“…Preliminary biological studies on the C(3) palmitoylate ester, 92b found it to be inactive 7 Synthesis of out,out -ingenane analogs by (a) alkylation/cyclization of 94 to give tricyclic 95 , − (b) intermolecular [6 + 4] thermal cyclocloaddition, − (c) intramolecular [6 + 4] thermal cycloaddition, (d) intramolecular [4 + 3] cycloaddition …”
“…Rigby has developed a route to construct the tetracyclic skeleton of ingenol utilizing an intermolecular [6 + 4] thermal cycloaddition reaction to give the important bicyclo[4.4.1]undecan-11-one system (Figure b). − Again the intrabridgehead stereochemical arrangement in this product is cis .…”
“…Preliminary biological studies on the C(3) palmitoylate ester, 92b found it to be inactive 7 Synthesis of out,out -ingenane analogs by (a) alkylation/cyclization of 94 to give tricyclic 95 , − (b) intermolecular [6 + 4] thermal cyclocloaddition, − (c) intramolecular [6 + 4] thermal cycloaddition, (d) intramolecular [4 + 3] cycloaddition …”
“…Rigby has developed a route to construct the tetracyclic skeleton of ingenol utilizing an intermolecular [6 + 4] thermal cycloaddition reaction to give the important bicyclo[4.4.1]undecan-11-one system (Figure b). − Again the intrabridgehead stereochemical arrangement in this product is cis .…”
“…The presence of the carbonyl function in 7 suggested enolate alkylation as a possible tactic for this carbon−carbon bond installation, and inspection of models indicated that the bridgehead proton was appropriately aligned with the carbonyl π system for deprotonation to occur. Previously, we have demonstrated that bridgehead enolates in the less strained bicyclo[4.4.1]undecane system are well-behaved, and it would be instructive to see if this trend extended to the in,out isomeric series as well. Thus, treatment of 7 with excess LDA followed by quenching with excess methyl iodide afforded the bis-methylated bicyclic product 8 ,, along with lesser amounts of the monoalkylated product 9 11 without loss of the in,out intrabridgehead stereochemical relationship in either compound!…”
“…While bridgehead metalation of small-bridge carbonyl compounds is expected to be problematic, with larger systems a transition to “normal” enolate chemistry should be evident …”
[reaction: see text] Contrary to expectations, a number of bridged carbonyl compounds undergo facile bridgehead metalation with lithium amide bases. Diketone, lactone, lactam, and imide functions are all demonstrated to participate in this type of "bridgehead enolate" chemistry, leading to a range of substituted products. Meso compounds can also be desymmetrized in very high ee by asymmetric bridgehead metalation.
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