Cyclopentanones stereoselectivity

A conceptually surprising and new route to prostaglandins was found and evaluated by C.R. Johnson in 1988. It involves the simple idea to add alkenylcopper reagents stereo-selectively to a protected chiral 4,5-dihydroxy-2-cyclopenten-l-one and to complete the synthesis of the trisubstituted cyclopentanone by stereoselective allylation of the resulting enolate. 

It is assumed that the reaction is initiated by a radical bromine abstraction to give 10-13, which after carbon monoxide insertion undergoes a rapid 5 -exo cycliza-tion onto the hydrazone moiety. The two diastereomeric hydrazinyl cyclopentanones 10-16 and 10-17 are formed with good yields, though with low stereoselectivity. 

Cyclopentanones form from CO and double bonds in 1,5-positions (example 43, Table VII). This is a very selective and stereoselective process, the 1,4- or 1,6-positions being not significantly reactive under the same conditions. o-Hydroxyphenylacetylenes also form 5-membered lactones (example 45, Table VII). In some cases ring closure leads to a new nickel-carbon bond into which a new molecule of carbon monoxide can be inserted. This process of alternative insertion of carbon monoxide and other unsaturated ligands can be repeated several times so that complex alicyclic structures can be formed (example 49, Table VII). This... 

Intramolecular C-H insertion reactions of metal carbenoids have been widely used for the stereoselective construction of substituted lactams, lactones, cyclopentanones, benzofurans, and benzopyrans. Several excellent reviews have been published covering the general aspects of intramolecular C-H insertion by metal carbenoids.46,47 62 71 99-104 The following section highlights the major advances made since 1994, especially in asymmetric intramolecular C-H insertion. 

In 2000, Tanaka, Sakai, and Suemune expanded the scope of these desymmetrization reactions to more highly substituted substrates (Eq. 16) [19], The high selectivity of Rh(I)/BINAP for addition to one of the enantiotopic olefins leads to the generation of adjacent quaternary and tertiary stereocenters with excellent stereoselection. Unfortunately, for these more sterically demanding substrates, neutral Rh(l)/BINAP complexes furnish a poor yield of the desired cyclopentanone. 

Another synthetic route via the Beckmann rearrangement, which is promoted by organoaluminum reagent along with alkylation, involves a new stereoselective reduction of the imino group. The starting oxime sulfonate (228) was synthesized from cyclopentanone (226) in three steps Reaction of 226 with 1-undecene in the presence of silver oxide produced the a-undecylcyclopentanone (227) which on successive treatment with hydroxylamine and methanesulfonyl chlo-ride-triethylamine gave the mesylate (228). Treatment of the oxime mesylate... 

A variation of this route was applied to the preparation of a-methylenecyclo-pentane 179, an intermediate that was employed for the synthesis of prostaglandin PGF2o, (180) (Scheme 6.82). The acetonide-protected oxime-diol 175 [derived from propanal (174)] was treated with sodium hypochlorite without the addition of base. This led to the tricyclic adduct 176 with high stereoselectivity. One of the side chains was subsequently elaborated and the fully protected cyclopentano-isoxazo-line (177), when exposed to Raney Ni/boron trichloride, gave the 2-hydroxymethyl-cyclopentanone (178). This compound was dehydrated using mesyl chloride/ pyridine to furnish enone (179) (324). In another related synthesis of PGF2q, the p-side-chain (3-hydroxyoctenyl) was introduced prior to the cycloaddition (325). 

As you can see, reduction of 2-substituted cyclopentanones may not be very stereoselective. The substituent probably occupies a pseudo equatorial position and the two faces of the ketone are very similar. 

While high stereoselection has been achieved in radical reactions which occur in a-position146 to a center substituted with a chiral auxiliary, diastereofacial control in the addition of achiral radicals to the P carbon is, in general, difficult to achieve.147 In connection with this, Toru et al. reported extremely high P-stereoselection in the addition of tertiary, secondary, and even primary alkyl radicals to chiral a-sulfinyl cyclopentanones in 1993.148 The effectiveness of the diastereoselective addition of achiral radicals has been shown to depend on the size of the substituent at the sulfmyl sulfur. Bulky chiral arylsulfmyl groups show excellent diastereoselectivi-ties (> 98 < 2). 

In the case of (45)-117, attacks of an alkyl radical from both re and si faces are inhibited by the isopropyl group on the phenyl ring and by the 4-methyl group on the cyclopentanone ring. Addition of terf-butyl radical to a 1 1 diastereomeric mixture of (5/ )- and (55)-methyl-2-[(2,4,6-triisopropylphenyl)sulfmyl]-2-cy-clopentenone 118 gave stereoselectively the cis adduct 120 as a single isomer... 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

Cyclopentanone annelation (10, 139-140) - The iterative cyclopentenone anne-lation has been extended to a synthesis of hirsutic acid (7) starting with the ester I. This alkene surprisingly does not react with chloromethylketene, but does react stereoselectively with dichloroketene to give 2 as the major product One of the chlorine atoms was replaced by methyl by treatment with (CH,) CuLi (3 equiv. ) and then with CH,I and HMPT. Ring... 

Stereoselective addition to an a, -enone. 4-Methylcyclopentenone (1) reacts with this reagent to give the adduct 2 with 97% stereoselectivity. The adduct can be converted into 3,4-disubstituted cyclopentanones with high. stereochemical control at three centers. 

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