Enantioselective Dichlorination of Allylic Alcohols

Nicolaou, K. C.; Simmons, Nicholas L.; Ying, Yongcheng; Heretsch, Philipp; Chen, Jason S.

doi:10.1021/ja202555m

Cited by 232 publications

(130 citation statements)

References 37 publications

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“…Importantly, the absence of chloriranium ion intermediates can circumvent the site selectivity issue inherent in the nucleophilic trapping of such species with chloride ion: a recognised, and as yet unsolved, problem in controlling the enantioselectivity of dichlorinations of electronically-unbiased, ( E )- or ( Z )-configured alkenes. 15 …”

Section: Discussionmentioning

confidence: 99%

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Catalytic, stereospecific syn-dichlorination of alkenes

2015

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As some of the oldest organic chemical reactions known, the ionic additions of elemental halogens such as bromine and chlorine to alkenes are prototypical examples of stereospecific reactions, typically delivering vicinal dihalides resulting from anti-addition. Whilst the invention of enantioselective variants is an ongoing challenge, the ability to overturn the intrinsic anti-diastereospecificity of these transformations is also a largely unsolved problem. In this Article, we describe the first catalytic, syn-stereospecific dichlorination of alkenes, employing a group transfer catalyst based on a redox-active main group element (i.e., selenium). Thus, with diphenyl diselenide (PhSeSePh) (5 mol %) as the pre-catalyst, benzyltriethylammonium chloride (BnEt3NCl) as the chloride source, and an N-fluoropyridinium salt as the oxidant, a wide variety of functionalized cyclic and acyclic 1,2-disubstituted alkenes, including simple allylic alcohols, deliver syn-dichlorides with exquisite stereocontrol. This methodology is expected to find applications in streamlining the synthesis of polychlorinated natural products such as the chlorosulfolipids.

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Section: Discussionmentioning

confidence: 99%

“…The daunting synthetic challenge of constructing such densely functionalized arrays of chlorinated stereogenic centers has provided impetus for the study of (external) diastereocontrol in the dichlorination of chiral alkene substrates, 12 as well as more recent efforts to effect enantioselective dichlorinations of allylic alcohols. 15 …”

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confidence: 99%

Catalytic, stereospecific syn-dichlorination of alkenes

2015

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“…12 In contrast, Burns et al have proposed a rather different role for the Lewis base (pre)catalyst (i.e., diol 12 ) in their enantioselective alkene dibromination protocol, suggesting that it may serve to accelerate the nucleophilic trapping of the bromiranium ion intermediate with (Ti-bound) bromide ion, rather than the formation of the bromiranium ion itself (Scheme 5). 15 If this were true, it would constitute “nucleophile activation” as opposed to “electrophile activation” (as depicted in Scheme 6), which is another well-recognized facet of Lewis base catalysis.…”

Section: Challenges For Stereoselective Catalysismentioning

confidence: 99%

“…A number of ( E )-configured, 3-aryl 2-propenyl alcohols are dichlorinated in moderate to good er (71.5:28.5 to 90.5:9.5 er), although O -protected, ( Z )-configured, or aliphatic allylic alcohols are generally less selective (<52.5:47.5 to 81:19 er) (Scheme 4). 12 …”

Section: Introduction: State Of the Artmentioning

confidence: 99%

Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities

2015

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Although recent years have witnessed significant advances in the development of catalytic, enantioselective halofunctionalizations of alkenes, the related dihalogenation of olefins to afford enantioenriched vicinal dihalide products remains comparatively underdeveloped. However, the growing number of complex natural products bearing halogen atoms at stereogenic centers has underscored this critical gap in the synthetic chemist's arsenal. This Review highlights the selectivity challenges inherent in the design of enantioselective dihalogenation processes, and formulates a mechanism-based classification of alkene dihalogenations, including those that may circumvent the "classical" haliranium (or alkene-dihalogen π-complex) intermediates. A variety of metal and main group halide reagents that have been used for the dichlorination or dibromination of alkenes are discussed, and the proposed mechanisms of these transformations are critically evaluated. AbstractCatalysis of alkene dihalogenation , under different activation modes, with control over both the absolute and relative stereochemical course of dihalogen addition, is one of the most vexing problems in stereoselective synthesis. Dihalogenations that circumvent the "classical" haliranium (or alkene-dihalogen π complex) intermediates provide new and exciting opportunities for catalysis, potentially having broader implications for the design of stereoselective alkene difunctionalizations.

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“…Ring opening of intermediate 16b with chloride ion at the reactive benzylic position would complete the double inversion and account for the experimentally observed stereochemistry. Nicolaou has demonstrated catalytic asymmetric addition of chlorine to allylic alcohols, where regioselectivity of chloronium ion ring opening is a prerequisite for good ee values 29 and Denmark has recently demonstrated that chiral chloronium ions, containing alkyl groups, are configurationally stable. 30 The generality of this novel dichlorination reaction remains to be fully evaluated, but it is significant that it failed with two (11a and 11c) out of three bicyclic substrates.…”

Section: Resultsmentioning

confidence: 99%

Reactions of enantiopure cyclic diols with sulfuryl chloride

et al. 2014

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Monocyclic allylic cis-1,2-diols reacted with sulfuryl chloride at 0 °C in a regio- and stereo-selective manner to give 2-chloro-1-sulfochloridates, which were hydrolysed to yield the corresponding trans-1,2-chlorohydrins. At -78 °C, with very slow addition of sulfuryl chloride, cyclic sulfates were formed in good yields, proved to be very reactive with nucleophiles and rapidly decomposed on attempted storage. Reaction of a cyclic sulfate with sodium azide yielded a trans-azidohydrin without evidence of allylic rearrangement occurring. An enantiopure bicyclic cis-1,2-diol reacted with sulfuryl chloride to give, exclusively, a trans-1,2-dichloride enantiomer with retention of configuration at the benzylic centre and inversion at the non-benzylic centre; a mechanism is presented to rationalise the observation.

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Enantioselective Dichlorination of Allylic Alcohols

Cited by 232 publications

References 37 publications

Catalytic, stereospecific syn-dichlorination of alkenes

Catalytic, stereospecific syn-dichlorination of alkenes

Catalytic, Stereoselective Dihalogenation of Alkenes: Challenges and Opportunities

Reactions of enantiopure cyclic diols with sulfuryl chloride

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