Tag Archives: Halogenation

On the road to the full control of the stereochemistry of dihalogenation reactions

The dihalogenation reactions of alkenes proceed with almost exclusive anti-diastereoselectivity and opposed to other well-known text book reactions, an enantioselective version seems quite elusive. In the last few years, I have been fascinated by two great advances towards the full control of the stereochemistry in reactions of dihalogenation of alkenes. First the discovery of enantioselective dihalogenation reactions and second the discovery of a catalytic syn-dichlorination of alkenes.

anti mechanism
The development of enantioselective versions is very elusive because racemization can easily occur via olefin-to-olefin halenium transfer and non-regioselective nucleophilic opening of the halonium intermediates. The first successful approach to this problem was done by the group of Scott Snyder who developed a stoichiometric dichlorination reaction using a chiral borane auxiliary that forms an in-situ complex with the substrate[1]. The chlorinated olefin was obtained with 87% e.e. and that was a tremendous success due to the difficulty of the reaction. A catalytic version adds the nonenantioselective background reaction to the existing problems. Later discoveries of catalytic enantioselective dichorinaton, dibromination and heterodihalogenation reactions of olefins by the groups of Nicolau, Burns and more recently Borhan are simply spectacular [2–5]. Nicolau and Borhan approach the problem using Sharpless dihydroxylation catalyst (DHQD)2PHAL while Burns uses a combination of a Titanium salt with a chiral promoter. But all these approaches have in common a wise election of substrates (allyl alcohols and amides) that can serve as an anchor to the catalysts to overcome the regioselectivity problem.

dihalogenation of olefins
The almost set-in-stone mechanism of the dihalogenation of alkenes involves the formation of a cyclic halonium ion followed by a backside nucleophilic opening that leads to the formation of the well stablished anti-product. Overturning the anti-diastereospecificity of this process is a major challenge. The group of Scott Denmark was able to develop the first syn-dichlorination of alkenes with a strategy based on a first step of anti-addition of an in-situ generated PhSeCl3 to an alkene followed by a nucleophilic displacement with a chloride ion source leading to a syn-dichlorination product overall.6
The process is made catalytic by adding an oxidant to the Ph-Se-Se-Ph precatalyst.
All these discoveries are impressive and I cannot help finding certain parallelism with the already Nobel Prize awarded hydrogenation and dihydroxylation reactions by Noyori, Knowles and Sharpless. I am very much looking forward to seeing further advances.

nobel prize2

References:
1. Snyder, S. A., Tang, Z.-Y. & Gupta, R. Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin. J. Am. Chem. Soc. 131, 5744–5745 (2009).
2. Nicolaou, K. C., Simmons, N. L., Ying, Y., Heretsch, P. M. & Chen, J. S. Enantioselective Dichlorination of Allylic Alcohols. J. Am. Chem. Soc. 133, 8134–8137 (2011).
3. Hu, D. X., Shibuya, G. M. & Burns, N. Z. Catalytic Enantioselective Dibromination of Allylic Alcohols. J. Am. Chem. Soc. 135, 12960–12963 (2013).
4. Hu, D. X., Seidl, F. J., Bucher, C. & Burns, N. Z. Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols. J. Am. Chem. Soc. 137, 3795–3798 (2015).
5. Soltanzadeh, B. et al. Highly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides. J. Am. Chem. Soc. 139, 2132–2135 (2017).
6. Cresswell, A. J., T.-C., E. & Denmark, S. E. Catalytic, stereospecific syn-dichlorination of alkenes. Nat Chem 7, 146–152 (2015).

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Syn-dichlorination of alkenes

Another post for the series “This blog is obsessed with dihalogenation reactions”. In previous posts I presented some of the reactions I consider of great relevance on the subject of enantioselective dihalogenation reactions (you can take a look here and here as well :D).  All these reactions having in common the synthesis of vicinal halides resulting from anti-addition as an inevitable consequence  of the ionic nature of the addition reaction of elemental halogens and related reagents to alkenes.

In other words, the challenge I’d like to highlight in this post is the difficulty of the development of straightforward methodologies for the syn-halogenation of alkenes. A great contribution to this topic is the first catalytic, syn-stereospecific dichlorination of alkenes developed by Denmark and co-workers.

challenge

The strategy used is based on a first step of anti-addition of an in-situ generated PhSeCl3 to an alkene followed by a nucleophilic displacement with a chloride ion source leading to a syn-dichlorination product overall. The process is made catalytic by adding an oxidant to the Ph-Se-Se-Ph precatalyst.

mechanism syn

This new methodology could be very useful for the synthesis of oligo- and polychlorinated compounds such as chlorosulfolipids, a family of synthetically challenging compounds originally discovered from the membranes of freshwater algae and associated to diarrhetic shellfish poisoning.

fosfolipids

Do you want to know more? Take a look to the original paper:

Catalytic, stereospecific syn-dichlorination of alkenes. Alexander J. Cresswell,              Stanley T.-C. Eey & Scott E. Denmark. Nature Chemistry 7, 146–152 (2015).

Enantioselective Dihalogenation of Allylic Alcohols

The development of a catalytic enantioselective reaction of bromination of alkenes can be at least as complicated as the corresponding dichlorination variant. The background reaction of bromine and other common dibrominating reagents capable of reacting rapidly with alkenes with no need of catalyst and the fact that bromonium ions can rapidly racemize in the presence of alkene do not make it any easier.

Recently in 2013 Burns and co-workers approached this challenge with a different strategy: to formally separate Br2 into electrophilic and nucleophilic components that are unreactive on their own. Diethyl dibromomalonate as the bromonium source and titanium bromide as the bromide anion source do the trick. To induce enantiocontrol a chiral TADDOL ligand is used as a chiral promoter and allylic alcohols capable to bind to the titanium metal centre are chosen as substrates. The TADDOL-type ligand used in the reaction has been found to induce good levels of enantioselectivity when used stoichiometrically and also lowering its loading to 20 mol%.

dibromacionNot happy with this incredible contribution Burns and co-workers have very recently published a follow up paper extending the methodoly to an enantioslective Bromochlorination version. Same strategy different actors, in this case Chlorotitanium triisopropoxide as the chloride source and N-bromosuccinimide as the bromonium source serve as a non-disproportionating equivalent to bromine monochloride and a tridentate Schiff base is used as chiral promoter.

dihalogenation
These new methodology will enable enantioselective synthesis of a wide variety of polyhalogenated natural products. As a proof of concept the paper also includes a short chemo-, regio-, and enantioselective synthesis of (+)-bromochloromyrcene and model subtrates leading to bromochlorocyclohexane motifs that can be found within several natural products including obtuso and preintricatol.

natural products           Do you want to know more? Why don’t you take a look to these references?

-Dennis X. Hu , Grant M. Shibuya , and Noah Z. Burns. Catalytic Enantioselective Dibromination of Allylic Alcohols. J. Am. Chem. Soc., 2013, 135, 12960–12963.

– Dennis X. Hu , Frederick J. Seidl , Cyril Bucher , and Noah Z. Burns. Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols. J. Am. Chem. Soc., 2015, 137, 3795–3798.

Asymmetric Chlorination of Olefins.

There is no need to argue the relevance of the study of the halogenation reactions. Alkyl halides are common and useful intermediates in organic synthesis and there are thousands of halogenated natural products with potential biological activity. But curiously and despite the chlorination of olefins is a well-known text book reaction, a general enantioselective variant is yet to be discovered. A great contribution to this challenge was the enantioselective olefin dichlorination developed by Snyder and co-workers in their total synthesis of napyradiomycin A1. The reaction requires the use of a stoichiometric chiral borane auxiliary that forms an in-situ complex with the substrate. According to the authors the enantioselectivity of the process can be due to an organizational π-stacking interaction with the substrate favouring the formation of a chloronium ion at the bottom face of the molecule. The chlorinated olefin is obtained with 87% e.e. (95% e.e. only after recrystallization) and that is a tremendous success due to the difficulty of the reaction.

Snyder

If you think that an enantioselective chlorination reaction promoted by a stoichiometric reagent is hard, try to make it catalytic. That can be just madness:

-It is strictly necessary to minimise the background reaction, chlorinating reagents can add to olefins with no need of a catalyst.

-Even in the case you are able to form enantioselectively the corresponding chloronium intermediate, complete loss of enantioselectivity can occur due to:

a) Chloronium transfer to a free olefin or

b) Non-regioselective nucleophilic opening by a chloride.

Racemization

The catalytic reaction challenge was admirably accepted by Nicolau and co-workers. Aryl-substituted allylic alcohols were wisely selected as model substrates in an attempt to overcome the difficulties of the reaction. The reaction is expected to occur via benzylic chloronium species that favour a regiocontrolled chloride attack and the hydroxyl group can serve as an anchor to the catalyst via hydrogen bonding rigidifying the system and providing stereocontrol. The reaction is also performed at low temperatures to slow down the background reaction. The best system to promote the catalytic dichlorination reaction was a combination of the cinchona alkaloid derivative (DHQ) 2PHAL (commonly used as a ligand in Sharplesasymmetric hydroxylation) with p-Ph(C6H4)ICl2 as chlorine source. Although the enantioselectivities obtained were moderate and controlled by substrate design, the work of Nicolaus group meant a great contribution to the field and there is (Im completely sure) much more to come in the future.

Nicolau

Do you want to know more? Take a look to these papers:

-Scott A. Snyder, Zhen-Yu Tang and Ritu Gupta. Enantioselective Total Synthesis of (−)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin. J. Am. Chem. Soc., 2009, 131, 5744–5745.

-K.C. Nicolaou, Nicholas L. Simmons,Yongcheng Ying, Philipp M. Heretsch, and Jason S. Chen. Enantioselective Dichlorination of Allylic Alcohols. J. Am. Chem. Soc. 2011, 133, 8134–8137.

-Mattia R. Monaco and Marco Bella. A Formidable Challenge: Catalytic Asymmetric Dichlorination. Angew. Chem. Int. Ed. 2011, 50, 2–5.