A Short and Efficient Stereoselective Synthesis of the Octalactin Lactone Using Enantioselective Crotyltitanations and a Cross-Metathesis Reaction

Abstract

The octalactin lactone was synthesized from the ­commercially available methyl 3-butenoate using enantioselective crotyltitanations to control the stereogenic centers at C3, C4, C7 and C8.

Key words

crotyltitanations - cross-metathesis - octalactin

References

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10

The yield was calculated for the two steps from (R,R)-I.

11

Spectroscopic data of compound 3: [α]_D ²⁵ +25.2 (c 1.08, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 5.72 (ddd, J = 7.9, 10.9, 16.5 Hz, 1 H), 5.02 (m, 2 H), 3.75 (m, 1 H), 3.62 (s, 3 H), 2.69 (s, 1 H), 2.39 (m, 2 H), 2.22 (m, 1 H), 1.00 (d, J = 6.7 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.2 (s), 139.4 (d), 115.8 (t), 71.0 (d), 51.5 (q), 43.2 (d), 38.6 (t), 15.6 (q). IR (neat): ν = 3450, 2940, 1740 cm^-1. MS (EI, 70 eV): m/z (%) = 158 (absent) [M], 127 (10), 103 (100), 83 (14), 71 (80), 61 (35), 56 (60).

12

The diastereoselectivity of the reaction was determined by ¹H NMR spectroscopy and the enantioselectivity by GC/MS spectrometry (HP 6890 Series Injector GC system coupled with HP 5973 Mass Selective Detector) of the corresponding Mosher esters.

13

Spectroscopic data of compound 4: [α]_D ²⁵ +18.9 (c 0.45, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.46 (d, J = 7.9 Hz, 1 H), 6.86 (dd, J = 7.9, 15.8 Hz, 1 H), 6.08 (ddd, J = 1.1, 7.9, 15.8 Hz, 1 H), 3.99 (m, 1 H), 3.64 (s, 3 H), 3.30 (d, J = 3.5 Hz, 1 H), 2.50 (m, 1 H), 2.41 (m, 2 H), 1.11 (d, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 194.0 (d), 173.0 (s), 159.0 (d), 133.3 (d), 70.7 (d), 51.9 (q), 42.2 (d), 39.0 (t), 15.7 (q). IR (neat): ν = 3500, 2950, 1750 cm^-1. MS (EI, 70 eV): m/z (%) = 186 (absent) [M], 155 (2), 109 (5), 103 (25), 95 (16), 84 (100), 42 (71), 61 (15), 55 (38).

14

The limiting step is the saponification.

16

Spectroscopic data of compound 10: [α]_D ²⁵ -54.6 (c 1.59, CHCl₃).^{17 1}H NMR (300 MHz, CDCl₃): δ = 9.65 (s, 1 H), 4.60 (ddd, J = 3.6, 7.1, 15.0 Hz, 1 H), 3.92 (d, J = 6.8 Hz, 1 H), 2.70-2.68 (m, 3 H), 1.92 (m, 1 H), 1.75-1.50 (m, 4 H), 1.08 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.85 (s, 9 H), 0.15 (s, 3 H), 0.00 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 202.4 (d), 170.8 (s), 76.8 (d), 72.7 (d), 50.6 (d), 39.7 (t), 38.5 (d), 31.4 (t), 25.8 (3 q), 25.7 (q), 23.0 (t), 18.0 (s), 10.4 (q), -4.2 (q), -5.1 (q). IR (neat): ν = 2955, 2928, 2855, 1721, 1461, 1253, 1180, 1086, 1036 cm^-1. MS (EI, 70 eV): m/z (%) = 271 (12), 185 (18), 171 (23), 157 (13), 145 (46), 119 (13), 115 (26), 109 (29), 101 (61), 93 (14), 75 (100), 73 (53), 59 (19), 55 (23).

17

In order to avoid the epimerization of the stereogenic center in the α-position of the aldehyde, and due to the instability of 10, τηε [α]_D was measured on the product obtained after extraction.