10, 20, 50 Years from Now…? Literature Review Organic ...web.stanford.edu/group/burnslab/...DXHhalogenation.pdf · halide synthesis help the development of ... Halonium ions generated

D. X. Hu Burns GroupTowards Catalytic Enantioselective Halogenation of Alkenes

Catalytic Enantioselective Halogenation

Literature Review

Organic Synthesis

October 6th, 2012

Relevant Problems:

Challenges in Enantioselective

Halofunctionalization

Strategies for Catalytic

Enantioselective Halofunctionalization

Research Proposal

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?

10, 20, 50 Years from Now…?

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 cross-

coupling methodology combined with a “chiral halide pool”

simplify the synthesis of “3D” molecules in the way palladium-

catalyzed cross-coupling trivialized the synthesis of many

“2D” molecules?

D. X. Hu Burns GroupLiterature Review: Catalytic Enantioselective Halogenation

Challenges in Enantioselective Halogenation:Facing Reality:

How many methods can you think of for secondary alkyl

halide synthesis?

How many mechanisms of halogenation can you think of?

Why are there so few?

Inter-alkene halonium transfer is fast, resulting in rapid loss of

optical activity:

For a bis-adamantyl olefin with Br2 and I2, the second-order

rate constants for inter-alkene transfer were found to be ~2 x

106 and ~7.6 x 106 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!

Halogens rarely form more than one covalent bond, resulting

in fewer orbital geometries for reactivity. More on this later.


Challenges in ES Halogenation (cont’d):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 non-

stereotopic intermediate (i.e. dynamic kinetic

resolution): this means we must invoke planar starting

materials or intermediates (alkenes, carbocations, or

rapidly interconverting radicals)

Halonium ions generated by solvolysis can be trapped

enantiospecifically in the absence of olefins, but addition of

olefin results in erosion of enantiospecificity (es):

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:

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.

Neutral halogens are non-basic compared to

chalcogens or pnictogens. This limits concerted

“halene”-type reactivity.


Challenges in ES Halogenation (cont’d):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).

Due to their valence saturation, halides cannot carry a

“leaving group,” further restricting concerted “halene”-type

reactivity.

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.

As a corollary, any stoichiometric halogenation agent

leaves behind a radical or anionic partner that must be

accounted for.

Due to their incredible reactivity, non-enantioselective

background reaction rates tend to be high.

Is there any hope?

With conjugated substrates (styrenyl or cinnamyl-type),

diastereomers often form through the intermediacy of an open

bromocarbocation.


Type I: Chiral Lewis Base CatalysisCurrent Catalytic ES Halogenation Methods:

Current strategies for catalysis of halofunctionalization

revolve around four paradigms:

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:


Type II: Chiral Ion Pairing CatalysisType 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.

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-bond-

forming cyclization.


Type II: Chiral Ion Pairing Catalysis (cont’d)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.

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:



A subset of chiral ion pairing catalysis is phase-transfer

catalysis. This strategy has been used effectively in

enantioselective fluorination to form oxazoline compounds.

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.



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.

Templation of carboxylic acid substrates with a chiral base

has been employed successfully for lactonization reactions.

Alcohols do not cyclize selectively.

Suggested transition state:


Type III: Hydrogen-Bonding Catalysts (cont’d)Type III: Hydrogen-Bonding Catalysts

Most Lewis-base catalysts also need hydrogen-bonding

coordination or activation for successful stereochemical

transfer.

In many cases the source of selectivity-induction is not well

understood.


Type III: Hydrogen-Bonding Catalysts (cont’d)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.

There is experimental evidence that the stoichiometric

oxidant’s counterion is associated with the quinuclidine

complexes during the product-determining step.


Type III: Hydrogen-Bonding Catalysts (cont’d)Type III: Hydrogen-Bonding Catalysts (cont’d)

Cinchona-derived catalysts have been used in many different

types of halofunctionalization effectively.

There is experimental evidence that the stoichiometric

oxidant’s counterion is associated with the quinuclidine

complexes during the product-determining step.


Type IV: Lewis-Acid MediatedType 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.

Most methods for Lewis acid mediated halofunctionalizations

involve coordination of the substrate to the Lewis acid.


Type IV: Lewis-Acid MediatedType IV: Lewis-Acid Mediated (cont’d)

A key point is that Lewis acid mediated processes must

generate a chiral counterion.

In more specific cases, Lewis acid activation probably

proceeds by activating carbonyl groups in the substrate rather

than the halogen-donor.


Other Important Precedents (cont’d):Other Important Precedents:

Alpha-halogenation of carbonyls is another popular field of

research. Organocatalysts and metal catalysts have been

employed to great effect.

Documents

10, 20, 50 Years from Now…? Literature Review Organic ...web.stanford.edu/group/burnslab/...DXHhalogenation.pdf · halide synthesis help the development of ... Halonium ions generated