Marine Puupehenone and Puupehedione: Synthesis and Future Perspectives.

Puupehenone and puupehedione are natural products isolated from marine organisms. These compounds display a broad spectrum of biological activities, the in vitro antitubercular activity of puupehenone being a stand out, and are equipped with an interesting structural complexity. These products have served to stimulate the continual interest of the synthetic community. The first part of this article is a review of their total synthesis, using natural compounds which have the potential to be transformed into these marine compounds as starting materials; the synthetic routes employed to generate the basic skeleton; and the advances made to synthesize the pyran C ring with the required diastereoselectivity to obtain the natural products. Finally, this perspective shows a personal reflection of the authors on a possible unified and efficient retrosynthetic route that could allow easy access to these natural products, as well as their epimers at the C8 carbon and which could be used to address future biological issues in the production of pharmacologically active compounds.

A Concise Diastereoselective Total Synthesis of α-Ambrinol.

(-)-cis-α-Ambrinol is a natural product present in ambergris, a substance of marine origin that has been highly valued by perfumers. In this paper, we present a new approach to its total synthesis. The starting material is commercially available α-ionone and the key step is an intramolecular Barbier-type cyclization induced by CpTiCl2, an organometallic compound prepared in situ by a CpTiCl3 reduction with Mn.

Unifying the Synthesis of a Whole Family of Marine Meroterpenoids through a Biosynthetically Inspired Sequence of 1,2-Hydride and Methyl Shifts as Key Step.

Marine meroterpenoids have attracted a great deal of attention from synthetic research groups due to their attractive and varied biological activities and their unique and diverse structures. In most cases, however, further biological studies have been severely limited mainly to the scarcity of natural supply and because almost none of the reported syntheses methods has enabled unified access for a large number of marine meroterpenoids with aureane and avarane skeletons. Based on our previous publications and the study of recent manuscripts on marine meroterpenoids, we have conceived a unified strategy for these fascinating marine compounds with aureane or avarane skeletons using available drimane compounds as starting materials. The key step is a biosynthetic sequence of 1,2-hydride and methyl shifts. This strategy is of great synthetic value to access marine meroterpenoids through easy chemical synthetic procedures. Finally, several retrosynthetic proposals are made for the future synthesis of several members of this class of meroterpenoids, focused on consolidating these 1,2-rearrangements as a versatile and unified strategy that could be widely used in the preparation of these marine meroterpenoids.

Fatty acid profiling in the genus Pinus in relation to its chemotaxonomy and nutritional or pharmaceutical properties.

To develop and utilize the oil of Pinus seeds and explore natural resources rich in pinolenic acid (PNLA), twenty-one Pinus taxa were evaluated in a search of Δ5-unsaturated polymethylene-interrupted fatty acids (Δ5-UPIFA)-rich oils. While the fatty acid (FA) composition was determined by GC-FID and GC-MS, NMR of crude oils proved to be a fast method for establishing the ratio between Δ5-UPIFA and total FA. For all analyzed taxa, both the geographical origin and the concentration of total FA in the seeds are provided. PNLA and sciadonic acids occurred in all samples, while taxoleic and bishomopinolenic acids were present in most taxa. PNLA reached a maximum of 28.3% of total FA in P. mugo, and P. koraiensis showed the highest total FA amount (66.8 g/100 g seeds). The previously unanalyzed taxon P. ponderosa var. scopulorum can be considered a new PNLA source (17.1%). Principal Component Analysis showed that the similarities in FA profiles allow the grouping of the various taxa within Pinus subsections and confirmed the differential metabolic activities of Δ5 and Δ9 desaturase enzymes. This study showed that several underutilized Pinus taxa could be developed into renewable woody oil species, and their seeds could be used as raw materials for Δ5-UPIFA-rich oils extraction.

Enantioselective total synthesis of putative dihydrorosefuran, a monoterpene with an unique 2,5-dihydrofuran structure.

An original synthesis of the structure of dihydrorosefuran, a compound allegedly identified in Artemisia pallens and Tagetes mendocina, has been developed. The key steps in the five-step 36% overall yield synthesis are a CpTiIIICl2 mediated Barbier-type allenylation of a linear aldehyde and the formation of a 2,5-dihydrofuran scaffold through a Ag(I)-mediated cyclization. Neither of the reported spectral data for dihydrorosefuran match those of the synthetic product, suggesting that the isolated compound from Tagetes mendocina is in fact the natural product rosiridol, while the real structure of the product from Artemisia pallens remains unknown.

Buglossoides spp. seeds, a land source of health-promoting n-3 PUFA and phenolic compounds.

Ahiflower oil© is extracted from the seeds of Buglossoides arvensis, which contains high amounts of stearidonic acid (SDA, 18:4n-3), while its phenolic composition still is unreported. Moreover, several Buglossoides taxa remain unstudied and could become natural sources of SDA. In this work, seeds of several Buglossoides taxa and Ahiflower oil© were screened for fatty acids, phenolic compounds, and in vitro antiproliferative activities against colorectal cancer cells. Four flavonoids and 16 phenolic acids were identified and quantified. Among Buglossoides taxa, the highest amounts of phenolic compounds were found in samples collected in Spain, under a warm Mediterranean climate. Rosmarinic and lithospermic acids were the main phenols found in Buglossoides seeds. The MTT assay showed dose- and time-dependent inhibitory effects of B. arvensis extracts on HT-29 cancer cells, with a GI50value of ∼280 µg/mL after 72 h of cell exposure to seed extracts. The latter showed lower antiproliferative activity than that of pure phenolics due to the simultaneous presence of other compounds in the extracts, as evidenced by 1H NMR. This work constitutes the first approach to evaluate the seeds of several Buglossoides taxa as functional oils-providers to use them as functional foods.

Marine Terpenic Endoperoxides.

Organic extracts of marine invertebrates, mainly sponges, from seas all over the world are well known for their high in vitro anticancer and antibiotic activities which make them promising sources of compounds with potential use as pharmaceutical leads. Most of the structures discovered so far have a peculiar structural feature in common: a 1,2-dioxane ring. This is a highly reactive heterocycle that can be considered as an endoperoxide function. Together with other structural features, this group could be responsible for the strong biological activities of the substances present in the extracts. Numerous research programs have focused on their structural elucidation and total synthesis since the seventies. As a consequence, the number of established chiral centres and the similarity between different naturally occurring substances is increasingly higher. Most of these compounds have a terpenoid nature, mainly diterpene and sesterterpene, with several peculiar structural features, such as the loss of one carbon atom. Although there are many reviews dealing with the occurrence of marine peroxides, their activities, or potential pharmaceutical uses, no one has focused on those having a terpene origin and the endoperoxide function. We present here a comprehensive review of these compounds paying special attention to their structural features and their biological activity.

Divergent Strategy in Marine Tetracyclic Meroterpenoids Synthesis.

The divergent total synthesis strategy can be successfully applied to the preparation of families of natural products using a common late-stage pluripotent intermediate. This approach is a powerful tool in organic synthesis as it offers opportunities for the efficient preparation of structurally related compounds. This article reviews the synthesis of the marine natural product aureol, as well as its use as a common intermediate in the divergent synthesis of other marine natural and non-natural tetracyclic meroterpenoids.

The Proven Versatility of Cp2TiCl.

In the last two decades, titanocene monochloride has been postulated as a monoelectronic transfer reagent capable of catalyzing an important variety of chemical transformations. In this Perspective, our contributions to this growing field of research are summarized and analyzed. Especially known have been our contributions in C-C bond formation reactions, hydrogen-atom transfer from water to radicals, and isomerization reactions, as well as the development of a catalytic cycle that has subsequently allowed the preparation of a great variety of natural terpenes. It is also worth mentioning our contribution in the postulation of this single-electron transfer agent (SET) as a new green catalyst with a broad range of applications in organic and organometallic chemistry. The most significant catalytic processes developed by other research groups are also briefly described, with special emphasis on the reaction mechanisms involved. Finally, a reflection is made on the future trends in the research of this SET, aimed at consolidating this chemical as a new green reagent that will be widely used in fine chemistry, green chemistry, and industrial chemical processes.

Lesiones papilares intraductales mamarias: nuestra experiencia 2007-2017 / Intraductal papillary lesions of the breast: our experience 2007-2017

OBJETIVOS: Revisión y análisis de los casos de lesiones papilares intraductales mamarias diagnosticados en nuestro centro entre enero del 2007 y diciembre del 2017. Estudiar la asociación de las lesiones papilares con el cáncer de mama. PACIENTES Y MÉTODOS: Estudio descriptivo retrospectivo utilizando la base de datos de Anatomía Patológica. Se incluyó a 135 pacientes que en el periodo descrito tuvieron un diagnóstico anatomopatológico de lesión papilar (papiloma benigno aislado, papilomatosis múltiple, papiloma con carcinoma in situ, papiloma con atipia o carcinoma papilar intraductal). Las variables principales a analizar fueron la edad de las pacientes, las pruebas diagnósticas realizadas, la presencia de lesiones de mayor grado asociadas a la lesión papilar y el desarrollo de neoplasia de mama durante el seguimiento. RESULTADOS: La edad media de las pacientes fue de 50 años. La ductoscopia demostró ser una prueba con alta sensibilidad diagnóstica (88%). En 12 casos (9%) existía carcinoma en la lesión papilar o en sus alrededores (8 carcinomas in situ y 4 infiltrantes) y en 4 casos (3%) encontramos hiperplasia atípica asociada. Con un seguimiento medio de 34 meses, 6 pacientes tuvieron una recidiva en forma de lesión papilar (una papilomatosis múltiple y 5 papilomas), 3 pacientes recidivaron en forma de lesión neoplásica y una paciente desarrolló una neoplasia contralateral. CONCLUSIONES: Ante la sospecha de una lesión papilar y la presencia de secreción por el pezón, debemos considerar la realización de una ductoscopia por su alta sensibilidad. La alta incidencia de una neoplasia asociada a la lesión papilar o su aparición durante el seguimiento justifica su exéresis quirúrgica completa y un seguimiento estricto

OBJECTIVES: To provide a review and analysis of cases of intraductal papillary breast lesions diagnosed at our centre between January 2007 and December 2017, and to study the association between papillary lesions and breast cancer. PATIENTS AND METHODS: We performed a retrospective descriptive study using the pathology database of our centre. We included 135 patients with a pathological diagnosis of papillary lesion (isolated benign papilloma, multiple papillomatosis, papilloma with carcinoma in situ, papilloma with atypia or intraductal papillary carcinoma). The main variables were age, the diagnostic procedures performed, the presence of higher-grade lesions associated with the papillary lesion, and the development of breast neoplasms during follow-up. RESULTS: The patients' mean age was 50 years. Ductoscopy had high sensitivity (88%). Twelve patients (9%) had carcinomas on the papillary lesion or its surrounding areas (8 carcinomas in situ and 4infiltrating carcinomas) and 4 patients (3%) had associated atypical hyperplasia. With a mean follow-up of 34 months, 6 patients had recurrence as a papillary lesion (one multiple papillomatosis and 5papillomas), 3 patients relapsed with a neoplastic lesion, and one patient developed a contralateral neoplasm. CONCLUSIONS: In the presence of a suspected papillary lesion and nipple secretion, ductoscopy should be considered due to its high sensitivity. The high incidence of neoplasms associated with papillary lesions or their development during follow-up justifies their complete surgical excision and strict follow-up

A Concise Route for the Synthesis of Tetracyclic Meroterpenoids: (±)-Aureol Preparation and Mechanistic Interpretation.

A new concise general methodology for the synthesis of different tetracyclic meroterpenoids is reported: (±)-aureol (1), the key intermediate of this general route. The synthesis of (±)-aureol (1) was achieved in seven steps (28% overall yield) from (±)-albicanol. The key steps of this route include a C-C bond-forming reaction between (±)-albicanal and a lithiated arene unit and a rearrangement involving 1,2-hydride and 1,2-methyl shifts promoted by BF3•Et2O as activator and water as initiator.

Stereoselective Barbier-Type Allylations and Propargylations Mediated by CpTiCl3.

CpTiCl2, prepared in situ by manganese reduction of CpTiCl3, is an excellent new system for the Barbier-type allylation and propargylation of carbonyl compounds. It can be used in catalytic amounts when combined with Et3N·HBr/TMSBr, which acts as a regenerating system. The high regio- and stereoselectivity shown by this system makes it useful for prenylation and crotylation processes in the synthesis of natural products.

Cp2TiCl/D2O/Mn, a formidable reagent for the deuteration of organic compounds.

Cp2TiCl/D2O/Mn is an efficient combination, sustainable and cheap reagent that mediates the D-atom transfer from D2O to different functional groups and can contribute to the synthesis of new deuterated organic compounds under friendly experimental conditions and with great economic advantages.

Unprecedented Spectroscopic and Computational Evidence for Allenyl and Propargyl Titanocene(IV) Complexes: Electrophilic Quenching of Their Metallotropic Equilibrium.

The synthesis and structural characterization of allenyl titanocene(IV) [TiClCp2 (CH=C=CH2 )] 3 and propargyl titanocene(IV) [TiClCp2 (CH2 -C≡C-(CH2 )4 CH3 )] 9 have been described for the first time. Advanced NMR methods including diffusion NMR methods (diffusion pulsed field gradient stimulated spin echo (PFG-STE) and DOSY) have been applied and established that these organometallics are monomers in THF solution with hydrodynamic radii (from the Stokes-Einstein equation) of 3.5 and 4.1 Šfor 3 and 9, respectively. Full (1) H, (13) C, Δ(1) H, and Δ(13) C NMR data are given, and through the analysis of the Ramsey equation, the first electronic insights into these derivatives are provided. In solution, they are involved in their respective metallotropic allenyl-propargyl equilibria that, after quenching experiments with aromatic and aliphatic aldehydes, ketones, and protonating agents, always give the propargyl products P (when carbonyls are employed), or allenyl products A (when a proton source is added) as the major isomers. In all the cases assayed, the ratio of products suggests that the metallotropic equilibrium should be faster than the reactions of 3 and 9 with electrophiles. Indeed, DFT calculations predict lower Gibbs energy barriers for the metallotropic equilibrium, thus confirming dynamic kinetic resolution.

The PUFA-enriched fatty acid profiles of some frozen bison from the early Holocene found in the Siberian permafrost.

Knowledge concerning the availability of n-3 fatty acids for humans in prehistoric times is highly relevant in order to draw useful conclusions on the healthy dietary habits for present-day humans. To this end, we have analysed fat from several frozen bison found in the permafrost of Siberia (Russia). A total of 3 bison were included in this study, all them very close to the early Holocene (8,000; 8,200; and 9,300 years BP). All samples were analysed by gas-liquid chromatography-mass spectrometry (GLC-MS) and GLC flame-ionization detection (GLC-FID). Fat samples from two bison showed two well-differenced areas, i.e. brown and white, the latter being saturated fatty acid enriched, corresponding to an intermediate stage of adipocere formation, while the brown ones yielded α-linolenic acid in higher percentages than found in present-day bison. As demonstrated in this work, the subcutaneous fat of bison consumed by Mesolithic hunters contained amounts of n-3 fatty acids in higher quantities than those found in current bison; thus, the subcutaneous fat of bison could have contributed to meet today's recommended daily intake of essential fatty acids for good health in the Mesolithic to a greater extent than previously thought.

Synthesis of (±)-aureol by bioinspired rearrangements.

A bioinspired and sustainable procedure for the straightforward synthesis of (±)-aureol has been achieved in eight steps (14% overall yield) from epoxyfarnesol. The key steps are the titanocene(III)-catalyzed radical cascade cyclization of an epoxyfarnesol derivative and a biosynthetically inspired sequence of 1,2-hydride and methyl shifts.

Selective reduction of aromatic ketones in aqueous medium mediated by Ti(III)/Mn: a revised mechanism.

An experimental study on the role played by each of the reagents involved in the selective reduction of aromatic ketones in aqueous medium is reported. In this reaction, the reduction of aromatic ketones is mediated by Cp2TiCl. Moreover, the presence of Mn in the reaction medium is mandatory. To account for these findings, a substantially revised mechanism is proposed.

The fat from frozen mammals reveals sources of essential fatty acids suitable for Palaeolithic and Neolithic humans.

The elucidation of the sources of n-3 fatty acids available for the humans in the Upper Palaeolithic and Neolithic is highly relevant in order to ascertain the availability of such nutrients in that time frame as well as to draw useful conclusions about healthy dietary habits for present-day humans. To this end, we have analysed fat from several frozen mammals found in the permafrost of Siberia (Russia). A total of 6 specimens were included in this study: 2 mammoths, i.e. baby female calf called "Lyuba" and a juvenile female called "Yuka", both specimens approximately from the same time, i.e. Karginian Interstadial (41,000 and 34,000 years BP); two adult horses from the middle Holocene (4,600 and 4,400 years BP); and two bison very close to the Early Holocene (8,200 and 9,300 years BP). All samples were analysed by gas-liquid chromatography-mass spectrometry (GLC-MS) and GLC-flame ionization detector (GLC-FID). As demonstrated in this work, the fat of single-stomached mammals often consumed by Palaeolithic/Neolithic hunters contained suitable amounts of n-3 and n-6 fatty acids, possibly in quantities sufficient to meet the today's recommended daily intake for good health. Moreover, the results also suggest that mammoths and horses at that time were hibernators.

Ti-catalyzed straightforward synthesis of exocyclic allenes.

Exocyclic allenes constitute useful building blocks in organic synthesis and have recently been identified as key intermediates in the synthesis of natural products. Here the first general method for the most straightforward synthesis of exocyclic allenes reported to date is presented. This method is based on the Barbier-type cyclization of propargyl halides catalyzed by titanium; a safe, abundant, and ecofriendly metal. The reaction proceeds under mild conditions compatible with different functional groups and provides good yields of five-, six-, and seven-membered carbocycles and nitrogen-containing heterocycles bearing an exocyclic allene group. Experimental evidence supporting the proposed reaction mechanism is also provided. Moreover, this procedure can be carried out in an enantioselective manner by using chiral titanocene(III) catalysts. The utility of this method has been proved in the synthesis of the natural alkaloid stemoamide.