Asymmetric Induction in Aldol Additions

Abstract

The selectivity of aldol reactions involving kinetic enolates is related to various factors such as the nature of the Lewis acid (Li, Mg, B, Al, Ti, Sn, etc.), the presence of stereogenic centers in both the substrates and reagents, the nature of their substituents and the reaction conditions. Another factor of major importance is the nature of the enolate double bond (Z or E) [1].In general, it is well known that in aldol reactions involving metal enolates, which proceed through a six-membered cyclic transition state, the Z-enolate leads to the formation of 1,2-syn aldol adducts and the E-enolate affords aldol adducts with the 1,2-anti configuration. A rationalization for the observed selectivities of these aldol reactions was proposed by Zimmerman and Traxler (Scheme 5.1) [2]. According to this model, the nature of the double bond geometry plays a primary role in determining the energies of the competing transition states. For Z-enolates, the transition state TS2 is more destabilized than transition state TS1 because of the 1,3-diaxial interactions between the R 1 and R 3 substituents as well as between these substituents and one of the metal ligands (L). Therefore, the Z-enolate preferentially leads to the formation of the 1,2-syn aldol adduct.For the E-enolate, 1,3-diaxial interactions between the R 1 and R 3 substituents and between both R 1 and R 3 and one of the metal ligands are present in transition state TS4. Therefore, the 1,2-anti aldol adduct is obtained from the lower energy transition state TS3.Modern aldol reactions use preformed enolates to obtain good yields by preventing side reactions. This methodology has proven to be very effective for various Lewis acids derived from lithium, titanium, tin, and boron. By using preformed enolates with chiral substrates and reagents, it is possible to obtain aldol adducts with an excellent degree of asymmetric induction.The IUPAC defines asymmetric induction as the traditional term describing the preferential formation in a chemical reaction of one enantiomer (or diastereomer) over the other as a result of a chiral feature present in the substrate, reagent, catalyst, or the environment [3].

A highly diastereoselective “super silyl” governed aldol reaction: synthesis of α,β-dioxyaldehydes and 1,2,3-triols

“…In this case, it is known that the stereochemical outcome of the reaction can be controlled by the chirality of the substrate (1,2-asymmetric induction). 7 , 8…”

Highly enantioselective asymmetric direct aldol reaction promoted by aziridine amides constructed on chiral terpene scaffold

“…Stereoselective direct aldol reaction is a very useful and commonly applied tool for the synthesis of various chiral organic junctions . Among various catalysts, proline, its differently modified amides, and other various amine‐functionalized compounds are the most frequent examples of chiral promotors for asymmetric aldol reaction.…”

“…[2][3][4] Stereoselective direct aldol reaction is a very useful and commonly applied tool for the synthesis of various chiral organic junctions. [5][6][7][8] Among various catalysts, proline, 9 its differently modified amides, [10][11][12][13] and other various aminefunctionalized compounds 14,15 are the most frequent examples of chiral promotors for asymmetric aldol reaction. This type of organic reaction is traditionally performed under anhydrous conditions; however, the number of reports describing the asymmetric aldol condensation in the presence of water is still growing in the chemical literature.…”

Synthetic Studies toward the Total Synthesis of Tautomycetin

“…The endgame steps of our proposed strategy (see Scheme ) relied on a key boron-mediated aldolization to forge and control the relative stereochemistry of the C12–C13 bond followed by a final removal of all protecting groups. Knowing that 1,2- anti adducts are mostly like to be obtained via E -boron enolates, we tried the condensation by pre-mixing fragment C13–C25 with (cHex) 2 BCl (which favors E -enolate formation) in the presence of Et 3 N in Et 2 O at −30 °C followed by the addition of aldehyde C1–C12 at −78 °C (Scheme ). The usually recommended oxidative quench was avoided because of the presence of double bonds on both fragments which are prone to oxidation.…”