A Catalytic Asymmetric Ene Reaction for Direct Preparation of α-Hydroxy 1,4-Diketones as Intermediates in Natural Product Synthesis

Asymmetric access to α-hydroxy-1,4-diketones has been achieved by direct ene coupling of silyl enol ethers with glyoxal electrophiles, mediated by a chiral N,N′-dioxide–nickel(II) complex catalyst. Successful union of a polyketide silyl enol ether with an α-quaternary glyoxal, generated by dioxirane oxidation of an α-diazo ketone, models a proposed C5–C6 disconnection of the polyketide and spirocyclic imine domains of the marine natural product, portimine.

Carbon–Carbon Bond Construction

Carlo Siciliano and Angelo Liguori of the Università della Calabria showed (J. Org. Chem. 2012, 77, 10575) that an amino acid 1 could be both protected and activated with Fmoc-Cl, so subsequent exposure to diazomethane delivered the Fmoc-protected diazo ketone 2. Pei-Qiang Huang of Xiamen University activated (Angew. Chem. Int. Ed. 2012, 51, 8314) a secondary amide 3 with triflic anhydride, then added an alkyl Grignard reagent with CeCl3 to give an intermediate that was reduced to the amine 4. John C. Walton of the University of St. Andrews found (J. Am. Chem. Soc. 2012, 134, 13580) that under irradiation, titania could effect the decarboxylation of an acid 5 to give the dimer 6. Jin Kun Cha of Wayne State University demonstrated (Angew. Chem. Int. Ed. 2012, 51, 9517) that a zinc homoenolate derived from 7 could be transmetalated, then coupled with an electrophile to give the alkylated product 8. The Ramberg-Bäcklund reaction is an underdeveloped method for the construction of alkenes. Adrian L. Schwan of the University of Guelph showed (J. Org. Chem. 2012, 77, 10978) that 10 is a particularly effective brominating agent for this transformation. Daniel J. Weix of the University of Rochester coupled (J. Org. Chem. 2012, 77, 9989) the bromide 12 with the allylic carbonate 13 to give 14. The Julia-Kocienski coupling, illustrated by the addition of the anion of 16 to the aldehyde 15, has become a workhorse of organic synthesis. In general, this reaction is E selective. Jirí Pospísil of the University Catholique de Louvain demonstrated (J. Org. Chem. 2012, 77, 6358) that inclusion of a K+-sequestering agent switched the selectivity to Z. Yoichiro Kuninobu, now at the University of Tokyo, and Kazuhiko Takai of Okayama University constructed (Org. Lett. 2012, 14, 6116) the tetrasubstituted alkene 20 with high geometric control by the Re-catalyzed addition of 19 to the alkyne 18. André B. Charette of the Université de Montréal converted (Org. Lett. 2012, 14, 5464) the allylic halide 21 to the alkyne 22 by displacement with iodoform followed by elimination. In an elegant extension of his studies with alkyl tosylhydrazones, Jianbo Wang of Peking University added (J. Am. Chem. Soc. 2012, 134, 5742) an alkyne 24 to 23 to give 25.

The Reisman Synthesis of (+)-Salvileucalin B

Salvileucalin B 3 exhibits modest cytotoxicity against A549 (human lung adenocarcinoma) and HT-29 (human colon adenocarcinoma) cell lines. The compelling interest of 3 is its complex, highly functionalized heptacyclic skeleton. Sarah E. Reisman of the California Institute of Technology envisioned (J. Am. Chem. Soc. 2011, 133, 774) that the intramolecular cyclization of the diazo ketone 1 could offer an efficient entry to 2 and thus to 3. The key intermediate for the preparation of 1 was the acid 11. It was not possible to achieve communication between the two stereogenic centers of 11, so the decision was taken to establish these independently. This led to a strategy centered on the construction of the 1,2,3,4-tetrasubstituted aromatic ring. The absolute configuration of the stereogenic center of 8 was set by enantioselective addition of 5 to the commercial aldehyde 4. The absolute configuration of the second center was set using the Myers protocol. Although 10 could not be hydrolyzed without epimerization, cyclization followed by hydrolysis was effective, delivering 11 as a 10:1 mixture of diastereomers. From the algebra of mutual resolution, the major diastereomer, separated at a later stage, was of high enantiomeric purity. The acid 11 was homologated, first by the Arndt-Eistert procedure, then by condensation of the methyl ester so prepared with the anion of acetonitrile. Exposure of the derived diazo nitrile 1 to Cu catalysis under brief microwave irradiation led to smooth cyclization to the hexacyclic ketone 2. Although the skeleton of 2 was readily assembled, it is highly strained. This was made clear on Dibal reduction of the derived enol triflate. The product was clearly not the desired aldehyde 2, but rather 12, the product of Claisen rearrangement. Reasoning that the Claisen rearrangement is thermally reversible, and that the ether 12 would be stable to hydride, they carried forward with Dibal reduction—and were rewarded by the appearance of the desired primary alcohol from the reduction of 2. Pd-mediated cyclocarbonylation delivered 13, which was selectively oxidized to (+)-salvileucalin B 3.

Natural Product Synthesis by C–H Functionalization: (±)-Allokainic Acid (Wee), (–)-Cameroonan-7α-ol (Taber), (+)-Lithospermic Acid (Yu), (–)-Manabacanine (Kroutil), Streptorubin B, and Metacycloprodigiosin (Challis)

Andrew G.H. Wee of the University of Regina showed (Org. Lett. 2010, 12, 5386) that with the bulky BTMSM group on N and the electron-withdrawing pivaloyloxy group deactivating the alternative C–H insertion site, the diazo ketone 1 cleanly cyclized to 2, with 21:1 diastereocontrol. Oxidative cleavage of the arene followed by amide reduction and methylenation of the ketone converted 2 into (±)-allokainic acid 3. Intermolecular C–H insertion was the key step in a complementary route to (±)-kainic acid reported (Org. Lett. 2011, 13, 2674) by Takehiko Yoshimitsu of Osaka University. Rh-mediated intramolecular C–H insertion was also the first step in our (J. Org. Chem. 2011, 76, 1874) synthesis of (–)-cameroonan-7α-ol 6. In the course of that synthesis, seven of the C–H bonds of 4 were converted to C–C bonds. Jin-Quan Yu of Scripps/La Jolla oxidatively activated (J. Am. Chem. Soc. 2011, 133, 5767) the ortho H of 8 with catalytic Pd, then engaged that intermediate with 7 in a Heck coupling, to give 9, and thus (+)-lithospermic acid 10. The starting acid 8 was prepared by enantioselective Rh-mediated intramolecular C–H insertion. Wolfgang Kroutil of the University of Graz found (Angew. Chem. Int. Ed. 2011, 50, 1068) that berberine bridging enzyme (BBE) from the California poppy could be used preparatively to cyclize a variety of tetrahydroisoquinolines, including 11 to give (–)-manibacanine 13. Although this is clearly a Mannich-type cyclization, a simple Mannich reaction gave a 40:60 mixture of regioisomers, each of them racemic. The enzyme effected cyclization to a 96:4 ratio of regioisomers, and only one enantiomer of 11 participated. Gregory L. Challis of the University of Warwick harnessed (Nature Chem. 2011, 3, 388) the [2Fe-2S] Rieske cluster enzyme RedG of Streptomyces coelicolor to effect oxidative cyclization of 14 to streptorubin B 15. An ortholog of the enzyme cyclized 14 to metacycloprodigiosin 16. It is interesting to speculate as to whether the cyclizations are initiated by the activation of an H on the alkyl sidechain or by oxidation of the pyrrole.

Studies Directed Towards the Preparation of Probes for the Photoaffinity Labelling of Gibberellin Receptors

Model studies for the preparation of photoaffinity probes designed to explore the nature of gibberellin receptor sites have provided a wide range of gibberellin derivatives that should afford useful scaffolds incorporating auxiliary groups attached to C-2 and C-12. Methodology features the stereocontrolled opening of 2β,3β-epoxy gibberellins by attack on the lower face at C-2, while functionalization of C-12 was effected by the rhodium acetate-catalyzed CH insertion reaction of a 17-diazo ketone. Compounds were screened for bioactivity in growth and barley endosperm-based bioassays.