Acyl radicals cyclizations

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. 

D. Batty and D. Crich, Acyl radical cyclizations in synthesis. Part 4. Tandem processes The l-endo/5-exo serial cyclizations approach to enantiomerically pure bicyclo[5.3.0]decan-2-ones, J. Chem. Soc. Perkin Trans 7 3193 (1992). 

The kinetics of 5-exo and 6-endo acyl radical cyclizations have been investigated under a variety of reaction conditions.28 The presence of the 6-endo product was found to arise either by a direct cyclization (2.0 x 104 s 1) or by a ring expansion (4.2 x 103 s ) from the 5-exo radical product (1.6 x 10s s 1). Consequently, cyclization in the presence of high concentrations of fast H-donors (e.g. B113S11H) furnished 5-exo products whereas reactions under high dilution conditions or with poor H-donors gave rise to 6-endo products. 

Radical carbonylation can also be conducted in a zinc-induced reduction system. A similar three-component transformation reaction to that illustrated in the second equation of Scheme 6.14 can be attained using zinc and protic solvents (Scheme 6.38) [59]. The observed stereochemical outcome is identical to that for the tin hydride-mediated reaction, providing a additional evidence for free-radical generation, radical carbonylation, and acyl radical cyclization taking place simultaneously, even in the zinc-induced system. In this system, however, the final step is reduction to form a carbanion and protonation. 

Acyl radical cyclization to cyclohexanones.n Acyl radical cyclization to five-membered rings is well known, but this reaction is also useful for synthesis of substituted cyclohexanones as shown by a recent synthesis of the a-methylenecyclo-hexanone 3. Thus treatment of the selenol ester 1 with Bu3SnH and AIBN in C6H6 at 80° provides a 1 1 mixture of cyclohexanones 2 in 91 % yield. Oxidation of 2 with... 

An intramolecular acyl radical cyclization of acyl selenide 1024 uses a (Z)-vinylogous sulfonate to control rotamer population, affording ry -2,6-disubstituted tetrahydropyran-4-one 1025, a key intermediate during synthesis of the tetrahydropyran unit of mucocin (Equation 399) <1997TL5249>. This methodology is also applicable to the synthesis of polycyclic ethers <1996JOC4880>. 

The ipso cyclization of an ort/io-(phenylsulfonyloxy)benzoyl radical generated by hydrogen abstraction from the corresponding aldehyde <98J(P1)67>, followed by rearomatization of the spirodienyl radical intermediate by elimination of sulfur dioxide constitutes an isolated example of acyl radical cyclization upon a benzene ring, developed by Motherwell for the synthesis of 2-hydroxyaryl aryl ketones <00TL9667>. 

A variety of indirect and direct methods are now available for ketone synthesis by radical reactions. Due to space limitations, this section will focus on selected topics, and only a few examples are shown for cases of frequently investigated approaches by acyl radical cyclizations. A recent review article on acyl radical chemistry provides a comprehensive survey of acyl radical cyclizations [la]. 

The synthesis of cyclic ketones via acyl radical cyclizations represent by far the most frequently investigated approaches in the past two decades and such cyclizations are well discussed in a recent review [la]. Two recent examples of the application to natural product synthesis are given here. A seven-membered ring, a key compound in the overall synthesis of (-i-)-confertin, was prepared by Shishido and co-workers, utilizing 1-endo-trig acyl radical cyclization which occurred in a highly efficient manner (Scheme 4-39) [66]. 

The alkyl radical cyclization onto an N-C double bond proceeds in both nitrogen-philic and carbon-philic modes (Scheme 4-50) [86]. On the other hand, vinyl radical cyclizations favor the carbon atom of the N-C double bond (Scheme 4-50) [87]. An important issue, in this regard, is the preference for acyl radical cyclization. 

As can be seen from the examples in Scheme 4-51, acyl radical cyclizations proceed in complete nitrogen-philic mode to give good yields of lactams. The... 

The acyl radical cyclizations have been cleverly applied to the synthesis of complex natural and unnatural products (Eq. (13.4)). In one example, tandem radical cyclization of 14 provides access to the steroidal skeleton. The reaction proceeds through a 6-endo-trig cyclization to form the A/B ring and a macrocycliza-tion/transannulation to establish the C/D ring [12]. More recently, a cascade cyclization initiated by an acyl radical has allowed for the establishment of fourteen chiral centers in a single step [13]. Once again the formation of the polycyclic compound 17 involves sequential 6-endo-trig reactions. 

Unlike the 4-alkenyl/CO system, the following two cyclization systems, based on C-N double bonds, are completely selective and favor a five-membered ring (Scheme 8). Fallis and Brinza who used a diphenylhydrazone derivative as an acyl radical trap [32] reported the first example in this series. As shown in the first two examples in Table 3, radical carbonylation gave 2-hydrazinocyclopentanones in good yields. Ryu, Komatsu and coworkers reported acyl radical cyclization onto N C double bond, which proceeds exclusively in a 5-exo manner to give pyrrolidi-nones in good yield (runs 3-5) [33]. For an aromatic substrate, it is necessary to use a ketimine rather than an aldimine, since aromatic radical abstracts an imine hy-... 

A further variant on the radical carbonylation/acyl radical cyclization theme involves the silylcarbonylation of 1,5-hexadienes [48]. Here, the sequence is initiated by the addition of a tris(trimethylsilyl)silyl radical to the least substituted terminus of the diene. Carbonylation and acyl radical cyclization then ensues in the normal way. It should be noted that this type of carbonylation cannot be achieved with tin hydride, since the carbonylation rate is not sufficient to capture y -tin-attached alkyl radical, which quickly reverts to tin radical and the 1,5-diene. 

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). 

Acyl radical cyclization of ) -alkoxyacrylates provides five-, six-, and seven-mem bered oxacyclic ketones with high stereoselectivity [45], In a key step in the synthesis of (—)-kumausallene (55) by Evans, the tetrahydrofuran-3-one 69 was obtained stereoselectively from the acyl selenide 68 [46] (Scheme 24). 

Irradiation of 99 in benzene at reflux gave 100 in high yields as the products of acyl radical cyclization with ArTe group transfer, along with an elimination product 101 (Eq. 68). 

The importance of radical processes in the chemistry of pyrroles and indoles remain vital in expanding the repertoire of reaction processes available to these heterocycles. For example, Allin and Mclnally have devised a novel approach lo (l,2-a -fused pyrroles 76 via intramolecular acyl radical cyclization of Al-(oi-acyl)-radicals 75 generated from acyl-selenide precursors 74 <01TL7887>. This reaction can be conducted even in the absence of CO and has also been shown feasible on electron rich pyrrole rings. 

Batty D, Crich D, Font SM (1989) Synthesis of la, 25-dihydrovitamin D3 ring model by an acyl radical cyclization. J Chem Soc Chem Coinmun 1366-1368... 

The first total synthesis of the antibiotic acanthodoral (1) 118 has been achieved from 3-methyl-2-cyclohexen-l-one in 19 steps in 2.1% overall yield. This synthesis involves the use of a Pd-ene reaction in the presence of CO to form the endocyclic alkene 116, a nonreductive acyl radical cyclization and ring contraction by the Wolff rearrangement of ll ." ... 

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. 

SCHEME 25.40. Thiol-catalyzed acyl radical cyclizations of alkenals. 

Another example using the same methodology is found in the first enantiocontrolled total synthesis of meroterpe-noid brevione C, in which a regioselective 1-endo-trig mode of acyl radical cyclization (91 —> 92) is a key reaction step (Scheme 25.42). Breviones A—E were first isolated from Penicillium brevicompactum and inhibit etiolated wheat coleoptile growth. 

K. Thiol-catalyzed acyl radical cyclization of alkenals. J. Org. Chem. 2005 70(2) 681 83. 

Zhang L, Koreeda M. Total synthesis of (-l-)-acanthodoral by the use of a Pd-catalyzed metal-ene reaction and a nonreduc-tive 5-ex o-acyl radical cyclization. Org. Lett. 2004 6 (4) 537-540. 

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