Enantioselective free radical reactions

Enantioselective free-radical reactions of oxazolon-2-ones 99ACR163. 

Synthetic applications 39 Enantioselective free radical reactions 40 Living free radical polymerization 40 Persistent-radical effect 41... 

By incorporating all of the issues outlined above, researchers have met the challenge of performing highly enantioselective free-radical reactions with great success. Sibi and Porter have recently summarized this progress in a comprehensive review... 

Enantioselective free-radical reactions of oxazolon-2-ones 99ACR163. Oxazol-5(4//)-ones as intermediates in the formation of macrolides, cyclodep-sipeptides, and cyclopeptides 99JHC1539. 

Sibi MP, Porter NA. Enantioselective free radical reactions. Accounts Chem Res. 1999 32 163-171. 

Alkylation reactions of ketones and esters using 1 have been reported with good enantioselection. Free radical-mediated alkylation of a y-lactam proceeded with good enantioselection (eq 6). Malonate alkylation provides the 1,3-diphenyl allylation product... 

It has been observed that addition of Lewis acids to the free radical allylation improved the chemical yield [101]. When substrates with a chiral auxiliary were subjected to free radical allylation in the presence of a Lewis acid, the desired allylated products were obtained with high stereoselectivity [94 d]. In these reactions the Lewis acid plays a pivotal role in fixing the conformation of radical intermediates. Recently Sibi indicated that an elevated reaction temperature accelerated inversion of the stereochemistry of the radical-centered carbon giving rise to greater diastereoselectivity (Scheme 12.39) [102]. When enantiomerically pure Lewis acids were employed as chiral auxiliaries enantioselective free radical allylation of sulfones [103] and oxazolidinones [104] were realized. In the latter reaction two contiguous chiral centers were generated successfully in a single operation with excellent stereoselectivity via tandem C-C bond formation both enantiomers can be se-... 

Enantioselective free-radical additions to N-acyl hydrazones mediated by chiral Cu(II) Lewis acids have been demonstrated by Friestad and coworkers [16]. Addition of a variety of alkyl radicals to valerolactam-derived N-acyl hydrazone (54) catalyzed by one equivalent of dehydrated [Cu((S,S)-tBu-box)(H20)2(OTf)](OTf) (55) proceeds with moderate to good yield and high enantioselectivity (Scheme 17.11). Catalytic loadings could be decreased without loss of reactivity, but significant erosion of enantioselectivity was observed. Nevertheless, this methodology represents a viable alternative to classical Strecker and Mannich reactions for asymmetric amine synthesis. 

Wu JH, Radinov R, Porter NA. Enantioselective free radical carbon-carbon bond forming reactions chiral Lewis acid promoted acyclic additions. J. Am. Chem. Soc. 1995 117 (44) 11029-11030. 

Pattenden, G. and Robertson, G.M. (1986) Free radical reactions in synthesis. Total synthesis of isoamijiol. Tetrahedron Lett., 27,399-402. Mehta, G. and Krishnamurthy, N. (1987) An enantioselective approach to dolastane diterpenes. Total synthesis of marine natural products (+)-isoamijiol and (+)-dolasta-l(15),7,9-trien-14-ol. Tetrahedron Lett., 28, 5945-5948. 

Scheme 3.33. Lewis acid-promoted free radical domino cyclization reaction and enantioselective approach.

In a related approach, Padovani et al. prepared copolymers of styrene and a styrene derivative containing two pendant ester bonds using free-radical polymerization (Scheme 15) [108], Transesterification reactions were conducted with Novozym 435 as the catalyst and benzyl alcohol or (rac)-l-phenylethanol as the nucleophile. Interestingly, the ester bond closest to the polymer backbone (position A in Scheme 15) remained unaffected, whereas ester bond B reacted in up to 98% to the corresponding benzyl ester. The transesterification was not only highly chemoselective but also enantioselective. Conversion of (rac)-l-phenylethanol in the transesterification reaction amounted to a maximum conversion of 47.9% of the (/ )-alcohol, and only at the ester position B. 

TABLE 9.26 ENANTIOSELECTIVE ALIX)L REACTION MEDIATED BY BU-BOX, 566 TABLE 9.27 Cu(II)-BU-BOX-MEDIATED MUKAIYAMA ALDOL REACTIONS, 566 TABLE 9.28 PHE-BOX-MEDIATED FREE RADICAL CONJUGATE ADDITION, 567... 

Scheme 9.29. Enantioselective three-component free-radical addition—allyl-transfer reaction.

Scheme 9.30. Enantioselective tandem intermolecular free-radical addition-trapping reaction of enoates.

Free-radical reductions mediated by chiral stannanes, germanes, and silanes may occur with enantioselectivities in excess of 99% ee. Owing to the involvement of radical intermediates and the mild reaction conditions, this process is applicable for a large variety of simple or even complex target molecules that are incompatible to asymmetric reductions that require ionic reaction conditions. 

Lastly, Gualtieri reported the use of binaphthyl-substituted germanes (8, 9) in enan-tioselective radical chemistry26. For example, an enantioselectivity of 59% was reported for the reaction of 126 with 8 at —60° (equation 127). To the best of our knowledge, this represents the first account of the use of a chiral germanium hydride in free-radical reduction chemistry. 

Peroxidases are ubiquitous, and many are b-type heme proteins. Several good reviews summarize years of peroxidase research and describe peroxidase applications [57 -61]. Some of the reactions catalyzed by peroxidases are listed in Tab. 10.2 and include oxidation of aromatic and heteroatom compounds, epoxidation, enantioselective reduction of racemic hydroperoxides, free radical oligomerizations and polymerizations of electron-rich aromatics, and the oxidative degradation of lignin [58, 60],... 

In their enantioselective total synthesis of (+)-triptocallol (3-79), a naturally occurring terpenoid, Yang and coworkers made use of a concise Mn(OAc)rmediated and chiral auxiliary-assisted oxidative free-radical cyclization [39]. Reaction of 3-77, bearing a (R)-pulegone-based chiral auxiliary, with Mn(OAc)3 and Yb(OTf)3 yielded tricyclic 3-78 in a twofold ring closure in 60% yield and a diastereomeric ratio of 9.2 1 (Scheme 3.20). A further two steps led to (-i-)-triptocallol (3-79). For the interpretation of the stereochemical outcome, the authors proposed the hypothetical transition state TS-3-80, in which chelation of the (3-keto ester moiety with Yb(OTf)3 locks the two carbonyl groups in a syn orientation. The attack of the Mn -oxidation-generated radical onto the proximate double bond is then restricted to the more accessible (si)-face, as the (re)-face is effectively shielded by the 8-naphthyl moiety. 

Data related to the enantioselectivity of organotin hydrides containing chiral PhN ligand in free radical reductions have been published . Reaction of the tin hydrides 233a and 233c with methanol was also reported to proceed with abstraction of H2 and formation of the methoxy derivatives Me2PhNSnOMe and MePhPhNSnOMe, respectively . 

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