Organosamarium intermediates

Davies used Sml2 and D20 to carry out a highly diastereoselective conjugate reduction of benzylidene diketopiperazine templates en route to (2S3R)-dideuteriophenylalanine.57 The new stereocentres arise from diastereoselective protonation of a Sm(III) enolate and the protonation of a stereodefined organosamarium intermediate (Scheme 4.46).58... 

As organosamariums are formed from radical intermediates, it is important to note that competing radical processes may be problematic if they proceed at a rate that is greater than the rate of reduction of the intermediate radical to the organosamarium (see Chapter 3, Section 3.2). In general, Barbier conditions should be used when the organosamarium intermediate is prone to dimerisation (e.g. allylic and benzylic organosamariums), decomposition (e.g. 

Surprisingly, upon treatment with Sml2, only tertiary alcohol 100 was obtained from the reaction. This finding appears to be at odds with the idea that Sml2-mediated Barbier reactions proceed through alkyl radicals that are then reduced to organosamarium intermediates the formation of an alkyl radical should result in at least some cyclisation (Scheme 5.62).114... 

Molander reported a variant of this sequential process that results in alkenyl transfer.20 For example, treatment of bromide 36 with SmI2-HMPA resulted in the formation of cyclopentanone 37. Subsequent intramolecular ketyl radical addition to the enol ether and collapse of the resultant organosamarium intermediate 38 gave cyclopentanol 39 in good overall yield (Scheme 6.15).20... 

A nice extension of this chemistry to sequential anionic/radical/anionic sequence was also provided [5, 9]. Normally after acyl addition and radical cyclization onto a C = C bond, the newly formed carbon radical is reduced to an organosamarium intermediate which is subsequently protonated. However, as depicted in Scheme 5, this organosamarium may be trapped in the presence of a ketone substrate, thus terminating this three-step process. In another demonstration of how such anions may be further exploited, substrates possessing vinyl ethers as the radical acceptor were found to under-... 

Samarium diiodide is a one electron reductant that is capable of reducing both alkyl halides and carbonyl compounds. The rate of the reduction depends on the nature of the substrate and the reaction conditions. The mechanism of the addition of alkyl halides to carbonyls was extensively studied. In case of the samarium Grignard processes, it was concluded that the reaction proceeds through an organosamarium intermediate. However, the mechanism of the samarium Barbier processes is not fully understood and there is no unambiguous evidence in favor of any of the possible pathways. 

Molander, G. A., McKie, J. A. A facile synthesis of bicyclo[m.n.1]alkan-1-ols. Evidence for organosamarium intermediates in the samarium(ll) iodide promoted intramolecular Barbier-type reaction. J. Org. Chem. 1991,56,4112-4120. 

Curran, D. P., Gu, X., Zhang, W., Dowd, P. On the mechanism of the intramolecular samarium Barbier reaction. Probes for formation of radical and organosamarium intermediates. Tetrahedron 1997, 53, 9023-9042. 

The Sm(OTf)3 reagent mediates the Grignard-type reaction in THF-HMPA. Alkylation, allylation and benzylation of ketones and aldehydes with alkyl, allyl or benzyl halides proceeded via stable organosamarium intermediates [69] (Scheme 29). 

Many of these studies incorporate reaction cascades, wherein the aryl radical initially created cyclizes, and the resulting radical is further reduced to afford an organosamarium intermediate. This nucleophile can be trapped by a number of electrophiles, further enhancing the value of the sequential method (Scheme 2) [2b, 3, 23, 25]. 

A-Benzyl PRT groups. An obvious solution to the conformation problem discussed above is the use of or/Z/u-halobenzyl PRT groups instead of the benzoyl derivatives [117]. Ito [121] and Undheim [122] have demonstrated the synthetic potential of this approach. Under classical tin hydride conditions, excellent yields for the alkylation of amines have been obtained as shown in Scheme 33 (Eq. 33.1) [122]. Starting from a chiral 1,3-oxazolidine, a novel approach for the functionalization of aminoalcohols has been reported [123]. When samarium iodide was used for such reactions, the formation of an organosamarium intermediate at the a-N position was achieved. This corresponds to the metallation of an amine under non-basic conditions. Subsequent reaction of the organosamarium species with electrophiles such as ketones [121, 124, 125[ (Eq. 33.2) and isocyanides [121, 124[ has been reported. 

Sml2 can reductively cleave several C-X bonds (X = -SO2R, -OP(0)(OR)2, -OAc, -OTs) by single electron transfer (Kagan and Namy, 1986). The resultant radicals formed are further reduced to organosamarium intermediates. These intermediates can couple easily to carbonyl substrates. 

One pathway involves the reaction of free Sml2 with the substrate prior to the reaction with the alcohol. The second pathway involves coordination of Sml2 to ROH resulting in the formation of a unique reducing species, the Sml2-ROH complex. This complex reduces the substrate by SET to form a radical-anion intermediate that on intra-complex protonation forms a radical intermediate. This radical is further reduced by another mole of Sml2-ROH complex to form an anionic, basic, organosamarium intermediate. 

In order to effect the overall ring contraction, two complete reaction sequences are necessary. These include a reductive dealkoxyhalogenation to give the ring-opened hex-5-enal followed by an intramolecular ketyl-olefin reductive coupling, to afford the ring contracted organosamarium intermediate. A complete mechanism for the two individual subsequent steps is depicted in Scheme 3.30. 

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