Robinson annulation, chiral

Figure 14. Reaction scheme for the chiral Robinson annulation using the Wichterle reagent.

The asymmetric Michael addition of chiral nonracemic ketone enolates has most frequently been used as part of the Robinson annulation methodology in the synthesis of natural products171-172. The enolates are then derived from carbocyclic chiral ketones such as (+)-nopinone, (-)-dihydrocarvone, or (-)-3-methylsabinaketone. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

In 1986, Puchot et al.104 studied the nonlinear correlation between the enantiomeric excess of a chiral auxiliary and the optical yield in an asymmetric synthesis, either stoichiometric or catalytic. Negative NLEs [(—)-NLEs] were observed in the asymmetric oxidation of sulfide and in [.S ]-proline-mediated asymmetric Robinson annulation reactions, while a positive NLE [(+)-NLEs]... 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

In summary, we have demonstrated the first efficient enantio-selective alkylation via phase transfer catalysis. This alkylation was expanded to include an enantioselective Robinson annulation. The methodology was developed for the preparation of either enantiomer. Finally, our kinetic studies have provided additional mechanistic insight into the chiral PT alkylation. 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

An asymmetric Robinson annulation is available in which the ketone is reacted with a chiral amine to provide a chiral imine, which is then added to MVK to furnish, after annulation, the chiral product. 

The continued fascination chemists possess with asymmetric synthesis provides the basis for the next four procedures. The synthesis of (R)-(-)-10-METHYL-l(9)-OCTALONE-2 is a nice demonstration of an asymmetric Michael addition by a chiral imine followed by an aldol—in short an asymmetric Robinson annulation. The asymmetric glycolization to STILBENE DIOL (R,R-l,2-DIPHENYL-I,2-ETHANEDIOL) represents an olefin oxidation using catalytic alkaloids in tandem with osmium tetroxide. As reagents for a variety of asymmetric alkylations, the preparation of 2-CYANO-6-PHENYLOXAZOLOPIPERIDINK is pavscnicd as well as another route to... 

Claisen rearrangement of the acrylic esters 14 and 15 followed by Robinson annulation leads to bi- and tricyclohexyl derivatives via the known 1,3-chirality transfer645. 

Many modifications of the fundamenuil Robinson annulation sequence have appeared over the years, one of which uses silyl derivatives such as 559. An important modification uses chiral precursors or chiral... 

There is also one example in which a chiral phosphoric acid has been employed as catalyst in the reaction. In particular, the addition of several cyclic p-ketoesters to methyl vinyl ketone was found to occur smoothly in the presence of several chiral phosphoric acids (Scheme 4.35). As mentioned earlier, a key feature of the chiral phosphoric acid catalyst is the backbone binaphthyl axial chirality together with the incorporation of bulky substituents at the 2 positions. In this case, 60b was identified as an appropriate promoter of the reaction leading to the corresponding Michael adducts in excellent yields, although with moderate enantioselectivity. In addition, the authors succeeded in applying this reaction to a procedure to carry out a subsequent Robinson-type annulation. 

In 2000, Barbas carried out the Robinson annulation between 2-methyl-1,3-cyclohexanedione and methyl vinyl ketone catalyzed by several chiral amines, reporting that the process stopped in many cases after the conjugate addition step. However, neither yields nor enantioselectivities were given for those cases. T. Bui and C. F. Barbas III, Tetrahedron Lett., 2000, 41, 6951. 

Anilide 2a catalysed asymmetric intramolecular Michael reaction of formyl enones to chiral cyclic keto-aldehydes in excellent yields with good stereoselectivity (eqn. (1) in Scheme 6.3). The intramolecular Michael addition of a ketosulfone to an unsaturated ketone (eqn. (2) in Scheme 6.3) catalysed by 15e has heen used as a key step in the synthesis of the carbon tricyclic framework of Lycopodine. The same sulfonylprolinamide served as catalyst in the construction of all-carhon substituted quaternary stereocentre via Robinson-type annulation process (eqn. (3) in Scheme 6.3). 

Although asymmetric organocatalysis is now considered as a powerful tool for the synthesis of chiral compounds this research held experimented its own revolution. It was restricted after the seventies only to the nse of simple a-amino acids as catalyst for the Robinson annulations and above all with the application of proline to the enantioselective intermolecular aldol reaction. 

In the Robinson annulation, cyclization to give the ketol intermediate can produce possibly five stereocenters. The dehydration process that follows minimizes the number of possible chiral centers to three or less. " ... 

There are different approaches for stereocontrol for the Robinson annulation the control can either arise fi-om the inherent nature of the starting ketone and/or the vinyl ketones substituents in combination with the reaction conditions, or by the use of a chiral catalyst. In the first case, an example is the stereoselective aldol cyclization to give the ketol intermediate 50. In this case the cyclization is kinetically controlled under protic basic conditions of sodium ethoxide and ethanol as it gives the cw-fused adduct rather than the more stable trans-fased ketol, which is not detected at any time during the reaction. 

A more efficient approach to control the stereochemical outcome for the Robinson annulation can be through the use of chiral catalysts such as in the case of the enantioselective Hajos-Wiechert variation introduced earlier. There are other chiral agents other than the popular (S)-proline-mediated annulation reaction that are used for these transformations—for example the use of (Bronsted acid such as trifluoroacetic (TFA). This new catalyst for the Robinson annulation was reported in 2007 by Endo et. al., where the Bronsted acid, contrary to Hajos-Wiechert reaction, gives the (i )-isomer of the Wieland-Miescher ketone 44 in a moderate yield of 47% and 75% ee. 

In 2009 Miro et al. reported the use of phosphoric acids as a chiral catalyst for enantioselective transformation of the Robinson annulation. Chrial phosphoric acids 61 and 62 are used in sequence first for the Michael reaction step and are then followed by the cyclization step. Synthesis of the aimulation adduct 64 is shown as an example in the group s report. The cyclized adduct is formed from the reaction of the P-keto ester 63 in the presence of the phosphoric acid 61 at 40 °C for 24 h and is followed by... 

Figure 3.3 The 3D structures of TS3 and TS4. (From Yamanaka, M. et al. Kinetic Resolution in Chiral Phosphoric Acid Catalyzed Aldol Reactions Enantioselective Robinson-Type Annulation Reactions. Eur. J. Org. Ghent. 2012. 24, 4508-4514. Copyright Wiley-VCH Verlag GmbH Co. KGaA. Adapted with permission.)...

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