An Alkynylboronic Ester Annulation: Development of Synthetic Methods for Application to Diversity-Oriented Organic Synthesis

Abstract

Diversity-oriented synthesis aims to prepare complex and diverse small molecules efficiently. These molecules can be used to explore biology-our goal is to be able to do so in a systematic way. [1] Whereas complex molecules can be synthe-sized efficiently using coupled complexity-generating reactions, [2] the goal of developing diversity-generating pathways yielding products with a high degree of skeletal diversity has not yet been realized. The development of synthetic pathways incorporating branch points holds promise as an effective route to skeletal diversity. [1] One such pathway, which diverges from common starting materials, aims to exploit the diverse reactivity of alkyl-, allyl-, pentadienyl-, alkenyl-and dialkenylboronic acids (Scheme 1). [3] This approach should enable the branching architecture of diversity-oriented synthesis pathways by using the diverse reactivity associated with these classes of reagents. [4] Previously we reported annulation reactions of allylboronic esters with allylic and propargylic alcohols that stereospecifically provide allylboronic acids 1 and pentadienylboronic acids 2. [3] Here we report new annulation reactions of electron-deficient alkynylboronic esters with homoallylic alcohols that provide functionalized dialkenylboronic acids 3. In addition, we demonstrate oxidation and allene-forming hydroxyalkylation reactions of the resulting cyclic alkenyl boronic acids that further illustrate diversity-generating, branching reaction pathways.Based on our earlier work on the allylboronic ester annulation, [3] we anticipated that the transesterification of an alkynylboronic ester 4 and a homoallylic alcohol 5 would afford a transient, mixed organoboronic ester 6 (Scheme 1), which could be trapped using ring-closing ene-yne methathesis to afford cyclic dialkenylboronic esters 3. As expected, treatment of the homoallylic alcohol 8 with the n-propylsubstituted alkynylboronic ester 9 [5] and the Grubbs catalyst 7 [6] in benzene at 65 8C afforded the cyclic dialkenylboronic acid 12 in 69 % yield (Table 1, entry 1). The annulation ZUSCHRIFTEN 3406 3409 Scheme 5. Synthetic pathway incorporating a branched network of reactions based on the boronic ester annulation chemistry presented here and in our earlier report. [3]

Recent Advances in Boron‐Substituted 1,3‐Dienes Chemistry: Synthesis and Application

“…In 2002, Schreiber and Micalizo showed that allyldialkoxyboranates 147 react with allyl alcohols 148 and propargyl alcohols 150 giving allyloxy‐ or propargyloxyalkoxyallylboranes respectively, which were later used in ring closing metathesis reaction to form cyclic boric acid ester compound 149 and 151 (Scheme ). These products are often used for the synthesis of enones . Analogous cyclic products can be obtained in similar reactions of alcohols with alkynyldialkoxyboranes …”

Small‐Molecule Diversification from Iterated Branching Reaction Pathways Enabled by DNA‐Templated Synthesis

“…More recently, researchers have introduced libraries based on “folding pathways”, in which library intermediates undergo diverse rearrangements, and “differentiation pathways”, in which intermediates are treated with different reagents to yield different scaffolds 3. Incorporating such branching reaction pathways into library syntheses is a promising strategy for the creation of small‐molecule diversity beyond what can be accessed by using nonbranched synthetic routes 6…”

A Planning Strategy for Diversity‐Oriented Synthesis

“…These reagent‐based skeletal diversity‐generating transformations are, therefore, also referred to as differentiating processes. For example, the unsaturated, cyclic dialkenylboronic ester 41 has potential for diverse reactivity, and thus, different reagents can be used to transform this common, pluripotent substrate into different products (Scheme ; two are shown), each having a distinct molecular skeleton 31. Treatment of 41 with hydrogen peroxide and sodium hydroxide effects an oxidation which leads to enone 42 .…”