Asymmetric Acylations

Among the most successful classes of asymmetric acyl anion equivalents are the dioxane-containing a-amino nitriles 99 introduced by Enders and coworkers. These are deprotonated by EDA, and the resulting anions act as efficient equivalents of RCO for addition to a, (3-unsaturated esters [90AG(E)179],... 

Oxathiane 101 is readily deprotonated using s-BuLi, and the resulting anion reacts with alkyl halides, ketones, and benzonitrile (85JOC657). The majority of work in this area, however, is due to Eliel and coworkers and has involved chiral 1,3-oxathianes as asymmetric acyl anion equivalents. In the earliest work it was demonstrated that the oxathianes 102 and 103, obtained in enantiomeri-cally pure form by a sequence involving resolution, could be deprotonated with butyllithium and added to benzaldehyde. The products were formed with poor selectivity at the new stereocenter, however, and oxidation followed by addition... 

Chiral N,N-disubstituted 2-(aminomethyl)pyrrolidines as catalysts for asymmetric acylation of alcohols 99YGK598. 

Substitutcd I- Iethyl-l//-indents by Asymmetric Acylation General Procedure80 ... 

Alternative catalytic asymmetric acylation reactions studied prochiral silyl imi-noketenes 89 [110] (Fig. 44, top) and silyl ketene acetals 90 [111, 112] (Fig. 44, middle), leading to the formation of quaternary stereocenters. Furthermore, the... 

Mermerian AH, Fu GC (2005) Nucleophile-catalyzed asymmetric acylations of silyl ketene imines application to the enantioselective synthesis of verapamil. Angew Chem Int Ed 44 949-952... 

TABLE 3-3. Asymmetric Acylation Using (2A,5A)-24 and Subsequent Stereoselective Reduction with Zinc Borohydride in THF at —78°C... 

In asymmetrically acylated lipid A, the four primary hydroxy-fatty acids possess the same chain length of 14 carbon atoms [thus far, with one exception (193b), only 14 0(3-OH) was identified]. 

The asymmetric Mannich addition of carbon nucleophiles to imines catalyzed by the cyclohexane-diamine catalysts has developed significantly in the past decade. List and co-workers reported the asymmetric acyl-cyanantion of imines catalyzed by a cyclohexane-diamine catalyst [103], Using a derivative of Jacobsen s chiral urea catalyst, the authors optimized reaction conditions and obtained chiral iV-acyl-aminonitriles in high yield and enantioselectivities (Scheme 51). The scope of the reaction was explored with both aliphatic and aromatic imines, providing good to high selectivities for a variety of substrates. 

Abstract An overview of the area of organocatalytic asymmetric acyl transfer processes is presented inclnding O- andiV-acylation. The material has been ordered according to the structnral class of catalyst employed rather than reaction type with the intention to draw mechanistic parallels between the manner in which the varions reactions are accelerated by the catalysts and the concepts employed to control transfer of chiral information from the catalyst to the substrates. 

The preparation of stereochemically-enriched compounds by asymmetric acyl transfer using chiral nucleophihc catalysts has received significant attention in recent years [1-8]. One of the most synthetically useful and probably the most studied acyl transfer reaction to date is the kinetic resolution (KR) of ec-alcohols, a class of molecules which are important building blocks for the synthesis of a plethora of natural products, chiral ligands, auxiliaries, catalysts and biologically active compounds. This research area has been in the forefront of the contemporary organocatalysis renaissance [9, 10], and has resulted in a number of attractive and practical KR protocols. 

The mechanism by which chiral nucleophiles catalyze asymmetric acyl transfer in the KR of, yec-alcohols can be seen as a three-step process (Scheme 1) [2]. 

NB. The Q symbol indicates the stereochemistry determining step Scheme 1 General catalytic cycle for the asymmetric acylation of iec-alcohols [2]... 

In general, catalytic asymmetric acyl transfer reactions can be classified into two main types depending on the nature of the nucleophile and the acyl donor (Scheme 2) [2]. 

Scheme 2 Classification of catalyzed asymmetric acyl transfer process [2]...

It should be noted that asymmetric acyl transfer can also be catalyzed by chiral nucleophilic A-heterocyclic carbenes [27-32] and by certain chiral Lewis acid complexes [33-37] but these methods are outside the scope of this review. Additionally, although Type I and Type II tr-face selective acyl transfer processes have been reported to be catalyzed by some of the catalysts described in this review, these also lie outside the scope of this review. 

Fig. 1 Chiral phosphines screened by Vedejs as asymmetric acyl transfer catalysts [42]...

As indicated in the introdnction, Wegler and coworkers were the first to report suc-cessfnl asymmetric acylation nsing naturally occurring fert-amine-based alkaloids (e.g. brucine) in their KR studies on 1-phenylethanol [23], While the selectivities achieved were rather modest, proof-of-concept was thereby established. 

Spivey AC, McDaid P (2007) Asymmetric acyl transfer reactions. In Dalko P (ed) Handbook of asymmetric organocatalysis. Wiley, Weinheim, pp 287-329... 

Scheme 6.51 Dihydroisoquinolines obtained form asymmetric acyl-Mannich reaction of substituted isoquinolines promoted by 52.

The reaction of nucleophiles with 2-alkyl-2-methoxyoxazolidines offers a general method for asymmetric acylation (91T7925). 

The asymmetric acylation reaction has proven utility in the synthesis of biologically relevant targets. This is demonstrated by the plethora of applications of lipases and esterases in total syntheses [ 1 ]. While these enzymes often display superb selectivities, their application to a broad class of substrates may be difficult and unpredictable [2]. To increase access to these materials in optically pure form, over the past decade several groups have developed small molecule catalysts for the asymmetric acylation reaction [3,4], In addition, these catalysts... 

A variety of unfunctionalized secondary alcohols, including saturated and unsaturated carbinols, are resolved by catalyst 25 with moderate to high selectivi-ties (fcrei=4 to >50, see Scheme 5) [25]. Octapeptide 25 was discovered by screening a split-pool library of peptide catalyst candidates for acylation of 1-phe-nylethanol (3), using a reactivity-based fluorescence screen [26], followed by structure optimization with directed libraries. While substrates with increased steric bulk about the alcohol are resolved with highest selectivities, even 2-butanol is resolved with modest selectivity (fcrei=4). Peptide-based catalysts have also been applied to the resolution of tertiary alcohols, a relatively unexplored area of nonenzymatic asymmetric acylation catalysis [27-29], By using a fluores-... 

Recent years have seen enormous advances in the field of catalytic asymmetric acylations. Most of the work has been devoted to the kinetic resolution of racemic alcohols. For this application the most efficient catalysts currently available are... 

Oriyama, T. Imai, K. Sano, T. Hosoya, T. Highly efficient catalytic asymmetric acylation of meso- 1,2-diols with PhCOCl in the presence of a chiral diamine combined with NEt3. Tetrahedron Lett. 1998, 39, 3529-3532. 

Ishihara, K. Kubota, M. Yamamoto, H. First application of hydrogen bonding interactions to the design of asymmetric acylation of meso-diols with optically active acyl halides. Synlett 1994, 611-614. 

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

The preparation of stereochemically enriched compounds by asymmetric acyl transfer in a stoichiometric sense can be divided into two broad classes [1] (1) those in which a racemic or achiral /weso nucleophile reacts diastereoselectively with an enantiomerically highly enriched acyl donor (Type I, see below) and (2) those in which an enantiomerically highly enriched nucleophile reacts diastereoselectively with a racemic or achiral/meso acyl donor (Type II, see below). When a racemic component is involved, the process constitutes a kinetic resolution (KR) and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoeselectivity - is 50%. When an achiral/meso component is involved, the process can constitute a site-selective asymmetric desymmetrization (ASD) or, in the case of 7r-nucleophiles and reactions involving ketenes, a face-selective addition process and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoselectivity - is 100% (Scheme 8.1). 

Scheme 8.1 Classification of stoichiometric asymmetric acyl transfer processes. ASD = asymmetric desymmetrization.

Until the last decade or so, the only synthetically useful catalytic asymmetric acyl transfer processes were biotransformations using hydrolase enzymes particularly lipases and esterases [24]. Various lipases and esterases provide high levels of stereoselectivity (s) for the acylative KR and ASD of a wide variety of sec-alcohols and some amines, although the latter transformations have been less thoroughly explored [25-28]. However, the preparative use of enzymes is associated with a number of well-documented limitations, including their generally... 

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