Iterative Deoxypropionate Synthesis Based on a Copper‐Mediated Directed Allylic Substitution

Abstract

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...

Highly Efficient, Convergent, and Enantioselective Synthesis of Phthioceranic Acid

“…[1] They represent afamily of structurally diverse compounds with ab road range of biological activities and pharmacological properties, [2] e.g., neutral sphingomyelinase inhibitor (+ +)-scyphostatin, [3] cytotoxic agents (À)-borrelidine [4] and (À)-doliculide, [5] pheromone (+ +) -4,6,8,10,16,18-hexamethyldocosane, [6] calcium ionophore ionomycin, [7] as well as the long-chain aliphatic phthioceranic acid (Figure 1). [9] Since deoxypropionates are devoid of heterofunctional groups that could assist asymmetric CÀCorC ÀHbond formation, most of the currently known and widely used methods for their constructions have to install temporary functional or chiral directing groups that are to be removed later. [9] Since deoxypropionates are devoid of heterofunctional groups that could assist asymmetric CÀCorC ÀHbond formation, most of the currently known and widely used methods for their constructions have to install temporary functional or chiral directing groups that are to be removed later.…”

“…[8] In view of the abundant presence of deoxypropionatecontaining natural products with diverse fascinating biological activities,intense efforts for the development of efficient and stereoselective methods for their synthesis have been made. [9] Since deoxypropionates are devoid of heterofunctional groups that could assist asymmetric CÀCorC ÀHbond formation, most of the currently known and widely used methods for their constructions have to install temporary functional or chiral directing groups that are to be removed later. [9] These methods construct deoxypropionate units in al inear-iterative fashion:o ne deoxypropionate unit after another is typically attached to the growing alkyl chain, and one iteration cycle typically requires 3-6 steps to introduce one methyl-branched chiral center.…”

“…[9] Since deoxypropionates are devoid of heterofunctional groups that could assist asymmetric CÀCorC ÀHbond formation, most of the currently known and widely used methods for their constructions have to install temporary functional or chiral directing groups that are to be removed later. [9] These methods construct deoxypropionate units in al inear-iterative fashion:o ne deoxypropionate unit after another is typically attached to the growing alkyl chain, and one iteration cycle typically requires 3-6 steps to introduce one methyl-branched chiral center. Thus,t hey suffer from long synthetic steps,l ow efficiency, and/or use of stoichiometric amount of chiral auxiliaries.…”

Strategies for the Synthesis of Deoxypropionates

“…In a series of papers, Breit explored an enantioselective ortho-diphenylphosphanylbenzoate (o-DPPB) directed allylic substitution (Scheme 8). [42][43][44][45][46] The idea behind this concept is that the leaving group of the allylic carboxylate 69 contains a coordinating unit, e.g., a phosphane, which controls the stereochemistry of the incoming nucleophile by tethering the copper species resulting in almost perfect 1,3chirality transfer. Furthermore, the directing o-DPPB group acts as a traceless auxiliary, so that deoxypropionate fragment 71 can be used directly for further transformations.…”

Short Enantioselective Total Synthesis of Tatanan A and 3‐epi‐Tatanan A Using Assembly‐Line Synthesis

“…Iterative strategies are highly attractive for the synthesis of complex molecules, [1] particularly when minimal or no functional-group manipulations between chain-extension steps are required. [2,3] Iterative aldol reactions provide one such strategy, [3] but if the target molecule is devoid of appropriate functional-group handles,a lternative methodologies are required.…”