Chiral DMAP

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... 

Carbon dioxide is one of the most abundant carbon resources on earth. It reacts with an epoxide to give either a cyclic carbonate or a polycarbonate depending on the substrates and reaction conditions. Kinetic resolution of racemic propylene oxide is reported in the formation of both cyclic carbonate and polycarbonate. The fe ei value defined as ln[l-(conversion)(l+%ee)]/ln[l-(conversion)(l% ee)] reached 6.4 or 5.6 by using a Co(OTs)-salen complex with tetrabutylammonium chloride under neat propylene oxide or using a combination of a Co-salen complex and a chiral DMAP derivative in dichloromethane, respectively. 

A number of laboratories have targeted chiral DMAP analogs as acylation catalysts with perhaps the best success realized by Fu s planar chiral ferrocenyl... 

Vedejs (1996), Miller/Fu (1998) chiral phosphines, minimal peptides, chiral DMAP analogs Acyi-Anion Cataiysis... 

Interestingly, this catalyst and related systems typically function as chiral DMAP-type catalysts.However, in this case, mechanistic studies suggest that the role of 36 is to serve as a conjugate base for the protic catalyst derivative. 

Scheme 12 Fu s, Vedejs , Johannsen s and Richards chiral DMAP-catalyzed rearrangements of O-acyl azlactones [103-107]...

Fu and co-workers have detailed the use of planar chiral DMAP and PPY analogs as catalysts for the resolution of secondary unsaturated alcohols (Fig. 1) [15]. Both ferrocene and ruthenocene-based catalysts have been examined, with the iron-based catalysts generally proving less reactive but more selective [16]. Catalysts are prepared in racemic form and are subsequently resolved by preparative chiral HPLC. 

Scheme 4. Planar chiral DMAP analog 10 as a catalyst for kinetic resolution of secondary alcohols...

An interesting approach to translating remote chirality into enantiomer discrimination relies upon blocking one face of the heterocycle using axially chiral DMAP analogs. To this end, Spivey and co-workers have examined catalysts 39 and 40, obtained in optically pure form by preparative HPLC [38]. Catalyst 39 is effective for the kinetic resolution of aryl alkyl carbinols with good selec-tivities (krei=8.4-27, see Scheme 7). The substitution on the 4-position nitrogen... 

The preparation of optically active /Mactams by asymmetric synthesis is also a topic of major interest, because of the pharmaceutical and biochemical importance of those molecules [44]. A typical and economical route consists of a [2+2]-cycloaddition of a ketene to an imine. Many diastereoselective versions of this reaction type are known [45] as well as catalytic processes involving chiral (metal) catalysts [46, 47] or biocatalysts [48]. A [2+2]-cycloaddition of a ketene to an imine, however, can also be performed very efficiently when applying nucleophilic amines as chiral catalysts [49-60]. Planar-chiral DMAP derivatives have also been found to be suitable catalysts [61]. 

The Vedejs group also reported the centrally chiral DMAP derivatives 8 and 9... 

Later studies focused on the planar chiral DMAP derivative 21c as catalyst and use of acetic anhydride as an inexpensive and readily available acyl donor [19]. Under these conditions (2 mol% catalyst loading, r.t.) kinetic resolution of several racemic alcohols could be achieved with selectivity factors up to 52 (Scheme 12.7). As a consequence, enantiomerically highly enriched alcohols (> 95% ee) could be obtained at conversions only slightly above 50%. 

The axially chiral DMAP derivatives 22a-d were developed by Spivey et al. [23-25], In these catalysts the chiral axis is positioned meta to the pyridyl nitrogen... 

Jeong, Kim et al. reported use of the chiral DMAP derivative 22e, which was synthesized from 3-amino-DMAP, Kemp s triacid, and N-acetyl-2,2 -diamino-l,l -binaphthyl [26], As summarized in Scheme 12.11, selectivity factors up to 21 were observed with 1 mol% modular catalyst 22e in the kinetic resolution of a variety of secondary alcohols with acetic anhydride in tert-amyl alcohol as solvent, conditions first described by Fu et al. [20]. 

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... 

Selectivity in enantiotopos-differentiating acylation and phosphorylation of meso-diols can rival that of enzymes. The organocatalysts employed include chiral phosphines, chiral diamines, chiral DMAP derivatives and peptides identified from combinatorial libraries. The highest selectivity in meso diol desymmetrization has been achieved with a planar-chiral Fu catalyst. It seems the substrate scope of this process is not yet broadly explored. Because of their sequential variability it is to be... 

The planar chiral DMAP derivative 79a proved successful also in the dynamic kinetic resolution of racemic azlactones by ring-opening with alcohols (Scheme... 

Construction of quaternary stereocenters by enantiocontrolled oxygen to carbon acyl shift is not limited to the azlactone structure. Using the pentaphenylated planar chiral DMAP derivative 79c (Scheme 13.42) Fu and Hills achieved rearrangement of O-acylated oxindoles 84 (Scheme 13.45) and benzofuranones 85 (Scheme 13.46) with very good yields and enantiomeric excesses up to 99% [88]. 

The MacMillan group has also shown that cycloaddition reactions (see also Chapter 8) can be performed highly diastereo- and enantioselectively. The [3+2]-cycloaddition of nitrones and a,/i-un saturated carbonyl compounds in the presence of 20 mol% of a phenylalanine-derived imidazolidinone acid salt led to products with 99% ee [32]. An example of an enantioselective rearrangement reaction (see also Section 13.6) with 99% ee has been reported by the Fu group [33], who used 2 mol% of a planar chiral DMAP derivative as catalyst. 

Table 8.3 Spivey s axially chiral DMAP-catalyzed KR of sec-alcohols [83].

Scheme 8.11 Preparation of a (—)-baclofen intermediate using Fu s planar chiral DMAP 4b [54].

This process proceeds as a DKR [13, 190] because the DMAP catalyst promotes not only the asymmetric alcoholysis of the azlactone but also its racemization under the reaction conditions the N-benzoyl a-amino acid ester product does not racemize under these conditions. Johannsen has also screened chiral DMAP 21 (Fig. 8.4) for this transformation, but obtained poorer yields and selectivities [102],... 

Nucleophilic ring opening of racemic 5(4//)-oxazolones by alcohols catalyzed by chiral DMAP complex 118 occurs under a dynamic kinetic process to give enantiomerically enriched a-amino esters 119. The enantioselectivity is critically affected by the solvent and the alcohol nucleophile (Equation 6) <1998JOC3154>. 

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]. 

The enantioselective discrimination of one of the hydroxyl groups of meso-diols can give chiral monoprotected diols, which serve as versatile intermediates for asymmetric organic synthesis. In addition to the enzymatic methods, a number of chemical approaches have been reported using chiral 1,2-diamine catalysts, chiral phospholane-based catalysts, planar chiral DMAP derivatives, and oligopeptide-based catalysts [2,28], Surprisingly, however, relatively a few publications are devoted to this reaction with cinchona-based organocatalysts. 

Chiral DMAP Epoxidation reactions Unwanted kinetic resolutions Enzymes... 

Another chiral DMAP 11 has been developed by Fu.8 This contains neither a chiral centre nor an axis of chirality and is probably best described as having planar chirality. The s factor was improved from 14 to a very useful 43 simply by changing the solvent and reaction temperature The references contain useful sample experimental procedures.8,9 Several alcohols including 12-15 have been resolved with this but in looking at the ees, remember to note the conversion necessary to achieve them. Clearly the acetylene 15 was more difficult to resolve.9... 

While we are on the subject of chiral DMAP it is worth noting that even phosphines10 can be used to catalyse acylation reactions and some of the s values that can be achieved are quite spectacular. The phosphines are bicyclic compounds 16 and 18. The nature of the phosphine is very important and the focus of the work was not on enantiomeric excess but rather the all-important s value. 

With a parallel kinetic resolution, the two reactions should not interfere with one another. In the example above, both reactions were acylations but the use of stoichiometric reagents meant that the right acylating group was attached to the right enantiomer. Even here, Vedejs does not rule out a small amount of leakage between the paths (once the chiral DMAP is liberated it can get in on the act with the other pathway). A PKR becomes more difficult if, in addition to the reactions being related, they are also catalytic. 

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