Organic Chemistry Portal
Organic Chemistry Highlights

Monday, April 21, 2014
Tristan H. Lambert
Columbia University

Total Synthesis of C-O Natural Products

Weiping Tang at the University of Wisconsin at Madison reported (J. Am. Chem. Soc. 2013, 135, 12434. DOI: 10.1021/ja406255j) the total synthesis of the tropone-containing norditerpenes hainanolidol (6) and harringtonolide (7) by making use of a strategic [5+2] oxidopyrylium cycloaddition. First, the known ketone 1 was converted through a number of steps to cycloaddition precursor 2. Treatment with DBU then effected the key cycloaddition to furnish the complex polycyclic compound 3. Additional manipulations revealed structure 4 with the lactone ring in place. The tropone ring of the natural structures was constructed by reaction of the cycloheptadiene moiety of 4 with singlet oxygen followed by Kornblum-DeLaMare rearrangement with DBU to afford ketone 5. Double elimination using TsOH then produced hainanolidol (6). The free hydroxyl of 6 was engaged in a C-H-functionalizing cyclization using Pd(OAc)4 to yield harringtonolide (7) as well.

Hanfeng Ding at Zhejiang University developed (Angew. Chem. Int. Ed. 2013, 52, 13256. DOI: 10.1002/anie.201307426) a concise route to indoxamycin F (12) (as well as the related indoxamycins A and C). The complex intermediate 9 was accessed in only four steps from the bicyclic ketone 8, which in turn was prepared in by a route involving an Ireland-Claisen rearrangement and a reductive 1,6-enyne cyclization (not shown). An impressive oxa-conjugate addition / methylenation reaction to produce 11 was accomplished by treatment of 9 with Grignard 10 followed by Eschenmoser’s salt. Some final decorative work then led to indoxamycin F (12).

The strained polycyclophane natural product cavicularin (18) was synthesized in enantioenriched form by an innovative strategy reported (Angew. Chem. Int. Ed. 2013, 52, 10472. DOI: 10.1002/anie.201304929) by Keisuke Suzuki at the Tokyo Institute of Technology. After assemblage of the polyaromatic 13, racemic cyclophane 14 was produced by SNAr cyclization induced by CsF and CaCO3. Deracemization of 14 was achieved by the unusual step of swapping of the racemic sulfoxide moiety for an enantioenriched one (using reagent 15), and a subsequent diastereoselective (41:1 dr) deprotection of one of the phenolic MOM ethers then furnished enantioenriched 16. A series of steps were used to convert 16 to aryl iodide 17 to set up the penultimate radical cyclization with TTMS and AIBN, which forged the final ring of the natural product. Global deprotection of 17 then yielded (+)-cavicularin (18).

Armen Zakarian at the University of California at Santa Barbara disclosed (J. Am. Chem. Soc. 2013, 135, 14552. DOI: 10.1021/ja408231t) a route to the notoriously challenging maoecrystal V (25). The strategy was centered on creation of the core tetrahydrofuran ring of the natural product by way of a C-H functionalizing cyclization of 19 to form 20 with 10:1 dr. This material was converted to the vinyl silane 21, which underwent intramolecular Diels-Alder cycloaddition to produce the tricycle 22. After processing to selenocarbonate 23, the lactone ring-containing 24 was forged by radical cyclization with TTMS and AIBN. Further manipulations and strategic use of ring-closing metathesis (not shown) then completed the total synthesis of maoecrystal V (25).

T. H. Lambert, Org. Chem. Highlights 2014, April 21.