C6 Stereocenters

C6 stereocenters. R.K. Boeckman Jr. and co-workers had to overcome the stereochemical preference of the thermal rearrangement by using a bidentate Lewis acid promoter (TiCU) that coordinated to both the oxygen of the vinyl ether and the ester. This coordination enforced a boatlike conformation for the existing six-membered ring in the transition state. The rearrangement itself took place via a chairlike transition state. 

Synthesis of the Cl-Cll domain of the epothilones at first appeared quite forbidding because of the need to gain facile control over the stereocenters at C3, C6, C7, and C8. Indeed, this region has been the scene of many variations in strategy and synthetic design. [12] Our first generation synthesis of the Cl-Cll acyl domain, al-... 

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. 

Alternatively, a macrolactonization route can be followed, where formation of the C6-C7 aldol by chromium-Reformatsky and esterification are interchanged. However, this route is longer and less selective in formation of the C6 and C7 stereocenters, giving both syn products [50, 86-88]. 

We have reported one of the shortest total syntheses of epothilone D so far. A large moiety of the 16-membered macrocycle is derived from the easily available isoprenoid nerol. Only four C-C bond formations and three protective groups are required. Only one step requires the use of a (recoverable) chiral auxiliary. The other stereocenters are constructed by catalytic hydrogenation (C8), resolution (C15), and induction (C6, C7). In particular the northern half synthesis is well suited for large-scale preparation because of the combination of cheap reagents and catalytic processes. Using essentially the same method, a number of epothilone D5 analogues were synthesized. 

Amino acid-based norbomene random and block copolymers have been synthesized by Sanda, Masuda et al. [178]. The blocks were constructed with monomers containing either the ester or carboxyl amino acid forms, and C4 was used. While the random copolymers were partially soluble in acetone, the block copolymers were soluble through formation of reverse micelles (Scheme 24). Moreover, the diameter of these aggregates was around 100 nm as measured by DLS and AFM. Amino acid-based ROMP monomers with a different cyclic core, i.e., cyclobutenecarbonyl glycine methyl esters, were polymerized by Sampson et al., leading to head-to-tail-ordered polymers without stereocenters [179]. C6 was used and polydispersities between 1.2 and 1.6 were obtained. 

In the concluding steps, manipulation of the furan ring of 89 gave 90 as a mixture of positional isomers. These were collectively converted to the unsaturated diol 91. The last crucial step, installation of two hydroxyl groups on the double bond, was achieved using a standard osmylation reaction [84]. In a second approach for the same step, the Sharpless asymmetric dihydroxylation of 91 was used and yielded one diastereoisomer 92 almost exclusively [85]. This second approach concluded with the synthesis of a lactone containing all correct stereocenters of the squalestatin core with the exception of that at C6. 

The total synthesis of (+)-deethylibophyiiidine was achieved by J. Bonjoch et ai. using a tandem Pummerer rearrangement/thionium ion cyclization to generate the quaternary spiro center.The suifoxide was exposed to an equimoiar mixture of TFA/TFAA and heated for 2h to form the quaternary stereocenter at C7 with the desired stereochemistry, but at C6 a mixture of epimers were formed. Reductive desuifurization with Raney-Ni followed by photochemical rearrangement afforded the natural product. 

Wender extended the studies of the intramolecular cycloaddition by examining substituted oxidopyrylium intermediates with stereocenters in the tethers [58 a]. Pyran 44 underwent smooth cycloaddition with complete stereoselectivity to give 45 due to the methyl group at Cn assuming an equatorial position in the chair-like conformation of the olefinic side-chain, Eq. 30. The stereocenter at Cn effectively controlled the stereochemistry at C6, C8, and C9. The reaction proceeded with heating or at room temperature with a catalytic amount of base. 

Citronellol. The COSY spectrum of citronellol (see the structural formula on p. 534) is a third example. The spectrum (Fig. 10.14) is rather complex in appearance. Nevertheless, we can identify certain important coupling interactions. Again, lines have been drawn to help you identify the correlations. The proton on C6 is clearly coupled to the protons on C5. Closer examination of the spectrum also reveals that the proton on C6 is coupled through allylic (four-bond) coupling to the two methyl groups at C8 and C9. The protons on Cl are coupled to two nonequivalent protons on C2 (at 1.4 and 1.6 ppm). They are nonequivalent, owing to the presence of a stereocenter in the molecule at C3. The splitting of the methyl protons at CIO by the methine proton at C3 can also be seen, al-... 

The earliest examples of Ireland-Claisen rearrangements of allyl silyl ketene acetals bearing a stereocenter at C6 were reported by Cha and Lewis in 1984 (Scheme 4.36) [40]. In contrast to the nitrogen C6 substituents, oxygen substituents exhibited considerably less facial bias. Rearrangements of the acetate esters of either the Eor Z alkenes gave only 1.3 1 and 1.4 1 C3,C6 anti.syn ratios, respectively. 

Mulzer and Mohr used a glycolate Claisen to establish the C6, C7 stereocenters in an asymmetric synthesis of the asteltoxin Ws-tetrahydrofuran fragment (Scheme 4.127) [121]. Rearrangement occurred via the expected Z-silyl ketene acetal and chair transition state to afford the adjacent carbinol and 4° carbon stereocenters. The high stereoselectivity of the rearrangement using a tetrasubsti-tuted aUyUc alkene is noteworthy. 

Erythronolide A 3 is a derivative of a C15 fatty acid [16] which carries at every second carbon a methyl branch constituting a stereogenic center. Oxygen functionalities are found at most of the even numbered carbon atoms leading to stereocenters at C3, C5, Cll, and C13. In addition there are two tertiary stereogenic centers at C6 and Cl2. 

A quick analysis of 9(S)-dihydroerythronolide A 19 shows that 7 of the 11 stereocenters could be created using reagent control of diastereoselectivity by crotylboration reactions. The stereogenic centers at C6 and C12 having a tertiary alcohol function are presently outside the scope of stereoselective crotylboration reactions. Here we have to rely on other methods. For instance, the use of lactic acid enolates developed by Seebach [28] appeared attractive to generate the tertiary centers both at C6 and Cl2. 

The Sharpless epoxidation turned out to be similarly successful in the generation of the tertiary stereocenter at C6 when compared to other routes such... 

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