Alcohols acyl transfer

Acyl transfer from an acid an hydride to an alcohol is a standard method for the prep aration of esters The reaction IS subject to catalysis by either acids (H2SO4) or bases (pyri dine)... 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

This work has been extended to transesterification with secondary alcohols [23], and of phosphonate esters [24], Movassaghi and co-workers have demonstrated that NHCs effectively catalyse the amidation of esters with amino alcohols, although an alternative mechanism involving the NHC acting as a Brpnsted base, resulting in nucleophilic activation of the alcohol for an initial transesterification event, followed by rapid O- to iV-acyl transfer, has been proposed [25, 26],... 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

In 1982 Cardillo used a three-step sequence involving two supported reagent systems to convert /i-iodoamines into amino alcohols (Scheme 2.23) [45]. Polymer-supported acetate ions were used for the substitution of the iodide which immediately underwent acyl transfer to the amine. The resulting compound (10) was directly treated with hydrochloric acid to cleave the amide and the free base was subsequently obtained from the reaction by treatment with a resin-bound carbonate. This was of particularly synthetic value because of the high water solubiHty of these amino alcohol compounds that would have made aqueous work-up challenging. 

Mechanism of esterification of carboxylic acids The esterification of carboxylic acids with alcohols is a kind of nncleophilic acyl snbstitntion. Protonation of the carbonyl ojq gen activates the carbonyl gronp towards nncleophilic addition of the alcohol. Proton transfer in the tetrahedral intermediate converts the hydrojq l group into - 0H2 group, which, being a better leaving group, is eliminated as neutml water molecule. The protonated ester so formed finally loses a proton to give the ester. 

A proposed mechanism for this transformation, provided in Scheme 42, is based on the identification of alcohol-carbene complexes by Movassaghi and Schmidt. Mesityl substituted imidazolinylidine carbene acts as a Brpnsted base as transesterification occurs to produce LXVII. Upon O N acyl transfer, the observed product is formed. The evidence provided for this mechanism includes the control experiment in which LXVII is resubjected to the reaction conditions and proceeds with amide formation. A similar mechanism has recently been reported in a theoretical study of transesterification by Hu and co-workers [139], In light of this work, it seems reasonable to suggest a similar that mechanism is operative in the transesterification reactions discussed throughout this section. 

Amine, Alcohol and Phosphine Catalysts for Acyl Transfer Reactions... 

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]. 

Finally, Inanaga s contribution to the development of chiral 4-dialkylaminopyrid-ine based catalysts for enantioselective acyl transfer relied on the use of C -symmetric 4-PPY derivative 36 (Fig. 7) [130]. This compound was obtained in an enantiopure form by selective cleavage of a carbamate intermediate using Sml, and allowed the KR of various. yec-alcohols with selectivity factors ranging from y = 2.1 to 14. 

Hulshof et al. introduced 10 as an alcohol racemization catalyst [31]. Alcohol DKR was performed with 0.1mol% of 10, CALB, isopropyl butyrate as the acyl donor, potassium carbonate and about 20mol% of the corresponding ketone at 70°C (Scheme 1.23). Without the ketone, yield and optical purity of the product ester were decreased significantly. 2-Propanol produced by the acyl transfer reaction was removed at reduced pressure during the DKR to shift the equilibrium to acylated products. 

The mechanism for bacterial synthesis of PHA is not the simple dehydration reaction between alcohol and carboxyl groups. It is more complicated and involves the coenzyme A thioester derivative of the hydroxyalkanoic acid monomer (produced from the organic feedstock available to the bacteria) [Kamachi et al., 2001], Growth involves an acyl transfer reaction catalyzed by the enzyme PHA synthase (also called a polymerase) [Blei and Odian,... 

Kinetic optical resolution of racemic alcohols and carboxylic acids by enzymatic acyl transfer reactions has received enormous attention in recent years56. The enzymes generally employed are commercially available lipases and esterases, preferentially porcine liver esterase (PLE) or porcine pancreatic lipase (PPL). Lipases from microorganisms, such as Candida cylindracea, Rhizopus arrhizus or Chromobacterium viscosum, are also fairly common. A list of suitable enzymes is found in reference 57. Standard procedures are described in reference 58. Some examples of the resolution of racemic alcohols are given39. 

The reaction of 14 may remind one of the well-established reaction mechanism for chymotrypsin (Fig. 5) (20). By comparing the acyl-trans-fer reaction of complex 14 with that of chymotrypsin 17, we find that the alcoholic nucleophiles in 14 and 17 are activated by Zn11—OH- and imidazole (in a triad), respectively. Several common features should be pointed out (i) Both reactions proceed via two-step reaction (i.e., double displacement), (ii) The basicity of Zn11—OH (pKa = 7.7) is somewhat similar to that of imidazole (plfa = ca. 7). (iii) The initial acyl-transfer reactions to alcoholic OH groups are rate determining, (iv) In NA hydrolysis with chymotrypsin, the pH dependence of both the acylation (17 — 18) and the deacylation (19 — 17) steps point to the involvement of a general base or nucleophile with a kinetically revealed piFCa value of ca. 7. A major difference here is that while the... 

Vedejs and co-workers have explored the use of chiral phosphines as acyl transfer catalysts. The viability of this approach was proven when phosphine 1 was shown to catalyze the resolution of secondary alcohols with promising selectiv-ities (Scheme 2) [10,11]. 

A new class of chiral 4-A,A-dialkylaminopyridine acyl-transfer catalysts has been developed that are capable of exploiting both van der Waals (jt) and H-bonding interactions to allow remote chiral information to control stereochemically the kinetic resolutions of secondary alcohols with moderate to excellent selectivity (S = 6-30). Catalysts derived from (.S )- , -diarylprolinol (89 Ar = Ph, 2-naphthyl) in combination with isobutyric anhydride were found to possess high activity and selectivity across a broad range of substrates 89... 

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

A common explanation of the DMAP acceleration suggests that DMAP, as a stronger nucleophile than the alcohol, reacts with the O-acylisourea leading to a reactive amide ( active ester ). This intermediate cannot form intramolecular side products but reacts rapidly with alcohols. DMAP acts as an acyl transfer reagent in this way, and subsequent reaction with the alcohol gives the ester. 

Acyl transfer to alcohols and amines is related mechanistically to ester hydrolysis but yields a complementary set of products that are useful in their own right and as chiral synthons for the preparation of more complex materials. Such transformations can be difficult to achieve in water, however, because the solvent, which is present in vast excess, can participate directly in the reaction as a reactant. Enzyme-like specificity is thus required to favor the bimolecular reaction between alcohol and ester and prevent spontaneous hydrolysis of the acyl donor. 

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... 

Diastereo- and enantiopure 1,2-amino alcohols and differentially protected 1,2-diols are motifs that occur widely in bioactive natural products and pharmaceutical substances [132]. Their preparation by KR of the corresponding racemates has been explored widely [133], particularly by asymmetric acyl transfer because these substrates provide a convenient scaffold for probing the influence of H-bonding and n-n-stacking effects on the efficiency of chirality transfer by various catalyst systems. 

One of the first effective chiral PPY derivatives to be developed for asymmetric acyl transfer was catalyst 7, which was shown by Fuji and Kawabata in 1997 to be effective for the acylative KR of various racemic mono-benzoylated ds-diol derivatives [76]. Subsequently, it was also successfully applied in the KR of N-protected cyclic ds-amino alcohols [77]. Using 5 mol% of PPY 7 in the presence of a stoichiometric amount of collidine in CHCI3 at rt, a variety of cyclic ds-amino alcohol derivatives were resolved with moderate selectivities (s = 10-21) (Table 8.6). 

Type II catalytic asymmetric acyl transfer processes have been most extensively developed for the case of ASD of meso-anhydrides by nucleophilic ring-opening with alcohols, and so these processes will be the first type II processes considered here. 

An interesting version of the transesterification reactions was reported by Movassaghi et al., with the amidation of unactivated esters with amino alcohols (Scheme 9.27) [73]. The amidation was explained by carbene-alcohol interactions. A nucleophilic activation of the hydroxyl group of the aminoalcohol 90 by the catalyst 11 is followed by transesterification to the ester 91 which is in-situ-converted to the amide 92 through a N —> O acyl transfer. Various aliphatic and aromatic esters with different functionalities, as well as chiral aminoalcohols, are suitable for this reaction. 

Thus, the hydrazide or its azo analogue not only plays a key-role in the catalytic cycle as a hydrogen acceptor and a reductant for the copper catalyst, but it also acts as an acyl transfer reagent generating competitively the undesired mixed carbonate 20. This by-product presumably originates from the inter- or intra-molecular nucleophilic attack of the alcohol on either the copper-hydrazide or azo complexes 13 or 18 respectively, resulting ultimately in the deactivation of the catalyst. To minimize this undesired trans-acylation reaction, steri-cally demanding azo-derivatives were tested (Fig. 7). Whilst di-isopropyl... 

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