Cuprate, reaction with epoxides

Sn2 Reactions with epoxides and aziridines are also synthetically useful. An example of epoxide cleavage with an organocopper reagent with sp carbon moieties is the enantioselective synthesis of (3S, 4S)-4-methyl-3-heptanol (53), an elm bark beetle (Scolytus multistriatus) pheromone [42]. The chiral epoxy oxazolidine 51 [43], prepared from (R)-phenylglycinol, reacted with a propylmagnesium bromide-derived cuprate at —70 °C to afford the oxazolidine 52 in 74% yield (Scheme 9.12). Compound 52 was converted into the target molecular 53 by conventional procedures. 

A. Alexakis, G. Cahiez, and J. F. Normant, Tetrahedron, 1980, 36, 1961. (Z)-Alkenyl cuprate reactions with various electrophiles, e.g., CO2, epoxides, aldehydes, ot,jS-enones, and alkynes. 

Scheme 4.10 gives some examples of application of alkyne carboalumination in synthesis. The reaction in Entry 1 was carried out as part of a synthesis of the immunosuppressant drug FK-506. The vinyl alane was subsequently transmetallated to a cuprate reagent (see Chapter 8). In Entry 2, the vinyl alane was used as a nucleophile for opening an epoxide ring and extending the carbon chain by two atoms. In Entries 3 to 5, the vinyl alane adducts were converted to vinyl iodides. In Entry 6, the vinyl alane was converted to an ate reagent prior to reaction with formaldehyde. 

R2Cu(CN)Li2 reaction with vie-epoxy mesylatesA higher-order cuprate reacts selectively with the epoxide group of the epoxy mesylate 1 to provide 2 with inversion at C3. Ring closure of 2 furnishes the epoxide 3, which reacts with a second equivalent of the higher-order cuprate to furnish meso-4, with inversion at both C, and C3. This two-step reaction provides a route to acyclic alcohols with useful stereocontrol at both adjacent centers. 

Scheme 3.27. Regioselectivity in reactions of silyllithium and silyl cuprate reagents with allylic carbamates and epoxides...

Alkylation reactions reveal a mechanistic aspect of the cuprate reactions different from that of addition reactions. Theoretical analyses of reactions of alkyl halides (Mel and MeBr) [123, 124] and epoxides (ethylene oxide and cyclohexene oxide) [124] with lithium cuprate clusters (Me2CuLi dimer or Me2CuLi-LiCl, Scheme 10.11) resolved long-standing questions on the mechanism of the alkylation reaction. Density functional calculations showed that the rate-determining step of the... 

These cuprates react more readily than R2CuLi reagents with epoxides. Reaction occurs cleanly at the less sterically hindered position with the expected inversion of configuration.10 Yields are consistently higher than those obtained with RCu(CN)Li."... 

The alkylation of compounds 591 and 592 can be performed with primary alkyl bromides and iodides824,865,866,871 887. This procedure, followed by different transformations of the alkylated products, has been applied extensively in organic synthesis. However, the alkylation with epoxides gave very poor yields with intermediates 591 and 592, so they have to be transmetallated to low-order cuprates 594888 and 595889 in order to undergo reaction with these electrophiles in THF at 0 to 20 °C. 

Addition of 10% Cul to the reaction of allylic Grignard reagents with epoxides exerts a marked efiect on the regioselectivity. The catalyst also increases the rate of reaction. The a-products are also the main products when sufficient Cul is added to form the stoichiometric dialkyl cuprate of the Grignard reagent, but yields are lower than in the copper-catalyzed reaction. ... 

Related a,p-Unsaturated Esters. Similar a,p-unsaturated esters bearing a heterocyclic chiral auxiliary of a-amino acid origin at the p-position are known and have been utilized in asymmetric synthesis. Effective asymmetric conjugate additions of cuprates to (2), (3), and (5)J epoxidations of (3), and dipolar cycloadditions of (2) have been reported. Although oxazoli-dine (4) is only obtained as an 86 14 equilibrating mixture of stereoisomers, reactions with the lithium (Z)-enolate of methyl N-benzylideneglycinate (see Ethyl N-Benzylideneglycinate) are exclusively diastereoselective. 

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