Oxidation states, adjusting

Some wet chemical sample preparation such as pH or oxidation state adjustment is normally required for most metal ion determinations. Then complexometric titration using EDTA, as already mentioned, or diphenylthio-carbazone ( dithazone Eq. 4.27) may be used for cadmium, copper, lead, mercury, or zinc determinations. 

After the establishment of sHA core, the next stage of our work was focused on the deprotections and oxidation state adjustments. Careful planning of the deprotection order for various functional groups and strategy for the oxidation of C-6 OH is critical for the success of sHA syntheses. 

Chiral 4-ethyl butyrolactone derivatives can be prepared by carbene insertion reactions. Coupling with tryptamine and oxidation state adjustment gives access to... 

In this case, the ability to use a sulfide in place of a sulfoxide, with the oxidation-state adjustment and subsequent Mislow-Evans to occur later, provided a solution to the recalcitrant Claisen rearrangement. This strategy f Scheme 18.51) was particularly appealing in this case, because terminal thioethers are known to be strongly activating for [3,3]-sigmatropic anionic oxy-Cope rearrangements. ... 

As an alternative, 153 was converted 157 by a series of oxidation state adjustments. The ester 157 was then converted to 158 and hydrogenolysis of the W-benzyl group provided 159. Introduction of the 6-methoxytryptophyl group provided 160 to set the stage for the now-familiar endgame. 

Reduction of an intermediate radical from the convex face of the cis-bicyclic ring system was to control stereochemistry at C20- Compound 163 was to be prepared from 164, which was to come from quinic acid (165) through a series of protections and oxidation state adjustments. 

When 90 was heated in toluene, the hydroxylamine added to the alkyne to afford nitrone 91 (after tautomerization of a presumed intermediate N-hydroxyenamine) which was trapped by styrene in an intermolecular 1,3-dipolar cycloaddition to provide 92. An oxidation state adjustment (with removal of the chiral auxiliary) gave 93. The TBDPS protecting group was removed and the resulting primary alcohol was oxidized with IBX (94) (related to the Dess-Martin periodinane) to give aldehyde 95. Application of the Yamamoto variation of the Peterson olefmation gave 96 with decent control over olefin geometry. 

The first synthesis of morphine was reported by Marshall Gates (University of Rochester). It was a remarkable achievement. The plan is outlined briefly here. The idea was that if compound 6 could be obtained, it would be possible to move forward to morphine. In parallel studies it was shown that morphine could be degraded to 6, thus providing a relay point for any synthesis effort, since morphine was in abundant supply and synthetic 6 would no doubt be difficult to obtain in large quantities. Structure 6 could clearly be obtained through a cycloaddition of an appropriate dienophile with 1,3-butadiene. The question is which dienophile. The choice ulitimately became o-naphthoquinone 8. A cycloaddition between this electron-deficient dienophile and 1,3-butadiene would provide 7, which one might convert to 6 via a reductive amination and additional oxidation state adjustments. 

In principle, all that remained to do to reach erythronolide (2) was to deprotect the Ci3 hydroxyl group of 62, conduct the macrolactonization, remove the acetonides, and carry out an oxidation state adjustment at C9. Of course this was easier said than done. The macrolactonization turned out to be very difficult. The Woodward group degraded Erythromycin A (1) to 17 thiopy-ridyl ester substrates, only three of which underwent lactonization under the Corey-Nicolaou conditions. Two of these derivatives gave low yields, but 63 cyclized to 64 in good yield. This effort established that (1) the 5-configuration was essential at C9 and (2) the C3-C5 and C9-C11 diol units had to be protected as cyclic acetals. Based on this information, carbamate-acetal 65 was eventually prepared Ifom the natural product and found to cyclize to 66 in 70% yield. Thus, to complete a total synthesis, it was necessary to convert w-acetorude 62 to 65, and move 66 forward to erythromycin A (1). 

Oxidative cleavage to the aldehyde followed by reductive amination gave 10, that looks as though it could be poised for intramolecular displacement of the secondary chloride. Nonetheless, Lewis acid mediated ionization followed by cyclization proceeded smoothly, to establish the fourth ring of the natural product. Oxidation state adjustment then completed the synthesis of (-)-Acutumine 3. 

The coupling of allgrl halides with Cu(i) nucleophiles has proved to be a powerful method, enabling both Csp -Csp and Csp -Csp disconnections. Such a strategy was demonstrated in a 2001 publication from Abbott Laboratories (Scheme 11.63). °° Use of a Cu(i)-catalysed Grignard alleviation allowed the use of readily available starting materials and enabled the synthesis of a key y-arylbutanal (isolated as its sodium bisulfite adduct 51) in only two steps. In contrast, alternative routes exemplified in the literature required multiple steps for C-C bond construction and oxidation state adjustment. 

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