From 2,2‘-Methylenedifuran to All Stereomeric Pentadecane-1,3,5,7,9,11,13,15-octols

Abstract

A great variety of natural products of biological interest includes polyketides (1,3-polyoxo, 1,3-polyols, aldols). 1 Several approaches for their synthesis have been proposed. 2,3 Inspired by the work of Lautens 4 and Hoffmann and co-workers, 5 who have converted 8-oxabicyclo[3.2.1]oct-6-en-3-one into 7-carbon-1,3-polyols and analogues, 6 and by that of Kaku et al.,7 who have transformed cyclohept-3-ene-1,6-diol into 1,3-polyols, we have proposed a new, noniterative asymmetric synthesis of longchain 1,3-polyols starting from the now readily available 2,2′-methylenedifuran (1). 8 The method imployed the double [3+4]-cycloaddition of the 1,1,3-trichloro-2-oxyallyl cation to 1. After reductive workup, a 45:55 mixture of meso-2 and (()-threo-2 was obtained in 55% yield and separated by fractional crystallizations. The meso compound was converted into meso-3, which was desymmetrized into diol (-)-4 by means of the Sharpless asymmetric dihydroxylation. 9 Further transformations imploying the combinations of Evans' anti 10 and Nasaraka's syn 11 aldol reductions with Mitsunobu reaction 12 allow to prepare, in principle, 16 diastereomeric pentadecane-1, 3,5,7,9,11,13,15-octols (e.g., (-)-5) and analogues (Scheme 1). If the syn relationship between the 4-methoxybenzoates at C-3 and C-13 (atom numbering of (-)-5) could be changed into an anti relative configuration, all possible stereomeric pentadecane-1,3,5,7,9,11,13,15-octols could be reached in both enantiomeric forms. We report here a solution to that problem.As already described, 8 diol (-)-4 was converted (Scheme 2) into tetrol (-)-6 in 75% overall yield. Treatment of (-)-6 with (MeO) 2 CMe 2 in acetone under acidic conditions (pyridinium paratoluenesulfonate) gave acetonide (-)-7 in 92% yield. Heating (-)-7 in acetonitrile in the presence of 12 equiv of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) induced the isomerization of (-)-7 into the primary paramethoxybenzoate (-)-8. Equilibrium ([(-)-8]/[(-)-7] ) 3.0) was reached after 4 h at 80 °C, and (-)-8 could be isolated in 70% yield (Scheme 2). This result can be interpreted in terms of acyl group migration from the C-3 to the C-1 position (atom numbering of (-)-5; IUPAC numbering: 2′′′,4′′′, see (-)-8), the primary ester (-)-8 being more stable than (-)-7 for steric reasons. Also for steric reasons, the intramolecular migration of the paramethoxybenzoyl group from the 1-oxy position to the 6-hydroxy group of the cycloheptenol moiety is forbidden. Attempts to displace the acyclic secondary alcohol at C-3 (atom numbering of (-)-5; IUPAC: 2′′′) using the Mitsunobu reaction ((EtOOC) 2 N 2 , PPh 3 , 4-NO 2 C 6 H 4 COOH) 12 were not met with success. They led to complex mixtures. Selective sulfonylation of the acyclic alcohol at C-3 (IUPAC: 2′′′) with CH 3 SO 2 Cl and p-TsCl (pyridine, Et 3 N) also led to intractable mixtures.Selective methanolysis of the acyclic paramethoxybenzoate at C-3 (IUPAC: 6′) was possible on treating (-)-7 in MeOH containing 7.2 equiv of Mg(OMe) 2 (40 °C, 8 h). This furnished triol (-)-9 in 68%...

An Expeditious Asymmetric Synthesis of Polyfunctional 1,7‐Dioxaspiro[5.5]undecanes

“…1 H NMR spectra: Bruker ARX 400 spectrometer (400 MHz); δ(H) in ppm relative to the solvent's residual 1 H signal (CHCl 3 : δ ϭ 7.27 ppm; CH 3 OD: δ ϭ 3.34 ppm; C 6 H 6 : δ ϭ 7.3 ppm) as internal reference; all 1 H assignments were confirmed by 2D-COSY-45 and 2D-NOESY spectra. 13 C NMR spectra: Same instrument as above (100.6 MHz); δ(C) in ppm relative to solvent's 13 …”

Noniterative approach to the total asymmetric synthesis of 15-carbon polyketides and analogs with high stereodiversity

“…Kinetic resolution with Candida cylindracea lipase-catalyzed transesterification with vinyl acetate allows one to obtain enantiomerically enriched diacetate (+)-18 (98 % ee) and diol (-)-17 (98 % ee) [12]. Diacetate (+)-18 has been converted into (-)-19 (Scheme 3) [13] by the same procedure [9] as that converting meso-2 into 3 (Scheme 1). Double ozonolysis of (-)-19, followed by the diastereoselective reduction of the resulting double β-hydroxyketone intermediate applying Evans' [10] and Narasaka's [11] conditions allows the preparation of enantiomerically pure (98 % ee) polyols (-)-20 (65 %) and (-)-22 (60 %), respectively.…”

“…Methanolysis of 3 (R = BOM) (derived from endo-23 [9]) gave diol 24 (52 % based on endo-23) that was submitted to ozonolysis and subsequent Narasaka's reduction furnishing a 6:1 mixture of hexols 25 and 26 in 62 % yield. Pure 25 was obtained by flash chromatography and was converted into the bis-acetonide 27 (77 %).…”

“…Further transformations allow one to prepare, in principle, all possible stereoisomers of pentadeca-1, 3,5,7,9,11,13,15-octols [9]. Bu 4 NF liberated the pyranose (+)-15 which could be reduced under Evans' conditions [10] into the semi-protected long-chain polyol (-)-16 (Scheme 2) [9].…”

An Expeditious, Non‐Iterative, and Asymmetric Synthesis of 3,5,7,9,11,13,15‐Heptahydroxypentadecanals

“…[8] Further transformations allow one to prepare, in principle, all possible stereoisomers of pentadecane-1, 3,5,7,9,11,13,15-octol. [9] In the meantime we have found a method to convert threo-2 into diacetate (ϩ)-5 (40% yield, 98% ee). [10] We now present an efficient route for its conversion into a 3,5,7,9,11,13,15-heptahydroxypentadecanal derivative and into several pentadecane-1, 3,5,7,9,11,13,15-octol derivatives, based on the double ozonolysis of (1R,1ЈR,6R,6ЈR)-3,3Ј-methylenebis{6-[(benzyloxy)methoxy]cyclohept-3-en-1-ol} [(Ϫ) -8].…”