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Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created de novo through an inverse-electron demand Diels-Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination-aromatization reaction. Mechanistic investigation of this step using deuterium-labeling studies indicated the intermediacy of a carbene which undergoes a 1,2-hydrogen shift and subsequent aromatization. The methodology was applied to a modular and stereoselective total synthesis of the antiplatelet drug beraprost in only 8 steps from a key enal-lactone. This lactone provided the core of beraprost to which both its sidechains could be appended through a 1,4-conjugate addition process (lower ω-sidechain), followed by de novo construction of beraprost's dihydrobenzofuran (upper α-sidechain) using our newly developed methodology. Additionally, we have demonstrated the breadth of our newly established protocol in the synthesis of functionalized indolines, which occurred with high levels of regiocontrol. According to density-functional theory (DFT) calculations, the high selectivity originates from attractive London dispersion interactions in the TS of the Diels-Alder reaction.
RESUMO
Difunctionalization reactions of C-C σ-bonds have the potential to streamline access to molecules that would otherwise be difficult to prepare. However, the development of such reactions is challenging because C-C σ-bonds are typically unreactive. Exploiting the high ring-strain energy of polycyclic carbocycles is a common strategy to weaken and facilitate the reaction of C-C σ-bonds, but there are limited examples of highly strained C-C σ-bonds being used in difunctionalization reactions. We demonstrate that highly strained bicyclo[1.1.0]butyl boronate complexes (strain energy ca. 65 kcal/mol), which were prepared by reacting boronic esters with bicyclo[1.1.0]butyl lithium, react with electrophiles to achieve the diastereoselective difunctionalization of the strained central C-C σ-bond of the bicyclo[1.1.0]butyl unit. The reaction shows broad substrate scope, with a range of different electrophiles and boronic esters being successfully employed to form a diverse set of 1,1,3-trisubstituted cyclobutanes (>50 examples) with high diastereoselectivity. The high diastereoselectivity observed has been rationalized based on a combination of experimental data and DFT calculations, which suggests that separate concerted and stepwise reaction mechanisms are operating, depending upon the migrating substituent and electrophile used.
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Prostaglandins have been attractive targets in total synthesis for over 50â years, resulting in the development of new synthetic strategies and methodologies that have served the broader chemical community. However, these molecules are not just of academic interest, a number of prostaglandin analogues are used in the clinic, and some are even on the WHO list of essential medicines. In this personal account, we describe our own approach to the family of prostaglandins, which centers around the synthesis of a key enal intermediate, formed from the l-proline catalysed dimerization of succinaldehyde. We highlight the discovery and further optimization of this key reaction, its scale up, and subsequent application to a range of prostaglandins.
Assuntos
Aldeídos/química , Prostaglandinas/síntese química , Catálise , Dimerização , Prolina/química , Prostaglandinas/químicaRESUMO
Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate's stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate's configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies: (1) a direct asymmetric coupling approach, and (2) a multicomponent approach, which exhibits statistical amplification of enantiopurity. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect.
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BACKGROUND AND PURPOSE: Thromboxane A2 (TXA2) is a prostanoid produced during platelet activaton, important in enhancing platelet reactivity by activation of TP receptors. However, due to the short half-life, studying TXA2 signalling is challenging. To enhance our understanding of TP receptor-mediated platelet biology, we therefore synthesised mono and difluorinated TXA2 analogues and explored their pharmacology on heterologous and endogenously expressed TP receptor function. EXPERIMENTAL APPROACH: Platelet functional and signalling responses were studied using aggregometry, Ca2+ mobilisation experiments and immunoblotting and compared with an analogue of the TXA2 precursor prostaglandin H2, U46619. Gαq/Gαs receptor signalling was determined using a bioluminescence resonance energy transfer (BRET) assay in a cell line overexpression system. KEY RESULTS: BRET studies revealed that F-TXA2 and F2-TXA2 promoted receptor-stimulated TP receptor G-protein activation similarly to U46619. Unexpectedly, F2-TXA2 caused reversible aggregation in platelets, whereas F-TXA2 and U46619 induced sustained aggregation. Blocking the IP receptor switched F2-TXA2-mediated reversible aggregation into sustained aggregation. Further BRET studies confirmed F2-TXA2-mediated IP receptor activation. F2-TXA2 rapidly and potently stimulated platelet TP receptor-mediated protein kinase C/P-pleckstrin, whereas IP-mediated protein kinase A/P-vasodilator-stimulated phosphoprotein was more delayed. CONCLUSION AND IMPLICATIONS: F-TXA2 is a close analogue to TXA2 used as a selective tool for TP receptor platelet activation. In contrast, F2-TXA2 acts on both TP and IP receptors differently over time, resulting in an initial wave of TP receptor-mediated platelet aggregation followed by IP receptor-induced reversibility of aggregation. This study reveals the potential difference in the temporal aspects of stimulatory and inhibitory pathways involved in platelet activation.
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Platelet activation results in the generation of thromboxane A2 (TxA2), which promotes thrombus formation by further amplifying platelet function, as well as causing vasoconstriction. Due to its role in thrombus formation and cardiovascular disease, its production is the target of antiplatelet drugs such as aspirin. However, the study of TxA2-stimulated cellular function has been limited by its instability (t 1/2 = 32 s, pH = 7.4). Although more stable analogues such as U46619 and difluorinated 10,10-F2-TxA2 have been prepared, we targeted a closer mimic to TxA2 itself, monofluorinated 10-F-TxA2, since the number of fluorine atoms can affect function. Key steps in the synthesis of F-TxA2 included α-fluorination of a lactone bearing a ß-alkoxy group, and a novel synthesis of the strained acetal. F-TxA2 was found to be 105 more stable than TxA2, and surprisingly was only slightly less stable than F2-TxA2. Preliminary biological studies showed that F-TxA2 has similar potency as TxA2 toward inducing platelet aggregation but was superior to F2-TxA2 in activating integrin αIIbß3.
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A chemoselective tandem reaction of a multi-reactive, two electrophile + two nucleophile, system is reported. An allylation/cross-coupling process of a haloaryl aldehyde, an aryl BPin, and an allyl BPin can be controlled using a temperature gradient to overcome natural reactivity profiles and allow two sequential chemoselective C-C bond formations without intervention. This process offers efficient access to an array of functionalised products including pharmaceutical and natural product scaffolds.