Total synthesis of 8,14-dihydromorphinandienone alkaloids.

A collective synthesis of 8,14-dihydronorsalutaridine, 8,14-dihydrosalutaridine, norisosinomenine, and isosinomenine is reported. The strategy provides direct access to the correct oxidation level of the products. The combination of an organocatalyst guanidine superbase, a tertiary amine base, and a dehydrating agent was necessary for the successful Henry-Michael-dehydration cascade to form the phenanthrene motif. The required selective aliphatic nitro reduction could only be achieved under heterogeneous transfer-hydrogenation conditions.

Concise synthesis of the hasubanan alkaloid (±)-cepharatine A using a Suzuki coupling reaction to effect o,p-phenolic coupling.

Suzuki coupling of 10 and 11 resulted in 9, which was O-alkylated to provide 12. Treatment of 12 with CsF in DMF resulted in the formation of the completed core structure 13 in a single step. Reductive amination of 13 completed the synthesis of (±)-cepharatine A, 4.

Access to 7ß-analogs of codeine with mixed µ/δ agonist activity via 6,7-α-epoxide opening.

(-)-Codeine 1 was converted into previously unknown 7ß-methyl-7,8-dihydrocodeine/morphine derivatives such as 13 via classical diaxial opening of α-epoxide 3. Several analogs exhibited dual µ/δ-agonist activity.

Lewis acid catalyzed α-functionalization of ketals for the regioselective synthesis of α-carbamoyl ketals.

Treatment of 1 with DEAD in the presence of BF(3)·OEt(2) gave 2 (R = H), which was N-alkylated to give 2 (R = CH(2)CO(2)Et), and insitu eliminated (E1cb) to give α-carbamoyl ketals.

Formal synthesis of (±)-methyl rocaglate using an unprecedented acetyl bromide mediated Nazarov reaction.

To date the prototype Nazarov cyclization of a cross-conjugated pentadienone to the core structure of the rocaglate natural products has not been successful (9 into 12). It has been found that this conversion can be achieved by the use of acetylbromide in excellent yield and results in a strategically very direct route to these antitumor agents.

Concise formal total synthesis of platensimycin mediated by a stereoselective autoxidation and hydroxyl group directed conjugative reduction.

The synthesis of 13, an advanced intermediate in the Nicolaou synthesis of platensimycin 1, was made from 9 by autoxidation to give 10, which was stereoselectively reduced providing 12. Finally, dehydration of 12 by heating in DMSO resulted in 13.

Synthesis of carbamates from diethoxycarbonyl hydrazine derivatives by E1cB eliminative cleavage of the N-N'-bond rather than reduction.

Treatment of diethoxycarbonyl hydrazine derivatives with methyl bromoacetate/Cs(2)CO(3)/MeCN at 50 degrees C followed by heating to 80 degrees C resulted in N-N' bond cleavage to the corresponding carbamates.

Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative.

Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 degrees C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (+/-)-narwedine 2. Since 2 has been converted into (-)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitromethane/base gave 12, which was reduced to provide 13. Reduction of the nitro group in 13 to an amine, followed by reductive amination under acidic conditions, arrives at the codeine skeleton 15. Elaboration of 15 into (+/-)-codeine proceeds via the previously unknown alpha-epoxide derivative 18. This is the shortest synthesis of codeine (13 steps, 20% overall yield) and, for the first time, allows access to codeine without having to reduce codeinone.

Intramolecular cyclopropene-furan [2 + 4] cycloaddition followed by a cyclopropylcarbinyl rearrangement to synthesize the BCD rings of cortistatin A.

Synthesis of the BCD ring system of cortistatin A has been accomplished in 9 steps and 30% overall yield starting from commercially available 2-methylcyclopent-2-enone. Key transformations include the addition of cyclopropenyllithium 16 to aldehyde 15, an intramolecular cyclopropene-furan [2 + 4] cycloaddition leading to epimers 18/19, and a subsequent cyclopropylcarbinyl rearrangement to afford 24.

An expedient formal total synthesis of (-)-diazonamide A via a powerful, stereoselective O-aryl to C-aryl migration to form the C10 quaternary center.

During the course of studies on the synthesis of diazonamide A 1, an unusual O-aryl into C-aryl rearrangement was discovered that allows partial control of the absolute stereochemistry of the C-10 quaternary stereogenic center. Treatment of 30 with TBAF/THF gave the O-tyrosine ethers 31 and 32 (1:1), which on heating each separately in chloroform at reflux rearranged to 33 and 34 in ratios of 84:16 and 56:44, respectively. This corresponds to a 70% yield of the correct C-10 stereoisomer 33 and a 30% yield of the wrong C-10 stereoisomer 34. Attempts to convert 34 into 33 by ipso-protonation and equilibration were unsuccessful. Confirmation of the stereochemical outcome of the rearrangement was obtained by converting 33 into 37, an advanced intermediate in the first synthesis of diazonamide A by Nicolaou et al. It was also found that the success of the above rearrangement is sensitive to the protecting group on both the tryptophan nitrogen atom and the tyrosine nitrogen atom.

Studies towards the synthesis of the marine alkaloid chartelline C.

The 2,6-dibromoindole 5 underwent regioselective Sonogashira coupling at the 2 position with simple acetylenic partners. While, the imidazole-acetylene 16 failed to couple to 5, the cyclic carbonate 19 succeeded to give 20, which was further elaborated into the indole-imidazole 23.

Thermal and acid-catalyzed Hofmann-Martius rearrangement of 3-N-aryl-2-oxindoles into 3-(arylamino)-2-oxindoles.

[reaction: see text] The Hofmann-Martius rearrangement of 3-N-aryl-2-oxindoles into 3-(arylamino)-2-oxindoles under thermal and acid-catalyzed conditions is described.

Proposed biogenetic origin of secu'amamine A from allosecurinine: a model study to support the intermediacy of the putative aziridinium ion.

[reaction: see text] A model study to support the intermediacy of the aziridinium ion in the proposed biogenetic origin of secu'amamine A from allosecurinine is described.

A mild thermal and acid-catalyzed rearrangement of O-aryl ethers into ortho-hydroxy arenes.

[reaction: see text] An unusual rearrangement of an O-aryl ether to an ortho-hydroxyaryl system was discovered during our studies on the synthesis of diazonamide A. We discuss the exploration of this rearrangement under mild thermal and both Brønsted and Lewis acid-catalyzed conditions.

Synthesis of the tetrahydroisoquinoline alkaloid (+/-)-renieramycin G and A (+/-)-lemonomycinone analogue from a common intermediate.

The total synthesis of tetrahydroisoquinoline alkaloids (+/-)-renieramycin G (4) and a lemonomycinone analogue (7) is described. A general strategy to synthesize both the mono- and bistetrahydroisoquinoline alkaloids from a common advanced intermediate, 17, is presented.

Stereospecific synthesis of (+/-)-1,2-anhydro methyl rocaglate.

The rocaglates and analogues thereof have recently become targets for synthesis because of their potent antitumor activity. One of the major difficulties has been the control of stereochemistry of the adjacent -Ph and -An groups. In this letter we show that 14 is converted into 5 as a single stereoisomer and subsequently transformed into 1,2-anhydro methyl rocaglate 20. [reaction: see text]

New strategy for the synthesis of tetrahydroisoquinoline alkaloids.

[reaction: see text] A general strategy for the formation of 1,3-cis-substituted tetrahydroisoquinolines is described from ortho-iodo imines involving Larock isoquinoline synthesis, addition of organolithium compounds to unactivated isoquinolines, and ionic hydrogenation. In addition, a new synthesis of lactams via an unprecedented azide cyclization in the presence of a sulfonium ion is described.

Anodic Coupling of Diphenylbenzo[k]fluoranthene: Mechanistic and Kinetic Studies Utilizing Cyclic Voltammetry and Electrogenerated Chemiluminescence.

Upon oxidation at a platinum electrode, (7,12-diphenyl)benzo[k]fluoranthene (1) undergoes intermolecular dehydrogenative coupling to form bis-4,4'-(7,12-diphenyl)benzo[k]fluoranthene (2). Further oxidation of this product results in a much slower intramolecular coupling reaction that yields dibenzo{[f,f']-4,4',7,7'-tetraphenyl}diindeno[1,2,3-cd:1',2',3'-lm]perylene (3). 2 can be synthesized via bulk electrolysis of 1 and also by the chemical coupling of 4-bromo-7,12-diphenylbenzo[k]fluoranthene (4) with a nickel catalyst. Compounds 1-3 are capable of electrogenerated chemiluminescence (ECL), and their coupling reactions have been detected and followed using this technique. Cyclic voltammograms of 1 have been digitally simulated to provide mechanistic and kinetic insight into the initial intermolecular oxidative coupling reaction. Evidence supports an EC(2)()EE mechanism, in which the coupling of radical cations of 1 is the rate-limiting step. A second-order rate constant of k = 7500 M(-)(1) s(-)(1) has been determined for the dimerization process by fitting experimental data to theoretical working curves.