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Synlett 2007(4): 0623-0627  
DOI: 10.1055/s-2007-967978
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Flexible Synthetic Approach to the Hennoxazoles

Eric J. Zylstra, Miles W.-L. She, Walter A. Salamant, James W. Leahy*
Department of Chemistry, University of California, Berkeley, CA 94720-1460, USA
Fax: +1(650)8378177; e-Mail: jleahy@exelixis.com;
Further Information

Publication History

Received 24 July 2006
Publication Date:
21 February 2007 (online)

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Abstract

Three advanced intermediates corresponding to the carbon skeleton of the hennoxazoles have been prepared. Central to the strategy is the synthesis of the oxazoles prior to coupling with the other fragments and a dithiane addition to allow for the generation of diastereomers of the natural product.

Key words

hennoxazole A - isopentylidene - bisoxazole - β,γ-unsaturated aldehyde - skipped polyene

    References and Notes

  • 2 Ichiba T. Yoshida WY. Scheuer PJ. Higa T. Gravalos DG. J. Am. Chem. Soc.  1991,  113:  3173 
    CrossrefGoogle Scholar
  • 3 Higa T. Tanaka J.-I. Kitamura A. Koyama T. Takahashi M. Uchida T. Pure Appl. Chem.  1994,  66:  2227 
    Google Scholar
  • 4 For a review on oxazole-containing natural products, see: Yeh VSC. Tetrahedron  2004,  60:  11995 
    CrossrefGoogle Scholar
  • 5a Wipf P. Lim S. J. Am. Chem. Soc.  1995,  117:  558 
    Google Scholar
  • 5b Wipf P. Lim S. Chimia  1996,  50:  157 
    Google Scholar
  • 6 Williams DR. Brooks DA. Berliner MA. J. Am. Chem. Soc.  1999,  121:  4924 
    CrossrefGoogle Scholar
  • 7 Barrett AGM. Kohrt JT. Synlett  1995,  415 
    Article in Thieme ConnectGoogle Scholar
  • 8 Smith TE. Balskus EP. Heterocycles  2002,  57:  1219 
    Google Scholar
  • 9a Cheng Z. Hamada Y. Shioiri T. Synlett  1997,  109 
    Google Scholar
  • 9b Shioiri T. McFarlane N. Hamada Y. Heterocycles  1998,  47:  73 
    Google Scholar
  • 9c Yokokawa F. Asano T. Shioiri T. Org. Lett.  2000,  2:  4169 
    Google Scholar
  • 9d Yokokawa F. Asano T. Shioiri T. Tetrahedron  2001,  51:  6311 
    Google Scholar
  • 10 Hanessian SH. Ugolini A. Dubé D. Glamyan A. Can. J. Chem.  1984,  62:  2146 
    CrossrefGoogle Scholar
  • 11a

    This method improves upon preceding methods for isopentylidene synthesis, for it requires only commercially available reagents.

  • 11b

    Procedure for Isopentylidene Synthesis: To a 1-L flask under N2 were added the S-enantiomer of triol 5 (21.01 g, 0.1980 mol), 3-pentanone (80 mL, 0.79 mol), trimethyl orthoformate (33 mL, 0.30 mol), p-TsOH (0.44 g, 0.023 mol), anhyd MeOH (75 mL), and distilled CH2Cl2 (150 mL). The mixture was heated to reflux and stirred for 15 h. Et3N (1.8 mL, 0.013 mol) was added, and the mixture was stirred for 30 min. H2O (100 mL) was added, and the aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The combined organic phases were dried over NaSO4, filtered, and concentrated to a clear, yellow-brown liquid. Flash chromatography (20% EtOAc-hexanes) yielded the 1,2-isopentylidene-protected 5 as a clear, yellow-tinged liquid (29 g, 85%). IR: 3510, 2950, 1460, 1170, 1080 cm-1. 1H NMR (300 MHz): δ = 0.87-0.93 (m, 6 H), 1.59-1.69 (m, 4 H), 1.79-1.85 (m, 2 H), 2.26 (t, J = 5.0 Hz, 1 H), 3.54 (t, J = 8.0 Hz, 1 H), 3.81 (dd, J = 6.0, 12.0 Hz, 2 H), 4.10 (dd, J = 6.0, 7.9 Hz, 1 H), 4.25 (m, 1 H).

  • 12a Anelli PL. Biffi C. Montanari F. Quici S. J. Org. Chem.  1987,  52:  2559 
    CrossrefGoogle Scholar
  • 12b Leanna MR. Sowin TJ. Morton HE. Tetrahedron Lett.  1992,  33:  5029 
    CrossrefGoogle Scholar
  • 13a Keck GE. Krishnamurthy D. Grier MC. J. Org. Chem.  1993,  58:  6543 
    CrossrefGoogle Scholar
  • 13b Keck GE. Geraci LS. Tetrahedron Lett.  1993,  34:  7827 
    CrossrefGoogle Scholar
  • 15 For preparation of a related bisoxazole, see: Sakakura A. Kondo R. Ishihara K. Org. Lett.  2005,  7:  1971 
    CrossrefGoogle Scholar
  • 16a Szczepankiewicz B. Ph.D. Thesis   University of California at Berkeley; USA: 1995. 
    CrossrefGoogle Scholar
  • 16b Lafontaine JA. Leahy JW. Tetrahedron Lett.  1995,  36:  6029 
    CrossrefGoogle Scholar
  • 19 Barrish JC. Singh J. Spergel SH. Han W.-C. Kissick TP. Kronenthal DR. Mueller RH. J. Org. Chem.  1993,  58:  4494 
    CrossrefGoogle Scholar
  • 20a Shapiro R. J. Org. Chem.  1993,  58:  5759 
    CrossrefGoogle Scholar
  • 20b

    For best results we suggest purifying the amine 12 shortly before amide synthesis, as yields for the bisoxazole cyclization dropped by as much as 30% in other cases.
    Crossref
  • 22 Matsuda F. Tomiyoshi N. Yanagiya M. Matsumoto T. Tetrahedron  1990,  46:  3469 
    CrossrefGoogle Scholar
  • 24 We tested the enantiomeric purity of aldehyde 17’s enantiomeric purity by reducing a sample to the alcohol and comparing its rotation to the alcohol produced by lithium borohydride reduction of ester 16. We observed only 1.5% racemization, which we judged acceptable. See: Roush WR. Palkowitz AD. Ando K. J. Am. Chem. Soc.  1990,  112:  6348 
    CrossrefGoogle Scholar
  • 25a Joe D. Ph.D. Thesis   University of California at Berkeley; USA: 1994. 
    Google Scholar
  • 25b

    The phosphonate is prepared by Arbuzov reaction between methyl 2-bromopropionate and trimethyl phosphite. This method is capricious and highly sensitive to the purity of the starting materials.

  • 25c

    The lithium enolate was deprotonated with n-BuLi (1.01 equiv) in Et2O (0.125 M) at 0 °C to r.t.

  • 26a Nagaoka H. Kishi Y. Tetrahedron  1981,  37:  3873 
    CrossrefGoogle Scholar
  • 26b

    The unusual Z selectivity is only maintained for the olefination reagent with methyl ester and methyl phosphonate.
    Crossref
  • 26c The stereochemistry of the two isomers of 19 was corroborated by chemical shift calculations: Silverstein RM. Bassler GC. Morrill TC. Spectrometric Identification of Organic Compounds   5th ed.:  John Wiley & Sons; New York: 1991.  p.215 
    CrossrefGoogle Scholar
  • 27 Yoon NM. Gyoung YS. J. Org. Chem.  1985,  50:  2443 
    CrossrefGoogle Scholar
  • 28 Dess DB. Martin JC. J. Org. Chem.  1983,  48:  4155 
    CrossrefGoogle Scholar
  • 29a

    The β,γ-unsaturated aldehyde could survive at room temperature for over a day without appreciable decomposition. In contrast, the benzoate-protected analogue would decompose within hours, and it could only be synthesized in low yield (33-56%).

  • 29b

    Spectral data for the (S)-β,γ-unsaturated aldehyde: [α]D 20 +135 (c = 0.54, CHCl3). 1H NMR (300 MHz): δ = 1.05 (d, J = 6.9 Hz, 3 H), 1.94 (d, J = 1.2 Hz, 3 H), 2.95-3.00 (m, 1 H), 3.58 (d, J = 10.6 Hz, 1 H), 3.68 (d, J = 10.6 Hz, 1 H), 5.07 (d, J = 9.5 Hz, 1 H), 7.21-7.48 (m, 15 H), 9.38 (d, J = 1.3 Hz, 1 H). 13C NMR (100 MHz): δ = 14.1, 22.3, 46.0, 62.7, 86.7, 123.8, 127.0, 127.7, 128.6, 137.8, 143.9, 201.2.

  • 30a Schlosser M. Schaub B. J. Am. Chem. Soc.  1982,  104:  5821 
    CrossrefGoogle Scholar
  • 30b Maryanoff BE. Reitz AB. Mutter MS. Inners RR. Almond HR. Whittle RR. Olofson RA. J. Am. Chem. Soc.  1986,  108:  7664 
    CrossrefGoogle Scholar
  • 31a

    Spectral data for diene 4: 1H NMR (300 MHz): δ = 0.99 (t, J = 5.1 Hz, 3 H), 1.61-1.68 (m, 3 H), 1.76-1.78 (m, 3 H), 3.08 (m, 1 H), 3.42-3.50 (m, 1 H), 3.96-4.18 (m, 2 H), 5.10-5.38 (m, 3 H).

  • 31b

    Spectral data for ent-(S)-20: IR: 3022, 2947, 2855, 2307, 1112, 1085, 702 cm-1. 1H NMR (300 MHz): δ = 0.94 (d, J = 6.7 Hz, 3 H), 1.02 (s, 9 H), 1.89 (d, J = 1.1 Hz, 3 H), 2.40-2.50 (m, 1 H), 3.38 (dd, J = 1.7, 9.5 Hz, 2 H), 3.48 (d, J = 10.4 Hz, 1 H), 3.75 (d, J = 10.4 Hz, 1 H), 5.10 (d, J = 9.5 Hz, 1 H), 7.24-7.63 (m, 25 H). 13C NMR (100 MHz): δ = 17.5, 19.1, 22.0, 26.7, 34.9, 62.8, 68.5, 86.4, 126.7, 127.4, 127.6, 128.6, 129.3, 131.1, 133.0, 133.8, 133.8, 135.5, 135.5, 144.3.

  • 33 For the synthesis of 2-phenyl-1,3-dithiane, see: Roberts RM. Cheng C.-C. J. Org. Chem.  1958,  23:  983 
    CrossrefGoogle Scholar
  • 34 Cink RD. Forsyth CJ. J. Org. Chem.  1995,  60:  8122 ; and supplementary material
    CrossrefGoogle Scholar
  • 35a Corey EJ. Erickson BJ. J. Org. Chem.  1971,  36:  3553 
    CrossrefGoogle Scholar
  • 35b Trost BM. Grese TA. J. Org. Chem.  1992,  57:  686 
    CrossrefGoogle Scholar
  • 36 Chen K.-M. Hardtmann GE. Prasad K. Repic O. Shapiro MJ. Tetrahedron Lett.  1987,  28:  155 
    CrossrefGoogle Scholar
  • 38 Williams DR. Brooks DA. Meyer KA. Tetrahedron Lett.  1998,  39:  8023 
    CrossrefGoogle Scholar
  • 39 Liu P. Panek JS. Tetrahedron Lett.  1998,  39:  6147 
    CrossrefGoogle Scholar
1

Current addresses: E. J. Zylstra, 166 Chilton Ave, San Francisco, CA 94131, USA; M. W.-L. She, 3952 Angelo Ave, Oakland, CA 94619, USA; W. A. Salamant, Department of Chemistry, University of California, Irvine, California 92697, USA; J. W. Leahy, Exelixis Pharmaceuticals, Inc., 210 East Grand Ave, Box 511, South San Francisco, CA 94083, USA.

14

Spectral data for diol 8: 1H NMR (300 MHz): δ = 1.50 (ddd, J = 2.9, 7.8, 14.6 Hz, 1 H), 1.62-1.76 (m, 4 H), 2.19 (dd, J = 7.6, 13.8 Hz, 1 H), 2.47 (dd, J = 5.5, 13.7 Hz, 1 H), 2.85 (s, 2 H), 3.40 (dd, J = 6.8, 11.2 Hz, 1 H), 3.56 (dd, J = 3.3, 11.2 Hz, 1 H), 3.78 (s, 3 H), 3.82-3.90 (m, 1 H), 3.91-4.02 (m, 1 H), 4.42 (d, J = 11.0 Hz, 1 H), 4.56 (d, J = 11.0 Hz, 1 H), 4.76 (s, 1 H), 4.81 (s, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 7.26 (d, J = 8.6 Hz, 1 H). 13C NMR (100 MHz): δ = 22.8, 36.2, 42.1, 55.2, 66.9, 69.0, 70.9, 74.5, 113.3, 113.9, 129.5, 130.1, 142.2, 159.3.

17

Attempts with serine ethyl ester afforded a higher yield for the amidation (80%) and comparable yields for the first oxazole synthesis; however, as the ethyl ester was less readily accessible, the methyl ester was used.

18

General Procedure for Oxazoline Synthesis: To a dry 100-mL flask under N2 was added a solution of the amide 10 (1.00 g, 3.39 mmol) in anhyd MeCN-CH2Cl2 (4:1, 15 mL), Ph3P (1.33 g, 5.08 mmol), and DIPEA (0.94 mL, 5.47 mmol). After the mixture was cooled in an ice-bath for 90 min, CCl4 (0.50 mL, 5.16 mmol) was added slowly. After 14 min, the mixture was allowed to warm to r.t. and stirred for 5.25 h. The mixture was cooled in an ice bath. EtOAc (30 mL) and sat. aq NaHCO3 (9 mL) were added, and after 10 min, the biphasic mixture was diluted with H2O (21 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL); the combined organic layers were washed with brine (1 × 20 mL), dried over NaSO4, filtered, and concentrated to a yellow solid. Flash chromatography (25-50% EtOAc gradient in hexanes) yielded the water-sensitive oxazoline as a clear yellow oil (0.66 g, 70%). 1H NMR (300 MHz): δ = 1.98 (m, 2 H), 2.47 (m, 2 H), 3.54 (t, J = 6.1 Hz, 2 H), 3.46 (dd, J = 8.8, 10.6 Hz, 1 H), 3.79 (s, 3 H), 4.46-4.50 (m, 3 H), 4.66-4.69 (m, 1 H), 7.27-7.36 (m, 5 H).

21

The reduction of the bisoxazole was a sensitive reaction; during a repetition on larger scale, yields dropped to 30% because of competitive decomposition.

23

Spectral data for dithiane 3: 1H NMR (300 MHz): δ = 2.03-2.18 (m, 4 H), 2.94-3.00 (m, 6 H), 3.56 (t, J = 6.1 Hz, 2 H), 4.50 (s, 2 H), 5.18 (s, 1 H), 7.26-7.32 (m, 5 H), 7.74 (s, 1 H), 8.16 (s, 1 H). 13C NMR (100 MHz): δ = 24.9, 25.1, 26.8, 30.3, 41.4, 68.7, 72.8, 127.5, 127.5, 128.2, 130.0, 135.7, 138.1, 138.3, 140.5, 155.2, 165.7.

32

A test reaction conducted with the aldehyde derived from ent-20 and tetraethylphosphonium bromide did favor the E-olefin (E/Z = 4.8:1), but in unacceptably low yield (9%).

37

The model 26 was prepared from racemic N-benzoyl serine methyl ester by methods analogous to those used for the synthesis of oxazole 11 and dithiane 3.