2,3-epoxy alcohols nucleophilic epoxide opening

Schomaker et al found that the Payne rearrangement is useful for controlling the regioselectivity of the reaction of dimethylsulfoxonium ylide with the epoxy alcohol 22. Thus the rearrangement of chiral non racemic epoxy alcohol 21 led to the more sterically accessible terminal epoxide 22, which then underwent nucleophilic epoxide opening with the ylide at C-1 to afford bis alkoxide 23. The 5-exo-tet ring closure of 23 resulted in the formation of 2,3-disubstituted tetrahydrofuran ring 24. 

Hale et al. reported on the synthesis of the biyostatin B ring by acid-catalyzed nucleophilic epoxide opening (Scheme 29) [58], Their goal was to convert O-mesylate epoxide precursor 90 directly into THP 92 by treatment with two equivalents of sodium hydride and imidazole. However, the mily product isolated was epoxy alcohol 91 in 80 % yield. To effect the desired 6-exo-tet ring closure, epoxide 91 was treated with a catalytic amount of camphorsulfonic acid. Tetrahydropyran 92 was acquired as the sole product in 87 % yield as a single diastereomer. 

In general, 2-substituted allylic alcohols are epoxidized in good enantioselectivity. Like glycidol, however, the product epoxides are susceptible to ring opening via nucleophilic attack at the C-3 position. Results of the AE reaction on 2-methyl-2-propene-l-ol followed by derivatization of the resulting epoxy alcohol are shown in Table 1.6.1. Other examples are shown below. 

The 2,3-epoxy alcohols are often obtained in high optical purity (90% enantiomeric excess or higher), and are useful intermediates for further transformations. For example by nucleophilic ring opening the epoxide unit may be converted into an alcohol, a /3-hydroxy ether or a vicinal diol. 

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,... 

The wide scope application of this transformation arises not only from the utility of epoxide compounds but also from the subsequent regiocontrolled and stereocontrolled nucleophilic substitution (ring-opening) reactions of the derived epoxy alcohol. These, through further functionalization, allow access to an impressive array of target molecules in enantiomerically pure form. 

Ti(IV) isopropoxide is an effective reagent for promoting regioselective attack by nucleophiles at the 3-position of 2,3-epoxy alcohols [69], 2,3-epoxy acids [70], and 2,3-epoxy amides [70]. It has been proposed that this process involves coordination to the metal center in the bidentate manner shown for a 2,3-epoxy alcohol in structure 44. Such Ti-assisted nucleophilic opening of epoxides is thought to play a role in the in situ reactions leading to 41 and 43. 

With good nucleophiles, under relatively mild conditions, 2,3-epoxy alcohols will undergo epoxide ring opening at C-2 or C-3. In simple cases, nucleophilic attack at C-3 is the preferred mode of reaction. However, as the steric congestion at C-3 is increased, or if substituents play a significant electronic role, attack at C-2 can predominate.86... 

Mechanistic studies of the opening of the epoxide point to catalyst activation of both nucleophile and electrophile in a bimetallic array [79]. The Cr complex results in moderate ee only when used with thiol nucleophiles but enhancement is feasible by using a dithiol in a two-step selection process [80]. Enantioselective epoxide opening with carboxylic acids is more efficient with (salen)Co(III) complexes (often obtained via in situ oxidation of the Co(II) complex) than with the Cr analogs (Table 6, entries 4 and 5) [81]. This methodology was successfully extended to intramolecular desym-metrization of meso epoxy alcohols [82]. 

Nucleophilic Opening at C(l). The latent reactivity at C(l) can be activated via the Payne rearrangemenf by treatment of 2,3-epoxy alcohol A with aqueous NaOH in the presence of a cosolvent. This results in equilibration of A with the isomeric 1,2-epoxy 3-ol B. Even if epoxide A is preferred at equilibrium, C(l) in isomer B is steri-cally less hindered and hence should react faster with the nucleophile in an 8 2 manner. Once B is formed, it will react selectively and irreversibly with the nucleophile to furnish product C. The success of epoxide opening (B C) by nucleophiles depends on whether the reagent is compatible with the alkaline aqueous medium required for the Payne reaiTangement. 

Nucleophilic Opening at C(2) and C(3). This opening depends on steric and electronic factors. For example, in the presence of camphorsulphonic acid, nucleophilic attack by methanol occurs at the more substituted carbon. However, with epoxy alcohols having the same number of substituents at C(2) and C(3), epoxide opening with nucleophiles occurs preferentially at C(3) because the presence of the electron-withdrawing OH group at C(l) retards 8 2 substitution at C(2). 

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. 

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