Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28

A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28 fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22 fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-butyne-1,4-diol and cis-2-butene-1,4-diol respectively.     

Production and Characterization of Iturinic Lipopeptides as Antifungal Agents and Biosurfactants Produced by a Marine Pinctada martensii-Derived Bacillus mojavensis B0621A

Bacillus mojavensis B0621A was isolated from a pearl oyster Pinctada martensii collected from South China Sea. While screening for cyclic lipopeptides potentially useful as lead compounds for biological control against soil-bone fungal plant pathogens, three lipopeptides were isolated and purified from the fermentation broth of B. mojavensis B0621A via vacuum flash chromatography coupled with reversed-phase high performance liquid chromatography (RP-HPLC). The structural characterization and identification of these cyclic lipopeptides were performed by tandem mass spectrometry (MS/MS) combined with gas chromatography-mass spectrometry (GC-MS) analysis as well as chemical degradation. These lipopeptides were finally characterized as homologues of mojavensins, which contained identical amino acids back bones of asparagine₁, tyrosine₂, asparagine₃, glutamine₄, proline₅, asparagine₆, and asparagine₇ and differed from each other by their saturated β-amino fatty acid chain residues, namely, iso-C14 mojavensin, iso-C16 mojavensin, and anteiso-C17 mojavensin, respectively. All lipopeptide isomers, especially iso-C16 mojavensin and anteiso-C17 mojavensin, displayed moderate antagonism and dose-dependent activity against several formae speciales of Fusarium oxysporum and presented surface tension activities. These properties demonstrated that the lipopeptides produced by B. mojavensis B0621A may be useful as biological control agent to fungal plant pathogens.     

Synthesis of the C9-C29 fragments of ajudazols A and B

The syntheses of both C9-C29 fragments 3 and 4 of the myxobacteria metabolites ajudazols A (1) and B (2) are described. The key steps were a cyclodehydration to form the oxazole, Sonogashira coupling to form the C18-C19 bond and a P-2 Ni mediated partial alkyne hydrogenation to install the C17-C18 Z-alkene. The C15 alkene in the ajudazol A fragment 3 was introduced in the final steps by elimination of the corresponding primary alcohol.     

Synthesis of a highly fluorinated fatty acid analog

A five-step synthesis of Z-11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,18-heptadecafluoro-octadec-8-enoic acid is reported, starting from 1,8-octanediol and 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-10-iododecane. The key step is a Wittig reaction to form the C8-C9 double bond with a Z:E isomeric ratio of 10:1. The route should be generally applicable to the synthesis of highly fluorinated monounsaturated fatty acids.     

Application of stereocontrolled aldol coupling to synthesis of segments of immunosuppressants FK-506 and rapamycin

The sector comprising C24-C34 of FK-506 containing five of the stereogenic centers in this macrolide was synthesized from (−)-quinic acid. Aldol coupling of the C24-C34 unit with a methyl ketone representing C20-C23 of FK-506 proceeded with complete Felkin stereoselectivity to afford the C20-C34 portion of the immunosuppressant. A chelate transition state invoking coordination of a lithium enolate with a trityl ether is proposed to explain this stereoselectivity. The strategy adopted for construction of the C26-C34 moiety of FK-506 was extended to the C34-C42 subunit of rapamycin. A Mukaiyama asymmetric anti-aldol coupling was used to set in place the vicinal diol functionality at C27,28 in the C26-C33 segment of this macrolide.     

Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.     

Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin

The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction of the aglycon provided aurisides A and B.     

Stereoselective synthesis of the C1-C20 segment of the microsclerodermins A and B

An enantioselective route for the synthesis of key fragment C1-C20 resident in microsclerodermins A and B is described. The route features deoxygenative rearrangement of an hydroxy-alkynoate and a highly enantio- and diastereo-controled iterative dihydroxylation as key reactions, starting from S-(−)-citronellol.     

Improved synthesis of the polyhydroxylated central part of phoslactomycin B

A new approach to the C(7)-C(13) intermediate for the synthesis of phoslactomycin B was investigated. Asymmetric dihydroxylation of the β,γ-unsaturated ester proceeded cleanly to afford the β-hydroxyl-γ-lactone with 97.6% ee, which upon protection as the PMB ether followed by hydride reduction furnished a diol. After selective protection of the prim-OH, oxidation of the sec-OH and chelation-controlled addition of CH₂CHMgBr afforded the C(7)-C(11) segment. Later on, the C(11) stereocentre was constructed by the asymmetric transfer hydrogenation using the Noyori catalyst.     

Symbiodinolide, a novel polyol macrolide that activates N-type Ca channel, from the symbiotic marine dinoflagellate Symbiodinium sp.

A 62-membered novel polyol macrolide with a molecular weight of 2859 mu, symbiodinolide, was isolated from the symbiotic dinoflagellate Symbiodinium sp. Symbiodinolide exhibited a potent voltage-dependent N-type Ca²⁺ channel-opening activity at 7 nM and immediately ruptured the tissue surface of the acoel flatworm Amphiscolops sp. at 2.5 μM. The planar structure of symbiodinolide was elucidated by spectroscopic analysis and chemical degradations including hydrolysis and ethenolysis using the second-generation Grubbs' catalyst. Symbiodinolide was found to be a structural congener of zooxanthellatoxins. The relative stereochemistries of C26-C32, C44-C51, and C64-C66 parts, and the absolute stereochemistries of C69-73, C83-C103, and C3′-C18′ parts in symbiodinolide were established.     

Total synthesis of rutamycin B and oligomycin C

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.     

Synthetic studies toward miroestrols: trials for elongation of the methyl group of 5-substituted 2-methyl-2-cyclohexanone to 3-methyl-2-butenyl function

Toward total synthesis of miroestrols (miroestrol and deoxymiroestrol), 3-methyl-2-butenyl function (endo-C5 unit) on D ring as a carbon chain for C and E rings was prepared by elongation of the methyl group in α-methyl-α,β-unsaturated ketone unit, and 3,5-dinitrobenzoyl group was introduced as a potential leaving group for the construction of B ring. The former was accomplished through a sequence of epoxide ring-opening, microwave-irradiated siloxy-Cope rearrangement, and isomerization of 3-methyl-3-butenyl function (exo-C5 unit) to endo-C5 unit.     

Towards a simplified peloruside A: synthesis of C1-C11 of a dihydropyran analogue

A simplified analogue of the C1-C11 fragment of peloruside A has been synthesised starting from a monoprotected 2,2-dimethylpropane-1,3-diol. Oxidation, asymmetric allylation and acryloylation provided a substrate for ring-closing metathesis to a δ-lactone. Reduction, acylation and homologation with trimethyl(vinyloxy)silane provided a protected C3-C11 analogue in a stereoisomer manner. Introduction of the C1-C2 fragment and incorporation of the 2,3-syn stereochemistry was achieved by a boron-mediated Evans aldol reaction.     

Sequosempervirin A, a novel spirocyclic compound from Sequoia sempervirens

A novel spirocyclic compound (4R)-4-(4-hydroxy-benzyl) spiro [4,5] dec-1-en-8-ol (sequosempervirin A) was isolated from the branches and leaves of Sequoia sempervirens. Its structure and relative stereochemistry were mainly determined by MS, 2D NMR and X-ray means, which is the first naturally occurring norlignan containing one spirocycle with C6 (cyclohexane)-C2-C3-C6 skeleton.     

A joint study based on the electron localization function and catastrophe theory of the chameleonic and centauric models for the Cope rearrangement of 1,5-hexadiene and its cyano derivatives

A novel interpretation of the chameleonic and centauric models for the Cope rearrangements of 1,5-hexadiene (A) and different cyano derivatives (B: 2,5-dicyano, C: 1,3,4,6-tetracyano, and D: 1,3,5-tricyano) is presented by using the topological analysis of the electron localization function (ELF) and Thom's catastrophe theory (CT) on the reaction paths calculated at the B3LYP/6-31G(d,p) level. The progress of the reaction is monitorized by the changes of the ELF structural stability domains (SSD), each being change controlled by a turning point derived from CT. The reaction mechanism of the parent reaction A is characterized by nine ELF SSDs. All processes occur in the vicinity of the transition structure and corresponding to a concerted formation/breaking of C(1)-C(6) and C(3)-C(4) bonds, respectively, together with an accumulation of charge density onto C(2) and C(5) atoms. Reaction B presents the same number of ELF SSDs as A, but a different order appears; the presence of 2,5-dicyano substituents favors the formation of C(1)-C(6) bonds over the breaking of C(3)-C(4) bond process, changing the reaction mechanism from a concerted towards a stepwise, via a cyclohexane biradical intermediate. On the other side, reaction C presents the same type of turning points but two ELF SSD less than A or B; there is an enhancement of the C(3)-C(4) bond breaking process at an earlier stage of the reaction by delocalizing the electrons from the C(3)-C(4) bond among the cyano groups. In the case of competitive effects of cyano subsituents on each moiety, as it is for reaction D, seven different ELF SSDs have been identified separated by eight turning points (two of them occur simultaneously). Both processes, formation/breaking of C(1)-C(6) and C(3)-C(4) bonds, are slightly favored with respect to the parent reaction (A), and the TS presents mixed electronic features of both B and C. The employed methodology provides theoretical support for the centauric nature (half-allyl, half-radical) for the TS of D.     

Toward the synthesis of norzoanthamine: complete fragment assembly

The complex marine alkaloid norzoanthamine (2) was envisioned to be assembled from three key building blocks: the C1-C5 fragment A, the C6-C10 fragment B, and the C11-C24 fragment C. The synthesis of fragment A was achieved in 14 steps and 33% overall yield from (R)-gamma-hydroxymethyl-gamma-butyrolactone. Fragment B was made in two steps from PMB-protected 4-pentynol in 76% yield. The C11-C24 fragment C was made from (S)-carvone via (R)-isocarvone in 18 steps (6% overall yield). The convergent stereoselective synthesis of the entire carbon framework (C1-C24) of the target molecule was achieved via the following assemblage. Alkenyl iodide 20 derived from the C11-C24 fragment C was coupled to fragment B (C6-C10) through a high-yielding Stille coupling reaction of these two sterically very demanding coupling partners, affording the key Diels-Alder precursor 24. The intramolecular Diels-Alder reaction proceeded smoothly in excellent yield and diastereoselectivity, generating the tricyclic trans-anti-trans perhydrophenanthrene motif of norzoanthamine (C6-C24). The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product.     

Synthetic studies of carzinophilin. Part 2: Synthesis of 3,4-dibenzyloxy-2-methylidene-1-azabicyclo[3.1.0]hexane systems corresponding to the C1-C17 fragment of carzinophilin

A model compound bearing the C1-C17 fragment of carzinophilin was synthesized. The synthesis involved coupling reaction of a cyclic thioimidate with the 4H-oxazol-5-one derivative, ring-opening of the 4H-oxazol-5-one to furnish a dehydropeptide system, elaboration of the C1-C6 enolamide, and construction of the aziridine ring as key steps.     

Synthesis of the C12-C24 fragment of peloruside A by silyl-tethered diastereomer-discriminating RCM

The C12-C24 fragment of peloruside A has been synthesized using, as a key step, a silyl-tethered ring closing metathesis reaction to form the C16-C17 (Z)-alkene. The metathesis reaction discriminates between diastereoisomers of the starting material. A diphenylsilyl bis-ether provides simultaneous protection for the C15 and C24 hydroxyl groups, and is expected to lead to high 1,5-anti selectivity in subsequent aldol reactions of the methyl ketone, allowing for a convergent stereoselective synthesis of peloruside A.     

Total synthesis of phorboxazole a. 1. Preparation of four subunits

[Structure: see text] Four subunits of the potent antitumor agent phorboxazole A were constructed; fragments C20-C32 and C9-C19 containing tetrahydropyrans A and B, respectively, were assembled using palladium-catalyzed intramolecular alkoxycarbonylation.     

Synthesis of the C8-C20 and C21-C30 segments of pectenotoxin 2

In this study, we synthesized the C8-C20 and C21-C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8-C20 segment was assembled from a phosphonate corresponding to the C8-C15 segment (prepared from l-malic acid in 19 steps) and an aldehyde corresponding to the C16-C20 segment (synthesized from 3-methyl-3-butenol in nine steps) by a twelve-step process including the Horner-Wadsworth-Emmons reaction, regio- and stereoselective reduction of the resulting enone, diastereoselective epoxidation, and 5-exo epoxide cleavage forming the C-ring. The C21-C30 segment was constructed in 13 steps from (S)-glycidol via a route involving E-ring formation by 5-exo epoxide cleavage and stereoselective methylation at C27 by the Evans method.