Asymmetric Synthesis of 4,5-Disubstituted 3-Hydroxy δ-Lactones: Prelactone B and Prelactone V

Abstract

An efficient asymmetric synthesis of δ-lactones such as prelactone B has been developed. As key steps, the SAMP/RAMP-hydrazone methodology for the synthesis of 2-methylenated 1,3-diols and a homogenous hydrogenation were used.

asymmetric synthesis - prelactone B - hydrazones - hydrogenation - Crabtree’s catalyst

References

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<A NAME="RG20703ST-9">9</A>

General Procedure for 4,6-Disubstituted 2,2-Dimethyl-1,3-dioxan-5-ones: t-BuLi (5 mmol, 15% in pentane) was added dropwise to a solution of RAMP-hydrazone (5 mmol) in anhyd THF (25 mL) at -78 °C. After stirring for 2 h the mixture was cooled to -100 °C and the electrophile (6 mmol) was added slowly. The mixture was allowed to warm up to r.t. over 15 h. The reaction mixture was quenched with a buffer solution (pH = 7, 5 mL) and diluted with Et₂O (30 mL). The aq layer was extracted with Et₂O. The combined organic layers were washed with brine, dried over MgSO₄ and concentrated in vacuo. For alkylation at α′-position the procedure was repeated. The product hydrazone was dissolved in Et₂O (50 mL) and a sat. aq solution of oxalic acid was added at r.t. The bi-phase system was stirred vigorously at r.t. until the reaction was completed (TLC control). The layers were separated and the aq phase was extracted with Et₂O. The combined organic layers were washed with brine and dried over MgSO₄. The solvent was removed under reduced pressure. Purification was carried out by flash chromatography (SiO₂; pentane-Et₂O, 2:1).

<A NAME="RG20703ST-10">10</A>

Prelactone B (1a): Mp 90 °C; [α]_D ²⁵ +37.8 (c 1.10, MeOH). IR: 3473, 2970, 2929, 2882, 1717, 1468, 1383, 1310, 1273, 1230, 1192,3, 1103, 1064, 1004, 847, 819, 705, 620, 579
cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.93 (d, J = 6.9 Hz, 3 H, 6-CH₃), 1.07 (d, 3 H, J = 6.6 Hz, 4-CH₃), 1.10 (d, 3 H, J = 7.1 Hz, 6-CH₃), 1.75 (ddq, J = 10.2 Hz, 8.2, 6.6, 1 H, H-4), 1.99 (dsept, J = 2.2 Hz, 7.0, 1 H, H-5), 2.49 (dd, J = 7.9 Hz, 17.3, 1 H, H-2a), 2.93 (dd, J = 6.0 Hz, 17.3, 1 H, H-2b), 3.77 (m, 2 H, H-3, H-5). ¹³C NMR (100 MHz, CDCl₃): δ = 13.76, 14.24, 20,18, 29.09, 39.13, 39.20, 69.93, 86.33, 171.61. MS (EI, 70 eV): m/z (%) = 130 (30), 129 (100), 112 (6), 111 (90), 100 (10), 87 (78), 84 (15), 83 (14), 82 (8), 73 (20), 72 (8), 71 (25), 69 (9), 59 (40), 58 (84), 57 (23), 55 (22). Anal. Calcd. for C₉H₁₆O₃: C, 62.77; H, 9.36. Found: C, 63.00; H, 9.57.

<A NAME="RG20703ST-11">11</A>

(R,R,R,)-Tetrahydro-4-hydroxy-5,6-methyl-2H-pyran-2-one (prelactone V, 1b): Mp 46 °C; [α]_D ²⁵ +38.9 (c 1.17, MeOH). IR: 3435, 2980, 2932, 1730, 1383, 1267, 1095, 1046, 979 cm^-1. ¹H NMR (400 MHz, C₅D₅N): δ = 1.09 (d,
J = 7.0 Hz, 3 H, 5-CH₃), 1.28 (d, J = 6.1 Hz, 3 H, 4-CH₃), 1.75 (ddq, J = 10.2 Hz, 7.2, 6.8, 1 H, H-4), 2.82 (dd, J = 7.2 Hz, 16.6, 1 H, H-2a), 3.13 (dd, J = 5.6 Hz, 16.6, 1 H, H-2b), 3.93 (dtr, J = 5.7 Hz, 7.2, 2 H, H-3), 4.00 (q, J = 6.2 Hz, 10.1, 2 H, H-3). ¹³C NMR (100 MHz, C₅D₅N): δ = 14.12, 19.49, 39.90, 44.06, 69.23, 78.65, 170.91. MS (CI): m/z (%) = 146 (10), 145 (73), 117 (90), 109 (13), 102 (9), 89 (100), 85 (56), 83 (17), 81 (7) 71 (11). Anal. Calcd. for C₇H₁₂O₃:
C, 58.32; H, 8.39. Found: C, 58.15; H, 8.10.