Stereospecific hydroxylations

In a further extension of this reaction Winstein and Dauben showed that the action of the methylene-transfer reagent (1) on A -cycloal-kenols, e.g., (2), proceeds by stereospecific cis addition to give the cw-cyclo-propyl carbinol (5). It was also observed that both the rate and yield of the hydroxyl-assisted reaction are increased substantially. It has been suggested that the high stereoselectivity observed in these instances is best explained by complex formation or reaction of the reagent (1) with the hydroxyl group of (2) followed by intromolecular transfer of methylene. 

A method for achieving net anti hydroxylation of alkenes combines two stereospecific processes epoxidation of the double bond and hydrolysis of the derived epoxide. 

The first objective was the conversion of L-tryptophan into a derivative that could be converted to pyrroloindoline 3, possessing a cis ring fusion and a syn relationship of the carboxyl and hydroxyl groups. This was achieved by the conversions shown in Scheme 1. A critical step was e. Of many variants tried, the use of the trityl group on the NH2 of tryptophan and the t-butyl group on the carboxyl resulted in stereospecific oxidative cyclization to afford 3 of the desired cis-syn stereochemistry in good yield. 

For the construction of oxygen-functionalized Diels-Alder products, Narasaka and coworkers employed the 3-borylpropenoic acid derivative in place of 3-(3-acet-oxypropenoyl)oxazolidinone, which is a poor dienophile in the chiral titanium-catalyzed reaction (Scheme 1.55, Table 1.24). 3-(3-Borylpropenoyl)oxazolidinones react smoothly with acyclic dienes to give the cycloadducts in high optical purity [43]. The boryl group was converted to an hydroxyl group stereospecifically by oxidation, and the alcohol obtained was used as the key intermediate in a total synthesis of (-i-)-paniculide A [44] (Scheme 1.56). 

The introduction of halogen into organic molecules can be carried out by a variety of addition or substitution reactions. The classical methods for the addition of halogen to double bonds or the substitution of halogen for hydroxyl by hydrohalic acids are too well known to bear repetition here. Discussed below, then, are methods that are of interest because of their stereospecific outcome or because they may be used on sensitive substrates. 

N,O-acetal intermediate 172, y,<5-unsaturated amide 171. It is important to note that there is a correspondence between the stereochemistry at C-41 of the allylic alcohol substrate 173 and at C-37 of the amide product 171. Provided that the configuration of the hydroxyl-bearing carbon in 173 can be established as shown, then the subsequent suprafacial [3,3] sigmatropic rearrangement would ensure the stereospecific introduction of the C-37 side chain during the course of the Eschenmoser-Claisen rearrangement, stereochemistry is transferred from C-41 to C-37. Ketone 174, a potential intermediate for a synthesis of 173, could conceivably be fashioned in short order from epoxide 175. 

It was anticipated all along that the vinylsilane residue could serve as a vinyl iodide surrogate. After protection of the C-14 secondary hydroxyl in 180 in the form of a triisopropylsilyl ether, the vinyltrimethylsilyl function can indeed be converted to the requisite vinyl iodide with AModosuccinimide (NIS) (see 180—>181, Scheme 43). Vinyl iodide 181 is produced stereospecifically with retention of the A17,18 double bond geometry. This transformation is stereospecific since the stereochemistry of the starting vinylsilane and the vinyl iodide product bear a definite relationship to each other.67b 75... 

The oxirane ring in 175 is a valuable function because it provides a means for the introduction of the -disposed C-39 methoxy group of rapamycin. Indeed, addition of CSA (0.2 equivalents) to a solution of epoxy benzyl ether 175 in methanol brings about a completely regioselective and stereospecific solvolysis of the oxirane ring, furnishing the desired hydroxy methyl ether 200 in 90 % yield. After protection of the newly formed C-40 hydroxyl in the form of a tert-butyldimethylsilyl (TBS) ether, hydrogenolysis of the benzyl ether provides alcohol 201 in 89 % overall yield. 

The synthesis of the key intermediate aldehyde 68 is outlined in Schemes 19-21. The two hydroxyls of butyne-l,4-diol (74, Scheme 19), a cheap intermediate in the industrial synthesis of THF, can be protected as 4-methoxybenzyl (PMB) ethers in 94% yield. The triple bond is then m-hydrostannylated with tri-n-butyl-tin hydride and a catalytic amount of Pd(PPh3)2Cl238 to give the vinylstannane 76 in 98 % yield. Note that the stereospecific nature of the m-hydrostannylation absolutely guarantees the correct relative stereochemistry of C-3 and C-4 in the natural product. The other partner for the Stille coupling, vinyl iodide 78, is prepared by... 

Osmate esters are important intermediates in the reactions of 0s04 in the stereospecific m-hydroxylation of alkenes and other unsaturated molecules [182],... 

Thus, it appears that the stereospecific part of the sugar ring, in terms of glycol arrangements, must reside within the hydroxyl groups on C-2, -3, and -4. 

This enantiomeric specificity has been of interest in other contexts, and stereospecific biotransformation has been observed. Examples include the enantiomeric oxidation of sulfides to sulfoxides (Chapter 11, Part 2) and steroid and triterpene hydroxylation (Chapter 7, Part 2). 

The oxidation by strains of Pseudomonas putida of the methyl group in arenes containing a hydroxyl group in the para position is, however, carried out by a different mechanism. The initial step is dehydrogenation to a quinone methide followed by hydration (hydroxylation) to the benzyl alcohol (Hopper 1976) (Figure 3.7). The reaction with 4-ethylphenol is partially stereospecific (Mclntire et al. 1984), and the enzymes that catalyze the first two steps are flavocytochromes (Mclntire et al. 1985). The role of formal hydroxylation in the degradation of azaarenes is discussed in the section on oxidoreductases (hydroxylases). 

Bauveria sulfurescens stereospecifically hydroxylated an azabrendane at the quaternary carbon atom (Figure 7.46) (Archelas et al. 1988). 

Macrolide aggregation pheromones produced by male cucujid beetles are derived from fatty acids. Feeding experiments with labeled oleic, linoleic, and palmitic acids indicate incorporation into the macrolide pheromone component [ 117 ]. The biosynthesis of another group of beetle pheromones, the lactones, involves fatty acid biosynthetic pathways. Japonilure and buibuilactone biosynthesized by the female scarab, Anomalajaponica, involves A9 desaturation of 16 and 18 carbon fatty acids to produce Z9-16 CoA and Z9-18 CoA,hydroxylation at carbon 8 followed by two rounds of limited chain shortening and cyclization to the lactone [118]. The hydroxylation step appears to be stereospecific [118]. 

PHA synthases exhibit a remarkably low substrate specificity. In general, the specificity of PHA synthases regarding the length of the hydroxyalkyl moiety of the coenzyme A thioester as well as of the position of the hydroxyl group, the presence of other substituents, and the position of double bonds, is low. In contrast, the stereospecificity of PHA synthases is strict the hydroxyl carbon atom must have the R-configuration. 

Figure 11.4 The overall result of epoxidation followed by acid-catalyzed hydrolysis is a stereospecific anti hydroxylation of the double bond. ds-2-Butene yields the enantiomeric 2,3-butanediols tra x-2-butene yields the meso compound.

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