Geminal dialkylation

The bishydroxylation of peripheral C —C double bonds of porphyrins, e.g. 6, with hydrogen peroxide under acidic conditions or with osmium(VlII) oxide yields the corresponding diols, e.g. 10, which on pinacol rearrangement are transformed into geminally dialkylated chlorins, e.g. 11.9,97... 

Cyclopropane-fused chlorins are formed in good yields from copper porphyrins with ethyl diazoacetatc in benzene in the presence of copper(I) iodide.200,21 In the case of copper oc-taethylporphyrin 10, which gives a diastereomeric mixture of cyclopropane adducts 11, ethyl me o-porphyrincarboxylate 12 and a geminally dialkylated chlorin 13 (a rearrangement product of the cyclopropane chlorin 11) are observed as minor byproducts.200... 

The important biological role of the isobacteriochlorins has decisively influenced the development of synthetic approaches leading to the isobacteriochlorin class of compounds. All of the naturally occurring isobacteriochlorins contain geminally dialkylated structural parts in the saturated pyrrole rings, which require special approaches for their synthesis. Until the discovery of siroheme and sirohydrochlorin, this structural element could only be found in vitamin B,2. Using the synthetic potential, which was invented during numerous syntheses of... 

These are the use of the geminal dialkyl effect, the decrease of the current density and especially the use of an electrophilic double bond that increases the addition... 

In contrast to alkylations of oximes and oxime ethers, geminal dialkylation can be achieved with the cyclic analogs15, e.g., preparation of the 4,4-dimethyl derivative 3. 

Leaving groups other than halides are also suitable for this type of geminal dialkylation reaction. Thus, diethyl spiro[3.4]oct-6-ene-2,2-dicarboxylate (5) is isolated in 75% yield from the reaction between diethyl malonate and 3-cyclopentene-1,1-dihydroxymethyl di-4-bro-mobenzenesulfonate (4).19... 

Alkylene chains with geminal dialkyl substitution have been shown to cyclize more readily than the corresponding unsubstituted compounds (Scheme 9.12). This effect can be used to achieve cyclization which might not occur without geminal disubstitution (see, e.g., Scheme 9.21) [32]. The magnitude of this effect is, however, highly dependent on the type of reaction and product, as illustrated by the examples in Scheme 9.12. 

The stereoselectivity of this reaction rises when more bulky nucleophiles are employed (compare entries 7, 3,1, and 5). This is most impressively demonstrated by comparison of the y-lactol reduction with its allylation leading to 205 or 206, respectively (Scheme 10). Formation of tetrahydrofuran derivative 208, dihydrofuran 209, or unsaturated a-methylen-y-butyrolactone 207 illustrate that various modes of straightforward work-up procedures provide two different five membered heterocycles 93 b-96). A second example without the geminal dialkyl substitution at C-3 of the siloxy-cyclopropane depicted in Eq. 86 making available the annulated tetrahydrofuran-3-carboxylate 210 underlines the generality of the C-C-bond forming hydroxyalkylation reaction via ester enolates. 

Scheme 10. Reaction sequence for the synthesis of tri-, tetra-, and penta(isopropyl)cyclo-pentadienes (34,35) from di(isopropyl)-Cp (59) via a series of metallations/alkylations. Tri(isopropyl)-Cp is obtained in a 4 1 mixture of the 1,2,4- and 1,2,3-substituted isomers. The C—H acidic tetra(isopropyl) isomers are separated from the 5,5 -geminal dialkylated forms by their transformation in the sodium salt and evaporation of the nonmetallated components. Subsequent hydrolysis yields l,2,3,4-tetra(isopropyl)cyclopentadiene in an iso-merically pure form. Similarly, l,2,3,4,5-penta(isopropyl)-Cp is purified after separation of the 1,2,3,S,5 derivative as the main alkylation product. For more details and the respective yields, see Refs. 34 and 35.

The above transformation has two different goals 21,22) 1) To increase chemo-, regio-, diastereo- and enantioselectivity in the reaction with carbonyl compounds (Sections C-E), and 2) to make certain reaction types amenable which do proceed readily with classical reagents, e.g., methylation of tertiary alkyl halides, alcohols and ethers, and direct geminal dialkylation of ketones (Section F). It turns out that organotitanium compounds are usually complementary to Li, Mg, Zn, Fe, Ni, Cu and Pd reagents. So far, experience in the above two areas points to the following positive aspects ... 

Refoimatsky Reactions. The Reformatsky reaction of a-halooxazolidinones provides an alternative to the more conventional aldol reaction. Although the traditional zinc-mediated Reformatsky using valine-derived compounds proceeds nonselectively, the Sn modification with 2-bromo-2-methylpropionyloxazolidinone proceeds well (eq 46). In this particular case, however, the geminal dialkyl substiments favor the endocyclic carbonyl acyl transfer of the auxiliary by the aldolate oxygen. 

Geminal Dialkylation of Aldehydes and Ketones 1.532 Alkylative Amination... 

A number of functionalities at the four-position of the heterocyclic ring were also investigated. Geminal dialkyl substitution was found to be essential for activity. Maximum effectiveness was... 

Treatment of 1,1-dibromocyclopropanes with methyllithium normally leads to allenes and bi-cyclo[l. 1.0]butanes, but certain 1,1 -dibromocyclopropanes undergo geminal dialkylation under the right conditions most examples of this reaction give products, e.g. [3]-propellanes, containing a new three-membered ring. 

The geminal dialkyl effect, namely the introduction of two methyl groups into the... 

A novel method for the geminal dialkylation of carbonyl compounds... 

The extremely high sensitivity of bacteriochlorins to various reaction conditions makes their chemistry very diflScult. This might be one reason why methods for the total synthesis of bacteriochlorins had not, until very recently, been developed. Total synthesis of a tolyporphin model 86 which contains geminally dialkylated structural parts was reported by Kishi <97TL6811> using an approach that is very closely related to Eschenmoser s syntheses of hexahydroporphyrins from reduced linear tetrapyrroles by cyclization (see Section 1,5). 

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