A rule to predict which enantiomer of a secondary alcohol reacts faster in reactions catalyzed by cholesterol esterase, lipase from Pseudomonas cepacia, and lipase from Candida rugosa

The early promise for the biological activity of the derivatives of ingenol 3 has been borne out by the clinical efficacy of the derived angelate, recently approved by the US Food and Drug Administration for the treatment of actinic keratosis. Phil S. Baran of Scripps La Jolla envisioned (Science 2013, 341, 878) a route to 3 based on a rearrangement of 2, available by the Pauson–Khand cyclization of the allenyl alkyne 1. One of the partners for the preparation of 1 was available following the Sugai (Synlett 1997, 1297) procedure, by the Claisen rearrangement of triethyl orthopropionate 5 with the propargyl alcohol 4 to give 6. Reduction delivered a racemic mixture of alcohols. On exposure of the mixture to vinyl acetate and Pseudomonas cepacia lipase, the undesired enantiomer was selectively acetylated to 7, leaving residual 8 of high ee. IBX was found by the Scripps group to be effective at oxidizing 8 without racemization. The other component of 1 was prepared from the inexpensive (+)-3-carene 10. Chlorination followed by ozonolysis delivered 11, that was reduced to the enolate, then alkylated with methyl iodide. Exposure to LiHMDS gave a new enolate, that was added to the aldehyde 9 to give 12. Addition of ethynyl magnesium bromide to the now more open face of 12 proceeded with high diastereoselectivity. Selective silylation of the secondary alcohol followed by silylation of the tertiary alcohol set the stage for the Pauson–Khand cyclization. Following the Brummond protocol, 1 was cyclized to 2. Methyl magnesium bromide was added, again to the more open face of the ketone, to give a new tertiary alcohol. Exposure to stoichiometric OsO4 converted the more available alkene to the cis diol, that was protected as its cyclic carbonate 13. A central challenge in the total synthesis of the ingenanes is the construction of the “inside–outside” skeleton. This was achieved by the pinacol rearrangement of 13 with BF3•OEt2, to give 14. All that remained to complete the synthesis was selective oxidation. Allylic oxidation with stoichiometric SeO2 installed the secondary alcohol, that was acetylated to give 15. The other secondary alcohol was then freed, and dehydrated with the Martin sulfurane, to give 16. A last allylic oxidation completed the synthesis of ingenol 3.

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Highly Efficient Lipase Catalyzed Monoaminolysis Reaction of Diesters with Benzylamine

Natural Product Communications ◽

10.1177/1934578x19859980 ◽

2019 ◽

Vol 14 (6) ◽

pp. 1934578X1985998

Author(s):

Gerardo Valerio-Alfaro ◽

Patricia Harumi Castillo-Carrasco ◽

Olaya Pirene Castellanos Onorio ◽

Jorge Bautista Naranjos

Keyword(s):

Immobilized Lipase ◽

Candida Rugosa ◽

Diethyl Malonate ◽

Rhizomucor Miehei ◽

Solvent Polarity ◽

Pharmaceutical Products ◽

Pseudomonas Cepacia ◽

Butyl Ether ◽

Highly Efficient ◽

Diethyl Succinate

Preparation of amides by biocatalyzed aminolysis reactions has greatly increased because these processes play an important role in the preparation of some pharmaceutical products and their intermediates. A highly efficient synthesis of malonic (5), succinic (6), and malic (8) monoamide esters by desymmetrization transformations (mono aminolysis reactions) of their diesters is presented. The immobilized lipase from Candida antarctica (CaL-B, Novozym 435) catalyzed the mono aminolysis of bifunctional compounds: diesters such as diethyl malonate (1), diethyl succinate (2), and ( R, S)-malate (3), leading to their corresponding monoamides (5), (6), and (8), respectively, with high conversions after a 24 hour reaction in the presence of an organic solvent. Increasing the solvent polarity from toluene, methyl t-butyl ether to dioxane led to an improved conversion. According to qualitative and quantitative GC-MS analysis, conversions of diesters (1), (2), and (3) into their mono amide esters were in the range 65%-97%. CaL-B was the best biocatalyst of the commercial lipases used, including those from Candida rugosa, Rhizomucor miehei, Carica papaya, and Pseudomonas cepacia. Likewise, a yield of 91% regioisomeric, but virtually racemic ( R,S)-mono amide (8) was obtained as the single product in dioxane.

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