Double Catalytic Kinetic Resolution (DoCKR) of Acyclic anti‐1,3‐Diols: The Additive Horeau Amplification

Abstract

The concept of asynergistic double catalytic kinetic resolution (DoCKR) as described in this article was successfully applied to racemic acyclic anti-1,3-diols,acommon motif in natural products.This process takes advantage of an additive Horeau amplification involving two successive enantioselective organocatalytic acylation reactions,a nd leads to diesters and recovered diols with high enantiopurities.Itwas first developed with C 2 -symmetrical diols and then further extended to non-C 2symmetrical anti diols to prepare useful chiral building blocks. The protocol is highly practical as it only requires 1mol %o f ac ommercially available organocatalyst and leads to easily separable products.This procedure was applied to the shortest reported total synthesis of (+ +)-cryptocaryalactone,an atural product with anti-germinative activity.How can one improve the enantioselectivity outcome of ar eaction on aw ide scope?T his question arises during the development of any given catalytic enantioselective transformation. Theindispensable optimization stage improves the enantiomeric ratio (e.r.) of ar eaction through the variations of the chemical and/or physical parameters of the transformation. Usually,e .r. enhancement is rapidly accompanied by an arrowing of the reaction scope.M ost of the time,t he rational design of the catalyst structure is the only option to improve reactivity and selectivity.T his fine-tuning is nonetheless time consuming because of the difficulty of considering all the parameters involved in the enantiodetermining transition state,e ven though it can result in negligible improvements.In contrast, the Horeau principle [1] is responsible for the improvement of enantioselectivity in some reactions which rely on polyfunctionalized substrates.Byapplying at least two identical successive enantioselective transformations,t he second reaction can act as an additional stereocontrolling filter to improve the enantiopurity of the final product. Since the pioneering works of Horeau in the 70's, such amplification of enantioselectivity was observed in several catalytic trans-formations. [2,3,5e] In enantioselective catalysis,t he Horeau amplification can be divided into two main categories: 1) In the subtractive Horeau amplification, the minor enantiomer obtained after the first transformation is the substrate of the second transformation. Thep olyfunctionalized substrates involved in this first category are either prochiral [3,4] or meso compounds. [3,5] 2) In the additive Horeau amplification, the major enantiomer formed after the first reaction is rapidly consumed in the second enantioselective (or diastereoselective) transformation. [6] However,i nc ontrast to the subtractive processes,e xamples of additive amplifications involving starting materials with pre-existing stereocenters are extremely scarce (Scheme 1). [7] Although observed many times,the Horeau amplification is still considered an anecdotal phenomenon. By considering the synthetic potential supported by the Horeau principle in enantioselect...

Rationalizing the Extent of the “Sergeants‐and‐Soldiers” Effect in Supramolecular Helical Catalysts: Effect of Copper Coordination

“…Non‐linear effects, [1,2] asymmetric auto‐replication, [3] and additive Horeau amplification of enantioselectivity [4] all refer to an enhancement of the optically purity of small molecules relatively to expectations, and as such, their implication in the emergence of biological homochirality is attractive, even though speculative yet [5,6] . Taming the chiral nature of macromolecules offers another angle to tackle the challenging question of the origin of homochiral nature of biopolymers as well as to construct innovative chiral materials [7] .…”

Stereoretentive enantioconvergent reactions

“…Importantly, this coupling step will lead to statistical amplification of enantiopurity (i.e., the Horeau Principle 6 ), meaning that even when using a moderately selective KR the final product 7 will be formed in exceptionally high enantiopurity. [22][23][24] Kinetic modelling of this multi-component process illustrates how impressive this amplification of enantiopurity will be (Fig. 3B-C).…”