Achiral Enantiomerization Pathways

Enantiomerization of chiral tetraatomic molecules by unimolecular processes unavoidably requires the intermediacy of achiral structures, as, for example, in the racemization of NHDF by inversion at nitrogen or of H2O2 by rotation about the O — O bond. Abstractly considered, it is easily seen that any chiral set of four differently labeled points ABCD in 

FIGURE 6 Labeled triangles in the plane. Enantiomorphs are characterized by the orientation, clockwise vs anticlockwise, of the vertices arranged in the order /I - B - C. R and L spaces are separated by a subspace of one-dimensional (degenerate) triangles. 

The existence of chiral pathways in this molecule is made possible by the existence of the two independent degrees of freedom that govern internal motion, rotation, and inversion. As molecular complexity increases, the number of degrees of freedom also increases and, unless an achiral pathway is energetically much preferred, it becomes more and more likely that enantiomerization proceeds by a chiral pathway. For example, it is extremely improbable that reversal of helicity in a polymeric chain involves an achiral intermediate or transition state. There is a strong resemblance here to the stochastic achirality of ensembles of achiral molecules discussed previously. 

A formal limit is reached when, due to structural constraints, all achiral pathways along the enantiomerization trajectory become energetically inaccessible under normal laboratory conditions. Chiral pathways then remain the only alternative. In 1954 it was pointed out that a compound of the type 4-[( )-5ec-butyl]-4 -[(S)- ec-butyl]-2,2, 6,6 -tetra-methylbiphenyl consists entirely of asymmetric molecules that undergo rapid enantiomerization, and that conformational racemization, in the 

FIGURE 7 Graph of conformational interconversion paths for NHDOH. Edges represent 90° rotations (r) about the N — O bond or inversions (/) at nitrogen. Planar conformations are represented by solid circles. 

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Returning to the evaluation of stereoisomers for candidates as ultimate phosphoranes, the isomer number is further reduced from four to two in each sector since ring strain effectively prevents access to the star-points (eering). Accordingly, the ultimate phosphoranes derived from cis-18 via 15 and 25 are identified as 24 and 14, respectively, for retention and 14 and 24, respectively, for inversion. The ultimate phosphoranes are the same, but the stereochemistry of displacement is reversed, when one starts from trans 18 via 25 and 15. Since enantiomers are indistinguishable under achiral conditions, further discussion need only consider one of the two enantiomeric pathways, e.g., the pathway on the top of the hexagon. 

Interestingly, anti adducts predominate in MgBr2-promoted additions of -methyl-crotyl tributyltin to a-oxygenated aldehydes (Eq. 11) [17]. Evidently the -methyl substituent causes the synclinal transition state to be favored in the chelation-con-trolled addition. The effect is not present in BF3 OEt2-promoted additions, which proceed as expected to afford the syn adducts. The two pathways are shown for enantiomeric aldehydes to assist in direct comparison of the two transition states. The actual additions were conducted with achiral (R = H) or racemic (R = Me) aldehydes)... 

Because enantiomers have oppositely signed pseudoscalar properties, chiral zeroes are unavoidable at some stage in the conversion of a molecule into its enantiomer along a chiral pathway. This is true of chirally connected enantiomeric conformations in chemically achiral molecules, such as (lf )-menthyl (15)-menthyl 2,2, 6,6 -tetranitro-4,4 -diphenate, and of chirally connected enantiomers, such as ( + )- and (- )-isopro-pylmalonamic acids. More generally, as previously noted, any chiral molecule composed of five or more atoms is in principle always capable of conversion into its enantiomer by chiral as well as by achiral pathways, provided that this is energetically feasible. Hence, unless it can be demon-... 

The Lewis acid-promoted addition of ) -alkoxyallylstannanes to achiral aldehydes was shown to proceed in high diastereoselectivity by an anti Se pathway (Scheme 10-64) [102]. An acyclic antiperiplanar transition structure (very similar to that shown in Fig. 10-3) was proposed to rationalize the stereoselectivity. When enantiomerically enriched allylstannanes are employed, the reaction proceeds in high enantio- and diastereoselectivity to give the homoallylic alcohols [102b]. The stereochemical outcome of the reaction is consistent with an anti Se pathway. 

Because both cinnamic acid and molecular bromine are achiral, two enantiomeric bromonium ions are formed at equal rates. Ring opening of each bromonium ion may preferentially occur as shown here at the carbon bearing the phenyl group, since this carbon bears more fractional positive charge than the carbon adjacent to the carboxyl group. Because the two reaction pathways shown here are enantiomeric, they proceed at equal rates to produce racemic ery thro-1,3 - dibromo- 3 -phenylpropanoic add ... 

The tetrahydrofuran motif is common across many natural product classes and important bioactive compounds. The formation of this important motif can be accessible through a number of synthetic pathways. Deska developed a four-step procedure converting the achiral ether 30 to the 2,5-tra 5-disubstituted dihydrofuran-3-one 33 in modest enantiomeric excess and diastereomeric ratio. Tanperature conditions for the cyclization were at room temperature or lower to... 

Chiral oxazaborolidines are also efficient catalysts for the enantioselective reduction of aldehydes labeled with isotopic hydrogen at the carbonyl function. Treatment wifli cate-cholborane in the presence of (/ )- or (S)-B-n-butyloxazaborolidine (3 d) affords Cl-deuteriated or tritiated primary alcohols with enantiomeric excesses generally exceeding 90%. Use of catecholborane is essential, since for BH3 THF the achiral uncatalyzed process is competitive with the chiral catalyst-mediated pathway, thereby reducing the enantiomeric purity of products. Enantiomerically enriched [ 1 - H]- and [ 1- H] alcohols have been extensively used in the study of enzymatic mechanisms and biosynthetic pathways , and as precursors for chiral [ H, H, H]acetic acid and [ H, H]fluoroacetic acid . Equivalent results are obtained when BusSnH is employed in the presence of BITIP (58, prepared in situ from (R)- or (5)-l,l -bi-2-naphthol and Ti(0-/-Pr)4 2 1) ° (Figure 11.23). 

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