Asymmetric Synthesis of Pseudo C ₂ -Symmetric 2-Methyl Substituted 1,3-Diols

Abstract

The diastereo- and enantioselective synthesis of pseudo C ₂-symmetric, 2-methyl substituted, acetonide protected (4) and free 1,3-diols 5 employing the SAMP-hydrazone mothodology with virtually complete asymmetric induction (de ≥ 96%, ee ≥ 98-99%) is reported. The efficient protocol involves the asymmetric α,α"-bisalkylation of hydrazone 1, the epimerization-free Wittig olefination of the resulting ketones 2 and subsequent hydrogenation of the exo-methylene derivatives 3 with PtO₂·H₂O or Wilkinson’s catalyst to afford the acetonide protected title compounds 4 in very good overall yields. Quantitative deprotection with trifluoroacetic acid to the free diols 5 is demonstrated.

Key words

asymmetric synthesis - diols - hydrogenation - Wittig reaction - hydrazones

References

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5

Synthesis of 4,6-disubtituted 2,2-Dimethyl-1,3-dioxan-5-ones (S,S)-2: t-Butyllithium (11 mmol, 15% in pentane) was added dropwise to a solution of SAMP-hydrazone (S)-1 (10 mmol) in anhyd THF (40 mL) at -78 °C. After stirring for 2 h the mixture was cooled to -100 °C and the electrophile (11 mmol; dissolved in 1 mL anhyd THF), was added slowly. After further stirring for 2 h the reaction mixture was allowed to warm to r.t. over 15 h. The mixture was quenched with pH 7-buffer solution (2 mL) and diluted with Et₂O(80 mL). The organic layer was washed with pH 7-buffer solution (10 mL) and brine (2 × 10 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The resulting monoalkylated SAMP-hydrazone was alkylated again at the α"-position as described above. The obtained 4,6-disubtituted SAMP-hydrazone was dissolved in dichloromethane (50 mL) and flushed with ozone
(60 Lh^-1) at -78 °C for 15 min. The reaction mixture was allowed to warm to r.t. and flushed with argon. After removal of the solvent under reduced pressure the crude products were purified by flash chromatography (SiO₂; pentane-Et₂O) to afford 4,6-disubtituted 2,2-dimethyl-
1,3-dioxan-5-ones (S,S)-2.

8

Synthesis of the exo-Methylene Derivatives (S,S)-3: t-Butyllithium (26.4 mmol, 15% in n-pentane) was added dropwise to a suspension of methyltriphenylphosphonium bromide (26.4 mmol) in dry THF (125 mL) at -78 °C and stirring was continued for 15 min. Then the mixture was allowed to warm to r.t. over 30 min and cooled again to
-78 °C. Ketone (S,S)-3 (4.4 mmol; dissolved in 8 mL dry THF), was added and the reaction mixture was allowed to warm to r.t. over 15 h. The mixture was quenched with water (10 mL) and the aq layer was extracted with diethyl ether (3 × 20 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The crude products were purified by flash chromatography (SiO₂; pentane-Et₂O) to afford the alkenes (S,S)-3.
Analytical data of compound (S,S)-3e: [α]_D ²⁴ = -94.6 (1.04, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ = 1.40 (s, 6 H, CH ₃), 1.83 (m, 2 H, CHHCO), 2.04 (m, 2 H, CHHCO), 2.65 (ddd, J = 13.9, 9.5, 7.1 Hz, 2 H, CHHPh), 2.86 (m, 2 H, CHHPh), 4.26 (m, 2 H, CHO), 4.78 (t, J = 1.8 Hz, 2 H, CH ₂C), 7.14-7.30 (m, 10 H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ = 25.0 (CH₃), 31.4 (CH₂Ph), 34.3 (CH₂CO), 69.2 (CO), 100.4 (CCH₃), 103.9 (CH₂C), 125.8 (pCH), 128.3, 128.5 (CH, mCH), 142.1 (CPh), 152.9 (CCH₂); MS (CI, methane) m/z = 337 [M⁺+1], 279, 278, 262, 261, 173, 133, 131, 117(100); IR (CHCl₃): 3085, 3061, 3026, 2986, 2953, 2933, 2860, 1944, 1870, 1803, 1745, 1652, 1604, 1584, 1544, 1496, 1455, 1432, 1411, 1378, 1323, 1281, 1226, 1183, 1159, 1115, 1087, 1057, 1031, 1000, 970, 957, 896, 865, 819, 802, 750, 700, 652, 622, 582, 518, 486 cm^-1; Anal. Calcd for C₂₃H₂₈O₂: C, 82.10; H, 8.39. Found: C, 81.97; H, 8.65.

15

Synthesis of 4,6-disubstituted 2,2,5-Trimethyl-1,3-dioxanes (S,S)-4: The methylenated 1,3-dioxan-5-ones (S,S)-3 (0.5 mmol) and chlorotris(triphenylphosphine)rhodium(I) (10 mol%) were dissolved in anhyd benzene (10 mL) and vigorously stirred at r.t. under hydrogen atmosphere (1 atm) for 4 h. The solvent was removed under reduced pressure and the residue was filtered through silica gel, washed with pentane-Et₂O (10:1), filtered through florisil^®, washed with pentane and dried in vacuo to give (S,S)-4 as colorless oils.
Analytical data of compound (S,S)-4e: [α]_D ²⁴ = -2.8 (1.03, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 0.78 (d, J = 6.9 Hz, 3 H, CH ₃CH), 1.36 (d, J = 7.1 Hz, 6 H, CH ₃C), 1.60 (m, 2 H, CHHCO), 1.79 (m, 3 H, CHHCO, CHCH₃), 2.56 (m, 2 H, CHHPh), 2.81 (m, 2 H, CHHPh), 3.22 (dt, J = 8.2, 3.8 Hz, 1 H, CHO), 3.85 (m, 1 H, CHO), 7.15-7.29 (m, 10 H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 11.7 (CH₃CH), 24.0 (CH₃C), 25.1 (CH₃C), 32.2, 32.3, 32.4, 36.2 (4 C, CH₂), 40.1 (CHCH₃), 68.4 (CHO), 74.0 (CHO), 100.5 (CCH₃), 125.5, 125.6 (2 C, pCH), 128.1, 128.1, 128.2 (4 C, CH, mCH), 142.0 (2 C, CPh); MS (EI, 70 eV): m/z = 338 [M⁺], 323, 146, 134, 131, 117, 104, 92, 91(100); IR (CHCl₃): 3513, 3085, 3062, 3026, 2985, 2936, 2875, 2674, 1943, 1870, 1804, 1746, 1713, 1622, 1604, 1585, 1496, 1455, 1432, 1380, 1361, 1279, 1227, 1192, 1161, 1130, 1062, 1038, 997, 961, 941, 910, 871, 800, 749, 700, 618, 573, 514, 480 cm^-1; Anal. Calcd for C₂₃H₃₀O₂: C, 81.61; H, 8.93. Found: C, 81.17; H, 9.00.

16

Synthesis of (3S,5S)-4-Methyl-1,7-diphenylheptane-3,5-diol (S,S)-5: TFA (0.05 mL) was added to (S,S)-4e (0.3 mmol) in THF (2 mL) and water (1 mL). The mixture was stirred at r.t. until the reaction was completed (TLC control). Concd NH₃ (0.5 mL) and water (1.5 mL) were added and the aq layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The crude product was purified by flash chromatography (SiO₂; pentane-Et₂O 1:1) to give (S,S)-5 (99%) as colorless solid.
Analytical data of compound (S,S)-5: Mp: 97 °C; [α]_D ²⁴ =
-34.5 (1.01, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 0.94 (d, J = 7.2 Hz, 3 H, CH ₃), 1.60-1.72 (m, 2 H, CHHCO), 1.77-1.90 (m, 3 H, CHHCO, CHCH₃), 2.63 (m, 2 H, CHHPh), 2.78-2.85 (m, 4 H, CHHPh, OH), 3.67 (m, 1 H, CHOH), 3.98 (m, 1 H, CHOH), 7.16-7.30 (m, 10 H, ArH); ¹³C NMR (100 MHz, CDCl₃): δ = 11.6 (CH₃), 32.2, 32.7, 35.7, 37.3 (4 C, CH₂), 41.6 (CHCH₃), 72.2 (CHOH), 75.4 (CHOH), 125.7, 125.7 (pCH), 128.2, 128.2, 128.3 (4 C, CH, mCH), 141.8, 141.8 (CPh); MS (CI, isobutane): m/z = 299(100) [M⁺ +1], 281, 263; IR (CHCl₃): 3855, 3840, 3822, 3808, 3752, 3736, 3712, 3690, 3677, 3650, 3630, 3333, 3084, 3060, 3023, 2940, 2918, 2863, 2371, 2190, 1948, 1870, 1808, 1736, 1719, 1702, 1686, 1655, 1637, 1604, 1543, 1497, 1455, 1440, 1409, 1307, 1232, 1167, 1141, 1121, 1083, 1043, 1004, 949, 930, 907, 886, 810, 770, 731, 480, 466 cm^-1; Anal. Calcd for C₂₀H₂₆O₂: C, 80.50; H, 8.78. Found: C, 80.45; H, 9.06.

17

All new compounds showed suitable spectroscopic data (NMR, MS, IR) and correct elemental analyses.