Synthesis of Bistramide A and Analogues, Part 1: Stereoselective Access to Normethyl Tetrahydropyran Subunit

Abstract

A stereoselective synthesis of normethyl C1-C13 fragment of bistramide A is described. The key steps involve an asymmetric Sharpless epoxidation, a cross-metathesis reaction and an intramolecular oxa-Michael reaction. The trans-2,6-disubstituted tetrahydropyran subunit has been synthesized in an overall yield of 7% with 96% ee. The cis isomer was prepared by a similar pathway with the same efficiency and enantioselectivity.

bistramide A - normethyl - Sharpless epoxidation - cross-metathesis reaction - intramolecular oxa-Michael reaction

References and Notes

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17 Crisóstomo FRP. Carrillo R. León LG. Martín T. Padrón JM. Martín VS. J. Org. Chem.  2006,  71:  2339 

18

Epoxy alcohol 2: [α]_D ²⁰ +38.8 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.54-1.58 (m, 4 H), 1.85 (br s, 1 H), 2.03-2.16 (m, 2 H), 2.91-2.95 (m, 2 H), 3.61 (dd, J = 4.1, 12.6 Hz, 1 H), 3.90 (dd, J = 2.3, 12.6 Hz, 1 H), 4.28-5.04 (m, 2 H), 5.78 (ddt, J = 6.6, 10.2, 17.0 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 25.4, 31.2, 33.6, 56.1, 58.9, 62.0, 115.2, 138.5. IR: 3800-3100, 3075, 2975, 2932, 2859, 1747, 1640, 1458, 1258, 1093, 911 cm^-1.

19

Boc-derivative of epoxy alcohol 2: [α]_D ²⁰ +24.3 (c = 1, CHCl₃), literature data for the enantiomer:¹³ [α]_D ²⁵ -19.9
(c = 1.1, CHCl₃).

20a Finan JM. Kishi Y. Tetrahedron Lett.  1982,  23:  2719 

20b Ma P. Martin VS. Masamune S. Sharpless KB. Viti SM. J. Org. Chem.  1982,  47:  1378 

21

Diol 5: [α]_D ²⁰ +6.3 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.36-1.72 (m, 6 H), 2.02-2.06 (m, 2 H), 3.37 (br s, 2 H, 2 × OH), 3.72-3.87 (m, 3 H), 4.91-5.02 (m, 2 H), 5.78 (ddt, J = 6.6, 10.4, 17.1 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 25.1, 33.9, 37.4, 38.5, 61.7, 72.0, 114.9, 138.9.

22

Silyl ether 6: [α]_D ²⁰ +12.4 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.06 (s, 6 H, 2 × Me), 0.88 (s, 9 H, 3 × Me), 1.36-1.64 (m, 6 H), 2.02-2.09 (m, 2 H), 3.75-3.92 (m, 3 H), 4.91-5.02 (m, 2 H), 5.79 (ddt, J = 6.6, 10.4, 17.1 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.35, -5.32, 18.3, 25.0, 26.1 (3 × C), 34.0, 37.2, 38.6, 63.0, 72.0, 114.6, 139.1. IR: 3600-3100, 3075, 2931, 2859, 1642, 1472, 1256, 1090, 1005, 910, 836, 777 cm^-1.

23 Chaterjee AK. Choi T.-L. Sanders DP. Grubbs RH. J. Am. Chem. Soc.  2003,  125:  11360 

24

Hydroxy ester 7: [α]_D ²⁰ +11.2 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.05 (s, 6 H, 2 × Me), 0.86 (s, 9 H, 3 × Me), 1.39-1.64 (m, 6 H), 2.17-2.21 (m, 2 H), 3.45 (br s, 1 H, OH), 3.68 (s, 3 H), 3.69-3.99 (m, 3 H), 5.80 (d, J = 15.6 Hz, 1 H), 6.89-6.99 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ =
-5.3 (2 × C), 18.4, 24.3, 26.1 (3 × C), 32.4, 37.2, 38.5, 51.6, 63.2, 72.2, 121.3, 149.7, 167.4. IR: 3600-3100, 3075, 2931, 2859, 1642, 1472, 1256, 1090, 1005, 910, 836, 777 cm^-1.

25 Banwell MG. Bui CT. Pham HTT. Simpson GW. J. Chem. Soc., Perkin Trans. 1  1996,  967 

26

Compound 8 (trans isomer): [α]_D ²⁰ -43.1 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.04 (s, 6 H, 2 × Me), 0.88 (s, 9 H, 3 × Me), 1.24-1.48 (m, 2 H), 1.51-1.70 (m, 5 H), 1.90-2.02 (m, 1 H), 2.41 (dd, J = 5.5, 14.7 Hz, 1 H), 2.59 (dd, J = 8.3, 14.7 Hz, 1 H), 3.60-3.67 (m, 2 H), 3.67 (s, 3 H), 3.89-3.94 (m, 1 H), 4.10-4.16 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.0 (2 × C), 18.6, 18.8, 26.3 (3 × C), 29.9, 30.4, 35.9, 39.9, 51.9, 60.2, 67.9, 69.1, 172.3. IR: 2928, 2856, 1746, 1463, 1361, 1288, 1256, 1206, 1159, 1092, 1050, 836, 776. cis-Isomer: [α]_D ²⁰ -18.2 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 0.03 (s, 6 H, 2 × Me), 0.88 (s, 9 H, 3 × Me), 1.18-1.25 (m, 2 H), 1.46-1.73 (m, 5 H), 1.79-1.84 (m, 1 H), 2.38 (dd, J = 5.8, 14.7 Hz, 1 H), 2.53 (dd, J = 7.5, 14.7 Hz, 1 H), 3.40-3.48 (m, 1 H), 3.66-3.77 (m, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.0 (2 × C), 18.6, 23.8, 26.3 (3 × C), 31.6, 31.7, 39.9, 42.0, 51.9, 59.9, 74.6, 75.0, 172.3. IR: 2931, 2858, 1746, 1469, 1437, 1255, 1196, 1091, 1047, 836, 776 cm^-1.

27

Compound 9: trans isomer: [α]_D ²⁰ -51.3 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.21-1.42 (m, 2 H), 1.51-1.91 (m, 6 H), 2.38 (dd, J = 4.7, 14.4 Hz, 1 H), 2.86 (dd, J = 10.2, 14.4 Hz, 1 H), 3.64-3.77 (m, 5 H), 3.92-3.99 (m, 1 H), 4.28-4.36 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.7, 29.5, 30.9, 36.7, 38.3, 52.1, 60.8, 69.0, 70.4, 172.5. IR: 3437, 2940, 2868, 1739, 1439, 1290, 1257, 1206, 1153, 1047, 1021 cm^-1.

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

29 Marton D. Stivanello D. Tagliavini G. J. Org. Chem.  1996,  61:  2731 

30 Huang SL. Swern D. J. Org. Chem.  1978,  43:  4537 

31

trans-1: [α]_D ²⁰ -11.3 (c = 0.25, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.35-1.39 (m, 2 H), 1.62-1.91 (m, 4 H), 1.90 (dd, J = 1.5, 6.8 Hz, 3 H), 2.44 (dd, J = 5.8, 14.9 Hz, 1 H), 2.62 (dd, J = 6.6, 15.2 Hz, 1 H), 2.66 (dd, J = 8.1, 14.9 Hz, 1 H), 2.88 (dd, J = 6.6, 15.2 Hz, 1 H), 3.66 (s, 3 H), 4.17-4.30 (m, 2 H), 6.13 (dq, J = 1.5, 15.6 Hz, 1 H), 6.85 (dq, J = 6.8, 15.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.6, 23.5, 31.2, 31.5, 41.9, 47.0, 51.9, 74.8, 75.0, 132.7, 143.6, 172.0, 198.8. IR: 2938, 2860, 1739, 1668, 1626, 1433, 1373, 1352, 1289, 1200, 1066 cm^-1. HRMS (CI): m/z [M + H⁺] calcd for C₁₃H₂₁O₄: 241.1440; found: 241.1436. Chiral HPLC: ChiralPak AD, hexane-i-PrOH (90:10), λ = 225 nm, flow rate: 0.5 mL/min, t _R = 22.4 min (minor) and 25.5 min (major).

32

Compound 9: cis isomer: [α]_D ²⁰ +10.9 (c = 1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.18-1.36 (m, 2 H), 1.46-1.84 (m, 6 H), 2.40 (dd, J = 4.5, 15.0 Hz, 1 H), 2.50 (dd, J = 8.3, 15.0 Hz, 1 H), 3.55-3.62 (m, 1 H), 3.67 (s, 3 H), 3.72-3.82 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 23.5, 31.3, 31.5, 38.2, 41.6, 52.1, 62.0, 74.8, 79.3, 172.2. IR: 3449, 2937, 2857, 1740, 1439, 1375, 1344, 1287, 1251, 1200, 1040 cm^-1.

33

cis-1: [α]_D ²⁰ +10.0 (c = 0.94, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.12-1.27 (m, 3 H), 1.49-1.66 (m, 3 H), 1.89 (dd, J = 1.5, 6.9 Hz, 3 H), 2.37 (dd, J = 5.6, 14.9 Hz, 1 H), 2.46-2.53 (m, 2 H), 2.80 (dd, J = 6.8, 15.3 Hz, 1 H), 3.65 (s, 3 H), 3.69-3.86 (m, 2 H), 6.13 (dq, J = 1.5, 15.6 Hz, 1 H), 6.84 (dq, J = 6.9, 15.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.6, 23.5, 31.2, 31.5, 42.9, 47.0, 51.8, 74.8, 75.0, 132.7, 143.6, 172.0, 198.8. IR: 2937, 2857, 1740, 1668, 1627, 1434, 1375, 1350, 1289, 1198, 1066 cm^-1. HRMS (CI): m/z [M + H⁺] calcd for C₁₃H₂₁O₄: 241.1440; found: 241.1437. Chiral HPLC: ChiralPak AD, hexane-i-PrOH (90:10), λ = 225 nm, flow rate: 0.5 mL/min, t _R = 18.2 min (minor) and 19.9 min (major).

34

After submission of this manuscript, a similar approach was reported in the literature, see: Bates, R. W.; Palani, K. Terahedron Lett. 2008, 49, 2832.