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Catalytic Enantioselective Synthesis of 2,6-Disubstituted Dihydropyrones by Hetero-Diels–Alder Reaction Using Chiral BINOL-Ti(IV) Complex Enantiosel ctiveSynthesi of2,6-DisubstiutedDihydropyrones Huang,b Xiaoming Feng,*a Bin Wang,b Guolin Zhang,c Yaozhong Jiang*b Yaozong a
Abstract: Highly efficient enantioselective synthesis of optically active 2,6-disubstituted dihydropyrones was easily available by hetero-Diels–Alder reaction of aldehydes in presence of 20 mol% (R)-(+)-BINOL-Ti(IV) complex under mild reaction conditions. All reaction products were obtained in moderate to excellent yields (up to 99%) with high enantioselectivities (up to 99% ee). Key words: hetero-Diels–Alder reaction, dihydropyrones, BINOL
Unsaturated pyrones, a class of compounds with extensive use in organic synthesis,1 are usually prepared by heteroDiels–Alder reaction of activated dienes (such as Danishefsky’s diene) and aldehydes or ketones. During the last two decades, asymmetric catalysis of the above reaction was reported by a number of groups.2 Recently, we synthesized dihydropyrones via the same reaction using chiral (R)-H8-BINOL-Ti(IV) complex, in which the aromatic, heteroaromatic, conjugated and aliphatic aldehydes could afford the corresponding product in moderate to high isolated yield with quite high enantioselectivity.3
TMSO
TMSO
TMSO 1
Figure 1
OCH3
OCH3
OCH3
OCH3
TMSO 3
2
OCH3
TMSO 4
5
Dienes 1–5
It is known that the substituted dihydropyrones could be prepared by replacing Danishefsky’s diene with substituted derivates (Figure 1). For example, the 2,5- disubstituted dihydropyrones could be synthesized by heteroDiels–Alder reaction of diene 2. 2,3-Disubstituted dihy-
dropyrones could also be prepared through the same reaction of diene 3 with aldehydes. Similarly, asymmetric synthesis of 2,3,5-trisubstituted products was the same case when compound 4 was used as substrate. To this day, there have been some examples of synthesis of the above substituted dihydropyrones reported by some investigators when the hetero-Diels–Alder reaction of Danishefsky’s diene 1 was studied,4,5 while the synthesis of 2,6disubstituted dihydropyrones, which are also important intermediates in organic synthesis, has not yet been fully studied except for a few examples. Danishefsky’s group developed their synthesis and application using Eu(fod)3, MgBr2 and BF3 as catalysts.6 Low enantioselectivity (18% ee) was achieved by Togni using chiral vanadium as a catalyst in the early 90’s.2b In addition, it seemed as if the studies on catalytic enantioselective synthesis of the 2,6disubstituted dihydropyrones ceased thereafter, to the best of our knowledge. Based on Keck’s investigation of the hetero-Diels–Alder reaction using (R)-(+)-BINOL-Ti(IV) complex and our previous results, we hoped that the method of enantioselective hetero-Diels–Alder reaction of diene 5 with aldehydes in the presence of (R)-(+)-BINOLs/ Ti(i-PrO)4 complex was easily available to yield optically active 2,6-disubstituted dihydropyrones. At first, compound 5 was synthesized in a manner similar to Brassard’s diene (Scheme 1)7. Initial material 6 were treated with HC(OCH3)3 and catalytic amount of H2SO4 to afford the precursor 7, to which were added LDA and TMSCl to yield the target diene 5. With the diene in hand, our studies started with PhCHO as a test substrate (Scheme 2). The results were summarized in Table 1. Initial hetero-Diels–Alder reactions were performed by generating the catalyst (20 mol%) from (R)-
OCH3 O
O
HC(OMe)3, H2SO4
OCH3O
1) LDA/THF, –78 °C 2) TMSCl TMSO
6
Scheme 1
The synthesis of compound 5
Synlett 2002, No. 12, Print: 02 12 2002. Art Id.1437-2096,E;2002,0,12,2122,2124,ftx,en;U07902ST.pdf. © Georg Thieme Verlag Stuttgart · New York ISSN 0936-5214
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5
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Sichuan Key Laboratory of Green Chemistry and Technology, The Faculty of Chemistry, Sichuan University, Chengdu 610064, China Fax +86(28)85412907; E-mail:
[email protected] b Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China c Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China Received 27 September 2002
(+)-H8-BINOL and Ti(i-PrO)4 in toluene (1 mL), after which PhCHO (0.25 mmol) and diene 5 (0.30 mmol) were added sequentially. Stirring for 48 h at 0 °C followed by usual workup produced the dihydropyrone in quite high enantioselectivity (98% ee) but with low yield (23%) (entry 1). Further efforts to increase the yield largely failed, only a slightly higher yield (47%) was achieved when 1.5 equivalents of diene per PhCHO were utilized (entry 2). Surprisingly, lower yield (28%) and decreased enantiomeric excess (78% ee) were obtained when the reaction was carried out at room temperature (entry 3). Similarly, (R)-(+)-BINOL-Ti(IV) complex was also used instead of (R)-H8-BINOL-Ti(IV) catalyst to catalyze this reaction under the above reaction conditions. To our surprise, the yield (49%) was higher than that in (R)-H8-BINOL-Ti(IV) catalytic system while the ee was almost unchanged (entry 1). Good yield (70%) was obtained when the amount of diene per PhCHO was changed from 1.2 equivalents to 1.5 equivalents (entry 2), which indicated that the concentration of substrate was important to the reaction yield. Further studies on temperature effect showed that reaction temperature was important for the reaction activity. The best results were obtained at 0 °C (entry 2). Some solvents, including CH2Cl2, THF, Et2O and C6H6, were screened. It indicated that toluene was the optimal solvent in (R)-BINOL-Ti(IV) catalyst. Based on this, we proposed that under the same reaction conditions, the catalytic activity of (R)-BINOL-Ti(IV) complex was higher than that of (R)-H8-BINOL-Ti(IV) catalyst in this hetero-Diels–Alder reaction. O + R
Table 1 Hetero-Diels–Alder reaction of Diene 5 with aldehydes promoted by BINOL-Ti(IV) complexa Entry Substrate
Ratiob
Temp. (°C)
Yield (%)c
Ee (%)d
1
PhCHO
1.2:1
0
49(23)
97(98)
2
PhCHO
1.5:1
0
70(47)
98(98)
3
PhCHO
1.5:1
rt
60(28)
98(78)
4
p-CH3C6H4CHO
1.5:1
0
93
98
5
m-CH3C6H4CHO
1.5:1
0
73
99
6
o-CH3C6H4CHO
1.5:1
0
55
88
7
p-ClC6H4CHO
1.5:1
0
81
99
8
m-ClC6H4CHO
1.5:1
0
83
98
9
o-ClC6H4CHO
1.5:1
0
90
83
10
m-CH3OC6H4CHO
1.5:1
0
61
98
11
p-NO2C6H4CHO
1.5:1
0
99
99
a
The reactions were stopped after 48 h. The ratio of diene 5 to aldehydes. c All yields refer to chromatographically isolated pure compounds, whose structures were confirmed by 1H NMR and 13C NMR analyses. The yields in parentheses were obtained by the catalysis of (R)-H8BINOL-Ti(IV) complex. d Enantiomeric excesses were determined by HPLC analysis using Daicel Chiralcel OD column, and enantiomeric excesses in parentheses were obtained by the catalysis of (R)-H8-BINOL-Ti(IV) complex. b
O
OCH3 1) 20% BINOL-Ti(IV), 0 °C H 2) TFA/CCl4
TMSO
Scheme 2
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Enantioselective Synthesis of 2,6-Disubstituted Dihydropyrones
O
H R
Hetero-Diels–Alder reaction of aldehydes
Encouraged by the result obtained above (entry 2), we applied the optimal conditions to the reaction of substituted aldehydes. As shown in Table 1, moderate to excellent yield and quite high enantioselectivity were achieved (entries 4–11). The experimental results revealed the negative effect on enantioselectivity by ortho-substituents on benezaldehyde. Hetero-Diels–Alder reaction of orthochloro and ortho-methylbenzaldehydes yielded the corresponding dihydropyrones with 88% and 83% ee, respectively, which were lower than enantioselectivities (98– 99% ee) afforded by hetero-Diels–Alder reaction of metaor para-substituted aldehydes (entries 4–9). This was probably due to the strong steric hindrance effect at the ortho-substituents, which significantly weakened the coordination of the aldehydes and consequently lowered the enantioselectivity of reaction, which was identical to our previous result about hetero-Diels–Alder reaction of Danishefsky’s diene 1.3 However, as can be seen from the data for reaction of substituted aldehydes, there was no apparent electronic influence on enantiocontrol. Excellent enantioselectivities were also achieved when strong elec-
tron-withdrawing (nitro) and electron-donating (methoxy) substituted aldehydes were used as substrates (entries 10 and 11). These results were consistent with the expectation that the electronic effects from the starting materials were less significant than the steric hindrance effect on the enantioselectivity of the reaction. In conclusion, we reported a highly enantioselective hetero-Diels–Alder reaction of aldehydes in the presence of 20 mol% (R)-(+)-BINOL-Ti(IV) complex to afford 2,6-disubstituted dihydropyrones in moderate to excellent yields with high ee. Since (R)-BINOL is easily available and the reaction conditions are mild, this method is expected to have excellent potential for synthetic purpose. Future efforts will be devoted to further investigate the difference among various dienes and search for effective catalysts for aliphatic aldehyde and ketone systems. In a typical experimental procedure, a mixture of (R)BINOL (15.8 mg, 0.055 mmol), Ti(i-PrO)4 (1 M in toluene, 50 L, 0.05 mmol), and activated powered 4 Å MS (120 mg) in toluene (1 mL) was heated at 35 °C for 1 h. The red mixture was cooled to room temperature, and PhCHO (26 mL, 0.25 mmol) was added. The mixture was stirred for 10 min, cooled to 0 °C, and diene 5 (69.7 mg, 0.375 mmol) was added. The contents were stirred at 0 °C for 48 h, then saturated NaHCO3 (2mL) was added to destroy the catalyst. The mixture was stirred for 15 min, fil-
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tered through a plug of Celite®. The organic layer was separated, and the aqueous layer was extracted with ether (5 ´ 3 mL). The combined organic layers were dried over Na2SO4 and concentrated. The intermediate product was dissolved in CCl4 (5 mL) and then TFA was added to this solution (5 drops). After the mixture was stirred overnight to afford the final product (monitored by TLC), saturated NaHCO3 (2 mL) was added, then the contents were stirred for 15 min, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (5 ´ 3 mL), then the combined organic layers were dried over Na2SO4 and concentrated. The crude final product was purified by flash chromatography (petroleum ether–ethyl acetate, 5:1) to afford (R)-6-methyl-2-phenyl-2, 3-dihydro-4H-pyran-4one (33 mg, 70%) as red solid. HPLC analysis revealed that the dihydropyrone had an ee of 98% [Daicel Chiralcel OD column; i-PrOH–hexane, 90:10, 254 nm UV detector, 10.07 min (S) and 12.16 min (R)] using a racemic sample as reference.
Acknowledgment We are grateful for the financial support from the National Science Foundation of China (No.29832020 and No.20072037) and the Ministry of Education, P. R. China.
References (1) For reviews, see: (a) Danishefsky, S. J. Chemtracts 1989, 273. (b) Danishefsky, S. J.; De Ninno, M. P. Angew. Chem., Int. Ed. Engl. 1987, 26, 15. (c) Danishefsky, S. J. Aldrichimica Acta 1986, 19, 59. (d) Jørgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 3558; for application in total synthesis. (e) Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org. Lett. 2000, 2, 231.
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(2) For hetero-Diels–Alder reaction of Danishefsky’s diene with aldehydes, see: (a) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 310. (b) Togni, A. Organometallics 1990, 9, 3106. (c) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907. (d) Gao, Q.; Ishihara, K.; Maruyama, T.; Mouri, M.; Yamamoto, H. Tetrahedron 1994, 50, 979. (e) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998. (f) Hanamoto, T.; Furuno, H.; Sugimoto, Y.; Inanaga, J. Synlett 1997, 79. (g) Schaus, S. E.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 403. (h) Simonsen, K. B.; Svenstrup, N.; Roberson, M.; Jørgensen, K. A. Chem.–Eur. J. 2000, 6, 123. (i) Doyle, M. P.; Phillips, I. M.; Hu, W. J. Am. Chem. Soc. 2001, 123, 5366. (j) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc. 2002, 124, 10. (k) For hetero-Diels–Alder reaction of Danishefsky’s diene with ketones, see: Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jørgensen, K. A. J. Am. Chem. Soc. 1998, 120, 8599. (3) (a) Wang, B.; Feng, X.; Cui, X.; Liu, H.; Jiang, Y. Chem. Commun. 2000, 1605. (b) Wang, B.; Feng, X.; Huang, Y.; Liu, H.; Cui, X.; Jiang, Y. J. Org. Chem. 2002, 67, 2175. (4) (a) See refs.2a,b,d (b) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. Org. Lett. 2002, 4, 1221. (5) Compound 2 and 4 were also synthesized by us and applied to the hetero-Diels–Alder reaction of aldehydes promoted by BINOLs-Ti complexes. It was found that (R)-H8-BINOLTi(IV) catalytic system could give better enantioselectivity and diastereoselectivity than (R)-BINOL-Ti(IV) complex. (6) (a) Danishefsky, S.; Harvey, D. F.; Quallich, G.; Uang, B. J. J. Org. Chem. 1984, 49, 392. (b) Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F. J. Am. Chem. Soc. 1984, 106, 2455. (c) Danishefsky, S. J.; Pearson, W. H.; Segmuller, B. E. J. Am. Chem. Soc. 1985, 107, 1280. (7) (a) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 20, 4911. (b) Midland, M. M.; Graham, R. S. J. Am. Chem. Soc. 1984, 106, 4294.
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