(+)-sitophilure
IUPAC Name: (4S,5R)-5-hydroxy-4-methylheptan-3-one | CAS Registry Number: 71699-35-9
Synonyms: Sitophilure, CID155663, 3-Heptanone, 5-hydroxy-4-methyl-, (R*,S*)-, 71699-35-9
Synonyms: Sitophilure, CID155663, 3-Heptanone, 5-hydroxy-4-methyl-, (R*,S*)-, 71699-35-9
(+)-(4S,5R)-5-Hydroxy-4-methyl-3-pentanone (1)
To a solution of oxalyl chloride (0.013 mL, 0.15 mmol) in CH2Cl2 (1.0 mL) at -78 °C was added dimethyl sulfoxide (0.020 mL, 0.31 mmol) dropwise. The solution was stirred 10 min at -78 °C and a solution of a mixture of 11 and 12 (0.023 g, 0.089 mmol) in CH2Cl2 (1.0 mL) was added. The mixture was stirred 1.5 h at -78 °C,
and treated with triethylamine (0.06 mL, 0.46 mmol). After warming to
room temperature, the reaction was quenched with water, the layers were
separated and the aqueous layer was extracted with CH2Cl2 (3 x 2 mL). The combined organic phases were washed with brine (4 mL), dried over MgSO4
and concentrated under reduced pressure. The residue (0.019 g) was
dissolved in THF (1 mL) at room temperature and treated with 1.0 M
solution of TBAF (0.1 mL, 0.1 mmol) in THF. The mixture was stirred 1
day at room temperature, diluted with Et2O (10 mL) and treated with aq. NH4Cl (3 mL). The layers were separated and the aqueous layer was extracted with Et2O (3 x 4 mL). The combined organic layers were dried over MgSO4 and concentrated. Silica gel chromatography (30% AcOEt in hexanes, v/v) afforded (+)-1 (0.0074 g, 0.052 mmol) in 60% yield, as a colorless oil.
1H-NMR (CDCl3, 300 MHz): d 0.96 (t, 3H, J = 7 Hz); 1.06 (t, 3H, J = 7 Hz); 1.14 (d, 3H, J = 7 Hz); 1.37 (ddq, 1H, J = 15, 7 and 3 Hz); 1.51 (ddq, 1H, J = 15, 8 and 7 Hz); 2.42-2.70 (m, 3H); 2.86 (br s, 1H); 3.83 (ddd, 1H, J = 8, 5 and 3 Hz).
13C-NMR (CDCl3, 75.5 MHz): d 7.6; 9.9; 10.4; 26.8; 35.1; 49.3; 72.6; 216.8.
IR (film): 3453; 1701; 1460 cm-1. [a]D +24.8 (c1.24, Et2O). lit.2: [a]D +27.0 (c1.24, Et2O).
J. Braz. Chem. Soc. vol.10 no.5 São Paulo Sept./Oct. 1999
http://dx.doi.org/10.1590/S0103-50531999000500005
The Asymmetric Synthesis of (+)-Sitophilure, the Natural Form of the Aggregation Pheromone of Sitophilus oryzae L. and Sitophilus zeamais M.
Ronaldo A. Pilli*, and Valéria B. Riatto
Instituto de Química, UNICAMP, C.P. 6154, 13083-970 Campinas - SP Brazil
*e-mail: pilli@iqm.unicamp.br and vbriatto@iqm.unicamp.br
Ronaldo Aloise Pillihttp://www.google.com/patents/US20090298147............
In 1984, Burkholder and coworkers isolated the male-produced aggregation pheromone of the pests rice weevil (Sitophilus oryzae L.) and maize weevil (Sitophilus zeamais M.), which is named Sitophilure.[8] This biologically-active compound was first identified as (4R,5S)-5-hydroxy-4-methyl-3-heptanone, from the extracts of thousands of insects. All four stereoisomers of this pheromone were synthesized and it was proved that the active form of this compound is the (4S,5R) enantiomer.[9] Since then, several total syntheses of racemic,[10] or other stereoisomers[11] and the natural form[12] of this pheromone have been published.
Serious economic losses of stored cereal grains (maize, rice and grain) are mainly caused by three weevils of the genus Sitophilus (Sitophilus zeamais, Sitophilus oryzae, Sitophilus granarius respectively) throughout the world. Early detection of infestations is critical in order to avoid further damage to the grains and the subsequent economic losses. Traps that contain very small amounts of synthetic (+)-sitophilure have been shown to be very effective in the early detection of all three species of weevils,[13] however a simple scalable and economic method for the synthesis of this weevil attractant pheromone is still lacking.[9-12] As a result, all of the commercially available traps for the early detection of these weevils are food-based.
The absolute stereochemistry of the enantiomers B and D (Scheme 3) was found to be (4S,5R) and (4S,5S) respectively, taking into account that the relative stereochemistry of the product D is anti and of the product B syn.
In large scale, the reaction is completed in 24 hours, producing the pheromone with chemical yield 85%, de 96%, ee >99%, and chemical purity >99%, utilizing catalytic amounts of the NADPH cofactor (0.81% relative to the substrate), which was recycled in situ using Glucose Dehydrogenase (GDH). The corresponding 4-methyl-3,5-heptanedione can be readily produced from the commercially available 3,5-heptanedione (Scheme 4).
Synthesis of (4S,5R)-5-hydroxy-4-methyl-3-heptanone
A phosphate-buffered solution (16 mL, pH 6.5, 200 mM) containing 84 mM (1.35 mmol, 192 mg) of 4-methyl-3,5-heptanedione, NaCl (200 mM, 200 mg), glucose (130 mM, 375 mg), NADPH (0.69 mM, 0.011 mmol, 10 mg), glucose dehydrogenase (10 mg) and KRED-A1C (10 mg) was stirred at 25° C. for 24 hours, until GC analysis of crude extracts showed complete reaction. Periodically the pH was readjusted to 6.5 with NaOH (2 M). The product was isolated by extracting the crude reaction mixture with EtOAc (15 mL×2). The combined organic layers were then extracted with saturated NaCl solution, dried over MgSO4 and evaporated to dryness. Pure (4S,5R)-5-hydroxy-4-methyl-3-heptanone (165 mg) was obtained in 85% yield. 1H NMR (CDCl3 500 MHz, δ ppm): 1H NMR (CDCl3 500 MHz, δ ppm): 3.77-3.85 (m, 1H), 2.72 (s, OH), 2.41-2.64 (m, 3H), 1.32-1.58 (m, 2H), 1.12 (d, J=7.1 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3 300 MHz, δ ppm): 216.7, 72.6, 49.3, 35.1, 26.9, 10.4, 9.9, 7.6.
Determination of the Enantiomeric Purity of (4S,5R)-5-hydroxy-4-methyl-3-heptanone: GC (column: 30 m×0.25 mm×0.25 μm chiral capillary column, 20% permethylated cyclodextrin 65° C. for 100 min, rate: 1° C./min, final temp.: 100° C.; carrier gas: N2, press 70 kPa). tR=100.0 min [98%, (4S,5R)-5-hydroxy-4-methyl-3-heptanone], tR=105.1 min [2%, (4R,5R)-5-hydroxy-4-methyl-3-heptanone]. The enantiomeric purity was estimated to be >99% and the diastereomeric purity 96%.
A phosphate-buffered solution (16 mL, pH 6.5, 200 mM) containing 84 mM (1.35 mmol, 192 mg) of 4-methyl-3,5-heptanedione, NaCl (200 mM, 200 mg), glucose (130 mM, 375 mg), NADPH (0.69 mM, 0.011 mmol, 10 mg), glucose dehydrogenase (10 mg) and KRED-A1C (10 mg) was stirred at 25° C. for 24 hours, until GC analysis of crude extracts showed complete reaction. Periodically the pH was readjusted to 6.5 with NaOH (2 M). The product was isolated by extracting the crude reaction mixture with EtOAc (15 mL×2). The combined organic layers were then extracted with saturated NaCl solution, dried over MgSO4 and evaporated to dryness. Pure (4S,5R)-5-hydroxy-4-methyl-3-heptanone (165 mg) was obtained in 85% yield. 1H NMR (CDCl3 500 MHz, δ ppm): 1H NMR (CDCl3 500 MHz, δ ppm): 3.77-3.85 (m, 1H), 2.72 (s, OH), 2.41-2.64 (m, 3H), 1.32-1.58 (m, 2H), 1.12 (d, J=7.1 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3 300 MHz, δ ppm): 216.7, 72.6, 49.3, 35.1, 26.9, 10.4, 9.9, 7.6.
Determination of the Enantiomeric Purity of (4S,5R)-5-hydroxy-4-methyl-3-heptanone: GC (column: 30 m×0.25 mm×0.25 μm chiral capillary column, 20% permethylated cyclodextrin 65° C. for 100 min, rate: 1° C./min, final temp.: 100° C.; carrier gas: N2, press 70 kPa). tR=100.0 min [98%, (4S,5R)-5-hydroxy-4-methyl-3-heptanone], tR=105.1 min [2%, (4R,5R)-5-hydroxy-4-methyl-3-heptanone]. The enantiomeric purity was estimated to be >99% and the diastereomeric purity 96%.
Administração e Biblioteca do Instituto de Química da UNICAMP, Campinas.
Instituto de Química - Unicamp
Lab. de Ensino, Biblioteca e Administração| Campinas | |||
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| Municipality | |||
| The Municipality of Campinas | |||
Images from top, left to right: Metropolitan Cathedral, an avenue in Campinas's downtown, an old railway station, Mogiana Palace, a monument to the heroes of Constitutionalist Revolution (in Saudade Cemetery), a bus terminus, Central area of Campinas as seen from Torre do Castelo, a belvedere.
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| Nickname(s): Cidade das Andorinhas, Brazilian Silicon Valley, Princesa d'Oeste | |||
 Location of Campinas |
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Campinas
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| Coordinates: 22°54′3″S 47°03′26″W | |||
| Country |  Brazil |
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| Region | Southeast | ||
| State | São Paulo | ||
| Founded | July 14, 1774 | ||
| Government | |||
| • Mayor | Jonas Donizette (PSB) | ||
| Area | |||
| • Municipality | 795.667 km2 (307.209 sq mi) | ||
| • Metro | 3,645 km2 (1,407 sq mi) | ||
| Elevation | 555-780 m (1,821–2,559 ft) | ||
| Population (2012) | |||
| • Municipality | 1,098,630 (14th) | ||
| • Density | 1,358.6/km2 (3,519/sq mi) | ||
| • Metro | 2,633,523 | ||
| Time zone | Brasilia Official Time (UTC-3) | ||
| • Summer (DST) | Brazilian Daylight Saving Time (UTC-2) | ||
| Postal Code | 13000-000 | ||
| Area code(s) | +55 19 | ||
| Website | Campinas, São Paulo | ||
History
Campinas in 1878
Maps of railways in Campinas in 1929
Regatas Club in Cambuí neighborhood.
Formação Acadêmica
MS-6, Professor Titular; Bel. Instituto de Quimica, UNICAMP (1976),
Dr. Sc. (UNICAMP, 1982); Pós-doutorado (University of California,
Berkeley,1982-84); Professor Titular (UNICAMP, 2002)
Contato
Instituto de QuímicaCaixa Postal 6154
Campinas, SP
13083-862 Sala D-353
Fax 55 19 3521 3023
Fone 55 19 3521-3422
pilli@iqm.unicamp.br
Currículo Lattes
Pesquisa
- Síntese Orgânica- Síntese de Produtos Naturais
- Síntese Assimétrica de Fármacos
- Estudos de Estrutura x Atividade Biológica
Publicação
1. PILLI, R. A. ; Ângelo de Fátima ; Luciana Konecny Kohn ; CARVALHO,
J. E. . Cytotoxic Activity of (S)-goniothalamin and Analogues Against
Human Cancer Cells. Bioorganic & Medicinal Chemistry, Estados
Unidos, v. 14, p. 622-631, 2006.2. PILLI, R. A. ; Andrea Leal de Sousa . A concise route to the azaspirodecane moiety of halichlorine and structurally related alkaloids. Organic Letters, Washington, DC, v. 7, p. 1617-1619, 2005.
3. PILLI, R. A. ; MALDANER, A. O. ; CORREA JR., I. R. ; ROSSO, G. B. . Total Synthesis and Structural Elucidation of Natural Products: (-)-Delactonmycin, (+)-Plumerinine and (-)-Parvistemoamide . Pure and Applied Chemistry, Grã-Bretanha, v. 77, p. 1153-1160, 2005.
4. PILLI, R. A. ; SANTOS, L. S. ; RAWAL, V. . Enantioselective Total Syntheses of (+)-Arborescidine A, (-)-Arborescidine B, and (-)-Arborescidine C. Journal of Organic Chemistry, Washington, DC, v. 69, p. 1283-1288, 2004.
5. PILLI, R. A. ; CORREA JR., I. R. . Total Synthesis and Structural Elucidation of (-)-Delactonmycin. Angewandte Chemie, Alemanha, v. 42, p. 3017-3020, 2003.
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