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Natural products from nonracemie building blocks: synthesis of pine sawfly pheromones
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
Responsible organisation
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 [en]
Organic chemistry, Total synthesis, diastereoselective addition, dimethylzinc, Lewis acid, alkyllithium
Keyword [sv]
Organisk kemi
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-128ISBN: 91-7283-952-X (print)OAI: oai:DiVA.org:kth-128DiVA: diva2:7094
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
List of papers
1. Syntheses of the sixteen stereoisomers of 3,7,11-trimethyl-2-tridecanol, including the (2S,3S,7S,11R) and (2S,3S,7S,11S) stereoisomers identified as pheromone precursors in females of the pine sawfly Microdiprion pallipes (Hymenoptera : Diprionidae).: Diprionidae)
Open this publication in new window or tab >>Syntheses of the sixteen stereoisomers of 3,7,11-trimethyl-2-tridecanol, including the (2S,3S,7S,11R) and (2S,3S,7S,11S) stereoisomers identified as pheromone precursors in females of the pine sawfly Microdiprion pallipes (Hymenoptera : Diprionidae).: Diprionidae)
2001 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 2, 353-363 p.Article in journal (Refereed) Published
Abstract [en]

All sixteen stereoisomers of 3,7,11-trimethyl-2-tridecanol were synthesised in high stereoisomerical purities (> 95%), for use in the identification of the stereoisomers present in females of the pine sawfly Microdiprion pallipes (Fallen) (Hymenoptera: Diprionidae) as the precursor of the actual sex pheromone (which is the propionate), and also for investigation of the biological activities of the esters. The key step in the syntheses was the coupling of each of the enantiomers of cis-3,4-dimethyl-gamma -butyrolactone with each of the four pure stereoisomers of 1-lithio-2,6-dimethyloctanes. The four corresponding alcohols were obtained by lipase-catalysed (Amano PS) kinetic separation, based on selective acylation of either (2R/S,6S)- or (2R/S,GR)-2,6-dimethyl-1-octanol (obtained from the optically pure enantiomers of citronellal). Additionally, a mixture of the 16 possible stereoisomers of 3,7,11-trimethyl-2-tridecanol was also prepared.

Keyword
Asymmetric synthesis, Lipase, Microdiprion pallipes, Pheromones, Total synthesis, 3, 7, 11 trimethyl 2 tridecanol, alcohol, decanol, ester, gamma butyrolactone derivative, lactone derivative, octanol, propionic acid, sex pheromone, triacylglycerol lipase, unclassified drug, acylation, article, drug activity, enantiomer, enzyme kinetics, female, fly, Hymenoptera, nonhuman, stereoisomerism, synthesis
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-25543 (URN)10.1002/1099-0690(200101)2001:2<353 (DOI)000166621900015 ()
Note
QC 20101026Available from: 2010-10-26 Created: 2010-10-26 Last updated: 2017-12-12Bibliographically approved
2. Diastereoselective addition of methylmetal reagents to 2-methylaldehydes.
Open this publication in new window or tab >>Diastereoselective addition of methylmetal reagents to 2-methylaldehydes.
2001 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 57, no 35, 7541-7548 p.Article in journal (Refereed) Published
Abstract [en]

The preparation of compounds incorporating the 3-hydroxy-2-methyl-1-butyl moiety of high diastereomeric purity is described. These compounds can serve as potential building blocks for the preparation of several kinds of natural products. The diastereoselective addition of a number of methylmetal derivatives to three 3-substituted 2-methylaldehydes in various solvents was studied. An excellent diastereomeric. ratio (95:5 anti-Cram/Crain) was obtained with 2-methyl-3-(phenylsulfanyl)propanal (5) and Me2Zn in the presence of TiCl4.

Keyword
addition, asymmetric induction, diastereoselection, chelation
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-25544 (URN)10.1016/S0040-4020(01)00713-X (DOI)000170631700013 ()
Note
QC 20101026Available from: 2010-10-26 Created: 2010-10-26 Last updated: 2017-12-12Bibliographically approved
3. Enantiopure building blocks for the synthesis of 3-methyl-2-alkanols. Diastereoselective methylmetal addition to a chiral 2-methylaldehyde followed by lipase catalysed esterification
Open this publication in new window or tab >>Enantiopure building blocks for the synthesis of 3-methyl-2-alkanols. Diastereoselective methylmetal addition to a chiral 2-methylaldehyde followed by lipase catalysed esterification
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.

Keyword
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:nbn:se:kth:diva-6646 (URN)10.1016/j.tetasy.2004.07.049 (DOI)000224333100032 ()
Note
QC 20101020Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2017-12-14Bibliographically approved
4. Enantioselective synthesis of an active potential pheromone component of the pine sawfly Microdiprion pallipes.
Open this publication in new window or tab >>Enantioselective synthesis of an active potential pheromone component of the pine sawfly Microdiprion pallipes.
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-25545 (URN)
Note
QC 20101026Available from: 2010-10-26 Created: 2010-10-26 Last updated: 2010-10-26Bibliographically approved
5. Diastereoselective addition of organozinc reagents to 2-alkyl-3-(arylsulfanyl)propanals
Open this publication in new window or tab >>Diastereoselective addition of organozinc reagents to 2-alkyl-3-(arylsulfanyl)propanals
2004 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 60, no 47, 10659-10669 p.Article in journal (Refereed) Published
Abstract [en]

The preparation of compounds incorporating the 3-hydroxy-2-methyl-1-alkyl moiety of high diastereomeric purity is described. Such compounds can serve as potential building blocks for the preparation of several kinds of natural products. Diastereoselective synthesis of two potential pine sawfly pheromone components, one the pure racemic threo-isomer of 3-methylpentadecan-2-ol and the other the racemic erythro-isomer of 3-methyltridecan-2-ol are described. The diastereoselective addition of R2Zn (R = Me, Et and n-Bu) to several 2-alkyl-3-(arylsulfanyl)propanals in the presence of a Lewis acid and CH2Cl2 as solvent was studied. An excellent diastereomeric ratio (95/5 anti-Cram/Cram) was obtained with 2-[(phenylsulfanyl)methyl]pentanal, 2-[(phenylsulfanyl)methyl]decanal and 2-[(phenylsulfanyl)methyl]dodecanal and Me2Zn in the presence of TiCl4.

Keyword
diastereoselective additions, dimethylzinc, titanium tetrachloride, chelation, pheromones
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-25547 (URN)10.1016/j.tet.2004.09.005 (DOI)000224715100008 ()
Note
QC 20101026Available from: 2010-10-26 Created: 2010-10-26 Last updated: 2017-12-12Bibliographically approved

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