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Enantiopure building blocks for the synthesis of 3-methyl-2-alkanols. Diastereoselective methylmetal addition to a chiral 2-methylaldehyde followed by lipase catalysed esterification
Mittunivesitetet.
Mittuniversitetet.
Mittuniversitetet.
Mittuniversitetet.
2004 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 15, 2907-2915 p.Article in journal (Refereed) Published
Abstract [en]

The racemic synthetic building block (2R*,3R*)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R*,3R*)-2 was obtained in a high diastereomeric ratio [95:5, (2R*,3R*)/(2R*,3S*)-ratio] by Lewis acid catalysed dimethylzinc addition to racemic 2-methyl-3-(phenylsulfanyl)propanal (rac-1). Two consecutive acylations with vinyl acetate catalysed by Chirazyme L-2 (immobilised Candida antarctica lipase 13, CAL-B) led to preferential esterification of three of the four stereoisomers leaving (2S,3S)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2S,3S)-2 of 98:2 dr and 98% ee. The stereoisomerically impure acetate of (2R,3R)-3-methyl-4-(phenyisulfanyl)butan-2-ol (2R,3R)-2, obtained in the first CAL-B-catalysed acylation step, was hydrolysed and reesterified using CAL-A (immobilised Novozyme SP 525) as the catalyst, which left (2R,3R)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R,3R)-2 of 98:2 dr and 99% ee as the remaining substrate. The individual enantiomers of 2-methyl-3-(phenylsulfanyl)propanal 1 were prepared from readily available (S)- and (R)-3-hydroxy-2-methylpropanoic acid methyl ester and reacted with dimethylzinc to give both enantiomers of (2R*,3R*)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2R, 3R)- or (2S,3S)-2 of both high dr and ee. These products were purified by lipase catalysed acylation to give the enantiomerically and diastereomerically highly pure enantiomers (>99.5:0.5 dr, >99.9% ee). Pure (2S,3S)-3-methyl-4-(phenylsulfanyl)butan-2-ol (2S,3S)-2 was transformed into a potential pheromone precursor isolated from some pine sawflies of the genus Gilpinia, (2S,3R)-3-methylpentadecan-2-ol in 54% yield over eight steps.

Place, publisher, year, edition, pages
2004. Vol. 15, 2907-2915 p.
Keyword [en]
hypophosphite combination system, enantioselective total synthesis, candida-antarctica lipase, sex-pheromone, secondary alcohols, raney-nickel, reductive desulfurization, macrodiprion-nemoralis, microdiprion-pallipes, neodiprion-sertifer
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-6646DOI: 10.1016/j.tetasy.2004.07.049ISI: 000224333100032OAI: oai:DiVA.org:kth-6646DiVA: diva2:11411
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Enzymes as catalysts in synthesis of enantiomerically pure building blocks: secondary alcohols bearing two vicinal stereocenters
Open this publication in new window or tab >>Enzymes as catalysts in synthesis of enantiomerically pure building blocks: secondary alcohols bearing two vicinal stereocenters
2005 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Enzymes as tools in organic synthesis have provided enormous advantages. This thesis deals with the applications of enzymes in the kinetic resolutions of racemic compounds. The stereochemistry of chiral compounds and the kinetics of α/β hydrolase lipases are presented. From a practical point of view, the handling of a large number of parameters that influences the kinetic resolutions, especially enantioselectivity (E-value) are systematically described. A variety of approaches employed for raising the yields to over 50% are additionally discussed.

Methods for the preparation of synthetically useful chiral building blocks were developed in this thesis. Thus, resolution of secondary alcohols bearing two vicinal stereocentres are studied. These building blocks can serve as starting materials for the synthesis of various enantiomerically pure compounds for agrochemistry, pharmaceuticals, chemical industry, and particularly for the total synthesis of pheromones.

Racemic 3-substitued 2-hydroxybutane derivatives were produced in fairly high diastereomeric purities by a variety of chemical approaches, such as epimerization, metal-catalysed asymmetric addition etc. Kinetic resolution of these racemates was achieved by enzyme-catalysed reactions. Two lipases, Candida antarctica lipase B and Pseudomonas cepacia lipase were found to be useful in acylations as well as hydrolyses. In the biotransformations studied, the presence and nature of the second vicinal stereocentre in the chiral secondary alcohols investigated seemed to be important, e.g. in terms of the efficiencies of sequential kinetic resolutions, and altering the selectivities as well.

Place, publisher, year, edition, pages
Stockholm: KTH, 2005. vi, 65 p.
Series
Trita-IOK, ISSN 1100-7974 ; 2005:96
Keyword
enzyme, kinetic resolution, enantioselectivity, lipase, diastereoselectivity, epimerisation, metal-catalysed transformation, intramolecular alkylation.
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:kth:diva-424 (URN)91-7178-129-3 (ISBN)
Public defence
2005-09-30, Sal K2, Teknikringen 28, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-10-20Bibliographically approved
2. Natural products from nonracemie building blocks: synthesis of pine sawfly pheromones
Open this publication in new window or tab >>Natural products from nonracemie building blocks: synthesis of pine sawfly pheromones
2005 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

This thesis describes a number of synthetic approaches for obtaining chiral, enantiomerically pure natural products, in particular some semiochemicals. This has been accomplished by using various strategies; by starting from compounds from the chiral pool, by using chiral auxiliaries, via enzymatic resolutions or by chemical asymmetric synthesis.

Hence, the sexual pheromone of Microdiprion pallipes, a propanoate ester of one or several isomers of 3,7,11-trimethyltridecan-2-ol, was synthesised, both as a mixture of all isomers and as the sixteen pure, individual stereoisomers. These compounds were obtained by joining different enantiopure building blocks stemming from the chiral pool.

When compared with some synthetic blends, both the propanoate esters of the stereoisomeric erythro-3,7,11-trimethyltridecan-2-ols originally found in the extract from the female of M. pallipes, surprisingly, showed lower activities in biological studies. Indeed, the propanoates of two threo-isomers gave significantly higher responses in biological tests, than did the propanoates of the two natural erythro-ones. Because the synthetic strategy used earlier was not very efficient for the preparation of the threo-isomers of 3,7,11-trimethyltridecan-2-ol, we were encouraged to look for alternative synthetic approaches.

The new synthetic strategy chosen led us to two key synthetic building blocks, an O-protected derivative of (2S,3S)-3-methyl-4-(phenylsulfonyl)butan-2-ol butanol and (3R,7R)-1-iodo-3,7-dimethylnonane. Deprotonation of the former followed by alkylation with the latter should give a compound with the desired carbon skeleton.

For efficient preparation of the first building block, we developed a new diastereoselective addition reaction of dialkylzincs to some chiral aldehydes, the products of which were diastereomerically enriched 1,2-dialkyl-alkanols. Using this method, each enantiomer of the desired building block was obtained via efficient diastereoselective addition of dimethylzinc to each enantiomer of a 2-methylaldehyde. The resulting product, a diastereomerically and enantiomerically highly enriched 3-methyl-2-alkanol was further purified by enzyme catalysed acylation followed by some functional group interconversions.

The second building block was prepared via convergent multistep synthesis, starting from a single, enantiomerically pure compound, (R)-2-methylsuccinic acid 4-t-butyl ester, derived from the chiral pool.

The two enantiomerically pure building blocks, so obtained, were coupled together. Some additional functional group manipulations of the product produced furnished the desired isomer, which had shown the highest activity in field tests of the M. pallipes, namely the propanoate ester of (2S,3R,7R,11R)-3,7,11-trimethyltridecan-2-ol.

This thesis describes a number of synthetic approaches for obtaining chiral, enantiomerically pure natural products, in particular some semiochemicals. This has been accomplished by using various strategies; by starting from compounds from the chiral pool, by using chiral auxiliaries, via enzymatic resolutions or by chemical asymmetric synthesis.

Hence, the sexual pheromone of Microdiprion pallipes, a propanoate ester of one or several isomers of 3,7,11-trimethyltridecan-2-ol, was synthesised, both as a mixture of all isomers and as the sixteen pure, individual stereoisomers. These compounds were obtained by joining different enantiopure building blocks stemming from the chiral pool.

When compared with some synthetic blends, both the propanoate esters of the stereoisomeric erythro-3,7,11-trimethyltridecan-2-ols originally found in the extract from the female of M. pallipes, surprisingly, showed lower activities in biological studies. Indeed, the propanoates of two threo-isomers gave significantly higher responses in biological tests, than did the propanoates of the two natural erythro-ones. Because the synthetic strategy used earlier was not very efficient for the preparation of the threo-isomers of 3,7,11-trimethyltridecan-2-ol, we were encouraged to look for alternative synthetic approaches.

The new synthetic strategy chosen led us to two key synthetic building blocks, an O-protected derivative of (2S,3S)-3-methyl-4-(phenylsulfonyl)butan-2-ol butanol and (3R,7R)-1-iodo-3,7-dimethylnonane. Deprotonation of the former followed by alkylation with the latter should give a compound with the desired carbon skeleton.

For efficient preparation of the first building block, we developed a new diastereoselective addition reaction of dialkylzincs to some chiral aldehydes, the products of which were diastereomerically enriched 1,2-dialkyl-alkanols. Using this method, each enantiomer of the desired building block was obtained via efficient diastereoselective addition of dimethylzinc to each enantiomer of a 2-methylaldehyde. The resulting product, a diastereomerically and enantiomerically highly enriched 3-methyl-2-alkanol was further purified by enzyme catalysed acylation followed by some functional group interconversions.

The second building block was prepared via convergent multistep synthesis, starting from a single, enantiomerically pure compound, (R)-2-methylsuccinic acid 4-t-butyl ester, derived from the chiral pool.

The two enantiomerically pure building blocks, so obtained, were coupled together. Some additional functional group manipulations of the product produced furnished the desired isomer, which had shown the highest activity in field tests of the M. pallipes, namely the propanoate ester of (2S,3R,7R,11R)-3,7,11-trimethyltridecan-2-ol.

This thesis describes a number of synthetic approaches for obtaining chiral, enantiomerically pure natural products, in particular some semiochemicals. This has been accomplished by using various strategies; by starting from compounds from the chiral pool, by using chiral auxiliaries, via enzymatic resolutions or by chemical asymmetric synthesis.

Hence, the sexual pheromone of Microdiprion pallipes, a propanoate ester of one or several isomers of 3,7,11-trimethyltridecan-2-ol, was synthesised, both as a mixture of all isomers and as the sixteen pure, individual stereoisomers. These compounds were obtained by joining different enantiopure building blocks stemming from the chiral pool.

When compared with some synthetic blends, both the propanoate esters of the stereoisomeric erythro-3,7,11-trimethyltridecan-2-ols originally found in the extract from the female of M. pallipes, surprisingly, showed lower activities in biological studies. Indeed, the propanoates of two threo-isomers gave significantly higher responses in biological tests, than did the propanoates of the two natural erythro-ones. Because the synthetic strategy used earlier was not very efficient for the preparation of the threo-isomers of 3,7,11-trimethyltridecan-2-ol, we were encouraged to look for alternative synthetic approaches.

The new synthetic strategy chosen led us to two key synthetic building blocks, an O-protected derivative of (2S,3S)-3-methyl-4-(phenylsulfonyl)butan-2-ol butanol and (3R,7R)-1-iodo-3,7-dimethylnonane. Deprotonation of the former followed by alkylation with the latter should give a compound with the desired carbon skeleton.

For efficient preparation of the first building block, we developed a new diastereoselective addition reaction of dialkylzincs to some chiral aldehydes, the products of which were diastereomerically enriched 1,2-dialkyl-alkanols. Using this method, each enantiomer of the desired building block was obtained via efficient diastereoselective addition of dimethylzinc to each enantiomer of a 2-methylaldehyde. The resulting product, a diastereomerically and enantiomerically highly enriched 3-methyl-2-alkanol was further purified by enzyme catalysed acylation followed by some functional group interconversions.

The second building block was prepared via convergent multistep synthesis, starting from a single, enantiomerically pure compound, (R)-2-methylsuccinic acid 4-t-butyl ester, derived from the chiral pool.

The two enantiomerically pure building blocks, so obtained, were coupled together. Some additional functional group manipulations of the product produced furnished the desired isomer, which had shown the highest activity in field tests of the M. pallipes, namely the propanoate ester of (2S,3R,7R,11R)-3,7,11-trimethyltridecan-2-ol.

Place, publisher, year, edition, pages
Stockholm: KTH, 2005. ix, 60 p.
Series
Trita-IOK, ISSN 1100-7974 ; 2005:94
Keyword
Organic chemistry, Total synthesis, diastereoselective addition, dimethylzinc, Lewis acid, alkyllithium, Organisk kemi
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-128 (URN)91-7283-952-X (ISBN)
Public defence
2005-02-18, Sal 0102, Åkroken, Mittuniversitetet, Sundsvall, 10:00 (English)
Opponent
Supervisors
Note
QC 20101026Available from: 2008-12-11 Created: 2008-12-11 Last updated: 2010-10-26Bibliographically approved

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