Enantioselective Synthesis of an Advanced Intermediate for the Synthesis of Brefeldin A and Analogues

Abstract

A synthesis of methyl (1R,2R,4S)-2-[(E)-2-iodovinyl]-4-(methoxymethoxy)cyclopentanecarboxylate is described in nine steps from a prochiral anhydride. A desymmetrization reaction followed by an epimerization and a Takai reaction are the key steps of the transformation. Based on previous work, this vinylic iodide product should be a useful precursor for the synthesis of brefeldin A and analogues.

brefeldin A - desymmetrization reaction - Takai reaction

References and Notes

See, inter alia:

1a Cherfils J. Chardin P. Trends Biochem. Sci.  1999,  24:  306 

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2 Singleton VL. Bohonos N. Ullstrup AJ. Nature (London)  1958,  181:  1072 

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9

Heating 9 in Ac₂O (or in Ac₂O with a catalytic amount of DMAP) at reflux failed to give anhydride 6. Failure was also encountered while attempting distillation of 9 in the presence of a catalytic amount of sulfuric acid. However, 6 could be obtained in low yields when 9 was treated with ClCO₂Me and NMM (1.1 equiv each) in THF at 20 °C for 30 min (35%) or with TFA (4 equiv) in dioxane at 75 °C for 2 h (38%).

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12

Enantiomeric ratio was determined by GPC using a Lipodex E column; t _R (the injector and detector temperatures were 220 °C): 74.9 min (major enantiomer) and 76.6 min (minor enantiomer).

13

This reaction was also performed under several other reduction conditions: NaBH(OAc)₃ ds (4R) = 90%, 76%; NaBH₄, ds (4R) = 95%, 88%; t-(BuO)₃AlLiH, ds (4R) = 99%, 87%.

14

Treatment of monoacid 16 and diacid 18 with diazomethane in Et₂O afforded the corresponding cis and trans diastereomeric methyldiesters that could be easily differentiated by NMR spectroscopy [cis-isomer, δ = 3.67 (CO₂Me), 3.01 (H1, H2) ppm; trans-isomer: δ = 3.70 (CO₂Me), 3.39 (H1 or H2), 3.15 (H1 or H2) ppm].

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19

Preparation of Methyl (1 R ,2 R ,4 S )-2-[( E )-2-Iodovinyl]-4-(methoxymethoxy)cyclopentanecarboxylate (4)To a suspension of anhyd CrCl₂ (1 g, 8.1 mmol) in anhyd and thoroughly degassed THF (5.1 mL) were added, under a nitrogen atmosphere, recrystallized CHI₃ (1.1 g, 2.8 mmol) and aldehyde-ester 21 (300 mg, 1.4 mmol) dissolved in anhyd and thoroughly degassed dioxane (30 mL). After being stirred at r.t. for 72 h, the resulting brown reaction mixture was filtered through a pad of mixed Celite and neutral alumina. The filter cake was rinsed several times with EtOAc and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatog­-raphy on a column of silica gel using EtOAc and PE as eluents (0:10 then 1:9) to afford pure 4 as a colorless oil (414 mg, 1.23 mmol, 88%). The Z/E ratio at the double bond (3:97) was evaluated by ¹H NMR spectroscopic analysis from the area ratio of the signals of the vinylic protons. Spectral Data and Specific Rotation R _f = 0.5 (silica, EtOAc-PE, 1:9); [α]_D ²⁰ -42.4 (c 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.60 (m, 1 H, 1H3), 2.04 (m, 2 H, H5), 2.26 (m, 1 H, H3), 2.80 (m, 2 H, H1, H2), 3.35 (s, 3 H, OMe), 3.68 (s, 3 H, CO₂Me), 4.21 (m, 1 H, H4), 4.61 (s, 2 H, OCH₂O), 6.10 (d, 1 H, J = 14.4 Hz, CHI), 6.52 (dd, 1 H, J = 14.4, 7.6 Hz, vinyl CH). ¹³C NMR (75 MHz, CDCl₃): δ = 37.0 (C5), 38.8 (C3), 47.7 (C1), 48.2 (C2), 52.0 (CO₂CH₃), 55.5 (OCH₃), 75.7 (CHI), 77.0 (C4), 95.6 (OCH₂O), 148.1 (vinyl CH), 175.1 (CO₂Me). FT-IR (KBr): 3054, 2949, 1735, 1437, 1206, 1098, 1041 cm^-1. MS (ESI+): m/z 309 [MH + MeOH]⁺; 341 [MH]⁺; 363 [M + Na]⁺. HRMS (ESI+): m/z calcd for C₁₁H₁₇IO₄Na: 363.0067; found: 363.0069 [M + Na]⁺.

20

Crystal Data for 25C₁₉H₂₆I₂O₆, Mr = 604.2, monoclinic, P2₁, a = 6.2760(4), b = 8.3184(5), c = 22.5860(12) Å, β = 96.918(8), V = 1170.55(12) ų, Z = 2, ρ_calcd = 1.714 g cm^-3, µ = 2.72 mm^-1, F(000) = 588, colorless needle, 0.60 × 0.11 × 0.05 mm³, 2θ _max = 60°, T = 298 K, 19062 reflections, 5818 unique (98% completeness), R _int = 0.042, 249 parameters, GOF = 1.57, wR2 = 0.0926, R = 0.0351 for 5107 reflections with I > 2σ(I). CCDC 660932 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.