Total synthesis of (−) verbenalol and (−) epiverbenalol

The first asymmetric synthesis of (−) verbenalol and (−) epiverbenalol, starting from the organometallic complex (−) 1, is described.     

The synthesis of (−)-cis- and (−)-trans-crobarbatic acid

The synthesis of both cis- and trans-crobarbatic acid is reported. The five-step sequence proceeds in high yield and with control of both relative and absolute stereochemistry. The key step in the synthesis is the Birch reductive alkylation of a chiral furoic acid which sets the absolute stereochemistry of the products. The stereochemistry of the compounds described was proven unambiguously by X-ray crystallography on one synthetic intermediate and on trans-crobarbatic acid.     

Electrochemical studies of (−)-epigallocatechin gallate and its interaction with DNA

In this paper, an electrochemical investigation of (−)-epigallocatechin gallate (EGCG) and its interaction with DNA is presented. Via an electrochemical approach assisted by ultraviolet–visible (UV–Vis) spectroscopy, we propose that EGCG can intercalate into DNA strands forming a nonelectroactive complex, which results in the decrease of the anodic peak current of EGCG. Meanwhile, an electrochemical study with the DNA–Cu(II)–EGCG system shows that damage to DNA can be recognized electrochemically via the increase in the anodic peak current resulting from the oxidation of guanine and adenine bases. The damage can also be recognized spectrophotometrically via an increase in the 260 nm absorption band. In addition, it was found that EGCG is able to discriminate dsDNA from ssDNA, making a potential electrochemical indicator for the detection of DNA hybridization events. A rapid and convenient method of detecting EGCG was also developed in this work. Figure Interaction of EGCG with DNA and damage to DNA in the presence of Cu(II) Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

A convenient synthesis of (+)-albicanol based on enzymatic function: total syntheses of (+)-albicanyl acetate, (−)-albicanyl 3,4-dihydroxycinnamate, (−)-drimenol, (−)-drimenin and (−)-ambrox

By using lipase ‘PL-266’ from Alcaligenes sp. enantioselective acetylation of (±)-albicanol 4 with isopropenyl acetate gave the enantiomerically pure (+)-albicanyl acetate 3 and (+)-albicanol 4. Deprotection of (+)-3 afforded the natural (+)-albicanol 4 which was converted to the natural products (−)-albicanyl 3,4-dihydroxycinnamate 7, (−)-drimenol 8, (−)-drimenin 9 and (−)-ambrox 10.     

Biogenetically-modelled total syntheses (−)-nocardicin A and (−)-nocardicin G

A protected form of L-seryl-D-(p-hydroxyphenyl)glycine was cyclized in a biogenetic sense and partially deprotected to give (−)-t-butyl 3-amino nocardicinate (5) from which (−)-nocardicin A (1) and (−)-nocardicin G (11) were prepared.     

Stereospecific Synthesis of (−)-β-Turmerone and (−)-Bisacurol

The structure of (+)-β-turmerone ((+)- 1a ), a constituent of the rhizomes of Curcuma longa Linn. , and Curcuma xanthorriza, is established as (1′R,6S)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-one by synthesis of its enantiomer (−)- 1a , and of the corresponding (1′S,6S)-diastereoisomer (+)- 1b as well. In a stereospecific seventeen-step procedure, the monoterpene diols 2a and 2b of well-established configuration are converted into the target compounds (−)- 1a and (+)- 1b , respectively. Moreover, (−)-bisacurol (−)- 3a (II), the enantiomer of another bisabolane sesquiterpene derived from Curcuma xanthorriza, is obtained as a single stereoisomer and shown to be (1′S,6R)-2-methyl-6-(4′-methylenecyclohex-2′-en-1′-yl)hept-2-en-4-ol, the relative configuration at the remaining OH-substituted chiral center C(4) still being unknown.     

Total Synthesis of (−)-Rotundone and (−)-epi-Rotundone from Monoterpene Precursors

The first total synthesis of (−)-rotundone has been accomplished from (+)-(R)-limonene and therefore for the first time from an unrelated monoterpene instead of modifying structurally closely related sesquiterpene precursors such as α-guaiene. Challenges such as intermediates with stereocenters prone to epimerization by enolization were overcome by designing a β-methyl-keto route starting from (+)-(R)-limonene which finally gave (−)-rotundone by Nazarov cyclization of a precursor 13a . Diastereomer (−)-epi-rotundone was separated from (−)-rotundone chromatographically. An alternative route from rac-citronellal provided a diastereomer mixture of racemic Nazarov precursor 13 through a TRIP-catalyzed intramolecular aldolization, thus indicating that the Nazarov cyclization precursor 13a is in principle accessible from (−)-(S)-citronellal. The 11-step synthesis from (+)-(R)-limonene with ca. 1 % overall yield confirmed the absolute configuration of (−)-rotundone and provided samples of good olfactory quality.     

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)-Trinervine,Vellosimine, (+)-Normacusine B,and (−)-Alstomutinine C

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)-trinervine, (+)-vellosimine, (+)-normacusine B, and (−)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)-alstomutinine C.     

Enantioselective access to (−)-indolizidines 167B, 209D, 239AB, 195B and (−)-monomorine from a common chiral synthon

An enantioselective access to (?)-indolizidine alkaloids 167B, 209D, 239AB, 195B and (?)-monomorine from a new chiral synthon is described. The use of (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy)butanal, obtained from l-aspartic acid, has provided efficient access of the indolizidine frame work through a Horner–Wadsworth–Emmons reaction and reductive cyclization as the key steps.     

Expedient syntheses of indolizidines (−)-167B and (−)-209D

Indolizidine alkaloids (−)-167B and (−)-209D were synthesized via an expedient route using hydroacylation and amination.     

Synthesis and some transformations of (−)-carveol

Reduction of the oxo group in (?)-carvone with LiAlH₄, NaBH₄, and (i-Bu)₂AlH was performed. It was found that the reduction with the system CeCl₃ · 7 H₂O-NaBH₄ in methanol at 20°C is the most practical procedure for the synthesis of (?)-carveol. Solvolysis of (?)-carvyl methanesulfonate gave products of S_N2 and S_N2′ replacement of the methylsulfonyloxy group, the latter slightly prevailing. Overman rearrangement of (?)-carveol resulted in the formation of the corresponding trichloroacetamide derivative, and intramolecular iodoetherification of the title compound afforded 6-iodomethyl-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-ene.     

Enantioselective Synthesis and Racemization of (−)-Sinoracutine

Sinoracutine is a recently isolated alkaloid with unusual stereochemical and biological properties. It features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to a cyclopentenone. Interestingly, both enantiomers of sinoracutine have been independently isolated from the same plant, yet the molecule does not appear to occur as a racemate. Here, we present a short synthesis of (−)-sinoracutine that relies on a highly diastereoselective Pauson–Khand reaction and a Mandai–Claisen reaction to install the quaternary stereocenter. Our work establishes the absolute configuration of the levorotatory isomer and suggests that the optical purity of sinoracutine varies in nature due to its gradual racemization. Experimental evidence supports this proposal, and a plausible mechanism for the racemization is provided.     

Total syntheses of macrosphelides (+)-A, (−)-A and (+)-E

Total syntheses of (+)-macrosphelide A 1 (18.5% overall yield in 11 steps) and (+)-macrosphelide E 2 (23.9% overall yield in 11 steps) have been achieved via the chemoenzymatic reaction product (4R,5S)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4. The enantiomer (−)-A (1) (14.2% overall yield in 11 steps) of (+)-1 was also synthesized from the chemoenzymatic reaction product (4S,5R)-4-benzyloxy-5-hydroxy-2(E)-hexenoate 4.     

Total Syntheses of (−)-Minovincine and (−)-Aspidofractinine through a Sequence of Cascade Reactions

We report 8-step syntheses of (−)-minovincine and (−)-aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta- and hexacyclic frameworks. These cascade transformations included organocatalytic Michael-aldol condensation, a multistep anionic Michael-S_N2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo- and regioselective transformations.     

Unified Asymmetric Total Syntheses of (−)-Alotaketals A–D and (−)-Phorbaketal A

The novel tricyclic spiroketal alotane-type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)-alotaketals A–D and (−)-phorbaketal A were accomplished [29–31 steps from (−)-malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ-keto-alcohols to forge the common tricyclic spiroketal intermediate, 2) a late-stage allylic C−H oxidation, and 3) olefin cross-metathesis to install the different side chains.     

An efficient stereocontrolled synthesis of (−)-10-epi-5β,11-dihydroxyeudesmane and (−)-4,10-epi-5β,11-dihydroxyeudesmane

A concise and efficient synthesis of (−)-10-epi-5β,11-dihydroxyeudesmane 1 and (−)-4,10-epi-5β,11-dihydroxyeudesmane 2, via (−)-10-epi-γ-eudesmol 5, was accomplished starting from (+)-dihydrocarvone. The salient feature of our synthesis is the utilization of substrate-directable epoxidation and homogeneous hydrogenation to control the stereochemistry at the C-4 and C-5 positions of the title compounds.     

Total synthesis and cytotoxicity of (−)-jorumycin and its analogues

(?)-Jorumycin and its 15 C-22 analogues were prepared employing l-tyrosine as the chiral starting material via 21 steps. These analogues, along with (?)-jorumycin itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, Ketr3, A2780, MCF-7, A549, BGC-823, Hela, HELF, and KB cells. The IC₅₀ values of the cytotoxicity of most of these analogs were at the level of nM, which was similar to that of (?)-jorumycin. Among these analogs including (?)-jorumycin, hippuric acid ester derivative 23 exhibited the most potent and broad-spectrum cytotoxic activity against the ten cell lines with an average IC₅₀ of 2.12 nM.     

Chiral Pyrrolidinium Ionic Liquids with (−)-Borneol Fragment in the Cation – Synthesis,Physicochemical Properties and Application in Diels-Alder Reaction

A series of chiral pyrrolidinium salts containing (1 S)-endo-(−)-born-2-yloxymethyl substituent in the structure of the cation and six different anions: chloride, tetrafluoroborate [BF₄]⁻, hexafluorophosphate [PF₆]⁻, trifluoromethanesulfonate [OTf]⁻, bis(trifluoromethylsulfonyl)imide [NTf₂]⁻, bis(pentafluoroethylsulfonyl)imide [NPf₂]⁻ and perfluorobutanesulfonate [C₄FS]⁻ were efficiently prepared and extensively characterized. The enantiomeric purity of them was confirmed by NMR analysis with a chemical shift reagent. All salts were characterized with the specific rotation, the solubility in commonly used solvents, thermal properties, including phase transition temperatures and thermal stability. Salts with [PF₆]⁻, [C₄FS]⁻, [NTf₂]⁻ and [NPf₂]⁻ anions were classified as chiral ionic liquids (CILs). Moreover, salts with [NTf₂]⁻ and [NPf₂]⁻ anions were in the liquid state at room temperature and below. Therefore, density and dynamic viscosity, the surface tension and the contact angle on three different surfaces were also measured for them. Additionally, these chiral ionic liquids were tested as solvents in Diels-Alder reaction.     

Synthesis of (+)- and (−)-Phaselic Acid

The syntheses of both enantiomers of phaselic acid (2-O-caffeoylmalate) are described. The previously unreported acetate-protected caffeic acid anhydride was used with appropriately protected malic acid derivatives as coupling partners to provide fully protected phaselic acid. Sequential unmasking of the protecting groups afforded phaselic acid in an acceptable overall yield.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Inclusion complex of (−)-linalool and β-cyclodextrin

(?)-Linalool is a monoterpene alcohol which is present in the essential oils of several aromatic plants. Recent studies suggest that (?)-linalool has antimicrobial, anti-inflammatory, anticancer, antioxidant, and antinociceptive properties in different animal models. The aim of this study was to prepare and characterize inclusion complexes of (?)-linalool with β-cyclodextrin (β-CD). Equimolar binary (?)-linalool/β-CD systems were prepared by physical mixture, paste (PM), and slurry methods (SC) and characterized by differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy, X-ray diffractometry, Karl Fisher titration, and scanning electron microscopy. Thermal characterization indicates the occurrence of complexation, mainly in paste complexes, which is present in the interval from 140 to 280 °C a gradual mass loss (4.6 %), probably related to (?)-linalool loss. FT-IR spectra showed changes that may be related to the formation of intermolecular hydrogen bonds between (?)-linalool and β-CD. The new solid-phase formed using the PM and SC methods, had a crystal structure which was different from the original morphology of β-CD.