Rhodium-Catalyzed Desymmetrization of meso-Glutaric Anhydrides to Access Enantioenriched anti,anti-Polypropionates

Abstract

An expedient desymmetrization of 3,5-dimethyl-4-alkoxyglutaric anhydrides to access anti,anti-polypropionates is described. The previously unknown anhydrides are rapidly assembled from readily available precursors. A Rh(I)·t-BuPHOX catalyst system was found to provide good yield and high selectivities. With these conditions, the trisubstituted anhydrides were desymmetrized with various alkyl zinc reagents to provide synthetically useful enantioenriched anti,anti-2,4-dimethyl-3-hydroxy-δ-ketoacids. An identical catalyst system also affords access to syn,syn-stereotriads as well as a partial kinetic resolution of a chiral anhydride.

Key words

anhydride - desymmetrization - polypropionate - rhodium - zinc

• References and Notes

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• 22 Determination of a k _rel selectivity factor in this reaction was frustrated by anhydride hydrolysis and decomposition on workup.
• 23 General Procedure To a 5 mL flask was added [Rh(nbd)Cl]₂ (5 mol%) and (S)-t-BuPHOX (10 mol%). In some cases, Zn(OAc)₂(10 mol%) was also added. The flask was capped with a septum, placed under vacuum, and the atmosphere was replaced with argon. The solids were dissolved in THF (0.4 M vs anhydride) and freshly prepared organozinc reagent (see below; 0.2 M in THF, 1.7 equiv) was added by syringe producing a deep red solution. The appropriate anhydride (1 equiv) was dissolved in THF (0.25 M) and was added to the reaction by syringe taking care to remove all air from the headspace. The reaction was stirred at r.t. for 16–24 h, quenched with 1 M HCl and extracted in to EtOAc (3×).
• 24 Representative Example (2R,3R,4S)-3-(Benzyloxy)-2,4-dimethyl-5-oxohexanoic Acid (2b) Following the general procedure on 1 g scale of the anhydride and using MeZnBr, a colorless oil was isolated (0.91 g, 87%). Conversion into the methyl ester utilizing diazomethane allowed for enantiomeric excess determination: Chiralpak IA column eluting with 99:1 hexanes/isopropanol, eluting at 1.0 mL/min, showing 92% ee, with the major enantiomer eluting at 19.26 min and the minor at 22.74 min. R_f = 0.26 (59:40:1, hexane/EtOAc/AcOH). [α]_D ²⁰ = –6.5 (c 0.011 g/mL, CH₂Cl₂). IR (thin film): ν_max = 3090, 3032, 2982, 2886, 1738, 1711, 1456, 1379, 1190, 1067, 738, 699 cm^–1. ¹H NMR: (300 MHz, CDCl₃): δ = 11.12 (br, 1 H), 7.24–7.18 (5 H, m), 4.53 (1 H, d, J = 11.2 Hz), 4.45 (1 H, d, J = 11.2 Hz), 3.96 (1 H, dd, J = 4.0, 8.0 Hz), 2.90 (1 H, quint, J = 7.2 Hz), 2.78 (1 H, dq, J = 4.4, 7.2 Hz), 2.17 (3 H, s), 1.25 (3 H, d, J = 7.2 Hz), 1.07 (3 H, d, J = 7.2 Hz). ¹³C NMR (101 MHz, CDCl₃): δ = 211.1, 179.1, 137.6, 128.4, 127.8, 82.7, 74.4, 49.2, 41.6, 30.3, 12.9, 12.6. LRMS (ESI, pos.): m/z calcd for C₁₅H₂₀O₄Na [M + Na]⁺: 287.30; found: 287.1.