The First Broad Examination of Michael Reactions in the Presence of a Diverse Array of Acidic Spectator Functional Groups: Enantioselective Synthesis
Final Report Abstract
Michael reactions are numerous because they can be defined by a broad range of unique nucleophile/electrophile starting material pairings. This grant focused on aldehyde Michael addition to ß-nitrostyrene electrophiles and to a lesser extent on maleimide electrophiles. It was previously know that Michael reactions to ß-nitrostyrene are well tolerated when the latter contain a wide breadth of electron donating or withdrawing ortho, meta, or para-substituents; but missing from that list of spectator functional groups were examples of weakly acidic functional groups, e.g. primary or secondary amides, N-phenylamides (aniline amides), benzylic alcohols, phenolic hydroxyl groups, catechol groups, thiophenols, carboxylic acids, boronic acids, etc. and that general category of ‘acids’ is what we successfully targeted during this grant. A spectator carboxylic acid moiety allows the challenge to be clearly framed: no prior literature examples existed for the addition of an aldehyde or a ketone to a ß-nitrostyrene with a co-exsiting carboxylic acid present on one of the starting materials. This is true whether the reaction is racemic or enantioselective. Through the insights and labor of this research, four common acidic groups that can now be tolerated during Michael reactions. The key finding, Michael substrate breath expansion, is a result of employing the correct catalysis, i.e., catalysts capable of enamine catalysis and simultaneous salt bridge assembly of the starting materials. In short, we successfully achieved the goals laid out in the submitted and approved grant, and those findings can be summarized as being in three distinct areas: (i) Highly enantioselective Michael reactions of alpha-branched aldehydes to: (a) ß-nitrostyrene electrophiles containing N-phenylamides, phenolic OH groups, catechols, or carboxylic acids groups; and (b) maleimide electrophiles containing a free NH moiety. (ii) Michael reactions in which both the electrophile and the nucleophile contain an acidic functional group, e.g., we have successfully reacted an aldehyde (containing a phenolic OH group): (a) with a ß-nitrostyrene (containing a phenolic OH group), and (b) with a maleimide (containing an unprotected NH group). (iii) All Michael reactions in this study generated a quaternary carbon in the product and thus expand the construction possibilities for these challenging carbon centers. To show the application potential of these reactions, we devised and executed the shortest and highest yielding enantioselective synthesis of (R)-Pristiq (O-desmethyl venlafaxine), a commercially used anti-depressant. In conclusion, we have shown that a previously unreliable area of research has now been put on firmer ground, i.e., practicing chemists can now reliably perform highly enantioselective Michael reactions in good yields, under simple reaction condition, when an acidic spectator groups is present. These findings are likely not restricted to Michael reactions and may be extendable to other enamine based catalysis reactions and alternative acidic functional groups. Finally, the Michael reaction was a good proving grounds for demonstrating the noted concept because of the diverse number of possible products. This last point lends greater access to advanced chiral building block products which in turn allow greater access to bioactive molecule synthesis (pharmaceutical drugs).
Publications
- Carboxylate Salt Bridge-Mediated Enamine Catalysis: Expanded Michael Reaction Substrate Scope and Facile Access to Antidepressant (R)-Pristiq.
Advanced Synthesis & Catalysis, Vol. 359. 2017, Issue 1, pp. 2824-2831.
Thomas C. Nugent, Hussein Ali El Damrany Hussein, Shahzad Ahmed, Foad Tehrani Najafian, Ishtiaq Hussain, Tony Georgiev, Mahmoud Khalaf Aljoumhawy
(See online at https://doi.org/10.1002/adsc.201700801)
