- Trost asymmetric allylic alkylation
The Trost asymmetric allylic alkylation or Trost AAA or allylic asymmetric substitution is an
organic reaction used inasymmetric synthesis . [Trost, B. M.; Fullerton, T. J. "New synthetic reactions. Allylic alkylation." "J. Am. Chem. Soc." 1973, "95", 292–294. doi|10.1021/ja00782a080.] [Trost, B. M.; Dietsch, T. J. "New synthetic reactions. Asymmetric induction in allylic alkylations." "J. Am. Chem. Soc." 1973, "95", 8200–8201. doi|10.1021/ja00805a056.] [Trost, B. M.; Strege, P. E. "Asymmetric induction in catalytic allylic alkylation." "J. Am. Chem. Soc." 1977, "99", 1649–1651. doi|10.1021/ja00447a064.] ["Asymmetric Transition-Metal-Catalyzed Allylic Alkylations:Applications in Total Synthesis" Trost, B. M.; Crawley, M. L.Chem. Rev. ; (Review); 2003; 103(8); 2921-2944. DOI|10.1021/cr020027w ]In the reaction an allylic
leaving group in anorganic compound is displaced by anucleophile while at the same time palladium is coordinated to the allyldouble bond as aΠ complex . A typical substrate in this reaction is an allylic compound with a good leaving group such as anacetate group. The reaction was originally developed with acatalyst based on palladium supported theTrost ligand . The nucleophile can be aphenol , aphthalimide or simply water.reaction mechanism
Zerovalent palladium is generated in situ from a palladium(II) source and aphosphine ligand such as theTrost ligand . The metal coordinates to the alkene forming a η2 π-allyl-Pd0Π complex . The next step isoxidative addition in which theleaving group is expelled withinversion of configuration and a η3 π-allyl-PdII is created. Thenucleophile then adds to the proximus or distal carbon atom of the allyl group regenerating the η2 π-allyl-Pd0 complex. The palladium compound detaches from the alkene in the completion of the reaction and can start again in thecatalytic cycle . The chirality stored in the ligand is transferred to the final product in one of the complexes formed.Scope
An AAA example is the synthesis of an intermediate in the combined total synthesis of galanthamine and
morphine [Trost, B. M.; Tang, W.; Toste, F. D. "Divergent Enantioselective Synthesis of (−)-Galanthamine and (−)-Morphine." "J. Am. Chem. Soc." 2005, "127", 14785–14803. doi|10.1021/ja054449+.] with 2.5 mol% Pd2dba3, 7.5 mol% ("S,S")Trost ligand , andtriethylamine indichloromethane solvent atroom temperature resulting (−)-enantiomer of the aryl ether in 64%chemical yield and 77%enantiomeric excess .Ongoing research is taking place into new asymmetric ligands such as one based on biphenyl and
fenchol . [Goldfuss, B.; Löschmann, T.; Kop-Weiershausen, T.; Neudörfl, J.; Rominger, F. "A superior P-H phosphonite: Asymmetric allylic substitutions with fenchol-based palladium catalysts." "Beilstein J. Org. Chem." 2006, "2", 7–11. doi|10.1186/1860-5397-2-7.] .AAA-Wagner-Meerwein shift
The reaction substrate is also extended to
allene s and in a specific ring expansion the AAA reaction is accompanied by aWagner-Meerwein rearrangement [Trost, B. M.; Xie, J. "Palladium-Catalyzed Asymmetric Ring Expansion of Allenylcyclobutanols: An Asymmetric Wagner-Meerwein Shift." "J. Am. Chem. Soc." 2006, "128", 6044–6045. doi|10.1021/ja0602501.] in Scheme 3 [The co-catalysts arebenzoic acid andtriethylamine .Molecular sieve s (MS) prevent hydrolysis.] :External links
* [http://pharma.dow.com/pharma/sm_molecules/capabilities/allylic.htm catalyst supplier]
* "Asymmetric allylic substitution: mechanism and recent advances using palladium and molybdenum" Kyle D. Bodine [http://www.scs.uiuc.edu/chem/gradprogram/chem435/Abstract%20Bodine1.pdf Review]References
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