Synthesis of Some Members of the Hydroxylated Phenanthridone Subclass of the <i>Amaryllidaceae</i> Alkaloid Family

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (±)-Lycoricidine and (±)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels−Alder cycloaddition cascade to construct the core skeleton. The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 °C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required π-bond in the C-ring of (±)-lycoricidine, and (2) conversion of the initially formed Diels−Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B−C ring junction of (±)-7-deoxypancratistatin

An Efficient Synthesis of (±)-Lycoricidine Featuring a Stille−IMDAF Cycloaddition Cascade

A highly efficient total synthesis of (±)-Lycoricidine is described. The synthesis features the ready preparation of the Lycoricidine skeleton by a Stille−IMDAF cycloaddition cascade. The resulting cycloadduct is then used for the stereocontrolled installation of the other functionality present in the C-ring of the target molecule

Synthesis of Some Members of the Hydroxylated Phenanthridone Subclass of the <i>Amaryllidaceae</i> Alkaloid Family

The total synthesis of several members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family has been carried out. (±)-Lycoricidine and (±)-7-deoxypancratistatin were assembled through a one-pot Stille/intramolecular Diels−Alder cycloaddition cascade to construct the core skeleton. The initially formed [4 + 2]-cycloadduct undergoes nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone on further heating at 160 °C. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered vinyl group oriented exo with respect to the oxygen bridge. The resulting cycloadduct was used for the stereocontrolled installation of the remaining functionality present in the C-ring of the target molecules. Key features of the synthetic strategy include (1) a lithium hydroxide induced tandem hydrolysis/decarboxylation/elimination sequence to introduce the required π-bond in the C-ring of (±)-lycoricidine, and (2) conversion of the initially formed Diels−Alder adduct into an aldehyde intermediate which then undergoes a stereospecific decarbonylation reaction mediated by Wilkinson's catalyst to set the trans-B−C ring junction of (±)-7-deoxypancratistatin

Total Synthesis of (±)-Strychnine via a [4 + 2]-Cycloaddition/Rearrangement Cascade

A new strategy for the synthesis of the Strychnos alkaloid (±)-strychnine has been developed and is based on an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium-catalyzed enolate-driven cross-coupling of an N-tethered vinyl iodide

Total Synthesis of (±)-Strychnine via a [4 + 2]-Cycloaddition/Rearrangement Cascade

A new strategy for the synthesis of the Strychnos alkaloid (±)-strychnine has been developed and is based on an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium-catalyzed enolate-driven cross-coupling of an N-tethered vinyl iodide

A One-Residue Switch Reverses the Orientation of a Heme <i>b</i> Cofactor. Investigations of the Ferriheme NO Transporters Nitrophorin 2 and 7 from the Blood-Feeding Insect <i>Rhodnius prolixus</i>

This study represents the identification of a single amino acid residue that has the major responsibility for the isomeric orientation of a heme b cofactor in a ferriheme protein. The insertion of hemin b into the asymmetric environment of a protein pocket facilitates two cofactor orientations, A and B, which is often called “heme rotational disorder”. The proteins studied herein are nitrophorins, a class of ferriheme proteins found in the saliva of the blood-sucking insect Rhodnius prolixus, in this case NP2 and NP7. NMR spectroscopy (pH* 5.5) of the imidazole complex of NP7 revealed solely the A orientation, whereas NP2 shows primarily the B orientation (∼1:5 A:B). The glutamate 27 residue in NP7 is an obvious difference in the heme pocket compared to those of NP1−4, all of which present a valine residue [valine 24 (NP2 and NP3) or valine 25 (NP1 and NP4)] at the same position. Consequently, the mutant NP2(V24E) was prepared and shown to reverse the heme orientation to exclusively A, whereas NP7(E27V) revealed an ∼1:3 A:B ratio. The reversal A ↔ B following the change glutamine ↔ valine was further indicated in circular dichroism (CD) spectroscopy with a positive (A) or negative (B) Δε of the heme Soret band. Moreover, CD spectroscopy was applied to the mutant NP7(E27Q) and indicated mainly the A orientation, which allows us to conclude that the steric hindrance provided by the glutamate residue is responsible for the heme orientation rather then the carboxylate charge

Sequential Aminodiene Diels−Alder Approach to the Ergoline Skeleton

Through a novel sequence of aminodiene Diels−Alder reactions, several substituted amidofurans were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system is the result of a ring opening and dehydration of a transient oxabicyclic adduct formed by an intramolecular Diels−Alder cycloaddition of an amidofuran with a cyclohexenone moiety tethered such that it participates in the cycloaddition as the 2π component. A convenient way to construct the cyclohexenone is to make use of some aminodiene chemistry developed by Rawal. An angular carbomethoxy group is required in order to activate the olefin toward cycloaddition with Rawal's diene. The presence of this activating group not only prevents the isomerization of the advanced ergoline intermediate to a naphthalene but can also be leveraged for an oxidation to provide Uhle's ketone (13). The easily formed Kornfeld ketone analogue 25 was readily transformed into the corresponding triflate 41 by the action of triflic anhydride and a base. Oxidative addition of vinyl triflate 41 to Pd(0) and the ability of the resulting vinyl palladium species to undergo cross-coupling with terminal alkynes prompted us to devise an expeditious route to lysergic acid. Unfortunately, our inability to carry out a regioselective Heck reaction using vinyl triflate 41 and the methylene amino acrylate ester 48 thwarted the completion of the synthesis of lysergic acid

Sequential Aminodiene Diels−Alder Approach to the Ergoline Skeleton

Through a novel sequence of aminodiene Diels−Alder reactions, several substituted amidofurans were readily converted to tricyclic ketones in good yield. The formation of the tricyclic ketone system is the result of a ring opening and dehydration of a transient oxabicyclic adduct formed by an intramolecular Diels−Alder cycloaddition of an amidofuran with a cyclohexenone moiety tethered such that it participates in the cycloaddition as the 2π component. A convenient way to construct the cyclohexenone is to make use of some aminodiene chemistry developed by Rawal. An angular carbomethoxy group is required in order to activate the olefin toward cycloaddition with Rawal's diene. The presence of this activating group not only prevents the isomerization of the advanced ergoline intermediate to a naphthalene but can also be leveraged for an oxidation to provide Uhle's ketone (13). The easily formed Kornfeld ketone analogue 25 was readily transformed into the corresponding triflate 41 by the action of triflic anhydride and a base. Oxidative addition of vinyl triflate 41 to Pd(0) and the ability of the resulting vinyl palladium species to undergo cross-coupling with terminal alkynes prompted us to devise an expeditious route to lysergic acid. Unfortunately, our inability to carry out a regioselective Heck reaction using vinyl triflate 41 and the methylene amino acrylate ester 48 thwarted the completion of the synthesis of lysergic acid

Total Synthesis and Structural Revision of Vannusals A and B: Synthesis of the True Structures of Vannusals A and B

Having determined through total synthesis that the originally assigned structure of vannusals A and B were incorrect, we set out to uncover the identity of the true structures of these novel marine natural products. Our search was based on intelligence gathered by NMR spectroscopy and chemical synthesis and took us through the total synthesis of eight diastereomeric vannusal B structures [2, d-2, 3, d-3, 4, d-4, 5, and d-5, Figure 2]. The true structures of vannusals A and B were finally determined to be d-5 and d-1, respectively. Their total synthesis was based on a highly convergent and efficient strategy that involved fragments vinyl iodide (−)-6 and aldehyde (±)-94, and featured a stereoselective lithium-mediated coupling reaction and a samarium-induced cyclization process that forged the final ring of the carbon framework. The synthetic strategies and technologies developed in these investigations expand the scope of chemical synthesis and render these compounds readily available for biological evaluation, while the NMR spectroscopic insights gained should prove useful in future structural determination endeavors

Total Synthesis and Structural Revision of Vannusals A and B: Synthesis of the True Structures of Vannusals A and B

Having determined through total synthesis that the originally assigned structure of vannusals A and B were incorrect, we set out to uncover the identity of the true structures of these novel marine natural products. Our search was based on intelligence gathered by NMR spectroscopy and chemical synthesis and took us through the total synthesis of eight diastereomeric vannusal B structures [2, d-2, 3, d-3, 4, d-4, 5, and d-5, Figure 2]. The true structures of vannusals A and B were finally determined to be d-5 and d-1, respectively. Their total synthesis was based on a highly convergent and efficient strategy that involved fragments vinyl iodide (−)-6 and aldehyde (±)-94, and featured a stereoselective lithium-mediated coupling reaction and a samarium-induced cyclization process that forged the final ring of the carbon framework. The synthetic strategies and technologies developed in these investigations expand the scope of chemical synthesis and render these compounds readily available for biological evaluation, while the NMR spectroscopic insights gained should prove useful in future structural determination endeavors