Hydroxycyclopropanes

Cleavage of carbonyl-containing selenoxides and sulfones Fragmentation of epoxy hydrazones Rearrangement of vinylic hydroxycyclopropanes Rearrangement of 3-hydroxy-1,5-dienes (oxy-Cope)... 

This hydroxycyclopropanation of a terminal double bond also works perfectly well in an intramolecular situation, e. g. with terminally alkenyl-substituted esters, to yield substituted l-hydroxybicyclo[n.l.O]alkanols [85a,85b,100], aminobicyclo[n.l.O]alkanols [85c], and heterocyclic analogues [99a,99b,100], in which five- and six-membered rings are formed (Table 11.7). 

Table 11.7. Substituted cyciopropanols by intramolecular hydroxycyclopropanation of a terminally alkoxycarbonyl-substituted alkene (selected examples).

In the hydroxycyclopropanation of alkenes, esters may be more reactive than N,N-dialkylcarboxamides, as is illustrated by the exclusive formation of the disubstituted cyclopropanol 75 from the succinic acid monoester monoamide 73 (Scheme 11.21) [91]. However, the reactivities of both ester- as well as amide-carbonyl groups can be significantly influenced by the steric bulk around them [81,91]. Thus, in intermolecular competitions for reaction with the titanacydopropane intermediate derived from an alkylmagnesium halide and titanium tetraisopropoxide or methyltitanium triisoprop-oxide, between N,N-dibenzylformamide (48) and tert-butyl acetate (76) as well as between N,N-dibenzylacetamide (78) and tert-butyl acetate (76), the amide won in both cases and only the corresponding cyclopropylamines 77 and 79, respectively, were obtained (Scheme 11.21) [62,119]. 

Scheme 11.21. Competition between aminocyclopropanation and hydroxycyclopropanation reactions [91,119],...

Thus, in a novel synthesis of hypoglycine A (96), hydroxycyclopropanation of ethenyl-acetaldehyde diethyl acetal (93) followed by formal dehydration of the cyclopropanol 94 via its tosylate intermediate gave the methylenecyclopropane species 95, a key precursor to the target amino acid (Scheme 11.26) [92]. 

Scheme 11.26. Novel synthesis of hypoglycine A (96) by hydroxycyclopropanation of ethenylacetaldehyde diethyl acetal (93) [92],...

Progress has also been reported in applying titanium-mediated cydopropanation reactions as a key step in the preparation of natural products. For example, racemic stigmo-lone (8-hydroxy-2,5,8-trimethylnonan-4-one) 163, a pheromone of the myxobacterium Stigmatella aurantiaca, has been synthesized in 67% overall yield by the titanium-mediated hydroxycyclopropanation of 2-methyl-5-hexen-2-ol 161 with ethyl isovalerate 160 followed by base-induced ring-opening of the resulting 2-(3-hydroxy-3-methylbutyl)-1-isobutyl-l-cyclopropanol 162 (Scheme 11.41) [139]. 

Azetidin-2-one can be synthesized by treating 1-ethoxy-1-hydroxycy-clopropane with aqueous sodium azide at pH 5.5 (Scheme 8.7a). This type of construction has wider applications and A-substituted derivatives are formed from 1-amino-1-hydroxycyclopropanes in two steps first A-chlorination with tert- miy hypochlorite [2-methylpropan-2-yl chlo-rate(I)], and then treatment with silver ion in acetonitrile (ethanenitrile) to release chloride ion and trigger ring expansion of the tricycle (Scheme 8.7b). 

Base-catalysed ring fission of 3,4-diphenylcyclobut-3-ene-l,2-diones (103) in 50% (v/v) aqueous DMSO proceeds by rapid reversible addition of hydroxide ion followed by rate-determining benzilic acid-type rearrangement to form an intermediate 1-hydroxycyclopropane-1-carboxylic acid which ring opens to the corresponding (Z)-2-oxo-3,4-diphenylbut-3-enoic acid (Scheme 8).173 This is supported by the value of Hammett p = 1.3 (for variation of substituents on one or both rings), the kinetic solvent effects, and the three-oxygen enrichment of (107) from reaction of (103) in 50% H2 180-DMSO. 

Hydroxycyclopropanation, /fvmr-/3-deutero-styrene, 4, 275 Hydroxy-diyne ligand, with trinuclear Os clusters, 6, 742 /3-Hydroxy esters, via indium-mediated Reformatsky reactions, 9, 706... 

The l-hydroxybicyclo[ .1.0] system is obtained by the reaction of esters bearing a terminal double bond [123]. The hydroxycyclopropanation of the unsaturated ester... 

The ring contraction of 1,2-cyclobutanediones was first postulated in order to account for the formation of an a-ketoacid from 2-phenylcyclobutanedione , and in the acid- or base-catalysed ring contraction of a 1,2-dichlorocyclobutanecarbonate . It has been shown that 1,2-cyclobutanediones undergo ring contraction to 1-hydroxycyclopropane-carboxylic acids (equation 171). 

More detailed isotopic labeling studies have also been performed. Hydroxycyclopropanation of trans-f.3-deutero-styrene 273 under Kulinkovich conditions furnishes m-2-phcny 1-1 -cyclopropanol, 274, indicating retention of configuration at the carbon bound to titanium and is consistent with frontside attack of the Ti-C bond on a titanium-bound carbonyl.220 For the related de Meijere cyclopropylamine synthesis, the opposite outcome has been observed where a 3 1 mixture of A, Wdimethyl-W(/ra t-3-deutero-/ra j-2-phenylcyclopropyl)amine 278 and -dim ethyl-. V-((7.i-dcutcro-t7r-2-phony Icyclopropy I )amine 277 is produced. These products require inversion of configuration at the carbon bound to titanium and are consistent with a W-shaped transition structure for ring closure (Scheme 46). 

Dialkoxotitanacyclopropane derivatives Ti(CH2CR)(OPr1)2 react with esters to afford cycopropanols via a Kulinkovich hydroxycyclopropanation reaction, an efficient, fast, exothermic, and irreversible organic synthetic method. A detailed mechanism for this process has been explored with density functional theory calculations.286... 

Thus, addition of one equivalent of bromine to a solution of l,2-bis(trimethylsiloxy)cy-clobutenes in dichloromethane at — 10°C, followed by hydrolysis with sodium hydroxide, sodium carbonate or sodium bicarbonate, gave after acidification, the 1-hydroxycyclopropane-carboxylic acids 8 (R = H) in high yields (80-100%). The hydrolysis can be performed with ice-water alone, but more slowly. 

Very few cyclopropyloxy phosphorus compounds have been prepared directly from the corresponding cyclopropanol derivatives. Methyl 1-hydroxycyclopropanecarboxylate (1) was treated with sodium hydride followed by diethyl chlorophosphate to give the corresponding cyclopropyl diethyl phosphate 2. 2-Trimethylsilylethoxymethyl 1-hydroxycyclopropane-carboxylate (3) reacted in a similar manner with diphenyl chlorophosphate in the presence of 4-(dimethylamino)pyridine and triethylamine to give phosphate 4 in 70% isolated yield. ... 

Numerous other examples for the conversion of oxygen functionalized cyclopropanes with electrophiles in the presence of transition-metal complexes have been reported. 1-Vinyl-or 1-acetylenyl-substituted siloxycyclopropanes in similar conversions lead to cyclopentanone derivatives. Hydroxycyclopropanes with enolates give other l,n-diketones in inter- and... 

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