Many biologically relevant natural products of polyketide origin contain a fully reduced 1,3,5,n("skip")-polymethylsubstituted carbon chain.[1] Such structures, referred to as "deoxypropionate oligomers", are usually constructed through an iterative asymmetric enolate alkylation of the type introduced by Evans et al. [2] Although the use of amide enolates based on pseudoephedrine [3] and azaenolates derived from (R)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP) hydrazones [4] have led to significant improvements in this methodology, disadvantages still include the often low reactivity of the enolate intermediate towards the alkylating agent, and the cost and removability of the chiral auxiliary. These drawbacks prohibit large-scale applications. We report herein an alternative iterative strategy based on a stereospecific copper-mediated directed allylic substitution. This flexible approach allows the preparation of any desired oligo(deoxypropionate) stereoisomer. The strategy is outlined in Scheme 1.The key step of our strategy is an S N 2' reaction of the organometallic reagent 3 with the electrophile 2 derived from an allylic alcohol, to furnish the bis(deoxypropionate) building block 1. Oxidative cleavage of the alkene in the bis(deoxypropionate) 1 followed by conversion of the product into a new organometallic nucleophile should then make it possible to carry out an iterative process. This approach is complementary to the known enolate-alkylation strategy, as the growing propionate chain is introduced as a nucleophile and not as an electrophile ("Umpolung"). Key to the success of this strategy is the availability of an allylic substitution reaction that occurs in acyclic systems with complete chemo-, regio-, and stereoselectivity, as well as complete 1,3-chirality transfer. Our recently developed "directed" copper-mediated allylic substitution reaction with o-diphenylphosphanylbenzoate (o-DPPB) as the reagent-directing leaving group meets these requirements.[5] However, its compatibility with enantiomerically pure Grignard reagents 3 that are branched in the b position remained untested. Furthermore, it was necessary to develop a practical route to enantiomerically pure building blocks 2 and 3.Enzyme catalysis was selected as a suitable method for the preparation of large quantities of both enantiomers of allylic electrophiles 2. Thus, the allylic alcohol rac-6 was subjected to enzymatic resolution with Novozym 435 (Scheme 2).[6] Enantiomerically pure (S)-6 was obtained at 55 % conversion (enantioselectivity factor E = 52). The acetate (R)-7 (82 % ee) formed in the reaction underwent hydrolysis (also catalyzed by Novozym 435) to furnish (R)-6 (96-97 % ee). Both enantiomers of 6 were transformed into the corresponding odiphenylphosphanylbenzoate compounds 8, which were purified by crystallization. In this way, gram quantities of both enantiomers of 8 could be prepared in enantiomerically pure form. The crystalline allylic o-DPPB esters 8 could be stored Scheme 1. Iterative strategy for the enantioselective const...