Stereodifferentiation. double

Double stereodifferentialing Hiyarna reactions are the key steps in the total synthesis of ( + )- and (-)-nephromopsinic acid12 and (-)- and ( + )-dihydrocanadensolide33. The enantiomcrically pure diterpene cycloaraneosene is assembled by two chromium(II) chloride mediated coupling reactions from (3S,87 )-9-benzyloxy-7-chloroirid-1-ene (3) and (3[Pg.444]

The combination of metal tuning and double stereodifferentiation helps to prepare chelation and nonchelation products in the imine series7. In the case of an alkoxy substituent adjacent to the aldimino, the chelation product 10 is predominantly obtained with allylmagnesium chloride, chloromagnesium allyltriethylaluminate or allylzinc bromide, while the use of allyl-boronates or allyltitanium triisopropoxide, which lack the requisite Lewis acidity for chelation, gives 11 with good Cram selectivity. 

Asymmetric Bond Formation with Double Stereodifferentiation... 

Zirconocene dichloride 121 derived from (l-phenylethyl)cyclopentadienyl ligand is formed as a mixture of diastereomers from which the racemic form can be isolated by fractional crystallization. This complex was studied by X-ray diffraction methods and revealed a virtually chiral C2-symmetrical conformation in which the chiral ring-substituents are arranged in a synclinal position relative to the five-membered ring. It was proposed that this conformation is preserved in solution. Using 121 as catalyst the influence of double stereodifferentiation during isospecific polymerization of propylene (Eq. 32) was demonstrated for the first time [142],... 

Chelation can also be involved in double stereodifferentiation. The lithium enolate of the ketone 7 reacts selectively with the chiral aldehyde 6 to give a single stereoisomer.116 The enolate is thought to be chelated, blocking one face and leading to the observed product. 

Scheme 2.5 gives some additional examples of double stereodifferentiation. Entry 1 combines the steric (Felkin) facial selectivity of the aldehyde with the facial selectivity of the enolate, which is derived from chelation. In reaction with the racemic aldehyde, the (R)-enantiomer is preferred. 

Scheme 2.5. Examples of Double Stereodifferentiation in Aldol and Mukaiyama...

In Entry 5, the aldehyde is also chiral and double stereodifferentiation comes into play. Entry 6 illustrates the use of an oxazolidinone auxiliary with another highly substituted aldehyde. Entry 7 employs conditions that were found effective for a-alkoxyacyl oxazolidinones. Entries 8 and 9 are examples of the application of the thiazolidine-2-thione auxiliary and provide the 2,3-syn isomers with diastereofacial control by the chiral auxiliary. 

With unhindered aldehydes such as cyclohexanecarboxaldehyde, the diastereoselec-tivity is higher than 95%, with the F-boronate giving the anti adduct and the Z-boronate giving the syn adduct. Enantioselectivity is about 90% for the F-boronate and 80% for the Z-boronate. With more hindered aldehydes, such as pivaldehyde, the diastere-oselectivity is maintained but the enantioselectivity drops somewhat. These reagents also give excellent double stereodifferentiation when used with chiral aldehydes. For example, the aldehydes 3 and 4 give at least 90% enantioselection with both the E- and Z-boronates.43... 

The synthesis in Scheme 13.37 also used a me,ro-3,4-dimethylglutaric acid as the starting material. Both the resolved aldehyde employed in Scheme 13.36 and a resolved half-amide were successfully used as intermediates. The configuration at C(2) and C(3) was controlled by addition of a butenylborane to an aldehyde (see Section 9.1.5). The boronate was used in enantiomerically pure form so that stereoselectivity was enhanced by double stereodifferentiation. The allylic additions carried out by the butenylboronates do not appear to have been quite as highly stereoselective as the aldol condensations used in Scheme 13.37, since a minor diastereoisomer was formed in the boronate addition reactions. 

In Step D another thiazoline chiral auxiliary, also derived from cysteine, was used to achieve double stereodifferentiation in an aldol addition. A tin enolate was used. The stereoselectivity of this reaction parallels that of aldol reactions carried out with lithium or boron enolates. After the configuration of all the centers was established, the synthesis proceeded to P-D lactone by functional group modifications. 

Effective double stereodifferentiation is possible in intramolecular C-H insertion.199 For example, catalytic decomposition of enantiopure (lY,2Y)-diazoacetate 74 by Rh2(4A-MEOX)4 directed the reaction toward the preferential formation of y-lactone (lY)-75, whereas the corresponding reaction catalyzed by Rh2(4i -MEOX)4 prefers initially forming y-lactone (lY)-76 (Equation (66)). Similarly, treatment of (lY,2i )-diazoacetate 77 with Rh2(5A-MEPY)4 or Rh2(4i -MPPIM)4 gave (lY)-78 or (lY)-79, respectively (Equation (67)).199... 

Double stereodifferentiation This refers to the addition of a chiral enolate or allyl metal reagent to a chiral aldehyde. Enhanced stereoselectivity can be obtained when the aldehyde and reagent exhibit complementary facile preference (matched case). Conversely, diminished results might be observed when their facial preference is opposed (mismatched pair). 

Scheme 15. Double-stereodifferentiating experiments aimed at elucidating solution geometry of 55c Cu(II) dienophile complexes. [Adapted from (200).].

Scheme 2.6 provides an overall view of our strategy towards solving this problem. As depicted, our late generation synthesis embraces three key discoveries that were crucial to its success. We anticipated that the difficult Cl-Cll polypropionate domain could be assembled through a double stereodifferentiating aldol condensation of the C5-C6 Z-metalloenolate system B and chiral aldehyde C. Two potentially serious problems are apparent upon examination of this strategy. First was the condition that the aldol reaction must afford the requisite syn connectivity between the emerging stereocenters at C6-C7 (by uk addition) concomitant with the necessary anti relationship relative to the resident chirality at C8 (by Ik diastereoface addition). Secondly, it would be necessary to steer the required aldol condensation to C6 in preference to the more readily enolizable center at C2. 

As a corollary to the cases above, the aldehyde may also contain a proximal center of asymmetry. In these cases the resident chirality in both the enolate and the aldehyde can influence the generation of new asymmetry in either a mutually cooperative (consonant) or an antagonistic (dissonant) fashion. The consonant or dissonant diastere oface selection imparted to both condensation partners has been referred to as double stereodifferentiation (83,109). This issue becomes important in the lasalocid A aldol bond construction illustrated in eq. [93]. This pivotal aldol condensation has been examined in detail... 

The observation that aldehyde diastereoface selection is interrelated with allylborane geometry has important implications for the related aldol processes. The reactions of (-)-180a and (-)-180b with both enantiomers of aldehyde 181 revealed both consonant and dissonant double stereodifferentiation. For the Cram-selective ( )-crotyl... 

Relative stereoselective induction and the "Cram s rule problem" "Double stereodifferentiation ". 

The above observations are quite pertinent here since they introduce us to "relative stereoselective induction" (or "double stereodifferentiation") studied by Heathcock [23]- and to "double asymmetric induction" [29] developed by Masamune [22]. 

In order to test these assumptions Heathcock prepared different chiral ketones. Thus, the aldol condensation of the fructose-derived ketone and the acetonide of (/ )-glyceraldehyde gave poor results in the double stereodifferentiation, since an almost equal mixture of the two jyn-aldols 68a and 68b were obtained. However, the reaction with the (5)-aldehyde gave only one syn adduct (69a) (Scheme 9.22) ... 

In the oxidation of aryl methyl sulfides catalyzed by chloroperoxidase from Caldariomyces fumago with racemic 1-phenylethyl hydroperoxide instead of H2O2 as oxygen donor, it was found that (k)-sulfoxides, the (S)-hydroperoxides and the corresponding (k)-alcohol are produced in moderate to good enantiomeric excesses by double stereodifferentiation of the substrate and oxidant (Eq. 2, Table 3) [68]. 

Up to this point, we have considered primarily the effect of enolate geometry on the stereochemistry of the aldol condensation and have considered achiral or racemic aldehydes and enolates. If the aldehyde is chiral, particularly when the chiral center is adjacent to the carbonyl group, the selection between the two diastereotopic faces of the carbonyl group will influence the stereochemical outcome of the reaction. Similarly, there will be a degree of selectivity between the two faces of the enolate when the enolate contains a chiral center. If both the aldehyde and enolate are chiral, mutual combinations of stereoselectivity will come into play. One combination should provide complementary, reinforcing stereoselection, whereas the alternative combination would result in opposing preferences and lead to diminished overall stereoselectivity. The combined interactions of chiral centers in both the aldehyde and the enolate determine the stereoselectivity. The result is called double stereodifferentiation,67... 

The synthesis in Scheme 13.30 uses stereoselective aldol condensation methodology. Both the lithium enolate and the boron enolate method were employed. The enol derivatives were used in enantiomerically pure form, so the condensations are examples of double stereodifferentiation (Section 2.1.3). The stereoselectivity observed in the reactions is that predicted for a cyclic transition state for the aldol condensations. 

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