Diastereoselectivity in rings

Higher diastereoselectivities in ring opening of bicyclic anhydrides are obtained through their diphenylboryl trifluoromethanesulfonate catalyzed reaction with (7 )-l-diphenylboryloxy-2-methoxy-l-phenylethane in toluene at 0CC98. 

Diastereoselectivity in rings generally follows a few simple principles ... 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Another possibility to increase the diastereoselectivity in an asymmetric synthesis can arise from different thermodynamic stabilities of the diasteieoisomeric products. If the thermodynamic stabilities of these are different enough, then, under conditions of equilibrium, a complete conversion of the less stable into the more stable can be achieved. For example, the diastereoselective hydrogenation of naphthalene derivates over Pd/C catalyst leads to a mixture of dihydronaphtalenes in which the cA-isomer predominates. The conversion of this isomer into the tram occurs by changing the properties of the reaction medium, namely by equilibration with a base. For such a purpose, NaOMe in IHF can be used [263], Generally, such an increase in stability in the six-membered rings can result from a rearrangement of the substituents from an axial to an equatorial position. 

Since diastereoselection in linear systems may be very difficult to achieve, in the past few years chemists have developed different strategies aimed at solving the problem (see Diagram 8.1). As has already been stated, the "classical solution" is to introduce temporary bridges or auxiliary rings which are then eliminated after the stereoselection has been accomplished. 

Scheme 6.7. Diastereoselectivity in conjugate addition of organocuprates to chiral cyclic enones of medium ring size.

The X-ray crystal structure of fZ)-4-[(5)-2,2-dimethyl-l,3-dioxolan -ylmethyl-ene]-2-phenyl-5(4//)-oxazolone has been determined. " The analysis shows an almost planar disposition for the entire molecule with the exception of the dioxolane ring that adopts an envelope conformation. As such, the dioxolane ring is mainly situated on the si,si diastereotopic face of the olefinic bond, a situation that accounts for the observed diastereoselectivity in Diels-Alder reactions. 

Steric control elements are also important for the diastereoselectivity in alkylations of mono-cyclic cyclohexanone enolates. However, electronic control becomes more evident in these systems compared to monocyclic cyclopentanone enolates The flexibility of the six-membered ring system, and the large number of possible ring conformations, makes predictions of the diastereoselectivity difficult. In general, one may conclude that the diastereoselectivity in alkylations of enolates derived from monocyclic cyclohexanones is not as high as in alkylations of cyclopentanone enolates. The syntheses of compounds 21-27 demonstrate the effect of substitution in each position of the six-membered ring49,61 -7°. 

The opportunity for chelation in the various enolate intermediates offers a possible explanation for the observed diastereoselectivities. In the dianions derived from l-acyl-2-pyrrolidinemethanols strong chelation of both of the lithium cations should lead to a rigid enolate structure 9. It is reasonable to assume that the pyrrolidine ring is locked in one conformation. Since, according to models, it is difficult to attribute the observed high diastereoselectivity to steric hindrance, it is probable that the lone pair on the nitrogen directs the facial selectivity of electrophilic attack (see Section 1.1.1.3.3.1.) to one side of the enolate a-carbon. 

The mechanism of (3-lactam formation has been investigated extensively. But the rationale for the observed diastereoselectivity in certain cases remains unknown. It has been demonstrated that the stereoselectivity depends on the structure of the imine, acid-chloride, order of addition of the reagents, solvent, temperature, bases, and many other conditions. In many cases, cis (3-lactam was found to be the exclusive or major product when acid chloride (equivalent) was added drop-wise at low-to-room temperature to the solution of imines and a base. However, a trans (3-lactam was the major or exclusive product obtained when a tertiary base was slowly added to the imine and acid chloride (equivalent) solution at high temperature. Georg and Ravikumar established a few rules regarding stereoselectivity in the formation of (3-lactam rings [122]. Computer-assisted calculations were advanced to explain the stereochemical preferences [140-144]. Cossio et al. [140-143] and... 

Diastereoselectivities in the tetrabutylammonium cyanide-catalysed cyanosilylation of cyclic a -epoxyketones are dependent on ring size, with a switchover in selectivity between flve-membered and larger rings being explained through computation of... 

Sugimura et al. investigated diastereoselectivity in the photocycloaddition of arene and alkene connecting by optically active 2,4-pentanediol [239], High di-astereofacial differentiation was observed at the addition step and sufficient re-giocontrol of the subsequent ring-closure step. 

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