SOMO Activation

The electron loss may be performed photochemically/ but in tbe original paper the oxidant ceric ammonium nitrate was employed. The radical cation has been observed by mass spectrometiy with DFT calculations supporting the electronie distribution shown (88 and 88a) arising from a mixture of two resonance structures but which may be best conceptualized as an all l radical conjugated to an iminium ion (88a). It may also be possible for the enamine to react as is with an incoming radical cation i.e., the same reaction pathway but where the enamine is the somophile).  

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An enantioselective radical substitition (termed SOMO activation ) involving pyrroles has been reported <07SCI582>. For example, treatment of pyrrole 58 with octanal 59 and chiral amine 60 in the presence of CAN gave chiral 2-alkylated pyrrole 61. The mechanism included the formation of an enamine radical. A radical alkylation of 3-substituted pyrroles with xanthates produced 2,3-disubstituted pyrroles regioselectively <07TL4515>. 

Enantioseleetive organo-SOMO (singly occupied moleeular orbital) eatalysis is a unique and versatile organocatalytic activation mode that features the transient generation of a 3n-radical cation species, whieh ean partieipate in asymmetrie bond construction reactions with a variety of n-rieh nueleophiles or electron-neutral SOMO-philes. Since its introduction in 2007, the enantioselective organo-SOMO activation mode has been utilized to overeome... 

An intramolecular application of this type of catalysis was included in his first publication on this process, whereby the SOMO activated enamine cyclized onto an unactivated alkene using catalyst 103 (Scheme 1.26). 

Qrgano-SOMO activation as a new concept was presented by D. W. C. MacMillan in the following conferences in 2006 March 31, 2006, Amen (Thousand Oaks) April 27, 2006 (Manchester) June 13, 2006, lUPAC (Merida) July 25, 2006, lUPAC (Kyoto) September 11, 2006, ACS (San Rrancisco). 

Ror more crucial features involved in the organo-SOMO activation process and experimental evidence of the radical cation itermediate formed in organo-SOMO catalysis, see (a) J. J. Devery, III, J. C. Conrad, D. W. C. MacMillan, R. A. Rlowers, II, Angew. Chem. Int. Ed. 2010,49, 6106-6110 (b) R. Beel, S. Kobialka, M. L. Schmidt, M. Rngeser, Chem. Commun. 2011, 47, 3293-3295. 

Different from the hydroxyalkylation reactions using carbonyl compounds as substrates, Nicolaou s and Macmillan s groups developed independently the intramolecular asymmetric Friedel-Crafts-type a-arylation of aldehydes with electron-enriched arenes based on the SOMO activation strategy. Using chiral imidazolidione as catalyst, a series of cyclic aldehydes were obtained in good yields and enantioselectivities with cerium ammonium nitrate (CAN) as single electron transfer oxidant [46]. 

MacMillan and co-workers [57] have applied the SOMO activation developed in their lab for the enantioselective synthesis of chiral cyclohexanes. Enolizable aldehydes bearing a nucleophile such a tiophene (87) react with an alkene (88) catalyzed by imidazolidinone catalyst XXVII. The final cyclohexanes 89 were afforded in good yields and excellent enantioselectivities (Scheme 10.25). 

In 2009, Nicolaou and co-workers reported an organocatalytic total synthesis of demethyl calamenene (168), a potent cytotoxic agent, which is a beautiful application of SOMO-activated catalysis (Scheme 17.29) [68]. The key step involved an asymmetric intramolecular Friedel-Crafts reaction of aldehyde 166 to achieve the bicyclic aldehyde 167 using imidazolidinone 122 as a SOMO-activated catalyst (56% yield, 90% ee). 

LUMO activation HOMO activation SOMO activation... 

Scheme 80 Single-electron oxidation of a transiently formed enamine for the formation of a three-7t-electron radical cation (SOMO activation)...

Scheme 81 SOMO-activation for the stereoselective a-allylation of aldehydes...

Scheme 82 SOMO-activated Friedel-Crafts-type a-arylation in the synthesis of demethyl calamenene (359)...

MacMillan et al. developed a SOMO-activation protocol for the stereoselective a-chlorination of aldehydes and for the formation of terminal epoxides starting from aldehydes (317). This method was employed recently by the Christmann... 

Scheme 83 SOMO-activated epoxide formation in the synthesis of the C-5-C-14 fragment (366)...

Table 4 Organocatalysts employed in SOMO-activated natural product syntheses ...

Beeson TD, Mastracchio A, Hong JB, Ashton K, MacMillan DWC (2(X)7) Enantioselective Organocatalysis Using SOMO Activation. Science 316 582... 

In 2007, the groups of MacMillan and Sibi almost simultaneously introduced a new mode of organocatalytic activation, termed SOMO (singly occupied molecular orbital) catalysis, which was founded upon the transient production of a 37r-electron radical cation species that could function as a generic platform of induction and reactivity. This new mode of organocatalytic activation, was founded upon the mechanistic hypothesis that one-electron oxidation of a transient enamine intermediate, derived from the aldehyde and the chiral amine catalyst, rendered a 37i -electron SOMO-activated species, which could readily participate in asymmetric bond construction. 

SOMO Activation Within the field of aminocatalysis, asymmetric organo-SOMO (singly occupied molecular orbital) catalysis has recently emerged as a powerful technique for the preparation of optically active compounds. In this context, MacMillan and coworkers described in 2008 the formation of y-oxyaldehydes from aldehydes and styrenes by organo-SOMO catalysis [25]. The condensation between the amine catalyst 46 and an aldehyde gave rise to an enamine intermediate, which was then oxidized by ceric ammonium nitrate (CAN) to give a radical cation. Reaction of this radical cation with a nonactivated olefin, namely styrene, led to the... 

Scheme 12.22 Organocatalytic carbo-oxidation by SOMO activation.

The mechanism proposed by them is based on the reaction of a SOMOphilic enamine 3 with an electron-deficient radical, which is the converse mechanism to their previously reported SOMO activation studies [33]. It is noteworthy that the present catalytic system can allow us an easy access to various optically active a-alkylated aldehydes 4 in high yields with excellent enantioselectivity. 

So far, only catalytic heterocoupling of silicon enolates has been achieved by a singly occupied molecular orbital ( SOMO ) activation, as disclosed by MacMillan and coworkers [267]. The method is illustrated in Scheme 5.136 for a series of silyl enol ethers 556 that are reacted with octanal. Ceric(IV) ammonium nitrate (2 equiv.) serves as the oxidant and imidazolidinone 557 (20 mol%) as the... 

The use of chiral primary or secondary amines as covalent catalysts allows for the activation of carbonyl componnds for different reactions. Either the initially formed imininm species are the reactive intermediate (LUMO lowering), which is mainly the case when using a,p-unsatnrated carbonyl compounds, or the derived enamine can be ntilized for enolate-type reactions (HOMO activation), or, after a single electron oxidation of the enamine, a singly occnpied molecular orbital (SOMO) activation is possible (Scheme 6.18) [14, 31, 32], In addition, by combining these complementary activation modes, it has been possible to carry out organocascade reactions with excellent control of... 

SCHEME 6.24 Selected reports of asymmetric organocatalysis using SOMO activation. 

MacMillan s group reported the first catalytic enantioselective cyclization strategy for accessing steroidal and terpe-noidal frameworks using organocatalysis [53]. This strategy represents an ambient temperature protocol, which is unprecedented in SOMO activation catalysis with respect to carbon—carbon bond formation (Schane 9.40). 

Enamine Radical Cation The Concept of SOMO Activation... 

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