Carbon chain extension

In the course of the first total synthesis of (+)-halichlorine <1999TL6513, 1999AGE3542>, the spiroquinolizidine unit 460 was constructed by a two-carbon chain extension in compound 458 through a crossed Claisen condensation, leading to 459, and an intramolecular Mannich reaction of this compound with formaldehyde (Scheme 109). 

The overall yield in the three-carbon chain extension of 2 to 6 is 37%. However, chain extension of 4 in the usual way failed, and only a 36% yield was obtained in the one-step conversion of 6 to 7. Further conversion of 7 to L-ribose is straightforward and essentially quantitative. 

Nonetheless, homoenolates have been much talked about as a species useful for carbon-carbon chain extension, and a number of "homoenolate equivalents have been prepared and used for organic synthesis. Reviews on these species have been published [6]. 

Four-carbon-chain extensions have been very successful with conjugated dienes as the functionalized olefins. We have used a few other compounds also, but they are of limited value, such as N-3-butenylphthalimide. The last compound is only useful with aromatic or certain vinyl halides where mixtures of allylic amines would not be formed. A typical diene example is the reaction of vinyl bromide with butadiene and piperidine which gives E-N-(2,5-hexadienyl)-piper-idine in 70% yield (7). The product of this reaction can be reacted again and used to extend the carbon chains by six atoms (see below). The reactions of conjugated dienes can be used to produce conjugated trienes also (4). 

To our knowledge, such a facile 1,3-migration of a phosphon-ium group has not been reported before, although one example of apparently related behavior has been observed (9). The phosphon-ium salt 6 has previously been reported, as its bromide, and used as a three carbon chain extension reagent for aldehydes (10). 

In contrast, the hemolymph of females of the arctiid moth Spilosoma imparilis were found to contain significant levels of the polyunsaturated hydrocarbons corresponding to the epoxide pheromone components produced by this species (Wei el al., 2003). In a biosynthetic study with the arctiid Syntomoides imaon, the pheromone of which consists of a blend of 3Z,6Z,9Z-21 H and 1,3Z,6Z,9Z-21 H (Matsuoka el al., 2008), the lipids extracted from oenocytes and peripheral fat bodies associated with the abdominal integument contained both (llZ,14Z,17Z)-eicosa-ll,14,17-trienoic acid and (13Z,16Z,19Z)-docosa-13,16,19-trienoic acid, the intermediates predicted by elongation of linolenic acid by one or two cycles of 2-carbon chain extension (Ando et al., 2008). The latter acid is likely to be the direct biosynthetic precursor to 3Z,6Z,9Z-21 H (Ando et al., 2008). 

Lactone 7 (derived from D-isoascorbic acid) reacted readily with the aryllithium formed from bromide 8 to produce lactol 9 (Scheme 16.3). The latter underwent a facile ring-opening and Wittig olefination with methylenetriphenylphosphorane to give 6 in excellent overall yield. After 0-trifLation, a two-carbon chain extension was performed on 10 with the azaenolate derived from A-cyclohexylacetaldimine 11 and lithium diisopropylamine (LDA). After acid hydrolysis of the product imine, aldehyde 12 was isolated in 83% yield for the two steps. The (2-azaallyl)stannane 5 was prepared from aldehyde 12 in quantitative yield by treatment with (aminomethyl)tri-n-butylstannane. 

The simultaneous insertion of an alkene bond and a carboxyl function into a sugar molecule is very attractive for carbohydrate chemistry in view of the further useful derivatization possible. This problem has been successfully solved by employment of the Wittig reaction, as well as its phosphonate modification (see p. 259). The compounds thus far synthesized are not numerous, although their transformations have been studied in detail and have resulted in a new method for the carbon-chain extension of carbohydrates.26... 

In further research on the carbon-chain extension of monosaccharides by reaction of free sugars with (alkoxycarbonylmethylene)-triphenylphosphoranes, Kochetkov and coworkers have reported93... 

A formal total synthesis of (+)-aspicilin, an 18-membered ring lactone isolated from the lichen Aspicilia gibbosa, is accomplished by the FDP aldolase protocol.46 The three carbon chain extension of benzyl protected 4-hydroxy-butanal is achieved with DHAP under the influence of FDP aldolase. The acid... 

Two-carbon chain extension at the carboxyl end, mimicking biosynthesis, uses the malonic ester route (102). After reduction of the carboxyl to an alcohol, the readily displaced mesylate is prepared and reacted with sodium diethylmalonate. Saponification and decarboxylation gives the chain extended product in high yield. 

A quite similar method is employed in the one-carbon chain extension of a 5 -phosphonate isostere of pyridoxal 5 -phosphate (Scheme 5.50) The a , 3-O-isopropylideneisopyridoxal is converted into an oc,P-unsaturated phosphonate in yields up to 65% by condensation with sodium tetraethyl methylenediphosphonate. Selective hydrolysis with 10% HCOjH at reflux gives the key diethyl 2-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)vinylphosphonate intermediate in 98% yield. After catalytic hydrogenation of the double bond using 5% Pd/C in EtOH, a comparison of methods for the oxidation of the alcohol has been made, including use of MnOi in water, CrO, Py, and DMSO-DCC. Finally, oxidation with activated MnO2 in CHCl, was found to proceed smoothly to give the diethyl 2-(4-formyl-3-hydroxy-2-methyl-5-pyridyl)cthylphosphonate. ... 

After oxidation to the aldehyde trans-(5S)-S6, the latter was reacted with the Wollenberg reagent, 4-lithio-l-methoxybutadiene, to effect a four-carbon chain extension to trans-(5S)-SS. Corey subsequently reported that the use of the Wollenberg reagent was difficult to reproduce, and described an improved procedure using 4-lithio-l-methoxybut-l-en-3-yne. A Wittig reaction with 46 (Scheme 3.19) then yielded LTA4 methyl ester. 

Trost, B.M., Surivet, J.-P. and Dean Toste, F.D. (2001) An atom-economical three-carbon chain extension of alkynes to form E-enol silanes. Journal of the American Chemical Society, 123, 2897-2898. 

Thus treatment of the cyclohexanone ketal 36 with 2-pyridyllithium gave the hydroxy ketal 37 which by hydrolysis and a two-carbon chain extension sequence yielded the diol 38. Acid treatment of 38 produced a mixture of the hydroxy lactone 39 and the unsaturated... 

Hydromagnesiation followed by carbon-chain extension also serves as a stereoselective preparation of the trisubslituled double bonds frequently found in terpencs. The reaction often works in a complementary manner to the existing methods, which is illustrated in the preparation of (E,Z)-and ( ,f. )-fanicsols (Scheme 3.9) 71.I0I. When the propargyl alcohol was treated with /-BuMgCI... 

Addition reactions. - Electron-deficient arenes, such as aromatic nitriles and ketones, add to unsaturated silanes in the presence of the Ru catalyst. Carbon chain extension occurs at the ortho position of the CN or CO group. 

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