Efficient Synthesis of Cryptophycin‐52 and Novel para‐Alkoxymethyl Unit A Analogues

Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multi‐drug‐resistant tumour cells. Cryptophycins are composed of four building blocks (units A–D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para‐alkoxymethyl analogues from which cryptophycin‐52 and three analogous cryptophycins were prepared. Macrocyclisation of the seco‐depsipeptides was based on ring‐closing metathesis.     

A Total Synthesis of Spirastrellolide A Methyl Ester

A concise total synthesis of spirastrellolide A methyl ester ( 1 a , R¹=Me) as the parent compound of a series of highly cytotoxic marine macrolides is disclosed, which exploits and expands the flexibility of a synthesis plan previously developed by our group en route to the sister compound spirastrellolide F methyl ester ( 6 a , R¹=Me). Key to success was the masking of the signature Δ^15,16‐bond of 1 a as a C16‐carbonyl group until after the stereogenic center at C24 had been properly set by a highly selective hydrogenation of the C24 exo‐methylene precursor 66 . Conformational control over the macrocyclic frame allowed the proper stereochemical course to be dialed into this reduction process. The elaboration of the C16 ketone to the C15–C16 double bond was accomplished by a chemoselective alkenyl triflate formation followed by a palladium‐catalyzed hydride delivery. The role of the ketone at C16 as a strategic design element is also evident up‐stream of the key intermediate 66 , the assembly of which hinged upon the addition of the polyfunctionalized dithiane 37 to the similarly elaborate aldehyde fragment 46 . Other crucial steps of the total synthesis were an alkyl‐Suzuki coupling and a Yamaguchi lactonization that allowed the Northern and the Southern sector of the target to be stitched together and the macrocyclic perimeter to be forged. The lateral chain comprising the remote C46 stereocenter was finally attached to the core region by a modified Julia–Kocienski olefination. The preparation of the individual building blocks led to some methodological spin‐offs, amongst which the improved procedure for the N–O‐bond cleavage of isoxazolines by zero‐valent molybdenum and the ozonolysis of a double bond in the presence of other oxidation‐prone functionality are most noteworthy. Preliminary biological data suggest that the entire carbon framework, that is the macrocyclic core plus the lateral chain, might be necessary for high cytotoxicity.     

Total Synthesis of Marinomycin A Based on a Direct Dimerization Strategy

The asymmetric total synthesis of (+)‐marinomycin A, a 44‐membered macrodiolide antitumor agent and antibiotic isolated from a marine actinomycete, Marinispora strain CNQ‐140, is reported. The key features of the synthesis include the highly convergent stereocontrolled construction of the monomeric hydroxy salicylate starting from asymmetric epoxidation of the σ‐symmetrical dialkenyl carbinol, and an unprecedented direct dimerization through NaHMDS‐promoted double transesterification.     

Stereocontrolled Total Synthesis of Polygalolide A

The total synthesis of polygalolide A, a secondary metabolite that was isolated from a Chinese medicinal plant, is reported. A key issue in this synthesis was construction of an oxabicyclo[3.2.1] skeleton, which was solved by the development of an intramolecular Ferrier‐type C‐glycosylation of a glucal with siloxyfuran as an internal nucleophile. The substrate was prepared from D ‐glucal by the introduction of trimethylsilylacetylene and siloxyfuran groups. Although C‐glycosylation did not occur under the conditions found from model experiments, further examination revealed that the combination of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,4,6‐collidine successfully afforded the desired product as a single diastereomer. The siloxy group at the C3 position played a crucial role in the stereocontrol of this reaction. The product was further transformed into a tetracyclic compound as follows: The vinyl ether and acetylenic moieties were reduced and the siloxy group was removed with a Barton–McCombie reaction. The construction of the six‐membered ether and the γ‐lactone provided the tetracyclic compound. Finally, a phenolic moiety was introduced by using a Mukaiyama aldol reaction to furnish polygalolide A.     

Formal Total Synthesis of Diazonamide A by Indole Oxidative Rearrangement

A short formal total synthesis of the marine natural product diazonamide A is described. The route is based on indole oxidative rearrangement, and a number of options were investigated involving migration of tyrosine or oxazole fragments upon oxidation of open chain or macrocyclic precursors. The final route proceeds from 7‐bromoindole by sequential palladium‐catalysed couplings of an oxazole fragment at C‐2, followed by a tyrosine fragment at C‐3. With the key 2,3‐disubstituted indole readily in hand, formation of a macrocyclic lactam set the stage for the crucial oxidative rearrangement to a 3,3‐disubstituted oxindole. Notwithstanding the concomitant formation of the unwanted indoxyl isomer, the synthesis successfully delivered, after deprotection, the key oxindole intermediate, thereby completing a formal total synthesis of diazonamide A.     

Total Synthesis of Hopeahainol A and Hopeanol

Similar, but different : Possessing almost the same but not identical structures, the recently discovered natural products hopeahainol A ( 1 ) and hopeanol ( 2 ) exhibit important but differing biological properties (see structures). Their first total synthesis has now been achieved through a series of novel cascade reactions and skeletal rearrangements.

     

Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue

We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem‐like leukemia cells. Key transformations include a diastereoselective organocatalytic cross‐aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist‐type Horner—Wadsworth—Emmons (HWE) macrocyclization, and a new DSC‐mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia‐selective activity.     

Total Synthesis of Diterpenoid Steenkrotin A

A concise and diastereoselective total synthesis of the diterpenoid (±)‐steenkrotin A is described for the first time. The strategy mainly features three key ring formations: 1) a rhodium‐catalyzed O? H bond insertion followed by an intramolecular carbonyl‐ene reaction to build up the tetrahydrofuran subunit; 2) sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations to construct the [5,7] spirobicyclic skeleton; and 3) an intramolecular aldol condensation/vinylogous retro‐aldol/aldol sequence to form the final six‐membered ring with inversion of the relative configuration at the C7 position.