Enantioselective Synthesis of the C(1)-C(6’) Subunit of Zaragozic Acid C

Article

Enantioselective Synthesis of the C(1)-C(6’) Subunit of Zaragozic Acid C

Erick M. Carreira*, and Brian E. Ledford

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125

Received: August 10, 1998

A preparação da subunidade C(1)-C(6’) do ácido zaragózigo é descrita. O estereocentro C(5’), contendo uma metila, é instalado através de uma abertura rápida e estereosseletiva de um fenilciclopropil carbinol utilizando o catalisador de Pearlman (1atmosfera de H₂) em metanol contendo 2% de ácido trífilico.

Preparation of the C(1)-C(6’) subunit of Zaragozic acid C is described. The C(5’) methyl-bearing stereocenter is installed by rapid, regioselective opening of a phenylcyclopropyl carbinol with Pearlman’s catalyst (1 atm H₂) in 2% triflic acid/methanol.

Keywords: enantioselective synthesis, Zaragozic acid

Introduction

Zaragozic acid C is a member of a class of mammalian squalene synthetase inhibitors (K_i 29 - 78 pM) isolated by researchers at Merck and Glaxo¹. These remarkable natural products, which include the zaragozic acids and squalestatins, share a common [3.2.1]-dioxabicyclooctane core but differ exclusively at the C(6) acyl sidechain and C(1) bridgehead subunit². In addition to inhibiting the first committed step in cholesterol biosynthesis³, a modified zaragozic acid has been reported to inhibit post-translational farnesylation of the ras gene product⁴. Thus, these natural products represent important leads in the development of squalene synthetase and farnesyl-protein transferase inhibitors. The great excitement engendered by these natural products has led to numerous studies on their chemistry and pharmacology⁵. Herein, we describe the preparation of the C(1)-C(6’) subunit 4 (Scheme 1) of zaragozic acid C⁶. The route described differs considerably from our previously reported syntheses, and documents a novel approach to the construction of propionate subunits exemplified by C(1)-C(6’).

In our retrosynthetic analysis, synthon 1 is disconnected into acyl-sidechain 2 and subunits 3 and 4 (Scheme 1). This disconnection strategy incorporates flexibility in the subsequent construction of the C(1)-C(7) bond in zaragozic acid C and related analogs. Central to the synthetic plan for the C(1)-C(6’) subunit is the regioselective, reductive opening of cyclopropyl carbinol 5 to afford 4 (Scheme 1). The cis-substituted cyclopropane 5 could be prepared from chiral, allylic alcohol 6; it was anticipated that 6 could be accessed from the addition product of a 4-pentenylmetal reagent to phenylpropynal^7-10.

In contrast to the reported enantioselective Ti(IV)-catalyzed addition of distilled MeTi(OⁱPr)3 to benzaldehyde (enantioselection > 98:2),^7b the derived 4-pentenyltitanium reagent¹¹ with 20% catalyst 10 afforded 11 in 65% yield and 50% enantiomeric excess¹². The corresponding alkylzinc reagents were then investigated (Scheme 2). Generation of 4-pentenyllithium 9 (Scheme 2) (1-iodo-4-pentene, 2.0 equiv tert-BuLi, Et₂O, 15 min, -78 °C), transmetalation (1 equiv ZnCl₂ in Et₂O, 1 h, 23 °C) and filtration of the resulting suspension gave a solution of a 4-pentenylzinc reagent. Use of this reagent in the Ti(OⁱPr)₂TADDOL-catalyzed addition to phenylpropynal failed to provide the desired adduct. The optimal reaction conditions involved coupling of the 4-pentenylzinc generated from 12 in a manner similar to that described by Seebach7a. Preparation of 12 (bromo-4-pentene, Mg, Et₂O, 23 °C, 2 h), transmetalation with zinc chloride (1.0 equiv ZnCl₂ in Et₂O, 2 h, 23 °C), and removal of the precipitates formed upon addition of dioxane afforded a solution of 4-pentenylzinc reagent which was used directly in the Ti(OⁱPr)₂TADDOL-mediated addition (8 h, 0 °C) to give 11 in good yields (70%) and excellent enantioselectivity (94:6). Using this procedure, the addition of 4-pentenylzinc to phenylpropynal has been conducted routinely on large scale (50 mmol) without diminution in yield or enantioselectivity.

Having established the C(4’) carbinol stereocenter, 11 was selectively ozonolyzed and the resulting hydroperoxide subjected to reductive work-up (NaBH₄) to give diol 13 in 92% yield (Scheme 3). Semihydrogenation of alkyne 13 (Pd/BaSO₄, H₂, pyridine, 23 °C) provided allylic alcohol 14 (78%) exclusively. Treatment of 14 with Et₂Zn/CH₂I₂¹³ in toluene then furnished cyclopropyl carbinol 15 in 75% yield a single diastereomer as judged by analysis of its ¹H NMR spectrum¹⁴.

The reductive opening of cyclopropyl carbinol 15 was then addressed. It was expected that conditions could be found to effect regioselective scission of the more accessible C(6’)–C(7’) cyclopropane bond. Treatment of 15 with Hg(ClO₄)₂ in MeOH (23 °C, 12 h)¹⁵ provided an organomercurial intermediate which was then reduced (LiAlH₄/Et₂O) to afford a 2:1 diastereomeric mixture of 16 and 17 in only 30% yield (Eq 1). Alternatively, hydrogenolysis of 15 (Pd(OH)₂/C, MeOH, 1 atm H₂, 23 °C) proceeded at a slow rate (40% conversion, 24 h) to give a 1:1 mixture of isomeric diols 18 and 19 (Eq 2). Dramatic effects on regioselectivity and rate of the reduction were observed when the reaction was conducted in methanol containing 2% (v/v) triflic acid. Under these strongly acidic conditions, reductive cleavage was complete in 2 h (23 °C) to give 18 as the major product in 63% isolated yield. This result contrasts with the reported cleavage of cis-1-methyl-2-phenylcyclopropane with Li in NH₃ at -33 °C which gives exclusively n-butylbenzene¹⁶. It is worth noting that in the absence of Pd(OH)₂, treatment of 15 with 2% triflic acid/methanol solution does not yield 17 (Eq 1), but instead produces homoallylic ether 20 at a slow rate (40% conversion, 12h) (Eq 3)¹⁷. Since no intermediates were observed in any of the cyclopropane-opening reactions (Eqs. 2 and 3) an explanation for the combined role of triflic acid, Pd(OH)₂, and H₂ awaits further experimentation.

The synthesis was completed (Scheme 3) by selective protection of the primary carbinol in 18 (TBSCl, 82% yield), and acetylation of the resulting secondary alcohol (Ac₂O, DMAP, 80% yield). Desilylation (HF, aq CH₃CN, 98% yield) and subsequent oxidation of the ensuing primary alcohol with the Dess-Martin periodinane furnished aldehyde 21 in 95% yield. Alternatively, oxidation with chromic acid provided the corresponding carboxylic acid 22 in 87% yield (Scheme 3).

In summary, we have prepared the C(1)-C(6’) subunit of zaragozic acid C. The regioselective, reductive opening of cyclopropane 15 efficiently incorporates the C(5’) methyl-bearing stereocenter. The addition of 2% triflic acid to a suspension of Pearlman’s catalyst in methanol (1 atm H2) effects rapid, regioselective cleavage of a phenylcyclopropyl carbinol.

Acknowledgment

This research has been supported by a generous gift from the National Science Foundation (CHE-9221945), a Camille and Henry Dreyfus New Faculty Award (#NF-92-46).

References and Notes

1. For leading references on the recent isolation, see: (a) Wilson, K.E.; Burk, R.M.; Biftu, T.; Ball, R.G.; Hoogsteen, K. J. Org. Chem. 1992, 57, 7151; (b) Bartizal, K.F.; Milligan, J.A.; Rozdlisky, W.; Onishi, J.C. U.S. Patent 5,055,487, 1991; (c) Sidebottom, P.J.; Highcock, R.M.; Lane, S.J.; Procopiou, P.A.; Watson, N.S. J. Antibiot. 1992, 45, 648. Wilson, K.E.; Burk, R.M.; Biftu, T.; Ball, R.G.; Hoogsteen, K. J. Org. Chem. 1992, 57, 7151, and references therein; (d) Dufresne, C.; Wilson, K.E.; Zink, D.; Smith, J.; Bergstrom, J.D.; Kurtz, M.; Rew, D.; Nallin, M.; Jenkins, R.; Bartizal, K.; Trainor, C.; Bills, G.; Meinz, M.; Huang, L.; Onishi, J.; Milligan, J.; Mojena, M.; Pelaez, F. Tetrahedron 1992, 48, 10221; (e) Hensens, O.D.; Dufresne, C.; Liesch, J.M.; Zink, D.L.; Reamer, R.A.; VanMiddlesworth, F. Tetrahedron Lett. 1993, 34, 399.

2. Nineteen additional squalestatins containing different alkyl and O-acyl side chains as well as the first report of five related structures containing the 6-deoxy, 7-deoxy, or 6,7-dideoxy dioxabicyclooctane core have been recently described, see: Blows, W.M.; Foster, G.; Lane, S.J.; Noble, D.; Piercy, J.E.; Sidebottom, P.J.; Webb, G. J. Antibiot. 1994, 47, 740.

3. (a) Dawson, M.J.; Farthing, J.E.; Marshall, P.S.; Middleton, R.F.; O’Neil, M.J.; Shuttleworth, A.; Stylli, C.; Tait, M.; Taylor, P.M.; Wildman, H.G.; Buss, A.D.; Langley, D.; Hayes, M.V. J. Antibiot. 1992, 45, 639; (b) Hasumi, K.; Tachikawa, K.; Sakai, K.; Murakawa, S.; Yoshikawa, N.; Kumazawa, S.; Endo, A. J. Antibiot. 1993, 46, 689; (c) Bergstrom, J.D.; Kurtz, M.M.; Rew, D.J.; Amend, A.M.; Karkas, J.D.; Bostedor, R.G.; Bansal, V.S.; Dufresne, C.; VanMiddlesworth, F.L.; Hensens, O.D.; Liesch, J.M.; Zink, D.L.; Wilson, K.E.; Onishi, J.; Milligan, J.A.; Bills, G.; Kaplan, L.; Nallin-Omstead, M.; Jenkins, R.G.; Huang, L.; Meinz, M.S.; Quinn, L.; Burg, R.W.; Kong, Y.L.; Mochales, S.; Mojena, M.; Martin, I.; Pelaez, F.; Diez, M.T.; Alberts, A.W. Proc. Nat. Acad. Sci. USA 1993, 90, 80.

4. Gibbs, J.B.; Pompliano, D.L.; Mosser, S.D.; Rands, E.; Lingham, R.B.; Singh, S.B.; Scolnick, E.M.; Kohl, N.E.; Oliff, A. J. Biol. Chem. 1993, 268, 7617.

5. The total synthesis of several members of this class of natural products have been reported, see: (a) Carreira, E.M.; DuBois, J. J. Am. Chem. Soc. 1994, 116, 10825; (b) Carreira, E.M., Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106. (c) Nicolaou, K.C.; Yue, E.W.; Yoshimitsu, N.; De Riccardis, F.; Nadin, A.; Leresche, J.E.; La Greca, S.; Yang, Z. Angew. Chem., Int. Ed. Engl. 1994, 33, 2184; (d) Nicolaou, K.C.; Nadin, A.; Leresche, J.E.; La Greca, S.; Tsuri, T.; Yue, E.W.; Yang, Z. Angew. Chem., Int. Ed. Engl. 1994, 33, 2187; (e) Nicolaou, K.C.; Nadin, A.; Leresche, J.E.; Yue, E.W.; La Greca, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 2190; (f) Zaragozic acid C, see: Evans, D.A.; Barrow, J.C.; Leighton, J.L.; Robichaud, A.J.; Sefkow, M.J. J. Am. Chem. Soc. 1994, 116, 12111; (g) Caron, S.; Stoermer, D.; Mapp, A.K.; Heathcock, C.H. J. Org. Chem. 1996 61, 9126; (h) Stoermer, D.; Caron, S.; Heathcock, C.H. J. Org. Chem. 1996, 61, 9115; (i) Sato, H.; Nakamura, S.; Watanabe, N.; Hashimoto, S. Synlett 1997, 5, 451; (j) Nicolaou, K.C.; Yue, E.W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J.E.; Tsuri, T.; Naniwa, Y.; Dericcardis, F. Chem. Eur. J. 1995, 1, 467; (k) Armstrong, A.; Jones, L.H.; Barsanti, P.A. Tetrahedron Lett. 1998, 39, 3337.

6. For leading reports on the synthesis of the zaragozic acid sidechains, see: (a) Robichaud, A.J.; Berger, G.D.; Evans, D.A. Tetrahedron Lett. 1993, 34, 8403; (b) Santini, C.; Ball, R.G.; Berger, G.D. J. Org. Chem. 1994, 59, 2261; (c) Parsons, J.G.; Rizzacasa, M.A. Tetrahedron Lett. 1994, 35, 8263.

7. For a review, see: Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.

8. For a recent application in a multistep synthesis, see: Evans, D.A.; Black, W.C. J. Am. Chem. Soc. 1993, 115, 4497.

9. (a) Bussche-Hunnefeld, J.-L.; Seebach, D. Tetrahedron, 1992, 48, 5719; (b) Seebach, D.; Plattner, D.A.; Beck, A.K.; Wang, Y.M.; Hunziker, D. Helv. Chim. Acta. 1992, 75, 2171; (c) Rozema, M.; Sidduri, A.R.; Knochel, P. J. Org. Chem. 1992, 57, 1956.

10. Throughout this letter TADDOL refers specifically to (4S, 5S)-a,a,a‘,a‘-pentaphenyl-1,3-dioxolane-4,5-dimethanol 10 (Scheme 2), see: Beck, A.K.; Bastani, B.; Plattner, D.A.; Seebach, D.; Braunschweiger, H.; Gysi, P.; LaVecchia, L. Chimia 1991, 45, 238.

11. The reagent was prepared by treatment of 4-pentenyllithium 9 with 1.0 equiv of TiCl(OⁱPr)₃ in Et₂O at -78 °C for 1 h; removal of the precipitate by filtration under an inert atmosphere then affords a solution of 4-pentenyl-1-tri-isopropoxy-titanium.

12. The enantiomeric purity was assayed by ¹H-NMR analysis of the diastereomeric triplet resonances (5.73-major and 5.81-minor ppm in CDCl₃) observed for the carbinol proton of the derived Mosher ester (Dale, J.A.; Mosher, H.S. J. Am. Chem. Soc. 1973, 95, 512). The absolute configuration was secured by direct correlation to authentic alcohol prepared by (S)-Alpine-Borane reduction of the monoprotected ketone corresponding to 13.

13. (a) For a leading reference to the Wittig-Furukawa reagent, see: Denmark, S.E.; Edwards, J.P.; Wilson, S.R. J. Am. Chem. Soc. 1992, 114, 2592; (b) For a discussion of the directed cyclopropanation of allylic alcohols, see: Hoveyda, A.H.; Evans, D.A.; Fu, G.C. Chem. Rev. 1993, 93, 1307.

14. An authentic mixture of diastereomers was intentionally generated for comparison by selective protection of diol 15 (TBSCl, DMAP), oxidation (Dess-Martin periodinane), reduction (NaBH₄), and deprotection (TBAF, THF). For a leading reference to the stereospecific cyclopropanation of substituted olefins, see: Molander, G.A.; Etter, J.B.; J. Org. Chem. 1987, 52, 3942.

15. Collum, D.B.; Still, W.C.; Mohamadi, F. J. Am. Chem. Soc. 1986, 108, 2094.

16. Staley, S.W.; Rocchio, J.J. J. Am .Chem. Soc. 1969, 91, 1565.

17. (a) Julia, J.M.; Julia, S.; Tchen, S-Y. Bull. Soc. Chim. Fr. 1961, 1849. (b) Marshall, J.A.; Ellison, R.H. J. Am. Chem. Soc. 1976, 98, 4312.

Publication Dates

• Publication in this collection
  30 Oct 2002
• Date of issue
  Aug 1998

History

• Received
  10 Aug 1998