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.

crotyltitanations - cross-metathesis - octalactin

References

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<A NAME="RY06105ST-9B">9b</A> Shiina I. Ikuba R. Kubota M. Tetrahedron Lett.  2002,  43:  7535 

<A NAME="RY06105ST-10">10</A>

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

<A NAME="RY06105ST-11">11</A>

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).

<A NAME="RY06105ST-12">12</A>

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.

<A NAME="RY06105ST-13">13</A>

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).

<A NAME="RY06105ST-14">14</A>

The limiting step is the saponification.

<A NAME="RY06105ST-15A">15a</A> Shiina I. Ikuba R. Kubota M. Chem. Lett.  2002,  286 

<A NAME="RY06105ST-15B">15b</A> Shiina I. Kubota M. Oshiumi H. Hashizume M.
J. Org. Chem.  2004,  65:  1822 

<A NAME="RY06105ST-16">16</A>

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).

<A NAME="RY06105ST-17">17</A>

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.