Diastereoselective acyl radicals

Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two examples are shown in Reaction (80), where treatment of 100 with E3B, air, and (TMS)3SiH provided the tricycle 101 in excellent yields as a single diastereomer. Interestingly, the bulky silyl ether moiety is not required to achieve stereoselectivity in this process. 

The diastereoselectivity in 5-exo cyclization of a range of chiral acyl radical equivalents derived from 1,3-dioxolanes and dioxanes has been investigated. Results indicate that selectivity was poor for radicals which cyclised via a twist-boat conformation but high when l,3-dioan-2-yl radicals containing an imposed chair-like conformation were used.173 The 5-exo cyclizations of a-phenylsulfenyl radicals,... 

Free-radical cyclization of phenyl selenide 15 to indolizidinone 16 represented a key step in the total synthesis of (—)-slaframine (equation 52). The two pairs of diastereomers were first separated and then hydrolyzed to the corresponding alcohols in 76% overall yield77. (TMS)3SiH-mediated acyl radical reactions from phenylseleno esters 17 have recently been utilized for the stereoselective synthesis of cyclic ethers78. In fact, the experimental conditions reported in equation 53 are particularly good for both improving cis diastereoselectivity and suppressing decarbonylation. 

Among reports related to radicals, ab initio calculations have been used to model intramolecular additions of acyl radicals to imines.83 Imines and oxazolines bearing a pendant acyl radical at carbon have been cyclized to give 2-piperidones through a selective 6-emfo-cyclization at nitrogen.84 The acyl radical is generated via CO (g) insertion into a suitable precursor. A diastereoselective example is also reported. 

TMS)3SiH-mediated acyl radical reactions of phenylseleno esters have been utilized for the diastereoselective synthesis of cyclic ethers by Evans s group. Equation 44 shows that the acyl selenide 83 affords the cA-disubstituted tetrahydrofuran 84 in good yield on exposure at room temperature to (TMS SiH and the Et3 B/02 combination as the initiator via a 5-exo-trig cyclization97 98. 

DIB, BTI and perfluoro-DIB were suitable precursors the last was most effective under photochemical conditions, whereas DIB and BTI were used either thermally or photochemically for DIB, best results were obtained with added trifluoroacetic acid, photochemically. Not only alkyl but other more complex free radicals could also be introduced, notably acyl radicals. Products derived from acids bearing sugar moieties were obtained in low to moderate yield. In the case of acetonides complete retention of the initial configuration was observed. This high diastereoselectivity... 

Sibi and Ji reported that acyl radicals, generated from acyl bromides, can participate in Lewis acid-mediated diastereoselective radical addition reactions (Scheme 4-26) [49]. Using triethylborane/02 as a radical initiator, the reaction was conducted at -78 °C. 

Evans and Roseman [40] explored the 1-exo trig acyl radical cyclization for the generation of cyclic ethers 161 and 162 starting from the selenoesters 160. The efficiency and the diastereoselectivity of these reactions were found to increase when tristrimethylsilylsilane was used instead of BusSnH. The generality of this reaction was further established with the corresponding vinylsulfones (instead of acrylates) and also with the corresponding vinyl bromides (instead of selenoesters). 

Radical reactions in synthetic organometallic chemistry are rare but gain increasing importance. A recent example demonstrated that molybdenum difluoroboroxycarbenes may serve as radical precursors and allow to generate acyl radicals under mild reaction conditions. [91] Coupling of molybdenum difluoro-boroxycarbene 84 to vinylketone 85 and aldehyde 86 leads diastereoselectively to vr -P-hydroxyketone 87 (Scheme 38). Using the chiral aldehyde 88 a diastereofacial selectivity of more than 99% d.e. was observed for the formation of 89 (Scheme 39). 

Another example of acyl radical cyclization is given in eq 29. The careful choice of the configuration of the double bond combined with conformational features of the preexisting ring in the starting material can improve the poor diastereoselectivity of 6-exo-trig cycUzations. 

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

Bach and coworkers investigated the photocycloaddition of 7V-acyl, 7V-alkyl enamines 125 with benzaldehyde [125]. The 3-amido oxetanes 126 were formed with excellent regioselectivity (analogous to reactions with enolethers—vide supra) and good diastereoselectivity (Sch. 41). Enamines, not deactivated by acylation at the nitrogen atom are poor substrates for Paterno-Buchi reactions due to preferred electron transfer reactivity (formation of the corresponding enamine radical cation and subsequent reactions). 

The photo Diels-Alder reaction of a-acetylnaphthalene 82 with the chiral oc-enaminonitril 83 yielded the cycloadduct 84 with excellent diastereoselec-tivity (Sch. 16) [57]. The intermediary formed biradical Y is particular stable due to delocalization of the radical on the aromatic moiety and to a captodative effect on the enamine part. The chiral induction occurred in two steps [58]. In the first step, a stereogenic center is created in the a-position of the acyl group. In the second step of the diastereoselection, one of the two diasteromeric intermediates undergoes preferentially cyclization to yield the final product 84, while the other one is more readily decomposed to form the starting material. For a more detailed discussion of the mechanism see Ref. [59]. 

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