Formal Total Synthesis of (−)‐Taxol through Pd‐Catalyzed Eight‐Membered Carbocyclic Ring Formation

A formal total synthesis of (?)‐taxol by a convergent approach utilizing Pd‐catalyzed intramolecular alkenylation is described. Formation of the eight‐membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd‐catalyzed intramolecular alkenylation of a methyl ketone affording the cyclized product in excellent yield (97 %), indicating the high efficiency of the Pd‐catalyzed intramolecular alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5‐hydride shift, generating the C3 stereogenic center and subsequently forming the C1–C2 benzylidene, was discovered and utilized in the preparation of a substrate for the Pd‐catalyzed reaction.     

Catalytic Asymmetric Total Synthesis of (−)‐Galanthamine and (−)‐Lycoramine

The catalytic asymmetric total syntheses of (?)‐galanthamine ( 1 ) and (?)‐lycoramine ( 2 ) have been achieved by using a conceptually new strategy featuring two metal‐catalyzed reactions as the key steps. A new method for the construction of 3,4‐fused benzofurans has been developed through a palladium‐catalyzed intramolecular Larock annulation reaction, which was successfully applied to the construction of the ABD tricyclic skeleton of 1 and 2 . To achieve the asymmetric synthesis of 1 and 2 , a Sc^III/N,N′‐dioxide complex was used to catalyze the enantioselective conjugate addition of 3‐alkyl‐substituted benzofuranone to methyl vinyl ketone for the construction of a chiral quaternary carbon center.     

Total Synthesis of (−)‐Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃‐mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)‐glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

An Enantioselective Total Synthesis of (−)‐Isoschizogamine

A concise enantioselective total synthesis of (?)‐isoschizogamine, a complex bridged polycyclic monoterpene indole alkaloid, was accomplished. N‐Alkylation of an enantio‐enriched imine with an alkyl iodide afforded an iminium salt, which, upon heating by microwave irradiation in the presence of pivalic acid, was converted into the hexacyclic structure of natural product by a complex but ordered domino sequence. The one‐pot process leading to the formation of one C? C bond and three C? N bonds created three rings and three contiguous stereogenic centers with complete control of both the relative and absolute stereochemistry.     

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.     

Enantiocontrolled Total Synthesis of (−)‐Mersicarpine

A racemic synthesis of mersicarpine ( 1 ) was achieved by the Mizoroki–Heck reaction and a DIBALH‐mediated reductive ring‐expansion reaction. Based on a first‐generation synthesis, a second‐generation enantiocontrolled total synthesis of (?)‐mersicarpine ( 1 ) was achieved by an 8‐pot/11‐step sequence in 21 % overall yield from commercially available 2‐ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d’Angelo and Desmaële), and phenylhydrazine to modified Fischer indole conditions provided a six‐membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH‐mediated reductive ring‐expansion reaction, gradually increasing the reaction temperature and in situ‐protection of the nitrogen in an oxygen‐sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high‐yielding process. With these methodologies, the short‐step and efficient synthesis of (?)‐mersicarpine was accomplished. Several synthetic efforts are also described.     

Total Synthesis of (−)‐Enigmazole A

Total synthesis of (?)‐enigmazole A, a marine macrolide natural product with cytotoxic activity, has been accomplished. The tetrahydropyran moiety was constructed by means of a domino olefin cross‐metathesis/intramolecular oxa‐Michael addition of a δ‐hydroxy olefin. After coupling of advanced intermediates, the macrocycle was formed through gold‐catalyzed rearrangement of a propargylic benzoate, followed by ring‐closing metathesis of the resultant α,β‐unsaturated ketone.     

A Chemoenzymatic and Fully Stereocontrolled Total Synthesis of the Antibacterial Natural Product (−)‐Platencin

The natural product (?)‐platencin is a potent antibacterial agent that exerts its effects through a novel mode of action. As such, it is an important lead in the development of next‐generation antibacterials that are urgently needed because of the rapidly developing resistance to current therapies. The work reported here concerns the development of a convergent and chemoenzymatic total synthesis of (?)‐platencin by methods that should provide access to a range of biologically relevant analogues. The key step involves a thermally promoted and facially selective intramolecular Diels–Alder (IMDA) cycloaddition reaction to give an adduct that embodies the tricarbocyclic core of (?)‐platencin. This adduct was elaborated over thirteen steps to the natural product. The substrate for the IMDA reaction was prepared by Stille cross‐coupling of a Z‐configured alkenylstannane with an iodinated diene obtained in an enantiomerically pure form through the whole‐cell biotransformation of iodobenzene.     

Total Synthesis of (+)‐ and (±)‐Hosieine A

Described herein is a concise total synthesis of the highly potent nicotinic acetylcholine receptor ligand hosieine A in racemic and enantioenriched forms. The synthesis requires only seven steps and features a telescoped reaction sequence initiated by a gold‐catalyzed Rautenstrauch reaction.     

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.     

Enantioselective Total Synthesis of (−)‐Martinellic Acid

An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu‐catalyzed enantioselective alkynylation using the chiral imidazole‐based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd‐catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional‐group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date.     

Total Synthesis of (+/−)‐Frondosin B and (+/−)‐5‐epi‐Liphagal by Using a Concise (4+3) Cycloaddition Approach

A recently developed (4+3) cycloaddition between dienes and furfuryl alcohols, as precursors of oxyallyl‐type cations, has been used as a key step in the racemic syntheses of two natural products: frondosin B and liphagal. This work demonstrates the synthetic potential of this cycloaddition reaction, and offers a short synthetic route to an interesting family of natural products. A full account of these synthetic studies is presented, further illustrating the mechanism, scope, and limitations of this straightforward synthetic method for seven‐membered rings.     

Total Synthesis of (−)‐Norzoanthamine

No bones about it : (?)‐Norzoanthamine, a promising candidate for an anti‐osteoporotic drug, was the target of a total synthesis (see scheme). The final bisaminal formation with AcOH/H₂O gave the DEFG ring, while the cyclization precursor was prepared by installing the remaining bisaminal unit after oxidative cleavage of the cyclopentanol moiety.

     

Total Synthesis of (−)‐Nakadomarin A

A highly efficient 12‐step synthesis of the marine alkaloid (?)‐nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson–Khand reaction, an Overman rearrangement reaction, a ring‐closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (?)‐nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.