Total synthesis of garsubellin A

A concise approach to the laboratory synthesis of garsubellin A is described. Garsubellin A, an effective inducer of choline acetyltransferase (ChAT), has been shown to have potential as a therapeutic agent for the treatment of Alzheimer's disease. Starting from 3,5-dimethoxyphenol, the synthesis has provided garsubellin A in an 18-step sequence. Notable transformations include dearomative allylation, diastereoselective vinylogous lactonization, iodocarbocyclization, transannular Wurtz, and bridgehead functionalization reactions.     

Synthesis of polyprenylated acylphloroglucinols using bridgehead lithiation: the total synthesis of racemic clusianone and a formal synthesis of racemic garsubellin A

The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.     

Progress toward the Synthesis of garsubellin A and related phloroglucins: the direct diastereoselective synthesis of the bicyclo[3.3.1]nonane core

[reaction: see text] A highly diastereoselective single-step cyclization reaction provides access to the bicyclo[3.3.1]nonane core of the polyprenylated phloroglucin natural product garsubellin A. Further elaboration to a more functionalized analogue involves a sequential Claisen rearrangement/Grubbs olefin cross-metathesis strategy. Additionally, this strategy was extended to the preparation of the bis-quaternary carbon array found at the bridgehead positions of the phloroglucin natural products.     

Total synthesis of (+/-)-garsubellin A

The first total synthesis of garsubellin A, a neurotrophic compound with potent choline acetyltransferase-inducing activity, is described. Keys for success were (1) stereoselective intermolecular aldol reaction at the C-4 position with acetaldehyde, (2) stereoelective Claisen rearrangement to introduce an allyl group to the most sterically crowded position at C-6, (3) ring-closing metathesis to construct the B-ring, and (4) Wacker-type oxidative C-ring formation. This synthetic route can be extended to an asymmetric synthesis of garsubellin A using the Koga catalytic enantioselective alkylation, which produced enantioenriched alpha-prenyl cyclohexenone with excellent enantioselectivity (95% ee).     

Synthesis of 2-aryl-6-methyl-5-nitroquinoline derivatives as potential prodrug systems for reductive activation

A range of novel 2-aryl-5-nitroquinolines have been synthesised as potential prodrug systems for bioreductive activation. Thus 5-nitroquinoline underwent vicarious nucleophilic substitution at C-6 with bromoform anion to give, after hydrolysis and reduction, the quinoline-6-methanol. Introduction of chlorine at C-2 was followed by palladium-catalysed Suzuki coupling to install the 2-aryl substituent. A fluorescent model ‘drug’, 7-hydroxy-4-methylcoumarin was coupled to the 6-hydroxymethyl group, and its fragmentation upon reduction of the nitro group was investigated.     

Phosphol-3-ene 1-oxides and -sulfides. A systematic investigation via carbon-13 nuclear magnetic resonance spectroscopy

¹³C NMR chemical shifts and ¹³C? ³¹P couplings are reported for 18 phosphol-3-ene 1-oxides and 18 corresponding sulfides. The effects of methyl substitution at positions 3 and 4 on the carbon shifts have been systematically explored and substituent parameters derived. One bond couplings from phosphorus to C-2 and C-5 have been related to the sum of the exocyclic substituent group electronegativities (covalent boundary potential values).     

Trifluoroacetylation of pyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyrazines

A study was carried out on the reaction of pyrrolo[1,2-a]pyrazines containing an alkyl, aryl, or aralkyl substituent at C-1 with trifluoroacetic anhydride. Trifluoroacetylation products may be formed either by reaction in the pyrrole ring or at the aryl or aralkyl groups at C-1. Products of electrophilic substitution at C-6 are formed in the trifluoroacetylation of pyrrolo[1,2-a]pyrazines containing at C-1 a substituent bulkier than a methyl group but lacking substituents at C-6 (the α-position of the pyrrole ring). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1226–1233, August, 2007.     

Synthesis of 1-hydroxy-substituted pyrazolo[3,4-c]- and pyrazolo[4, 3-c]quinolines and -isoquinolines from 4- and 5-aryl-substituted 1-benzyloxypyrazoles

1-Hydroxypyrazolo[3,4-c]quinoline (22), 1-hydroxypyrazolo[4, 3-c]quinoline (21), 1-hydroxypyrazolo[3,4-c]isoquinoline (20), and 1-hydroxypyrazolo[4,3-c]isoquinoline (19) were prepared from 1-benzyloxypyrazole (6), establishing the pyridine B-ring in the terminal step. The pyridine ring of pyrazoloquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1-benzyloxypyrazole. The pyridine ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a 2-formylphenyl substituent at C-4 or C-5 with an iminophosphorane group installed at C-5 or C-4 of 1-benzyloxypyrazole by lithiation followed by reaction with tosyl azide and then with tributylphoshine utilizing the Staudinger/aza-Wittig protocol. The 2-aminophenyl and the 2-formylphenyl substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation to the pyrazolylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodoaniline or 2-bromobenzaldehyde. The order of reactions and use of protecting groups in the individual sequences have been optimized. The 1-benzyloxy-substituted pyrazoloquinolines and isoquinolines thus obtained were debenzylated by strong acid to the corresponding 1-hydroxy-substituted pyrazoloquinolines and isoquinolines 19-22.     

Electron ionization mass spectral studies of bridgehead-substituted norbornan-2-ones: camphor derivatives

The electron ionization (EI) mass spectra of a series of bridgehead-substituted 3,3-dimethylnorbornan-2-ones, derived from natural (1R)-(+)-camphor, have been studied and their cleavage mechanisms rationalized on the basis of the substituent shifts as well as on the identification of relevant peaks through accurate mass measurements and collision-induced dissociation (CID) tandem mass spectrometric experiments. The fragmentation patterns are very dependent on both the structural nature and the electronic properties of the bridgehead substituent. The driving force for the main fragmentation pathways are competitive cleavages of the C(1)-C(2) and C(2)-C(3) bonds directed by the bridgehead substituent and either the gem-dimethyl or carbonyl groups. These cleavages lead to distonic ions in which the charge is preferentially located either at the C(1), C(2) or C(3) positions depending on the electronic character and structural nature of the bridgehead substituent. This charge distribution determines the subsequent rearrangements and fragmentations.     

Type 3 ring opening reaction of cyclopropanated oxabenzonorbornadienes with alcohol nucleophiles

The first examples of a Type 3 ring opening reaction of cyclopropanated oxabenzonorbornadiene (CPOBD) were found to occur using alcohol nucleophiles under acid catalyzed conditions, yielding seven-membered rings via ring expansion. Optimization of the reaction determined the ideal conditions to be 10?mol% pTsOH at 40?°C using excess alcohol nucleophile as the solvent. The scope of the reaction investigated diverse alcohol nucleophiles and bridgehead substituents on the CPOBD; in both cases the steric properties of the substituent was found in influence the yield of the reaction. Alternative Type 3 products were observed when the bridgehead substituent was an ethyl or hydroxymethyl group and limited examples of Type 3 products were formed using a palladium catalyst with alcohol nucleophiles. Mechanisms have been proposed for the formation of the Type 3 product as well as the alternative Type 3 products.     

The conformations of bicyclo[3.1.0]hexane derivatives by 1H and 13C NMR

The ¹H and ¹³C spectra of bicyclo[3.1.0]hexanes and thujanes have been recorded and assigned. Application of the Karplus equation has yielded dihedral angles, and a computer calculation of the angle of ring buckle as a function of the main dihedral angles has been carried out. The calculated angles of ring buckle agree well with known values in the bicyclo[3.1.0]hexanes, but for 1-methylbicyclo[3.1.0]hexanes and thujanes the results are not self consistent. It is suggested that the bridgehead substituent causes the boat to twist, although the twist can be reduced by an axial methyl substituent on C-4.     

The effect of a lateral aromatic branch on the orientational ordering of laterally alkoxy substituted nematics

Two new mesogenic series have been synthesized. They have the same main core which contains four aromatic rings, with two lateral substituents on the same side of one of the inner rings. One of the substituents is a 4-chlorobenzyloxy group and the second is an alkoxy chain. The positions of the lateral substituents are different in the two series. Despite the large aromatic branch, an enantiotropic nematic phase is obtained for most of the compounds. The orientational ordering behaviour of these new compounds has been investigated by C-13 NMR, and two isomeric compounds containing a lateral dodecyloxy chain were chosen for the study. The order parameters of the chain were obtained by a 2D C-13 NMR technique with variable angle spinning. The temperature dependence of the order parameters was determined using the C-13 chemical shifts with slow spinning of the sample parallel to the magnetic field. The first methylene fragment in each lateral substituent of each compound has a positive C-H bond order parameter, implying that this fragment adopts a cis conformation in the nematic phase. The two lateral substituents are folded back along the mesogenic core in opposite directions. The lateral chain is found to be roughly aligned along the molecular long axis imposed by the core, whereas the para -axis of the phenyl ring in the lateral aromatic branch makes a considerable angle with the molecular long axis. It was also found that the different patterns of substitution do not affect the position of the molecular long axis to any large extent.     

Stereoselective C-glycosylation reactions of ribose derivatives: electronic effects of five-membered ring oxocarbenium ions

The factors controlling the highly alpha-selective C-glycosylation of ribose derivatives were determined by examining the stereoselective reactions of 18 ribose analogues differing in substitution at C-2, C-3, and C-4. The lowest energy conformers of the intermediate oxocarbenium ions display the C-3 alkoxy group in a pseudoaxial orientation to maximize electrostatic effects. To a lesser extent, the C-2 substituent prefers a pseudoequatorial position, and the alkyl group at C-4 has little influence on conformational preferences. In all cases, the product was formed by stereoelectronically preferred inside attack on the lowest energy conformer.     

Nucleoside synthesis from 3-alkylated sugars: role of 3beta-oxy substituents in directing nucleoside formation

Using Vorbrüggen's protocol, reaction of persilylated uracil with xylofuranose derivatives having 3beta-oxy-3alpha-alkyl substitution produced both alpha- and beta-nucleosides. Only the beta-nucleosides were formed from substrates having the reverse stereochemistry at C-3 or lacking the 3-alkyl substituent. Participation of the 3beta-oxy substituent in stabilizing the incipient C-1 carbonium ion (or oxonium ion) intermediate has been suggested from analysis of energy-minimized conformations.     

Diastereoselective synthesis of enantiopure morpholines by electrophilic selenium-induced 6-exo cyclizations on chiral 3-allyl-2-hydroxymethylperhydro-1,3-benzoxazine derivatives

Enantiopure morpholine derivatives have been prepared by selenocyclofunctionalization of chiral 3-allyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The cyclization occurs in high yields and diastereoselection, although the temperature of the reaction and the structure of the substituent at C-2 and the substitution pattern of the double bond can modify the regio- and stereochemistry of the final products.     

Two pentasaccharide resin glycosides from Argyreia acuta

Two new compounds of acutacosides 1 and 2, pentasaccharide resin glycosides were isolated from the aerial parts of Argyreia acuta. The core of the two compounds was operculinic acid A, and they were esterfied at the same position, just one substituent group was linked at C-2 of Rha. The absolute configuration of the aglycone in the two compounds was established by Mosher's method, which was (11S)-hydroxyhexadecanoic acid (jalapinolic acid). Their structures were established by a combination of spectroscopic and chemical methods.     

Four ring achiral ferroelectric liquid crystals of 1,2,4-oxadiazoles: synthesis and characterisation

A novel series of four-ring achiral ferroelectric liquid crystals containing 1,2,4-oxadiazole cores with unsymmetrical substitutions at C-3 and C-5 positions are synthesised and characterised. A fluoro substituted biphenyl moiety is prepared by Suzuki coupling reaction and is directly attached to the oxadiazole core at the C-5 position for the first time in the literature. An octyl benzoate is attached to the oxadiazole core at the C-3 position of it. All the compounds exhibit polar smectic (B₂) mesophases with ferroelectric switching along with the orthogonal smectic-A mesophases. These compounds possess high mesomorphic thermal ranges of polar smectic phases and are towards the ambient temperatures. The influence of a more electronegative fluorine substituent on the electron rich biphenyl moiety (at the C-5 position) of the oxadiazole core is analysed for the prevalence and abundance of polar smectic (ferroelectric) mesophases.     

Synthesis of Benzo‐ and Naphthoquinonyl Boronic Acids: Exploring the Diels–Alder Reactivity

Substituted 2‐quinonyl boronic acids have been synthesised from 1,4‐dimethoxy aromatic derivatives in two steps: regiocontrolled boronation and oxidative demethylation. The study of their dienophilic behaviour evidenced that the boron substituent significantly increases the reactivity and triggers an efficient domino process in which the Diels–Alder reaction was followed by a protodeboronation or dehydroboronation, depending on the substitution on both the quinone and diene partners. The boronic acid acts as a temporary controller, opening a direct access to trans‐fused meta‐regiosomeric adducts when 3‐methyl‐substituted 2‐quinonyl boronic acids react with dienes with a substituent at C‐1. A particularly valuable synthetic result was obtained in the reaction between 3,6‐dimethyl‐2‐quinonyl boronic acid and piperylene under an oxygen atmosphere; trans‐fused 8a‐hydroxy‐2,4a,8‐trimethyl tetrahydronaphthoquinone was formed directly, in excellent yield and in a highly diastereoselective manner.     

Negative electrospray ionization tandem mass spectrometric investigation of ent-kaurane diterpenoids from the genus Isodon

ent-Kaurane diterpenoids are a class of natural compounds isolated from genus Isodon, which have been found to have important bioactivities. Negative electrospray ionization tandem mass spectrometry ((-)ESI-MS(n)) was used to investigate the fragmentation pattern of C-20-nonoxygenated ent-kauranes and two subtypes of C-20-oxygenated ent-kauranes by using an ion trap instrument and accurate mass measurement on an ESI-Q-time-of-flight (TOF) mass spectrometer. The analysis revealed that loss of CH(2)O or CO(2) is the predominant process for 7, 20-epoxy and 7, 20 : 14, 20-diepoxy subgroup of C-20-oxygenated ent-kauranes. In addition, compounds of C-20-nonoxygenated ent-kauranes with a conserved core structure but different substituent groups, such as a hydroxyl, aldehyde, carboxyl, and acetyl moiety, resulted in diagnostic product ions through losses of H(2)O, CO, CO(2), and AcOH, respectively. This work clearly demonstrates the utility of tandem mass spectrometry for studies on the rationalization of the diagnostic fragmentation of a series of compounds from two main types of the ent-kaurane diterpenoids.     

Synthesis of new bridgehead substituted azabicyclo-[2.2.1]heptane and -[3.3.1]nonane derivatives as potent and selective α7 nicotinic ligands

New azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives containing a pyridinyl substituent at the bridgehead position have been synthesized via an efficient ten chemical steps pathway. Both chemical series were then evaluated in vitro for their affinity at α7 nicotinic receptors revealing nanomolar potency with notably excellent selectivity over the α4β2 nicotinic subtype.