Epoxide opening with cuprate

A similar reaction pathway was found for the Sn2 substitution of an epoxide with a lithium cuprate cluster [124]. In contrast to that in the MeBr reaction, the stereochemistry of the electrophilic carbon center is already inverted in the transition state, providing the reason for the preferred trans-diaxial epoxide-opening widely observed in synthetic studies. The TS for the Sn2 reaction of cyclohexene oxide is shown in Eq. 10.12. 

Similar to the epoxides, the most frequently encountered synthetic transformation for aziridines is nucleophilic ring-opening, whereby carbon- and heteroatom-based nucleophiles are comparably important. As an example of the former type, aziridine-2-carboxylates 100 can be ring-opened with higher order cuprates to give the protected amino acid derivatives 101, corresponding to attack at the less-substituted aziridine carbon [95TL151],... 

Chiral all-syn-l,3-polyols. A reiterative route to these polyols from an optically active epoxide (1) involves ring opening with a cuprate derived from vinyllithium and copper(I) cyanide (11, 366-367) to give an optically active homoallylic alcohol (2). This is converted into the fepoxide (4) via a cyclic iodocarbonate (3) by a known procedure (11, 263). Repetition of the cuprate cleavage results in a homoallylic 1,3-diol (5). The ratio of desired syn- (o anfi-diols is 10-15 1. This two-step sequence can be repeated, with each 1,3-diol unit formed being protected as the acetonide. The strategy is outlined in Scheme (I). 

Methyl chloroacetate reacts with the anion of (7 )-methyl p-tolyl sulfoxide to give the corresponding 8-chloro-p-keto sulfoxide (eq 10), which can be easily transformed into the corresponding 3-hydroxy sulfoxide which gives, in presence of a base, the optically active a-sulfinyl epoxides. As illustrated here, a-sulfinyl epoxides can be opened by cuprates, leading to chiral homoallylic alcohols. ... 

FIGURE 16 6 Polystyrene/divinylbenzene sulfmate [432] resin was used to prepare the indicated sulfone oxirane on a solid phase. This was subjected to epoxide ring-opening with Grignard and cuprate reagents. Subsequent oxidation of the secondary alcohol was accomplished with simultaneous release from the resin, affording substituted cyclopent-2-enones. 

The treatment of one equivalent of 5-lithio-2,3-dihydro-1,4-dioxin with 0.5 equivalent of copper(I) cyanide solubilized as its lithium chloride (0.5 equiv.) complex at — 15°C affords the corresponding cyanocuprate. The reactivity of this cuprate was assessed by its conjugate addition to cyclic enones, and by nucleophilic epoxide opening the presence of boron trifluoride etherate led to enhancement... 

In the presence of ethanol, butanolides 149 or 150 undergo mild cleavage with tri-methylsilyl iodide to form the iodohydrin 159 in good yield. Cyclization of 159 to epoxide 160 under basic conditions (e.g., sodium carbonate) leads to isomerization within 5 min, but use of silver oxide affords 160 with no racemization. Opening the epoxide with cuprates furnishes j -hydroxyesters 161 with >99% ee (Scheme 21) [57]. The scope of this reaction can be extended to include cuprates derived from substituted vinyl halides. 

Coehlo and coworkers synthesized the carboxylic acid precursor of (+)-efaroxan (118), an 0.2 adrenoreceptor antagonist, which is a treatment for neurodegenerative disease, migraine, and type II diabetes. The synthesis opened with an MBH reaction which afforded key moieties. Thus, 2-fluorobenzaldehyde 120 was converted to the MBH adduct 121 under ultrasound conditions in 90% yield. After acetylation of the hydroxyl group, the acetylated MBH adduct was treated with dimethyl cuprate to furnish the trisubstituted olefin 122 via an Sn2 reaction. The methyl ester of 122 was reduced to the allylic alcohol which then underwent a Sharpless asymmetric oxidation to furnish the epoxide 123. In several steps, the epoxy alcohol 123 was then converted to the carboxylic acid 124. Upon treatment with sodium hydride the a-hydroxy carboxylic acid, 124 cyclized to deliver the hydrobenzofuran 119 in 65% yield and hence the precursor of (+)-efaroxan (118). 

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. 

Ethyl 2,3-epoxypropanoate is a very interesting chiron. It may be opened by various organometallic compounds such as dialkyl, diaryl, and divinyl lithium cuprates, dialkylmagnesium cuprates, trialkylalanes and aluminum acetylides.5 6 The epoxide ring is attacked regiospecifically at the p-position and produces a-hydroxy esters exclusively without racemization. The same result is observed with... 

Activated aziridines should be as useful as epoxides for carbon-carbon bond formation, with the advantage that the product will already incorporated the desired secondary aminated stercocentcr. To date, a general enantioselective method for the aziridination of alkcncs has not been developed. Eric Jacobsen of Harvard University (Angew. Chem. hit. Ed. 2004,43, 3952) has explored an interim solution, based on the resolution of racemic epoxides such as I. The cobalt catalyst that selectively hydrolyzes one enantiomer of the epoxide also promotes the addition of the imidc to the remaining enantiomerically-enriched epoxide. As expected, the aziridine 4 is opened smoothly with dialkyl cuprates. 

Cuprates have also been shown to be effective nucleophiles. Cuprates are formed when copper salts are added to organohthium reagents [89]. As shown in Scheme 6.56, these reagents, when added to anhydro sugars, readily form new carbon-carbon bonds with ring opening of the epoxide and... 

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