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Org. Synth. 2015, 92, 328-341
DOI: 10.15227/orgsyn.092.0328
4-Methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]octane
Submitted by Michael J. Di Maso, Michael A. St. Peter, and Jared T. Shaw*1
Checked by Sunna Jung and Keisuke Suzuki
1. Procedure
A. 3-(Phenylsulfonyl)propanoic acid (1). To a 1-L three-necked round-bottomed flask equipped with a 4.5 cm, oval Teflon-coated magnetic stirring bar is added maleic anhydride (10.9 g, 111 mmol, 1.0 equiv) in deionized water (370 mL). The mixture is cooled to 0 °C in an ice-water bath and, in order, benzenesulfinic acid sodium salt (20.0 g, 122 mmol, 1.1 equiv) and glacial acetic acid (8 mL, 140 mmol, 1.2 equiv) are added (Notes 1 and 2). The flask is equipped with a reflux condenser, and the reaction is heated to reflux in an oil bath (bath temp = 110 °C) open to the air for 16 h (Note 3) (Figure 1).
v92p0328-2.jpg
Figure 1. Reaction mixture formed in Step A
The hot reaction mixture is vacuum filtered through a Büchner funnel into a 1-L Erlenmeyer flask to remove small oil droplets, if present (Note 4). The filtrate is cooled to 0 °C with an ice water bath and then acidified to pH ~1 with concentrated HCl (approx. 25 mL). The precipitate is filtered on a Büchner funnel and washed with cold hexanes (150 mL). The product is transferred to a 200-mL beaker and dried in a vacuum oven (60 °C, 0.5 mmHg) overnight to give 16.7 g (70%) of 3-(phenylsulfonyl)-propanoic acid 1 as a white solid (Notes 5, 6 and 7) (Figure 2).
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Figure 2. Product formed in Step A
B. (3-Methyloxetan-3-yl)methyl 3-(phenylsulfonyl)propanoate (2). A 2-L, three-necked round-bottomed flask is equipped with a 4.5 cm, oval Teflon-coated magnetic stirring bar. Two necks are fitted with rubber septa and the middle neck is fitted with a nitrogen stopcock inlet. The flask is flame dried under vacuum and backfilled with nitrogen. The septum is removed to add 3-(phenylsulfonyl)propanoic acid (1) (13.5 g, 64.0 mmol, 1 equiv). The septum is replaced, and 315 mL of methylene chloride is added by syringe (Note 8). The septum is removed to add dimethylaminopyridine (2.31 g, 18.9 mmol, 0.3 equiv) in one portion. The septum is reinserted and (3-methyloxetan-3-yl)methanol (9.9 mL, 0.10 mol, 1.6 equiv) (Note 9) is added to the reaction mixture by syringe over one min. The reaction mixture is cooled to 0 °C in an ice water bath. After cooling, the septum is removed to allow for the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.5 g, 75.6 mmol, 1.2 equiv) (Note 10) in one portion (Figure 3).
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Figure 3. Color of reaction after addition of EDC
The septum is quickly replaced, and the reaction is allowed to warm slowly to room temperature by allowing the ice water bath to warm to room temperature overnight (Note 11). When the reaction is determined to be complete by TLC (~16 h) (Note 12), the reaction mixture is concentrated on a rotary evaporator (20 mmHg, 40 °C). The crude mixture is partitioned between diethyl ether (200 mL) and water (200 mL), and the phases are separated in a 500-mL separatory funnel. The aqueous phase is extracted with diethyl ether (2 x 200 mL). The combined organic layers are washed with 1M HCl (2 x 250 mL) and brine (300 mL) in a 1-L separatory funnel. The organic layer is dried over sodium sulfate (~10 g), gravity filtered into a tared 300-mL round-bottomed flask (Note 13), and concentrated on a rotary evaporator (40 °C, 20 mmHg) to give a viscous oil that crystallizes after several times of co-evaporation with hexanes (250 mL) (Note 14). The solid is dried overnight at 0.01 mmHg to give 15.8 g (84%) of (3-methyloxetan-3-yl)methyl 3-(phenylsulfonyl)propanoate (Notes 15, 16 and 17).
C. 4-Methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]octane (3). (3-Methyloxetan-3-yl)methyl 3-(phenylsulfonyl)propanoate (2) (13.5 g, 46.3 mmol, 1 equiv) and 60 mL of methylene chloride (Note 8) are added to a flame-dried three-necked 300-mL round-bottomed flask equipped with a 4.5 cm Teflon-coated, oval magnetic stirring bar. Two necks are fitted with rubber septa and the middle neck is fitted with a nitrogen stopcock inlet. The flask is evacuated and backfilled with nitrogen. The solution is cooled to 0 °C with an ice water bath. Once cooled, boron trifluoride diethyl etherate (1.5 mL, 12 mmol, 0.25 equiv) (Note 18) is added by syringe over a period of 15 sec and the reaction is stirred at 0 °C (Note 19). When the reaction is complete (Note 20) (~2 h), triethylamine (1.6 mL, 12 mmol, 0.25 equiv) (Note 21) is added by syringe over a period of fifteen sec (Note 22). The reaction is diluted with diethyl ether (200 mL) and water (200 mL). The mixture is transferred to a 500-mL separatory funnel and the layers are separated. The aqueous layer is extracted with diethyl ether (2 x 200 mL). The combined organics are dried over sodium sulfate (~15 g), gravity filtered into a 1-L, round-bottomed flask, and concentrated on a rotary evaporator to give 15.84 g of crude 4-methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]octane. After adding hexanes (200 mL) and ethyl acetate (200 mL), the suspension is heated until the solid dissolves completely to form a clear solution (oil bath temperature 85 ºC). The solution is allowed to cool to room temperature and then cooled to -20 °C overnight. The resulting crystals are collected by suction filtration on a Büchner funnel (Note 23), washed with 200 mL of cold hexanes, transferred to a 200 mL beaker and dried overnight at 0.01 mmHg to provide 8.8 g (65%) of 4-methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]-octane as a white powder (Notes 24, 25, and 26).
2. Notes
1. Maleic anhydride briquettes (99%) were purchased from Sigma Aldrich and were pulverized in a mortar and pestle before use. Benzenesulfinic acid, sodium salt (97%) was purchased from Sigma Aldrich (checkers) and was used without further purification. Glacial acetic acid was purchased from Tokyo Chemical Industry Co., Ltd. (checkers) and used without further purification.
2. The procedure was revised during the checking process to include cooling of the aqueous solution during the addition of reagents. In the absence of cooling the checkers observed formation of a dark brown suspension, which could be avoided by cooling the reaction solution.
3. The submitters report no change in yield when reaction times varied from 12 to 24 h.
4. The mixture is filtered while still nearly boiling (80-100 °C). Advantec qualitative filter paper, Grade 1 (checkers) or Whatman qualitative filter paper, Grade 1 (submitters) was used on the Büchner funnel. Oil droplets, which are believed to be polymeric byproducts, can be formed in the procedure. The filtration is performed to remove these oil droplets (Figure 4).
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Figure 4. Residue obtained after filtration
5. The purity of 3-(phenylsulfonyl)propanoic acid (1) was checked by quantitative NMR using 1,3,5-trimethoxybenzene (purified by sublimation: 60 ºC, 0.40 mmHg) as an internal standard. The purity of the white powder was found to be 99+% pure by weight.
6. The checkers received yields of 1 that ranged from 13.7-16.7 g (58-70%).
7. 3-(Phenylsulfonyl)propanoic acid (1) is bench stable. Physical properties: mp = 121.4-122.8 ºC; 1H NMR pdf(600 MHz, CD3 OD) δ: 2.66 (t, J = 7.4 Hz, 2H), 3.50 (t, J = 7.4 Hz, 2H), 7.66 (t, J = 7.5 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.95 (d, J = 7.5 Hz, 2H); 13C NMR pdf(150 MHz, CD3OD) δ: 28.5, 52.4, 129.3, 130.6, 135.3, 140.0, 173.4; IR(ATR) 2935 (broad), 1700, 1447, 1435, 1413; HRMS (ESI-TOF) m/z calcd for C9H9O4S (M-H)- 213.0227, found 213.0222; Anal. Calcd. for C9H10O4S: C, 50.46; H, 4.70; S, 14.97. Found: C, 50.17; H, 4.67; S, 14.71. Proton NMR was also taken in dimethylsulfoxide to test for an exchangeable proton: 1H NMR pdf(600 MHz, DMSO-d6) δ: 2.52 (t, J = 7.4 Hz, 2H), 3.52 (t, J = 7.4 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 12.57 (s, 1H).
8. The checkers purchased methylene chloride from Kanto Chemical Co., Inc., (dehydrated, ≥99.5%), and the submitters purchased methylene chloride from Fischer Scientific and purified the solvent by passage through a bed of activated alumina.
9. 4-(Dimethylamino)pyridine (99%) was purchased from Tokyo Chemical Industry Co., Ltd. (checkers) or from Acros Organics (submitters) and was used without further purification. 3-Hydroxymethyloxetane (98%) was purchased from Tokyo Chemical Industry Co., Ltd. (checkers) or from AK Scientific (submitters) and was used without further purification.
10. 1-(3-Dimethylaminoproply)-3-ethylcarbodiimide hydrochloride (98%) was purchased from Tokyo Chemical Industry Co., Ltd. (checkers) or from TCI America (submitters). In both cases the reagent was used without further purification.
11. The reaction mixture turned into a dark brown solution after addition of 1-(3-dimethylaminoproply)-3-ethylcarbodiimide hydrochloride (EDC) (Figure 3).
12. The progress of the reaction was followed by TLC analysis on silica gel with 5:95 methanol:methylene chloride and visualized with a UV-lamp. 3-(Phenylsulfonyl)propanoic acid (1), Rf = 0.2; (3-Methyloxetan-3-yl)methyl 3-(phenylsulfonyl)propanoate (2), Rf = 0.6.
13. Portions of the organic layer are filtered into the 300-mL, round-bottomed flask and concentrated repetitively to transfer the product into the flask. Alternatively, the entire organic layer can be filtered into a 1-L, round-bottomed flask for evaporation, after which the oil can be transferred to a smaller flask using methylene chloride.
14. The co-evaporations were performed three to five times using 250 mL of hexanes each time. The submitters report that the viscous oil crystallizes on standing.
15. The purity of (3-methyloxetan-3-yl)methyl 3-(phenylsulfonyl)-propanoate (2) was determined by quantitative NMR using 1,3,5-trimethoxybenzene (purified by sublimation: 60 °C, 0.40 mmHg) as an internal standard. The purity of 2 was found to be 96% pure by weight.
16. (3-Methyloxetan-3-yl)methyl 3-(phenylsulfonyl)propanoate (2) is bench stable. Physical properties: mp = 48.8-50.8 °C; 1H NMR pdf(600 MHz, CDCl3) δ: 1.31 (s, 3H), 2.81 (t, J = 7.6 Hz, 2H), 3.45 (t, J = 7.6 Hz, 2H), 4.15 (s, 2H), 4.38 (d, J = 6.0 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 7.60 (t, J = 7.6 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 2H); 13C NMR pdf(150 MHz, CDCl3) δ: 21.1, 27.6, 38.9, 51.3, 69.6, 79.4, 128.1, 129.5, 134.1, 138.4, 170.1; IR (ATR) 2951, 2936, 2874, 1726, 1299 cm-1; HRMS (ESI-TOF) m/z calcd for C14H19O5S (M+H)+ 299.0948, found 299.0954; Anal. Calcd. for C14H18O5S: C, 56.36; H, 6.08; S, 10.75. Found: C, 56.16; H, 6.00; S, 10.47.
17. The yields of the reaction ranged from 79-84%.
18. boron trifluoride diethyl etherate was purchased from Sigma Aldrich (checkers and submitters) and was distilled following a modified procedure of Armarego and Chai prior to use.2 To a 50-mL, round-bottomed flask were added calcium hydride (~2 g) and boron trifluoride diethyl etherate. The flask was fitted with a short path vacuum distillation head equipped with two receiving flasks and placed under an argon atmosphere. The flask is heated with an oil bath. Several drops are collected at 63 °C (50-51 mmHg) before changing the receiving flask and collecting the main drops (63 ºC, 50-51 mmHg) as a colorless liquid. When the distillation is complete, the flask containing boron trifluoride diethyl etherate is filled with argon and then sealed. The submitters report that using undistilled reagent leads to lower yields and difficulty in purifying the final product.
19. The checkers observed that the reaction turns light yellow after addition of boron trifluoride diethyl etherate.
20. The progress of the reaction was followed by TLC analysis on silica gel with 50:50 ethyl acetate:hexanes and visualized with potassium permanganate stain. (3-Methyloxetan-3-yl)methyl 3-(phenylsulfonyl)-propanoate (2), Rf = 0.3. 4-Methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]octane (3), Rf = 0.5.
21. Triethylamine (99.5%) was purchased from Tokyo Chemical Industry Co., Ltd. (checkers) or from Fisher Scientific (submitters) and was used without further purification.
22. The checkers observed that the reaction turns light orange upon addition of triethylamine.
23. The checkers report that concentrating the filtrate and recrystallizing the resulting solid (from 100 mL of hexane and 10 mL of ethyl acetate), additional product (3) of lower purity can be obtained.
24. Purity of 3 was determined by quantitative NMR using 1,3,5-trimethoxybenzene (99+%) as an internal standard. 4-Methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]octane (3) was found to be 98 % pure by weight.
25. Physical properties: mp = 161.3-162.6 °C; 1H NMR pdf(600 MHz, CDCl3) δ: 0.77 (s, 3H), 2.01-2.04 (m, 2H), 3.25-3.27 (m, 2H), 3.83 (s, 6H), 7.55 (t, J = 7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H); 13C NMR pdf(151 MHz, CDCl3) δ: 14.4, 30.4 (x2), 51.3, 72.7, 107.7, 128.2, 129.3, 133.7, 138.7; IR(ATR) 2958, 2936, 2882, 1273, 1229, 1144 cm-1; HRMS (ESI-TOF) m/z calcd for C14H19O5S (M+H)+ 299.0948, found 299.0955; Anal. Calcd. for C14H18O5S: C, 56.36; H, 6.08; S, 10.75. Found: C, 56.39; H, 6.04; S, 10.44. Two carbons overlap in CDCl3. A spectrum in deuterated acetonitrile provided better resolution: 13C NMR pdf(150 MHz, CD3CN) δ: 14.2, 31.0, 31.4, 51.7, 73.3, 108.4, 128.9, 130.5, 134.9, 139.9.
26. The yields of the bench stable 4-methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]octane (3) ranged from 56-65%.
Working with Hazardous Chemicals
The procedures in Organic Syntheses are intended for use only by persons with proper training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at http://www.nap.edu/catalog.php?record_id=12654). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red "Caution Notes" within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.
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3. Discussion
In 1986, Leon Ghosez published the synthesis of his orthoester sulfone reagent (Scheme 1).3 This reagent was synthesized in a two pot sequence to yield the trimethyl orthoester from cheap, readily available starting materials. The orthoester-sulfone provides two key reactive sites. The sulfone imparts nucleophilic character to the terminal carbon while the orthoester carbon can be deprotected in situ to reveal an electrophilic center. This reagent thus functions as a useful d3-synthon or homoenolate equivalent as well as a masked electrophilic carbonyl in the acid oxidation state. The reagent has found special use with enantiomerically pure epoxides and aziridines to form enantiomerically pure lactones and lactams, respectively.4,5
v92p0328-6.gif
While this reagent has been useful in many natural product syntheses, it suffers from well documented reproducibility issues in the published synthetic route (Scheme 2A).5 While an alternative synthetic route to the trimethyl orthoester is available from the Parham laboratory and was recently used in the total synthesis of alstonerine,6 the preparation warns that the product decomposes on attempting to purify the product via vacuum distillation (Scheme 2B).7 While this seems to solve the reproducibility problem, it requires significantly more expensive reagents to arrive at the desired trimethyl orthoester. The low yields increase the overall cost and render this synthetic sequence economically unviable for continued large-scale preparation. In addition to the difficulties of synthesizing this trimethyl-orthoester, the reagent suffers from often needing to be used in 2,8 3,9 or even 4 equivalents10 upon optimization of the desired reaction.
v92p0328-7.gif
In our studies to synthesize 6,6'-binaphthopyranone natural products, we encountered difficulties in synthesizing Ghosez's reagent and developed a reliable route to an analogous reagent.11 Replacing the trimethyl orthoester with a 2,6,7-trioxabicyclo[2.2.2]octane (OBO) orthoester, originally developed by Corey,12 allowed for a facile synthesis from mostly commodity chemicals on multi-gram scale to provide a reagent that is bench stable for months without degradation.

References and Notes
  1. Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California, 95616, jtshaw@ucdavis.edu. We thank the NIH/NIAID (R01AI08093) for support. M.J.D. thanks the University of California, Davis for Bradford Borge and Dow/Corson Fellowships and the Department of Education for a GAANN fellowship.
  2. Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals (Sixth Edition), Chai, W. L. F. A. L. L., Ed. Butterworth-Heinemann: Oxford, 2009.
  3. De, L. S.; Nemery, I.; Roekens, B.; Carretero, J. C.; Kimmel, T.; Ghosez, L. Tetrahedron Lett. 1986, 27, 5099-102.
  4. Carretero, J. C.; De, L. S.; Ghosez, L. Tetrahedron Lett. 1987, 28, 2135-8.
  5. Craig, D.; Lu, P.; Mathie, T.; Tholen, N. T. H. Tetrahedron 2010, 66, 6376-6382.
  6. Craig, D.; Goldberg, F. W.; Pett, R. W.; Tholen, N. T. H.; White, A. J. P. Chem. Commun. 2013, 49, 9275-9277.
  7. Parham, W. E.; McKown, W. D.; Nelson, V.; Kajigaeshi, S.; Ishikawa, N. J. Org. Chem. 1973, 38, 1361-5.
  8. Surivet, J.-P.; Vatele, J.-M. Tetrahedron Lett. 1996, 37, 4373-4376.
  9. 9. Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40, 3842-3846.
  10. Nicolaou, K. C.; Patron, A. P.; Ajito, K.; Richter, P. K.; Khatuya, H.; Bertinato, P.; Miller, R. A.; Tomaszewski, M. J. Chem. - Eur. J. 1996, 2, 847-868.
  11. Grove, C. I.; Di Maso, M. J.; Jaipuri, F. A.; Kim, M. B.; Shaw, J. T. Org. Lett. 2012, 14, 4338-4341.
  12. Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571-5574.

Appendix
Chemical Abstracts Nomenclature (Registry Number)

Maleic Anhydride: 2,5-Furandione; (108-31-6)

Benzenesulfinic acid sodium salt: Benzenesulfinic acid, sodium salt; (873-55-2)

Glacial acetic acid: acetic acid; (64-19-7)

3-(Phenylsulfonyl)propanoic acid; (1) (10154-71-9)

Dimethylaminopyridine: 4-Pyridinamine, N,N-dimethyl-; (1122-58-3)

(3-Methyloxetan-3-yl)methanol: 3-Methyl-3-oxetanemethanol; (3143-02-0)

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide: 1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride; (25952-53-8)

(3-Methyloxetan-3-yl)methyl 3-(phenylsulfonyl)propanoate; (2) (1394135-60-4)

Boron trifluoride diethyl etherate: Boron, trifluoro[1,1'-oxybis[ethane]]-, (T-4)-; (109-63-7)

Triethylamine: Ethanamine, N,N-diethyl-; (121-44-8)

4-Methyl-1-(2-(phenylsulfonyl)ethyl)-2,6,7-trioxabicyclo[2.2.2]octane; (3) (1394135-62-6)

Jared Shaw received his Ph. D. from Keith Woerpel at UC Irvine in 1999 and then moved to Harvard as an NIH postdoctoral fellow with David Evans. Dr. Shaw became an institute fellow at the Institute for Chemistry and Cell Biology (ICCB) at Harvard Medical School where he helped found the Center for Chemical Methodology and Library Development (CMLD) in 2003, which later became part of the Broad Institute of Harvard and MIT. In 2007, Jared joined the faculty of the University of California, Davis as an assistant professor and was promoted to associate professor in 2012. He works on the development of new methods for the synthesis of natural products and other molecules that modulate biological phenomena.
Michael J. Di Maso received his B.A./M.S. in chemistry from Northwestern University, where he worked under the supervision of Professor Karl A. Scheidt. In 2011, he began graduate research under the supervision of Jared Shaw at the University of California, Davis. His graduate research focuses on synthetic methodology and alkaloid natural product total synthesis.
Michael St. Peter is an undergraduate researcher at the University of California, Davis majoring in Pharmaceutical Chemistry and Food Science. He began working in Prof. Shaw's lab in 2014 on synthetic methodology and natural product total synthesis.
Sunna Jung was born in 1988 in Seoul, Korea. She received her B. Sc. degree in dept. of chemistry from Pohang University of Science and Technology (POSTECH) in 2010. Then she moved to Tokyo Institute of Technology and obtained M. Sc. Degree in 2012 under the supervision of Prof. Keisuke Suzuki. Currently, she is continuing her Ph. D. research in the same group working on cyclophane chemistry.