Trost asymmetric allylic alkylation

The Trost asymmetric allylic alkylation or Trost AAA or allylic asymmetric substitution is an organic reaction used in asymmetric 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 an organic compound is displaced by a nucleophile while at the same time palladium is coordinated to the allyl double bond as a Π complex. A typical substrate in this reaction is an allylic compound with a good leaving group such as an acetate group. The reaction was originally developed with a catalyst based on palladium supported the Trost ligand. The nucleophile can be a phenol, a phthalimide or simply water.

reaction mechanism

Zerovalent palladium is generated in situ from a palladium(II) source and a phosphine ligand such as the Trost ligand. The metal coordinates to the alkene forming a η² π-allyl-Pd⁰ Π complex. The next step is oxidative addition in which the leaving group is expelled with inversion of configuration and a η³ π-allyl-Pd^II is created. The nucleophile 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 the catalytic 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, and triethylamine in dichloromethane solvent at room 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 allenes and in a specific ring expansion the AAA reaction is accompanied by a Wagner-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 are benzoic acid and triethylamine. Molecular sieves (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