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Synthesis 2005(4): 644-661  
DOI: 10.1055/s-2004-837294
FEATUREARTICLE
© Georg Thieme Verlag Stuttgart · New York

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A1

Roman Lopeza, Jean-Christophe Poupona, Joëlle Prunet*a, Jean-Pierre Férézou*a,, Louis Ricardb
a Laboratoire de Synthèse Organique, UMR CNRS 7652, Ecole Polytechnique, DCSO, 91128 Palaiseau, France
b Laboratoire Hétéroéléments et Coordination, UMR CNRS 7653, Ecole Polytechnique, DCPH, 91128 Palaiseau, France
e-Mail: joelle.prunet@polytechnique.fr;
Further Information

Publication History

Received 25 May 2004
Publication Date:
17 December 2004 (online)

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Abstract

Studies dealing with the diastereoselective installation of nine stereogenic centers of the C-12-C-25 subunit of bafilomycin A1 1 are described. A spiroketal precursor has been chosen as a rigid scaffold owing to the central spiro center, the configuration of which is dictated by predictable anomeric effects. A strategy using a previously described anti-Danishefsky condensation of chiral anti-aldehyde 6( O TES) with pentan-2,4-dione bis(trimethylsilyl)ether 7 (M = TMS), followed by an oxalate condensation to the other end of the pentanedione unit, afforded the required spiroketalic enone precursor 24. After generating the C-18 and C-17 centers through an enolate methylation reaction-Luche reduction sequence followed by a Mitsunobu inversion to give 27, the remaining C-16 methyl group was achieved via a hydroxy-directed cyclopropanation-reductive opening sequence to give the fully functionalized C-15-C-25 spiroketal 35. Further elongation at the C-14 center involved a Felkin-Ahn stereocontrolled addition of trimethylsilyl­acetylene followed by a one-pot O-methylation-desilylation, affording the acetylenic subunit 44, ready to be transformed into the vinylstannne required for the subsequent Stille coupling reaction with a C-1-C-11 subunit of bafilomycin A1. A 15-epi spiroketal intermediate has also been synthesized, as well as various 18-des­methyl analogues for comparative studies.

Key words

macrocycles - stereoselective synthesis - aldol reactions - diastereoselectivity - spiro compounds

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1

New address: Jean-Pierre Férézou, IPD-Farma, Avenida Churchill, 129; sl. 1003, CEP 20020-050 - Centro - Rio de Janeiro, RJ, Brazil. E-mail: ferezou@terra.com.br.

11

The present preliminary work has been developed from racemic aldehyde 6.

15

Submitted for publication.

23

Aldol 6 ( O TES) was isolated in 70% yield as a 9:1 mixture of two enol forms. The selectivity was determined by 1H NMR integration of the H-21 signal on the crude material.

29

X-ray crystal data for compound 29: Single crystals of 29 were grown by recrystallization from Et2O-MeOH at r.t. Data were collected at 293 (1)K on a Nonius Kappa CCD diffractometer using an Mo Kα (λ = 071073 Å) X-ray source and a graphite monochromator. Formula: C30H45NO9Si; M = 59176; triclinic; space group P-1; a = 97330 (2) Å, b = 120870 (3) Å, c = 155750 (4) Å, α = 902070 (16)°, β = 930680 (16)°, γ = 1095220 (15)°, V = 172403 (7) Å3; Z = 2; ρcalcd = 1140gcm-3; µ = 0115cm-1; F(000) = 636. Crystal dimensions: 0.20 × 0.20 × 0.20 mm. Total reflections collected 10453 and 4577 with I >2σ(I); maximum θ: 2503°. Goodness of fit on F2 1061; R[I>2σ (i)] = 00577, wR2 = 01778 (all data), 380 parameters; maximum/minimum residual density 0671 (0040)/-0305 (0040) eÅ-3. The crystal structure was solved in SIR 97 [30] and refined in SHELXL-97 [31] by full matrix least-squares using anisotropic thermal displacement parameters for all non-hydrogen atoms. Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. 239437. Copies of the data can be obtained free of charge on application to the CCDC 12 Union Road Cambridge CB2 1EZ UK (fax:+44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk).

35

For model experiments see ref. 10 and references therein.

38

X-ray analysis of a monocrystal from the major isomer confirmed that except for C-15, all the stereogenic centers possess the relative stereochemistry required for Bafilomycin A1, but the disorder resulting from the TBS groups renders the structure unpublishable (R = 15%).