Cyclic Allylic Alcohols

In 1963, Dauben and Berezin published the first systematic study of this syn directing effect (Scheme 3.15) [37]. They found that the cyclopropanation of 2-cyclohexen-l-ol 32 proceed in 63% yield to give the syn isomer 33 as the sole product. They observed the same high syn diastereoselectivity in a variety of cyclic allylic alcohols and methyl ethers. On the basis of these results, they reasonably conclude that there must be some type of coordinative interaction between the zinc carbenoid and the substrate. 

The ethers clearly do not interfere with the selective reaction by providing an alternative site for reagent coordination, a problem that will be addressed again later in the section on asymmetric catalysis. Cyclic allylic alcohols are cyclopropa-nated with high selectivity as well (Table 3.8, entry 8). 

Entry 15 also demonstrates the suprafacial specificity with a cyclic allylic alcohol. 

In acyclic secondary -allylic alcohols, epoxidation by the vanadium system shows opposite stereospecificity to that of peracid and molybdenum carbonyl-mediated epoxidation (see Scheme 6)22 The predominance of the erythro isomer in the former process is rationalized22 in terms of the energetically more favorable transition state (6, cf. 5) and in this context the mechanism has analogy in the epoxidation behavior of medium-ring cyclic allylic alcohols.23... 

Allyl Alcohols. Secondary cyclic allylic alcohols are reduced with the combination of Et3SiH and ethereal LiC104, even in the presence of a tertiary alcohol (Eq. 35) or ketal function.173 Primary allylic alcohols do not undergo deoxygenation under similar conditions.173... 

With an increase of conversion, the enantiopurity of unreacted (S)-substrate increases and the diastereoselectivity of the product decreases. Using Ru-((S)-binap)(OAc)2, unreacted (S)-substrate was obtained in more than 99% ee and a 49 1 mixture of anti-product (37% ee (2R,iR)) at 76% conversion with a higher kR ks ratio of 16 1 [46]. In the case of a racemic cyclic allyl alcohol 24, high enantiopurity of the unreacted alcohol was obtained using Ru-binap catalyst with a high kR ks ratio of more than 70 1 [Eq. (16)] [46]. In these two cases, the transition state structure is considered to be different since the sense of dia-stereoface selection with the (S)- or the (R)-catalysts is opposite if a similar OH/ C=C bond spatial relationship is assumed. 

Considering an olefinic functionality as a chromophore, the absolute configuration of cyclic allylic alcohols can be determined using a method that involves the conversion of the alcohol to the corresponding benzoate.60 This can also be extended to acyclic alcohols where the conformations are dynamic (see Fig. 117). Interested readers may consult the literature for details.61... 

Table 10 Direct catalytic substitution of cyclic allylic alcohols with amides...

Cyclic allylic alcohols have different steric requirements than the acyclic substrates discussed above. Sarzi-Amade and coworkers addressed the mechanism of epoxida-tion of 2-cyclohexen-l-ol by locating all the transition structures (TSs) for the reaction of peroxyformic acid (PFA) with both pseudoequatorial and pseudoaxial cyclohexenol con-formers. Geometry optimizations were performed at the B3LYP/6-31G level, and the total energies were refined with single-point B3LYP/6-311- -G //B3LYP/6-31G calculations. 

Aerobic Co(II) catalysed hydroperoxysiiyiation of allylic alcohols provides silyl peroxides that can be condensed with ketones to produce 1,2,4-trioxanes or 1,2,4-trioxepanes by a simple one-pot procedure (Scheme 35A). A recent improvement in the use of Co(acac)2 is the use of Co(thd)2 (thd = bis (2,2,6,6-tetramethyl-3,5-heptanedionato)). This more reactive catalyst allows cyclic allylic alcohols to be oxygenated and the resulting peroxysilyl alcohol can be transformed to spiro trioxanes, some of which have potent in vitro antimalarial activity (Scheme 35B). For example, compound 87 expresses activity around 20 nM (artemisinin = 10 nM). 

Numerous chiral cyclic allyl alcohol derivatives have been used as the chiral alkene part in 1,3-dipolar cycloadditions. In general, the more rigid conformational... 

Scheme 2.1.4.25 Asymmetric synthesis of cyclic allylic alcohols.

The reaction proceeded with extremely high syn diastereocontrol with five- and six-membered cyclic allylic alcohols with a variety of zinc carbenoids. One particnlarly interesting example of a highly functionalized starting material is in the introduction of the C19 methyl group of taxusin through a highly chemo- and diastereoselective cyclo-propanation (equation 50). ... 

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. 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

Allylic and cis-homoallylic alcohols are epoxidized readily, but frans-homoallylic and bishomoallylic alcohols react slowly, if at all. The stereoselectivity in the epoxidation of acyclic allylic alcohols is the same as and is comparable to that observed with r-BuOOH/VO(acac)2. The stereoselectivity in epoxidation of acyclic homoallylic alcohols is also the same but lower than that obtained with t-BuOOH/ VO(acac)2. Epoxidation of cyclic allylic alcohols proceeds more slowly and in lower yield than that of acyclic allylic alcohols. 

Table 6 O-Cyclization of Derivatives of Cyclic Allylic Alcohols and Amines Entry Ref.

Cyclizations of chloral hemiacetal derivatives of cyclic allyl alcohols were regio- and stereo-selective (Table 6, entry 1), but a mixture of regioisomers was obtained from analogous derivatives of acyclic allyl alcohols with a nonterminal double bond.93 Hemiacetal derivatives of allyl alcohols with a terminal vinyl group have been cyclized with mercury(II) acetate to give acetal derivatives of threo 1,2-diols with moderate selectivities (equation 54 and Table 15, entries 1 and 2).147 Moderate to excellent stereoselectivity has been observed in the iodocyclizations of carbonate derivatives of allyl alcohols (entries 3-5).94a The currently available results do not provide a rationale for the variation in observed stereoselectivity. 

The isomerization of cyclic allyl alcohols to produce ketones proceeds more cleanly [17]. Effective kinetic resolution of racemic cyclic allylic alcohols has been reported [18]. The isomerization of racemic 4-hydroxy-2-cyclopentanone (29) in the presence of 0.5 mol % of [Rh[(/ )-BlNAP](MeOH)2 + in THF proceeded with 5 1 enantiomeric discrimination at 0°C to give 1,3-cyclopentadione (31) via enol ketone 30, leaving the /(-starting allylic alcohol (91% ee and 27% recovery yield) at 72% conversion after 14 days (eq 3.12). (R)-4-Hydroxy-2-cy-clopentenone is a key building block for prostaglandin synthesis [19]. 

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). 

Bicyetic acetals.5 Cyclic allylic alcohols couple with ethyl vinyl ether when treated with Pd(OAc)2. Only a catalytic amount of Pd(II) is required if Cu(OAc)2 is present as a reoxidant. The absence of double-bond isomerization is a useful feature of this coupling. 

Cyclopropylcarbinyl radicalsGeneration of a radical adjacent to a cyclopropyl group is attended by cleavage of the cyclopropane ring. The precursors are available by cyclopropanation of a cyclic allylic alcohol followed by replacement of... 

Scheme 9. Kinetic resolution of racemic cyclic allyl alcohols (a) Rh[(R)-BINAP](MeOH)2 +, THF, 0°C, 14days.

When the alkene is neither terminal nor conjugated, addition appears to occur the other way round - to give a (3-alkoxylithium such as 34 - which eliminates Li20 under the conditions of the reaction.26 Cyclic allylic alcohols similarly give alkenes by elimination, and geminally disubstituted allylic alcohols such as 35 are simply unreactive.25... 

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