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Asymmetric Ylide MIRC

5 August 2005 Asymmetric cyclopropanation update

So what else is new in the field of asymmetric cyclopropanation. The asymmetric Simmons-Smith reaction has been around since 1992 but the new century has a lot to offer. In one method, part of a larger class of Michael-initiated ring-closure (MIRC) an ylide reacts with a Michael acceptor

The nucleophilic carbon atom of the ylide reacts with the Michael group first and in the second step the electrophilic part is displaced as the leaving group with ring closure. A chiral moiety can then interact or is part of either with the carbonyl group (amine organocatalysis) or with the leaving group. Pioneering work originates from Johnson & Schroeck using a oxosulfonium methylide (1968 DOI) and from Trost & Hammen (sulfonium ylide, 1973 DOI). Phosphonium ylide MIRC reactions exist since 1988 (Krief et al. DOI)

First of is Aggarwal whose group in 2001 building on asymmetric epoxidations and aziridations ( DOI) invented an complex indirect sulfonium ylide method (DOI).

The main substrate is chalcone reacting with a chiral sulfonium ylide derived from a chiral sulfide and the carbene Rh=CHPh (generated in-situ from a tosyl hydrazone and rhodium(II) acetate). The 2001 report has gathered 114 citations to date but the cyclopropanation method described has not yet been field-tested.

A direct chiral sulfonium ylide method is reported by Tang (Ye et al. 2002, 46 citations DOI).


Next up is Gaunt et al. (the Stephen Ley laboratory) who in 2004 came with the idea to employ ammonium ylides as Michael donors with a cinchona alkaloid as chiral catalyst. (DOI).

This reaction is organocatalytic. In the reaction mechanism the tertiary amine displaces a halide group in a haloketone and then a base (caesium carbonate) abstracts a proton to the ammonium ylide.



The first report clocks around 50 citations to date but is applied only once in a total synthesis of eicosanoids(DOI) and not very successfully as enantioselectivity for the particular step is poor.

A third method (Kunz/MacMillan, 2005) is a direct sulfonium ylide method DOI. An improved catalyst exists (DOI).

Other ylide reactions are reported: those base on arsenic (Zhao et al. 2007 DOI), those based on tellurium (Liao 2003 DOI) and those with azetidinium ylides (Couty 2007 DOI)

Dehydro Diels-Alder reaction

18 July 2008 - Synth. methods

Reaction name - Dehydro Diels-Alder reaction (DDA)
Extension of - Diels-Alder reaction
Most recent review - Chem. Rev. 2008, 108, 2051–2063 DOI


Main characteristics - in a DDA reaction one or more double bonds in a regular Diels-Alder are replaced by an alkyne. The primary cyclic reaction product contains an allene group. To reduce steric strain the cyclic allene will engage in secondary reactions, for instance secondary DA reactions or retro-DA reactions or those forming an arene compound. Depending on the nature of the reactants (alkene, alkyne, enyne diyne) 4 reaction types are identified. Reaction is thermal or photochemical and can be catalyzed by zerovalent palladium.

Debute - 1895 Michael & Bucher DOI DOI in a reaction of phenylpropiolic acid with acetic anhydride forming a phenyl substituted naphtalene . Earlier example: 1866 Berthelot in the trimerization of acetylene for which reaction in 1967 a butadiyne intermediate was found.
Reaction mechanism - in contrast to DA reactions (concerted) the DDA reactions involve diradicals.
Why - synthesise polycyclic aromatic compounds, complex carbon frameworks. No reports on industrial use.

Synthetic methods: Alkane H/D exchange

28 June 2008 - C-H bond activation

H/D exchange in organic chemistry is a simple tool in structure elucidation unmasking any proton (for example that of a alcohol or an amine) as an acidic proton simply by exposing it to heavy water (D2O). Extending this scope to simple alkanes is not exactly obvious but can be done with a little bit of help of organometallic chemistry.

Deuterated alkanes can be used as molecular markers in a whole range of applications. Shilov (see Shilov system) in 1969 using platinum observed deuteration in methane (no need bothering with DOI's for Soviet-Union era chemistry) opening up a new research field

In a 2008 contribution Sajiki et al. (DOI) use rhodium on carbon (think palladium on carbon), heavy water and (counter intuitively) hydrogen gas at 160°C for C-H bond activation of such compounds as dodecane (90% efficient) and cholestane (36%). Notable observations: reaction will not work without hydrogen, terminal positions are favored, the actual commercial source of Rh/C is key (Aldrich rules, Merck sucks) and organic solvents except for cyclohexane actually decrease the efficiency of this reaction. Plausible reaction mechanism: oxidative addition (activated by hydrogen) to R-H forming a R-Rh-H species, then H/D exchange to R-Rh-D followed by reductive elimination to R-D.

Synthetic methods: Oxa-Michael addition

28 June 2008 - Organic chemistry

The Michael reaction is the reaction of carbon nucleophiles in nucleophilic conjugate addition. In hetero-Michael additions the nucleophile is an amine, thiol, phosphine or in the specific case of a oxa-Michael addition an alcohol (Review DOI).

A base is required and the reaction product is a beta-alkoxy carbonyl. Note that the same carbon framework can also be obtained in an Aldol addition between two carbonyl units.

This reaction type was first reported in 1878 by Loydl (converting fumaric acid to malic acid) (DOI) actually preceding the Michael reaction. Disadvantages are availability of the Aldol reaction, low reactivity, lack of stereoselectivity and reversibility.

The employment of trapping agents in domino reactions and the use of novel bases for instance phosphatranes ( DOI) have mediated some of the drawbacks.

The reaction has recently been applied in a total synthesis of tocopherol as a diastereoselective tandem aldol addition / oxa-michael reaction with a proline based catalyst and capture of the hydroxyaldehyde as a hemiacetal (Liu et al 2008 (DOI):