Acylating agents enantioselective

We first examined the lipase-catalyzed resolution of azirine-2-methanol I, which we expected to have a versatile synthetic utility. As expected for primary alcohols, the enantioselectivity obtained in the transesterification with lipase PS in ether was low (E = 17 at best) at room temperature despite considerable efforts such as screening of lipases, solvents, additives, and acylating agents. 

These results indicate that the low-temperature method increases the enantioselectivity, at least above inversion temperature, and the enantioselectivity and reaction rate can be optimized by the use of Toyon/te-immobilized lipase and a suitable acylating agent. 

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

Compound 388 is an acylating agent for electron-deficient alkenes, in a Michael addition process. It is formed by treating molybdenum hexacarbonyl with an organolithium compound, followed by quenching the intermediate 387 with boron trifluoride (equation 104). The structure of 388 (R = Ph) can be elucidated by NMR spectroscopy. Other examples of enantioselective and diastereoselective Michael-type additions involving lithium-containing intermediates in the presence of chiral additives can be found elsewhere in the literature . 

Enantioselective enzymatic transesterifications have been successfully used for the synthesis of optically active silanes with the silicon atom as the center of chirality. As shown in Scheme 20, the prochiral bis(hydroxymethyl)silanes 86 and 88 were transformed into the corresponding chiral dextrorotatory isobutyrates (+)-87 and (+)-89, respectively, using Candida cylindracea lipase (CCL, E.C. 3.1.1.3) as the biocatalyst73. For these bioconversions, methyl isobutyrate was used as solvent and acylation agent. When using acetoxime isobutyrate as the acylation agent and Chromobacterium viscosum lipase (CVL ... 

A part from vinyl acetate, vinyl benzoate was used as acylating agent in the Mucor miehei lipase (MML) and Candida antarctica lipase (CAL)-catalysed benzoylation of 1,2-diols in organic solvents 87.87 The reaction proceeded with high regioselectivity and moderate enantioselectivity. 

The bicyclic aminoalcohol, 3-quinuclidinol, is an important synthon for the preparation of cholinergic receptor ligands [23], anesthetics [24], and drugs for the treatment of Alzheimer s disease and asthma [5]. P. Bossard at Lonza AG developed and patented an enantioselective acylation of racemic 3-quinuclidinol using ChiroCLEC -BL, the CLC form of subtilisin (Fig. 5) [25]. The reaction was run in 2-methyl-3-butanol with vinyl butyrate used as the acylating agent. 

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%. 

Suzuki et al. [74] and Maruoka and colleagues [75] made further progress in the enantioselective acylation of secondary alcohols 93. Suzuki et al. reported moderate enantiomeric excesses (up to 51% ee) when employing Ci symmetric chiral imidazolium salts 94 as precatalysts and vinyl acetate as acylation agent. How-... 

In a interesting example of organocatalysis, Suzuki et al. studied the enantioselective acylation of secondary alcohols using chiral NHCs [11,12]. The approach was partly based on the work of Nolan and Hedrick who had independently reported NHC-catalyzed transesterifications [13,14]. The enantioselective acylation was subsequently improved by using more sterically hindered acylating agents such as diphenylacetate derivatives (Scheme 4), leading to selectivity factors (s = kn, ) of up to 80 [15,16]. 

In an alternate process, enantioselective enzymatic acylation of racemic a-methyl-l,3-benzodioxole-5-ethanol (55, Fig. 17) was developed using Amano lipase PS-30 (lipase from Pseudomonas cepacia) with vinyl acetate as acylating agent in n-hexane benzene (2 1). This process gave (+)-56 in 54% yield with 80% ee and (-)-57 in 46% yield with 96% ee After separation of alcohol (+)-56 from acetate (-)-57 by methanolysis in the presence of K2CC)3, the acetate was converted to alcohol (-)-56 in 95% yield with 96% ee Mitsunobu inversion of (-)-56 provided (+)-56 in 94% yield with 96% ee The conversion of (.S )-alcohol 56 to (-)-talampanel was carried out in 54% overall yield (Easwar and Argade, 2003). 

Some groups have reported on their search for less reactive acylating agents, to suppress noncatalyzed chemical acylation and increase product enantiomeric excess. Irimescu and Kato carried out an enantioselective lipase catalyzed acylation of 1 phenylethylamine and 2 phenyl 1 propylamine by reacting the amines with carbox ylic acids in a nonsolvent system or in ionic liquids (Figure 14.9). The reaction equilibrium was shifted toward amide synthesis by the continuous removal of the... 

Reetz et al. [39] carried out the continuous kinetic resolution of chiral alcohols using IL/scCOj biphasic systems with high enantioselectivity. In this approach, the racemic alcohol and the acylating agent were transported into the reactor nsing scCOj as the mobile phase. The basis of the proposed approach is that one of the enantiomers is esterified selectively by the lipase in the ionic liqnid and the mixture of products is continuously extracted with the scCO stream. The ester and unreacted alcohol were then separated downstream by controlled density reduction via variation of temperature and/or pressure of CO. The authors found that vinyl laureate, which is a cheap acylation agent, renders an ester less soluble than the unreacted alcohol, which allows an efficient recovery of the former compound. 

Burke TR Jr, Jacobson AE, Rice KC, et al. Probes for narcotic receptor mediated phenomena. 12. c/s-( + )-3-Methylfentanyl isothiocyanate, a potent site-directed acylating agent for 5 opioid receptors. Synthesis, absolute configuration, and receptor enantioselectivity. J Med Chem 1986 29 1087-1093. 

Enantioselective alkylation occurs with alkenoylphosphonates [250], The preferred catalyst is a Sc(III)pybox triflate. ZV-Substituted indoles give somewhat higher enantioselectivity than indole itself. The acyl phosphonate adducts are reactive acylating agents and can be readily converted to esters or amides. 

A number of studies dealt with the design of chiral acylating agents able to effect enantioselective delivery of conventional acyl residues (R = alkyl and aryl) to racemic secondary alcohols, according to Equation 2.14 where X. is a chiral... 

Vedejs and Chen [39] described an efficient non-enzymatic system able to approach the efficiency of some of the lipase methods in enantioselectivity. The reaction was carried out in a 2 1 ratio racemic secondary alcohol acylating agent, in contrast to Evans procedure. The pyridinium salt 8 was prepared by reaction of the chiral 4-dimethylaminopyridine (DMAP) 6 with the commercially available chloroformate 7. This pyridinium salt proved to be unreactive to secondary alcohols. The reactivity was found only upon strict experimental conditions addition of a Lewis acid, then the racemic alcohol, followed by addition of a tertiary amine gave the carbonate 9. Under these conditions (using MgBr2 and triethylamine), (2-naphthyl)- -ethanol was converted (room temperature, 20 h and 54% conversion) into the (S)-carbonate (82% ee). The recovered alcohol showed 83% ee, revealing a stereoselectivity s=39 for the process. A number of 1-arylalkanols have been resolved by this procedure in 20-44% yield (based on the racemic material) and 80-94% ee. For the use of this system in enantiodivergent reactions, see Schemes 6.1 and 6.32. 

Kashima et al. used 2-acyl-3-phenyl-l-menthopyrazoles 10 as chiral acylating agents, in the presence of 1 equiv AICI3 [40]. Interestingly, addition of 1 equiv of diisopropylamine reversed the sense of the enantioselectivity. Such a process shows the power of KR to access either enantiomer, either by using the pyrazole derived from the (-)-menthol or by modifying the experimental conditions. 

In 2005, Jacobs and colleagues investigated the potential value of acid zeolites as heterogeneous alcohol-racemisation catalysts for the racemisation of benzylic alcohols. In this context, H-Beta zeolites were applied to the DKR of various benzylic alcohols in the presence of carboxylic acids as the acylating agents and Novozym 435 as the catalyst, which were conducted by means of a two-phase approach, providing the corresponding esters in yields well above 50% combined with excellent enantioselectivities, as shown in Scheme 3.32. 

---