Alcohols chiral acylation catalysts

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. 

Tao B, Ruble JC, Hole DA, Fu GC (1999) Nonenzymatic kinetic resolution of propargylic alcohols by a planar-chiral DMAP Derivative crystallographic characterization of the acylated catalyst. J Am Chem Soc 121 5091-5092... 

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. 

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. 

In 2004, Birman and coworkers set out to develop an easily accessible and highly effective acylation catalyst based on the 2,3-dihydroimidazo[l,2-a]-pyridine (DHIP) core. The first chiral derivative to be prepared and tested was (R)-2-phenyl-2,3-dihydroimidazo[l,2-fl]-pyridine 44 (H-PIP) [152]. Derived from R)-2-phenylglycinol, this catalyst afforded the KR of ( )-phenylethylcarbinol in 49% ee at 21% conversion s = 3.3). In order to improve the reactivity of the catalyst, the authors decided to introduce an electron-withdrawing substituent on the pyridine ring that would increase the electrophilicity of the acylated intermediate. Hence, three new derivatives (Br-PIP, NO -PIP and CF3-PIP) were synthesised and tested under rigorously identical conditions [152]. One of these easily accessible compounds, 2-phenyl-6-trifluoromethyl-dihydroimidazo[l,2-a]pyridine (45, abbreviated as CF3-PIP), proved to be particularly effective as, when combined with (EtC0)20 and iPr NEt, it resolved a variety of aryl alkyl iec-alcohols with good to excellent selectivities s = 26-85) (Table 7) [152]. 

The chiral bicyclic phosphines 5 (and in particular 5a [7b]) are currently the most active phosphorus-based acylation catalysts, enabling use of low reaction temperatures. Under these conditions (i.e. —40 °C) selectivity factors as high as 370-390 were achieved (Scheme 12.2). This is the best selectivity factor ever reported for metal-free, non-enzymatic kinetic resolution. As a consequence, very good enantiomeric purity of both the isobutyric esters 7 and the remaining alcohols 6 was obtained, even at substrate conversions approaching 50% (Scheme 12.2) [7, 8],... 

In principle, oxidative kinetic resolution of racemic alcohols can be achieved by using chiral oxidation catalysts such as TEMPO derivatives or dioxiranes. The selectivity achieved by use of these methods is, however, less than that observed in acylation reactions (Section 12.1). 

The same group subsequently discovered that the loading of the chiral diamine catalyst can be reduced substantially if triethylamine is added in stoichiometric amounts as an achiral proton acceptor [37b]. As shown at the top of Scheme 13.23, as little as 0.5 mol% catalyst 45 was sufficient to achieve yields and ee comparable with the stoichiometric variant (application of the Oriyama catalysts 44 and 45 in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). Oriyama et al. have also reported that 1,3-diols can efficiently be desymme-trized by use of catalysts 44 or 45. For best performance n-butyronitrile was used as solvent and 4-tert-butylbenzoyl chloride as acylating agent (Scheme 13.23, bottom) [38]. 

Fu et al. used the planar chiral DMAP derivative 46 (Scheme 13.24) [39]. Although this catalyst has been employed successfully for kinetic resolution of a large variety of racemic secondary alcohols (Section 12.1), substrate 47 seems to be the only meso-diol that has been desymmetrized by use of the acylation catalyst... 

This means that the chiral catalyst participates in nucleophilic attack on an achiral acyl donor to afford a reactive chiral acyl salt. Nucleophilic attack on this salt by an appropriate nucleophile (an alcohol, amine or 7r-nucleophile) then provides the acylated product and regenerates the catalyst. This latter step determines the stereochemistry, but knowledge of the precise mechanism by which stereochemical information is transferred in most of these processes is still rather limited. 

As most of the chiral nucleophilic catalysts that have been described to date were initially developed or tested for Type I acylative KR of sec-alcohols, these are the first class of reactions considered here. 

In 1993, Vedejs et al. [5,6] showed that tributylphosphine is a potent catalyst for the acylation of alcohols by acetic and benzoic anhydrides as efficient as 4-(di-methylamino)pyridine DMAP [7,8]. However, the DMAP catalyst is more versatile since it presents catalytic activity in the reaction of alcohols with a larger variety of electrophiles. Due to these properties, Fu [9] realized the design and synthesis of a new family of chiral nucleophilic catalysts illustrated by the planar-chiral DMAP derivative I which is a very efficient catalyst in different enantioselective reactions such as addition of alcohols to ketenes [10], rearrangement of O-acylated azalactones [11], and kinetic resolution of secondary alcohols [12-14]. 

Further modification of the chiral environment of the catalyst by replacing the Cp group of 3.61 by the bulkier CsPhs group allowed the development of new catalysts (—)-3.62 for the kinetic resolution of secondary alcohols during acylation of alcohols with anhydrides (Figure 3.23). 

But the Merck chemists noticed that amino alcohol itself, certainly once protected, has a remarkable similarity to Evans oxazolidinone auxiliaries anyway, and it turns out that this amino alcohol will function very successfully as a chiral auxiliary, which does not need to be removed, avoiding waste and saving steps The amino alcohol was acylated with the acyl chloride, and the amide was protected as the nitrogen analogue of an acetonide by treating with 2-methoxypropene (the methyl enol ether of acetone) and an acid catalyst. The enolate... 

During their studies on kinetic resolution (KR) of secondary alcohols, Connon et al. found that chiral pyridine catalyst 177 and its optimized analogue 178 promoted the synthetically useful KR of MBH adducts 179 derived from deactivated precursors (which were difficult to synthesize using catalytic asymmetric MBH reactions), allowing the convenient preparation of 179 in 62-90% ee and 82-97% ee, respectively (Scheme 2.87). This study also represents the first examples of effective non-enzymatic acylative KR of sec-sp -sp ... 

Scheme 22.1 Acylative kinetic resolution of racemic secondaiy alcohols with Fu s planar-chiral DMAP catalysts.

In addition, catalysts 2b and 6 have also been successfully applied to the KR of other aUyhc alcohols, such as that depicted in Scheme 3.2 [16h, 21]. On the other hand, Miller et al. [30] have demonstrated that a peptide could be employed as acylation catalyst for the KR of a functionaHzed cyclohexenol, which was recovered in enantioselectivity of >98% ee (Scheme 3.2). In addition, moderate selectivity factors (s < 4.5) have been obtained by using a novel chiral 4-dimethylaininopyridine (DMAP) bearing a sulfoxide as a chiral appendage [31], whereas the use of a novel C2-symmetric diferrocenyl-pyrrolidinopyridine nucleophihc catalyst allowed promising selectivity factors of up to 6 to be obtained [32]. Moreover, the first example of chiral N-heterocycHc carbenes as acylation catalysts for the KR of alcohols was reported, albeit providing low enantioselectivities (<37% ee) [33]. 

In addition, a chiral 1,2-diamine derived from L-proUne was investigated as a catalyst for the KR of primary alcohols with acyl chlorides by Oriyama et al. [50], providing the highest selectivity factors of up to 16 in the case of glycerol derivatives as substrates. Chiral Ph-BOX-Cu(II) complex 17 has also been successfully... 

The reaction proceeds via the formation of a first chiral zwitterionic intermediate from pivaUc anhydride and the amidine-based catalyst A mixed anhydride is then generated in the presence of the racemic carboxylic acid and activated by the chiral acyl-transfer catalyst to form the second zwitterionic intermediate. The latter species selectively reacts with a nucleophilic alcohol to afford the desired enantioenriched carboxyUc ester (Scheme 41.10). 

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