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 COMMUNICATIONS 3272 3275 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 Progress on Enyne Metathesis: Its Application to Syntheses of Natural Products and Related Compounds

“…In this reaction, enyne 27a should be formed as an intermediate. Treatment of cyclic boronic ester 25a with H 2 O 2 in aqueous NaOH gave diol 26a [42,43]. Silicon-tethered ring closing enyne metathesis of 27b by ruthenium carbene catalyst 1c gave 25b , which was subjected to Tamao oxidation to afford diol 26b [44,45].…”