D. X. Hu Towards Catalytic Enantioselective Halogenation of Alkenes Burns Group

Transcription

1 D. X. Hu Towards Catalytic Enantioselective Halogenation of Alkenes Burns Group Literature Review Organic Synthesis 10, 20, 50 Years from Now? Catalytic Enantioselective Halogenation October 6 th, 2012 Challenges in Enantioselective Halofunctionalization Strategies for Catalytic Enantioselective Halofunctionalization Relevant Problems: Research Proposal Today it is possible to couple unactivated secondary alkyl halides using transition-metal methodology. Could the development of simple methods for enantioselective alkyl halide synthesis help the development of stereoretentive alkyl halide cross-coupling methodology? Could the development of stereoretentive alkyl halide crosscoupling methodology combined with a chiral halide pool simplify the synthesis of 3D molecules in the way palladiumcatalyzed cross-coupling trivialized the synthesis of many 2D molecules? Tens of thousands of chiral halogenated compounds have been isolated from nature, with most of them from marine sources. Given that the sources of these natural products are difficult to trace due to the difficulty in culturing marine bacteria, how can scientists recreate these on large scale in the laboratory for further research on their functions?

2 Facing Reality: How many methods can you think of for secondary alkyl halide synthesis? Challenges in Enantioselective Halogenation: Inter-alkene halonium transfer is fast, resulting in rapid loss of optical activity: For a bis-adamantyl olefin with Br 2 and I 2, the second-order rate constants for inter-alkene transfer were found to be ~2 x 10 6 and ~7.6 x 10 6 M -1 s -1 at -80 C(!!) with most of the rate suppression due to a high entropy of activation (-21 eu). The incredibly low enthalpic barrier (~1.8 kcal/mol) results in the rate of reaction being dictated primarily by steric factors and the rate of diffusion! How many mechanisms of halogenation can you think of? Why are there so few? Halogens rarely form more than one covalent bond, resulting in fewer orbital geometries for reactivity. More on this later.

3 Challenges in ES Halogenation (cont d): Halonium ions generated by solvolysis can be trapped enantiospecifically in the absence of olefins, but addition of olefin results in erosion of enantiospecificity (es): Challenges in ES Halogenation (cont d): Limited range of mechanisms to work with to due the following requirements: Process requires a non-stereotopic substrate (i.e. true reagent control) or the formation of a nonstereotopic intermediate (i.e. dynamic kinetic resolution): this means we must invoke planar starting materials or intermediates (alkenes, carbocations, or rapidly interconverting radicals) This is detrimental to catalytic processes in which there is always an excess of alkene relative to halonium. This effect has been observed to be concentration dependent: Neutral halogens are non-basic compared to chalcogens or pnictogens. This limits concerted halene -type reactivity. The rate of halonium exchange may also be dependent on a number of other factors, such as counterion coordination ability, solvent nucleophilicity, and the presence of added Lewis bases.

4 Challenges in ES Halogenation (cont d): Due to their valence saturation, halides cannot carry a leaving group, further restricting concerted halene -type reactivity. Challenges in ES Halogenation (cont d): As a consequence of a lack of bonding modes and extreme energies of oxidation state >X(I), there are few orbital geometries available for reactivity, making transfer of stereochemistry difficult (i.e. linear σ* maximizes distance from covalent delivery partner). As a consequence of the lack of a stable halene, any enantioselective C-Br bond formation must be accompanied by a second C-X functionalization process. This results in an inevitable problem of regioselectivity except with C2- symmetric substrates. Due to their incredible reactivity, non-enantioselective background reaction rates tend to be high. As a corollary, any stoichiometric halogenation agent leaves behind a radical or anionic partner that must be accounted for. With conjugated substrates (styrenyl or cinnamyl-type), diastereomers often form through the intermediacy of an open bromocarbocation. Is there any hope?

5 Current Catalytic ES Halogenation Methods: Current strategies for catalysis of halofunctionalization revolve around four paradigms: Type I: Chiral Lewis Base Catalysis Early studies focused on the use of preformed halogen/amine complexes: For an enantioselective process, tactics are needed to maintain a chiral environment in the product-determining step: Such studies demonstrated the importance of both the activator and the counterion:

6 Type I: Chiral Lewis Base Catalysis (cont d) Electron-rich phosphines were found to be catalytically active with NIS and NBS for enantioselective halogenative polyene cyclizations with greater catalytic activity in DCM and toluene. Conversely, stoichiometric quantities of chiral phosphine were necessary for high enantioselectivity with better performance in toluene than in DCM. Type II: Chiral Ion Pairing Catalysis Phosphate bases have been shown to catalyze haloetherification, with hypo-halogen species being suggested as possible intermediates. It is also possible that interaction with the alcohol accelerates the ring-closure step and/or that anion exchange is faster than cyclization of an intermediate bromiranium. The authors propose a stereochemical model based on preferential approach to the phosphoramidite assuming that halogen delivery is the product-determing step. Denmark and co-workers, however, suggest that the product-determining step is not delivery of the halogen but the actual C-C-bondforming cyclization.

7 Type II: Chiral Ion Pairing Catalysis (cont d) The same catalyst under slightly different conditions provided the same result. Denmark and Shi provide different mechanistic proposals for stereoinduction it is likely that one or both are wrong. Type II: Chiral Ion Pairing Catalysis (cont d) An intermolecular coupling using this strategy has been attempted, and while product was formed in fair ee the product was formed in poor yield due to trapping of the bromiranium by the catalyst. Denmark s proposal: Shi s proposal:

8 Type II: Chiral Ion Pairing Catalysis (cont d) A subset of chiral ion pairing catalysis is phase-transfer catalysis. This strategy has been used effectively in enantioselective fluorination to form oxazoline compounds. Type II: Chiral Ion Pairing Catalysis (cont d) The use of an insoluble halogenation reagent is one strategy for preventing non-catalyzed background reaction. Tailoring the delivery agent also allowed bromocyclization and iodocyclizations to take place. While phase-transfer fluorination almost certainly involves fluoronium delivery as the product-determining step, this is not necessarily the case for bromination or iodination.

9 Type II: Chiral Ion Pairing Catalysis (cont d) It has been shown that a chiral hydrogen bond donor can catalyze a reaction through activation of a halogenating agent while also inducing product selectivity by leaving a chiral anion after halogen delivery. Type II: Chiral Ion Pairing Catalysis (cont d) Templation of carboxylic acid substrates with a chiral base has been employed successfully for lactonization reactions. Alcohols do not cyclize selectively. Suggested transition state:

10 Type III: Hydrogen-Bonding Catalysts Most Lewis-base catalysts also need hydrogen-bonding coordination or activation for successful stereochemical transfer. Type III: Hydrogen-Bonding Catalysts (cont d) In many cases the source of selectivity-induction is not well understood.

11 Type III: Hydrogen-Bonding Catalysts (cont d) Many Lewis-basic catalysts are susceptible to decay by the stoichiometric oxidants. Incubation of quinuclidine catalysts with NBS for a few hours prior to introduction of substrate results in dramatically diminished ee. Type III: Hydrogen-Bonding Catalysts (cont d) There is experimental evidence that the stoichiometric oxidant s counterion is associated with the quinuclidine complexes during the product-determining step.

12 Type III: Hydrogen-Bonding Catalysts (cont d) Cinchona-derived catalysts have been used in many different types of halofunctionalization effectively. Type III: Hydrogen-Bonding Catalysts (cont d) There is experimental evidence that the stoichiometric oxidant s counterion is associated with the quinuclidine complexes during the product-determining step.

13 Type III: Hydrogen-Bonding Catalysts (cont d) The key to this type of system appears to be having both acidic and basic functionalities in close proximity to the chiral environment, preferentially on the same molecule. Type IV: Lewis-Acid Mediated Most methods for Lewis acid mediated halofunctionalizations involve coordination of the substrate to the Lewis acid.

14 Type IV: Lewis-Acid Mediated (cont d) A key point is that Lewis acid mediated processes must generate a chiral counterion. Type IV: Lewis-Acid Mediated In more specific cases, Lewis acid activation probably proceeds by activating carbonyl groups in the substrate rather than the halogen-donor.

15 Other Important Precedents: Other Important Precedents (cont d): Alpha-halogenation of carbonyls is another popular field of research. Organocatalysts and metal catalysts have been employed to great effect.