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.

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

References and Notes

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.

2 Ichiba T. Yoshida WY. Scheuer PJ. Higa T. Gravalos DG. J. Am. Chem. Soc.  1991,  113:  3173 

3 Higa T. Tanaka J.-I. Kitamura A. Koyama T. Takahashi M. Uchida T. Pure Appl. Chem.  1994,  66:  2227 

4 For a review on oxazole-containing natural products, see: Yeh VSC. Tetrahedron  2004,  60:  11995 

5a Wipf P. Lim S. J. Am. Chem. Soc.  1995,  117:  558 

5b Wipf P. Lim S. Chimia  1996,  50:  157 

6 Williams DR. Brooks DA. Berliner MA. J. Am. Chem. Soc.  1999,  121:  4924 

7 Barrett AGM. Kohrt JT. Synlett  1995,  415 

8 Smith TE. Balskus EP. Heterocycles  2002,  57:  1219 

9a Cheng Z. Hamada Y. Shioiri T. Synlett  1997,  109 

9b Shioiri T. McFarlane N. Hamada Y. Heterocycles  1998,  47:  73 

9c Yokokawa F. Asano T. Shioiri T. Org. Lett.  2000,  2:  4169 

9d Yokokawa F. Asano T. Shioiri T. Tetrahedron  2001,  51:  6311 

10 Hanessian SH. Ugolini A. Dubé D. Glamyan A. Can. J. Chem.  1984,  62:  2146 

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 

12b Leanna MR. Sowin TJ. Morton HE. Tetrahedron Lett.  1992,  33:  5029 

13a Keck GE. Krishnamurthy D. Grier MC. J. Org. Chem.  1993,  58:  6543 

13b Keck GE. Geraci LS. Tetrahedron Lett.  1993,  34:  7827 

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.

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

16a Szczepankiewicz B. Ph.D. Thesis   University of California at Berkeley; USA: 1995. 

16b Lafontaine JA. Leahy JW. Tetrahedron Lett.  1995,  36:  6029 

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).

19 Barrish JC. Singh J. Spergel SH. Han W.-C. Kissick TP. Kronenthal DR. Mueller RH. J. Org. Chem.  1993,  58:  4494 

20a Shapiro R. J. Org. Chem.  1993,  58:  5759 

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.

21

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

22 Matsuda F. Tomiyoshi N. Yanagiya M. Matsumoto T. Tetrahedron  1990,  46:  3469 

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.

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 

27 Yoon NM. Gyoung YS. J. Org. Chem.  1985,  50:  2443 

28 Dess DB. Martin JC. J. Org. Chem.  1983,  48:  4155 

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 

30b Maryanoff BE. Reitz AB. Mutter MS. Inners RR. Almond HR. Whittle RR. Olofson RA. J. Am. Chem. Soc.  1986,  108:  7664 

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.

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%).

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

35a Corey EJ. Erickson BJ. J. Org. Chem.  1971,  36:  3553 

35b Trost BM. Grese TA. J. Org. Chem.  1992,  57:  686 

36 Chen K.-M. Hardtmann GE. Prasad K. Repic O. Shapiro MJ. Tetrahedron Lett.  1987,  28:  155 

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.

38 Williams DR. Brooks DA. Meyer KA. Tetrahedron Lett.  1998,  39:  8023 

39 Liu P. Panek JS. Tetrahedron Lett.  1998,  39:  6147