MOLECULAR SYMMETRY AND DESYMMETRIZATION REACTIONS IN ORGANIC SYNTHESIS. Molecular Symmetry has found several applications in Organic Chemistry. The aim of this article is to showcase its relevance as a tool for synthetic planning. Natural Products and synthetic compounds with pharmaceutical applications were selected to highlight desymmetrization reactions that make use of organocatalysis, biocatalysis or by transition metals. The recognition of structural patterns in retrosynthetic analysis is discussed for compounds that exhibit explicit or hidden symmetry. Limitations of the aforementioned strategies are also described, as well as the untapped potential, challenges and frontiers yet to be explored regarding these concepts.

Quantum chemical calculations of nuclear magnetic resonance (NMR) shifts and coupling constants have been extensively employed in recent years mainly to facilitate structural elucidation of organic molecules. When the results of such calculations are used to determine the most likely structure of a natural product in advance, guiding the subsequent synthetic work, the term “computer-guided synthesis” could be coined. This review article describes the most relevant examples from recent literature, highlighting the scope and limitations of this merged computational/experimental approach as well.

ABSTRACT In this overview, we present our analysis of the future of organic synthesis in Brazil, a highly innovative and strategic area of research which underpins our social and economical progress. Several different topics (automation, catalysis, green chemistry, scalability, methodological studies and total syntheses) were considered to hold promise for the future advance of chemical sciences in Brazil. In order to put it in perspective, contributions from Brazilian laboratories were selected by the citations received and importance for the field and were benchmarked against some of the most important results disclosed by authors worldwide. The picture that emerged reveals a thriving area of research, with new generations of well-trained and productive chemists engaged particularly in the areas of green chemistry and catalysis. In order to fulfill the promise of delivering more efficient and sustainable processes, an integration of the academic and industrial research agendas is to be expected. On the other hand, academic research in automation of chemical processes, a well established topic of investigation in industrial settings, has just recently began in Brazil and more academic laboratories are lining up to contribute. All these areas of research are expected to enable the future development of the almost unchartered field of scalability.

The Nobel Prize in Chemistry 2016 was granted to Jean-Pierre Sauvage, Sir James F. Stoddart and Bernard (Ben) L. Feringa. These scientists were responsible for the creation and development of molecular machines. The development of such systems represents a breakthrough in the field of supramolecular chemistry, nanotechnology and organic synthesis. This article aims to bring simple and objective information to the scientific community about the work of these three researchers.

Uma síntese total e eficiente da (+) e (-)-tripargina, alcalóide β-carbolínico isolado da pele da rã africana K. Senegalensis, foi realizada em 6 etapas e 38% de rendimento global, a partir da triptamina, tendo como base a construção do sistema β-carbolínico via reação de Bischler-Napieralski e a redução enantiosseletiva do intermediário diidro-β-carbolínico via reação de transferência de hidrogênio assimétrica usando o protocolo de Noyori.

A concise and efficient total synhesis of (+)- and (-)-trypargine (6 steps and 38% overall yield), a 1-substituted β-carboline guanidine alkaloid isolated from the skin of the African frog K. senegalensis, was developed based on the construction of the β-carboline moiety via Bischler-Napieralski reaction and the enantioselective reduction of the dihydro-β-carboline intermediate via an asymmetric transfer hydrogenation reaction using Noyori's protocol.

O curso estereoquímico da adição de enolatos de titânio quirais a gama-lactóis derivados do ácido (S)-glutâmico foi investigado. Quando gama-lactóis 5-substituídos foram tratados com enolatos de titânio quirais derivados de N-acetil-, N-propionil-, N-bromoacetil- e N-fenilacetil oxazolidin-2-onas somente dois diastereoisômeros foram obtidos, revelando um completo controle facial pelo enolato de titânio, enquanto que a discriminação facial do íon oxocarbênio mostrou-se dependente da natureza do grupo R³ do enolato. Dessililação com HF/CH3CN aquoso, seguida de redução com LiBH4, forneceu eficientemente dióis tetraidrofurânicos trans-2,5-dissubstituídos e recuperação do auxiliar quiral.

The sterochemical outcome of the addition of chiral titanium enolates to gamma-lactols derived from (S)-glutamic acid were examined. When 5-substituted gamma-lactols were treated with chiral titanium enolates of N-acetyl-, N-propionyl-, N-bromoacetyl- and N-phenylacetyl oxazolidin-2-ones, only two diastereoisomers were obtained, revealing complete facial control by the chiral titanium enolate while the oxocarbenium ion facial discrimination was dependent on the nature of the enolate R³ substituent. After desilylation with aqueous HF/CH3CN, LiBH4 reduction allowed the efficient preparation of the corresponding trans-2,5-disubstituted tetrahydrofuran diols and recovery of the chiral auxiliary.

The stereoselective addition of the titanium (IV) enolates derived from (S)-4-isopropyl-N-4-chlorobutyryl-1,3-thiazolidine-2-thione (8) and from (S)-4-isopropyl-N-4-chloropentanoyl-1,3-thiazolidine-2-thione (9) to N-Boc-2-methoxypyrrolidine (5b) afforded the addition products (+)-10 and (+)-11 in 84% yield in both cases, as 8.6:1 and 10:1 diastereoisomeric mixtures, respectively. A three-step sequence allowed to convert these adducts to (+)-isoretronecanol (1) and (+)-5-epi-tashiromine (2) in 43% and 49% overall yield, respectively.

(R)-Fluoxetina, um inibidor potente e seletivo da recaptação da serotonina, foi sintetizada em seis etapas, 50% de rendimento total e 99% de excesso enantiomérico a partir do benzaldeído via alilação catalítica assimétrica empregando-se o sistema catalítico desenvolvido por Maruoka e colaboradores.

(R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst.

(R)-Fluoxetina, um inibidor potente e seletivo da recaptação da serotonina, foi sintetizada em seis etapas, 50% de rendimento total e 99% de excesso enantiomérico a partir do benzaldeído via alilação catalítica assimétrica empregando-se o sistema catalítico desenvolvido por Maruoka e colaboradores.

(R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst.

Compostos (E)-1,2-dibromo vinílicos 11a-f foram preparados estereosseletivamente via reação de bromação de alcinos empregando-se tribrometo de piridínio em MeOH/CCl4 a baixa temperatura e utilizados na reação de duplo acoplamento com PhZnCl catalisada por Pd(0), segundo protocolo de Negishi, fornecendo as respectivas olefinas tri e tetrassubstituídas 14a-e. Tamoxifeno, um agente antiestrogênico de uso clínico na terapia do câncer de mama, foi preparado na forma de uma mistura Z:E de proporção 2.3:1, em 7 etapas em um rendimento global de 30% a partir do 4-iodofenol (3).

(E)-1,2-vinylic dibromides 11a-f were stereoselectively prepared via bromination of acetylenic compounds with pyridinium tribromide in MeOH/CCl4 at low temperature and double cross-coupled with PhZnCl under Pd(0) catalysis (Negishi protocol) to afford tri- and tetrasubstituted olefins 14a-e. Tamoxifen, a selective estrogen receptor modulator clinically prescribed in breast cancer therapy, was prepared in 7 steps and 30% overall yield from 4-iodophenol (3) as a 2.3:1 mixture of (Z)- and (E)-isomers.

A adição de 5-metil-2-tri-isopropilsililoxifurano (5) a N-carbobenziloxi-2-metoxipiperidina (6a) forneceu uma mixtura dos isômeros eritro e treo 7a and 8a, respectivamente, em rendimentos de moderado a bom (42-85%) e razão diastereoisomérica (7a : 8a) variando entre 1,1:1 _ 6:1, dependendo do sistema de solvente e do ácido de Lewis empregados. O isômero treo 8a foi transformado na (+/-)-homopumiliotoxina 223G (1) que foi obtida a partir de 6a em 5 etapas e 13% de rendimento total.

The addition of 5-methyl-2-triisopropylsilyloxyfuran (5) to N-carbobenzyloxy-2-methoxypiperidine (6a) afforded a mixture of the corresponding erythro and threo isomers 7a and 8a, respectively, in moderate to good yields (42-85%) and diastereoisomeric ratio (7a : 8a) ranging from 1.1:1 _ 6:1 depending on the solvent system and the Lewis acid employed. The threo isomer 8a was eventually converted to (+/-)-homopumiliotoxin 223G (1) which was prepared in 5 steps and 13% overall yield from 6a.

This review describes the use of catalytic asymmetric aldol reactions of silyl enol ethers and silyl (thio)ketene acetals with aldehydes (the Mukaiyama aldol reaction) in order to illustrate its synthetic utility. A variety of Lewis acid and basic reagents were employed for catalytic aldol reactions with high diastereo- and enantioselectivities. The origins of the selectivity of these reactions are discussed and some representative examples of their application in the synthesis of natural products are presented. New developments in chiral heterobimettalic lanthanoid catalysis and enantioselective aldol reactions in aqueous media are also included.