1.Regioselective asymmetric α,α-bisalkylation of ketones via complex-induced syn-deprotonation of chiral N-amino cyclic carbamate hydrazones.
Wengryniuk SE1, Lim D, Coltart DM. J Am Chem Soc. 2011 Jun 8;133(22):8714-20. doi: 10.1021/ja202267k. Epub 2011 May 12.
The first general method for the asymmetric α,α-bisalkylation of ketones having both α- and α'-protons is described. Both excellent regio- and stereoselectivity result. The transformation is enabled by complex-induced syn-deprotonation (CIS-D), which completely reverses the inherent preference of lithium diisopropylamide (LDA) to remove the less sterically hindered of two similarly acidic protons. CIS-D also overrides the normal tendency of LDA to remove the more strongly acidic proton in a substrate having protons differing significantly in their acidity. The regiochemical outcome is, thus, the opposite of that normally obtained for kinetic LDA-mediated deprotonation of ketones and (S)-1-amino-2-methoxymethylpyrrolidine/(R)-1-amino-2-methoxymethylpyrrolidine (SAMP/RAMP)hydrazones. Conveniently, this strategy allows access to either ketone enantiomer using a single enantiomer of the auxiliary. The utility of this method is demonstrated by a concise and highly efficient formal synthesis of both (R)- and (S)-stigmolone.
2.Asymmetric synthesis of (+)-altholactone: a styryllactone isolated from various Goniothalamus species.
Enders D1, Barbion J. Chemistry. 2008;14(9):2842-9. doi: 10.1002/chem.200701647.
The asymmetric total synthesis of (+)-altholactone (1), a member of the styryllactone family of natural products displaying cytotoxic and antitumor activities, is described. Key steps include a RAMP-hydrazone alpha-alkylation (RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) of 2,2-dimethyl-1,3-dioxan-5-one, a boron-mediated aldol reaction, a six- to five-membered ring acetonide shuffling, an oxidative 1,5-diol to delta-lactone conversion and a stereoselective ring-closure to generate the annulated tetrahydrofuran moiety with inversion of configuration.
3.Asymmetric total synthesis of (-)-pironetin employing the SAMP/RAMP hydrazone methodology.
Enders D1, Dhulut S, Steinbusch D, Herrbach A. Chemistry. 2007;13(14):3942-9.
A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C(8)-C(14) 2 and C(7)-C(2) 15 fragments, respectively, by using a Mukaiyama-aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)-1-amino-2-methoxymethylpyrrolidine, RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) methodology as a key step. An asymmetric alpha-alkylation of diethyl ketone permitted the introduction of the C(10) stereogenic center of 2, whereas the stereocenters C(4) and C(5) of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the alpha,beta-unsaturated delta-lactone was achieved by ring-closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.
