Unsaturated alcohols cyclization

Type III Reactions and Other Reactions of Acetals. Treatment of symmetric acetals with alkenols or al-kynols in the presence of TiCU results in transacetalization to give mixed acetals such as (285) which react further via cation (286) to give cyclic products such as (287) in 50-99% yield. In this one-pot procedure the alkenic acetal need not be isolated. Acetoxyalkoxyacetic esters, such as (288), prepared in two steps from methyl glyoxylate and unsaturated alcohols, cyclize under the influence of SnCU in CH2CI2 to give oxacyclic carboxylic esters such as (290). These reactions proceed through the intermediacy of methoxycarbonylcarbonium ion (289). 

The 7, i5-unsaturated alcohol 99 is cyclized to 2-vinyl-5-phenyltetrahydro-furan (100) by exo cyclization in aqueous alcohol[124]. On the other hand, the dihydropyran 101 is formed by endo cyclization from a 7, (5-unsaturated alcohol substituted by two methyl groups at the i5-position. The direction of elimination of /3-hydrogen to give either enol ethers or allylic ethers can be controlled by using DMSO as a solvent and utilized in the synthesis of the tetronomycin precursor 102[125], The oxidation of the optically active 3-alkene-l,2-diol 103 affords the 2,5-dihydrofuran 104 in high ee. It should be noted that /3-OH is eliminated rather than /3-H at the end of the reac-tion[126]. 

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

Cyclization of unsaturated alcohols with sulfenyl chlorides... 

The above methodology has been extremely useful for the synthesis of a variety of INOC precursors. For instance, treatment of 0-trimethylsilyl a-bro-moaldoximes 52b, e, f with F ion in presence of unsaturated alcohols 57 produces oximino ethers 58 which can be readily oxidized using NaOCl (Scheme 8) [29]. The transient nitrile oxide intermediates formed undergo spontaneous cyclization to fused isoxazolines 59. The preferred stereoisomer in the formation of the five-membered ring ethers is trans whereas in the six-membered ring ethers the cis isomer predominates (see Table 5). MM2 calculations helped rationalize the experimentally observed stereoselectivites (see Table 5). 

An interesting feature of the cyclization of y, -unsaturated alcohols is the marked effect on product isomer distribution by the nature of substituents remote from the double bond (cf. 42 and Scheme 59).98 Complete stereospecificity is observed for the phenyl derivative 42a in contrast to 42b and c, and the isomer ratio is reversed for 42d. The suggested mechanism98 is shown in Scheme 60 the trisubstituted alkene (45) is mainly converted into a pyran (46) rather than a tetrahydrofuran derivative (Scheme 61). 

Iodocyclization to hydroxy tetrahydrofurans. Cyclization of y,8-unsaturated alcohols to tetrahydrofurans (12, 254-256) can be directed by an allylic oxygen substituent, which also can increase the rate of cyclization. Thus derivatives of 4-pentene-l,3-diol undergo iodocyclization mainly to dr-3-hydroxy-2-iodomethylte-trahydrofurans. 

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). 

Highly regioselective cyclizations of 3,4-, 4,5- and 5,6-unsaturated alcohols to yield tetrahydrofuranols and tetrahydropyranols have been carried out with the TS-I-H2O2 system (this is a titanium silicate molecular sieve-H202 complex.) The reactions involve the intermediate formation of epoxides and their Ni ring opening. 

The synthetic utility of the described reactions is clearly illustrated by the reductive detel-luration of telluroethers with BujSnH, the entire telluration/detelluration process providing a cyclization under mild conditions for unsaturated alcohols. 

Reduced furans 93 with /3-methylene groups are obtained by an intramolecular reaction of unsaturated alcohols 91 with PhEOBFa (generated in situ from iodosobenzene and boron trifluoride etherate). This cyclization may proceed via intermediate 92 (85CPB989). 

Cyclization of olefinic acids 5-23 Hydrocarboxylation of unsaturated alcohols... 

Examples of cyclization of y,<5-unsaturated alcohols in the prostaglandin syntheses abound among the more recent is the tetrahydrofuran formation by cyclization of an intermediate iodonium ion (Scheme 51) (81JCS(P1)1312). 

Unsaturated alcohols, e.g., CH2=C(CH3)CH2CH2OH, cyclize with R-CN in the presence of concentrated sulfuric acid.143... 

Cyclizations of substrates in which internal oxygen nucleophiles have been attached to unsaturated alcohols provide a method for stereoselective formation of acyclic 1,2- and 1,3-diol functionalities, as outlined in Scheme 2. 

Cyclizations of systems in which nitrogen nucleophiles have been tethered to the oxygen atoms of unsaturated alcohols have been used for stereo- and regio-selective syntheses of 1,2- and 1,3-amino alcohols. A variety of nitrogen nucleophiles have been examined. 

A novel approach to enantiopure spirocyclic (3-lactams has been developed by Alcaide et al. [106] using different intramolecular metal catalyzed cyclization reactions with monocyclic unsaturated alcohols 142 (Scheme 35). Ring-closing metathesis is one of the most powerful and reliable methods to construct a ring system. Transformation of alcohols in diolefin precursors followed by ring-closing... 

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)]. 

A novel one-pot tandem oxidation-cyclization-oxidation process was successfully applied in the transformation of unsaturated alcohols 250 [Eq. (5.315)].860 The intermediate aldehyde formed by oxidation with pyridinium chlorochromate (PCC) undergoes a carbonyl-ene cyclization followed by an additional oxidation to form 3-substituted piperidinones. 

Iodolactonization of y, o-unsaturated alcohols results in preferential formation of tram-2, 5-disubstituted tetrahydrofuranes. However, the corresponding benzyl ethers cyclize preferentially to the cis-isomers. The alkyl group must be bulky enough to exert a steric effect, but not to prevent cyclization. Substituted benzyl ethers are particularly useful. Examples of this steric control are illustrated for the preparation of tram- and c/s-linalyl oxide (equations I and II).10... 

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