Total synthesis of the tricyclic marine alkaloids (-)-lepadiformine, (+)-cylindricine c, and (-)-fasicularin via a common intermediate formed by formic acid-induced intramolecular conjugate azaspirocyclization

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).     

Microfluidic reactions using [11C]carbon monoxide solutions for the synthesis of a positron emission tomography radiotracer

Microfluidic technology has been used to perform [(11)C]carbonylation reactions using solutions containing [(11)C]CO in the form of the complex, copper(i)tris(3,5-dimethylpyrazolyl)borate-[(11)C]carbonyl (Cu(Tp*)[(11)C]CO). The synthesis of the model compound [(11)C]N-benzylbenzamide and the known tracer molecule [(11)C]trans-N-[5-(2-flurophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofurane-1(3H),1'-cyclohexane]-4'-carboxamide ([(11)C]MK-0233), a ligand for the neuropeptide Y Y5 receptor, have been performed using this technique. Following semi-preparative HPLC purification and reformulation, 1262 ± 113 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 30 GBq μmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.2 ± 0.7%. Using a 3 mL vial as the reaction vessel, and following semi-preparative HPLC purification and reformulation, 1255 ± 392 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 15 GBq μmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.1 ± 2.2%.     

Synthesis of 11C-labelled N,N'-diphenylurea and ethyl phenylcarbamate by a rhodium-promoted carbonylation via [11C]isocyanatobenzene using phenyl azide and [11C]carbon monoxide

The reaction with phenyl azide and [11C]carbon monoxide to give N,N'-diphenyl[11C]urea and ethyl phenyl[11C]carbamate has been studied with the aim of development of a new methodology for carbonylation using [11C]carbon monoxide with high specific radioactivity. The synthesis of 11C-labelled N,N'-diphenylurea from phenyl azide and [11C]carbon monoxide, with 1,2-bis(diphenylphosphino)ethane-bound Rh(I) complex at 120 degrees C at a pressure of 35 MPa in the presence of aniline was accomplished in 82% trapping efficiency and 82% conversion yield. This approach was also useful for the synthesis of ethyl phenyl[11C]carbamate with lithium ethoxide as a nucleophilic reagent giving 90% trapping efficiency and 76% conversion yield. These reactions can be considered to proceed via a [11C]isocyanate or a [11C]isocyanate-coordinated Rh complex to give the corresponding 11C-products. This protocol provides the chemical basis for the synthesis of [11C]urea and [11C]carbamate derived from [11C]isocyanates.     

Total synthesis of (-)-indolactam V

The total synthesis of protein kinase C activator (-)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from L-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized from l-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using HATU in THF in good yield.     

Sonochemical synthesis of fluorescent 1,4-disubstituted triazoles using l-phenylalanine as an accelerator ligand in aqueous media

A green sonochemical protocol using l-phenylalanine as a water soluble promotor ligand has been developed for the regioselective synthesis of fluorogenic 1,4-disubstituted triazoles (3a-o) via well-known click reaction at 40?°C. l-Phenylalanine is a biocompatible, economical, commercially available and non-toxic ligand which not only serves to stabilize Cu(I) oxidation state but also prevents its disproportion to enhances and modulate the rate of reaction. The designed catalytic system exhibits broad substrate compatibility and can be recycled up to 5 cycles without appreciable loss in the yield of desired product. Gram scale synthesis was successfully accomplished with 92% yield.     

Enantioselective total synthesis of (+)-gliocladine C: convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors

A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11) in 10 steps and 11% overall yield from isatin is reported. In addition, the epipolythiodioxopiperazine (ETP) natural product (+)-gliocladine C (6) has been prepared in six steps and 29% yield from the di-(tert-butoxycarbonyl) precursor of 11. The total synthesis of 6 constitutes the first total synthesis of an ETP natural product containing a hydroxyl substituent adjacent to a quaternary carbon stereocenter in the pyrrolidine ring.     

Total synthesis of clavaminol A, C and H

The first total synthesis of clavaminol A and C, (2R,3S)-2-amino-3-alkanols from the Mediterranean ascidian Clavelina phlegraea has been achieved in 29% overall yield. The key step involved a palladium(II)-catalysed directed Overman rearrangement to create the C-N bond and install the erythro configuration while a one-pot, tributyltin hydride-mediated reduction allowed simultaneous formation of the methyl side-chain and N-acetyl group. Similarly, the first total synthesis of clavaminol H was completed in 48% overall yield using an approach that also provided the cytotoxic des-acetyl analogue.     

Efficient total syntheses of phytoalexin and (+/-)-paniculidine B and C based on the novel methodology for the preparation of 1-methoxyindoles

A general route to 2-unsubstituted-1-methoxyindoles, based on our methodology for the synthesis of 1-methoxyindoles, is reported. This synthesis renders accessibility to a variety of natural products possessing the said skeleton. A direct synthesis of phytoalexin (1), (+/-)-paniculidine B (2), and (+/-)-paniculidine C (3) is disclosed based on the methodology. The synthesis of paniculidine B (2) has been achieved from aldehyde 10 in only two steps in 88% yield and in five steps from a methoxyindole compound 8 obtained using our earlier methodology.     

A second-generation synthesis of the C1-C28 portion of the altohyrtins (spongistatins)

A practical second-generation synthesis of an advanced intermediate in our total synthesis of altohyrtin C (spongistatin 2) has been developed. A new approach to the C1-C15 (AB) portion features a vinyllithium addition to an aldehyde followed by a palladium-catalyzed allylic reduction to install the troublesome C13-C15 segment. Our general approach to the C16-C28 (CD) spiroketal has been retained, but some improvements have been made. Most notably, the kinetically controlled CD-spiroketalization reaction now proceeds in high yield with excellent diastereoselection. This new strategy uses the anti-aldol coupling used in our first-generation synthesis to join AB and CD fragments. A total of 9.6 g of intermediate 57 has been produced using this improved route.     

Aqueous mortar–pestle grinding: An efficient,attractive, and viable technique for the regioselective synthesis of β-amino alcohols

A green and highly regioselective approach for the synthesis of β-amino alcohols (with yields from 15 to 98%) via the aminolysis of epoxides by varied amines using LiBr under aqueous mortar–pestle grinding conditions has been described. Use of a mild catalyst, ordinary grinding, time economy, cost effectiveness, complete regioselectivity, and a very good to excellent yield of desired products makes this process an attractive route for the synthesis of biologically significant pharmacophores. Furthermore, the developed protocol has been successfully extended to the synthesis of novel series of β-amino alcohols (3r–ad) bearing benzofused 1,2,3-triazole heterocycle with complete regioselectivity. The structure of the synthesized molecules has been characterized by spectroscopic techniques such as ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and mass spectroscopy/elemental analysis.     

Host (nanocavity of zeolite-Y)–guest (molybdophosphoric acid) nanocomposite materials: An efficient catalyst for solvent-free synthesis and deprotection of 1,l-diacetates

In the present work, a mild and efficient method has been developed for the synthesis of acylals from aldehydes with acetic anhydride in the presence of molybdophosphoric acid encapsulated into dealuminated zeolite Y (MPA-DAZY) as a catalyst under solvent-free conditions at 45–55 °C in good to excellent yield. The deprotection of acylals has also been attained using this catalyst in acetonitrile. The catalyst was reused several times without efficient loss of its catalytic activity.     

Gram scale synthesis of the C(18)-C(34) fragment of amphidinolide C

The synthesis of the C(18)-C(34) fragment of amphidinolide C has been achieved via two routes, culminating in both the shortest (11 steps) and highest yielding (26% overall yield) approaches to this segment. The highly convergent approach will facilitate the synthesis of analogues, including the C(18)-C(29) fragment of amphidinolide F. Synthetic highlights include the selective methylation of a diyne, and the highly efficient use of a second generation cobalt catalyst in the Mukaiyama oxidative cyclization to form the trans-THF ring.     

Concise formal synthesis of the bryostatin southern hemisphere (C17-C27)

An efficient synthesis of Hale and co-workers' C17-C27 bryostatin southern hemisphere intermediate has been accomplished in six steps and 33% overall yield from (R)-2-(benzyloxy)propanal. The synthesis features a one-pot DIBALH/HWE ester homologation as well as a novel acetonide rearrangement/glycal formation cascade.     

A novel synthesis method for cyclodextrins from maltose in water-organic solvent systems

A novel enzymatic synthesis method of cyclodextrin (CD) from low-mol-wt maltose using cyclomaltodextrin glucanotransferase (CGTase) fromBacillus macerans has been developed in various water-organic solvent systems. A Β-CD was synthesized in a two-phase system consisting of water and cyclohexane. However, no CDs could be synthesized in an aqueous buffer solution. A maximal yield of Β- CD has been obtained at a cyclohexane content volume of 44%. This synthesis has been obtained only at low temperatures, i.e., 7‡C, and did not take place at 50‡C. In addition, various organic solvents have been used for the enzymatic synthesis of CD from maltose. Consequently, Β-CD could be synthesized in various water-organic solvent systems, e.g., cyclohexane, benzene, xylene, and chloroform, but no enzymatic reaction occurred using aliphaticn-hydrocarbon solvents such as hexane, dodecane, and hexadecane. Furthermore, α- and Β- CD could be synthesized in water mixture solutions using organic solvents having an alcoholic group (e.g., ethanol, propanol, butanol, and pentanol) in a wide range of the reaction temperatures, typically 7–50‡C. In this temperature range, α- and Β-CD were also formed and the maximal yield from maltose to Β-CD of approx 13% was reached in 60 h.     

Synthesis of cystothiazole E and formal syntheses of cystothiazoles A and C by Pd0-catalyzed cross-coupling reactions

The synthesis of the naturally occurring bithiazole (+)-cystothiazole E (1e) is described starting from oxazolidinone 2. It proceeded in 10 steps and an overall yield of 37%. The key reaction of the sequence was a Suzuki cross-coupling between bromobithiazole 4 and the (E)-alkenylboronic acid derived from alkyne 18 (94% yield). Prior to the synthesis, more general investigations related to the cross-coupling of bromobithiazole 4 were undertaken. Whereas Heck reactions failed Suzuki and Stille cross-coupling reactions were successfully conducted. By this means, the alkenylboronic acid derived from alkyne 11 and stannane 12 could be transformed into the corresponding alkenylbithiazoles 13 (92%) and 14 (52%). The Stille cross-coupling of compound 4 and stannane 5 allowed access to aldehyde 21 (97% yield) and paved the way for an alternative route to (+)-cystothiazole E (1e). In addition, aldehyde 21 was transformed into aldol product 22 (72%) which has been used in previous syntheses of cystothiazole A (1a) and C (1c). In this respect, the preparation of compound 21 represents a formal total synthesis of these cystothiazoles.     

Development of a Non-Directed Petasis-Type Reaction by an Aromaticity-Disrupting Strategy

The Petasis-type reaction, which couples an imine and boronic acid, is an important tool for C−C bond formation in organic synthesis. However, the generality of this transformation has been limited by the requirement for a directing heteroatom to enable reactivity. Herein, we report the development of a non-directed Petasis-type reaction that allows for the coupling of trifluoroborate salts with α-hydroxyindoles. By disrupting aromaticity to generate a reactive iminium ion, in conjunction with using trifluoroborate nucleophiles, the method generates a new C−C bond without the need for a directing group. This reaction is operationally simple, providing α-functionalized indoles in up to 99 % yield using sp, sp², and sp³-hybridized trifluoroborate nucleophiles. Finally, this reaction is applied as a novel bioconjugation strategy to link biologically active molecules and toward the convergent synthesis of non-natural heterodimeric bisindole alkaloid analogs.     

Total synthesis of (-)-senepodine G and (-)-cermizine C

An efficient, stereospecific synthesis of the alkaloids senepodine G (2) and cermizine C (1) has been completed using the BF3.Et2O-promoted stereospecific addition of Me2CuLi to alpha,beta-unsaturated lactam 6 to provide lactam 3, the addition of MeMgBr followed by HCl to convert 3 to senepodine G (2) (six steps, 40% overall yield), and the stereospecific NaBH4 reduction of 2 to give cermizine C (1) (seven steps, 40% overall yield).     

(+)-Phorboxazole A synthetic studies. A highly convergent, second generation total synthesis of (+)-phorboxazole A

[structure: see text] A second generation total synthesis of the potent antitumor agent (+)-phorboxazole A (1) has been achieved. The cornerstone of this approach comprises a more convergent strategy, involving late-stage Stille union of a fully elaborated C(1-28) macrocycle with a C(29-46) side chain. The second generation synthesis entails the longest linear sequence of 24 steps, with an overall yield of 4.2%.     

Selective and facile deacetylation of pentacyclic triterpenoid under methanolic ammonia condition and unambiguous NMR analysis

The acetyl ester plays an important role for protection of the hydroxyl groups in carbohydrates synthesis.In the present study,we described an efficient deprotection of acetyl group of pentacyclic triterpenoid by using methanolic ammonia in THF solution.Good selectivity for cleaving gal-C2-OAc group of 3β-hydroxy-olean-12-en-28-oic acid 28-N-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside(3) was achieved in the presence of methanolic ammonia within 4 h at low temperature(-60℃) in a yield of 56%.The reaction disclosed here provides a new method for the synthesis of C2 selective modified carbohydrates,which is more useful than conventional synthesis procedure that usually requires many steps including temporary regioselective protection and deprotection.When the reaction temperature was increased from -60℃ to room temperature,the cleavage of the other three acetyl groups of galactose in an order of C4-OAc>C3-OAc>C6-OAc was observed.Based on this study,a plausible route for the deacetylation reaction has been proposed.     

2-(4-Tolylsulfonyl)ethoxymethyl (TEM)-a new 2'-OH protecting group for solid-supported RNA synthesis

The 2-(4-tolylsulfonyl)ethoxymethyl (TEM) as a new 2'-OH protecting group is reported for solid-supported RNA synthesis using phosphoramidite chemistry. The usefulness of the 2'-O-TEM group is exemplified by the synthesis of 12 different oligo-RNAs of various sizes (14-38 nucleotides long). The stepwise coupling yield varied from 97-99% with an optimized coupling time of 120 s. The synthesis of all four pure phosphoramidite building blocks is also described. Two new reliable parameters, delta(C2')-delta(C3') and delta(H2')-delta(H3'), have been suggested for the characterization of isomeric 2'-O-TEM and 3'-O-TEM as well as other isomeric mono 2'/3'-protected ribonucleoside derivatives. The most striking feature of this strategy is that the crude RNA prepared using our 2'-O-TEM strategy is sufficiently pure (>90%) for molecular biology research without any additional purification step, thereby making oligo-RNAs easily available at a relatively low cost, saving both time and lab resources.