Cyclopropanone equivalents

Cyclopropanone equivalent. Unlike cyclopropanone, which is difficult to isolate, 1 is stable, easily obtained from 3-chloropropionic acid (Aldrich), and is a useful substitute for the ketone. Thus reaction of the silyl ether 2 with RMgBr provides adducts in which the OH group of 1 is replaced by R. The carbinol 1 is also a useful precursor to pyrroles, pyrrolines, and pyrrolizidines (equation I). 

In the preceding sections we have noted the biosynthesis and/or catabolism of cyclopropyl moieties by carbocation, by carbanion and by radical processes in specific contexts. At least two naturally occurring cyclopropyl metabolites and several synthetic ones have been observed to induce inactivation of specific target enzymes. The inactivation is presumptively related to chemical reactivity of loci at or adjacent to the cyclopropane equivalent. In the case of hypoglycine A (7) the methylene cyclopropane group is the problematic moiety, while in coprine (29) the hemiaminal is a latent cyclopropanone equivalent we shall analyze the proposed enzyme killing routes for each. Then we will turn to cyclopropyl... 

The third case for likely enzymatic generation of an a-cyclopropyl radical or a cyclopropanone equivalent leading to target enzyme destruction is in the oxidation of cyclopropanol by certain bacterial alcohol dehydrogenases which have a novel type of redox coenzyme stoichiometrically bound and required for catalysis. The coenzyme has been termed pyrroloquinoline quinone (PQQ) (174) or methoxatin and the trivial name... 

In this chapter, we will review methods for preparing cyclopropanones, their physical and spectroscopic properties, and the nature of their reactions with nucleophiles, electrophiles and in cycloaddition processes. Another part of the chapter will deal with cyclopropanone equivalents, 1,1-disubstituted systems which under certain conditions may provide carbonyl-related derivatives of the parent ketones. We will also discuss the role of cyclopropanones in biological phenomena and cite specific examples of the use of cyclopropanone intermediates as key units in the synthesis of natural products. 

Among the systems which have played the role of cyclopropanone equivalents have been cyclopropane derivatives containing both a secondary amino group and a hydroxyl substituent on the same carbon atom. These 1,1-disubstituted carbinol amines appear to be in equilibrium with the corresponding iminium salts and thereby act as reactive electrophilic sites for attack by a variety of nucleophiles. 

The most recent source of these iminium ion precursors is the amide derived from 3-chloropropionyl chloride. Using the procedure reported by Ruhlmann for the preparation of 1-methoxy-l-trimethylsilyloxycyclopropane, Wasserman and Dion " converted the piperidide (58) to the 1-piperidino-l-trimethylsilyloxycyclopropane (59) by treatment with sodium metal in dry ether at 0°C. This reaction, which takes place smoothly and in high yield, serves as a short, inexpensive way to form the stable cyclopropanone equivalent. Further reaction of the silyl derivative (59) with tetrabutylam-monium fluoride in THF yields the corresponding carbinol amine (60). 

In the path b process, the addition of a heterosubstituted carbene to an olefin is governed by the reactivity of each component. Bis-thiomethyl- and bis-thiobenzylcarbenes add only to electron-rich olefins, whereas dimethoxycarbene adds primarily to electron-poor systems. Ambiphilic carbenes such as phenoxychlorocarbene and methoxychlorocarbene add to a wide range of double bonds. Table 16 lists the cyclopropanone equivalents which have been prepared in this manner. 

Displacement reactions on 1,1-disubstituted cyclopropanes have been used to prepare other cyclopropanone equivalents. The most readily available 1,1-disubstituted cyclopropanes are geminal dihalo derivatives prepared by the addition of dihalocarbenes to olefins. Unfortunately, these materials do not undergo direct displacement easily and therefore do not provide a general route to other cyclopropanone derivatives. Solvolysis usually leads to ring-opened products, although dibromocyclopropanes with a barrier to... 

Gem-dibromocyclopropanes can be converted into synthetically useful cyclopropanone equivalents by a process consisting of lithium-halogen exchange followed by reaction of lithiocyclopropane (113) with dimethyl disulfide (Scheme 43) . The resulting bromo-methylthio derivative (114) undergoes a variety of substitution reactions. Methanolysis gives S,0-dimethylketal (115) which can be converted into l,l bis(methyl-thio)cyclopropane (116) with methyl mercaptan in trifluoroacetic acid. Reaction of 114 with other nucleophiles provides the derivatives shown in Scheme 44 . The sulfur-... 

As discussed in an earlier section, displacement reactions on appropriately 1,1-disubstituted cyclopropanes may give rise to new cyclopropanone equivalents (see Schemes 43, 44). These reactions occur by S 1 processes involving carbenium ions of structure 136. In addition to being susceptible to ring-opening (Scheme 18) and trapping... 

Coprine, isolated from the Coprinus atramentarius mushroom, and identified as hydroxycyclopropyO-L-glutamine ", 135, is the first example of a natural product containing a cyclopropanone equivalent. Coprine inhibits mouse liver aldehyde dehydrogenase in vivo but not in vitro Cyclopropanone hydrate (170), which can be derived from coprine by hydrolysis to 169 (equation 39), inhibits the enzyme both in vivo and in vitro. Cyclopropanone hydrate has thus been proposed as a metabolite of coprine which is the active agent causing the toxic effects ... 

Vinyl cyclopropanols have been prepared by the addition of alkenyl Grignard reagents to a variety of cyclopropanone equivalents. Upon treatment with acid, the vinyl cyclopropanols rearrange to a-substituted cyclobutanones. Alternatively, a variety of a-heteroatora-substituted cyclopropyllithiura reagents have been developed. These react with aldehydes and ketones to afford cyclopropylcarbinols which also rearrange to cyclobutanones under acid catalysis.Lastly, vinyl cyclopropanols and cyclopropylcarbinols have been prepared by the cyclopropanation of enol silyl... 

Conversion of -chloro amide 8 by sodium metal in diethyl ether in the presence of chlorotrimethylsilane at 0 C smoothly afforded l-[l-(trimethylsiloxy)cyclopropyl]piperidine (5) in high yield. Reaction of this silyl derivative with tetrabutylammonium fluoride in tetrahydro-furan yielded the corresponding hydroxyamine 9. These preparations of 5 and 9 serve as short, inexpensive ways of forming cyclopropanone equivalents. 

An examination of the epoxidation of a series of 1,2,5-trienes has led to a method for producing bicyclo[3,l,0]hexan-2-ones (37) in good to moderate yields. Allene oxides, cyclopropanones, and other cyclopropanone equivalents have been implica-ated, and the process may be envisaged as a [ 2 + 2 + 2] cycloaddition proceeding... 

The palladium-catalysed oxyamination of olefins is well known, and it has now been found that, by the use of chiral reagents, asymmetry can be induced in the amination step and that optically active tertiary amino-alcohols result. 1-Piperidino-l-trimethylsilyloxycyclopropane and the corresponding 1-hydroxy-compound have been prepared and examined for their utility as cyclopropanone equivalents. ... 

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