Enantioselective PTC

R V. Dehmlow, S. Wagner, A Muller, Enantioselective PTC Varying the Cinchona Alkaloid Motive , Tetrahedron 1999,55,6335-6346. 

Subsequent ion exchange of the metal cation with the quaternary ammonium ion catalyst provides a lipophilic ion pair (step 2), which either reacts with the requisite alkyl electrophile at the interface (step 3) or is partitioned into the electrophile-containing organic phase, whereupon alkylation occurs and the catalyst is reconstituted. Enantioselective PTC has found apphcation in a vast number of chemical transformations, including alkylations, conjugate additions, aldol reactions, oxidations, reductions, and C-X bond formations." ... 

The Michael addition is one of the favored reactions in enantioselective PTC. For instance, the reaction of an indanone similar to those in Scheme 5 with methyl vinyl ketone in the presence of catalyst 8 in a toluene system (50% NaOH) gave the Michael product in 95% yield and 80% ee [36]. 

Despite the great impact of PTC in organic synthesis since its discovery, catalytic asymmetric synthesis using chiral phase transfer catalysts has been poorly investigated for quite a long time, but has taken a fast growing pace in the last few years [58,59]. Only isolated examples [60] of asymmetric PTC appeared in the literature until O Donnell in 1989 reported the enantioselective PTC alkylation of the benzophenoneimine of glycine derivatives catalyzed by Cinchona alkaloid-derived ammonium salts (Scheme 14) [61]. 

Scheme 5.13 Enantioselective PTC Michael reaction using a,p,y,5-unsaturated ketones.

Scheme 5.14 Enantioselective PTC Michael reaction of P-ketoesters with allenic ketones.

The enantioselective PTC-aldol process between aromatic aldehydes and diazoester derivatives 218 has been successfully accomplished by cinchonidium salt catalyst 219 (Scheme 4.41). From all bases tested RbOH provided the best results, with... 

Several groups developed other catalysts for enantioselective PTC alkylation of 1—for example, quanidine-based catalysts (XXXVIII, Scheme 8.8) (Kita et al. [65]), Cs-symmetrical ammonium PTC (XXXXI) [66], biphenyl ammonium PTC (XXXX, Scheme 8.9) (Lygo et al. [67]), spiro bis-ammonium PTC (XXXIX) (Sasai, [68]), L-menthol-derived PTC (XXXXII, XXXXIII) (Ramachandran and coworkers [69]), pyrrolidine and piperidine-derived PTC (XXXXIV) (MacFarland and co-workers [70]), bimorpholine (XXXXV) (Kanger and co-workers [71]), but their use in asymmetric procedures involving alkylation is only hmited. 

Besides of these main types of the chiral TAA salts, numerous other chiral TAA salts and crown ethers acting as moderately enantioselective PT catalysts were reported. Chiral PTC was mostly used for enantioselective formation of chiral carbon centers via alkylation of carbanions (enolates), Michael addition, the Darzens reaction and other reactions of carbanions. There are also numerous examples of enantioselective PTC epoxidation of electron deficient alkenes (for review, see Ref 105). 

A. Loupy, A. Zaparucha, Asymmetric Michael Reaction under PTC Conditions without Solvent. Importance of re Interactions for the Enantioselectivity , Tetrahedron Lett. 1993, 34, 473-476. 

An important application of these precursors is the asymmetric synthesis of aminoacids, the key step being an enantioselective benzylation using a chiral auxiliary (route A, Scheme 25) [155] or a chiral phase transfer catalyst (PTC) [156] (route B, Scheme 25). This latter approach avoiding the use of dry reagents is particularly adapted to automated synthesis and enables the production of more than 7.4 GBq (200 mCi) of [6- F]fluoro-L-DOPA from 55.5 GBq (1.5 Ci) of starting [ F] fluoride [157]. 

Miscellaneous PTC Reactions The field of PTC is constantly expanding toward the discovery of new enantioselective transformations. Indeed, more recent applications have demonstrated the capacity of chiral quaternary ammonium salts to catalyze a number of transformations, including the Neber rearrangement (Scheme 11.19a), ° the trifluoromethylation of carbonyl compounds (Scheme 11.19b), ° the Mannich reaction (Scheme 11.19c), and the nucleophilic aromatic substitution (SnAt)... 

Several other practical syntheses of enantiopure amino acid derivatives have been accomplished recently from substrate 35 (Chart 10.6). The Imperiali group has used two techniques following PTC alkylations that occurred with modest enantioselectivity (50-53% ee). The first involved fractional recrystallization followed by subsequent deprotection/reprotection to give 39 (>99% ee). In the second method, enzymatic hydrolysis of the amino acid methyl ester with alkaline protease and then nitrogen acylation gave 40 (99% ee) [16]. Several other publications that deal with related purification techniques have appeared [17-19]. 

Protected glycine derivatives have been used as the nucleophilic partner in enantioselective syntheses of amino acid derivatives by chiral PTC (Scheme 10.9). Loupy and co-workers have reported the addition of diethyl acetylaminomalonate to chalcone without solvent with enan-tioselectivity up to 82% ee [44]. The recent report from the Corey group, with catalyst 8a used in conjunction with the benzophenone imine of glycine t-butyl ester 35, discussed earlier, results in highly enantioselective reactions (91-99% ee) with various Michael acceptors (2-cyclo-hexenone, methyl acrylate, and ethyl vinyl ketone) to yield products 71-73 [21], Other Michael reactions resulting in amino acid products are noted [45]. 

An early report of a promising level of asymmetric induction in the reduction of ketones by chiral PTC [62a] was disputed [26b,60c]. Several reviews concerning hydrogenation by enantioselective catalysis have appeared [5j-l]. 

Since Corey s group first reported 0(9)-allyl-N-(9-anthracenylmethyl) cinchonidi-nium bromide as a new phase-transfer catalyst [13], its application to various asymmetric reactions has been investigated. In particular, this catalyst represents a powerful tool in various conjugated additions using chalcone derivatives (Scheme 3.2). For example, nitromethane [14], acetophenone [15], and silyl eno-lates [16] produce the corresponding adducts in high enantioselectivity. When p-alkyl substrates are used under PTC conditions, asymmetric dimerization triggered by the abstraction of a y-proton proceeds smoothly, with up to 98% ee [17]. 

The first series of the dimeric cinchona-PTCs (3-8) to have a phenyl ring as a linker was designed to examine the primary effect according to the relationship of the attached position (Figure 4.6). One of the two independent cinchona alkaloid units can be located at the ortho-, meta-, or para-position against the other, respectively. The group envisaged that, both chemical yield and enantioselectivity of the asymmetric alkylation of 1 should be affected by the direction of each of the cinchona units. 

From an evaluation of the catalytic efficiency of 3-5 using standard catalytic phase-transfer benzylation of 1, it was found that all compounds had the ability to catalyze this phase-transfer benzylation, and in all cases the (S)-isomer of the benzylated imine 2a was formed in excess (Scheme 4.3). The 1,3-phenyl-linked dimeric PTC 4 showed the highest enantioselectivity among the three dimeric PTCs. The order of enantioselectivity of the three PTCs, along with the monomeric PTC M, was as follows 1,3-dimeric PTC 4 > 1,4-dimeric PTC 5 = monomeric PTC M 1,2-dimeric... 

The lack of any difference in enantioselectivity between the 1,4-phenyl-dimeric PTC S and the monomeric PTC M implies that the two cinchona alkaloid units of the 1,4-phenyl-dimeric PTC do not sterically affect each other. In the case of 1,2-phenyl-dimeric PTC 3, the severe steric repulsion between the two cinchona alkaloid units may lead to an unfavorable conformation, thereby affording poor enantioselectivity. 

By screening solvent and inorganic bases to establish the optimal reaction conditions for dimeric chiral PTCs, a toluenexhloroform (7 3, v/v) solvent system and a 50% aqueous KOH base were found to afford the best enantioselectivity and chemical yield within a reasonable reaction time. As dimeric cinchona-PTCs are very poorly soluble in toluene (one of the popular solvents in asymmetric alkylation), this might act as an obstacle for the catalyst to show its maximum ability. However, the addition of chloroform to toluene provided better results due to an improved solubility of the dimeric PTC. This difference in ability to dissolve the dimeric PTC might be heavily associated not only with the reaction rate but also with the chemical/ optical yield. However, the use of chloroform alone proved to be inadequate as an optimal solvent [10]. 

Figure 4.7 The probable structure of the dimeric cinchona-PTC 4 (top), and a stereoview of a plausible model ofthe preferred three-dimensional arrangement of the ion pair from 7 and one (ortwo) l -eriolate(s) ofl, based on an understanding of the enantioselectivity (bottom).

C, a very high enantioselectivity (98% ee) as well as ahigh chemical yield (95%) was obtained within a short reaction time (30 min). Notably, all of the PTCs were able to conserve their high catalytic efficiency in terms of both reactivity and enantioselectivity, even when present in smaller quantities (1 mol%). 

Having optimized the catalytic enantioselective phase-transfer alkylation system, the group explored the scope and limitations. A variety of electrophiles were reacted with the benzophenone imine glycine tert-butyl ester 1 catalyzed by 5 mol% of the selected chiral dimeric PTCs, benzene-linked-l,3-dimeric PTC 37, 2 -F-benzene-linked-1,3-dimeric PTC 41, and naphthalene-linked-2,7-dimeric PTC 39, at reaction temperatures of 0°C or — 20 °C (Scheme 4.8). 

With these anthracene-linked dimeric cinchona-PTCs, the Najera group investigated the counterion effect in asymmetric alkylation of 1 by exchanging the classical chloride or bromide anion with tetrafluoroborate (BF4 ) or hexafluorophosphate (PF6-) anions (Scheme 4.10) [17]. They anticipated that both tetrafluoroborate and hexafluorophosphate could form less-tight ionic pairs than chloride or bromide, thus allowing a more easy and rapid complexation of the chiral ammonium cation with the enolate of 1, and therefore driving to a higher enantioselectivity. However, when... 

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