Synthetic studies towards bruceantin. Part 1. Establishment of the carbon network

Abstract

SULTAN DARVESH, ANDREW S. GRANT, DAVID I. MAGEE, and ZDENEK VALENTA. Can. J. Chem. 69,712 (1991). In a synthetic approach to the biologically active quassinoid bruceantin 1, intermediate 47 was prepared, which contains all required C-atoms, rings A and B, and four of the 10 chiral centers of bruceantin. The possibilities for a convergent strategy were explored, in which a 5-carbon unit would be joined to a 15-carbon unit by three bonds. After the study of various alkylations and Michael additions needed for the key step, it was found that 3-iodo-1-trimethylsilyl-5-hexenyne 44 adds to the dianion of methyl ketone nitriles 3 and 13 chemo-, diastereo-, and enantioselectively.Key words: bruceantin, quassinoids, alkylation, Michael addition.SULTAN DARVESH, ANDREW S. GRANT, DAVID I. MAGEE et ZDENEK VALENTA. Can. J. Chem. 69,712 (1991) Dans une approche i la synthkse de la quassinoide bructantine (1) biologiquement active, on a prtpard I'intermtdiaire 47 qui contient tous les atomes de carbone requis, les cycles A et B ainsi que quatre des 10 centres chiraux de la bructantine. On a explort les possibilitks de strattgie convergente dans lesquelles une unit6 de cinq atomes de carbone serait relite i une unit6 de 15 atomes de carbone par trois liaisons. Aprts avoir ttudiC diverses alkylations et additions de Michael requises pour l'ttape clt, on a trouvt que le 3-iodo-I-trimtthylsilyl-hextn-5-yne (44) s'additionne aux dianions des mtthylcCtone-nitriles 3 et 13 d'une faqon chtmo-, diasttrdo-et tnantio-stlective.Mots clks : bructantine, quassinoides, alkylation, addition de Michael.[Traduit par la rtdaction]The last two decades have seen the Simaroubaceae family of the plant kingdom make a prominent mark in natural product chemistry. The bitter substances produced in plants of this family, known as the quassinoids (1, 2), have received increased attention with the finding that some of them possess strong antileukemic activity in the murine lymphocytic leukemia P-388 test system, in addition to antimalarial, amebicidal, and antiviral activities.The wealth of information gathered in the last two decades has shown what structural features are required for the antineoplastic activity exhibited by the quassinoids (3). An A-ring enone function, a C 6 or a C15 ester function, and an oxymethylene bridge between C 8 and C11 or C13 are essential for optimal activity. Due to this functional and stereochemical complexity, coupled with the potential use in cancer and other therapies, a considerable amount of synthetic activity has been expended towards these compounds (4). Four tetracyclic members of the C20 picrasane family have been synthesized, all in racemic form (5), and just recently an enantioselective synthesis has been reported for three others (4a). Finally, the synthesis of racemic 15-deoxybruceolide and a relay conversion of the naturally derived (-)-form of this compound into (-)-bruceantin 1 have been reported.(4/z). From the scarcity of completed syntheses, it is evident that much work is still required in this area, es...

Synthesis of 12‐epi‐Protopanaxadiol and Formal Synthesis of Ginsenoside Chikusetsusaponin‐LT8

“…As the bio‐inspired strategy did not afford the valuable intermediate, we have envisaged a “ring‐by‐ring” sequence to form the tetracyclic skeleton of protopanaxadiol (Scheme ). The B/C‐ring system has been prepared by the annulation of 2‐methylcyclohexa‐1,3‐dione ( 16 ) using ethyl vinyl‐ketone to afford a Wieland‐Miescher‐type ketone, which was further reduced into alcohol 17 . A second annulation using the ethyl vinyl‐ketone, followed by a reductive Birch‐alkylation, completed the construction of the A/B/C‐ring system of protopanaxadiol (compound 18 ), It is worth mentioning that compound 18 can be obtained with a good ee by utilizing an enzymatic resolution .…”

Diastereoselective Electrophile‐Directed Alkylations

“…The alkylations of lithiated acetonitriles with chiral electrophiles are usually not selective though the alkylation of phenylacetonitrile with (bromoethyl)benzene is anomalous because one diastereomer selectively crystallizes from the reaction mixture. [11c]An exception is the alkylation of the ketonitrile dianion derived from 66 performed during the synthesis of bruceantin (Scheme ) . The ketonitrile 66 effected kinetic resolution of the acetylenic iodide 67 .…”

Unexpected Racemization in the Course of the Acetalization of (+)-(S)-5-Methyl-Wieland–Miescher Ketone with 1,2-Ethanediol and TsOH under Classical Experimental Conditions

“…The (±)-(RS)-and (+)-(S)-and (-)-(R)-5-methyl-Wieland-Miescher ketones ((±)-(RS)-, (+)-(S)and (-)-(R)-5,8a-dimethyl-3,4,8,8a-tetrahydro-naphtalene-1,6(2H,7H)-diones) ((±)-1 , (+)-1, and (-)-1 , Figure 1) are important synthons in the diastereo and enantioselective synthesis of biological and/or pharmacological interesting compounds. Racemate (±)-1 can be obtained by the Robinson annulation of ethyl vinyl ketone 2 with 2-methyl-1,3-cyclohexanedione 3 (Scheme 1) [1][2][3][4][5][6][7][8][9][10][11][12]15,18,19,[21][22][23][24][92][93][94][95][96][97]. This process does not require the isolation of intermediate 4.…”