Enolization regioselectivity involving stereoisomeric 4a-methyl-5-methoxyperhydrobenzo[7]annulen-2-ones.

Efficient synthetic routes to the four isomers 17b-20b of the title ketone are described. Entry begins from the Wieland-Miescher homologue 3 whose pair of carbonyl groups are amenable to regiochemical manipulation. The compositions of the reaction mixtures generated under kinetic or thermodynamic control were defined by (1)H NMR analysis subsequent to chromatographic purification. The regiochemical trends are correlated with B3LYP/6-31G* calculations, the results of which conform to the preferred introduction of a 1,2- or 2,3-double bond.

Effect of sulfonyl protecting groups on the neighboring group participation ability of sulfonamido nitrogen.

The addition of elemental bromine dissolved in CH(2)Cl(2) to para-disubstituted benzodiazocines where X is the same (H, CH(3), Br, OMe, NO(2)) or a different substituent as X and Y (CH(3), Br; OMe, NO(2)) has been found to proceed in most cases with competition between two pathways. While conventional trans-1,2-addition operates predominantly, electron-releasing groups also foster a ring-contraction process with ultimate 1,3-positioning of the pair of bromine atoms. The observed regio- and stereoselectivities, confirmed where necessary by X-ray crystallographic analysis, establish the capability of sulfonamide nitrogen centers to engage in neighboring group participation.

Contrasting responses of pyrido[2,1-a]isoindol-6-ones and their sultam counterparts to photochemical activation.

A ring-closing metathesis-based strategy has allowed access to an unreported pair of pyridoisoindolones and their previously unknown sultam counterparts. The synthetic routing takes advantage of the ready availability of N-allylphthalimide and N-allylsaccharin and proceeds via the proper incorporation of small side chains into the heterocyclic ring. Positionally selective introduction of the conjugated diene functionality was realized efficiently. Detailed study of the excited-state chemistry of 7 and 8 showed both lactams to be subject to [4 + 2] dimerization under acetone-sensitized conditions. Different regioselectivities are involved, with the response of 8 being far more efficient than that exhibited by 7. No dimers could be isolated from the photolyzates of 9 and 10 under any conditions. While the latter sultam undergoes extensive polymerization, 9 is transformed via direct irradiation at 350 nm into 46 and 47 via [1,3]-sigmatropy involving the S-N bond and heterocyclic ring cleavage, respectively.

From D-glucose to enantiomerically pure cycloctanoses. The glycosidase inhibitory capacity of medium-ring carbasugars.

Exhaustive dihydroxylation of the pair of cyclooctadienols consisting of 4 and 5, which are available in enantiomerically pure form from d-glucose, resulted in the formation of two diastereomeric tetraols in each case. The difference in polarity of the 6/7 and 8/9 pairs facilitated their chromatographic separation. Ensuing acetylation and PMB deprotection allowed for the assignment of relative (and ultimately absolute) stereochemistry to the resulting monohydric alcohols on the basis of J(HH) analysis of their (1)H NMR spectra. The highly functionalized exomethylenecyclooctanes 14-17, which were derived by periodinane oxidation and Wittig olefination, were further elaborated by hydroboration and global deprotection. The eight members of the cyclooctanose family of carbasugars and their precursor intermediates consistently showed patterns of J(HH) values in line with the contiguous stereochemical relationships. Also assayed was their specific inhibitory behavior toward glycosidases.

Contiguously substituted cyclooctane polyols. configurational assignments via (1)H NMR correlations and symmetry considerations.

More advanced oxidation of the cyclooctadienol shown, readily available in enantiomerically pure form from D-glucose, has given rise to a series of intermediates whose relative (and ultimately absolute) configuration was assigned on the basis of (1)H/(1)H coupling constant analysis. The selectivities that were deduced in this manner were drawn from the sequential application of CrO3 oxidation in tandem with Luche reduction, two-step NMO-promoted osmylations bracketed by acetonide formation, and wholesale deprotection. The stereoselectivities of these reactions were traced by (1)H NMR spectroscopy, and the stereochemical assignments were confirmed by the presence or absence of symmetry in the final cyclooctane polyols (four shown) generated in this investigation.

Pinacol macrocyclization-based route to the polyfused medium-sized CDE ring system of lancifodilactone G.

The polyfused medium-sized CDE ring system of lancifodilactone G is assembled via B-alkyl Suzuki-Miyaura cross-coupling and SmI 2-mediated pinacol macrocyclization as the key strategic steps.

Neighboring group participation by sulfonamido nitrogen.

The ability of sulfonamido nitrogen to enter into neighboring group participation was established in two different reaction settings. The first was uncovered during the bromination of benzodiazocine 8 in dichloromethane at 0 degrees C, and the second during the base treatment of 15a en route to allene 18.

The carbohydrate-sesquiterpene interface. directed synthetic routes to both (+)- and (-)-fomannosin from D-glucose.

An enantiodivergent strategy for the total chemical synthesis of both naturally occurring (+)-fomannosin (1) and its (-)-antipode (ent-1) from alpha-D-glucose has been developed and successfully implemented. The key steps in the overall pathway include the following: (i) application of the zirconocene-mediated ring contraction of vinyl furanosides for the construction of highly substituted cyclobutanols; (ii) the use of ring-closing metathesis to form the pendant five-membered ring; (iii) making recourse to a monothio malonic ester to allow for chemoselective reduction to sensitive lactone intermediate 45; (iv) hydroxyl-directed dihydroxylation with OsO(4) to generate 48; and (v) sequential elimination via a cyclic sulfite and a cyclobutyl triflate. The bridge between the enantiomeric series consisted of a six-step linkup involving the structural modification of 22 so as to generate ent-30b. Optical activity was fully preserved throughout.

Studies directed toward the total synthesis of lancifodilactone G: an expeditious route to the ABC subunit.

An efficient entry to the ABC network of lancifodilactone G is outlined. The C ring is constructed by way of enyne ring-closing metathesis. The AB component is established via a base-mediated biomimetic oxy-Michael addition--lactonization sequence.

Stereocontrolled synthesis of the sterically encumbered F ring of lancifodilactone G.

A stereochemically linear strategy has been developed to prepare the heavily congested F-ring sector of lancifodilactone G (1) from commercially inexpensive (R)-carvone. Prominent operations in our synthesis include Negishi-type sp2-sp3 cross-coupling and intramolecular free-radical cyclization for the purpose of appending the sidearm links of the D and H rings onto the F platform.

7-Bromo-4b-methyl-7,8-dihydro-4bH-9-thia-8a-aza-fluorene 9,9-dioxide.

The title compound, C(12)H(12)BrNO(2)S, was isolated after direct irradiation (hν 350 nm, hexa-ne) of a mixture of stereoisomeric sulfonamides containing a vicinal dibromide and a conjugated diene. This product is one of a group of substrates that has contributed to our understanding of the photoreactivity patterns of non-bridged sulfonamides. The crystal structure was determined from a non-merohedrally twinned data set, where the twin law corresponded to a 180° rotation about the a* axis. The minor twin component refined to a value of 0.176 (3). The conformation of the mol-ecule is planar at one end, as the benzene ring and the adjacent fused five-membered ring are coplanar, and U-shaped at the other end, where the five-membered ring is fused to the heterocyclic six-membered ring containing an allyl bromide group.

X-ray crystallographic and mass spectrometric probing of the conformational and ionophoric properties of stereoisomeric hexatetrahydrofuranylhexane segments.

A full account of the synthesis of the 12 hexacyclic tetrahydrofuran isomers represented by the nearby formulas is first provided. The key steps involved in further elaboration of the spiro ethers 12, 15, 28, and 45 include controlled ozonolysis, 1,2-addition of the Normant reagent, and heterocyclization. Eight of the end products proved to be sufficiently crystalline to enable X-ray analysis and determination of their solid-state conformational features. The alkali metal ion selectivities of the 12 hexamers were evaluated by a picrate extraction method and by electrospray ionization mass spectrometry (ESI-MS) which indicated that small, but significant, selectivity differences exist within the groups of diastereomers. These results revealed that each hexamer demonstrated a preference for lithium ion complexation relative to sodium or potassium ion complexation. Stereoisomeric classification of the hexamers was based on the competition between two dissociation routes promoted by collision-induced dissociation. The preference for each of the two dissociation pathways, both of which involved cleavage at the midpoint of the hexamer, correlated with the stereochemical configurations (syn versus anti) of the THF groups near the termini.

Pestalotiopsin a. Enantioselective construction of potential building blocks derived from antipodal cyclobutanol intermediates.

D-Glyceraldehyde acetonide has been used as the starting point for accessing the enantiomeric cyclobutanols 11 in optically pure condition. The dextrorotatory enantiomer has been transformed in five steps into the [3.2.0] bicyclic lactone 22. While the deoxygenation of 22 proved to be problematical, the uncyclized variant 25 underwent the Barton process smoothly. These findings guided the related conversion of (-)-11 into 34. Use was also made of ring-closing metathesis to bring about the conversion of (+)-11 into [4.2.0] bicyclic lactone building blocks. In general, all three pathways are efficient and offer the prospect of practical side-chain appendage for the purpose of installing the nine-membered ring of pestalotiopsin A (1).

Pestalotiopsin A. Side chain installation and exhaustive probing of olefin metathesis as a possible tool for elaborating the cyclononene ring.

A program directed toward an asymmetric synthesis of pestalotiopsin A is described. The routing begins with the dextrorotatory cyclobutanol 37, which is combined with the enantiomerically defined building blocks ent-15 and 16. These units are incorporated via stereocontrolled 1,2-nucleophilic addition and anti-aldol coupling, respectively. With these straightforward reactions accomplished, the sequel involved the introduction of terminal double bonds in anticipation of the fact that the (E)-cyclononene substructure could be realized by ring-closing metathesis. This central issue was evaluated with several diene substrates and catalysts, all to no avail. Cross-metathesis experiments involving 59 and 65 with the functionalized heptene 60 revealed a marked difference in the inability to engage interaction with the ruthenium catalyst. This awkwardness could not be skirted.

Synthesis of, and structural assignments to the stereoisomers of bis (2,2')- and tris (2,2',2")-tetrahydrofurans: conformational features and ionic binding capacities of these gateway polycyclic networks.

Construction of the polytetrahydrofuranyl building blocks 6-10 from the common bissiloxyacetone precursor 11 is detailed. The approach is concise and, for the bis-(THF) pair, capitalizes on the full retention of configuration observed during the rhodium-promoted decarbonylation of aldehydes 18 and 19. The capability of the title compounds to associate with alkali metal ions in solution and the gas phase has demonstrated a preference for Li+ over Na+ and K+ in all cases, with 6 and 7 exhibiting somewhat higher binding selectivities than 8-10. The relative energy orderings of attainable conformations with the bis-THF and tris-THF series were explored computationally. The various envelope arrangements present in the individual THF units are shown to play a significant role alongside prevailing gauche interactions. The "gauche effect" is shown computationally not to be an accurate predictor of the lowest energy conformer.

Effects of a synthetic analog of polycavernoside A on human neuroblastoma cells.

BACKGROUND: Polycavernoside A is a glycosidic marine toxin first extracted from the red alga Polycavernosa tsudai in 1991 when 3 people died after the ingestion of this food. Polycavernoside A is an interesting molecule because of its complex macrolide structure and strong bioactivity. However, the target site of this toxin has not been characterized. METHODS: We studied the effects of a synthethic analog of polycavernoside A on human neuroblastoma cells by measuring changes in membrane potential with bis-oxonol and variations in intracellular calcium levels with fura-2. Fluorescent phalloidin was utilized for assaying activity on actin cytoskeleton. RESULTS: Data showed that this polycavernoside A analog induced a membrane depolarization and an increase in cytosolic calcium levels. CONCLUSION: These results provide the first insight into the mode of action of polycavernoside A, suggesting that: i) this toxin triggers an initial extracellular calcium entry neither produced across L-type voltage-gated calcium channels nor activation of muscarinic receptors ii) there is a depolarization induced by the toxin and due to the extracellular calcium entry.

A modular approach to marine macrolide construction. 4. Assembly of C36-C51 and C29-C44 building blocks and evaluation of key coupling reactions targeting spongistatin 1 (altohyrtin A).

Routes have been developed for the stereocontrolled elaboration of two highly functionalized sectors of spongistatin 1. The approach to ring F takes advantage of B-alkyl Suzuki-Miyaura coupling to install the C44-C45 bond. The E-ring pyran moiety was generated by acylation of an alpha-sulfonyl carbanion, the stereogenic centers of which were incorporated by sequential asymmetric aldol reactions. [structure: see text].

Pectenotoxin-2 synthetic studies. 3. Assessment of the capacity for stereocontrolled cyclization to form the entire C1-C26 subunit based upon the double bond geometry across C15-C16.

Second-generation synthetic routes to enantiopure sulfone 21 and aldehyde 24 are described. The union of these two intermediates by means of a Julia-Kocienski coupling gave rise to a series of E-configured building blocks that did not prove amenable to transannular cyclization. Alternatively, when the C15-C16 double bond was introduced with Z-geometry by Wittig olefination, spontaneous closure to generate a tetrahydrofuran culminated an ensuing direct dihydroxylation step. The structural assignment to 35, undergirded by detailed 1H and 13C NMR studies, is consistent with proper transannular bonding so as to deliver the entire C1-C26 fragment of PTX2.

Development of an access route to the c31-c52 central core of amphidinol 3.

[reaction: see text] An asymmetric synthesis of the heavily oxygenated inner sector of amphidinol 3 constituted of C31-C52 is described. The successful pathway highlights construction of the pair of identical tetrahydropyran subunits from a common intermediate.