Synthesis of (+)‐Patulolide C Using R‐(+)‐γ‐Valerolactone as a Chiral Synthon.

Abstract

The total synthesis of (+)‐Patulolide‐C is accomplished by using enantiopure R‐(+)‐γ‐valerolactone & R‐(+)‐epichlorohydrin as chiral synthons. The strategy adopted for the synthesis is a convergent approach wherein two advanced intermediates were synthesized independently using the chiral synthons and coupled to achieve the skeleton of Patulolide‐C. The important synthetic steps of the synthesis are two carbon homologation of the cyclic lactol, Julia olefination of enone with sulfone in DME, DIBAl‐H mediated regioselective opening of benzylidine acetal, selective oxidation of primary alcohol to aldehyde using BAIB/TEMPO and lactonization of seco‐acid adopting Yamaguchi protocol to afford the macrolide skeleton.

Stereoselective Synthesis of γ‐(Acyloxy)carboxylic Acids and γ‐Lactones Featuring the Switch of Stereopreference of Candida antarctica Lipase B in Sodium γ‐Hydroxycarboxylate Homologues

“…The funding from the Estonian State Forest Management Centre is greatly acknowledged by the Taltech authors (Contract: "Puidu biomassist saadava valerolaktooni kemoensümaatiline väärindamine"; Töövõtuleping nr. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The Taltech authors are also grateful to Estonian Research Council for funding from the program "Supporting resource valorization through R&D" (RESTA 10) in frames of the project "Chemical valorization of cellulose in environment of ionic liquids."…”

“…Pure enantiomers of γ-lactones are sources of higher quality and intensity aroma compared to racemic mixtures. [12] Enantiomers of GVL have been used as building blocks in the synthesis of biologically active chiral compounds, such as geodiamolide A, [13] (R)-and (S)-sulcatol, [14] (R)-(À )-and (S)-(+)-phoracantholide, [15] (+)-patulolide, [16] and cladospolide C. [17] Continuous efforts dedicated to the creation of more efficient methodology for the preparation of pure enantiomers of γ-lactones have been expended during decades. Attention has been paid mainly on two approaches -use of asymmetric hydrogenation catalysts based on transition metals and lipases.…”

“…[7b] Despite this large body of work, enantiomeric γ-lactones as well as 4-(acyloxy)carboxylic acids have so far not been sufficiently accessible to meet the increasing demands of research and development projects. The approaches studied include: 1) separation of γ-lactone enantiomers, either by preparative liquid chromatography over chiral stationary phase [18] or by co-crystallization with different hosts, like cholic acid [19] or tartaric acid derivatives; [20] or by kinetic resolution using lipase-catalyzed hydrolysis of racemic γ-lactones; [21] 2) separation of γ-lactone enantiomers via diastereomeric derivatives of the corresponding γ-hydroxycarboxylic acids, like amides, [22] or γ-acylates of iso-propyl esters; [16,22] 3) stereoselective catalytic hydrogenation [23] of the γ-keto group of γ-ketocarboxylic acids or their derivatives using biocatalytic reductions -either by yeast [24] or by engineered reductase [25] or using microbial reduction; [26] stereoselective hydrogenation of the γ-keto group based on metal catalysis using either Ru- [27] or Ir-based catalysts, [28] or a tartaric acid and NaBr-modified Ni-catalyst; [29] also, reduction with diisopinocampheylborane has been examined; [30] 4) lipase-catalyzed kinetic resolution of enantiomers of 4hydroxycarboxylic acid esters and amides; [31] this approach needs extra synthesis of esters and amides and hydrolysis after lipase-catalyzed treatment, therefore requiring an extended list of reagents compared to alkaline hydrolysis/ acidification proposed by us; [4] 5) tandem procedures involving isomerization and biocatalytic resolution; [32] 6) biocatalytic oxidation of 1,4-alkanediols and γ-lactols; bacterial oxidation of C5À C20 fatty acids; [33] 7) syntheses starting from γ-ketonitriles; [34] 8) lipase-catalyzed synthesis of enantiomeric γ-lactones from γhydroxycarboxylic acid derivatives (see comments in p. 4); [35] 9) miscellaneous multi-step syntheses of enantiomeric γlactones starting from a chiral pool, either from amino acids, [36] or carbohydrates [11a,37] or from other materials such as cyclopropane hemimalonates, [38] from chiral propargylic alcohols, [39] via selective epoxide opening [40] or others. [41] The overall goal of the current work has been to address this stereoselective...…”

“…Pure enantiomers of γ‐lactones are sources of higher quality and intensity aroma compared to racemic mixtures [12] . Enantiomers of GVL have been used as building blocks in the synthesis of biologically active chiral compounds, such as geodiamolide A, [13] ( R )‐ and ( S )‐sulcatol, [14] ( R )‐(−)‐ and ( S )‐(+)‐phoracantholide, [15] (+)‐patulolide, [16] and cladospolide C [17] …”

Applications of Wittig Reaction in the Total Synthesis of Natural Macrolides

“…In this route, lactol 47 was synthesized using diisobutylaluminium hydride (DIBALÀ H) from (R)-(+)-γ-valerolactone. [96] Then, lactol 47 was reacted with C2-Wittig reagent to and afforded compound 48 with an (E):(Z) ratio of 95 : 5. The latter, after several steps afforded enone 49.…”