Chiral auxiliaries chloromethylation

Although the racemization of the a-carbon can now be considered a potential problem, the synthesis of 32-peptides has been achieved in the same way as seen for 33-peptides. As the 32-amino acids cannot be prepared from the analogous a-amino acids, Seebach and co-workers 5,7 opted to use Evans oxazolidinone chemistry to produce enantiomerically pure 32-amino acids. Alkylation of 3-acyloxazolidin-2-ones 17 with A-(chloromethyl)benzamide yielded the products 18 with diastereomeric ratios between 93 7 and 99 1 (Scheme 8). Removal of the chiral auxiliary (Li0H/H202) and debenzoylation (refluxing acid) was followed by ion-exchange chromatography to yield the free 32-amino acids 20 which were converted by standard means into Boc 21 or benzyl ester 22 derivatives for peptide synthesis. 

Similarly, (/ ,i )-f-binaphthane 103 and (7 ,i )-binaphthane 104 were obtained in one step directly from 2,2 -bis(chloromethyl)-1,1 -binaphthyl 101 and corresponding phosphines. These molecules were shown to be highly efficient chiral auxiliaries in the enantioselective hydrogenation of acyclic imines <2001AGE3425, 19990L1679>. 

Three of the five fragments have now been assembled, and only the two amine alkylations remain. The first alkylation makes use of the epoxide to introduce the required 1,2-amino-alcohol functionality. The protected enantiomerically pure piperazine reacted with the epoxide, and the product was treated with acid to deprotect both the second piperazine nitrogen and the acetonide group left over from the earlier chiral auxiliary step. The newly liberated secondary amine was alkylated with the reactive electrophile 3-chloromethyl pyridine, and the final product was crystallized as its sulfate salt... 

Annulation /raw-3,4-Disubstituted tetrahydrothiophenes are obtained from conjugated carbonyl compounds and chloromethyl trimethylsilylmethyl sulfide in a reaction mediated by CsF. When the conjugated carbonyl component bears a chiral auxiliary, the process is amenable to synthesis of enantiopure derivatives. 

The classical reaction between a (haloalkyl)phosphonic diester and NaN3, best carried out in a polar solvent, e.g dmf has been developed into an asymmetric synthesis. The reaction between (chloromethyl)phosphonic dichloride and the chiral auxiliary (5)-(phenylaminomethyl)pyrrolidine (314) is followed by separation of the product 1,3,2-diazaphosph(V)olidines 315 (R = H X = Cl) and 316 (R = H X = Cl), obtained in yields of 36 and 45%. Alkylation (BuLi, RX) of the cyclic diamides and reaction between the products and NaN3, to give 315 and 316 (R = alkyl X = N3), is then followed by acidoly-... 

Methyl-1 -(chloromethyl)-2-pyrro-lidinone. 5(i )-Methyl-l-(chloromethyl)-2-pyrrolidi-none (68.1) has been proposed as an auxiliary reagent for absolute configuration (and % ee) determinations of chiral secondary alcohols by the formation of the corresponding A/ (alkoxymethyl)-2-pyrro-lidinone derivative 68.2 (see Figure 68). 

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