Diastereoselective synthesis of (±)-epianastrephin, (±)-anastrephin and analogs thereof
AssigneeThe United States of America as represented by the Secretary of Agriculture
InventorsSpencer S. Walse, Daniel Kuzmich
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Abstract
A process for the synthesis of trans-fused γ-lactones having Formula (IV) from substituted cyclic ketones having Formula (I). A diastereoselective synthesis of (±)-epianastrephin (1) (wherein: R1 is ethenyl, R2 and R3 is methyl, and n is 1), (±)-anastrephin (2) (wherein: R2 is ethenyl, R1 and R3 is methyl and n is 1), and analogs thereof (wherein: R1 is H, C1-5 alkyl, C2-6 alkenyl or C2-6 alkynyl, R2 is H, C1-5 alkyl, C2-6 alkenyl or C2-6 alkynyl, R1 and R2 together with the carbon atom they are attached form a C3-6 cycloalkyl ring, R3 is C1-5 alkyl and n is 0-2):
Claims41
A process of making trans-fused γ-lactones of the Formula (IV)
- wherein:
- R1 is H, C1-5 alkyl, C2-6 alkenyl or C2-6 alkynyl,
- R2 is H, C1-5 alkyl, C2-6 alkenyl or C2-6 alkynyl,
- R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl ring,
- R3 is C1-5 alkyl,
- n is 0, 1 or 2 to form a 5-, 6- or 7-membered ring, said process comprising:
- (a) reacting the cyclic ketone of Formula (I) with an organometallic reagent MCH2CO2R4 where M is Li, Na, K, or MgX, where X is Cl, Br or I, where is R4 is C1-4 alkyl, in a solvent to form the alcohol of Formula (II)
- (b) reacting the alcohol of Formula (II) with an acylating agent, or a chloroformate in the presence of a catalyst or a base in a solvent, or an acyl transfer reagent in the presence of an acid catalyst and organic catalyst in a solvent, to provide a compound of Formula (III) where R5 is —C(O)C1-6 alkyl or —C(O)OC1-6 alkyl
- (c) cyclizing the compound of Formula (III) with an organic acid or a Lewis acid in a solvent to form the trans-fused γ-lactone of Formula (IV)
A process of making compound 18, said process comprising hydrogenation of (±)-anastrephin (2) using a catalyst in a solvent to form compound 18:
A process of making the compound 20, said process comprising hydrogenation of (±)-epianastrephin (1) using a catalyst in a solvent to form the compound 20:
A process of making ketone 11 that may be used to make (±)-epianastrephin (1), said process comprising epimerization of ketone 15 using an acid catalyst in a solvent to provide the diastereomeric ketone 11;
- or using a base in a solvent followed by protonation to provide the diastereomeric ketone 11:
A process of making the aglycon 7 of suspensosides A and B (8) from an alcohol of Formula (II)
- wherein:
- R1 is ethenyl or methyl,
- R2 is ethenyl or methyl,
- R1 and R2 are not the same,
- R3 is methyl,
- R4 is methyl, ethyl, propyl, t-butyl, and
- n is 1 to form a 6-membered ring,
- said process comprising:
- (a) dehydrating alcohol 12A with a dehydrating agent in a solvent to provide olefin 19,or reacting alcohol 12A with sulfonyl chloride followed by elimination with a base to provide the olefin 19
- (b) deprotection of the t-butyl ester of compound 19 with an acid in a solvent to provide the aglycon 7 of suspensosides A and B (8)
A compound in the table below which may be used to make (±)-epianastrephin (1), said compound having the relative stereochemistry depicted in the table below:
- Structure
- Name
- Data(a)
- 2-(1-Hydroxyethyl)-2,6- dimethylcyclohexanone
- 13C NMR (75 MHz, CDCl3) δ 221.13 (q), 71.59 (d), 52.10 (q), 41.40 (d), 37.09 (t), 36.49 (t), 21.11 (t), 15.86 (s), 15.81 (s), 14.67 (s);
- minor diastereomer δ 216.81 (q), 69.95 (d), 53.28 (q), 41.31 (d), 37.53 (t), 35.81 (t), 20.53 (t), 17.39 (s), 16.05 (s), 15.19 (s)
- tert-Butyl 1-((1R*,2S*,6R*)-1- hydroxy-2,6-dimethyl-2- ethenylcyclohexyl) acetate
- IR (neat) 3447 (broad), 2929, 1700, 1147 cm−1;
- 1H NMR (300 MHz, CDCl3) δ 6.19 (ddd, J = 17.3, 11.2, 1.1 Hz, 1H), 5.14-5.00 (m, 2H), 2.44 (dd, J = 16.2, 1.1 Hz, 1H), 2.17 (dd, J = 16.1, 1.1 Hz, 1H), 1.92-1.75 (m, 1H), 1.75-1.54 (m, 1H), 1.45 (s, 6H), 1.61-1.37 (m, 4H), 1.33 (s, 1H), 1.30-1.18 (m, 1H),
- 1.06 (d, J = 1.1 Hz, 3H), 0.86 (dd, J = 6.4, 1.1 Hz,
- 3H);
- 13C NMR (75 MHz, CDCl3) δ 174.83 (q),
- 142.64 (d), 113.90 (t), 81.62 (q), 75.19 (q), 45.60
- (q), 38.15 (t), 38.09 (d), 35.17 (t), 30.49 (t), 28.01
- (s), 21.67 (s), 21.47 (t), 16.67 (s);
- GC-EIMS m/z
- (% rel. abundance) 212 (9), 194 (31), 96 (100)
- tert-Butyl 1-((1R*,2S*,6R*)-1- acetoxy-2,6-dimethyl-2- ethenylcyclohexyl) acetate
- IR (neat) 2976, 2933, 1734, 1151 cm−1;
- 1H NMR (300 MHz, CDCl3) δ 6.20 (dd, J = 17.5, 11.0 Hz, 1H), 5.50-4.81 (m, 2H), 3.17 (s, 2H), 2.44 (q, J = 6.9 Hz, 1H), 2.08 (s, 3H), 1.77 (ddd, J = 12.8, 11.1, 4.3 Hz, 1H), 1.57-1.43 (m, 3H), 1.39 (s, 9H), 1.12 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H);
- 13C NMR (75
- MHz, CDCl3) δ 170.61 (q), 169.86 (q), 142.30 (d),
- 114.17 (t), 88.51 (q), 79.97 (q), 46.01 (q), 37.26 (t),
- 36.25 (d), 35.75 (t), 30.16 (t), 28.02 (s), 22.98 (s),
- 22.53 (s), 20.40 (t), 17.95 (s);
- GC-EIMS m/z (% rel.
- abundance) 254 (3), 236 (7), 194 (62), 138 (59), 57
- (100).
A compound in the table below which may be used to make (±)-anastrephin (2), said compound having the relative stereochemistry depicted in the table below:
- Structure
- Name
- Data(a)
- tert-Butyl 1-((1R*,2R*,6R*)- 1-hydroxy-2,6-dimethyl-2- ethenylcyclohexyl) acetate
- IR (neat) 3443 (broad), 2977, 2933, 1699, 1149 cm−1;
- 1H NMR (300 MHz, CDCl3) δ 6.28 (dd, J = 17.7, 11.0 Hz, 1H), 5.10-4.94 (m, 2H), 2.46 (d, J = 15.9 Hz, 1H), 2.17 (d, J = 15.9, 1.0 Hz, 1H), 2.08- 1.87 (m, 1H), 1.81-1.68 (m, 1H), 1.43 (s, 9H), 1.31 (s, 1H), 1.03 (s, 3H), 0.84 (d, J = 6.6, 3H);
- 13C NMR
- (75 MHz, CDCl3) δ 174.64 (q), 146.49 (d), 112.75
- (q), 81.65 (q), 75.33 (q), 45.28 (q), 38.78 (t), 37.22
- (d), 34.43 (t), 30.53 (t), 28.05 (s), 21.50 (t), 17.91
- (s), 16.74 (s);
- GC-EIMS m/z (% rel. abundance)
- 212 (14), 194 (42), 96 (100)
- tert-Butyl 1-((1R*,2R*,6R*)- 1-acetoxy-2,6-dimethyl-2- ethenylcyclohexyl) acetate
- IR (neat) 2976, 2935, 1730, 1149 cm−1;
- 1H NMR (300 MHz, CDCl3) δ 6.12 (dd, J = 17.6, 11.0 Hz, 1H), 5.02 (ddd, J = 17.8, 11.2, 1.6 Hz, 2H), 3.32 (d, J = 15.9 Hz, 1H), 3.17 (d, J = 15.9 Hz, 1H), 2.46- 2.31 (m, 1H), 2.06 (s, 3H), 1.90 (m, 1H), 1.57-1.45 (m, 1H), 1.41 (s, 9H), 1.21-1.12 (m, 1H), 1.11 (s,
- 3H), 1.01 (d, J = 6.8 Hz, 3H);
- 13C NMR (75 MHz,
- CDCl3) δ 170.55 (q), 169.94 (q), 145.02 (d), 112.40
- (t), 89.06 (q), 80.17 (q), 45.68 (q), 37.51 (t), 35.88
- (d), 35.00 (t), 30.31 (t), 28.04 (s), 22.62 (s), 20.97
- (s), 20.45 (t), 17.94 (s).
The compound in the table below, said compound having the relative stereochemistry depicted in the table below:
- Structure
- Name
- Data(a)
- (3aS*,4S*,7aS*)-4,7a- Dimethyl-4- ethylhexahydrobenzofuran- 2(3H)-one
- IR (neat) 2939, 2871, 1770, 1028, 954, 928 cm−1, 1H NMR (300 MHz, CDCl3) δ 2.49 (dd, J = 16.3, 14.9 Hz, 1H), 2.31 (dd, J = 16.3, 6.5 Hz, 1H), 2.15-1.90 (m, 2H), 1.85-1.69 (m, 2H), 1.68-1.40 (m, 3H), 1.36 (s, 3H), 1.33-1.24 (m, 1H), 1.19- 0.97 (m, 1H), 0.91 (s, 3H), 0.85 (t, J = 7.5 Hz, 3H), 13C NMR (75 MHz, CDCl3) δ 176.62 (s),
- 86.57 (s), 56.81 (d), 37.68 (t), 36.36 (t), 35.68
- (s), 29.40 (t), 27.64 (q), 24.44 (t), 21.08 (q),
- 20.53 (t), 9.05 (q), GC-EIMS m/z (% rel.
- abundance) 181 (70), 167 (37), 153 (73), 139
- (25), 81 (93), 55 (100).
The compound in the table below which may be used to make analogs of (±)-epianastrephin (1) and (±)-anastrephin (2), said compound having the relative stereochemistry depicted in the table below:
- Structure
- Name
- Data(a)
- tert-Butyl 1-((1R*,6R*)- 1-acetoxy-2,2,6- trimethylcyclohexyl) acetate
- IR (neat) 2976, 2932, 1729, 1148 cm−1;
- 1H NMR (300 MHz, CDCl3) δ 3.34 (d, J = 15.8 Hz, 1H), 3.21 (d, J = 15.8 Hz, 1H), 2.42-2.24 (m, 1H), 2.05 (s, 3H), 1.78-1.63 (m, 1H), 1.55-1.39 (m, partially obscured by singlet at 1.42 ppm, 4H), 1.42 (s, 9H), 1.18-1.05 (m, 1H), 1.03 (d, partially obscured by
- singlets at 1.00 ppm, J = 6.6 Hz, 3H), 1.00 (s, 6H);
- 13C NMR (75 MHz, CDCl3) δ 170.78 (s), 170.28
- (s), 90.32 (s), 80.18 (s), 40.52 (s), 37.81 (t), 37.03
- (t), 35.75 (d), 30.63 (t), 28.01 (q), 27.08 (q), 24.26
- (q), 22.64 (q), 21.15 (t), 18.15 (q).
A process of making trans-fused γ-lactones of the Formula (IV)
- wherein:
- R1 is ethenyl or methyl,
- R2 is ethenyl or methyl,
- R1 and R2 are not the same,
- R3 is methyl,
- R4 is methyl, ethyl, propyl, t-butyl, and
- n is 1 to form a 6-membered ring,
- said process comprising:
- (a) reacting the cyclic ketone of Formula (I) with an organometallic reagent MCH2CO2R4 where M is Li, Na, K, or MgX, where X is Cl, Br or I, where R4 is C1-4 alkyl, in a solvent to form the alcohol of Formula (II)
- (b) reacting the alcohol of Formula (II) with an acylating agent, or a chloroformate in the presence of a catalyst or a base in a solvent, or an acyl transfer reagent in the presence of an acid catalyst and organic catalyst in a solvent, to provide a compound of Formula (III) where R5 is —C(O)C1-6 alkyl or —C(O)OC1-6 alkyl
- (c) cyclizing the compound of Formula (III) with an organic acid or a Lewis acid in a solvent to form the trans-fused γ-lactone of Formula (IV)
Dependencies are inferred from the claim text.