Enantioselective synthesis asymmetric protonation

All of the above methods introduce the aryl group during the enantiodetermining step. An alternative strategy would be to already have the aryl group in place and to generate the tertiary stereocentre via an asymmetric protonation of an enolate complex. This was first reahsed by the pioneering work of Yamamoto in this area with the use of Lewis acid assisted chiral Bronsted acid (LBA) catalysts in the enantioselective synthesis of a-aryl cyclohexanones ((2), Scheme 4.34). Initially developed with the use of stoichiometric quantities of a BlNOL-SnCLi catalyst for the asymmetric protonation of silyl enol ethers, [63] the extensive development of this reaction has resulted in a catalytic variant with an achiral proton donor [64] and expansion of the scope to include tertiary a-aryl carboxylic acids. [65] Further improvement was made with the development of a metal free IV-triflyl thiophos-phoramide BINOL derived proton source (126) [66] and more recently a Lewis base-tolerant chiral LBA [67]. 

The isoflavanone precursors 8a-e were then applied in the decarboxylative asymmetric protonation reaction. Recently Pd-catalysed decarboxylative reactions have emerged as a powerful tool in organic synthesis (see Sects. 4.3 and 4.4) [32, 33]. The often mild reaction conditions employed, coupled with the high yields and enantioselectivities attainable has seen this methodology applied in several syntheses [34—37] and continues to be an area of rapid growth in asymmetric catalysis. 

A highly enantioselective synthesis of a-amino acid derivatives employs an NHC-catalysed intermolecular Stetter reaction of an o, /3-unsaturated ester with an aldehyde. The key steps of (i) C-C bond formation between Breslow intermediate 0 and Michael acceptor and (ii) asymmetric protonation are efficiently combined, giving ees of 85-99%. 

Scheme 11.15 Enantioselective synthesis of 3-substituted tetrahydroquinolines via asymmetric protonation.

In this chapter, the enantioselective protonation of preformed and a-stabilized carbanions is disclosed. A second part is devoted to the asymmetric protonation of enolate species obtained in situ through a first chemical transformation with activated double bonds (i.e., ketenes or Michael acceptors). Herein, among all the advances made using these two main approaches, methodologies that have been used in total synthesis of natural and pharmacologically active products are emphasized. 

Impressively, a slightly modified protocol was adapted to industrial-scale reactors (lOOOL and 2500 L) to afford the corresponding (5)-a-damascone (5)-ll) in high yield (>85%) with good enantioselectivity (>65% ee). So far, this synthesis remains the unique application of asymmetric protonation in an industrial process. 

To the best of our knowledge, no synthesis of natural products or bioactive products involving the asymmetric protonation of ketenes was reported so far in the literature. However, because of the importance of this method, we disclose the most relevant methodologies and the mechanistic considerations of the enantioselective protonation of ketenes. 

However, despite the considerable efforts devoted to address the fundamental issues toward the development of asymmetric protonation, its applications to natural or bioactive synthesis remain sporadic. Herein, two main strategies, namely the enantioselective protonation of metal enolates, especially silicon enolates and the protonation of polar double bonds, i.e., Michael acceptors, were depicted trough the most relevant synthetic applications. These two strategies led to the synthesis of fragrance, natural products, ° bioactive compoundsand... 

Piva, O. and CarameUe, D., Asymmetric protonation of photodienols enantioselective synthesis of (R)-2-methylalkanols, Tetrahedron Asymm., 6, 831, 1995. 

Whilst the addition of a chiral NHC to a ketene generates a chiral azolium enolate directly, a number of alternative strategies have been developed that allow asymmetric reactions to proceed via an enol or enolate intermediate. For example, Rovis and co-workers have shown that chiral azolium enolate species 225 can be generated from a,a-dihaloaldehydes 222, with enantioselective protonation and subsequent esterification generating a-chloroesters 224 in excellent ee (84-93% ee). Notably, in this process a bulky acidic phenol 223 is used as a buffer alongside an excess of an altemativephenoliccomponentto minimise productepimerisation (Scheme 12.48). An extension of this approach allows the synthesis of enantiomericaUy emiched a-chloro-amides (80% ee) [87]. 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

The synthesis of menthol is given in the reaction scheme, Figure 5. 6. The key reaction [2] is the enantioselective isomerisation of the allylamine to the asymmetric enamine. It is proposed that this reaction proceeds via an allylic intermediate, but it is not known whether the allyl formation is accompanied by a base-mediated proton abstraction or hydride formation. 

The use of chiral complexes gives rise to enantioselectivity of carbon—carbon bond formation and this phenomenon has also been applied to resolution54 and enantioselective deuteration55 56 of amino acids. Both the kinetic acidity of the a-methylene protons and the enantioselectivity of bond formation are greatly enhanced by the formation of chiral complexes (32) and (33) of imines derived from the amino acid and salicylaldehyde or pyridoxal respectively.57-59 Similar use has been made of inline complexes (34) derived from pyruvic acid and the amino acid.60 61 Very recently, an asymmetric synthesis of threonine has been achieved using the chiral imine complex (35).62... 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. 

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