COMMUNICATION DOI: 10.1002/chem.201303650
syn- and Enantioselective Henry Reactions of Aliphatic Aldehydes and Application to the Synthesis of Safingol Dan-Dan Qin,[a] Wen Yu,[a] Jie-Dan Zhou,[a] Yan-Cheng Zhang,[b] Yuan-Ping Ruan,[a] Zhao-Hui Zhou,[a] and Hong-Bin Chen*[a] Dedicated to Prof. Khi-Rui Tsai on the occasion of his 100th birthday
Vicinal (b-) amino alcohol motifs are important and ubiquitous structural features in a diverse range of natural products and pharmaceutical agents as well as chiral ligands and auxiliaries used in (catalytic) asymmetric synthesis. In most cases, the biological activities and asymmetric induction capabilities of vicinal amino alcohols strongly depend upon their relative (absolute) configurations. Generally, chiral pool approaches were used to prepare such stereospecific vicinal amino alcohols.[1] However, some side effects, such as multistep reaction sequences, expensive reagents, and sometimes harsh reaction conditions, greatly constrained their practical applications. Consequently, the development of mild, efficient, and economic methods is still of significant importance. The catalytic asymmetric Henry (nitroaldol) reaction is a highly atom-economic and powerful tool in organic synthesis because the resulting b-nitro alcohols can easily be transformed into vicinal amino alcohols and other important intermediates.[2] Over the past two decades, an extensive collection of efficient catalysts have been developed to promote Henry reactions between carbonyls and nitromethane with high enantioselectivity.[3] In contrast, diastereo- and enantioselective Henry reactions still remain a great challenge because it is very difficult to rigorously control the stereochemistry of the two carbon stereocenters formed simultaneously and, hitherto, only a few successful examples in syn-selective[4] and anti-selective[5] Henry reactions have been reported. Chiral b-amino alcohols are one type of the most important ligands that are widely used in asymmetric catalysis,
whereas their applications in diastereo- and enantioselective Henry reactions are less explored.[6] Previously, we reported that an easily available b-amino alcohol copper catalyst 1 a efficiently promoted Henry reactions between nitromethane and aromatic aldehydes.[7] Herein, we report the results of recent studies into the application of b-amino alcohol ligands 1 and 2 (Scheme 1) in syn- and enantioselective
[a] D.-D. Qin, W. Yu, J.-D. Zhou, Prof. Y.-P. Ruan, Prof. Dr. Z.-H. Zhou, Prof. Dr. H.-B. Chen Department of Chemistry and State Key Laboratory of Physical Chemistry for Solid Surfaces College of Chemistry and Chemical Engineering Xiamen University, Xiamen, Fujian 361005 (P. R. China) Fax: (+ 86) 592-2185192 E-mail: [email protected]
Entry
[b] Y.-C. Zhang Nantong Huafeng Chemical Co. Ltd., Nantong Jiangsu, 226531 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303650.
Chem. Eur. J. 2013, 19, 16541 – 16544
Scheme 1. Chiral amino alcohol ligands.
Henry reactions and application to the synthesis of safingol. In the preliminary studies, ligands 1 and 2 were evaluated by using hexanal and 4-chlorobenzaldehyde as model substrates and nitroethane as a standard nucleophile. When the reaction was performed in the presence of 10 mol % of catalyst, in situ generated from the coordination reaction of amino alcohol and CuACHTUNGRE(OAc)2·H2O, both substrates gave the corresponding Henry adducts with different syn/anti ratios. For hexanal, ligands 1 a–e were superior to 2 a–e in terms of Table 1. Effect of the ligand structure upon the Henry reaction.[a]
1 2 3 4 5 6 7 8 9 10
Ligand
Yield [%][b]
1a 1b 1c 1d 1e 2a 2b 2c 2d 2e
72 66 61 38 70 23 48 24 25 46
d.r.[c] (syn/anti)
ee [%][c] (syn/anti)
2.9:1 7.6:1 3.3:1 3.0:1 4.8:1 1.8:1 1.3:1 1.5:1 1.2:1 1.9:1
95:81 97:72 88:73 79:30 88:75 3.5:5.9 33:21 37:34 44:31 38:14
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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diastereoselectivity and enantioselectivity (Table 1), among which 1 b distinguished itself as the best ligand, which resulted in a 7.6:1 syn/anti ratio and 97 % ee for syn (Table 1, entry 3), whereas for 4-chlorobenzaldehyde, 1 b was still the best ligand but could only give a 2.9:1 syn/anti ratio even under optimal reaction conditions (not listed herein). Considering that aliphatic b-nitro alcohols are also highly important in organic synthesis,[8] we only devoted our efforts to optimize the reaction conditions for aliphatic aldehydes. In the subsequent experiments, the effects of various solvents were examined. The results are summarized in Table 2 and clearly show that the reaction was highly sensitive to the nature of solvent employed, and THF was the best reac-
Table 4. Henry reaction of aliphatic aldehydes with nitroethane.[a]
Table 2. Effects of solvents upon the Henry reaction.[a]
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
Entry
Solvent
1 2 3 4 5 6 7 8 9
MeOH EtOH iPrOH CH2Cl2 THF Et2O Dioxane CH3CN EtOAc
Yield [%]
[b]
60 75 79 47 66 51 64 41 64
[c]
d.r. (anti/syn)
ee [%]
1.7:1 2.6:1 5.0:1 4.4:1 7.6:1 6.5:1 5.6:1 5.8:1 5.5:1
61:27 79:43 94:70 88:50 97:72 95:63 93:66 93:54 94:70
[c]
(syn/anti)
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
tion medium in terms of diastereomeric ratio (d.r.; syn/anti) and ee values for the syn adduct (Table 2, entry 5). Catalyst loadings also had a significant effect on the reaction (Table 3). When the amount of catalyst increased from 1 to 10 mol %, the isolated yield, d.r. (syn/anti), and ee value increased concomitantly (Table 3, entries 1–4). However, attempts to access higher d.r. (syn/anti) by raising the catalyst loading failed, 15 and 20 mol % of catalysts gave lower diastereoselectivity (entries 5 and 6). With the optimized reaction conditions in hand, a variety of aliphatic aldehydes were tested as substrates to demonstrate the reaction versatility (Table 4). In general, all the substrates proceeded well to afford the Henry adducts in
Entry
R1
1 2 3 4 6 7 8 9 10 11 12
CH3ACHTUNGRE(CH2)2 CH3ACHTUNGRE(CH2)3 CH3ACHTUNGRE(CH2)4 CH3ACHTUNGRE(CH2)5 CH3ACHTUNGRE(CH2)6 CH3ACHTUNGRE(CH2)10 C6H5CH2CH2 ACHTUNGRE(CH3)2CH2 ACHTUNGRE(CH3)2CHCH2 c-hexyl c-pentyl
Yield [%][b] 75 70 66 80 83 64 72 69 66 73 74
d.r.[c] (syn/anti)
ee [%][c] syn/anti
4.5:1 7.0:1 7.6:1 6.5:1 6.9:1 7.1:1 6.3:1 7.0:1 5.2:1 15.3:1 9.5:1
90:55 97:73 97:72 97:76 95.68 94:72 99:69 98:88 98:82 99:70 96:78
moderate to good yields with modest to excellent syn selectivities and excellent enantioselectivities. Further analysis revealed that the d.r. (syn/anti) was almost not affected by the chain length of linear aliphatic aldehydes (Table 4, entries 2–8) except that for butanal (entry 1); in addition, abranched isobutanal gave a higher d.r. (syn/anti) than that of b-branched isopentanal (entries 9 and 10), whereas in the case of aliphatic cyclic aldehydes, the corresponding Henry adducts were obtained with higher syn selectivity (entries 11 and 12), and cyclohexanecarboxaldehyde even gave up to 15.3:1 syn/anti ratio and 99 % ee for syn. In addition, 2-nitroethanol was also examined as the nucleophile towards different aliphatic aldehydes. The results were summarized in Table 5. It was apparent that the isolated yields and d.r. (syn/anti) of the produced 2-nitro-1,3-diols were higher than those obtained when using nitroethane, for example, the reaction of n-octanal with 2-nitroethanol gave the syn-adduct in 86 % isolated yield with 18.6:1 syn/anti ratio and 99 % ee for syn (entry 4). A likely reason for this was that the hydroxyl group of 2-nitroethanol formed additional intermolecular hydrogen bonds and hence greatly stabilized the reaction transition states.[7] Single-crystal X-ray diffraction analysis confirmed that our catalyst exclusively preferred the formation of the syn diastereomer and all the major syn isomers possessed (R,R)-configurations (see the Supporting Information). Finally, the practical utility of this syn-selective Henry reaction was demonstrated by the short asymmetric synthesis
Table 3. Effect of catalyst loading upon the Henry reaction.[a] Table 5. Henry reaction of aliphatic aldehydes with nitroethanol.[a]
Entry
Cat. [%]
1 2 3 4 5 6
1 2.5 5 10 15 20
Yield [%][b] 20 23 51 66 61 69
d.r.[c] (anti/syn)
ee [%][c] (syn/anti)
1.3:1 4.0:1 5.6:1 7.6:1 3.8:1 5.1:1
13:3 84:36 95:48 97:72 92:63 94:70
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
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Entry
R1
1 2 3 4 5
ACHTUNGRE(CH3)2CHCH2 CH3ACHTUNGRE(CH2)4 CH3ACHTUNGRE(CH2)5 CH3ACHTUNGRE(CH2)6 c-hexyl
Yield [%][b] 82 93 84 86 92
d.r.[c] (syn/anti)
ee [%][c] syn/anti
4.3:1 14.9:1 7.9:1 18.6:1 14.2:1
96:71 99:3.6 94:59 99:43 97:62
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16541 – 16544
Synthesis of Safingol
COMMUNICATION Keywords: aliphatic aldehydes · amino alcohols asymmetric synthesis · Henry reactions · safingol
Scheme 2. Synthesis of safingol.
of safingol 20 (Scheme 2). Safingol is a synthetic sphingosine that exhibits antineoplastic and antipsoriatic activities.[9] It is currently under a phase I clinical trial in combination with cisplatin for the treatment of advanced solid tumors.[10] In addition, several in vitro and in vivo studies demonstrated that safingol augmented the efficacy of other chemotherapeutic agents in a variety of tumor cell lines.[11] Numerous synthetic approaches have been developed to access safingol;[5g, 12] however, most of them were lengthy and hence not economic and suitable for large-scale preparation. Whereas based on our catalyst, safingol could be prepared in two steps with satisfactory overall yield. The reaction of hexadecanal with 2-nitroethanol in the presence of 10 mol % of catalyst ent-1 b furnished syn-nitro alcohol 19 in 79 % isolated yield with a d.r. (syn/anti) of up to 16.5:1 and an ee of up to 98 % for syn. Further experiments showed that when the reaction was performed on a 10.0 mmol scale, pure (2S,3S)-19 could be obtained by recrystallization with a yield of 68 %; in addition, ligand ent-1 b could be easily recovered by a simple operation (see the Supporting Information). Subsequently, 19 was catalytically hydrogenated to give safingol 20 in 72 % yield. Notably, in comparison with the La-LiBINOL (LLB) catalyst,[5g] our catalytic system seemed more simpler, milder, and efficient. In summary, we have successfully developed an amino alcohol copper(II) catalyst for syn- and enantioselective Henry reaction of aliphatic aldehydes. By using this catalyst, safingol was prepared in two steps with a 57 % overall yield. Further applications of this catalyst towards some bioactive molecules are currently in progress.
Experimental Section General method: Nitroethane (0.72 mL, 10.0 mmol) or 2-nitroethanol (0.273 g, 3.0 mmol) and aliphatic aldehyde (1.0 mmol) were sequentially added to a solution of CuACHTUNGRE(OAc)2·H2O (20 mg, 0.10 mmol) and ligand 1 b (26.7 mg, 0.10 mmol) in THF (3 mL). The reaction mixture was stirred at 20 8C for 48–72 h, and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether.
Acknowledgements This work was financially supported by the Fundamental Research Funds for the Central Universities (No. 2010121014) and the Natural Science Foundation of Fujian Province (No. 2013J10011).
Chem. Eur. J. 2013, 19, 16541 – 16544
·
[1] For reviews, see: a) O. K. Karjalainen, A. M. P. Koskinen, Org. Biomol. Chem. 2012, 10, 4311 – 4326; b) S. C. Bergmeier, Tetrahedron 2000, 56, 2561 – 2576. [2] For reviews, see: a) F. A. Luzzio, Tetrahedron: Asymmetry 2001, 12, 915 – 945; b) N. Ono, The Nitro Group in Organic Synthesis WileyVCH, New York, 2001. [3] For recent reviews, see: a) N. Ananthi, S. Velmathi, Ind. J. Chem. B 2013, 52, 87 – 108; b) Y. Alvarez-Casao, E. Marques-Lopez, R. P. Herrera, Symmetry 2011, 3, 220 – 245; c) J. Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua, Tetrahedron: Asymmetry 2006, 17, 3315 – 3326; d) C. Palomo, M. Oiarbide, A. Laso, Eur. J. Org. Chem. 2007, 2561 – 2574. [4] For selected syn-selective Henry reactions, see: a) W. Jin, X. C. Li, B. S. Wan, J. Org. Chem. 2011, 76, 484 – 491; b) L. Cheng, J. X. Dong, J. S. You, G. Gao, J. B. Lan, Chem. Eur. J. 2010, 16, 6761 – 6765; c) K. Kanagaraj, P. Suresh, K. Pitchumani, Org. Lett. 2010, 12, 4070 – 4073; d) T. Arai, R. Takashita, Y. Endo, M. Watanabe, A. Yanagisawa, J. Org. Chem. 2008, 73, 4903 – 4906; e) Y. Sohtome, N. Takemura, K. Takada, R. Takagi, T. Iguchi, K. Nagasawa, Chem. Asian J. 2007, 2, 1150 – 1160; f) Y. Sohtome, Y. Hashimoto, K. Nagasawa, Eur. J. Org. Chem. 2006, 2894 – 2897; g) H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki, J. Org. Chem. 1995, 60, 7388 – 7389. [5] For selected anti-selective Henry reactions, see: a) K. Lang, J. Park, S. Hong, Angew. Chem. Int. Ed. 2012, 51, 1620 – 1624; b) K. Xu, G. Y. Lai, Z. G. Zha, S. S. Pan, H. W. Chen, Z. Y. Wang, Chem. Eur. J. 2012, 18, 12357 – 12362; c) D. Uraguchi, S. Nakamura, T. Ooi, Angew. Chem. 2010, 122, 7724 – 7727; Angew. Chem. Int. Ed. 2010, 49, 7562 – 7565; d) T. Nitabaru, A. Nojiri, M. Kobayashi, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 13860 – 13869; e) S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga, M. Shibasaki, Angew. Chem. 2008, 120, 3274 – 3277; Angew. Chem. Int. Ed. 2008, 47, 3230 – 3233; f) D. Uraguchi, S. Sakaki, T. Ooi, J. Am. Chem. Soc. 2007, 129, 12392 – 12393; g) T. Ooi, K. Doda, K. Maruoka, J. Am. Chem. Soc. 2003, 125, 2054 – 2055. [6] a) Z. L. Guo, S. Zhong, Y. B. Li, G. Lu, Tetrahedron: Asymmetry 2011, 22, 238 – 245; b) M. Zielin´ska-Błajet, J. Skarz˙ewski, Tetrahedron: Asymmetry 2011, 22, 351 – 355; c) H. Y. Kim, K. Oh, Org. Lett. 2009, 11, 5682 – 5685. [7] D. D. Qin, W. H. Lai, D. Hu, Z. Chen, A. A. Wu, Y. P. Ruan, Z. H. Zhou, H. B. Chen, Chem. Eur. J. 2012, 18, 10515 – 10518. [8] M. G. A. Shvekhgeimer, Russ. Chem. Rev. 1998, 67, 35 – 68. [9] M. A. Dickson, R. D. Carvajal, A. H. J. Merrill, M. Gonen, L. M. Cane, G. K. Schwartz, Clin. Cancer Res. 2011, 17, 2484 – 2492. [10] USP Dictionary of USAN and International Drug Names; US Pharmcopia: Rockville, MD, 2000; p 636. [11] a) L. U. Ling, H. Lin, K. B. Tan, G. N. C. Chiu, Int. J. Oncol. 2009, 35, 1463 – 1471; b) T. K. Hoffmann, K. Leenen, D. Hafner, V. Balz, C. D. Gerharz, A. Grund, H. Ball, U. Hauser, H. Bier, Anticancer Drugs 2002, 13, 93 – 100; c) B. J. Maurer, L. Melton, C. Billups, M. C. Cabot, C. P. Reynolds, J. Natl. Cancer Inst. 2000, 92, 1897 – 1909; d) W. D. Jarvis, F. A. J. Fornari, R. M. Tombes, R. K. Erukulla, R. Bittman, G. K. Schwartz, P. Dent, S. Grant, Mol. Pharmacol. 1998, 54, 844 – 856; e) G. K. Schwartz, K. Farsi, P. Maslak, D. P. Kelsen, D. Spriggs, Clin. Cancer Res. 1997, 3, 1467 – 1472; f) C. W. Sachs, A. R. Safa, S. D. Harrison, R. L. Fine, J. Biol. Chem. 1995, 270, 22859; g) G. K. Schwartz, A. Haimovitz-Friedman, S. K. Dhupar, D. Ehleiter, P. Maslak, L. Lai, F. J. Loganzo, D. P. Kelsen, Z. Fuks, A. P. Albino, J. Natl. Cancer Inst. 1995, 87, 1394 – 1399. [12] a) M. V. Rao, K. K. S. Reddy, B. V. Rao, Tetrahedron Lett. 2012, 53, 5993 – 5995; b) M. E. Jung, S. W. Yi, Tetrahedron Lett. 2012, 53, 4216 – 4220; c) S. Prvost, T. Ayad, P. Phansavath, V. Ratovelomanana-Vidal, Adv. Synth. Catal. 2011, 353, 3213 – 3226; d) P. Kumar, A.
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Chem. Eur. J. 2013, 19, 16541 – 16544
syn- and Enantioselective Henry Reactions of Aliphatic Aldehydes and Application to the Synthesis of Safingol Dan-Dan Qin,[a] Wen Yu,[a] Jie-Dan Zhou,[a] Yan-Cheng Zhang,[b] Yuan-Ping Ruan,[a] Zhao-Hui Zhou,[a] and Hong-Bin Chen*[a] Dedicated to Prof. Khi-Rui Tsai on the occasion of his 100th birthday
Vicinal (b-) amino alcohol motifs are important and ubiquitous structural features in a diverse range of natural products and pharmaceutical agents as well as chiral ligands and auxiliaries used in (catalytic) asymmetric synthesis. In most cases, the biological activities and asymmetric induction capabilities of vicinal amino alcohols strongly depend upon their relative (absolute) configurations. Generally, chiral pool approaches were used to prepare such stereospecific vicinal amino alcohols.[1] However, some side effects, such as multistep reaction sequences, expensive reagents, and sometimes harsh reaction conditions, greatly constrained their practical applications. Consequently, the development of mild, efficient, and economic methods is still of significant importance. The catalytic asymmetric Henry (nitroaldol) reaction is a highly atom-economic and powerful tool in organic synthesis because the resulting b-nitro alcohols can easily be transformed into vicinal amino alcohols and other important intermediates.[2] Over the past two decades, an extensive collection of efficient catalysts have been developed to promote Henry reactions between carbonyls and nitromethane with high enantioselectivity.[3] In contrast, diastereo- and enantioselective Henry reactions still remain a great challenge because it is very difficult to rigorously control the stereochemistry of the two carbon stereocenters formed simultaneously and, hitherto, only a few successful examples in syn-selective[4] and anti-selective[5] Henry reactions have been reported. Chiral b-amino alcohols are one type of the most important ligands that are widely used in asymmetric catalysis,
whereas their applications in diastereo- and enantioselective Henry reactions are less explored.[6] Previously, we reported that an easily available b-amino alcohol copper catalyst 1 a efficiently promoted Henry reactions between nitromethane and aromatic aldehydes.[7] Herein, we report the results of recent studies into the application of b-amino alcohol ligands 1 and 2 (Scheme 1) in syn- and enantioselective
[a] D.-D. Qin, W. Yu, J.-D. Zhou, Prof. Y.-P. Ruan, Prof. Dr. Z.-H. Zhou, Prof. Dr. H.-B. Chen Department of Chemistry and State Key Laboratory of Physical Chemistry for Solid Surfaces College of Chemistry and Chemical Engineering Xiamen University, Xiamen, Fujian 361005 (P. R. China) Fax: (+ 86) 592-2185192 E-mail: [email protected]
Entry
[b] Y.-C. Zhang Nantong Huafeng Chemical Co. Ltd., Nantong Jiangsu, 226531 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303650.
Chem. Eur. J. 2013, 19, 16541 – 16544
Scheme 1. Chiral amino alcohol ligands.
Henry reactions and application to the synthesis of safingol. In the preliminary studies, ligands 1 and 2 were evaluated by using hexanal and 4-chlorobenzaldehyde as model substrates and nitroethane as a standard nucleophile. When the reaction was performed in the presence of 10 mol % of catalyst, in situ generated from the coordination reaction of amino alcohol and CuACHTUNGRE(OAc)2·H2O, both substrates gave the corresponding Henry adducts with different syn/anti ratios. For hexanal, ligands 1 a–e were superior to 2 a–e in terms of Table 1. Effect of the ligand structure upon the Henry reaction.[a]
1 2 3 4 5 6 7 8 9 10
Ligand
Yield [%][b]
1a 1b 1c 1d 1e 2a 2b 2c 2d 2e
72 66 61 38 70 23 48 24 25 46
d.r.[c] (syn/anti)
ee [%][c] (syn/anti)
2.9:1 7.6:1 3.3:1 3.0:1 4.8:1 1.8:1 1.3:1 1.5:1 1.2:1 1.9:1
95:81 97:72 88:73 79:30 88:75 3.5:5.9 33:21 37:34 44:31 38:14
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
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diastereoselectivity and enantioselectivity (Table 1), among which 1 b distinguished itself as the best ligand, which resulted in a 7.6:1 syn/anti ratio and 97 % ee for syn (Table 1, entry 3), whereas for 4-chlorobenzaldehyde, 1 b was still the best ligand but could only give a 2.9:1 syn/anti ratio even under optimal reaction conditions (not listed herein). Considering that aliphatic b-nitro alcohols are also highly important in organic synthesis,[8] we only devoted our efforts to optimize the reaction conditions for aliphatic aldehydes. In the subsequent experiments, the effects of various solvents were examined. The results are summarized in Table 2 and clearly show that the reaction was highly sensitive to the nature of solvent employed, and THF was the best reac-
Table 4. Henry reaction of aliphatic aldehydes with nitroethane.[a]
Table 2. Effects of solvents upon the Henry reaction.[a]
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
Entry
Solvent
1 2 3 4 5 6 7 8 9
MeOH EtOH iPrOH CH2Cl2 THF Et2O Dioxane CH3CN EtOAc
Yield [%]
[b]
60 75 79 47 66 51 64 41 64
[c]
d.r. (anti/syn)
ee [%]
1.7:1 2.6:1 5.0:1 4.4:1 7.6:1 6.5:1 5.6:1 5.8:1 5.5:1
61:27 79:43 94:70 88:50 97:72 95:63 93:66 93:54 94:70
[c]
(syn/anti)
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
tion medium in terms of diastereomeric ratio (d.r.; syn/anti) and ee values for the syn adduct (Table 2, entry 5). Catalyst loadings also had a significant effect on the reaction (Table 3). When the amount of catalyst increased from 1 to 10 mol %, the isolated yield, d.r. (syn/anti), and ee value increased concomitantly (Table 3, entries 1–4). However, attempts to access higher d.r. (syn/anti) by raising the catalyst loading failed, 15 and 20 mol % of catalysts gave lower diastereoselectivity (entries 5 and 6). With the optimized reaction conditions in hand, a variety of aliphatic aldehydes were tested as substrates to demonstrate the reaction versatility (Table 4). In general, all the substrates proceeded well to afford the Henry adducts in
Entry
R1
1 2 3 4 6 7 8 9 10 11 12
CH3ACHTUNGRE(CH2)2 CH3ACHTUNGRE(CH2)3 CH3ACHTUNGRE(CH2)4 CH3ACHTUNGRE(CH2)5 CH3ACHTUNGRE(CH2)6 CH3ACHTUNGRE(CH2)10 C6H5CH2CH2 ACHTUNGRE(CH3)2CH2 ACHTUNGRE(CH3)2CHCH2 c-hexyl c-pentyl
Yield [%][b] 75 70 66 80 83 64 72 69 66 73 74
d.r.[c] (syn/anti)
ee [%][c] syn/anti
4.5:1 7.0:1 7.6:1 6.5:1 6.9:1 7.1:1 6.3:1 7.0:1 5.2:1 15.3:1 9.5:1
90:55 97:73 97:72 97:76 95.68 94:72 99:69 98:88 98:82 99:70 96:78
moderate to good yields with modest to excellent syn selectivities and excellent enantioselectivities. Further analysis revealed that the d.r. (syn/anti) was almost not affected by the chain length of linear aliphatic aldehydes (Table 4, entries 2–8) except that for butanal (entry 1); in addition, abranched isobutanal gave a higher d.r. (syn/anti) than that of b-branched isopentanal (entries 9 and 10), whereas in the case of aliphatic cyclic aldehydes, the corresponding Henry adducts were obtained with higher syn selectivity (entries 11 and 12), and cyclohexanecarboxaldehyde even gave up to 15.3:1 syn/anti ratio and 99 % ee for syn. In addition, 2-nitroethanol was also examined as the nucleophile towards different aliphatic aldehydes. The results were summarized in Table 5. It was apparent that the isolated yields and d.r. (syn/anti) of the produced 2-nitro-1,3-diols were higher than those obtained when using nitroethane, for example, the reaction of n-octanal with 2-nitroethanol gave the syn-adduct in 86 % isolated yield with 18.6:1 syn/anti ratio and 99 % ee for syn (entry 4). A likely reason for this was that the hydroxyl group of 2-nitroethanol formed additional intermolecular hydrogen bonds and hence greatly stabilized the reaction transition states.[7] Single-crystal X-ray diffraction analysis confirmed that our catalyst exclusively preferred the formation of the syn diastereomer and all the major syn isomers possessed (R,R)-configurations (see the Supporting Information). Finally, the practical utility of this syn-selective Henry reaction was demonstrated by the short asymmetric synthesis
Table 3. Effect of catalyst loading upon the Henry reaction.[a] Table 5. Henry reaction of aliphatic aldehydes with nitroethanol.[a]
Entry
Cat. [%]
1 2 3 4 5 6
1 2.5 5 10 15 20
Yield [%][b] 20 23 51 66 61 69
d.r.[c] (anti/syn)
ee [%][c] (syn/anti)
1.3:1 4.0:1 5.6:1 7.6:1 3.8:1 5.1:1
13:3 84:36 95:48 97:72 92:63 94:70
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
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Entry
R1
1 2 3 4 5
ACHTUNGRE(CH3)2CHCH2 CH3ACHTUNGRE(CH2)4 CH3ACHTUNGRE(CH2)5 CH3ACHTUNGRE(CH2)6 c-hexyl
Yield [%][b] 82 93 84 86 92
d.r.[c] (syn/anti)
ee [%][c] syn/anti
4.3:1 14.9:1 7.9:1 18.6:1 14.2:1
96:71 99:3.6 94:59 99:43 97:62
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16541 – 16544
Synthesis of Safingol
COMMUNICATION Keywords: aliphatic aldehydes · amino alcohols asymmetric synthesis · Henry reactions · safingol
Scheme 2. Synthesis of safingol.
of safingol 20 (Scheme 2). Safingol is a synthetic sphingosine that exhibits antineoplastic and antipsoriatic activities.[9] It is currently under a phase I clinical trial in combination with cisplatin for the treatment of advanced solid tumors.[10] In addition, several in vitro and in vivo studies demonstrated that safingol augmented the efficacy of other chemotherapeutic agents in a variety of tumor cell lines.[11] Numerous synthetic approaches have been developed to access safingol;[5g, 12] however, most of them were lengthy and hence not economic and suitable for large-scale preparation. Whereas based on our catalyst, safingol could be prepared in two steps with satisfactory overall yield. The reaction of hexadecanal with 2-nitroethanol in the presence of 10 mol % of catalyst ent-1 b furnished syn-nitro alcohol 19 in 79 % isolated yield with a d.r. (syn/anti) of up to 16.5:1 and an ee of up to 98 % for syn. Further experiments showed that when the reaction was performed on a 10.0 mmol scale, pure (2S,3S)-19 could be obtained by recrystallization with a yield of 68 %; in addition, ligand ent-1 b could be easily recovered by a simple operation (see the Supporting Information). Subsequently, 19 was catalytically hydrogenated to give safingol 20 in 72 % yield. Notably, in comparison with the La-LiBINOL (LLB) catalyst,[5g] our catalytic system seemed more simpler, milder, and efficient. In summary, we have successfully developed an amino alcohol copper(II) catalyst for syn- and enantioselective Henry reaction of aliphatic aldehydes. By using this catalyst, safingol was prepared in two steps with a 57 % overall yield. Further applications of this catalyst towards some bioactive molecules are currently in progress.
Experimental Section General method: Nitroethane (0.72 mL, 10.0 mmol) or 2-nitroethanol (0.273 g, 3.0 mmol) and aliphatic aldehyde (1.0 mmol) were sequentially added to a solution of CuACHTUNGRE(OAc)2·H2O (20 mg, 0.10 mmol) and ligand 1 b (26.7 mg, 0.10 mmol) in THF (3 mL). The reaction mixture was stirred at 20 8C for 48–72 h, and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/petroleum ether.
Acknowledgements This work was financially supported by the Fundamental Research Funds for the Central Universities (No. 2010121014) and the Natural Science Foundation of Fujian Province (No. 2013J10011).
Chem. Eur. J. 2013, 19, 16541 – 16544
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