Enantioselective phase transfer alkylation process

Corey studied the X-ray crystal structures of cinchonidinium salts and has formulated a model which explains the highly enantioselective alkylation of the enolate of 3 [3]. This model accounts for the sense of asymmetric induction in this process and the importance of the size of the R1 substituent in the salts 1 and 2 the model can be used to rationalise other phase transfer catalysed processes involving similar catalysts. The enolate 37 is thought to be in close contact with the least hindered face of the tetrahedron formed by the four atoms surrounding the quaternary nitrogen atom (the rear face of this tetrahedron is blocked by the bulky 9-anthracenylmethyl group). Alkylation of the less hindered face of 37 leads to the observed enantiomer of the product (see Figure 1). 

The phase transfer alkylation of Schiff bases has been extended to several other alkyl bromides as a route to new amino acids [24], and the enantioselectivities in these cases are comparable (50 to 70% ee) to those reported by O Donnell. In addition, the methodology has been used for the synthesis of a-methylamino acids, with ee s of about 50% [25]. Futher optimization using an 0-alkylated catalyst and a no solvent process with solid KOH/K2CO3 led to improved ee s of 70%... 

Enantioselective phase-transfer catalysis (PTC) has been extensively applied for the alkylation, epoxidation, conjugate addition and related process, with the use of chiral ammonium salts being the typical transfer agent [293]. However, the related aldol... 

Indeed, several interesting procedures based on three families of active catalysts organometallic complexes, phase-transfer compounds and titanium silicalite (TS-1), and peroxides have been settled and used also in industrial processes in the last decades of the 20th century. The most impressive breakthrough in this field was achieved by Katsuki and Sharpless, who obtained the enantioselective oxidation of prochiral allylic alcohols with alkyl hydroperoxides catalyzed by titanium tetra-alkoxides in the presence of chiral nonracemic tartrates. In fact Sharpless was awarded the Nobel Prize in 2001. 

The salient feature of le as a chiral phase-transfer catalyst is its ability to catalyze the asymmetric alkylation of glycine methyl and ethyl ester derivatives 4 and 5 with excellent enantioselectivities. Since methyl and ethyl esters are certainly more susceptible towards nucleophilic additions than tert-butyl ester, the synthetic advantage of this process is clear, and highlighted by the facile transformation of the alkylation products (Scheme 5.3) [8],... 

Next, process chemistry for the practical synthesis of 7b (MGS0028) is discussed (Schemes 3.5-3.7) [42-45]. First, the synthesis of key intermediate (+)-29 from racemic acetoxycyclopentene (34) is shown in Scheme 3.5 [43]. The key reaction in this approach was Trost s asymmetric ally lie alkylation reaction of ethyl 2-fluoroacetoacetate with 34, which afforded 35 in high yield and high enantioselectivity, especially when a bulky tetra-n-hexyl ammonium bromide was used as a phase-transfer reagent (89% yield, 94-96%... 

Complementary to the above-presented enantioselective sequences Michael addition/a-alkylation of bromomalonates, a related powerful gem-dialkylative process was also proposed recently [38]. a-Dialkylation of imines 25 with 1,4-dihalo-but-2-ene 26 using a cinchonidine derivative J as phase-transfer catalyst proceeded smoothly in the presence of aqueous NaOH to give the (l/ ,25)-l-amino-2-vinylcyclopropanecarboxylic acid derivatives 27 with generally good diastereose-lectivity but with enantiomeric excesses not exceeding 80% (Scheme 5.10). 

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