Cyclic unsaturated alcohols

In cyclic unsaturated alcohols, a vast array of orientations of the hydroxy group relative to the double bond to be epoxidized may occur. For a general discussion of a force-field analysis of the peracid epoxidation see Section 4.5.1.1.1. 

The halocyclization of cyclic unsaturated alcohols to give fused 2,6-disubstituted tetrahydro-2//-pyrans proceeds quite predictably since the equatorial disubstituted isomer is generally formed whenever possible. The yields arc moderate to good and (V-iodosuccinimide and iodine have been employed as halonium sources. When the cyclization is performed under kinetic control with vV-iodosuccinimide in dichloromethane, and a tertiary carbocation is the intermediate in the reaction, electronic factors are responsible for tetrahydro-2//-pyran ring formation76. 

For example, in the case of cyclic unsaturated alcohols, face-selective hydrogenation occurs when the hydroxyl group binds to the Ir during hydrogenation of the double bond." ... 

Oxidative cyclization. The earlier observation of conversion of (-)-citro-nellol to ( —)-pulegone (7, 308) has been shown to be a general reaction for anne-lation of cyclic unsaturated alcohols or aldehydes. Several intermediates have been detected as shown for the oxidative cyclization of I to 2. 

Pineschi and Feringa reported that chiral copper phosphoramidite catalysts mediate a regiodivergent kinetic resolution (RKR) of cyclic unsaturated epoxides with dialkylzinc reagents, in which epoxide enantiomers are selectively transformed into different regioisomers (allylic and homoallylic alcohols) [90]. The method was also applied to both s-cis and s-trans cyclic allylic epoxides (Schemes 7.45 and 7.46,... 

At present, this rule fails only when functional neighboring substituents, capable of anchimeric assistance and in a convenient position with respect to the developing positive charge, can compete with bromine in the charge stabilization of the cationic intermediate (ref. 15). For example, the reaction of some unsaturated alcohols (ref. 16) goes through five- or six-membered cyclic oxonium ions, rather than through bromonium ions. 

The use of cyclic a,p-unsaturated ketones as starting materials in the enantioselective addition of dimethyl- and diethylzinc reagents catalysed by the HOCSAC ligand was introduced by Walsh and Jeon, in 2003. As shown in Scheme 4.16, the corresponding cyclic tertiary alcohols were formed in high enantioselectivities of up to 99% ee. 

In these reactions, the major diastereomer is formed by the addition of hydrogen syn to the hydroxyl group in the substrate. The cationic iridium catalyst [Ir(PCy3)(py)(nbd)]+ is very effective in hydroxy-directive hydrogenation of cyclic alcohols to afford high diastereoselectivity, even in the case of bishomoallyl alcohols (Table 21.4, entries 10-13) [5, 34, 35]. An intermediary dihydride species is not observed in the case of rhodium complexes, but iridium dihydride species are observed and the interaction of the hydroxyl unit of an unsaturated alcohol with iridium is detected spectrometrically through the presence of diastereotopic hydrides using NMR spectroscopy [21]. 

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

Sulfenoetherification. The reagent in combination with trifluoromethane-sulfonic acid converts suitably unsaturated alcohols into five- to seven-membered cyclic ethers. The cyclization is considered to involve an intermediate episulfonium ion. 

Scheme 13 Cyclic ethers and lactones by allyloxylation-cyclization of unsaturated alcohols and carboxylic acids.

We have studied the anodic oxidation of unsaturated alcohols using the controlled potential electrolysis (E = 1.9V vs SCE) in CH3CN-O.I mol/1 Et4NC104 solution in a divided cell [110]. The oxidation of 4-pentenol after consumption of 0.8 F/mol gave 2-methyltetrahydrofuran and tetrahydropyran as the major products. The oxidation of 5-pentenol gave 2-methyltetrahydro-pyran and oxepam, while the oxidation of 3-butenol under the same reaction conditions did not give the cyclic products. We rationalized this reaction as the electrongenerated acid (EGA) catalyzed intramolecular cyclization (Scheme 44). 

A variety of unsaturated alcohols with a cyclic structure and allyl phenols lead to bicycUc telluroethers. 

An example of a structural substituent that is often metabolized (bioactivated) to an electrophile is the allyl alcohol substituent (C=C—C—OH). Allyl alcohol moieties are found in many commercial chemical substances, either as the free alcohol or as an ester or ether. As illustrated in Scheme 4.1, allyl alcohols (and also as their esters or ethers) that contain at least one hydrogen atom on the alcoholic carbon can be oxidized in the liver by alcohol dehydrogenase (ALDH) to the corresponding a, 3-unsaturated carbonyl metabolite, which is toxic in many cases [29-31]. The hepatotoxicity of allyl alcohol (1), for example, is due to its oxidation by ALDH to acrolein (2), an a,(3-unsaturated aldehyde, which undergoes Michael addition with cellular nucleophiles in the liver [29] (Scheme 4.1). Cyclic allyl alcohols (Scheme 4.1) are expected to undergo similar enzymatic oxidation to yield a,(3-unsaturatcd carbonyl metabolites and are also likely to be toxic. 

Triethylammonium hydrogen fluorides (Et,N - nHF complexes, n = 4 6) allow the fluorocyclization of unsaturated aldehydes such as 2,6-dimethylhcpt-5-enal (7) to livc-mem-bered cyclic fluoro alcohols, such as 8 and 9 (yields 55-81 %).39s... 

Intramolecular oxysulfenylation.1 Intramolecular oxysulfenylation (11, 205) of y,8-unsaturated alcohols or acids can be used for preparation of cyclic ethers or lactones, respectively. A base is not essential, but optimal yields are obtained in the presence of diisopropylethylamine (1.1 equiv.). Formation of five-membered rings is favored over formation of six-membered rings. The reaction is carried out at 25° and requires 1-3 days. 

A number of linear and cyclic alkenes have been studied in this reaction. The presence of a base favoured the formation of diesters from linear alkenes, whereas cyclic alkenes gave diesters even in absence of base.519 In a further study using dienes and unsaturated alcohols, ketones and esters, the dicarboxylation reaction could quite generally be achieved in good yields.S20S21... 

The intramolecular alkoxy- or phenoxy-mercuration of unsaturated alcohols or phenols, respectively, provides an exceptionally useful process for the formation of cyclic ethers, particularly those bearing a five- or six-membered ring (equation 263).415... 

The demercuration of these cyclic mercurials is fraught with more problems than analogous mercurials formed by intermolecular processes. Alkaline sodium borohydride is once again the most common reducing agent, but elimination to the starting unsaturated alcohol is not unusual. The extent of elimination varies with the mercury ligand, the pH and the solvent used.434 Phase transfer approaches offer advant-... 

DDQ is able to aromatize many cyclic compounds.122 Although, aro-matizations sometimes compete with the oxidation of unsaturated alcohols,123 they normally require harsh conditions and selective oxidations of unsaturated alcohols are possible.124... 

Preparation Of Oxacycloalkanes. Unsaturated alcohols can be cyclized under superacid conditions to yield oxolane derivatives. Laali et al.685 have studied the protonation of homoallylic adamantylideneadamantyl alcohols. The pseudo-axial alcohol 157 was protonated in HSO3F-SCUOF to give the intermediate protonated cyclic ether observed by 1H and 13C NMR spectroscopy, which, upon quenching, furnished the corresponding ether [Eq. (5.243)]. 

The use of pyridinium-based chromium(vi) oxidising agents (cf. Section 5.7.1, p. 587) is illustrated by the use of the supported reagent, pyridinium chlorochromate-alumina, for the conversion of the cyclic allylic alcohol, carveol, into the corresponding oc,/ -unsaturated ketone, carvone125 (Expt 5.88). 

Chiral cyclic sultines result from the reaction of unsaturated alcohols with N-sulfinyl-4-toluenesulfonamide under Lewis acid catalysis. An N-toluenesulfonamide intermediate is proposed (95JOC8067). 

Effect of Phospholipids on Reaction Volatiles. As would be expected, the inclusion of phospholipids in the reaction mixtures produced many volatiles derived from lipid degradation these included hydrocarbons, alkylfurans, saturated and unsaturated alcohols, aldehydes and ketones. However, two other important observations were made. First, the concentrations of most of the hetero- cyclics, formed by the amino acid + ribose Maillard reaction, were reduced. For most of the major volatiles this reduction was of the order of 40 - 50%, but in the case of thiophenethiol and methyl- furanthiol the reduction was over 65%. This appears to support the findings that in meat and coconut, lipids exert a quenching effect on the amount of heterocyclic compounds formed in Maillard reactions during heat treatment (11,12). Second, and perhaps more important, the addition of phospholipid to the reaction mixtures resulted in the production of large amounts of compounds derived from the interaction of the lipid or its degradation products with Maillard reaction intermediates. 

A substantial improvement in yield (84-96%) was achieved by using the O-trimethylsilyl derivatives of the above alcohols. DIB was superior in these oxidations to lead tetraacetate. It is noted that l-silyloxy-bicyclo[n.l.O]alkanes (n = 4-7) on treatment with iodosylbenzene-tetrabutylammonium fluoride were converted into mixtures of cyclic unsaturated ketones (Section 5.2.1). 

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