Illustrating the power of singlet oxygen chemistry in a synthetic context: biomimetic syntheses of litseaverticillols A-G, I and J and the structural reassignment of litseaverticillol E

Biomimetic syntheses of the litseaverticillols A-G, I and J are reported herein. The syntheses rely heavily on the application of two different modes of reaction for photochemically generated singlet oxygen, namely, the [4+2] cycloaddition of singlet oxygen (1O2) with furans and the ene reaction of 1O2 with double bonds. The highlight of these syntheses is a one-pot cascade sequence, involving five synthetic operations initiated by a [4+2] reaction, to form the fully functionalised litseaverticillol core. A series of regioselective ene reactions are then used to appositely functionalise the side chains. The synthesis of litseaverticillol E (both its originally proposed and its actual structures) allows a structural reassignment of this natural product.     

Enantioselective total synthesis of litseaverticillols A and B

[reaction: see text] The first enantioselective total synthesis of the (1R,5S)-stereoisomer of litseaverticillols A and B, anti-HIV monocyclic sesquiterpenoids isolated from a perennial shrub found in Vietnam, was accomplished in six steps from homogeranic acid by employing the Evans asymmetric aldol reaction and a microwave-promoted cyclization of a stannylated thiol ester intermediate as the C-C bond-forming steps.     

Divergent total synthesis of aspinolides B,E and J

Stereoselective total synthesis of aspinolides B, E and J, naturally occurring 10-membered lactones, were accomplished by divergent strategies starting from the commercially available 2,3-O-isopropylidene-d-ribose and methyl d-lactate. The synthesis features rapid access to the both key fragments from chiral pool and the formation of 10-membered ring lactones containing trans double bond employing cross-metathesis reaction (CM) and intramolecular Shiina macrolactonization.     

First total synthesis and structural reassignment of (-)-aplysiallene

The first total synthesis of (-)-aplysiallene has been completed in 16 steps and features a key sequential Mukaiyama aerobic oxidative cyclization to prepare the fused bis-THF core. The original stereochemical assignment has been revised as shown.     

Biomimetic total synthesis of malbrancheamide and malbrancheamide B

The biomimetic total syntheses of both malbrancheamide and malbrancheamide B are reported. The synthesis of the two monochloro species enabled the structure of malbrancheamide B to be unambiguously assigned. The syntheses each feature an intramolecular Diels-Alder reaction of a 5-hydroxypyrazin-2(1H)-one to construct the bicyclo[2.2.2]diazaoctane core, which has also been proposed as the biosynthetic route to these compounds.     

First total synthesis and reassignment of absolute configuration of diosniponol A and B

Enantioselective first total synthesis of diosniponol A and B has been achieved starting from commercially available vanillin. Wittig reaction, Keck allylation, and Prins cyclization reactions are the key steps involved in the target synthesis.     

Highly efficient biomimetic total synthesis and structural verification of bistratamides E and J from Lissoclinum bistratum

The interesting biological activities of heterocycle-containing cyclic peptide-derived natural products, isolated from marine organisms over the past twenty years, have attracted the interest of many synthetic and natural products chemists. Bistratamides E-J, members of this class of natural products that were isolated very recently from Lissoclinum bistratum, exhibited cytotoxic activity against a human colon tumor (HCT-116) cell line. Here we report the first total syntheses of bistratamides E (1) and J (2) in overall yields of 19 and 34 %, respectively. The thiazole substructures have been synthesized by oxidation of their corresponding thiazoline substructures, which were obtained from cysteine containing peptides using a novel biomimetic approach wherein Val-Cys dipeptide units were converted to thiazolines by a bisphosphonium salt. The final macrocyclization was promoted efficiently using the combination of PyBOP and DMAP. This approach allows the use of readily available Fmoc-protected amino acids to make complex thiazole and oxazoline-containing natural products.     

Enantioselective total synthesis of convolutamydines B and E

[reaction: see text] The first enantioselective total synthesis of convolutamydines B and E has been achieved using our vinylogous Mukaiyama aldol reaction. The synthesis features highly diastereoselective vinylogous Mukaiyama aldol reaction with isatin instead of aldehydes to construct a chiral center of convolutamydines. Additionally, the absolute configuration of natural convolutamydine B has been determined as R by its CD spectrum.     

The total synthesis and reassignment of stereochemistry of dragonamide

The first total synthesis of dragonamide is reported. The synthesis has led to a reassignment of the configuration at the stereogenic centre on the alkyne-bearing fragment of the molecule.     

Biomimetic total synthesis of (+)-himbacine

On treatment with trifluoroacetic acid butenolide 14 undergoes N-Boc deprotection and condensation followed by an iminium ion activated intramolecular Diels-Alder cycloaddition to give the (+)-himbacine precursor 11 on reductive work up. Compound 11 was converted into (+)-himbacine in four synthetic steps. [reaction: see text]     

Biomimetic total synthesis of (+)-gelsemine

Challenging: (+)-gelsemine was synthesized from (R,R)-aziridine 1 in 25 steps with approximately 1 % overall yield. A multistep, one-pot enol-oxonium cyclization cascade was used to construct, simultaneously, the E ring, F ring, C3 stereocenter, and C7 quaternary stereocenter. This synthesis using the enol-oxonium cyclization reaction as a key step to make the cage structure has demonstrated the proposed biosynthetic pathway of the gelsemine family.     

First total synthesis of (-)-achilleol B: reassignment of its relative stereochemistry

The first total synthesis of (-)-achilleol B was achieved using a convergent approach with a longest linear sequence of 14 steps. Three key steps were employed, including an enantioselective Robinson annelation for the construction of the bicyclic moiety. The monocyclic synthon was prepared through a Ti(III)-mediated cylization of a chiral monoepoxide obtained via asymmetric dihydroxylation of geranylacetone. The asymmetric preparation of these subunits also permitted us to achieve the enantioselective synthesis of elegansidiol, achilleol A, and farnesiferol B.     

Biomimetic total synthesis of angelicoin A and B via a palladium-catalyzed decarboxylative prenylation-aromatization sequence

Five-step total syntheses of angelicoin A and B from 2,2,6-trimethyl-4-dioxinone are reported using late stage biomimetic aromatization reactions via diketo-dioxinones as intermediates. In addition, with angelicoin A, this aromatization was coupled with a palladium-catalyzed decarboxylative prenylation in a one-pot sequence as the key step.     

Biomimetic total syntheses of cassiarins A and B

Total syntheses of cassiarins A and B have been efficiently accomplished using a common strategy with biomimetic considerations. Key reactions involved in this synthesis include a Negishi-type coupling, a Ag(I)-promoted formation of the tricyclic 8H-pyrano[2,3,4-de]chromen-8-one core, and a sequential amine-condensation and cyclization. Three new analogues of cassiarin A bearing different substituents at the C-11 position were synthesized in parallel from the same intermediate. In addition, two other transformations to the key tricyclic cores and cassiarins A and B were achieved from corresponding chemically equivalent precursors.     

Biomimetic total syntheses of flinderoles B and C

A simple and efficient biomimetic synthesis of pyrrolo[1,2-a]indoles using a highly stereo- and regioselective [3 + 2] reaction cascade was developed and then further applied in the first total synthesis of flinderoles B and C, which proceeded in 17.2% yield over the longest linear sequence of 11 steps.     

Biomimetic synthesis of elysiapyrones A and B

[reaction: see text] The total synthesis of bicyclo[4.2.0]octane natural products elysiapyrones A and B is described.     

A practical enantioselective total synthesis of the bengamides B,E, and Z

[reaction: see text] A practical total synthesis of Bengamides B, E, and Z from a common polyol intermediate is described. Consecutive aldol condensations afford a protected polyol thioester side chain suitable for coupling to the Bengamides. A novel chiral phase transfer catalyzed enantioselective alkylation affords the more highly functionalized amino caprolactams required for Bengamides B and Z. Use of the 2-naphthylmethyl ether protecting group, compatible with the boron Lewis acids required for enantioselective aldol condensation, allows direct access to Bengamide B.     

First total synthesis of the E type I phytoprostanes

The first total synthesis of two E type I phytoprostanes from furan, azelaic acid monomethyl ester and rac-1,2-epoxybutane is described. The key features of our synthetic strategy encompass an enzymatic kinetic resolution of a hydroxycyclopentenone, a Co-salen hydrolytic kinetic resolution of a terminal epoxide and a tandem conjugate addition/diastereoselective protonation sequence to construct the protected phytoprostanes. Mild cleavage of the silyl protective groups followed by enzymatic ester hydrolysis afforded the free E-type phytoprostanes.