz, 2 H), 3.61 (dd, J = 5.0, 4.0 Hz, 1 H), 3.48 (dt, J = 5.5, 6.5 Hz, 1 H), 2.96 (dd, J = 5.5, 2.2 Hz, 1 H), 2.88 (dd, J = 4.0, 2.2 Hz, 1 H), 2.68 (ddq, J = 10.0, 5.0, 6.8 Hz, 1 H), 2.28 (t, J = 6.5 Hz, 2 H), 2.00 (d, J = 1.3 Hz, 3 H), 1.85 (d, J = 1.0 Hz, 3 H), 1.30 (t, J = 7.0 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 169.1, 142.7, 138.1, 134.5, 131.9, 125.9, 117.3, 73.6, 73.0, 60.6, 58.5, 57.2, 39.5, 37.7, 25.9 (× 3), 25.8 (× 3), 18.3, 18.2, 16.6, 15.7, 14.3, 14.0, -4.2, -4.4, -4.8, -4.9.

None of the intermediates in the way towards A nor compound A itself was crystalline. Therefore, X-ray analyses aimed at configurational confirmation could not be performed. However, the key asymmetric transformations used here (Evans aldolization, Sharpless epoxidation and Brown allylboration) are well-known processes with safely predictable stereochemical outcomes. We are thus confident that the structure of synthetic intermediate A is that depicted in Scheme [3] . Furthermore, a comparison of ¹H/¹³C NMR chemical shift and coupling constants values within the relevant fragment of FD-891 with those of compound A (see Table [1] below, atom numbering is shown in Figure [1] , coupling constant values are given in parenthesis) gives support to our structural assignment (the observed differences can be accounted for with the fact that the cyclic FD-891 is much more rigid than A from the conformational point of view; moreover, A bears two bulky TBSO groups instead of the free hydroxyls).

Preliminary experiments have shown that oxidative cleavage of the terminal double bond in A can be performed via sequential osmylation and NaIO₄ oxidation to yield an unstable aldehyde.

Table 1 Comparison of Spectroscopic Data of Compounds A and FD-891