2.3- Epoxy alcohols with nucleophiles

Ti(OPr1)4-mediated nucleophilic ring opening of 2,3-epoxy-alcohol with primary amine requires more rigorous conditions, and the product is a complex mixture. Lin and Zeng22 found that this problem could be overcome and moderate to good yields could be obtained under weak base conditions by in situ /V-acylation of the aminolysis product with benzoyl chloride. 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

The rate and regioselectivity (C-3 attack) of the oxirane ring opening of 2,3-epoxy alcohols by nucleophiles are markedly increased by the addition of Ti(OPr )4. Thus, the reaction of 2,3-epoxyhexanol with excess diethylamine in the presence of Ti(OPi )4, 1,2-diol (132) and 1,3-diol (133) were formed in 90% yield in a ratio of 20 1, while, in the absence of the alkoxide, (132) and (133) were obtained in 4% yields in a ratio of 3.7 1 (Scheme 58)." ... 

Reaction of Epoxy Alcohols with Carbon Nucleophiles... 

Nucleophilic Cleavage of 2,3-Epoxy Alcohols and Related Compounds. " Titanium alkoxides are weak Lewis acids which generally have no effect on simple epoxides. However, reaction of 2,3-epoxy alcohols (available, for example, from the Sharpless-type epoxidation of allylic alcohols) with nucleophiles in the presence of Ti(0-/-Pr)4 results in highly regioselective ring-cleavage reactions involving preferential nucleophilic attack at C-3 (eq 5). In the absence of the titanium alkoxide, no reaction is observed under otherwise identical conditions, except in the case of PhSNa. 

The reaction of both open-chain and cyclic 2,3-epoxy alcohols with molecular Bromine or Iodine in the presence of Ti(0-i-Pr)4 at 0 °C leads to the regioselective formation of halo diols (eq 9). Interestingly, if these reactions are conducted at 25 °C a 1 1 mixture of the C-2 and C-3 cleavage products is obtained, and the same outcome is observed, even at 0 °C, when the acetate derivative of the 2,3-epoxy alcohol is involved as substrate. Dialkylamine hydrochlorides can be used as sources of halide nucleophiles in these types of epoxide ring-cleavage reactions. ... 

The condensation leaves epoxy end groups that are then reacted in a separate step with nucleophilic compounds (alcohols, acids, or amines). Eor use as an adhesive, the epoxy resin and the curing resin (usually an aliphatic polyamine) are packaged separately and mixed together immediately before... 

A 6-endo cyclization by a y-epoxy alcohol can be accomplished through the presence of an appropriately disposed electron-withdrawing group, as found in the total synthesis of (+)-phonomactin. Treatment of the hydroxy-epoxy ketone 30 (R = H) with HC1 afforded the bicyclic compound 31, containing a pyran-4-one ring, in which nucleophilic attack of the y-OH group occurred at the oxirane carbon distal from the unfavorable electronic effect of the carbonyl group (Scheme 8.7) [20a]. 

A synthetically useful diastereoselectivity (90% dc) was observed with the addition of methyl-magnesium bromide to a-epoxy aldehyde 25 in the presence of titanium(IV) chloride60. After treatment of the crude product with sodium hydride, the yy -epoxy alcohol 26 was obtained in 40% yield. The yyn-product corresponds to a chelation-controlled attack of 25 by the nucleophile. Isolation of compound 28, however, reveals that the addition reaction proceeds via a regioselective ring-opening of the epoxide, which affords the titanium-complexed chloro-hydrin 27. Chelation-controlled attack of 27 by the nucleophile leads to the -syn-diastereomer 28, which is converted to the epoxy alcohol 26 by treatment with sodium hydride. 

These epoxide-opening conditions were originally developed by Sharpless and coworkers for the regiocontrolled opening of 2,3-epoxy alcohols [30]. It has been proposed that ligand exchange of the substrate with isopropoxide forms a covalently bound substrate-titanium complex (Chart 3.3). Nucleophilic attack on this complex at the 3-position is favored over attack at the 2-position. In the case of 49,... 

Payne rearrangement. The Payne rearrangement2 of a primary cts-2,3-epoxy alcohol to a secondary 1,2-epoxy alcohol usually requires a basic aqueous medium, but it can be effected with BuLi in THF, particularly when catalyzed by lithium salts. As a consequence, the rearrangement becomes a useful extension of the Sharpless epoxidation, with both epoxides available for nucleophilic substitutions. Thus the more reactive rearranged epoxide can be trapped in situ by various organometallic nucleophiles. Cuprates of the type RCu(CN)Li are particularly effective for this purpose, and provide syn-diols (3).3... 

Although the Payne rearrangement usually produces mixtures of epoxy alcohols, because the rate of reaction of 2 with any given nucleophile is faster than that of i, the l,2-epoxy-3-alcohols generated in situ can be selectively and irreversibly captured by a nucleophile to afford 3. 

In the reaction of the conformationally restricted epoxy alcohol 84 and methyl or benzyl isocyanate, the epoxy carbamate 85 was formed. Cycliza-tion of 85 in tetrahydrofuran in the presence of sodium hydride gave the oxazinone 86 in approximately 20% yield, and the oxazolidinone 87 (R = Me, CH2Ph) in 40-60% yield. The formation of the two products can be rationalized by different nucleophilic attacks on the urethane nitrogen. With increasing nucleophilicity of the nitrogen, the regioselectivity of the reaction is shifted toward the formation of 87 (92TL3009). 

It is well known 113,14 20 25> that the addition of hydroxyl-containing compounds (water, alcohols, phenols, acids) considerably promotes the interaction of epoxy compounds with amines and other nucleophilic reagents. In this case, the epoxy ring carbon atom becomes more sensitive to nucleophilic attack. The reaction proceeds through a trimolecular transition state initially suggested by Smith26 27) for the reactions of epoxy compounds with amines2... 

Cleavage ofl -epoxy alcohols.l Titanium(IV) isopropoxide (1-1.5 equiv.) not only increases the rate of reaction of nucleophiles with these alcohols but controls the regioselectivity resulting in highly selective attack at C3. Some other metal alkoxides are also effective, including Zr(0-i-Pr)4-/-PrOH and Lu(0-/-Pr)3.2... 

The value of this reaction is enhanced by the fact that the numerous selective transformations of the 2,3-epoxy alcohols at Ct, C2 and C3 with carbon, nitrogen, and oxygen nucleophiles are possible because of electronic and steric factors. 

A key reaction of 2,3-epoxy alcohols is the Payne rearrangement, an isomerization that produces an equilibrium mixture. This rearrangement then allows for the selective reaction with a nucleophile at the most reactive, primary position (Scheme 9.5).18,84... 

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