(+)-Sitophilure

(+)-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 

(+)-(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 

Article

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

http://www.scielo.br/scielo.php?pid=S0103-50531999000500005&script=sci_arttext

*e-mail: pilli@iqm.unicamp.br  and vbriatto@iqm.unicamp.br

Ronaldo Aloise Pilli


http://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.

As we can see in Scheme 3, the product from the reduction of 4-methyl-3,5-heptanedione with KRED-A1C has the same stereochemistry with that of the natural pheromone (+)-Sitophilure. These results clearly indicate that ketoreductases KRED-A1B, KRED-A1C and KRED-A1D showed unusual anti-Prelog selectivity, concerning reduction of the 5-keto group and successfully produced the keto alcohol with the desired stereochemistry 4S,5R. So the natural product can be produced easily from the corresponding diketone.
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). t_R=100.0 min [98%, (4S,5R)-5-hydroxy-4-methyl-3-heptanone], t_R=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%.

 

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• Mayor	Jonas Donizette (PSB)
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• Municipality	795.667 km2 (307.209 sq mi)
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History

Campinas in 1878

Maps of railways in Campinas in 1929

Regatas Club in Cambuí neighborhood.

   Instituto de Química

1. • 
2. 

 

 

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 Química
Caixa 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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Fig. 4.

1H NMR spectra (300 MHz) and structure of (R)-maconelliyl (S)-2-methylbutanoate.

Sex pheromone of the pink hibiscus mealybug,Maconellicoccus hirsutus, contains an unusual cyclobutanoid monoterpene

1. Aijun Zhang * , †, 
2. Divina Amalin ‡, 
3. Shyam Shirali *, 
4. Miguel S. Serrano §, 
5. Rosa A. Franqui ¶, 
6. James E. Oliver*, 
7. Jerome A. Klun *, 
8. Jeffrey R. Aldrich *, 
9. Dale E. Meyerdirk ∥, and 
10. Stephen L. Lapointe §

Author Affiliations

1. *Chemicals Affecting Insect Behavior Laboratory, Beltsville Agriculture Research Center West, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705; ‡Subtropical Horticulture Research Station, Agricultural Research Service, United States Department of Agriculture, Miami, FL 33158; §U.S. Horticultural Research Laboratory, Agricultural Research Service, United States Department of Agriculture, Ft. Pierce, FL 34945; ¶Agricultural Experimental Station, University of Puerto Rico, Rio Piedras, PR 00928; and ∥Plant Protection and Quarantine, Animal and Plant Health Inspection Service, Agricultural Research Service, United States Department of Agriculture, Riverdale, MD 20737

http://www.pnas.org/content/101/26/9601.full

E-mail: zhanga@ba.ars.usda.gov.

Two compounds that together constitute the female sex pheromone of the pink hibiscus mealybug (PHM),Maconellicoccus hirsutus, were isolated, identified, and synthesized. They are (R)-2-isopropenyl-5-methyl-4-hexenyl (S)-2-methylbutanoate [common name is (R)-lavandulyl (S)-2-methylbutanoate] and [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [which we refer to as (R)-maconelliyl (S)-2-methylbutanoate]. Maconelliol is an unusual cyclobutanoid monoterpene, and its structure has been established by enantioselective synthesis from precursors of known structure and configuration. A 1:5 synthetic mixture of the two RS esters (1 μg per rubber septum) proved to be a potent attractant of males in field bioassays. The pheromone component, maconelliyl 2-methylbutanoate, represents a heretofore undescribed natural product.

The 1H NMR spectrum (Fig. 4) of purified compound 2 (≈30 μg obtained by preparative GC) contained resonance for 26 protons, including six methyl groups, consistent with the assumed molecular formula C15H26O2. A doublet at 4.15 ppm (d, 2 H, J = 7.57 Hz) corresponded to a methylene in an ester (—O—CH2—CH—). Four distinct methyl signals were clearly displayed; two signals at 1.51 (s, 3 H) and 1.40 (s, 3 H) ppm from two methyl groups on the double bond (CH3—CC), and another two signals at 1.24 (s, 3 H) and 1.12 (s, 3 H) ppm corresponding to a geminal dimethyl [(CH3)2C—] or two methyl groups on quaternary carbons. The remaining two methyl groups supported the presence of a 2-methyl butyrate moiety CH3CH2CH(CH3)CO (δ 0.83, t, 3 H, J = 7.19 Hz; 1.077, d, 3 H, J = 6.82 Hz). Accordingly, in the absence of any olefinic protons, the tetra-substituted cyclobutane 2-methylbutanoate (compound 3 or 4, Fig. 3) were considered as reasonable pheromone candidates. The structure 3 was more consistent with the long-range homoallylic coupling (H—C—CC—CH) observed for the methylene group in the four-member ring. The two protons at the 4 position were not equivalent. Broad signals at δ 2.47 and 2.05 could be interpreted as the homoallylic long-range coupling with the terminal methyl groups on the double bond. Correspondingly, these two methyl groups (δ 1.51 and 1.40) also exhibited the same coupling pattern (coupling constant < 1 Hz). This homoallylic long-range coupling was confirmed by a 1H-1H COSY spectrum and decoupling experiments.

more.............

[(R)-2,2-Dimethyl-3-(1-methylethylidene)-cyclobutyl]methyl (S)-2-methylbutanoate

Formula:	C15H26O2
CAS#:
MW:	238.37

Reference(s) for synthesis of [(R)-2,2-Dimethyl-3-(1-methylethylidene)-cyclobutyl]methyl (S)-2-methylbutanoate

---

Zhang, A.J., and Nie, J.Y. 2005. Enantioselective synthesis of the female sex pheromone of the pink hibiscus mealybug, Maconellicoccus hirsutus. J. Agric. Food Chem. 53:2451-2455.

Zhang, A.J., Nie, J.Y., and Khrimian, A. 2004. Chiral synthesis of maconelliol: a novel cyclobutanoid terpene alcohol from pink hibiscus mealybug, Maconellicoccus hirsutus. Tetrahedron Lett. 45:9401-9403.

nmr..............

Reference(s)

Zhang, A.J., and Nie, J.Y. 2005. J. Agric. Food Chem. 53:2451-245

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[(R)-2,2-Dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [(R)-maconelliyl (S)-2-methylbutanoate] (2a). To a solution of 2.2 mL (20.1 mmol) of (S)-(+)-2-methylbutanoic acid {Aldrich, 99% ee, [α]²⁴ _D+24.0 (c 0.1, MeOH)} in 15 mL of benzene was treated with 2.2 mL (25.2 mmol) of oxalyl chloride and 10 μl of DMF. After 1.5 h at room temperature, the benzene and excess oxalyl chloride were removed followed by the addition of another 15 mL portion of benzene. The acid chloride residue was dissolved in 15 mL of benzene, and then a solution of 1.65 g (10.7 mmol) of 6a and 18 ml (22.2 mmol) of pyridine in 15 mL of benzene were added dropwise. After stirring at room temperature for 1 h, the solvent was removed. The residue was treated with 20 mL of water, and extracted with ether. The organic solution was washed with water, 1N hydrochloric acid, 1N aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and concentrated to afford yellow oil. Pure 2a (2.0 g, 79% yield) was obtained by chromatography (silica gel, 2% of ethyl acetate in hexanes). Optical purity: 99% ee; [α]²⁴ _D−0.79 (c 2.03, MeOH); ¹H NMR (C₆D₆): δ 0.84 (3H, t, J=7.19 Hz), 1.08 (3H, d, J=6.82 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.36 (1H, m), 1.40 (3H, bs), 1.51 (3H, t, J=1.89 Hz), 1.67 (2H, m), 2.05 (1H, m), 2.17 (1H, m), 2.27 (1H, m), 2.48 (1H, ddt, J=14.75, 8.79, 1.52 Hz), 4.15 (2H, d, J=7.57 Hz); ¹³C NMR (C₆D₆): δ 175.76, 137.48, 122.55, 65.30, 44.43, 41.39, 39.71, 28.62, 27.79, 27.13, 21.17, 19.60, 18.64, 16.85, 11.80; EI-MS m/z (%): 238 [M]⁺ (2), 136 (29), 121 (100), 107 (12), 93 (20), 81 (26), 67 (5), 57 (16), 41 (10); HREIMS: obsd. 238.1929, calcd. for C₁₅H₂₆O₂ (M⁺): 238.1933.......http://www.google.com/patents/US8062651...









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