Enantioselective Heck Arylations of Acyclic Alkenyl Alcohols Using a Redox-Relay Strategy

Werner, Erik W.; Mei, Tian Sheng; Burckle, Alexander J.; Sigman, Matthew S.

doi:10.1126/science.1229208

Cited by 430 publications

(262 citation statements)

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“…[5,10] We began the investigation using our previously reported conditions of Pd(TFA) 2 (5 mol %), bisoxazoline L1 (10 mol %), and basic zinc carbonate (0.1 equiv) in methanol at 60 8 8C, to obtain Omethyl-lactol 3a in 77 %yield with an enantiomeric ratio (er) of 95:5. However,o nly moderate level of regiocontrol (9:1) was observed in favor of the desired g-arylation.…”

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confidence: 99%

Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

2015

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We describe herein a highly regio- and enantioselective Pd-catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all-carbon quaternary stereogenic centers. Chiral N,N ligands of the pyrimidine- and pyrazino-oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to >99:1. Both linear and branched substituents on the olefins were well-tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O-methyl lactols and lactones containing quaternary stereocenters, together with a concise enantioselective total synthesis of the calcium channel blocker verapamil.

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confidence: 99%

Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

2015

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“…Author 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.…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

“…[3] In addition, no significant change was observed when the reaction temperature was decreased to 15 °C (entry 6). Surprisingly, switching to a Pd(0) precatalyst (Pd 2 (dba) 3 ) resulted in <5% product formation (entry 7). In contrast, Buchwald's precatalyst, known to form Pd(0) in situ upon heating or adding base, [12] furnished the desired product (2a) in 65% yield and 96:4 er.…”

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confidence: 98%

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

et al. 2017

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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...

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“…31,32 Distinct from the above-described approach, Sigman and co-workers have recently reported a Pd-catalyzed enantioselective redox-relay Heck reaction of acyclic alkenyl 1°and 2°a lcohols where aryl addition is followed by olefin migration through the carbon chain and eventually oxidation of the alcohol. 33 The authors capitalized on previous works which described similar outcome when allylic alcohols were employed. 34 Key to the success of this approach was the use of an electrophilic catalyst which favoured migration (i.e.…”

Section: Heck-typementioning

confidence: 99%

Recent trends in Pd-catalyzed remote functionalization of carbonyl compounds

Franzoni

Mazet

2014

Org. Biomol. Chem.

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Recent advances in the palladium-catalyzed remote functionalization of carbonyl derivatives are highlighted in this review. The structure of the article is based on the three strategies that have emerged in recent years as the most viable tactics to construct C(sp of at least three carbon atoms from the carbonyl functionality. The specific aspects of each of these approaches are discussed in detail (reaction conditions, substrate scope and limitations). As the reading progresses, their complementarity should also appear clearly.

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Enantioselective Heck Arylations of Acyclic Alkenyl Alcohols Using a Redox-Relay Strategy

Cited by 430 publications

References 50 publications

Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

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

Recent trends in Pd-catalyzed remote functionalization of carbonyl compounds

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