Synthesis of (E)‐4‐Bromo‐3‐methoxybut‐3‐en‐2‐one,the Key Fragment in the Polyhydroxylated Chain Common to Oscillariolide and Phormidolides A–C

The terminal bromomethoxydiene (BMD) moiety of the polyhydroxylated chain present in phormidolides and oscillariolides has been synthesized for first time. Several strategies for the stereoselective synthesis of the 4‐bromo‐3‐methoxybut‐3‐en‐2‐ones are described. Furthermore, a preliminary study to successfully introduce the BMD within the polyol chain and the fatty acid allowed us to corroborate the end structure of the polyol.     

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine,and (+)‐1‐epi‐Castanospermine

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐ 8 . The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34 , and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a . The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.     

Total Synthesis of (−)‐Caprazamycin A

Caprazamycin A has significant antibacterial activity against Mycobacterium tuberculosis (TB). The first total synthesis is herein reported and features a) the scalable preparation of the syn‐β‐hydroxy amino acid with a thiourea‐catalyzed diastereoselective aldol reaction, b) construction of a diazepanone with an unstable fatty‐acid side chain, and c) global deprotection with hydrogenation. This report provides a route for the synthesis of related liponucleoside antibiotics with fatty‐acid side chains.     

Total Synthesis of (−)‐Spirangien A,an Antimitotic Polyketide Isolated from the Myxobacterium Sorangium Cellulosum

A stereocontrolled total synthesis of the cytotoxic spiroacetal‐containing polyketide (?)‐spirangien A is described. This utilizes an aldol‐based strategy to construct a common stereotetrad intermediate that was elaborated into the spiroacetal core, followed by the introduction of the unstable pentaene‐containing side chain, performed with exclusion of light, using sequential Stille cross‐coupling reactions.

     

Total Syntheses of (+)‐Polygalolide A and (+)‐Polygalolide B: Elucidation of the Absolute Stereochemistry and Biogenetic Implications

The total syntheses of (+)‐polygalolide A and (+)‐polygalolide B have been completed by using a carbonyl ylide cycloaddition strategy. Three of the four stereocenters, including two consecutive tetrasubstituted carbon atoms at C2 and C8, were incorporated through internal asymmetric induction from the stereocenter at C7 by a [Rh₂(OAc)₄]‐catalyzed carbonyl ylide formation/intramolecular 1,3‐dipolar cycloaddition sequence. The arylmethylidene moiety of these natural products was successfully installed by a Mukaiyama aldol‐type reaction of a silyl enol ether with a dimethyl acetal, followed by elimination under basic conditions. We have also developed an alternative approach to the carbonyl ylide precursor based on a hetero‐Michael reaction. This approach requires 18 steps, and the natural products were obtained in 9.8 and 9.3 % overall yields. Comparison of specific rotations of the synthetic materials and natural products suggests that polygalolides are biosynthesized in nearly racemic forms through a [5+2] cycloaddition between a fructose‐derived oxypyrylium zwitterion with an isoprene derivative.     

A Hydrolase‐Catalyzed Cyclization Forms the Fused Bicyclic β‐Lactone in Vibralactone

Vibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual β‐lactone‐fused bicycle is derived from an aryl ring moiety by an oxidative ring‐expansion prior to an intramolecular cyclization. Herein, we report the discovery of the cyclase VibC which belongs to the α/β‐hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the Ser‐His‐Asp catalytic triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic β‐lactone. This presents a naturally occurring, new enzymatic reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical‐diversity expansion of natural products.     

Polyketide Cyclizations for the Synthesis of Polyaromatics

The folding and cyclization of poly‐β‐carbonyl chains controlled by the intricate enzymatic polyketide synthase machinery results in a remarkable diversity of aromatic natural products. Synthetic methods that allow for the preparation of highly reactive polyketide chains while governing their folding in ensuing cyclizations likewise lead to versatile divergent preparations of aromatic scaffolds valuable for numerous applications. Although biomimetic polyketide cyclizations have repeatedly been applied in the total synthesis of polyphenol natural products, their utility for the preparation of the broad range of polyaromatic architectures has yet to reach its full potential. This Minireview highlights some of the virtues of applying polyketide logic to the retrosynthetic analysis of polycyclic aromatic scaffolds, the increasing accessibility of precursors, and the potential of small‐molecule catalysts for controlling polyketide cyclizations to provide polyaromatic scaffolds.     

Total Synthesis of the Antimitotic Marine Macrolide (−)‐Leiodermatolide

Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin‐targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2 % yield) based on a convergent sequence of palladium‐mediated fragment assembly and macrolactonization. Boron‐mediated aldol reactions were used to configure the three key fragments 2 , 5 , and 6 by employing the appropriate enantiomer of the lactate‐derived ketone 7 .     

Enantioselective Syntheses of Lignin Models: An Efficient Synthesis of β‐O‐4 Dimers and Trimers by Using the Evans Chiral Auxiliary

We describe an efficient five‐step, enantioselective synthesis of (R,R)‐ and (S,S)‐lignin dimer models possessing a β‐O‐4 linkage, by using the Evans chiral aldol reaction as a key step. Mitsunobu inversion of the (R,R)‐ or (S,S)‐isomers generates the corresponding (R,S)‐ and (S,R)‐diastereomers. We further extend this approach to the enantioselective synthesis of a lignin trimer model. These lignin models are synthesized with excellent ee (>99 %) and high overall yields. The lignin dimer models can be scaled up to provide multigram quantities that are not attainable by using previous methodologies. These lignin models will be useful in degradation studies probing the selectivity of enzymatic, microbial, and chemical processes that deconstruct lignin.     

Synthesis of 5‐ and 8‐Deoxytetrodotoxin

Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products owing to its complex structure and potent biological activity, which leads to fatal poisoning. Continuous synthetic studies on tetrodotoxin and its analogues to elucidate biologically interesting issues associated with tetrodotoxin have led to the development of versatile routes for a variety of tetrodotoxin derivatives. With the aim of investigating the structure–activity relationship of tetrodotoxin with voltage‐gated sodium channels, this study describes the first total syntheses of 5‐deoxytetrodotoxin, a natural analogue of tetrodotoxin, and 8‐deoxytetrodotoxin, an unnatural analogue, from a newly designed, versatile intermediate in an efficient manner. An estimation of the biological activities of these compounds reveals the importance of the hydroxy groups at the C‐5 and C‐8 positions on the inhibition of voltage‐gated sodium channels.     

The Structure Elucidation and Total Synthesis of β‐Lipomycin

Here we describe the synthesis of β‐lipomycin, a secondary metabolite isolated from the fermentation broth of Corallococcus coralloides. The synthesis relies on the structural assignment made by a statistical method, the so‐called profile hidden Markov model. Using this protocol, not only the configuration of the secondary alcohol, but also of the adjacent methyl branch could be deduced. The synthesis therefore not only provides access to this natural product but also confirms the validity of this approach for configurational assignment at methyl branches of modular polyketides.     

Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

Enantioselective Synthesis of (+)‐Chamaecypanone C: A Novel Microtubule Inhibitor

A bicycle built for tubulin : The total synthesis of (+)‐chamaecypanone C has been achieved by using a tandem retro‐Diels–Alder/Diels–Alder cascade reaction (see scheme). Initial biological studies demonstrate that (+)‐chamaecypanone C is an inhibitor of tubulin assembly and binds at the colchicine site.