1.3- diketones desymmetrization

Grogan G, GA Roberts, D Bougioukou, NJ Turner, SL Flitsch (2001) The desymmetrization of bicyclic P-diketones by an enzymatic retro-claisen reaction. J Biol Chem 276 12565-12572. 

A desymmetrizing reduction of a dicarbonyl has also been achieved as a route to flMfi-aldol adducts. Yamada and coworkers have shown that a chiral cobalt complex catalyzes the desymmetrization of diaryl-1,3-diketones in excellent yield and enantioselectivity, greatly favoring the anti isomer [Eq. (10.65)]. Anti selectivity is rationalized using a Felkin-Anh model ... 

Desymmetrization via proline-catalyzed asymmetric intramolecular aldol reaction can, however, also be performed with acydic diketones of type 109 as has been reported by the Agami group [106], In the first step a prochiral acyclic diketone reacts in the presence of L-proline as catalyst (22-112 mol%) with formation of the aldol adduct 111 (Scheme 6.49). In this step reaction products with two stereogenic centers, 110, are formed. These chiral hydroxyketones 110 are subsequently converted, via dehydration, into the enones 111, by treatment with p-toluenesulfonic acid. 

The desymmetrization of meso diols requires selective chemical transformation of one of the two enantiotopic hydroxyl functions. Among other possibilities this transformation can consist in acylation or - less commonly - oxidation to a ketone (Scheme 13.19). It should be noted that the enantiomeric purity of the initial reaction products can be upgraded by subsequent conversion of the unwanted enantiomer into the diacylated compound (or diketone), i.e. by subsequent kinetic resolution. 

Grogan, G., Graf, J., Jones, A., Parsons, S., Turner, N. J. and Flitsch, S. L An asymmetric enzyme-catalyzed retro-Claisen reaction for the desymmetrization of cyclic diketones. Angew. Chem. 2001,113 1145-1148 [Angew. Chem. Int. Ed. 40 1111-1114]. 

The desymmetrization of 2-alkyl-1,3-diketones to the corresponding chiral hydroxyketones was also successfully achieved with the same catalyst system. For example, 2-methyl-l,3-diphenyl-l,3-propanedione was reduced with an equimolar amount of NaBH4 together with THFA and ethanol in the presence of 0.05 equivalents of (R,R)-15 to afford (lk,2S)-2-methyl-3-oxo-1,3-diphenyl-propane (anti syn=99 l) in 99% ee (Scheme 10) [55], 2-Allyl- and 2-benzyl-sub-... 

Indium trichloride mediates the intramolecular cyclization of the prochiral allylstannyl diketone to afford the desymmetrized cis-cis cyclohexanol predominantly (Equation (36)). The use of TiCU in place of InCl3 gives the cis-trans diastereomer.213... 

Wadamoto M, Phillips EM, Reynolds TE, Scheldt KA (2007) Enantioselective Synthesis of a,a-disubstituted cyclopentenes by an A-heterocyclic carbene-catalyzed desymmetrization of 1,3-diketones. J Am Chem Soc 129 10098-10099... 

Yamamoto has reported the desymmetrizing intra-molecular cyclization of the 1,3-diketone 97 for diastereoselective formation of cis-cis 98 vs. cis-trans 99. Optimized conditions with SnCU led to the jS-chelation in the synclinal arrangement 100 to give 98, whereas the use of TiCU facilitated rapid transmetalation of the organostannane yielding 99 (Scheme 5.2.22).22... 

Scheme 5.2.22 Desymmetrization of 1,3-diketone 97 via intramolecular allylatlon 5.2.6 Reactions of 7-(Alkoxy)allylstannanes...

The method could be applied to reduce 1,3-diaryl-1,3-diketones to 1,3-diaryl-1,3-propanediols in 93-100% yields and high ee s (>97% ee). The products were obtained as a mixture of diastereomers (81 19 - 90 10) and could be purified by recrystallization.Symmetrical 2-substituted-l,3-diaryl-1,3-diketones underwent reductive desymmetrization to give rise to /8-hydroxyketones (45-97% yields) in high ee s (>91% ee) and diastereoselectivities (dr>99 l) (eq 32). Unsymmetrical 2-alky 1-3-ary 1-1,3-diketones were reduced chemoselectively at the aryl-substituted carbonyl group to yield 2-alkyl-3-aryl-3-hydroxyketones (41-48% yields) in high ee s (>95%) and diastereoselectivities (( >97 3). The yields could be further improved by the addition of a stoichiometric amount of sodium methoxide in a one-pot reaction. 1,4-Diaryl-1,4-butanediones were reduced to enantiopure l,4-diaryl-l,4-butanediols (60-100% yields), which... 

Scheldt s group [50a] described a NHC-catalyzed homonenolate protona-tion/intramolecular aldol/acylation sequence. This domino reaction allowed the desymmetrization of 1,3-diketones by formation of a chiral enol during the process and has recently been used as an efficient strategy for the synthesis of the hydrindane... 

Scheme 2.117 Desymmetrization of prochiral diketones using HLADH...

Wadamoto, M., PhilUps, E. M., Reynolds, T. E., Scheldt, K. A. (2007). Enantioselective synthesis of a,a-disubstituted cyclopentenes by an N-HeterocycUc carbene-catalyzed desymmetrization of l,3-diketones. Journal of the American Chemical Society, 129,... 

The NHC-generated azolium enolate can also react in a Mannich [lid], Michael [108], or aldol fashion [86], such as in the desymmetrization of 1,3-diketones to access enantiomerically-enriched cyclopentenes following decarboxylation of the P-lactone product [109]. Scheldt and coworkers took advantage of this reaction in the total synthesis of bakkenolides 1, J, and S (Scheme 18.26) [110]. 

Scheldt and coworkers also reported an enantioselective desymmetrization reaction of 1,3-diketones 62 in the presence of triazolium salt 61. This new process combines an intramolecular aldol reaction followed by a decarboxylation process of P-lactone intermediates, giving chiral cyclopentenes 63 in moderate yields and with high ees. Notably, with aliphatic diketones 64 or 66, p-lactone products 65 or 67, respectively, were obtained (Scheme 36.17) [23]. 

Another cascade exploiting the MAO-N-mediated oxidation and an oo-TA-catalyzed asymmetric amination has been established to access diastereomerically pure 2,5-disubstituted pyrrolidines, an important scaffold found in diverse pharmaceuticals and natural products. The key steps involve a regioselective mono-amination of various substituted 1,4-diketones, followed by a MAO-N-catalyzed desymmetrization of the intermediate formed A -pyrroline (Scheme 2.46) [150]. 

Whereas the examples above used substrate control for stereoselective transannular aldol or related reactions, reagent control has also been reported for the transannular aldol reactions. One example is synthesis of the musk ordorants (R)-muscone and (R,Z)-5-muscenone by Knopff and co-workers. It involved enantioselective formation of 73 by the transannular aldol condensation of the symmetrical macrocyclic 1,5-diketone 72 using sodium ephedrate for desymmetrization (Scheme 20.19). The reaction was assumed to proceed by a reversible transannular aldol reaction followed by an enantioselective dehydration reaction. 

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