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Complement-mediated diseases or complementopathies, such as Paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), and transplant-associated thrombotic microangiopathy (TA-TMA), demand advanced complement diagnostics and therapeutics be adopted in a vast field of medical specialties, such as hematology, transplantation, rheumatology, and nephrology. The miracle of complement inhibitors as “orphan drugs” has dramatically improved morbidity and mortality in patients with otherwise life-threatening complementopathies. Efficacy has been significantly improved by upstream inhibition in patients with PNH. Different molecules may exert diverse characteristics in vitro and in vivo. Further studies remain to show safety and efficacy of upstream inhibition in other complementopathies. In addition, cost and availability issues are major drawbacks of current treatments. Therefore, further developments are warranted to address the unmet clinical needs in the field of complementopathies. This state-of-the-art narrative review aims to delineate novel insights into factor D inhibition as a promising target for complementopathies.

Based upon observations from our initial findings, additional myxopyronin B analogs have been prepared and tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against Escherichia coli and Staphylococcus aureus.

The Lewis acid-promoted reactions of alkyl azides with ketones can afford several products. Chief among these result from a Schmidt-like insertion of the azide into the carbon−carbon bond adjacent to the carbonyl group. Alternatively, an acid-promoted rearrangement of the azide to an iminium species can occur, mostly with benzylic azides; the iminium species can then be trapped by the enol of the carbonyl compound in a variation of the Mannich reaction. The scope of each of these reactions, the dependence of the observed products upon azide and ketone structure, and the nature of acid promotion are discussed. In broad strokes, cyclohexanones and other cyclic ketones react in the presence of TiCl4 to afford insertion products, whereas the Mannich route predominates when benzyl azide and triflic acid are used. The features that lead to each reaction type and possible mechanistic implications are discussed.

Dissection at the ring F oxocene of brevetoxin A formed the basis of the second generation strategy for the total synthesis of this molecule. In this case the planned hydroxy ketal cyclization was successful, and selective reduction of the resulting product gave the EFGH ring system of the target molecule.

A ten-year campaign was successfully completed by the first total synthesis of brevetoxin A (1). A Horner–Wittig type coupling of suitably functionalized BCDE and GHIJ ring systems proved to be the last key step in the total synthesis of this architecturally beautiful molecule.

Pivotal intermediates in the total synthesis of brevetoxin A are the BCDE and the GHIJ ring systems. Several of the previously developed methodologies such as hydroxy epoxide cyclizations, hydroxy dithioketal cyclizations, and Pd-catalyzed coupling with bis(cyclic ketene acetal phosphates) were employed to achieve these synthetic goals.

Dissection of brevetoxin A at the nine-membered ring site (ring E) formed the basis of the first generation strategy for the total synthesis of this molecule. Unfortuately the planned hydroxy dithioketal cyclization to form the crucial nonacene did not proceed as anticipated and this approach was discontinued.

Treatment of benzyl azide with triflic acid or titanium tetrachloride effects 1,2-phenyl migration with concomitant liberation of molecular nitrogen. The resulting N-phenyl iminium ion intermediate readily combines with enolizable carbonyl substrates to form Mannich bases.

Brevetoxin A is the most potent neurotoxin secreted by Gymnodinium breve Davis, a marine organism often associated with harmful algal blooms known as ‘red tides’1,2,3. The compound, whose mechanism of action involves binding to and opening of sodium channels4,5,6,7, is sufficiently toxic to kill fish at concentrations of nanograms per ml (refs 3, 4) and, after accumulation in filter-feeding shellfish, to poison human consumers. The precise pathway by which nature constructs brevetoxin A is at present unknown8,9, but strategies for its total synthesis have been contemplated for some time. The synthetic challenge posed by brevetoxin A reflects the high complexity of its molecular structure: 10 oxygen atoms and a chain of 44 carbon atoms are woven into a polycyclic macromolecule that includes 10 rings (containing between 5 and 9 atoms) and 22 stereogenic centres. Particularly challenging are the 7-, 8- and 9-membered rings which allow the molecule to undergo slow conformational changes and force a 90° twist at one of its rings1,2,3,4,5,6. Here we describe the successful incorporation of methods that were specifically developed for the construction of these rings10,11 into an overall strategy for the total synthesis of brevetoxin A in its naturally occurring form. The convergent synthesis reported here renders this scarce neurotoxin synthetically available and, more importantly, allows the design and synthesis of analogues for further biochemical studies.

Transcellular transport is one of the most important barriers facing the development of new therapeutic agents. However, little is known about the specific effects of structure and particularly stereochemistry on cell permeability. An attractive in vitro model has been developed for the direct assessment of cell transport, using the immortalized human epithelial cell line, Caco-2. The present study assesses the effects of stereochemistry on transport in a commonly used β-turn model system. Thus, l,l - and l,d -Ala-Ala were cyclized with aminocaproic acid, resulting in macrocycles in which the dipeptides correspond to the i + 1 and i + 2 positions of a β-turn. The transport of these dipeptides across a Caco-2 cell monolayer was determined, along with corresponding acyclic models ( l,l - and l,d -CH 3 CH 2 C(O)-Ala-Ala -n- Pr ) . The transport studies were carried out in the presence and absence of verapamil, a known inhibitor of the apically polarized efflux system present in Caco-2 cells. Both apical→basolateral and basolateral→apical transport were measured. Measurements made in the presence of verapamil showed that the cyclic peptides experienced a ca. 4–5-fold difference in intrinsic flux depending on stereochemistry, with the l,d isomer being transported at a higher rate. These differences disappeared in the acyclic cases examined (permeability coefficient ratios of the L, D / L, L isomers were 1.04–1.13). These observations are discussed in terms of the conformations and hydrogen-bonding characteristics of the compounds as determined by NMR spectroscopy.

The total synthesis of curacin A, a cytotoxic agent that interacts with the colchicine binding site on tubulin, is described. The convergent synthesis utilizes natural product and chiral pool starting materials (geraniol, serine) and asymmetric synthesis (chiral allylborane addition, Charette cyclopropanation) to procure the various chiral fragments in enantiomerically pure form. The assembly of the natural product involves carbon-carbon bond formation (Julia coupling) and heterocycle preparation (Wipf thiazoline synthesis).

Oxygenated pterocarpans and 5-azapterocarpans are prepared utilizing Lewis acid-promoted reactions of 2-alkoxy-1,4-benzoquinones with 2H-chromenes and N-tosyl-1,2-dihydroquinolines, respectively. Similarly, benzannulated analogues are prepared via reactions of 5-alkoxy-1,4-naphthoquinones with chromenes, and related 2-aryl-2,3-dihydrobenzofurans result from reactions of styrenes with the quinones. Syntheses of 5-thiapterocarpans are also described utilizing Pd(0)-coupling of o-chloromercuriophenols with 2H-chromenes.

In Ti(IV)-promoted reactions with 2-methoxy-1,4-benzoquinones 3, thioallenes 1 give 2+2 and/or 3+2 products via attack on a CC moiety of the quinone, whereas silylallene 2 gives products derived from attack on a carbonyl group of the quinone.

Alkenylethylzincs, obtained from the corresponding trialkenylboranes by transmetallation with diethylzinc, couple with aryl iodides in the presence of Pd(PPh 3 ) 4 , 0.19–0.28 mol%, to produce trisubstituted alkenes in good isolated yields. Both the transmetallation and subsequent coupling occur with complete retention of stereochemistry.

Curacin A (1) was synthesized in a convergent manner. The key steps were (1) a Julia coupling to establish the stereochemistry of the C(7–10) diene, (2) a Wittig reaction to establish the stereochemistry of the C(3–4) alkene, and (3) a dehydrative cyclization to form the thiazoline ring system.

The total synthesis of curacin A, a cytotoxic agent that interacts with the colchicine binding site on tubulin, is described. The convergent synthesis utilizes natural product and chiral pool starting materials (geraniol, serine) and asymmetric synthesis (chiral allylborane addition, Charette cyclopropanation) to procure the various chiral fragments in enantiomerically pure form. The assembly of the natural product involves carbon-carbon bond formation (Julia coupling) and heterocycle preparation (Wipf thiazoline synthesis).

Treatment of benzyl azide with triflic acid or titanium tetrachloride effects 1,2-phenyl migration with concomitant liberation of molecular nitrogen. The resulting N-phenyl iminium ion intermediate readily combines with enolizable carbonyl substrates to form Mannich bases.

Dissection of brevetoxin A at the nine-membered ring site (ring E) formed the basis of the first generation strategy for the total synthesis of this molecule. Unfortuately the planned hydroxy dithioketal cyclization to form the crucial nonacene did not proceed as anticipated and this approach was discontinued.

A series of myxopyronin B analogs has been prepared via a convergent synthetic route and were tested for in vitro inhibitory activity against DNA-dependent RNA polymerase and antibacterial activity against E. coli and S. aureus. The parent lead compound proved to be very sensitive to even small changes. Only the achiral desmethyl myxopyronin B (1a) provided enhanced potency.

(±)-Myxopyronin B was synthesized via the interconversions of pyrone and pyridone moieties. The key steps involve a BuLi-catalyzed aldol condensation and the conversion of an advanced N-methyl pyridone ester intermediate to the corresponding pyrone acid under basic hydrolysis.