A Flexible Synthetic Approach to the Hennoxazoles

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

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• 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).

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• 15 For preparation of a related bisoxazole, see: Sakakura A. Kondo R. Ishihara K. Org. Lett.  2005,  7:  1971 
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• 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.

• 22 Matsuda F. Tomiyoshi N. Yanagiya M. Matsumoto T. Tetrahedron  1990,  46:  3469 
• 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 
• 25a Joe D. Ph.D. Thesis   University of California at Berkeley; USA: 1994. 
• 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 
• 26b

  The unusual Z selectivity is only maintained for the olefination reagent with methyl ester and methyl phosphonate.

• 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 
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• 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 
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• 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 
• 34 Cink RD. Forsyth CJ. J. Org. Chem.  1995,  60:  8122 ; and supplementary material
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• 38 Williams DR. Brooks DA. Meyer KA. Tetrahedron Lett.  1998,  39:  8023 
• 39 Liu P. Panek JS. Tetrahedron Lett.  1998,  39:  6147 

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.