A new route to β-keto-δ-lactones: Practical preparation of (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one, a key intermediate in the asymmetric synthesis of tetrahydrolipstatin
“…The desired products were β-hydroxy δ-lactones, either hydroxy-protected or unprotected. Compounds such as 1 , 2 , and 13 (as well as its cis isomer) have been prepared in high enantiomeric purity by intramolecular chain elongations in two steps from β-hydroxy esters or imides . Combined with a diastereoselective reduction of the β-keto, or enol, function, these chain elongations would constitute a synthetic sequence which bears some resemblance to biosynthetic processes leading to polyketides.…”
Enol MEM ethers 4 and 15 and the corresponding enol acetates were hydrogenated over Pd/C with very high (>99%) diastereoselectivity to saturated delta-lactones. A stereochemical generalization can be formulated thus: trans-5,6-disubstituted 1-oxa-3-cyclohexen-2-ones (e.g. 14 and 15) are hydrogenated over Pd with high selectivity from the side trans to the C(6)-substituent. A mechanistic rationalization of the stereochemical outcome in the Pd-catalyzed hydrogenation of this as well as other types of substituted alpha,beta-unsaturated delta-lactones is presented. An analysis of X-ray crystallographic data for 67 compounds demonstrated a great conformational diversity of the saturated delta-lactone ring. Besides, ab initio calculations (HF/6-31G) indicated a very high conformational mobility. Thus, the lowest calculated transition state for the conversion of the half-chair, most stable, conformer of delta-valerolactone to the boat-type conformer lies only 1.93 kcal/mol above the former. Beside these two conformers, also chair, envelope and skew conformations are accessible; all lie less than 2 kcal/mol above the half-chair. The previous conformational paradigm comprising only boat and half-chair types is incomplete.
“…The desired products were β-hydroxy δ-lactones, either hydroxy-protected or unprotected. Compounds such as 1 , 2 , and 13 (as well as its cis isomer) have been prepared in high enantiomeric purity by intramolecular chain elongations in two steps from β-hydroxy esters or imides . Combined with a diastereoselective reduction of the β-keto, or enol, function, these chain elongations would constitute a synthetic sequence which bears some resemblance to biosynthetic processes leading to polyketides.…”
Enol MEM ethers 4 and 15 and the corresponding enol acetates were hydrogenated over Pd/C with very high (>99%) diastereoselectivity to saturated delta-lactones. A stereochemical generalization can be formulated thus: trans-5,6-disubstituted 1-oxa-3-cyclohexen-2-ones (e.g. 14 and 15) are hydrogenated over Pd with high selectivity from the side trans to the C(6)-substituent. A mechanistic rationalization of the stereochemical outcome in the Pd-catalyzed hydrogenation of this as well as other types of substituted alpha,beta-unsaturated delta-lactones is presented. An analysis of X-ray crystallographic data for 67 compounds demonstrated a great conformational diversity of the saturated delta-lactone ring. Besides, ab initio calculations (HF/6-31G) indicated a very high conformational mobility. Thus, the lowest calculated transition state for the conversion of the half-chair, most stable, conformer of delta-valerolactone to the boat-type conformer lies only 1.93 kcal/mol above the former. Beside these two conformers, also chair, envelope and skew conformations are accessible; all lie less than 2 kcal/mol above the half-chair. The previous conformational paradigm comprising only boat and half-chair types is incomplete.
“…[272][273][274] The reaction of the enantiomerically pure hydroxy-ester with 2-bromooctanoyl chloride leads after an in-tramolecular Reformatzky reaction to the δ-lactone. Another approach involves the Ivanov reaction of the benzyl-protected hydroxy-aldehyde with octanoic acid.…”
A boy who is born in Germany today has a probable life expectancy of around 77 years, and a girl one of 82 years -twice as long as in the year 1880. This increase is a consequence of both, better living circumstances -working conditions, food, clothing, housing -, and also a result of more comprehensive medical care. Thus, a whole range of infectious diseases has been wiped out, or brought at least under control, and the mortality rate for civilisation-and age-related diseases has dropped. Vaccinations and drugs play a key role in this outcome. The 20th century is characterised especially by the worldwide blossoming of the pharmaceutical industry. More and more, the targeted search for and development of new drugs have replaced serendipitous discoveries (Fig. 5.1).
Pharmaceuticals of the last century.
“…Especially tetrahydrolipstatin ( 4 ) is now approved as an antiobesity agent . Due to its promising pharmacological properties, this lipase inhibitor has served during the past decade as a target for the demonstration of the usefulness and versatility of new β-lactone syntheses. ,− 1 …”
mentioning
confidence: 99%
“…In comparison to the known syntheses for the oxetan-2-ones 11 and 12 the synthesis outlined here is extremely short. It requires only three steps from methyl 3-hydroxytetradecanoate, a starting material used also in several earlier multistep reactions. ,,, The number of steps could be reduced by application of the tandem aldol−lactonization and the use of the very labile 2-methoxyprop-2-oxy protecting group, which does not require an additional deprotection step.…”
mentioning
confidence: 99%
“…11 Due to its promising pharmacological properties, this lipase inhibitor has served during the past decade as a target for the demonstration of the usefulness and versatility of new β-lactone syntheses. 7,[12][13][14][15][16][17][18][19] A common feature of these syntheses is the construction of a (3S,4S)-oxetan-2-one with trans-orientated alkyl groups and an (S)-or (R)-configured hydroxy group in the 2-position of the 4-alkyl chain. The configuration of the hydroxy group determines whether the final esterification with an R-amino acid derivative requires inversion or retention of the configuration of this stereogenic center.…”
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