Asymmetric monoalkylation

Asymmetric Monoalkylation of Glycine Ester Schiff Bases... 

The requisite aldimine Schiff base 21 can be readily prepared by the simple imine formation between glycine tert-butyl ester and p-chlorobenzaldehyde in MeOH at room temperature, with the aid of MgS04. The asymmetric monoalkylation of 21 was... 

Table 5.4 Asymmetric monoalkylation of 21 under phase-transfer conditions catalyzed by chiral quaternary ammonium bromide (R,R)-le or (R)-16Aa.

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

This powerful quaternization method enabled the catalytic asymmetric synthesis of quaternary isoquinoline derivatives with 42 (R1 = Me) as a substrate. When 42 (R1 = Me) was treated with a,a -dibromo-o-xylene, CsOHH20 and (S,S)-le (1 mol%) in toluene at 0 °C, the transient monoalkylation product was rapidly produced, and subsequently transformed into the desired 44 (64%, 88% ee) during the work-up procedure. Catalytic asymmetric alkylation of 42 (R1 = Me) with functionalized benzyl bromide 45, followed by the sequential treatment with 1 M HC1 and then excess NaHC03, furnished the corresponding dihydroisoquinoline derivative 46 in 87% with 94% ee (Scheme 5.23) [25]. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

Monoalkylation of Clycinate Schiff Base Asymmetric Synthesis of a-Amino Acids... 

The synthesis of enantiomerically pure compounds is the challenging problem for organic chemists. The synthesis becomes obsolete if the intermediates produce racemic mixtures. The problem is particularly acute when the asymmetric centers do not reside in a rigid cyclic or polycyclic framework. To be able to carry out efficient syntheses of complex molecules, chemists have to control the sense of chirality at each chiral center as it is introduced in the course of synthesis. Monoalkyl- or dialkyl-boranes exhibit a remarkable chemo-, stereo-, and regioselectivity for the hydroboration of unsaturated compounds. This property, coupled with the capability for asymmetric creation of chiral centers with chiral hydroboration agents, makes the reaction most valuable for asymmetric organic synthesis. In some of the cases, however, this has been achieved by diborane itself as shown in the synthesis of monensin by Kishi et al. A stereospecific synthesis of its seven carbon. component has been accomplished by two hydroboration reactions (Eq. 129) 209. ... 

Synthesis of Phosphoric Acids and Their Derivatives. - A series of monoalkyl and dialkyl phosphorus acid chiral esters have been synthesised for use as carriers for the transport of aromatic amino acids through supported liquid membranes. The compounds acted as effective carriers but enantio-separation was at best moderate. A range of phosphono- and phosphoro-fluoridates have been prepared by treatment of the corresponding thio- or seleno- phosphorus acids with aqueous silver fluoride at room temperature (Scheme 1). In some cases oxidation rather than fluorination occurred. Stereospecifically deuterium-labelled allylic isoprenoid diphosphates, e.g. (1), have been synthesised from the corresponding deuterium-labelled aldehyde by asymmetric reduction, phosphorylation and Sn2 displacement with pyrophosphate (Scheme 2). ... 

O Donnell reported the asymmetric alkylation of the Schiff base of tert-h xty glycinate using TV-benzylcinchonium chloride (Scheme 3.26b, [151]). This process, which works for methyl, primary alkyl, allyl, and benzyl halides (Table 3.11), is noteworthy because the substrate is acyclic and because monoalkylation is achieved without racemization under the reaction conditions. The observed chirality sense may be rationalized by assuming an jE fO)-enolate and Jt-stacking of the benzophenone rings of the enolate above the quinoline ring on the catalyst, and approach of the electrophile as before. 

Asymmetric carbon-carbon bond formation reaction under solvent-free conditions was carried out by Bolm et al. in ball mill [58]. Here, nickel(II) complex 206 was used as a chiral auxiliary in alkylation with various bromides (Schane 2.67). Optimized reaction conditions were set to increase the stereoselectivity however, the desired monoalkylated product 207 was often accompanied by small amount of doubly alkylated side product 208. Two different bases were used (NaOMe/MgS04 or CS2CO3) and grinding of nickel complex 206 with bromides for 30-75 min afforded alkylation products in moderate to high yields and with complete stereoselectivity (selected examples. Table 2.54). 

Cyclobutane synthesis allows introduction of substituents on the cyclobutane ring in various patterns (Scheme 8.24) [55], Allyl bromide with boron trichloride and tri-ethylsilane yields the alkyldichloroborane 103, which is converted into pinacol (3-bro-mopropyl)boronate (104) and on to the cyano derivative 105 by standard methods. Transesterification of 105 and reaction with LiCHClj was used to make 100. However, 105 can be deprotonated and monoalkylated efficiently, and transesterification then yields 106. Transesterification with DICHED and asymmetric insertion of the CHCl group furnishes 107, which cyclizes to 108 or 109 with about the same 20 1 di-astereoselection as seen with the unsubstituted intermediate 100. The pattern of substitution shown by 111 was achieved via reaction of pinacol (bromomethyl)boronate (63) with lithioacetonitrile to form 110, which underwent chain extension and substitution in the usual manner. It was necessary to construct 110 in this way because substitution of a (p-haloalkyl)boronic acid is not possible. With R = H or CH3, substituents included Me, Bu, and OBn [55]. 

The catalytic (Al(ni) triamine catalyst) asymmetric [2+2] cycloaddition reaction of monoalkyl ketenes with aldehydes in benzotrifluoride at -20 °C affords the /3-lactones 217... 

The number of possible O-alkylation products of calix[5]arenes is greater than those of calix[4]arenes and consequently there are also more possibilities for constructing asymmetrical substituted derivatives by O-alkylation. In general, selective functionalization of calix[5]arenes is not yet very advanced. The crown ether derivatives which we recently obtained are the first examples of selective O-alkylation [21a]. Such a 1,3-crown ether (which has Cs symmetry as indicated) can be made asymmetric by further monoalkylation or monoacylation at one of the remaining proximal OH groups [21b]. 

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