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...

SULTAN DARVESH, ANDREW S. GRANT, DAVID I. MAGEE, and ZDENEK VALENTA. Can. J. Chem. 67, 2237Chem. 67, (1989. An intermediate (20) containing four of the five rings and seven of the ten chiral centers of bruceantin (1) was prepared. In a key reaction, 3-iodo-1 -trimethylsilyl-5-hexen-I -yne (9) was found to add chemoselectively and stereoselectively to a dianion. The sequence also includes a selective attack by a sulfinate (17) on the terminal acetylene C-atom of the dianion of a keto acetylene, a concomitant cyclization in which the acetylene acts as an electrophile, and the use of the resulting allyl sulfoxide for the introduction of oxygen functionality by a reductive rearrangement. Structural diversity (I), biological activity (2), and syntheti-8 cally challenging functionality have recently made the quassinoids frequent targets for total synthesis (3). We wish to report an exceptionally selective alkylation and the development of an efficient cyclization-0-functionalization sequence in a synthetic approach to the natural quassinoid bruceantin (1). The overall strategy is shown in the structural formula 2 in which H the three arrows point towards the electrophilic centers and the numbers indicate the order in which the bonds were formed.The necessary A,B-ring intermediate 8 was readily prepared from 2-methylcyclohexane-1,3-dione as shown in Scheme 1 .2 Addition of HCN to the selectively blocked diene dione 7, mp 1 148-150°C, gave a chromatographically separable mixture of cyanoketones 8a, H nmr signal at 6 1.47), and 8b, mp 182-183°C (Clo-methyl signal at 6 1.10) in a varying ratio.3 Treatment of 8a + 8 b with 2.2 equivalents of lithium pyrrolidide4 followed by a reaction with 1.2 equivalents of iodide 95 gave the alkylated product Figure 1 suggests a possible arrangement of the two reacting species to explain the observed enantioselectivity (C14 in 10). @ ; :This is supported by the X-ray study, which shows the side 21'0chain in 10 to be in a conformation similar to that shown in 2'Revision received July 17, 1989. 2~1 1 compounds described here are racernic. Enantiomerically pure compounds should be readily available using known methods (4).3The structures of 8a and 10 were determined by X-ray analysis by Dr. Peter S. White of this department.4This base, rather than a more conventional hindered base was used because it alone achieved an efficient dianion formation from both epimers of 8. The resulting py~~olidine did not react with 9 under the reaction conditions. 59 was prepared most conveniently in a seven-step sequence (32% overall yield) from propargyl alcohol via its THP derivative, silylation, hydrolysis of THP-ether, oxidation with pyridinium dichromate, allylGrignard reaction, mesylation, and displacement by I-.Can. J. Chem. Downloaded from www.nrcresearchpress.com by 34.215.51.103 on 05/11/18

In a synthetic approach to the quassinoid bruceantin (2), the key intermediate 8 obtained via alkylation of a dianion has been transformed into the pentacyclic intermediate 33 via an ABDC ring forming strategy. The key steps involved in this route are as follows: a unique acid catalyzed cyclization, 19 + 20; an intramolecular Michael reaction, 24 + 28; and an ally1 sulfoxide [2,3]-sigmatropic rearrangement to introduce the axial C12 alcohol, 31 + 33.

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Synthetic Studies Towards Bruceantin. Part 1. Establishment of the Carbon Network.-The alkyne (VIII) contains all required C-atoms, rings A and B, and four of the required 10 chiral centers of the biologically active quassinoid bruceantin (IX). Various alkylation and Michael addition procedures for the introduction of a suitable side-chain into the epimeric nitriles (VI) are studied; high chemo-and diastereoselectivities are obtained by alkylation of the hexenyne (VII) with the dianion of (VI). -(DARVESH, S.; GRANT, A. S.; MAGEE, D. I.; VALENTA, Z.; Can. J. Chem. 69 (1991) 4, 712-722; Dep. Chem., Univ. New Brunswick, Fredericton, New Brunswick, Can. E3B 6E2; EN)