Palladium‐Catalyzed Enantioselective Redox‐Relay Heck Alkynylation of Alkenols To Access Propargylic Stereocenters

Abstract

An enantioselective redox-relay Heck alkynylation of di-and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β-alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods. Graphical abstractA convenient redox-relay Heck strategy to synthesize enantiomerically enriched β-alkynyl carbonyl compounds from allylic alcohol substrates is described. Trisubstituted allylic alcohols are also promising substrates allowing for the formation of propargylic quaternary stereocenters. KeywordsHeck reaction; alkenes; propargylic stereocenter; alkynylation Intermolecular Heck reactions generally feature the coupling of an sp 2 -hybridized reaction partner to an alkene followed by β-hydride elimination towards the site of initial migratory insertion. This formally yields a sp 2 -sp 2 carbon-carbon connection. [1] Recently, this reaction has been expanded through both substrate and catalyst design to preferentially undergo β-hydride elimination away from the site of initial migratory insertion to both set a stereocenter and allow the formation of a sp 2 -sp 3 C-C bond. [2] Specifically, our group has reported a suite of such enantioselective redox-relay Heck reactions of acyclic alkenyl Correspondence to: Matthew S. Sigman. Supporting information for this article can be found under: http://dx.doi.org/ Conflict of interestThe authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript alcohols using aryldiazonium salts, [3] arylboronic acids, [4] and alkenyl triflates, [5] which provides direct preparation of carbonyl compounds that contain remote alkenyl/aryl stereocenters (Scheme 1A). However, this emerging strategy has thus far been limited to sp 2 -hybridized nucleophiles/electrophiles as coupling partners.In an effort to expand the breadth of products one can access with this approach, we selected to investigate the enantioselective Heck alkynylation of alkenols to construct propargylic stereocenters and forge sp-sp 3 C-C bonds (Scheme 1B). The successful development of an alkynyl Heck reaction would allow direct access to chiral β-alkynyl carbonyl compounds, which are versatile intermediates that have extensive applications in organic synthesis. [6] Traditionally, these types of compounds have been synthesized using enantioselective conjugate addition technologies, pioneered by Carreira, [7] Hayashi, [8] and others, through organometallic acetylide addition to α,β-unsaturated carbonyl substrates. [9] However, we envisioned that a redox-relay Heck approach that utilized allylic alcohol substrates would provide an attractive alternative to this field due to the ease of preparation, handling and improved stability of such alkenols. In addition, it was deemed possible, on the basis of our previous reports, that trisubstituted alkenols may be viable substrates. Using a traditional c...

Walking Metals for Remote Functionalization

“…Such a transformation enables the formation of acyclic quaternary stereocenters in high enantioselectivity, a long-standing challenge in organic synthesis, from trisubstituted olefins using different coupling partners such as diazonium salts, boronic acids, or vinyl triflates ( Figure 10 c). 62 − 71 A similar protocol was found to promote the remote functionalization of olefinic alcohols comprising a cyclopropane in the side chain with concomitant selective ring cleavage ( Figure 10 d). 72 Alternatively, the “chain-walking” can also be initiated by an in situ formed palladium hydride, resulting in an overall long-range redox isomerization of olefinic alcohols.…”

Recent Advances of Catalytic Enantioselective Heck Reactions and Reductive‐Heck Reactions

“…In 2017, Sigman and co‐workers employed TIPS‐EBX as an electrophilic alkynylation reagent to react with di‐ or tri‐substituted alkenols, which efficiently constructed propargylic stereocenters in excellent ees by using a chiral pyridine‐oxazoline ligand L24 . [ 46 ] Low yields but high ee values were obtained for the alkynylation of trisubstituted alkenols (Scheme 33).…”

Mechanistic Insights on the Selectivity of the Tandem Heck–Ring-Opening of Cyclopropyldiol Derivatives

“…However, we have recently revealed that the ring-opening selectivity can also be dictated by an unprecedented transformation of an alcohol into an aldehyde (Scheme , eqs 1b 1 , 1b 3 , and 1b 6 ) as a driving force. ,,, Evidence for the utility of this transformation in various reactions, notably the Heck − relay reaction, was previously reported. − …”