Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities

Cresswell, Alexander J.; Eey, Stanley T.-C.; Denmark, Scott E.

doi:10.1002/anie.201507152

Cited by 192 publications

(100 citation statements)

References 357 publications

(677 reference statements)

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“…Although the addition of molecular chlorine to carbon–carbon double bonds is one of the oldest known organic reactions, 1a the ability to control the enantioselectivity of alkene dichlorination has largely eluded chemists. 1b–d Meanwhile, in recent years there has been a growing interest in the stereoselective synthesis of polychlorinated sulfolipid natural products.…”

Section: Introductionmentioning

confidence: 99%

“…1b–d Meanwhile, in recent years there has been a growing interest in the stereoselective synthesis of polychlorinated sulfolipid natural products. Due to the scarcity of methods for enantioselective dichlorination of alkenes, syntheses of molecules within this class of natural products rely on multistep routes for establishing chlorine-bearing chiral centers in an enantioselective fashion.…”

Section: Introductionmentioning

confidence: 99%

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Catalytic Enantioselective Dihalogenation and the Selective Synthesis of (−)-Deschloromytilipin A and (−)-Danicalipin A

Landry

McKenna

et al. 2016

J. Am. Chem. Soc.

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A titanium-based catalytic enantioselective dichlorination of simple allylic alcohols is described. This dichlorination reaction provides stereoselective access to all common dichloroalcohol building blocks used in syntheses of chlorosulfolipid natural products. An enantioselective synthesis of ent-(–)-deschloromytilipin A and a concise, eight-step synthesis of ent-(–)-danicalipin A are executed and employ the dichlorination reaction as the first step. Extension of this system to enantioselective dibromination and its use in the synthesis of pentabromide stereoarrays relevant to bromosufolipids is reported. The described dichlorination and di-bromination reactions are capable of exerting diastereocontrol in complex settings allowing X-ray crystal structure analysis of natural and unnatural diastereomers of polyhalogenated stereohexads.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Catalytic Enantioselective Dihalogenation and the Selective Synthesis of (−)-Deschloromytilipin A and (−)-Danicalipin A

Landry

McKenna

et al. 2016

J. Am. Chem. Soc.

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“…4 First, molecular halogens and their surrogates are highly reactive and often exhibit nonselective background reactivity, even at reduced temperatures. Second, solely controlling the enantioselectivity of halonium formation is not sufficient in generating enantioenriched dihalide products (i.e.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Enantioselective Dihalogenation in Total Synthesis

Landry

Burns

2018

Acc. Chem. Res.

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CONSPECTUS To date, more than 5,000 biogenic halogenated molecules have been characterized. This number continues to increase as chemists explore chloride- and bromide-rich marine environments in search of novel bioactive natural products. Naturally-occurring organohalogens span nearly all biosynthetic structural classes, exhibit a range of unique biological activities, and have been the subject of numerous investigations. Despite the abundance of and interest in halogenated molecules, enantioselective methods capable of forging carbon-halogen bonds in synthetically-relevant contexts remain scarce. Accordingly, syntheses of organohalogens often rely on multistep functional group interconversions to establish carbon-halogen stereocenters. Our group has developed an enantioselective dihalogenation reaction and utilized it in the only reported examples of catalytic enantioselective halogenation in natural product synthesis. In this Account, we describe our laboratory’s development of a method for catalytic, enantioselective dihalogenation and the application of this method to the synthesis of both mono- and polyhalogenated natural products. In the first part, we describe the initial discovery of a TADDOL-mediated dibromination of cinnamyl alcohols. Extension of this reaction to a second-generation system capable of selective bromochlorination, dichlorination, and dibromination is then detailed. This system is capable of controlling the enantioselectivity of dihalide formation, chemoselectivity for polyolefinic substrates, and regioselectivity in the case of bromochlorination. The ability of this method to exert control over regioselectivity of halide delivery permits selective halogenation of electronically non-biased olefins required for total synthesis. In the second part, we demonstrate how the described dihalogenation has provided efficient access to a host of structurally diverse natural products. The most direct application of this methodology is in the synthesis of naturally-occurring vicinal dihalides. Chiral vicinal bromochlorides represent a class of >175 natural products; syntheses of five members of this class, including its flagship member, (+)-halomon, have been accomplished through use of the catalytic, enantioselective bromochlorination. Likewise, enantioselective dichlorination has provided selective access to two members of the chlorosulfolipids, a class of linear, acyclic polychlorides. Synthesis of chiral monohalides has been achieved through solvolysis of enantioenriched bromochlorides; this approach has resulted in the synthesis of five bromocyclohexane-containing natural products through an enantiospecific bromopolyene cyclization. In reviewing these syntheses, a framework for the synthesis of chiral organohalogens mediated by catalytic, enantioselective dihalogenation has emerged. The development of a selective dihalogenation method has been highly enabling in the synthesis of halogenated natural products. In this Account, we detail all examples of catalytic, enantioselective halogenation in...

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“…[1] This imbalance is particularly acute in the direct 1,2-difluorination of terminal C(sp 2 ) À C(sp 2 ) p-bonds,w here general, catalysis-based strategies are noticeable by their absence. [1] This imbalance is particularly acute in the direct 1,2-difluorination of terminal C(sp 2 ) À C(sp 2 ) p-bonds,w here general, catalysis-based strategies are noticeable by their absence.…”

mentioning

confidence: 99%

Enantioselective, Catalytic Vicinal Difluorination of Alkenes

et al. 2018

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The enantioselective,catalytic vicinal difluorination of alkenes is reported by I I /I III catalysis using an ovel, C 2symmetric resorcinol derivative.C atalyst turnover via in situ generation of an ArI III F 2 species is enabled by Selectfluor oxidation and addition of an inexpensive HF-amine complex. The HF:amine ratio employed in this process provides ah andle for regioselective orthogonality as af unction of Brønsted acidity.S electivity reversal from the 1,1-difluorination pathway( geminal) to the desired 1,2-difluorination (vicinal) is disclosed (> 20:1 in both directions). Validation with electron deficient styrenes facilitates generation of chiral bioisosteres of the venerable CF 3 unit that is pervasive in drug discovery (20 examples,upto94:06 e.r.). An achiral variant of the reaction is also presented using p-TolI (up to > 95 %yield).

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Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities

Cited by 192 publications

References 357 publications

Catalytic Enantioselective Dihalogenation and the Selective Synthesis of (−)-Deschloromytilipin A and (−)-Danicalipin A

Catalytic Enantioselective Dihalogenation and the Selective Synthesis of (−)-Deschloromytilipin A and (−)-Danicalipin A

Catalytic Enantioselective Dihalogenation in Total Synthesis

Enantioselective, Catalytic Vicinal Difluorination of Alkenes

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