Total Synthesis of (-)-Piericone D.

The total synthesis of (-)-piericone D, a potential antithrombotic dihydrochalcone featuring an [3.3.0] octane core, is reported. Salient features of our synthesis include a stereoselective ß-O-glycosylation to install the asebogenin aglycone and a late-stage global deprotection followed by simultaneous lactonization. The convergent synthesis paved the way for further structure-activity relationship (SAR) studies of (-)-piericone D.

Total Syntheses of Scabrolide A and Nominal Scabrolide B.

The marine natural product scabrolide A was obtained by isomerization of the vinylogous 1,4-diketone entity of nominal scabrolide B as the purported pivot point of the biosynthesis of these polycyclic norcembranoids. Despite the success of this maneuver, the latter compound itself turned out not to be identical with the natural product of that name. The key steps en route to the carbocyclic core of these targets were a [2,3]-sigmatropic rearrangement of an allylic sulfur ylide to forge the overcrowded C12-C13 bond, an RCM reaction to close the congested central six-membered ring, and a hydroxy-directed epoxidation/epoxide opening/isomerization sequence to set the "umpoled" 1,4-dicarbonyl motif and the correct angular configuration at C12.

A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I.

Many polycyclic marine alkaloids are thought to derive from partly reduced macrocyclic alkylpyridine derivatives via a transannular Diels-Alder reaction that forms their common etheno-bridged diaza-decaline core ("Baldwin-Whitehead hypothesis"). Rather than trying to emulate this biosynthesis pathway, a route to these natural products following purely chemical logic was pursued. Specifically, a Michael/Michael addition cascade provided rapid access to this conspicuous tricyclic scaffold and allowed different handles to be introduced at the bridgehead quarternary center. This flexibility opened opportunities for the formation of the enveloping medium-sized and macrocyclic rings. Ring closing alkyne metathesis (RCAM) proved most reliable and became a recurrent theme en route to keramaphidin B, ingenamine, xestocyclamine A, and nominal njaoamine I (the structure of which had to be corrected in the aftermath of the synthesis). Best results were obtained with molybdenum alkylidyne catalysts endowed with (tripodal) silanolate ligands, which proved fully operative in the presence of tertiary amines, quinoline, and other Lewis basic sites. RCAM was successfully interlinked with macrolactamization, an intricate hydroboration/protonation/alkyl-Suzuki coupling sequence, or ring closing olefin metathesis (RCM) for the closure of the second lateral ring; the use of RCM for the formation of an 11-membered cycle is particularly noteworthy. Equally rare are RCM reactions that leave a pre-existing triple bond untouched, as the standard ruthenium catalysts are usually indiscriminative vis-à-vis the different π-bonds. Of arguably highest significance, however, is the use of two consecutive or even concurrent RCAM reactions en route to nominal njaoamine I as the arguably most complex of the chosen targets.

Total Synthesis Provides Strong Evidence: Xestocyclamine A is the Enantiomer of Ingenamine.

Xestocyclamine A ((-)-1) is featured prominently in a biosynthesis pathway leading to a large family of polycyclic alkaloids. The first total synthesis now proves that the structure of this compound had originally been misassigned. The route to (-)-1 is based on a double Michael addition for the formation of the bridged diazadecalin core and a palladium-catalyzed decarboxylative allylation to install the quaternary bridgehead center. Ring-closing alkyne metathesis allowed a 13-membered cycloalkyne to be forged, which was selectively reduced during an involved sequence of hydroboration/selective protodeborylation/alkyl-Suzuki coupling used to close the 11-membered ring. Crystallographic data prove the identity of synthetic (-)-1 with nominal xestocyclamine, but the spectra differ from those of the authentic alkaloid. To clarify the point, the synthesis was redirected toward ingenamine (3), which is supposedly a positional isomer of 1. The recorded data confirm the assignment of this particular natural product and strongly suggest that xestocyclamine A is in fact the enantiomer of ingenamine (+)-3.

Total Synthesis of (-)-Sinulariadiolide. A Transannular Approach.

The constrained tricyclic skeleton of the nor-cembranoid sinulariadiolide (1) with a nine-membered nexus was obtained by a cascade of transannular Michael reaction, carbonate elimination, butenolide formation, and spontaneous oxa-Michael addition of MeOH. The required macrocyclic precursor was prepared by ring-closing alkyne metathesis followed by trans-hydrostannation/carbonylation.

A "Motif-Oriented" Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues.

The highly cytotoxic cyclodepsipeptides of the nannocystin family are known to bind to the eukaryotic translation elongation factor 1α (EF-1α). Analysis of the docking pose, as proposed by a previous in silico study, suggested that the trisubstituted alkene moiety and the neighboring methyl ether form a domain that might be closely correlated with biological activity. This hypothesis sponsored a synthetic campaign which was designed to be "motif-oriented": specifically, a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived, which allowed this potentially anchoring substructure to be systematically addressed at a late stage. This inherently flexible approach opened access to nannocystin Ax (1) itself as well as to 10 non-natural analogues. While the biological data confirmed the remarkable potency of this class of compounds and showed that the domain in question is indeed an innate part of the pharmacophore, the specific structure/activity relationships can only partly be reconciled with the original in silico docking study; therefore, we conclude that this model needs to be carefully revisited.

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families.

Indolosesquiterpenoids are a growing class of natural products that exhibit a wide range of biological activities. Here, we report the total syntheses of xiamycin A and oridamycins A and B, indolosesquiterpenoids isolated from Streptomyces. Two parallel strategies were exploited to forge the carbazole core: 6π-electrocyclization/aromatization and indole C2-H bond activation/Heck annulation. The construction of their trans-decalin motifs relied on two diastereochemically complementary radical cyclization reactions mediated by Ti(III) and Mn(III), respectively. The C23 hydroxyl of oridamycin B was introduced by an sp(3) C-H bond oxidation at a late stage. On the basis of the chemistry developed, the dimeric congener dixiamycin C has been synthesized for the first time. Evaluation of the antiviral activity of these compounds revealed that xiamycin A is a potent agent against herpes simplex virus-1 (HSV-1) in vitro.