Desymmetrization bridge

A similar desymmetrization approach was applied to the synthesis of bridged bicyclic systems. Reaction of 2-diazoacetyl-l,3-dioxane in the presence of a chiral rhodium catalyst allow the construction of the bicycle in 27-54% yield, but poor ee (4-12%) (Equation 51) <2003TA929>. 

The ligand, (5)-6,6 -[oxybis(ethylene)dioxy]biphenyl-2,2 -diol (1), is prepared in three steps from readily available 2,2, 6,6 -tetrahydroxybiphenyl (4). The steps involved are firstly asymmetric desymmetrization of secondly bridging of the 6,6 -position by diethylene ether, and finally selective deprotection of the propane diol to afford 1 (Figure 6.12). 

Giblin, G. M. P. Kirk, D. T. Mitchell, L. Simpkins, N. S. Bridgehead enolates substitution and asymmetric desymmetrization of small bridged carbonyl compounds by lithium amide bases. Org. Lett. 2003, 5, 1673-1675. 

A plane of chirality is encountered in molecules in which a molecular plane is desymmetrized by a bridge (ansa compounds and analogs). Examples include the paraphane derivatives XXXV and XXXVI, and wwts-cycloalkenes (XXXVII). 

Cope s classical papers (45, 46) on the successful optical resolution of trans-cyclooctene (21) (Figure 9) demonstrate a way to desymmetrize the Djh symmetry of ethylene by trans bridging. In this molecule, the -(CH2)6- bridge is short enough to prevent interconversion between the enantiomeric C2 con-formers 21 23 through the loop-jumping mechanism. 

Figure 9. Desymmetrization of D2j, symmetry of ethene by trans bridging.

The experimental enthalpy of activation for disrotatory thermal isomerization of cis-l,3,5-hexatriene to 1,3-cyclohexadiene in the gas phase at 100 C is 29.2 kcal/mol [13]. The reaction is exothermic by 14.5 kcal/mol [14, p. 127], so of the reverse reaction is 43.7 kcal/mol, but - in spite of its high activation energy - it is characterized as allowed by all of the common orbital symmetry criteria. In norcaradiene ([4.1.0]hepta-2,4-diene), the cyclopropane ring bridging Cl and Ce of cyclohexadiene has built the disrotation into the molecule, desymmetrizing it - and its monocyclic isomer, cycloheptatriene - to C, in which the 61 and ai orbitals correlate directly (Fig. 5.3). The rate of isomerization is so much faster that it had to be measured at low temperature (ca. 100 K) in a hydrocarbon glass [15] is only 6.3 kcal/mol ... 

If the reactants and product are set up in C, all of the occupied MOs would correlate across the diagram. Alternatively, a correspondence diagram, in which the reactants are set up in C2V and the product is anasymmetrized to that symmetry point group, would show that formal desymmetrization of the pathway to C, - i.e. to the true molecular symmetry of the product -is called for. The methylene bridge of cyclopentadiene is innocuous so, as it turns out, is the bridging carbonyl group in tropone. It will become evident from subsequent examples, however, that the presence of heteroatoms and/or multiple bonds can make a substantial difference to the conclusions drawn from an orbital symmetry analysis. 

The bicychc structure 7 is desymmetrized by reductive C-O bond splitting in the presence of the Ni complex of (5)-BINAP and diisobutylalumium hydride (DIBAL-H). This couple ensures enantioselective hydrometalation-elimination from one of the enantiotopic carbon atoms in the bridge to the C-O bond, affording dihydronaphthalenol (f )-8 in 88% yield and 98% e.e. In the following steps, protection of 8 as the sUyl ether 9 was completed before addition of bromine to the double bond in the presence of triethylamine. This intermediate was treated with DBU 1,8-diazabicyclo[5,4,0]undec-7-ene, strong, crowded base) without isolation, and on regioselective elimination of hydrogen bromide, vinylbromide 10 was isolated in 83% yield. 

The partially bridged compounds, with the inward orientation of the P=0 groups, were obtained by following the two-step synthesis previously described for the synthesis of triphosphonatocavitands (2009JOC3923). Contrary to the compounds of type Hi 162 or ACii 163, the ABii 164 structure can be desymmetrized by adding a third and different bridge onto the crown of the cavitand. 

Asymmetric desymmetrization of m sr>-cycloheptene-l,4-diol bis-silyl etho-d by using the Rh(I)-(5)-BINAP catalyst gave (S)-4-hydroxycycloheptanone (5) with 71 % ee (Scheme 3A.2). Asymmetric isomerization of 4-tert-butyl-1 -vinylcyclohexane (6) catalyzed by bis(indenyl)-titanium complex (8) bearing a chiral bridging moiety afforded (S)-4-te/t-butyl-l-ediylidenecy-clohexane (7) with up to 80% ee (Scheme 3A.3). " ... 

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