Asymmetric Total Synthesis of Fredericamycin A: An Intramolecular Cycloaddition Pathway

Abstract

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.

Access to Highly Functionalized Indanes from Arynes and α,γ-Diketo Esters

“… Specifically, Indinavir, one of World Health Organization’s List of Essential Medicines, is used for treating HIV/AIDS. Fredericamycin A displays potent antitumor activity against a variety of in vivo tumor models, involving P388 leukemia, B16 melanoma, and CD8F mammary. SB 209670 exhibits a highly potent antagonist selective for the endothelin receptors.…”

1-Alkoxyvinyl Ester as an Excellent Acyl Donor: Efficient Macrolactone Synthesis

“…The second approach was accomplished by a lipase-catalyzed desymmetrization and kinetic resolution followed by the aromatic Pummerer-type reaction. − In the total synthesis of racemic fredericamycin A, we demonstrated that only the aromatic Pummerer-type reaction could introduce the oxygen atom at the B-ring . Moreover, we reported the stereoselective synthesis of the ABCDE-ring by using the EVE-mediated desymmetrization .…”

Stereochemistry in control of photochemical reactivity: 2,6-Diaryl-4 H -spiro[cyclohexane-1,2′-indene]-1′,3′,4-triones

“…7 Derivatives 3 belonging to the same type of 2,2-disubstituted 1,3-indandiones are the focus of considerable synthetic efforts: over 30 research papers describing more than 400 new compounds of type 3 have been published only during the past five years. 8 The interest toward derivatives 3 is motivated by the presence of the spiro-1,3-indandione moieties in various biologically active compounds, both natural 9 and synthetic. 10 Currently, development of new catalytic approaches allows the preparation of these derivatives stereo-and enantio-selectively from available precursors in 1 -2 synthetic steps.…”