Diastereo- and Enantioselective Synthesis of Bicyclic α-Methylene-δ-valero­lactones by Asymmetric Michael Reaction

Abstract

A synthesis of optically active α-methylene-δ-valerolactones 7 and 13 with 97% ee was achieved by employing a highly stereoselective Michael reaction between chiral imines 2, 9 and the acrylate 3. Reduction of the carbonyl group of the resulting adducts 4 and 10 with KBH₄ followed by lactonization and HWE reaction with formaldehyde yielded the lactones 7 and 13 as mixtures of ­diastereoisomers. Diastereoselectivity in the reduction of chiral 5-oxoalkanoic acids 4 and 10 was improved by combination of metal salt and hydride reducing agent.

asymmetric synthesis - Michael reaction - 5-oxoalkanoic acids - α-methylene-δ-valerolactones

References

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17

Analytical data for 7a: colorless oil. ¹H NMR (250 MHz, CDCl₃): δ = 0.88 (3 H, s, CH ₃ ), 1.07-1.31 (2 H, m, CH ₂ ), 1.36-1.61 (4 H, m, 2 × CH ₂ ), 1.75-1.86 (2 H, m, CH ₂ ), 2.28 (1 H, dt, ⁴ J = 2.5 Hz, ^² J = 14.0 Hz, CH), 2.36 (1 H, dt, ⁴ J = 1.5 Hz, ^² J = 14.0 Hz, CH), 3.98 (1 H, dd, ^³ J = 5.0 Hz, ^³ J = 16.5 Hz, CHO), 5.49 (1 H, dt, ⁴ J = ^² J = 1.5 Hz, ⁴ J = 2.5 Hz, CH), 6.42 (1 H, dt, ⁴ J = ^² J = 1.5 Hz, ⁴ J = 2.5 Hz, CH). ¹³C NMR (62 MH z, CDCl₃): δ = 15.3 (CH₂), 20.8 (CH₂), 24.2 (CH₃), 27.1 (CH₂), 34.0 (C), 37.5 (CH₂)_, 44.2 (CH₂), 84.2 (CHO), 129.3 (CH₂), 133.8 (C), 165.9 (COO). Compound 7b: white solid; mp 71-73 °C; [α]_D -18.00 (c 0.5, MeOH). IR (KBr): 3079, 1748, 1625, 1234 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.07 (3 H, s, CH ₃ ), 1.15-1.30 (2 H, m, CH ₂), 1.38-1.67 (4 H, m, 2 × CH ₂ ), 1.70-1.90 (m, 2 H, CH ₂ ), 2.33 (1 H, dt, ⁴ J = 1.5 Hz, ^² J = 16.0 Hz, CH), 2.58 (1 H, dt, ⁴ J = 2.0 Hz, ^² J = 16.0 Hz, CH), 4.20 (1 H, dd, ^³ J = 3.0 Hz, ^³ J = 6.0 Hz, CHO), 5.53 (1 H, dt, ⁴ J = ^² J = 1.5 Hz, ⁴ J = 2.0 Hz, CH), 6.45 (1 H, dt, ⁴ J = ^² J = 1.5 Hz, ⁴ J = 2.0 Hz, CH). ¹³C NMR (62 MHz, CDCl₃): δ = 20.7 (CH₂), 20.8 (CH₂), 24.6 (CH₃), 28.1 (CH₂), 32.3 (CH₂), 32.5 (C), 39.9 (CH₂), 84.4 (CHO), 128.6 (CH₂), 133.0 (C), 165.6 (COO). Analytical data for racemic 13a and 13b have been previously reported (ref. [11] ). Compound 13a [α]_D -99.09 (c 1.0, MeOH). Compound 13b [α]_D -6.00 (c 1.20, MeOH).

18

The ee values were determined by GC analysis by comparison with racemates using a Lipodex E (50m × 0.25mm i.d.) column for 7a,b and a Gamma-dex (30m × 0.25mm i.d.) column for 13a,b after purification by column chromatography.

19 Pirkle WH. Sikkenga DL. J. Org. Chem.  1977,  42:  1370 

20

Analytical data for 14: white solid, mp 149-151 °C. IR (KBr): 2965, 1721, 1633, 1242 cm^-1. ³¹P NMR (101 MHz, CDCl₃): δ = 29.1, 29.00. ¹H NMR (250 MHz, CDCl₃): δ = 1.06 (3 H, s, CH ₃ ), 1.02-1.27 (6 H, m, 3 × CH ₂ ), 1.22 (3 H, t, ^³ J = 6.5 Hz, CH ₃ CH₂OP), 1.23 (3 H, t, ^³ J = 6.5 Hz, CH ₃ CH₂OP), 1.40-1.65 (8 H, m, 4 × CH ₂ ), 1.70-2.10 (12 H, m, 6 × CH ₂ ), 2.15-2.40 (2 H, m, CH ₂ ), 2.45-2.62 (2 H, m, CH ₂ ), 2.61 (1 H, ddd, ^³ J = 3.7 Hz, ^³ J = 6.9 Hz, ^² J _HP = 25.7 Hz, CHP, diaA), 2.64 (1 H, ddd, ^³ J = 1.0 Hz, ^³ J = 10.3 Hz, ^² J _HP = 25.7 Hz, CHP, diaB), 2.91-2.99 (2 H, m, 2 × CHN), 3.95-4.11 (4 H, m, 2 × CH ₂ OP). ¹³C NMR (62 MHz, CDCl₃): δ = 16.2 (CH₃CH₂OP), 16.3 (CH₃CH₂OP), 20.7 (CH₂, diaA), 20.9 (CH₂, diaB), 21.3 (CH₃, diaA), 22.3 (CH₃, diaB), 24.7 (4 × CH₂), 25.0 (2 × CH₂), 27.3 (CH₂, diaA), 27.5 (CH₂, diaB), 28.7 (2 × CH₂), 28.8 (2 × CH₂), 34.3 (CH₂, diaA), 34.4 (CH₂, diaB), 34.5 (CH₂, diaA), 34.6 (CH₂, diaB), 38.5 (d, ^² J = 13.1 Hz, CH₂CHP, diaA), 39.5 (d, ^² J = 28.6 Hz, CH₂CHP, diaB), 43.8 (d, ^¹ J = 123.8 Hz, CHP, diaA), 44.1 (d, ^¹ J = 123.6 Hz, CHP, diaB), 48.5 (d, ^³ J = 14.5 Hz, C, diaA), 49.2 (d, ^³ J = 14.0 Hz, C, diaB), 52.1 (2 × CHN), 61.5 (d, ^² J = 5.8 Hz, CH₂OP), 61.7 (d, ^² J = 5.8 Hz, CH₂OP), 171.7 (d, ^² J = 4.4 Hz, COO, diaA), 172.3 (d, ^² J = 4.4 Hz, COO, diaB), 214.8 (CO, diaA), 215.7 (CO, diaB).

21

Absolute configuration was determined by refinement of Flack parameter. Final value was 0.02 (4). Crystallographic data for the salt 14 have been deposited at the Cambridge Crystallographic Data Centre under number CCDC 241581.

22

Krawczyk, H.; Śliwiński, M.; Wolf, W. M. Acta Cryst. Sect. C 2004, submitted.

23

Crystallographic data for the lactone 13a have been deposited at the Cambridge Crystallographic Data Centre under number CCDC 241582.

24 Cavé C. Desmaële D. d’Angelo J. Riche C. Chiaroni A. J. Org. Chem.  1996,  61:  4361