page_title: Endiandric acid C
section_title: Biomimetic Total synthesis
hierarchical_section_title: Endiandric acid C / Biomimetic Total synthesis
caption_attribution_description: English: Reaction sequence in Nicolaou's 1982 biomimetic total synthesis of endiandric acid C, originally deriving from File:Biomimetic_synthesis.pdf, here [1], by graphically editing and cropping to correct error displaying diene side chain of produce early, instead of "X" substituent. Compare this and source PDF file to see difference. RELEVANT REFS: K. C. Nicolaou, 2009, Inspirations, Discoveries, and Future Perspectives in Total Synthesis, J. Org. Chem. 74(3):951–972, DOI: 10.1021/jo802351b, see [2], accessed 6 June 2014. AND K. C. Nicolaou, N. A. Petasis, R. E. Zipkin, 1982, The endiandric acid cascade. Electrocyclizations in organic synthesis. 4. Biomimetic approach to endiandric acids A-G. Total synthesis and thermal studies, J. Am. Chem. Soc. 104(20):5560–5562, DOI: 10.1021/ja00384a080, see [3], accessed 6 June 2014. Created by med0349 from indicated file by User:Sharlenech with GraphicConverter9. Le Prof.
context_page_description: Endiandric acid C, isolated from the tree Endiandra introrsa, is a well characterized chemical compound. Endiadric acid C is reported to have better antibiotic activity than ampicillin.
  This genus of trees is in the family Lauraceae. These trees are found in the north-eastern Australian rainforests and other tropical and subtropical regions. However, they are also found in southern Canada and in Chile. Endiandric acid C is also isolated from the species E. xanthocarpa. Endiandric acids are also found in Beilschmiedia trees, which were categorized under the genus Endiandra, but moved to their own genus as they found in cold, high latitude areas, and even in New Zealand. Other endiandric acids are found in B. oligandra and B. anacardioides, which are found in the Western Province of Cameroon.
context_section_description: K. C. Nicolaou's group successfully synthesized endiandric acid, 1, in 1982 as a test of Black's biosynthetic conjecture, using a biomimetic strategy involving series of sterocontrolled electrocyclic reactions. Specifically, they observed that the natural products endiandric acids A and C could have arisen from a common precursor, via slightly different 6π [4s+2s] cycloaddition (Diels-Alder) reactions. This key precursor was in turn accessible biosynthetically via two further thermally allowed sequential 6π electron and 8π electron electrocyclizations.
  The Nicolaou group therefore sought to synthesize endiandric acid C from an acyclic symmetric diacetylenic diol precursor, 14 (as shown); they began with "mild hydrogenation" in the presence of Lindlar catalyst and quinoline, anticipating tetraene diol 15, cyclooctatriene 16, or the fully cyclized bicyclo[4.2.0]octadiene (bicyclic diol) 17. Remarkably, following this 3-6 hour, 25ᵒC process, a 45-55% yield of bicyclic diol 17 could be isolated. Hence, it was not necessary to do anything specific to promote the required sequence of 8π conrotatory and 6π disrotatory cyclizations (further highlighted in supplementary image); they occurred spontaneously on generation of tetraene-diol 15.  Protection of a single alcohol moiety (as TBDPS) was accomplished using the silyl chloride via the corresponding tricyclic iodoether intermediate (not shown), with the internally masked remaining hydroxyl group being released on treatment with zinc dust in acetic acid (giving 18 in 70-80% yield). Bromination of the alcohol under Appel conditions followed by its displacement on treatment with sodium cyanide in HMPA gave nitrile 20, the key intermediate in all of this group's endiandric acid syntheses.
  The title compound was then pursued via DIBAL reduction of the nitrile at low temperature, followed by mild acidic hydrolysis to release aldehyde 21. A series of 7 further steps—condensation to form trans-butenoate 22, thermal intramolecular Diels-Alder reaction to create the tetracyclic endiantric core structure 23, desilylation to unmask alcohol  24, bromination and nitrile formation (as described above) to give  25 and  26, respectively, then hydrolysis of the methyl ester and repeat of the earlier DIBAL/acid hydrolysis sequence—generated the endiantric core structure with pendant aldehyde, 28, that was poised for the final step.  Its treatment with diethyl cinnamylphosphonate and LDA at low temperature in THF (generating en route the anionic olefination reagent) formed the desired diene in good yield in a "geometrically controlled manner", thus providing the desired endiandric acid C product.
caption: Reaction sequence in Nicolaou's 1982 biomimetic total synthesis of endiandric acid C.[citation needed]
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