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 (eFirst)

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.

    References

  • 2a Werner G. Hagenmaier H. Albert K. Kohlshorn H. Drautz H. Tetrahedron Lett.  1983,  24:  5193 
  • 2b Werner G. Hagenmaier H. Drautz H. Baumgartner A. Zähner H. J. Antibiot.  1984,  37:  110 
  • 2c For structure elucidation, see: Corey EJ. Ponder JW. Tetrahedron Lett.  1984,  25:  4325 
  • 2d Baker GH. Brown PJ. Dorgan RJJ. Everett JR. Ley SV. Slawin AMZ. Williams DJ. Tetrahedron Lett.  1987,  28:  5565 
  • 3 Bindseil KU. Zeeck A. Liebigs Ann. Chem.  1994,  305 
  • For a review on V-ATPases, see:
  • 4a Forgac M. Physiol. Rev.  1989,  69:  765 
  • 4b Finbow ME. Harrison MA. Biochem. J.  1997,  324:  697 
  • 4c Nishi T. Forgac M. Nat. Rev. Mol. Cell Bio.  2002,  3:  94 
  • 5 Review: Gagliardi S. Rees M. Farina C. Curr. Med. Chem.  1999,  6:  1197 
  • Total syntheses of Bafilomycin A1:
  • 6a Evans DA. Calter MA. Tetrahedron Lett.  1993,  34:  6871 
  • 6b Toshima K. Jyojima T. Yamaguchi H. Murase H. Yoshida T. Matsumura S. Nakata M. Tetrahedron Lett.  1996,  37:  1069 
  • 6c Toshima K. Yamaguchi H. Jyojima T. Noguchi Y. Nakata M. Matsumura S. Tetrahedron Lett.  1996,  37:  1073 
  • 6d Toshima K. Jyojima T. Noguchi Y. Yoshida T. Murase M. Nakata M. Matsumura S. J. Org. Chem.  1997,  62:  327 
  • 6e Scheidt KA. Tasaka A. Bannister TD. Wendt MD. Roush WR. Angew. Chem. Int. Ed.  1999,  38:  1652 
  • 6f Scheidt KA. Bannister TD. Tasaka A. Wendt MD. Savall BM. Fegley GJ. Roush WR. J. Am. Chem. Soc.  2002,  124:  6981 
  • 6g Hanessian S. Ma J. Wang W. J. Am. Chem. Soc.  2001,  123:  10200 
  • 6h Total Synthesis of Bafilomycin V2: Marshall JA. Adams ND. J. Org. Chem.  2002,  67:  733 
  • 7 Poupon J.-C. Demont E. Prunet J. Férézou J.-P. J. Org. Chem.  2003,  68:  4700 
  • Reviews:
  • 8a Boivin B. Tetrahedron  1987,  43:  3309 
  • 8b Perron F. Albizati KF. Chem. Rev.  1989,  89:  1617 
  • 8c Vaillancourt V. Pratt NE. Perron F. Albizati KM. In The Total Synthesis of Natural Products   Vol. 8:  ApSimon J. Wiley Interscience; New York: 1992.  p.533 
  • Representative examples:
  • 9a Hoye TR. Peck DR. Swanson TA. J. Am. Chem. Soc.  1984,  106:  2738 
  • 9b Bernet B. Bishop PM. Caron M. Kawamata T. Roy BL. Ruest L. Sauvé G. Soucy P. Deslongchamps P. Can. J. Chem.  1985,  63:  2818 , and preceding communications in the issue
  • 9c Ireland RE. Daub JP. Mandel GS. Mandel NS. J. Org. Chem.  1983,  48:  1312 
  • 9d Schreiber SL. Wang Z. J. Am. Chem. Soc.  1985,  107:  5303 
  • 9e Totah NI. Schreiber SL. J. Org. Chem.  1991,  56:  6255 
  • 9f Zhao Y. Pratt NE. Heeg MJ. Albizati KF. J. Org. Chem.  1993,  58:  1300 
  • 9g Martin SF. Lee W.-C. Pacofsky GJ. Gist RP. Mulhern TA. J. Am. Chem. Soc.  1994,  116:  4674 
  • 9h Oikawa M. Ueno T. Oikawa H. Ichihara A. J. Org. Chem.  1995,  60:  5048 
  • 9i Ireland RE. Longbin L. Roper TD. Tetrahedron  1997,  53:  13221 
  • 9j Ireland RE. Longbin L. Roper TD. Gleason JL. Tetrahedron  1997,  53:  13257 
  • 10 Poupon J.-C. Lopez R. Prunet J. Férézou J.-P. J. Org. Chem.  2002,  67:  2118 
  • 12 Roush WR. Bannister TD. Tetrahedron Lett.  1992,  33:  3587 
  • 13 Paterson I. Bower S. McLeod MD. Tetrahedron Lett.  1995,  36:  175 
  • 14 Henryon V. Lopez R. Prunet J. Férézou J.-P. Synthesis  2001,  2401 
  • 16a Johnson AW. Markham E. Price R. Org. Synth.  1973,  6:  785 
  • 16b Krägeloh K. Simchen G. Synthesis  1980,  30 
  • 17a

    See ref. 14: This aldehyde was prepared using the racemic version of the Hoppe homoaldolisation reaction (Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl. 1989, 28, 69). The asymmetric version of this reaction using (-)-sparteine instead of TMEDA (Zschage, O.; Hoppe, D. Tetrahedron 1992, 48, 5657) will easily provide the enantiopure aldehyde required for asymmetric synthesis of bafilomyin A1.

  • 17b For an alternative route to this aldehyde, see: Baker R. Swain CJ. Head JC. J. Chem. Soc., Chem. Commun.  1985,  309 
  • 17c See also: Baker R. Swain CJ. Head JC. J. Chem. Soc., Perkin Trans. 1  1988,  85 
  • 18a Evans DA. Duffy JL. Dart MJ. Tetrahedron Lett.  1994,  35:  8537 
  • 18b These authors have proposed the 1,3-merged model for explaining the observed diasteroselectivity: Evans DA. Dart MJ. Duffy JL. Yang M. J. Am. Chem. Soc.  1996,  118:  4322 
  • 18c See also: Evans DA. Dart MJ. Duffy JL. Yang M. Livingston AB. J. Am. Chem. Soc.  1995,  117:  6619 
  • 19 Hanessian S. Tehim A. Meng Q. Granberg K. Tetrahedron Lett.  1996,  37:  9001 
  • 20a Gatti PA. Gagliardi S. Cerri A. Farina C. Tetrahedron Lett.  1997,  38:  6949 
  • 20b

    From a mechanistic point of view a preliminary cyclization of 11 to 17 (that can exist in equilibrium with 18) followed by a base-catalyzed fragmentation of 18 exhibiting a favorable antiperiplanar disposition can be claimed to give enolate 19 or its ketone form 20, which can subsequently undergo a desilylation-cyclization reaction to give 15 or a β-elimination of the 21-acetoxy group to furnish 16 according to Scheme [12] :

  • 21 Use of montmorillonite K 10 for ketal formation, see: Taylor EC. Chiang CS. Synthesis  1977,  467 ; Under classical conditions (MeOH/acid), only rearrangement or elimination products were observed
  • 22a Férézou J.-P. Gauchet-Prunet J. Julia M. Pancrazi A. Tetrahedron Lett.  1988,  30:  3667 
  • 22b Férézou JP. Julia M. Li Y. Liu L.-W. Pancrazi A. Bull. Soc. Chim. Fr.  1995,  132:  428 
  • 24a Dellaria JF. Santarsiero BD. J. Org. Chem.  1989,  54:  3916 
  • 24b Williams RM. Im MN. J. Am. Chem. Soc.  1991,  113:  9276 
  • 24c Snyder L. Meyers AI. J. Org. Chem.  1993,  58:  7507 
  • 25 Barrett AGM. Carr RAE. Finch MAW. Florent J.-C. Richardson G. Walshe NDA. J. Org. Chem.  1986,  51:  4254 
  • 26 Gemal AL. Luche J.-L. J. Am. Chem. Soc.  1981,  103:  5454 
  • 27 Crimmins MT. O’Mahony R. J. Org. Chem.  1989,  54:  1157 
  • NaBH4 reduction of α-hydroxyesters has already been observed see for example:
  • 28a Epe B. Oelbermann U. Mondon A. Chem. Ber.  1981,  114:  757 
  • 28b Payard M. Mouysset G. Tronche P. Bastide P. Bastide J. Boas MJ. Eur. J. Med. Chem. Chim. Ther.  1985,  117 
  • 30 Altomare A. Burla MC. Camalli M. Cascarano G. Giacovazzo C. Guagliardi A. Moliterni AGG. Polidori G. Spagna R. SIR97, An integrated package of computer programs for the solution and refinement of crystal structures using single crystal data   1999. 
  • 31 Sheldrick GM. SHELXL-97   Universität Göttingen; Germany: 1997. 
  • 32 Mitsunobu O. Synthesis  1981,  11 
  • For more details on the mechanism of the Mitsunobu inversion reaction, see:
  • 33a Varasi M. Walker KAM. Maddox ML. J. Org. Chem.  1987,  52:  4235 
  • 33b Hughes DL. Reamer RA. Bergan JJ. Grabowski EJJ. J. Am. Chem. Soc.  1988,  110:  6487 
  • 33c Camp D. Jenkins ID. J. Org. Chem.  1989,  54:  3045 
  • 33d Hughes DL. Org. React.  1992,  42:  335 
  • 34a Lumin S. Yadagiri P. Falck JR. Tetrahedron Lett.  1988,  29:  4237 
  • 34b Ramesh NG. Balasubramanian KK. Tetrahedron  1995,  51:  255 
  • 36a Pedretti V. Mallet J.-M. Sinaӱ P. Carbohydr. Res.  1993,  247 
  • 36b Stork G. Khan M. J. Am. Chem. Soc.  1985,  107:  500 
  • 37 Compare, for example (one-pot sequences): Burke SD. Deaton DN. Olsen RJ. Armistead DM. Blough BE. Tetrahedron Lett.  1987,  28:  3905 
  • 39 Tabusa F. Yamada T. Suzuki K. Mukaiyama T. Chem. Lett.  1984,  405 
  • 40a Zhang HX. Guibé F. Balavoine G. J. Org. Chem.  1990,  55:  1857 
  • 40b Trost B. Li C.-J. Synthesis  1994,  1267 
  • 40c A first attempt of Pd-catalyzed hydrostannylation on small scale gave 2b (PG = TBS) along with its regioisomer (80%, 3:1 mixture). For comparison with alternative methodologies, see also: Betzer J.-F. Delaloge F. Muller B. Pancrazi A. Prunet J. J. Org. Chem.  1997,  62:  7768 
  • 41 Evans DA. Ratz AM. Huff BE. Sheppard GS. J. Am. Chem. Soc.  1995,  117:  3448 
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%).