A Novel Synthesis of 4-Methyl-1,3-Dioxolane-4-Carbaldehydes by Epoxidation of 5-Methyl-4H-1,3-Dioxins and Acid-Catalyzed Rearrangement

Abstract

A straightforward procedure for the synthesis of 4-methyl-1,3-dioxolane-4-carbaldehydes 2 is reported. The new procedure involves m-CPBA oxidation of 5-methyl-4H-1,3-dioxins 5 in dichloromethane to give 4-(m-chlorobenzoyloxy)-5-hydroxy-5-methyl-1,3-dioxanes 6 and acid-catalyzed rearrangement of 6 to carbaldehydes 2. By using commercially available m-CPBA the oxidation and rearrangement can be carried out as a one-pot reaction. The procedure is also applicable to 4H-1,3-dioxins. Oxidation of 5 in methanol led to 4-methoxy-5-hydroxy-1,3-dioxanes 7, which did not undergo acid-catalyzed rearrangement.Derivatives of 2-C-methylglyceraldehyde 1 such as 4-methyl-1,3-dioxolane-4-carbaldehydes 2 and related 4-hydroxymethyl-4-methyl-1,3-dioxolanes 3 ( Figure 1) have found many applications in natural product syntheses, e.g., the synthesis of brevetoxin B, 1 bicyclomycin, 2 tocopherol, 3 and pheromones. 4 Several methods have been developed for the preparation of 2 and 3. Enantiomerically pure carbaldehydes 2 and corresponding open-chain derivatives have been obtained from D-mannitol, 1,5 D-glucose, 6 penam derivatives, 7 or by resolution of racemic 3 8 in multi-step reaction sequences. Other syntheses involve enzymatic methods to give hydroxymethyl derivatives 3, which have been oxidized to carbaldehydes 2. 9 Sharpless epoxidation of 2-methyl-2-propen-1-ol and monoprotected 2-methylene-1,3-propanediol, respectively, or Sharpless dihydroxylation of O-protected 2-methyl-2-propen-1-ol derivatives gave precursors for the synthesis of 2 with 47-95% ee. 8,10 Figure 1Recently we reported a novel nickel-catalyzed asymmetric double-bond isomerization of 5-methylene-1,3-dioxanes 4, which afforded optically active 5-methyl-4H-1,3-dioxins 5 with high ee (5d 92% ee). 11 We envisaged, that dioxins 5 might be suitable building blocks for the synthesis of 1 by m-CPBA oxidation and subsequent hydrolysis (Scheme 1). To our knowledge the m-CPBA oxidation of cyclic vinyl acetals has not yet been investigated, but we concluded from the well-known m-CPBA oxidation of cyclic vinyl ethers 12 that reaction of 5 with m-CPBA should lead to acylals 6 rather than to epoxides, which should be hydrolyzed to give 1. Scheme 1However, first experiments on the m-CPBA oxidation of 5d in dichloromethane surprisingly afforded 4-methyl-1,3-dioxolane-4-carbaldehyde 2d in a single step upon distillative workup of the crude reaction mixture (Scheme 1). 11 Since 2d still carries the tert-butyl substituent in the 2-position of the dioxolane ring, we argued that the primarily formed oxidation product immediately undergoes either a thermal or an acid-catalyzed rearrangement. In order to get further information about the mechanism of this unexpected type of rearrangement, we studied the m-CPBA oxidation of 5-methyl-4H-1,3-dioxins 5a-e in various solvents (Tables 1, 2). Treatment of 5-methyl-4H-1,3-dioxins 5a-e with commercially available m-CPBA 13 in methanol readily afforded a diastereomeric mixture of 4-methoxy-5-hydroxy-1,3-dioxanes 7a-e (Scheme 2, Table 1). Acetals ...

5-Methyl-4H-1,3-dioxins, new chiral building blocks: transformation into (R)- and (S)-4-hydroxymethyl-4-methyl-1,3-dioxolanes via oxidation and rearrangement and determination of the absolute configuration

“…The precatalyst was activated with lithium triethylborohydride at room temperature in ether and then reacted with 4a at À70°C to give (À)-1a with 92% ee in 85% yield (Scheme 1). 2 Oxidation of (À)-1a with purified m-chloroperbenzoic acid 5,6 in THF led to a 95:2.3:2.3:0.4 mixture of diastereomers 5 in a virtually quantitative yield. After recrystallization from light petroleum, the main diastereomer could be isolated from the mixture in a diastereomerically pure form in 84% yield.…”

“…1 We have also reported that the one-pot m-CPBA oxidation/acid catalyzed rearrangement of dioxins 1 leads directly to 4-methyl-1,3-dioxolane-4-carbaldehydes 2. 1,2 Carbaldehydes 2 bearing a quarternary stereogenic centre in the 4-position and related compounds, for example, 4-hydroxymethyl-4-methyl-1,3-dioxolanes 3, have been used as chiral building blocks in a variety of natural product and asymmetric syntheses. 2,3 Therefore, we have studied the stereochemical course of the latter transformation in order to establish the hitherto unknown absolute configuration of dioxins 1 and to demonstrate a practical route for the synthesis of both enantiomers of compounds 2 and 3 on a multigram scale.…”

Adjusting to change

“…Die Bestimmung der Absolutkonfiguration der Isomerisierungsprodukte 3 gelingt über eine neuartige Ringverengung zu den 1,3‐Dioxan‐4‐carbaldehyden 5 und weitere Transformation zu 1,2,4‐Butantriol 7 oder 2‐Hydroxy‐ γ ‐butyrolacton 9 (Schema ). Schlüsselschritt der Reaktionssequenz ist die Umsetzung von (−)‐ 3 a – c mit m ‐Chlorperbenzoesäure,7 wobei die diastereomeren Carbaldehyde 5 a – c beim Erhitzen der Rohprodukte im Vakuum in Gegenwart von Säure direkt abdestillieren. Nachfolgende Reduktion mit Lithiumaluminiumhydrid und Acetalspaltung oder aber Oxidation, Acetalspaltung und Lactonisierung durch azeotrope Entwässerung führen zu ( R )‐(+)‐ 7 bzw.…”

Enzymatic Transformations 62. Preparative Scale Synthesis of Enantiopure Glycidyl Acetals using an Aspergillus niger Epoxide Hydrolase‐Catalysed Kinetic Resolution

“…Acetal-protected glycidaldehyde derivatives are important and widely used building blocks allowing for the synthesis of a variety of bioactive compounds like, for instance nucleoside analogues (antiviral and cytotoxic agents), [8] leukotriene B 4 (an anti-inflammatory drug), [9] phosphonate or dihydroxyacetone phosphate analogues [10] (aldolase inhibitors), sugar analogues, [11] bicyclomycin [12] (antibiotic), brevetoxin B [13] (neurotoxin) or a-tocopherol (vitamin E). [14] Surprisingly enough, methodologies enabling the preparation of these chirons are very scarce and are not easy. [15] We here describe a simple, novel and efficient methodology allowing for the preparation of five glycidaldehyde acetal derivatives (1)(2)(3)(4)(5) and of their corresponding vicinal diols (1d-5d), in enantiomerically enriched form.…”