First Enantioselective Synthesis of Tetracyclic Intermediates en route to Madangamine D

The enantioselective synthesis of advanced tetracyclic precursors of madangamine D, bearing rings ABCD of this alkaloid, is reported. The saturated 14-membered ring is assembled from functionalized diazatricyclic intermediates 10 following either ring-closing metathesis or macrolactamization strategies

Total Synthesis of (+)-Madangamine D

Madangamines are a group of bioactive marine sponge alkaloids, embodying an unprecedented diazapentacyclic skeletal type. The enantioselective total synthesis of madangamine D has been accomplished, and represents the first total synthesis of an alkaloid of the madangamine group. It involves the stereoselective construction of the diazatricyclic ABC core using a phenylglycinol-derived lactam as the starting enantiomeric scaffold and the subsequent assembly of the peripheral macrocyclic rings. The synthesis provides, for the first time, a pure sample of madangamine D and confirms the absolute configuration of this alkaloid family

Total synthesis of (+)-Madangamine D

Madangamines are a small group of marine alkaloids isolated from sponges of the order Haplosclerida collected by hand using scuba on reefs off Madang, Papua New Guinea. Madangamine A show significant in vitro cytotoxicity against murine leukemia (P388), human lung (A549), brain (U373) and breast (MCF-7). However, no bioactivity data have been reported for madangamines B-E, and further pharmacological research on this alkaloid group has been prevented by the minute amount of alkaloid samples. We present herein the enantioselective synthesis of (+)-madangamine D, which represents the first total synthesis of an alkaloid of the madangamine group. Using a phenylglycinol-derived bicyclic lactam as the starting enantiomeric scaffold we were able to control the stereochemistry of all three contiguous stereogenic centers on the BC ring system, while A ring was formed through a stereocontrolled cascade aminohydroxylation reaction, in which an “in situ generated” amine attacks an epoxide ring. This strategy provides a direct route to the diazatricyclic ABC core common to all madangamines, with the appropriate functionalization to allow the subsequent building of the macrocyclic D and E rings of these alkaloids. The saturated 14-membered D ring of madangamine D, leading to the tetracyclic ABCD system was efficiently constructed using a ring-closing metathesis reaction followed by a catalytic hydrogenation of the resulting double bond. The (Z,Z)-unsaturated 11-membered E ring, required to complete the synthesis of madangamine D was successfully assembled in a straightforward manner using a Z-stereoselective Wittig reaction followed by an intramolecular macrolactamization. Madangamine D showed significant in vitro cytotoxic activity against human colon HT29 (GI50 4.4 µg/mL) and pancreas PSN1 (GI50 7.4 µg/mL) cancer cell lines, but was inactive against lung NSCLC A549 and breast MDA-MB-231 cancer cell lines at the highest assayed concentration (10 µg/mL).Las esponjas del orden Haplosclerida representan una importante fuente de alcaloides estructuralmente diversos pero biogenéticamente relacionados, siendo las madangaminas uno de los menos estudiados desde el punto de vista sintético. En 1994 fue aislada el primer alcaloide de este grupo, la Madangamina A de la esponja marina Xestospongia ingens1 y unos años más tarde se aislaron cuatro nuevos alcaloides, las madangaminas BE.2 Estructuralmente, las madangamines son alcaloides pentacíclicos y se caracterizan por presentar un núcleo diazatricíclico (anillos ABC) y dos puentes de carbonados. El anillo macrocíclico D es diferente en cada madangamina en tamaño, así como en el grado y la posición de insaturación, mientras que el anillo E es idéntico en todas ellas. En la presente Tesis Doctoral presentamos la síntesis enantioselectiva de ()-madangamine D,3 que ofrece por primera vez una muestra pura de este producto natural y constituye la primera síntesis total de un alcaloide de la grupo de las madangamines. Usando de una lactama bicíclica derivada del fenilglicinol como el scafold enantiomérico de partida, nuestro enfoque consiste en la construcción inicial del núcleo diazatricíclico ABC y la posterior construcción de los anillos macrocíclicos D y E. La lactama de partida 2 es fácilmente accesible por ciclocondensación de oxoester 1 con el (R)-fenilglicinol, en un proceso en donde se instala el primer estereocentro. El intermedio diazatríclico se prepara a partir de una lactama insaturada derivada de 2. En este proceso son claves una reacción de adición conjugada estereoselectiva, el cierre del anillo carbocíclico mediante metátesis, una alquilación estereoselectiva y finalmente cierre del anillo A por aminohidroxilación. La anulación de los anillos macrocíclicos se lleva a cabo mediante una reacción de cierre del anillo por metátesis (anillo D) y una olefinación de Wittig seguida de macrolactamización (anillo E). Los datos de RMN de 1H y 13C de nuestra madangamina sintética fueron coincidentes con los reportados para el producto natural. La madangamina D sintética muestra citotoxicidad in vitro contra las líneas celulares de cáncer HT29 de colon humano y PSN1 páncreas

Model studies on the synthesis of madangamine alkaloids. Assembly of the macrocyclic rings

Using simplified model derivatives, the assembly of the macrocyclic rings of madangamines, including the 13- and 14-membered D rings of madangamines C-E, the all-cis-triunsaturated 15-membered D ring of madangamine A, and the (Z,Z)-unsaturated 11-membered E ring common to madangamines A-E, has been studied

Total synthesis of (+)-Madangamine D (Tesi)

[spa] Las esponjas del orden Haplosclerida representan una importante fuente de alcaloides estructuralmente diversos pero biogenéticamente relacionados, siendo las madangaminas uno de los menos estudiados desde el punto de vista sintético. En 1994 fue aislada el primer alcaloide de este grupo, la Madangamina A de la esponja marina Xestospongia ingens1 y unos años más tarde se aislaron cuatro nuevos alcaloides, las madangaminas BE.2 Estructuralmente, las madangamines son alcaloides pentacíclicos y se caracterizan por presentar un núcleo diazatricíclico (anillos ABC) y dos puentes de carbonados. El anillo macrocíclico D es diferente en cada madangamina en tamaño, así como en el grado y la posición de insaturación, mientras que el anillo E es idéntico en todas ellas. En la presente Tesis Doctoral presentamos la síntesis enantioselectiva de ()-madangamine D,3 que ofrece por primera vez una muestra pura de este producto natural y constituye la primera síntesis total de un alcaloide de la grupo de las madangamines. Usando de una lactama bicíclica derivada del fenilglicinol como el scafold enantiomérico de partida, nuestro enfoque consiste en la construcción inicial del núcleo diazatricíclico ABC y la posterior construcción de los anillos macrocíclicos D y E. La lactama de partida 2 es fácilmente accesible por ciclocondensación de oxoester 1 con el (R)-fenilglicinol, en un proceso en donde se instala el primer estereocentro. El intermedio diazatríclico se prepara a partir de una lactama insaturada derivada de 2. En este proceso son claves una reacción de adición conjugada estereoselectiva, el cierre del anillo carbocíclico mediante metátesis, una alquilación estereoselectiva y finalmente cierre del anillo A por aminohidroxilación. La anulación de los anillos macrocíclicos se lleva a cabo mediante una reacción de cierre del anillo por metátesis (anillo D) y una olefinación de Wittig seguida de macrolactamización (anillo E). Los datos de RMN de 1H y 13C de nuestra madangamina sintética fueron coincidentes con los reportados para el producto natural. La madangamina D sintética muestra citotoxicidad in vitro contra las líneas celulares de cáncer HT29 de colon humano y PSN1 páncreas.[eng] Madangamines are a small group of marine alkaloids isolated from sponges of the order Haplosclerida collected by hand using scuba on reefs off Madang, Papua New Guinea. Madangamine A show significant in vitro cytotoxicity against murine leukemia (P388), human lung (A549), brain (U373) and breast (MCF-7). However, no bioactivity data have been reported for madangamines B-E, and further pharmacological research on this alkaloid group has been prevented by the minute amount of alkaloid samples. We present herein the enantioselective synthesis of (+)-madangamine D, which represents the first total synthesis of an alkaloid of the madangamine group. Using a phenylglycinol-derived bicyclic lactam as the starting enantiomeric scaffold we were able to control the stereochemistry of all three contiguous stereogenic centers on the BC ring system, while A ring was formed through a stereocontrolled cascade aminohydroxylation reaction, in which an “in situ generated” amine attacks an epoxide ring. This strategy provides a direct route to the diazatricyclic ABC core common to all madangamines, with the appropriate functionalization to allow the subsequent building of the macrocyclic D and E rings of these alkaloids. The saturated 14-membered D ring of madangamine D, leading to the tetracyclic ABCD system was efficiently constructed using a ring-closing metathesis reaction followed by a catalytic hydrogenation of the resulting double bond. The (Z,Z)-unsaturated 11-membered E ring, required to complete the synthesis of madangamine D was successfully assembled in a straightforward manner using a Z-stereoselective Wittig reaction followed by an intramolecular macrolactamization. Madangamine D showed significant in vitro cytotoxic activity against human colon HT29 (GI50 4.4 µg/mL) and pancreas PSN1 (GI50 7.4 µg/mL) cancer cell lines, but was inactive against lung NSCLC A549 and breast MDA-MB-231 cancer cell lines at the highest assayed concentration (10 µg/mL)

Access to Enantiopure Advanced Intermediates en Route to Madangamines

The synthesis of enantiopure ABCE and ABCD tetracyclic advanced intermediates en route to madangamine alkaloids and studies for the construction of the triunsaturated 15-membered D ring of madangamine B and the saturated 13-membered D ring of madangamine E are reported

First Enantioselective Synthesis of Tetracyclic Intermediates en route to Madangamine D

The enantioselective synthesis of advanced tetracyclic precursors of madangamine D, bearing rings ABCD of this alkaloid, is reported. The saturated 14-membered ring is assembled from functionalized diazatricyclic intermediates 10 following either ring-closing metathesis or macrolactamization strategies

Total Synthesis of (+)-Madangamine D

Madangamines are a group of bioactive marine sponge alkaloids, embodying an unprecedented diazapentacyclic skeletal type. The enantioselective total synthesis of madangamine D has been accomplished, and represents the first total synthesis of an alkaloid of the madangamine group. It involves the stereoselective construction of the diazatricyclic ABC core using a phenylglycinol-derived lactam as the starting enantiomeric scaffold and the subsequent assembly of the peripheral macrocyclic rings. The synthesis provides, for the first time, a pure sample of madangamine D and confirms the absolute configuration of this alkaloid family

The Alkaloids of the Madangamine Group

This chapter is focused on madangamines, a small group of complex diamine alkaloids isolated from marine sponges of the order Haplosclerida, and covers their isolation, characterization, biogenesis, biological activity, and synthesis. Structurally, madangamines are pentacyclic alkaloids with an unprecedented skeletal type, characterized by a common diazatricyclic core and two peripheral macrocyclic rings. The isolation of these alkaloids from Xestospongia ingens (madangamines A E) and Pachychalina alcaloidifera (madangamine F) is described in detail. Physical and complete spectroscopic 1H and 13C NMR data are included. The proposed biogenesis of madangamines from ammonia, a functionalized three-carbon unit, and saturated or unsaturated linear long-chain dialdehydes, via partially reduced bis-alkylpyridine macrocycles, is discussed. The synthesis of alkaloids of the madangamine group has been little explored, with only one total synthesis reported so far, that of (þ)-madangamine D. This review also describes several model synthetic approaches to the diazatricyclic ABC core of these alkaloids, as well as model studies on the construction of the (Z,Z)-unsaturated 11-membered E macrocycle common to madangamines A E, the 13- and 14-membered D rings of madangamines C E, and the all-cistriunsaturated 15-membered D ring of madangamine A. Some members of this group have shown significant in vitro cytotoxicity against a number of cancer cell lines