手性双功能氨基酸酯-钛络合物催化醛的不对称硅腈化反应研究_百

1、 Asymmetric Cyanosilylation of AldehydesCatalyzed by a Chiral Bifunctional AminoAcid Ester-Ti(IV ComplexWang Fei,Xiong Yan, Liu Xiaohua, Feng Xiaoming*a Key Laboratory of Green Chemistry & Technology (Sichuan University, Ministry of Education, Collegeof Chemistry, Sichuan University, Chengdu 610064,

2、 ChinaFax +86(2885418249; E-mail: xmfengAbstractA new chiral bifunctional catalyst had been developed for the asymmetric cyanosilylationof aldehydes. The complex of 1d with Ti(O i Pr4 could efficiently promote the addition oftrimethylsilylcyanide (TMSCN to aldehydes in high yields (up to 99% with up

3、 to 76%ee. Based on the preliminary investigation, a possible catalytic cycle via dual activationhas been proposed to explain the origin of the activation and asymmetric inductivity.Keywords: aldehyde; asymmetric cyanosilylation;bifunctional catalyst; titanium1IntroductionThe asymmetric cyanation of

4、 aldehydes to give cyanohydrins is a highly versatile synthetic transformation, and the optically active cyanohydrins serve as important precursors of many useful organic compounds, such as -hydroxy acids, -amino alcohols and their derivatives.1 Over the last two decades, several efficient enzymatic

5、 methods2 and chemical methods3, including a variety of Lewis acids and Lewis bases catalysis have been employed successfully to promote the cyanosilylation of carbonyl compounds. Although significant advances in this area have been made, it is still a very active research effort to develop new cata

6、lysts for this addition reaction.In searching for new methodology, a lot of chiral bifunctional catalysts have been designed.Obviously, these catalysts must contain an acid center and a basic functional group which could simultaneously bind a basic substrate and an acidic reactant in a proper manner

7、. Shibasakis bifunctional P-oxide catalyst derived from BINOL and natural glucose4, Fengs bifunctional N-oxide3d,5,6 and amino acid salts3k were found to be very efficient for the asymmetric cyanosilylation of aldehydes, imines and ketones. Kobayashi reported that an amine might coordinate to TMSCN

8、to form the active hypervalent silicate7 and our early works revealed that titanium as a Lewis acid could efficiently catalyzed the asymmetric cyanosilylation of aldehydes8. We tired to design a new simple chiral bifunctional amine-titanium catalyst for the efficient addition of cyanide to aldehydes

9、. Herein, we wish to report its synthesis and application in the asymmetric cyanosilylation of aldehydes.2Results and discussionIn our initial studies, several amino acid esters (Figure 1, 1a-h which could be easily prepared from L-Boc-proline were mixed with Ti(O i Pr4, and the catalytic property f

10、or the cyanosilylation of benzaldehyde was investigated. As illustrated in Table 1, the reaction catalyzed by the Ti(IV complexof 1d gave higher enantioselectivity than that of ligands 1a, 1b, and 1c (entry 4 vs 1-3. More bulky substitutes at Y group of the ligand led to less enantioselectivity (ent

11、ry 5 and 6. Ligand 1g had a negative effect on the reactivity (entry 7. The tripeptide ligand 1h exhibited low enantioselectivity while keeping high reactivity (entry 8. Notably, The D-proline ligand 2 gave S product with 46% ee (entry 9, which revealed that the configuration of the proline dominate

12、d the face selectivity of the reaction. Therefore, 1d was identified as the most effective catalyst to optimize the reaction conditions. Figure 1: The Ligands Evaluated.Table 1: Asymmetric Cyanosilylation of Benzaldehyde Catalyzed by Ligand-Ti(O i Pr4 Complex.Entry Ligand Yield(%b ee(%c1 1a 92 63(R2

13、 1b 90 62(R3 1c 93 31(R4 1d 99 69(R5 1e 90 60(R6 1f 89 58(R7 1g 80 45(R8 1h 93 40(R9 2 94 46(Sa Reactions were carried out on a 0.2 mmol scale of benzaldehyde in 1.0 mL of CH2Cl2 with 20 mol%ligand and 10 mol% Ti(O i Pr4 . b Isolated yield. c The ee values were determined by HPLC on Chiral OD-H colu

14、mn after conversion to the corresponding acetates. The absolute configurations were determined by comparison of the reported optical rotation.To optimize the reaction, molar ratio of ligand 1d to Ti(O i Pr4,solvent effect, the reaction temperature, and catalyst loading were examined. All the results

15、 were summarized in Table 2. The enantioselectivity was markedly influenced by the molar ratio of ligand 1d to Ti(O i Pr4.The optimal molar ratio was 4:1, while increasing or decreasing the molar ratio led to the lower ee (entry 2 vs 1, 3. It was found that the reaction in CH2Cl2 proceeded better th

16、an in other solvents (entry 2 vs 6-8. When the reaction was carried out at -20 o C, the product was obtained with almost similar ee (entry 4. Moreover,increasing the catalyst loading decreased the ee(entry 5.Table 2: Optimization of the Reaction Conditions.Entry 1d (mol%Ti(O i -Pr4(mol%Solvent Temp(

17、 o CTime(hYield(%b ee(%c1 2010 CH 2Cl 2 0 o C 10 97 69(R 2 20 5 CH 2Cl 2 0 oC 10 99 76(R 3 20 2 CH 2Cl 2 0 oC 10 87 20(R 4 205 CH 2Cl 2 -20 oC 20 9074(R 5 40 10 CH 2Cl 2 0 oC 10 99 53(R 6 20 5 THF 0 oC 10 90 16(R 7 20 5 PhCH 3 0 oC 10 92 38(R 8 205 Et 2O 0 oC 10 9420(R aThe reaction was carried out

18、on a 0.2 M scale of benzaldehyde , TMSCN (1.5 eq. b Isolated yield. c Theee values were determined by HPLC on Chiral OD-H column.Under the optimized conditions, the asymmetric additions of TMSCN to a range of aromatic aldehydes were investigated. As delivered in Table 3, aromatic substrates includin

19、g different substituted ones afforded the desired products in excellent yields and with up to 76% ee. In general, alkyl, alkoxy at the para -position of aromatic ring and 2-Naphthaldehyde were tolerated well as the model reaction (entries 2, 5 and 7, subsitituents at the meta -position, ortho -posit

20、ion and 1-Naphthaldehyde gave lower ees (entries 3,4,6, 8.Table 3: Generality of Substrates.Entry Aldehyde Time(hYield(%b ee(%c 1 Benzaldehyde 10 99 76(R 2 4-Methylbenzaldehyde 30 86 68 3 3-Methylbenzaldehyde 12 85 20(R 4 2-Methylbenzaldehyde 12 75 32 5 4-Methoxylbenzaldehyde 12 82 72(R 6 1-Naphthal

21、dehyde 12 95 24(R 7 2-Naphthaldehyde 30 92 75(R 8 3-Chlorobenzaldehyde 12 86 58 9 4-Fluorobenzaldehyde 15 97 40(R aReactions were carried out on a 0.2 mmol scale of aldehyde in 1.0 mL of CH 2Cl 2 with 20 mol% 1d and10 mol% Ti(O i Pr4. b Isolated yield. c The ee values were determined by HPLC or GC a

22、fter conversion to the corresponding acetates.Based on the preliminary studies and steric and electronic considerations7, a possible dual activation mechanism was proposed, in which the titanium activated the aldehydes as a Lewis acid and the basic nitrogen of the pyrrolidine activated the TMSCN as

23、a Lewis base, respectively. We considered here that due to the strong coordination ability of carbonyl group to titanium, aldehyde is activated to generate a possible complex. Hypervalent silicate9, formed from amine and TMSCN, is assumed to be an active cyanide source with nucleophilicity enhanced

24、by the electron donation lewis base, and readily attack the activated aldehyde.3 ConclusionIn summary, the asymmetric cyanosilylation of aldehydes has been achieved by the bifunctional catalysis of 5 mol% of chiral amino acid ester-titanium complex giving the corresponding O-TMS ethers of cyanohydri

25、ns in high yields (up to 99% with up to 76% ee under mild conditions. Meanwhile, the ligand 1d was readily prepared from an inexpensive and readily available chiral amino acid. Further investigations should be devoted to optimization of the catalyst to enhance enantioselectivity and reactivity, and

26、clarify the mechanism of the reaction.Ack n ow l edgm en t sThe authors thank the National Natural Science Foundation of China (Nos. 202252206, 20390055 and 20472056, the Ministry of Education, China (Nos. 104209 and the Specialized Research Fund for the Doctoral Program of Higher Education (Nos. 20

27、030610021 for financial support.Ref e re nc es1 For reviews on enantioselective synthesis of cyanohydrins and their derivatives, see: (a Effenberger, F.Angew. Chem., Int. Ed. Engl. 1994, 33, 1555. (b Gregory, R. J. H. Chem. Rev. 1999, 99, 3649. (c Brunel, J.M.; Homles, L. P. Angew. Chem., Int. Ed. 2

28、004, 43, 2752. (d North, M. Tetrahedron: Asymmetry2003, 14, 147. (e Chen, F. X.; Feng, X. M. Synlett2005, 892. (f Kanai, M.; Kato, N.; Shibasaki, M. Synlett2005, 1491.2 (a Kanerva, L.T. Acta Chem. Scand. 1996, 50, 234. (b Effenberger, B. F.; Ziegler, T.; Frster, S. Angew.Chem., Int. Ed. Engl.1987, 2

29、6, 458. (c Niedermeyer, U.; Kula, M. R. Angew. Chem., Int. Ed. Engl. 1990, 29, 386. (d Han, S.; Chen, P.; Lin, G.; Huang, H.; Li, Z. Tetrahedron: Asymmetry2001, 12, 843.3 (a Belokon, Y. N; Green, B.; North, M.; Tararoy, V. I. Tetrahedron Lett. 1999, 40, 8147. (b Hamashima, Y.;Kanai, M.; Shibasaki, M

30、. J. Am. Chem. Soc. 2000, 122, 7412. (c Deng, H.; Snapper, M. L.; Hoveyda, A. H.Angew. Chem., Int. Ed. Engl. 2002, 41, 1009. (d Shen, Y. C;. Feng, X. M.; Zhang, G. L.; Jiang, Y. Z.Tetrahedron2003, 59, 5667. (e Tian, S.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900. (f Chen, F.X.; Zhou, H.; F

31、eng, X. M.; Zhang, G. L.; Jiang, Y. Z. Chem. Eur. J. 2004, 10, 4790. (g Li, Y.; He, B.; Feng, X. M.; Zhang, G. L. J. Org. Chem. 2004, 69 7910. (h He, B.;Chen, F. X.; Feng, X. M.; Zhang, G. L. Eur. J.Org. Chem. 2004, 4657. (i Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384. (j Fuerst, D. E

32、.;Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964. (k Liu, X. H.; Qin, B.; He, B.; Feng, X. M. J. Am. Chem.Soc. 2005, 127, 12224. (l Nitta, H.; Yu, D.; Mori, A.; Inoie, S. J. Am. Chem. Soc. 1992, 114, 7969. (m Hayashi, M.; Miyamoto, Y.; Oguni, N. J. Org. Chem. 1993, 58, 1515. (n Hayashi, M.; Inoue, T.; Miyamoto, Y.; Oguni, N. Tetrahedron1994, 50, 4385. (o Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8106.4 (a Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M.; J. Am. Chem. Soc. 1999, 121, 2641. (b Hamashima,Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M. Tetrahed