Catalytic, asymmetric halofunctionalization of alkenes--a critical perspective

Abstract

Despite the fact that halogenation of alkenes has been known for centuries, enantioselective variants of this reaction have only recently been developed. In the past three years, catalytic enantioselective versions of halofunctionalizations with the four common halogens have appeared and although important breakthroughs, they represent just the very beginnings of a nascent field. This Minireview provides a critical analysis of the challenges that accompany the development of general and highly enantioselective halofunctionalization reactions. Moreover, the focus herein, diverges from previous reviews of the field by identifying the various modes of catalysis and the different strategies implemented for asymmetric induction.

Figure 1

Nomenclature of halogen cations.

Figure 2

Classification of tactics for maintaining catalyst/haliranium ion association. LA = Lewis acid, LB = Lewis base.

Figure 3

Ishihara’s stereochemical model for phosphoramidite promoted iodocarbocyclization.

Figure 4

Proposed model of enantioselectivity in chiral phosphoric acid catalyzed bromocyclofunctionalizations.

Figure 5

Possible models of activation and asymmetric induction by catalyst 27.

Figure 6

Possible intermediates in the bromolactonization of (Z)-1,3-enynes.

Figure 7

Proposed model of selectivity for dichlorination.

Figure 8

Proposed model for enantioselectivity of Cr^III/salen-catalyzed iodocyclization.

Scheme 1

Spectroscopically observable haliranium ions.

Scheme 2

Mechanism of olefin-to-olefin transfer of bromenium ions.

Scheme 3

Erosion of enantiospecificity in acetolysis from olefin-to-olefin transfer. HFIP = hexafluoroisopropyl alcohol, Tf = trifluoromethanesulfonyl, Ts = 4-toluenesulfonyl. es = (ee_product/ee_{starting material}) × 100%.

Scheme 4

General strategies for catalysis of halofunctionalization.

Scheme 5

Iodolactonization using a stoichiometric amount of an amine/ICl complex.

Scheme 6

Mechanism of (collidinium)₂Br⁺-promoted bromoetherification.

Scheme 7

Phosphoramidite-promoted iodocarbocyclization.

Scheme 8

Enantioselective desymmetrization of meso haliranium ions by pairing with a chiral phosphate counterion. M.S. = molecular sieves.

Scheme 9

Scope of chiral phosphoric acid/achiral Lewis base cocatalyzed bromocycloetherification.

Scheme 10

Proposed mechanism of halogen activation and delivery in chiral phosphoric acid/achiral Lewis base cocatalyzed bromocycloetherifications.

Scheme 11

Scope of chiral phosphoric acid catalyzed bromocyclofunctionalizations. Trisyl = 2,4,6-triisopropylbenzenesulfonyl.

Scheme 12

Intermolecular bromoesterification.

Scheme 13

Enantioselective fluorocyclization by chiral phosphate, phase-transfer catalysis.

Scheme 14

Scope of iodolactonization using the amino/urea catalyst (R,R)-21.

Scheme 15

Proposed key intermediate and cyclization transition state for amino/urea-catalyzed iodolactonization.

Scheme 16

C₃-Symmetric trisimidazolinylbenzene-catalyzed bromolactonization.

Scheme 17

Enantioselective bromolactonization catalyzed by cinchonine-derived thiocarbamate 27.

Scheme 18

Bromolactonization of Z-1,3-enynes catalyzed by quinine-derived urea 31.

Scheme 19

Catalytic asymmetric chlorolactonization with (DHQD)₂PHAL.

Scheme 20

Catalytic asymmetric formation of chiral oxazolines and 4,5-dihydrooxazines.

Scheme 21

Observation of the hydantoin/catalyst complex and proposed modes of binding.

Scheme 22

Enantioselective chlorolactonizations employing chiral dichlorohydantoin 45.

Scheme 23

Catalytic dichlorination of allylic alcohols. TES = triethylsilyl.

Scheme 24

(DHQ)₂PHAL-catalyzed fluorocyclization of indoles. Boc = tert-butoxycarbonyl.

Scheme 25

Enantioselective bromine-induced semipinacol rearrangement.

Scheme 26

Asymmetric iodolactonization catalyzed by 48·HNTf₂.

Scheme 27

Enantioselective titanium-promoted iodocyclizations.

Scheme 28

Co^II/salen- and Cr^IIICl/salen-catalyzed halocyclizations.

Scheme 29

Scandium-catalyzed asymmetric haloamination of chalcones.

Scheme 30

Selected cyclizations that contradict the proposed haliranium ion pathway.