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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

(+)-(1S,5R,10S)-11,11-Dimeth-yl-4-oxa-tricyclo-[8.4.0.0]tetra-deca-ne-3,12-dione.

The title compound, C(15)H(22)O(3), was prepared via amino-acid-promoted Robinson annulation followed by tandem Pd/C-mediated hydrogenation and oxidative cyclization. This product was instrumental in determining the feasibility of a stereocontrolled hydrogenation in which the directing hydroxyl group is adjacent to the 6-7-ring network and its olefinic component. The asymmetric unit consists of a single mol-ecule with normal geometric parameters.

Studies toward the total synthesis of dumsin. 2. A second generation approach resulting in enantioselective construction of a functionalized ABC subunit of the tetranortriterpenoid insect antifeedant.

A synthesis of the ABC framework of dumsin is described. The optically active intermediate 9b, which is expeditiously assembled from 5-oxobornyl pivalate by the sequential implementation of an oxy-Cope rearrangement and an intramolecular ene reaction, proved to be suitably functionalized for ultimate conversion to 5. The synthesis plan relies on two approaches to this targeted intermediate.

Amino acid mediated intramolecular asymmetric aldol reaction to construct a new chiral bicyclic enedione containing a seven-membered ring: remarkable inversion of enantioselectivity compared to the six-membered ring example.

A detailed study to assess the enantioselectivity of the amino acid mediated intramolecular asymmetric aldol reaction of 1,3-cycloheptanedione bearing a C-2 methyl substituent has been undertaken. The cyclizations were mediated by a series of l-amino acids in the presence of an acid cocatalyst. Strikingly, the process is characterized by an inversion of enantioselectivity when compared to a similar reaction involving the 1,3-cyclohexanedione counterpart.

Direct comparison of the response of bicyclic sultam and lactam dienes to photoexcitation. Concerning the propensity of differing bond types to bridgehead nitrogen for homolytic cleavage.

A convergent strategy has allowed access to bridgehead sultam 9 and the related carboxamides 10 and 11. The synthetic routing proceeds via the coupling of a suitably constructed dienamine to either o-iodobenzenesulfonyl chloride or o-iodobenzoyl chloride to generate the amides. The application in sequence of ring-closing metathesis and an intramolecular Heck reaction gave rise to advanced tricyclic intermediates.

Diosphenol-based approach to the a-ring functionalization of advanced Taxol precursors.

Several different approaches to the A-ring functionalization of an advanced, highly functionalized diosphenol precursor to Taxol are described. The first phase of the undertaking consists of an assessment of those reagents conducive to reaction at the enolic oxygen (silylation, methylation, allylation, and acylation). Transformations involving an alternative attack at the enol carbon center (bromination, selenation) have also been defined.