Derivatives of secondary alcohols

This chapter shows how radical chemistry based on thiocarbonyl derivatives of secondary alcohols can be useful in the manipulation of natural products and especially in the deoxygenation of carbohydrates. From the original conception in 1975, the variety of thiocarbonyl derivatives used has increased, but the methyl xanthate function still remains the simplest and cheapest, when other functionality in the molecule does not interfere. Otherwise, selective acylation with aryloxythiocarbonyl reagents is important. Many of the functional groups present in carbohydrates and other natural products do not interfere with radical reactions. 

Figure 6. Capillary GC-separation of R-(+)-derivatives of secondary alcohols and their esters, isolated by preparative GC from yellow and purple passion fruits (DB 210, 30 m/0.33 mm i.d., 140 °C, pentanol-2 OV 101, 50 m/0.33 mm i.d., 170 °C, heptanol-2).

CHOH >CHi. A variety of thiocarbonyl derivatives of secondary alcohols are reductively cleaved by Bu,SnH. The S-methyl xanthate is a convenient derivative for use in this reaction because of convenience and low cost. ... 

Figure IV. Capillary GC-separation of (R)-(+)-MTPA-derivatives of secondary alcohols and their esters, isolated by preparative GC from yellow and purple passion fruits.

The isopropylidenation of propane-l, 3 triols provides a very sensitive measure of the relative stability of various dioxolane isomers. For example, the preference for the formation of isopropylidene derivatives of secondary alcohols in propane-1,2,3-triols is illustrated by the isopropylidenatin in Scheme 3.32 in which the more highly substituted /rnn -dioxolane is favoured at equilibrium. Mulzer and co-workers showed that isomerisation occurred easily when the dioxolane 33 1 [Scheme 3.33] was treated with mineral acid to give the rm/i -dioxolane 33 2. However, attempted isomerisation of the diastereoisomeric dioxolane 33 3 failed to occur under similar conditions demonstrating the penalty incurred on formation of the less stable cu-dioxolane 33 4. The isomerisation of the /rn/i5-fused dioxolane 34 1 to the m-fused dioxolane 34.2 is driven by the relief of strain [Scheme 3.34]. According to MM2 calculations, the difference in total energy between the cis- and rmm-fused dioxolanes is ca. 5 kcal/mol. 

Table 9. Selected and NMR Data for the Noe Derivatives of Secondary Alcohols of Known Absolute Configuration ...

In 2003, Sigman et al. reported the use of a chiral carbene ligand in conjunction with the chiral base (-)-sparteine in the palladium(II) catalyzed oxidative kinetic resolution of secondary alcohols [26]. The dimeric palladium complexes 51a-b used in this reaction were obtained in two steps from N,N -diaryl chiral imidazolinium salts derived from (S, S) or (R,R) diphenylethane diamine (Scheme 28). The carbenes were generated by deprotonation of the salts with t-BuOK in THF and reacted in situ with dimeric palladium al-lyl chloride. The intermediate NHC - Pd(allyl)Cl complexes 52 are air-stable and were isolated in 92-95% yield after silica gel chromatography. Two diaster corners in a ratio of approximately 2 1 are present in solution (CDCI3). 

Wilkinson s catalyst has also been utilized for the hydroboration of other alkenes. Sulfone derivatives of allyl alcohol can be hydroborated with HBcat and subsequently oxidized to give the secondary rather than primary alcohol. This reactivity proves to be independent of substituents on the sulfur atom.36 Similarly, thioalkenes undergo anti-Markovnikoff addition to afford a-thioboronate esters.37 The benefits of metal-catalyzed reactions come to the fore in the hydroboration of bromoalkenes (higher yields, shorter reaction times), although the benefits were less clear for the corresponding chloroalkenes (Table 3).38,39 Dienes can be hydroborated using both rhodium and palladium catalysts [Pd(PPh3)4] reacts readily with 1,3-dienes, but cyclic dienes are more active towards [Rh4(CO)i2].40... 

The phenylcarbamate derivative 23j also showed chiral recognition for many racemates in CDCI3 (Figure 3.38). Figure 3.39 shows the 1H NMR spectra of ( )-2-butanol in the absence and presence of 23j. In the case of secondary alcohols, such as 2-butanol, 2-heptanol, and 2-octanol, the methyl protons at the end of the longer chain and remote from the stereogenic center were enantiomerically separated in the presence of 23j, and the methine and... 

Chiral acetals/ketals derived from either (R,R)- or (5,5 )-pentanediol have been shown to offer considerable advantages in the synthesis of secondary alcohols with high enantiomeric purity. The reaction of these acetals with a wide variety of carbon nucleophiles in the presence of a Lewis acid results in a highly diastereoselective cleavage of the acetal C-0 bond to give a /1-hydroxy ether, and the desired alcohols can then be obtained by subsequent degradation through simple oxidation elimination. Scheme 2-39 is an example in which H is used as a nucleophile.97... 

The ability of hydrolases to hydrolyse esters derived from primary alcohols in the presence of esters derived from secondary alcohols has been recognized (Scheme 3)[11]. 

The synthetic method was also applicable to the conversion of secondary alcohol derivatives 167 into the corresponding internal allenes 168 (Scheme 3.86). 

We carried out a great deal of work on the relationship between the above physiological effects and chemical constitution, and it was shown conclusively that the more potent compounds were those derived from secondary alcohols.3 Thus, for example, di-isopropyl phosphorofluoridate is very much more potent than diethyl phosphorofluoridate or di-ra-propyl phosphorofluoridate and the toxicity of the dicycZohexyl ester is of a high order (L.C. 50 for mice, rats and rabbits was 0-11 mg./l.). Din-butyl phosphorofluoridate had low toxicity and produced only feeble... 

The oxidation of secondary alcohols (66) to (67) is possible by indirect electrooxidation utilizing thioanisole as an organic redox catalyst in a PhCN-2,6-lutidine-Et4NOTs-(C/Pt) system at 1.5 V vs. SCE (Scheme 25) [81] and is also performed in the presence of 2,2,2-trifluoroethanol [82]. It is suggested that the initially formed cation radical sulfide species derived from the direct discharge of the sulfide provides phenylmethyl-alkoxysulfonium ions, which are transformed to (67) and thioanisole. 

A series of imidate esters derived from secondary alcohols has been found to react with potassium benzoate or potassium phthalimide to give products of 5 n2 substitution in excellent yields and with clean inversion of stereochemistry. ... 

Oxidation of primary, secondary and benzylic alcohols with TBHP or CHP, mainly catalyzed by Mo and Zr derivatives, were performed by different authors. As an example, Ishii, Ogawa and coworkers reported the conversion of secondary alcohols such as 2-octanol to ketones mediated by catalyst 39 and TBHP. The oxidation of cyclic alcohols depended on steric factors. Zirconium alkoxides may act as catalysts in the conversion of different alcohol typologies with alkyl hydroperoxides . Secondary alcohols, if not severely hindered, are quantitatively converted to the corresponding ketones. The selectivity for equatorial alcohols is a general feature of the system, as confirmed by the oxidation of the sole cis isomer 103 of a mixture 103-bl04 (equation 68). Esters and acids could be the by-products in the oxidation of primary alcohols. 

Polymers derived from natural sources such as proteins, DNA, and polyhy-droxyalkanoates are optically pure, making the biocatalysts responsible for their synthesis highly appealing for the preparation of chiral synthetic polymers. In recent years, enzymes have been explored successfully as catalysts for the preparation of polymers from natural or synthetic monomers. Moreover, the extraordinary enantioselectivity of lipases is exploited on an industrial scale for kinetic resolutions of secondary alcohols and amines, affording chiral intermediates for the pharmaceutical and agrochemical industry. It is therefore not surprising that more recent research has focused on the use of lipases for synthesis of chiral polymers from racemic monomers. 

The salen-Cu complex 5a was shown to oxidize a selected number of secondary alcohols (e.g. l-phenylethanol) to the corresponding ketones, with a wider range of primary alcohols being further oxidized to the analogous carboxylic acids, in the presence of 5-15 equiv. of H2O2 as oxidant, while molecular oxygen proved inefficient as oxidant [152], The derivative 5b has been reported to catalyze the electrochemical oxidation of primary alcohols (but not secondary alcohols) into the corresponding aldehydes, with turnovers > 30 [153]. 

More recently, it was found that the incorporation of N-heterocychc car-bene ligands to the Cp lr moiety (Eq. 12) considerably enhances catalyst activity for alcohol oxidation reactions [50,51]. By way of example, the oxidation of secondary alcohols occurs with high turnovers, up to 3,200 for the oxidation of 1-phenylethanol and 6,640 for that of cyclopentanol (95% yield, 40 °C, 4 h) using the complex with the carbene derived from the tetram-ethyhmidazole (Eq. 12). 

Table 9 shows different chemical shifts for the three depicted most useful hydrogens and the respective carbons of selected lactols derived from secondary alcohols containing phenyl, nitrile, ethynyl and formyl groups directly bound to the stereogenic center. 

Radical chain chemistry is often employed for the transformation of an alcohol to the corresponding deoxy derivative. The secondary alcohol 1 is first converted into a suitable thiocarbonyl derivative. The first derivatives investigated were thioxobenzoates 2, xan-thates 3, and thiocarbonylimidazolides 4 (Scheme 2). On reduction with tributyltin hydride, these derivatives afforded a good yield of the appropriate deoxy compounds [8-10]. 

Styrene oxide is reduoed selectively to / -phenyletheno) over Raney nickel. 1 m0 On the other hand, substituted derivatives con-taming electron withdrawing groups yield substantial proportions of secondary alcohols,1 00 ae shown in Eq, (348). Those electronic effects... 

Support-bound primary or secondary aliphatic alcohols can be acylated under conditions similar to those used in solution, provided that these conditions are compatible with the chosen linker. For instance, acids can be activated with a carbodiimide either as symmetric anhydrides or as O-acylisoureas, which quickly react with alcohols in the presence of a catalyst, such as DMAP or another base, to yield esters (Table 13.12). Further acid derivatives suitable for esterification reactions on solid phase include acyl halides and imidazolides. HOBt esters react only slowly with alcohols, but enable the selective acylation of primary alcohols in the presence of secondary alcohols (Entry 5, Table 13.12). 

The radical deoxygenation of secondary alcohols through tri-n-butyltin hydride reduction of their xanthate derivatives was introduced in 1975 [227]. The reaction proceeds by thiophilic radical addition to the thiocarbonyl group of a tin radical followed by collapse of the carbon intermediate, as shown in the accompanying scheme. Hydrogen transfer completes the process. 

A vanety of secondary alcohols with terminal trifluoromethyl group are oxidized by the Dess-Martin periodinane reagent [52 53] (equation 48) Conversion of l,6-anhydro-4-0-benzyl-2 deoxy 2-fluoro-p-D-glucopyranose to the corresponding oxo derivative is earned out by ruthenium tetroxide generated in situ from ruthenium dioxide [54] (equation 49)... 

Cyclization of a variety of y-allenic alcohols with silver nitrate proceeds by 5-exo cyclization to form 2-alkenyltetrahydrofurans (equation 87).205c 206 Little stereoselectivity is seen in cyclizations of secondary alcohols. Cyclization by intramolecular oxypalladation/methoxycarbonylation or oxymercuration followed by transmetallation and methoxycarbonylation also showed no stereoselectivity (equation 88 and Table 24, entries 1 and 2).50 207 However, cyclization of the corresponding r-butyldimethylsilyl ether derivatives with mercury(II) trifluoroacetate followed by transmetallation/methoxycarbonylation pro-... 

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