Total synthesis of diastereomeric marine butenolides possessing a syn-aldol subunit at C10 and C11 and the related C11-ketone

Two diastereomeric marine butenolides, (4S,10R,11R)- and (4S,10S,11S)-4,11-dihydroxy-10-methyldodec-2-en-1,4-olide, possessing a syn-aldol subunit at C10 and C11 have been efficiently synthesized by using a three-module coupling strategy. The enantiomeric syn-aldol modules prepared by the syn-selective aldol reaction of the norephedrine-derived chiral propionates were coupled with the chiral C3-C7 module via 1,3-dithiane bisalkylation. The butenolide ring was then installed via a high-yielding ring-closing metathesis (RCM) reaction. Oxidation of the diastereomeric C11-alcohols furnished the corresponding C11-ketones, which are produced by the same marine microorganism.     

Synthesis of C18–C28 ketone fragment of micromonospolide B possessing 1,3-diene and 1,3-anti-diol functionalities

A highly stereocontrolled synthesis of the C18–C28 ketone fragment of the 16-membered plecomacrolide micromonospolide B has been accomplished. The C21–C23 syn–anti stereotriad is secured by the anti-selective aldol condensation of the ephedrine-derived chiral propionate with (E,E)-hexa-2,4-dienal and Sharpless asymmetric allylic epoxidation–regioselective reductive epoxide ring opening, respectively. The overall yield of this 14-step sequence is 18.4% and the target C18–C28 ketone was obtained in enantiomerically pure form.     

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.     

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.     

Stepwise and one-pot cross-coupling-heteroannulation approaches toward 2-substituted C5-, C6-, and C7-nitroindoles

A general and efficient synthesis of 2-substituted C5-, C6-, and C7-nitroindoles has been established. Starting from commercially available 2-amino nitrophenols, C5-, C6-, and C7-nitroindoles were synthesized via the stepwise Pd-catalyzed cross-coupling of nitro 2-trifloxyanilides with 1-alkynes followed by the t-BuOK-mediated heteroannulation. A Pd-catalyzed one-pot coupling-heteroannulation procedure was carried out by using nitro 2-trifluoroacetamidoaryl triflates.     

Synthesis of C1–C11 eribulin fragment and its diastereomeric analogues

A practical stereoselective synthesis of the central C1–C10 fragment of eribulin and its two diastereomeric analogues is developed. Our approach relied on the use of l-ascorbic acid as the starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having several required hydroxyl groups was then obtained. In a number of steps, the lactone was converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled intramolecular oxa-Michael reaction completed the synthesis of the C1–11 fragment having a trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in eribulin.     

Synthesis of the C22-C37 segment of prorocentin

The synthesis of the C22-C37 segment of prorocentin, isolated from the dinoflagellate Prorocentrum lima, was achieved. Because the relative stereochemical relationship between C26 and other stereocenters (C28/C31/C32 established as R*/R*/R*) in the C22-C37 region of natural prorocentin has not yet been determined, both epimers at C26 of the C22-C37 segment were selectively constructed. The synthesis was based on a 5-exo epoxide ring opening reaction to form an oxolane (E-ring), Brown asymmetric methallylation to install the C26-stereocenter, acryloylation of the resulting alcohol, and ring-closing olefin metathesis to establish the Z-olefin at C23/C24.     

Determination of absolute configuration of C14−C23 fragment in symbiodinolide

The degradation product C14−C23 2 was obtained using ethenolysis with the 2nd-generation Hoveyda-Grubbs catalyst from 62-membered lactone in symbiodinolide (1). The absolute configurations of three chiral centers in fragment 2 were assigned as 17R, 18R, and 21R by a combination of J-based configuration analysis and the Mosher-Riguera method.     

IRMS detection of testosterone manipulated with C labeled standards in human urine by removing the labeled C

Isotope ratio mass spectrometry (IRMS) is applied to confirm testosterone (T) abuse by determining the carbon isotope ratios (δ¹³C value). However, ¹³C labeled standards can be used to control the δ¹³C value and produce manipulated T which cannot be detected by the current method. A method was explored to remove the ¹³C labeled atom at C-3 from the molecule of androsterone (Andro), the metabolite of T in urine, to produce the resultant (A-nor-5α-androstane-2,17-dione, ANAD). The difference in δ¹³C values between Andro and ANAD (Δδ¹³C_Andro–ANAD, ‰) would change significantly in case manipulated T is abused. Twenty-one volunteers administered T manipulated with different ¹³C labeled standards. The collected urine samples were analyzed with the established method, and the maximum value of Δδ¹³C_Andro–ANAD post ingestion ranged from 3.0‰ to 8.8‰. Based on the population reference, the cut-off value of Δδ¹³C_Andro–ANAD for positive result was suggested as 1.2‰. The developed method could be used to detect T manipulated with 3-¹³C labeled standards.     

Reaction of MeO2C(H)C=C=C(H)CO2Me with Ru3(CO)12. New diruthenium complexes with bridging carboxylate-substituted allene ligands

The reaction of Ru₃(CO)₁₂ with MeO₂C(H)C=C=C(H)CO₂ Me has yielded two isomeric productsanti-Ru₂(CO)₆[μ-η ³-η ¹-MeO₂C(H)CCC(H)CO₂Me],1 in 70% yield andsyn-Ru₂(CO)₆[μ-η ³-η ¹-MeO₂C(H)CCC(H)CO₂Me],2 in 5% yield. Both compounds were characterized by single crystal X-ray diffraction analysis. Both products are diruthenium complexes with bridging di(carboxylate)allene ligands in which the oxygen atom of the carbonyl group of one of the carboxylate groupings is coordinated to one of the metal atoms. Compound1 isomerizes partially to2 at 68°C. Crystal Data for1: space group=P2₁/n,a=11.131(1) Å,b=10.228(2) Å,c=15.978(2) Å,β=102.01(1)°,Z=4, 1653 reflections,R=0.025; for2: space group=P $\bar 1$ ,a=9.340(1) Å,b=14.925(4) Å,c=6.778(2) Å,α=99-02(2)°,β=104 62(2)°,γ=94.58(2)°,Z=2, 1857 reflections,R=0.027.     

Assignment of C NMR spectrum for blepharismin C based on biosynthetic studies

Blepharismins, toxic pigments of the ciliate Blepharisma japonicum, are polycyclic ring-condensed compounds. Assignment of ¹³C NMR signals for blepharismin C, a major constituent of blepharismins, was achieved by analyses of the HMQC, HMBC, and INADEQUATE spectra of ¹³C-enriched samples obtained by feeding experiments using sodium [1-¹³C], [2-¹³C], and [1,2-¹³C₂]acetates.     

Concise synthesis of AHMHA unit in perthamide C. Structural and stereochemical revision of perthamide C

Diastereomers of 3-amino-2-hydroxy-6-methylheptanoic acid (AHMHA), a new amino acid unit in perthamides C and D, have been synthesized from commercially available 4-methylpentanol in a concise manner and 50% average overall yield. Comparison of the ¹H and ¹³C NMR data, optical rotation data and Marfey’s analysis of the resulting isomers with the natural fragment unambiguously allowed the configurational assignment of the natural residue as (2R,3R). A structural revision of perthamides C and D is also reported.     

Synthesis of (+)-agelasine C. A structural revision

An efficient synthesis of (+)-agelasine C has been achieved from ent-halimic acid. The structure and absolute configuration of the natural product (−)-agelasine C was established and a structure for epi-agelasine C, is proposed.     

Pulsed fourier transform NMR of substituted aryltrimethyltin derivatives : II. (119Sn-13C) coupling constants and 13C chemical shifts of meta- and para-derivatives

Carbon-13 NMR data are reported for thirteen para- and meta-substituted phenyltrimethyltin compounds, RC₆H₄Sn(CH₃)₃, where R = para-N(CH₃)₂, para-OCH₃, para-OC₂H₅, para-CH₃, meta-CH₃, -H, para-F, meta-OCH₃, para-Cl, para-Br, meta-F, meta-Cl and para-Sn(CH₃)₃. In the para-derivatives, correlation coefficients with Hammet σ-constants of greater than ca. 0.9 are obtained with the tin-carbon couplings to methyl, C₁ and C₄ carbons, and with the carbon-13 chemical shifts δ(C(1)). In the meta-derivatives, the couplings |J(Sn-CH₃)|:, |:J(Sn-C(1))|:, |:J(Sn-C(3))|: and |:J(Sn-C(6))|:, and the shifts δ(C(1)) and δ(C(5)) correlate well with Hammett σ. In the para-derivatives, sensitivity to change in substituent falls off C(4) > C(3, 5) > C(1) > C(2, 6) > CH₃ as registered by the δ(C), while in the meta-derivatives δ(C) changes decrease C(3) > C(2), C(4) > C(1) > C(5), C(6) > CH₃. The magnitudes of the tin coupling constants decrease C(1) > CH₃ > C(3, 5) > C(2, 6) > C(4) in the para-derivatives, while in the meta-series the order is C(1) > CH₃ > C(3), C(5) > C(2) > C(6) > C(4). The two sets of one-bond |:J(Sn-CH₃)|: and |:J(Sn-C(1)|: values correspond closely to the 0.25/0.33 ratio of coefficients in the LCAO approach, and are interpreted in terms of s-electron redistributions at the tin atom with change in substituent.     

Site-specific C content by quantitative isotopic C Nuclear Magnetic Resonance spectrometry: A pilot inter-laboratory study

Isotopic ¹³C NMR spectrometry, which is able to measure intra-molecular ¹³C composition, is of emerging demand because of the new information provided by the ¹³C site-specific content of a given molecule. A systematic evaluation of instrumental behaviour is of importance to envisage isotopic ¹³C NMR as a routine tool. This paper describes the first collaborative study of intra-molecular ¹³C composition by NMR. The main goals of the ring test were to establish intra- and inter-variability of the spectrometer response. Eight instruments with different configuration were retained for the exercise on the basis of a qualification test. Reproducibility at the natural abundance of isotopic ¹³C NMR was then assessed on vanillin from three different origins associated with specific δ¹³C_i profiles. The standard deviation was, on average, between 0.9 and 1.2‰ for intra-variability. The highest standard deviation for inter-variability was 2.1‰. This is significantly higher than the internal precision but could be considered good in respect of a first ring test on a new analytical method. The standard deviation of δ¹³C_i in vanillin was not homogeneous over the eight carbons, with no trend either for the carbon position or for the configuration of the spectrometer. However, since the repeatability for each instrument was satisfactory, correction factors for each carbon in vanillin could be calculated to harmonize the results.     

Structural and electrocatalytic properties of Pt/C and Pt-Ni/C catalysts prepared by electrochemical dispersion

The structural and electrocatalytic properties of Pt/C and Pt-Ni/C catalysts prepared by the electrochemical dispersion of metals under the action of pulse alternating current in a solution of NaOH were studied. Using X-ray diffraction analysis and scanning and transmission electron microscopy, it was found that the synthesized Pt/C catalysts contained active constituent particles with the average size D ₁₁₁ = 10.6 nm with a predominantly cubic shape. Upon the dispersion of a Pt₃Ni alloy, the Pt-Ni/C catalyst containing the particles of a stoichiometric metal phase of Pt₃Ni (D ₁₁₁ = 9.6 nm) and also Pt _x Ni particles (x > 3) enriched in platinum (D ₁₁₁ = 8.1 nm). The synthesized catalysts possessed high electrocatalytic activity and stability in the reaction of methanol oxidation. The characteristics of these catalysts as anodes in the membrane-electronic unit of a hydrogen-air solid-polymer fuel cell were studied.     

Electro-optic effects in smectic C liquid crystals

Electro-optic effects are observed in the smectic C states of 4-n-heptyloxybenzoic acid, 4-n-octyloxybenzoic acid. 4,4′-bis-n-heptyloxyazoxybenzene, and 4-n-decyloxy cinnamic acid under the application of an external ac electric field. The stripe domain pattern is observed for all the compounds studied above the first threshold. In the smectic C state there exists a second threshold at which the direction of the domain lines changes.     

Synthetic studies on amphidinolides C and F: synthesis of the C18-C29 segment of amphidinolide F

The C18-C29 segment of amphidinolide F is synthesised in 12 steps from 1,4-butanediol. Key steps include a mono-Sharpless dihydroxylation of a dienoate, iodocyclisation to construct the trans-THF ring and an E-selective Wittig reaction to introduce the C25-C26 olefin.     

C,C- and C,N-Chelated Organocopper Compounds

Copper-catalyzed and organocopper-involved reactions are of great significance in organic synthesis. To have a deep understanding of the reaction mechanisms, the structural characterizations of organocopper intermediates become indispensable. Meanwhile, the structure-function relationship of organocopper compounds could advance the rational design and development of new Cu-based reactions and organocopper reagents. Compared to the mono-carbonic ligand, the C,N- and C,C-bidentate ligands better stabilize unstable organocopper compounds. Bidentate ligands can chelate to the same copper atom via η²-mode, forming a mono-cupra-cyclic compounds with at least one acute C-Cu-C angle. When the bidentate ligands bind to two copper atoms via η¹-mode at each coordinating site, the bimetallic macrocyclic compounds will form nearly linear C-Cu-C angles. The anionic coordinating sites of the bidentate ligand can also bridge two metals via μ₂-mode, forming organocopper aggregates with Cu-Cu interactions and organocuprates with contact ion pair structures. The reaction chemistry of some selected organocopper compounds is highlighted, showing their unique structure–reactivity relationships.     

Total synthesis of (+)-blennolide C and (+)-gonytolide C via spirochromanone

We report the asymmetric total synthesis of (+)-blennolide C and (+)-gonytolide C isolated from endophytic fungi. The synthesis involved construction of a spirochromanone with a chiral quaternary carbon by the aldol reaction of o-hydroxyacetophenones and optically active α-oxygenated cyclohexenone, followed by cyclization under acidic conditions. Oxidative cleavage of the alkene moiety of the spirochromanone furnished the chromanone diester. Through treating the diester with a Lewis acid, the first total synthesis of (+)-blennolide C was achieved by deprotecting the oxygen functionality of the diester and simultaneous Dieckmann condensation. Total synthesis of (+)-gonytolide C was also achieved by lactone formation from the deprotected diester.