Total Synthesis of Ivorenolide A Following a Base-Induced Elimination Protocol Debendra K. Mohapatra,* Gonela Umamaheshwar, R. Nageshwar Rao, T. Srinivasa Rao, Sudheer Kumar R, and Jhillu S. Yadav* Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India * S Supporting Information ABSTRACT: A concise and stereocontrolled first total synthesis of Ivorenolide A (1) is reported in 16 longest linear steps with a 13.4% overall yield starting from (+)-diethyl tartrate (DET). Key features are base-induced elimination protocol for the construction of chiral propargyl alcohols in both fragments, Pd-catalyzed cross-coupling of terminal acetylenes, and Shiina’s 2-methyl-6-nitrobenzoic anhydride (MNBA) mediated macrolactonization. M acrolactones with polyacetylene moieties represent a unique family of natural products endowed with impressive biological properties such as immunosuppressive activities. Usually, immunosuppressive agents are used in the treatment of organ grafts and also for autoimmune chronic inflammatory disorders. In the past few decades, the discovery of cyclosporin (CsA) 1 and tacrolimus (FK506) 2 enabled successful transplantation of the major organs in humans. However, neither drug can be used for managing trans- plantation tolerance for the long-term. 3,4 Recently discovered immunosuppressants such as tetranactin, 5 didemnin B, 6 and discodermolide 7 all seem to have related but unique modes of action, suggesting that these compounds have discrete intracellular target mechanisms. In addition, the search for new immunosuppressants that possess better therapeutic effects or those which can be combined with currently used drugs for longer time maintenance and reduced side effects is of great interest. Traditional Chinese medicines (TCM) have been used for centuries in China to treat various immune-mediated disorders. 8 The search for immunosuppressants from TCM has led to the isolation of many limonoids from an antirheumatic Chinese herb Khaya ivorensis A. Chev. (Meliaceae), which has shown cytotoxic, anti-inflammatory, and antimalarial activities. 9 Very recently, Ivorenolide A (1) and B (2) were isolated by Yue et al. from the stem bark of K. ivorensis. 10 These natural products contain conjugated acetylenic bonds including five and four oxygenated centers embedded in 18- and 17- membered macrolides, respectively (Figure 1). Ivorenolide A has been reported to exhibit significant inhibition of ConA- induced T-cell proliferation and LPS-induced B-cell prolifer- ation. Owing to their interesting biological properties and intriguing structural motifs, the Ivorenolides have attracted the attention of synthetic chemists. Herein, a full account of our work is presented which culminated in the first total synthesis of Ivorenolide A, using our own developed protocol for the construction of chiral propargyl alcohols, 11 metal-catalyzed cross-coupling to con- struct a diacetylenic moiety, 12 and Shiina’s MNBA macro- lactonization 13 as a pivotal step. The initial disconnection in the retrosynthesis involved cleavage of the macrolactone linkage at C1 to provide a diyne system (Scheme 1). This diyne could be accessible from an alkyne and a bromoalkyne through a Sonogashira coupling strategy. The alkyne and bromoalkyne fragments could be easily accessible from (+)-DET and known aldehyde 8 16 respectively, by utilizing sequences which relied on the implementation of a chiral propargyl alcohol construction protocol. The synthesis of alkyne fragment 5 is delineated in Scheme 2, which was prepared in a stereoselective manner commenced with the primary alcohol 7 which was in turn obtained from (+)-DET. 14 TBS protected primary alcohol 7 was oxidized with Dess-Martin periodinane (DMP) 15 and subjected to a Wittig reaction with bromo(9-((4-methoxybenzyl)oxy)nonyl)- triphenyl phosphorane in the presence of LHMDS to afford olefin 9 as an exclusive Z-isomer in 78% yield. The TBS group was deprotected using TBAF to afford 10 in 97% yield. The primary alcohol was converted to chloride 11 using CCl 4 -Ph 3 P under reflux conditions, which was subjected to our protocol 11 of a base-induced elimination reaction to provide the chiral acetylenic alcohol 12, with n-BuLi at -78 °C, in 87% yield. The product was converted to its corresponding MOM ether 5 Received: January 15, 2015 Published: January 28, 2015 Figure 1. Structures of Ivorenolide A (1) and B (2). Letter pubs.acs.org/OrgLett © 2015 American Chemical Society 979 DOI: 10.1021/acs.orglett.5b00138 Org. Lett. 2015, 17, 979-981