Tricyclic Intermediates Research Articles

CP-225,917 synthetic studies: unusual hydroboration regioselectivity influenced by remote functional groups

Hydroboration–oxidation of 1,1-disubstituted alkenes with borane–methyl sulfide complex in bridged tricyclic intermediates of the CP-225,917 ring system were observed to produce significant quantities of tertiary alcohol products. This net Markovnikov addition of water across an alkene is influenced by a combination of remote functional groups. Computations at the B3LYP/6-31G ∗ level of theory correctly predicted this reversal in selectivity and directed the selective removal of functional groups to restore selectivity for the primary alcohol.

16-Aza-ent-beyerane and 16-Aza-ent-trachylobane: Potent Mechanism-Based Inhibitors of Recombinant ent-Kaurene Synthase from Arabidopsis thaliana

The secondary ent-beyeran-16-yl carbocation (7) is a key branch point intermediate in mechanistic schemes to rationalize the cyclic structures of many tetra- and pentacyclic diterpenes, including ent-beyerene, ent-kaurene, ent-trachylobane, and ent-atiserene, presumed precursors to >1000 known diterpenes. To evaluate these mechanistic hypotheses, we synthesized the heterocyclic analogues 16-aza-ent-beyerane (12) and 16-aza-ent-trachylobane (13) by means of Hg(II)- and Pb(IV)-induced cyclizations onto the Delta12 double bonds of tricyclic intermediates bearing carbamoylmethyl and aminomethyl groups at C-8. The 13,16-seco-16-norcarbamate (20a) was obtained from ent-beyeran-16-one oxime (17) by Beckmann fragmentation, hydrolysis, and Curtius rearrangement. The aza analogues inhibited recombinant ent-kaurene synthase from Arabidopsis thaliana (GST-rAtKS) with inhibition constants (IC50 = 1 x 10-7 and 1 x 10-6 M) similar in magnitude to the pseudo-binding constant of the bicyclic ent-copalyl diphosphate substrate (Km = 3 x 10-7 M). Large enhancements of binding affinities (IC50 = 4 x 10-9 and 2 x 10-8 M) were observed in the presence of 1 mM pyrophosphate, which is consistent with a tightly bound ent-beyeranyl+/pyrophosphate- ion pair intermediate in the cyclization-rearrangement catalyzed by this diterpene synthase. The weak inhibition (IC50 = 1 x 10-5 M) exhibited by ent-beyeran-16-exo-yl diphosphate (11) and its failure to undergo bridge rearrangement to kaurene appear to rule out the covalent diphosphate as a free intermediate. 16-Aza-ent-beyerane is proposed as an effective mimic for the ent-beyeran-16-yl carbocation with potential applications as an active site probe for the various ent-diterpene cyclases and as a novel, selective inhibitor of gibberellin biosynthesis in plants.

Photo-rearrangement of N-substituted pyridinium and meta-alkoxypyridinium ions

A computational study of the minimum-energy structures and transition states relevant to the photo-initiated rearrangement of N-substituted pyridinium and meta-alkoxypyridinium ions is reported. Density Functional Theory in the form of 6-31G(d) B3LYP computations has been used to determine the relative energies of the significant stationary points on the ground state potential energy surfaces, including the global minima, the bicyclic (prefulvene-like) and tricyclic (benzvalene-like) intermediates, and the connecting transition states. The S 0, S 1, and S 2 potential energy surfaces have been mapped along a reaction path from the C 2v-symmetry minimum on S 1 to the bicyclic intermediate on S 0 with multi-reference self-consistent-field computations. Two conical intersections are located along this path, the first occurs as the open-shell electron configuration becomes the ground state, and the second occurs as the closed-shell electron configuration of the bicyclic intermediate becomes the ground state. The impact of various N-substituents on the relative energies of the intermediates is also explored. Previously, experimental X-ray structures have firmly established the exo nature of the photohydration of N-substituted pyridinium and alkylpyridinium ions, however, endo solvation has been claimed for the photoaddition of alcohols to meta-alkoxypyridinium ions. The intermediate structures and energies reported here suggest that exo solvation should also be operative in the case of meta-alkoxypyridinium ions.

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. The final two steps involved bromination in liquid bromine and proper 2-fold dehydrobromination. The latter maneuver was best achieved with tetrabutylammonium fluoride in DMSO at elevated temperature. While the irradiation of 9 led principally via SO2-N bond homolysis and [1,5] sigmatropic rearrangement to generate 37, 10 proceeded via disrotatory cyclization to the exo cyclobutene 39, and 11 resisted photoisomerization. The inertness of 11 may stem from its distorted structural features which force its conjugated diene double bonds to be rigidly oriented 32 degrees out-of-plane. The unique ability of the sulfonamide linkage to excited-state homolysis holds comparative interest.

Divergent Enantioselective Synthesis of (−)-Galanthamine and (−)-Morphine

An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.

Total Syntheses of (+)‐Cylindricines C—E and (‐)‐Lepadiformine Through a Common Intermediate Derived from an aza‐Prins Cyclization and Wharton′s Rearrangement.

Enantioselective total syntheses of (+)-cylindricines C−E and (−)-lepadiformine through a common tricyclic intermediate are described here. These syntheses are concise and feature an aza-Prins cyclization and a seldom-used Wharton rearrangement en route to the common intermediate.

Synthetic studies toward the kempane diterpenes. Construction of a key tricyclic intermediate

A synthetic sequence is described for construction of the tricyclic portion (35) of kempane diterpenes. The central stereochemistry was established by a Diels-Alder addition of 2,6-dimethyl-para-benzoquinone to a 5-membered, dithiane-protected diene, and the addition of acetylide, with very high chemoselectivity, provided a suitably functionalized handle that will be incorporated into the final seven-membered ring. The remaining stereogenic centres about the decalin moiety were established by a series of equilibration and reduction steps.

Total Syntheses of (+)-Cylindricines C−E and (−)-Lepadiformine through a Common Intermediate Derived from an aza-Prins Cyclization and Wharton's Rearrangement

[reaction: see text] Enantioselective total syntheses of (+)-cylindricines C-E and (-)-lepadiformine through a common tricyclic intermediate are described here. These syntheses are concise and feature an aza-Prins cyclization and a seldom-used Wharton rearrangement en route to the common intermediate.

A novel synthesis of guanine PDE inhibitors via tricyclic imidazopyrimidines

A new method for the preparation of developmental tetracyclic guanine PDE inhibitors via a common tricyclic pyrimidine intermediate is described.

Enantioselective synthesis of (-)-codeine and (-)-morphine.

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.

A combined intramolecular Diels-Alder/intramolecular schmidt reaction: formal synthesis of (+/-)-stenine.

Four stereocenters and three rings are established in one step in a new formal synthesis of (±)-stenine (see scheme). This key reaction cascade consists of an intramolecular Diels–Alder reaction followed by an intramolecular Schmidt reaction. The resulting tricyclic intermediate was readily transformed into a known intermediate en route to stenine, thus completing the formal synthesis.

Metalated Epoxides as Carbenoids − Further Advances in the Stereospecific Synthesis of Spirocyclopropanes

The intramolecular cyclopropanation of β,γ-unsaturated metalated epoxides derived from 11 yielded the highly strained tricyclic intermediates 7. The facile hydrolysis of the latter species afforded the α-keto spirocyclopropanes 8 in a stereospecific fashion. Indeed, the stereochemistry of the starting alkenes 11d−e governs the relative configuration of the cyclopropanes 8d−e. Furthermore, these spiro systems readily underwent acid-mediated ring opening by various nucleophiles, leading to the substituted enones 12.

Metalated Epoxides as Carbenoids − Further Advances in the Stereospecific Synthesis of Spirocyclopropanes

The intramolecular cyclopropanation of β,γ-unsaturated metalated epoxides derived from 11 yielded the highly strained tricyclic intermediates 7. The facile hydrolysis of the latter species afforded the α-keto spirocyclopropanes 8 in a stereospecific fashion. Indeed, the stereochemistry of the starting alkenes 11d−e governs the relative configuration of the cyclopropanes 8d−e. Furthermore, these spiro systems readily underwent acid-mediated ring opening by various nucleophiles, leading to the substituted enones 12.

Total synthesis of asimicin and bullatacin.

The efficient total synthesis of asimicin, 1, and bullatacin, 2, has demonstrated the advantages of three different strategies for the synthesis of the tricyclic intermediates 6 and 7, which represent the key fragment of the bis-THF Annonaceous acetogenins. The naked carbon skeleton strategy is based on the production of all asymmetric centers by selective placement of the oxygen functions onto an unsaturated, nonfunctionalized carbon skeleton. Diversity in this approach arises from the relative timing of highly stereoselective reactions, such as the Sharpless asymmetric dihydroxylation (AD) reaction, the Kennedy oxidative cyclization (OC) with rhenium(VII) oxide, the Mitsunobu-type alcohol epimerization reaction, and the Williamson etherification reaction. The convergent strategy, which is based on the combinatorial coupling of two series of diastereomeric fragments, to produce intermediates such as 11 and 12, enjoys the advantages of both efficiency and versatility. The third approach, which is based on partially functionalized intermediates, such as 13, combines the advantages of both the linear and the convergent strategies-synthetic efficiency and diversity.

A short synthesis of donor-acceptor substituted CpCo-capped cyclobutadiene-superphanes

The reaction of 1,1,3,3-tetramethyl-1,3-disilanona-4,8-diyne ( 7) and 1,1,4,4-tetramethyl-1,4-disiladeca-5,9-diyne ( 8) with R-CpCo(CO) 2 (R=H, CH 3) allowed to stop the reaction at the stage of tricyclic intermediates, the latter could be reacted again with R-CpCoL 2(L 2=COD,(CO) 2) to yield CpCo-capped cyclobutadiene-superphanes with different substituents in the two Cp ligands.

ChemInform Abstract: Metalated Epoxides as Carbenoids. Stereospecific Synthesis of Functionalized Spiro Cyclopropanes via Highly Strained Tricyclic Intermediates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Metalated epoxides as carbenoids. Stereospecific synthesis of functionalized spiro cyclopropanes via highly strained tricyclic intermediates

Intramolecular cyclopropanation reaction of β-γ-unsaturated epoxides yields highly strained tricyclo[4,1,0,0 1,5]heptane compounds whose hydrolysis affords α-keto spiro cyclopropanes. Both steps of this one-pot reaction are stereospecific.

Formation of the 7-Oxa-1,4,10-triazatricyclo[8.2.2(5,12)]tetradecane-2,14-dione Ring System: Misrouted Synthesis of a Peptidomimetic.

An attempted synthesis of the tricyclic peptidomimetic 1, designed to imitate a beta-turn tripeptide in tendamistat, afforded instead the 6,6,8-ring system of 2. The key step in the synthesis entailed acylation of the hindered alpha,alpha'-disubstituted morpholine 4.2, which was approached by acylative ring opening of the 3,6-oxazabicyclo[4.2.0]octane 4.3. However, transannular rather than exocyclic cleavage occurred, giving the 1,6-oxazacyclooctane isomer 4.5. Subsequent ring closures to form the bi- and tricyclic intermediates 7.3 and 8.5 were difficult because of the strain being built into the ring systems. After completion of the synthesis, the structures of the intermediates and final product were elucidated by NMR, with three-bond, heteronuclear multiple-bond correlation experiments providing unambiguous evidence for the ring connectivity, and by molecular modeling, which allowed assignment of the stereochemistry. Compound 2 is a modest inhibitor of the target enzyme alpha-amylase (K(i) = 170 &mgr;M in 5% DMSO/water), binding with similar affinity to the tripeptide Ac-Trp-Arg-Tyr-OMe. Although the side-chain attachment points in the ring system of 2 correspond closely to the relative Calpha-positions in tendamistat (rmsd = 0.24 Å), the alignment of the Calpha-Cbeta bonds is poor, illustrating the importance of side-chain orientation in a peptidomimetic.

The Synthesis of Biphenyl Amino Acids and Related 2,3- Dihydroimidazo[1,2-a]dibenz[c,e]azepines

Abstract The synthesis of biphenyl amino acids, designed as potential metabotropic glutamate receptor ligands, is described. Some unexpected tricyclic intermediates were characterised and one such intermediate was further transformed into the related 2,3-dihydroimidazo[1,2-a]dibenz[c,e] azepines.

The chemistry of thujone. XVII. The synthesis of ambergris fragrances and related analogues

A strategy to utilize the thujone-derived enone 1 for the development of a synthetic route to ambergris fragrances is presented. Thujone (8) is transformed to the tricyclic enone 9, via the Robinson annulation reaction, and the latter is then elaborated to the cis-fused tricyclic intermediates 10, 11, and 12. Extrusion of the isopropyl side chain in 12 is achieved through an initial ozonation reaction and the resulting ketone 14 is then treated with m-CPBA to afford 16. Cyclopropyl ring opening in 16 is performed via initial saponification to the alcohol 17 and the latter is then reacted with FeCl3 and sodium acetate to enone 1. The necessary elaboration of a tetrahydrofuran ring attached to ring B of 1 is achieved through reaction of 1 with vinylmagnesium bromide, alkylation, hydroboration, and final acid-catalyzed ring closure of the 1,5-diol 4. The route affords the opportunity of synthesizing a variety of analogues within the Ambrox series.