Diastereoselectivity cyclopentanones

The prochiral meso form of 2-cyclopenlen-1,4-diol (101) reacts with the (Z)-alkenyl iodide 102 to give the 3-substituted cyclopentanone 103 with nearly complete diastereoselectivity (98 2)[92], The reaction is used for the synthesis of prostaglandin. The alkenyl iodide 102 must be in the Z form in order to obtain the high diastereoselectivity. The selectivity is low when the corresponding (Z)-alkenyl iodide is used[93]. 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

Similar to cyclohexanones, substituted cyclopentanones also adopt a conformation with the substituents in a sterically favorable position. In the case of 2-substituted cyclopentanones 1 the substituent occupies a pseudoequatorial position and the diastereoselectivity of nucleophilic addition reactions to 1 is determined by the relative importance of the interactions leading to predominant fra s(equatorial) or cw(axial) attack of the nucleophile. When the nucleophile approaches from the cis side, steric interaction with the substituent at C-2 is encountered. On the other hand, according to Felkin, significant torsional strain between the pseudoaxial C-2—H bond and the incipient bond occurs if the nucleophile approaches the carbonyl group from the trans side. 

Generally, in contrast to 2-substituted cyclopentanones, the diastereoselectivity of addition reactions to 3-substituted cyclopentanones is nearly independent of the nucleophile and the substituent in the 3-position. Thus, addition of various Grignard reagents, including ethynyl reagents, to 3-methyl- and 3-ferf-butylcyclopentanone leads to almost the same ratio of diastereomers (Table 3)3,4 6, 27,2s... 

Optically active y-alkoxycyclopentenones have become popular in the diastereoselective synthesis of hms-3,4-disubstituted cyclopentanones. The Michael addition to these cyclic enones catalyzed by sodium ethoxide in ethanol277 or by potassium tm-butoxide278 279 proceeds under kinetic control trans with respect to the y-substituent. 

The lithium enolates of cyclopentanone and cyclohexanone undergo addition-elimination to the 2,2-dimethylpropanoic acid ester of ( )-2-nitro-2-hepten-l-ol to give 2-(l-butyl-2-nitro-2-propenyl)cycloalkanones with modest diastereoselection. An analogous reaction of the enolate ion of cyclohexanone with the 2,2-dimethylpropanoic acid ester of (Z)-2-nitro-3-phenyl-2-propenol to give 2-(2-nitro-l-phenyl-2-propenyl)cyclohexanones was also reported. The relative configuration of these products was not however determined6. 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

Diastereoselective ring-opening of bicyclic compound led to simple isolation of the desired cyclopentanone. 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

For example, an oxaspirohexane <52, readily available by condensing cyclobutanone 61 with dimethylsulfonium methylide, rapidly rearranges (isomerizes) to the cyclopentanone 63 upon exposure to a catalytic amount of lithium bromide55). The high diastereoselectivity of the initial cyclobutanone formation translates into a high diastereoselectivity for cyclopentanone annulation as this example of Eq. 74 demonstrates. 

The influence of stereocenters in the backbone has been investigated [74]. A racemic substrate 101 can be subjected to standard Stetter reaction conditions leading to disubstituted cyclopentanones 102. The reaction provides both cis and trans diastereomers in high enantiomeric excess but with very poor diastereoselectivity (Table 10). Adding steric bulk did not significantly change the outcome of the reaction (entry 2). The same trend was observed with substitution at the... 

High diastereoselectivity is usually observed in the alkylation of enolates of 3-monosubstituted cyclopentanones. Representative examples are the alkylations of the enolates 9 and 11. 

Steric control elements are also important for the diastereoselectivity in alkylations of mono-cyclic cyclohexanone enolates. However, electronic control becomes more evident in these systems compared to monocyclic cyclopentanone enolates The flexibility of the six-membered ring system, and the large number of possible ring conformations, makes predictions of the diastereoselectivity difficult. In general, one may conclude that the diastereoselectivity in alkylations of enolates derived from monocyclic cyclohexanones is not as high as in alkylations of cyclopentanone enolates. The syntheses of compounds 21-27 demonstrate the effect of substitution in each position of the six-membered ring49,61 -7°. 

The following application of the synthetic equivalent 110 was carried out. Complex 107 was utilized for the total syntheses of trichothecene (122), trichodiene and trichodermol, applying the reaction of cationic complex 107 with a /f-kcto ester or tin enolate [28]. The tin enolate of cyclopentanone 119 reacted with the complex 107 with high diastereoselectivity to give the diene complex 120 in high yield. After... 

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). 

Reaction of a-ketoenamines with a series of cyclic and acyclic nitroolefins gave aminocyclopentene derivatives with high diastereoselectivity, as products of kinetic control instead of the expected 1,2-oxazine N-oxides (see Section III.D.2)45,46. For example, ketoenamine 62 when reacted with cyclic nitroalkene 61 afforded 65 as a single diastereoisomer46, first through the dipolar intermediate 63 and later through the betaine-type intermediate 64. Hydrolysis of this enamine furnished the cyclopentanone derivative 66, also as a single diastereoisomer (equation 11). 

Chiral cyclopentanones. The rcgiosclectivc cyclization of a diazo-(i-keto esters to cyclopentanones (11, 4.59) is also cnantiosclcctivc with substrates derived from chiral alcohols. Preliminary studies show that steric factors affect the diastereoselectivity the highest diastereoselectivity is obtained with esters of the alcohol 1. which is available from camphor, and in which both the bornane and the naphthalene rings can exert steric effects on the diastereoselectivity. 

A related reductive cyclisation has been developed by Schafer et al. in which the cathodic cyclisation of A-(oxoalkyl)pyridinium salts led to indolizidine and quinolizidine derivatives <95AG(E)2007, 03EJO2919>. Electrolyses of the pyridinium salts were carried out in a divided beaker-t5q)e cell at a mercury pool cathode under constant current, using 1 M aqueous sulfuric acid as the electrolyte. In this way, cyclisation of cyclopentanone 129 to the isomeric quinolizidines 130 and 131 was achieved in high yield and with excellent diastereoselectivity (Scheme 38). The stereochemical course of the reaction with cyclohexanone 133 was not as well defined, with three of the four possible diastereoisomers being given in a ratio of 10 21 26 (for 134,135 and 136 respectively). 

This reaction is a diastereoselective de Mayo reaction. Its stereochemistry is controlled by the configuration of substrate 7. The P-face of cyclopentanone 7 is effectively shielded by the dimethylphenylsilyl moiety. Therefore, the triplet state of 7 attacks the cyclobutene 6 via the a-face, forming the fourth annulated cyclobutane ring of the ladderane core. Typically for cyclopentanone systems, the annulation proceeds syn-selectively and the product is obtained as a 7 1 mixture of diastereomers 8 and 20, which is separated by preparative TLC yielding pure 8. 

---