The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED-P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.

In order to produce bioactive derivatives of carvacrol and thymol, nine derivatives of each compound were prepared through modifications the phenolic hydroxyl group. The structures of compounds were confirmed by spectral data from MS, IR and NMR. Carvacrol, thymol and derivatives were submitted to the evaluation of the inhibition of the enzyme acetylcholinesterase, using a colorimetric method in which the inhibition of the enzyme is measured by coloration, and larvicidal activity against Aedes aegypti. Derivatives carvacryl acetate-1b and thymyl hexanoate-2b showed the best results for the inhibition of the acetylcholinesterase enzyme, and for the larvicidal activity the derivatives 1a, 1b, 1c, 3h, 2a, 2b, 2c and 4h showed positive results, emphasizing compound thymyl 4-methoxybenzoate-4h which showed LC50 values of 23.60 ppm, considered a very good result.

A síntese de derivados do tianfenicol, catalisada por lipases, foi investigada através da realização das reações de acilação e de hidrólise, como abordagens complementares, sendo a lipase Candida antarctica B o biocatalisador mais eficiente para as modificações seletivas de ambos, o tianfenicol e o correspondente diacetato do tianfenicol, respectivamente. Os melhores resultados foram obtidos nas reações de acilação com diferentes ésteres vinílicos, contendo cadeias carbônicas de comprimento variável, levando aos correspondentes 3'-monoésteres com excelentes rendimentos e em tempos reacionais curtos. As condições reacionais foram analisadas em termos de concentração de substrato, carga de enzima e tipo de doador de acila. Foi demonstrado o reuso da enzima por cinco vezes sem perda significativa de atividade. Alternativamente, a abordagem hidrolítica propiciou a preparação de alguns 1'-monoésteres em bons rendimentos, ainda que os níveis de reatividade e seletividade foram mais baixos que os obtidos na reação complementar de acetilação.

The lipase-catalyzed synthesis of thiamphenicol derivatives has been studied through complementary acylation and hydrolytic approaches, finding Candida antarctica lipase B as the most efficient biocatalyst for the selective modification of both thiamphenicol and thiamphenicol diacetate, respectively. The best results have been obtained using acylation reactions with different vinyl esters of variable length, yielding the corresponding 3'-monoesters with excellent yields and in short reaction times. The conditions have been analyzed in terms of substrate concentration, enzyme loading and type of acyl donor. The reuse of the enzyme for five-times without significant loss of the activity has also been demonstrated. Alternatively, the hydrolytic approach has allowed the preparation of some 1'-monoesters in good yields, although the reactivity and selectivity levels were lower than the ones achieved for the complementary acetylation reaction.

No presente trabalho descreve-se a composição química dos óleos essenciais de Rollinia leptopetala R.E. Fries (Annonaceae) e as atividades larvicidas dos óleos essenciais, do extrato metanólico das raízes desta espécie e do alcalóide oxoaporfinico, liriodenina (1), frente às larvas no terceiro estágio do mosquito Aedes aegypti. O extrato metanólico mostrou-se ativo com CL50 64,6 ± 1,5 ppm e uma forte atividade foi exibida para o composto (1), CL50 3,6 ± 0,4 ppm. Os óleos essenciais das folhas e galhos também mostraram atividade com CL50 104,7 ± 0,2 and 34,7 ± 0,3 ppm, respectivamente. Estes dados sugerem que R. leptopetala é fonte potencial de larvicidas naturais. A composição química do óleo essencial e as atividades descritas são comunicadas pela primeira vez.

The aim of present study was to describe the chemical composition of the essential oils from the leaf and stem of Rollinia leptopetala R. E. Fries (Annonaceae) and to evaluate the larvicidal activities of these essential oils, of the methanol extract from roots of this plant and of the oxoaporphine alkaloid, liriodenine (1) against the third-instar of Aedes aegypti larvae. The methanol extract from the roots showed larvicidal activity with LC50 64.6 ± 1.5 ppm. Higher activity was observed for the isolated alkaloid liriodenine (1), LC50 3.6 ± 0.4 ppm. The essential oils from the leaves and stems, also exhibited larvicidal activity with LC50 104.7 ± 0.2 and 34.7 ± 0.3 ppm, respectively. These results suggest R. leptopetala as a source of natural larvicidal compounds. This is the first report about the chemical composition and larvicidal activity of the leaf and stem essential oils of R. leptopetala.

A adição de Michael entre o acetoacetato de etila 1 e a chalcona 2, sob condições de Catálise de Transferência de Fase Sólido/Líquido (CTF-SL), sem solvente, produziu o aduto de Michael 3 e o composto cíclico 4, com bom rendimento. O composto 4 foi obtido majoritariamente via um processo de anelação do aduto de Michael 3. A proporção de 4 na razão 3/4 foi dependente da estrutura do cátion de amônio quaternário. Os resultados foram interpretados com base na organofilicidade e acessibilidade dos catalisadores e invocando-se um estado de transição cíclico de 6 membros, para a formação de 4, associado ao grau de quelação com Q+.

The Michael addition of ethyl acetoacetate 1 to chalcone 2 under Solid/Liquid Phase Transfer Catalysis (SL-PTC), solvent free, afforded Michael adduct 3 and an annulated compound 4 in good yield. The cyclic compound 4 was obtained in the majority via an annulation process of the Michael adduct 3. The proportion of 4 in the ratio of 3/4 was dependant on the structure of the quaternary ammonium cation. The results were interpreted on the basis of the organophilicity and accessibility of the catalysts as well as by invoking a 6-membered ring transition state for the formation of 4 due to the chelation level with Q+.