ORGANIC LETTERS
BINOLAM, a Recoverable Chiral Ligand for Bifunctional Enantioselective Catalysis: The Asymmetric Synthesis of Cyanohydrins†
2002 Vol. 4, No. 15 2589-2592
Jesu´s Casas,‡ Carmen Na´jera,*,‡ Jose´ M. Sansano,‡ and Jose´ M. Saa´*,§ Departamento de Quı´mica Orga´ nica, UniVersidad de Alicante, Apartado 99, 03080-Alicante, Spain, and Departament de Quı´mica, UniVersitat de les Illes Balears, 07071-Palma de Mallorca, Spain
[email protected] Received May 23, 2002
ABSTRACT
A new bifunctional catalytic system based on a monometallic aluminum complex is used for the efficient enantioselective cyanation of aldehydes. The ligand (S)- or (R)-2,2′-bis(diethylaminomethyl)-substituted binaphthol (BINOLAM) used is recovered for recycling. This methodology is used for the synthesis of a precursor of epothilone A.
A new generation of chiral bifunctional catalysts1 that try to imitate nature’s enzymatic processes have been designed in search for high efficiency in asymmetric synthesis.2 At the very least, these catalysts must contain an acid center and a basic functional group capable of simultaneously binding a basic substrate and an acidic reactant in a proper manner, so as to facilitate control over the three main issues of asymmetric catalysis, namely, kinetics of the rate-determining step, stereochemistry, and overall kinetics. In contrast with nature, however, the acid in most man-made catalysts is a Lewis acid metal properly designed so as to become a chiral † Dedicated to Prof. Marcial Moreno-Man ˜ as on the occasion of his 60th birthday. ‡ Universidad de Alicante. § Universitat de les Illes Balears. (1) For a recent review, see: Rowlands, G. J. Tetrahedron 2001, 57, 1865-1882. (2) (a) Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E. Houben-Weyl Methods of Organic Chemistry, StereoselectiVe Synthesis; Thieme: Stuttgart/New York, 1995; Vol. E21. (b) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim, Germany, 2000. (c) ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
10.1021/ol0262338 CCC: $22.00 Published on Web 07/02/2002
© 2002 American Chemical Society
center to which the prochiral substrate should bind. Among others, the most representative examples of this concept3 are the chiral oxazaborolidine-mediated (CBS) reduction of ketones4 and the addition of dialkylzinc reagents to carbonyl compounds by means of chiral amino alcohols,5 developed by the groups of Corey and Noyori, respectively. Very recently, Shibasaki et al. reported a series of bifunctional Lewis acid-Lewis base (LALB) catalysts 1 (Figure 1) derived from BINOL as the chiral scaffold, where an aluminum atom of a bisaryloxyaluminum chloride moiety should act as the Lewis acid center (LA) and an appropriate functionality at the 3,3′-positions should work as the Lewis base (LB) unit.6 In particular, the phosphane oxide-derived (3) Gro¨ger. H. Chem. Eur. J. 2001, 7, 5246-5251. (4) For a review, see: Corey, E. J.; Helal, C. J. Angew. Hem. Int. Ed. 1998, 37, 1987-2012. (5) Relevant reviews: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49-69. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856. (c) Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. (d) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
recoverable chiral ligand for the preparation of new bifunctional monometallic catalysts 3 capable of achieving the enantioselective cyanation of aldehydes,7,14 for the synthesis of enantiomerically pure cyanohydrins.15 Expectations were that the C2-symmetric BINOL template would impart chirality unto the aluminum atom, which should act as a Lewis acid center to ligate the aldehyde, while the amino grouping could work as a Lewis base, activating the nucleophile (Figure 1). In this model system, recycling of the precious ligand would be facilitated by its eventual extraction with an aqueous acid. Initial studies were carried out by treating benzaldehyde with trimethylsilyl cyanide in the presence of the selected Lewis acid under different reaction conditions (Table 1). The
Table 1. Cyanation of Benzaldehyde Catalyzed by Preformed Lewis Acid-(S)-3 Complexes
Figure 1.
catalysts 1 (R ) H; X ) POAr2) were found to be very efficient for the asymmetric cyanosilylation of aldehydes7 and imines8 (Strecker synthesis) as well as for the addition of cyanide to quinoline or isoquinoline derivatives (Reisserttype reaction).9 An additional requirement for high efficiency, at least for industrial batch processing, is catalyst recovery10 and reusability.11 Catalyst recovery is meant here to describe the recovery not of the usually unstable organometallic species but of the chiral organic ligand. A polymer-supported catalyst 1 [R ) linker-polymer; X ) P(O)Ph2] was developed by Shibasaki et al. for the Strecker-type reaction though, unfortunately, with some loss of enantioselectivity.8 Therefore, the development of recoverable ligands in enantioselective catalysis is also an important additional goal for achieving overall efficiency in asymmetric synthesis. We disclose herein our preliminary results on the use of a bifunctional catalyst for the enantioselective synthesis of cyanohydrins by means of the addition of HCN to aldehydes. We envisaged that 3,3′-bis(diethylaminomethyl)-1,1′-bi-2naphthol (BINOLAM) 2 (Figure 1),12,13 easily available in both enantiomeric forms, could be a good candidate as a (6) For a review, see: Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511-524. (7) (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 2641-2642. (b) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M. Tetrahedron 2001, 57, 805-814. (8) Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652. (9) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6327-6328. (10) Gladysz, J. A. Pure Appl. Chem. 2001, 73, 1319. (11) Sophisticated strategies are being developed for recovery and recycling of chiral catalysts: Chiral Catalyst Immobilization and Recycling; De Vos, D. E., Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH: Weinheim, Germany, 2000. 2590
run
Lewis acid
solvent
t (h)
4a (%)a
er (%)b
1 2 3 4 5 6 7 8 9
TiCl2(OPri)2 TiCl2(OPri)2 Ti(OPri)4 AlClMe2 AlClMe2c AlClMe2d AlClMe2c AlClMe2c AlClEt2c
CH2Cl2 PhCH3 PhCH3 PhCH3 PhCH3 PhCH3 PhCH3 CH2Cl2 PhCH3
24 24 1 26 3 20 6 14 8
65 83 99 87 99 99 99 99 99
55/45 88/12 78/22 67/33 88/12 75/25 >99/1 77/23 90/10
a Isolated yields given refer to the cyanohydrin obtained after acidic hydrolysis. b Enantiomeric ratios were determined by chiral HPLC analysis (Chiralcel OD-H). c Triphenylphosphane oxide (40 mol %) was added. d Reaction was performed with 40 mol % triphenylphosphane oxide, though in the absence of 4 Å MS.
catalysts were prepared by mixing the ligand (S)-2 and the Lewis acid at room temperature for 1 h in the appropriate (12) Diethylamino-substituted (S)- and (R)-BINOLAM 2 were the most suitable phase-transfer catalysts for the enantioselective alkylation of the aldimine Schiff bases of alanine esters: Casas, J.; Na´jera, C.; Sansano, J. M.; Gonza´lez, J.; Saa´, J. M.; Vega, M. Tetrahedron: Asymmetry 2001, 12, 699-702. For addition of diethylzinc to aldehydes, see: Kitajima, H.; Iti, K.; Katsuki, T. Chem. Lett. 1996, 343-344. (13) BINOLAM 3 was easily prepared from methyl 3-hydroxy-2naphthalenecarboxylate employing a chemical resolution using L-leucine methyl ester hydrochloride following a known procedure. (a) Feringa, B.; Wynberg, H. Tetrahedron Lett. 1977, 4447-4450. (b) Brussee, J.; Groenendijk, J. L. G.; Koppele, J. M.; Jansen, A. C. A. Tetrahedron 1985, 41, 3313-3319. (c) Cram, D. J.; Helgeson, R. C.; Peacock, S. C.; Kaplan, L. J.; Domeier, L. A.; Moreau, P.; Koga, K.; Mayer, J. M.; Chao, Y.; Siegel, M. G.; Hoffman, D. H.; Sogah, G. D. Y. J. Org. Chem. 1978, 43, 19301946. (14) For recent selected examples, see: (a) You, J. S.; Gan, H.-M.; Choi, M. C. K. Chem. Commun. 2000, 1963-1964. (b) Belokon, Y. N.; CavedaCepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev, V. S.; Moscalenko, M. A.; North, M.; Orizn, C.; Tararov, V. I.; Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 39683973. (c) Hwang, C. D.; Hwang, D.-R.; Uang, B. J. J. Org. Chem. 1998, 63, 6762-6763. (d) Mori, M.; Imma, H.; Nakai, T. Tetrahedron Lett. 1997, 38, 6229-6232. Org. Lett., Vol. 4, No. 15, 2002
solvent. Then, benzaldehyde and trimethylsilyl cyanide (TMSCN) were added in one portion at 0 °C in the presence of 4 Å molecular sieves (MS). Preliminary studies with titanium(IV) salts as Lewis acids were not completely satisfactory as it was found that chemical yields did not parallel those of enantioselection (Table 1, entries 1-3). In contrast, aluminum catalysts offered better prospects. Thus, when dimethylaluminum chloride was used as the Lewis acid, the reaction took place quantitatively in 3 h in 88:12 er, though only when both MS16,17 and triphenylphosphane oxide18 were employed as additives (Table 1, cf. entries 4-6). Lowering the temperature to -20 °C (Table 1, entry 7) led to a significant leap forward in enantioselectivity (er higher than 99:1) while keeping the reactivity high (quantitative chemical yield in 6 h). Using diethyl instead of dimethylaluminum chloride gave somewhat poorer results (Table 1, entry 9). The presence of both 4 Å MS (200 mg/ mmol of aldehydes, ca. 1 equiv)16 and triphenylphosphane oxide was crucial for achieving high enantioselectivities in all cases studied (Table 1, entries 4-6). On the other hand, in coping with solvent effects, we found that operating with toluene (the reaction mixture is somewhat heterogeneous under these conditions) yielded higher ers than when dichloromethane (the reaction mixture is homogeneous) was employed as the solvent (Table 1, entries 7 and 8). In contrast, operating without 4 Å MS but in the presence of water (the same amount determined to be present in the molecular sieves) gave a very low yield and a poor enantiomeric ratio of the resulting cyanohydrin 4. So, we can reckon that 4 Å MS are an excellent carrier of a limited amount of water, as recently demonstrated in a related case.19 These optimized reaction conditions were used for the cyanation of a number of other aldehydes (Table 2). Aromatic aldehydes gave excellent results (Table 2, entries 1-10) with the exception of furfural and p-phenoxybenzaldehyde. In these cases, better ers were reached when operating at -40 °C (Table 2, entries 9 and 10). A prototypic R,β-unsaturated aldehyde such as cinnamaldehyde also yielded the cyanohydrin in excellent yield and er (Table 2, entries 11 and 12). On the other hand, enatioselectivities of aliphatic aldehydes were poorer than those of aromatic aldehydes at -20 °C and were improved by working at -40 °C (Table 2, entries 13 and 14). Alternatively, (R)-BINOLAM can be used for (15) Enantiopure cyanohydrins are important building blocks for the synthesis of 1,2-bifunctional compounds such as R-hydroxycarbonyl compounds, β-amino alcohols, and R-amino acids and also for the generation of new materials: (a) Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 27022708. (b) Gro¨ger, H. AdV. Synth. Catal. 2001, 343, 547-558. (c) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649-3682. (d) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555-1564. (e) Kruse, C. G. In Chirality in Industry; Collins, A. N., Schedrake, G. N., Crosby, J., Eds.; Wiley: Chichester, UK, 1992; Chapter 14. (f) North, M. Synlett 1993, 807-820. (16) Thermogravimetric analysis of “dry” MS (dried at 120 °C for 4 h) revealed a 7.5% water content. (17) The role of 4 Å MS as an H2O donor has been demonstrated for the case of binaphthol-derived titanium complexes: Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Chem. Commun. 1997, 281-282. (18) The influence of Ph3PO on prevention of oligomerization of the catalyst and activation of trimethylsilyl cyanide has been pointed out: Vogl, E. M.; Gro¨ger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 15701577. (19) Shimizu, M.; Ogawa, T.; Nishi, T. Tetrahedron Lett. 2001, 42, 5463-5466. Org. Lett., Vol. 4, No. 15, 2002
Table 2. Enantioselective Synthesis of Cyanohydrins Catalyzed by Complexes 3
entry
aldehyde
3
T (°C)
t (h)
4
1 2 3 4 5 6 7 8 9 10 11 12 13 14
PhCHO PhCHO PhCHO 4-(MeO)C6H4CHO 2-ClC6H4CHO 4-ClC6H4CHO 4-(PhO)C6H4CHO 4-(PhO)C6H4CHO 2-FurylCHO 2-FurylCHO PhCHdCHCHO PhCHdCHCHO PhCH2CH2CHO CH3(CH2)5CHO
(S) (R) (S)c (S) (R) (S) (S) (S) (S) (S) (S) (R) (R) (R)
-20 -20 -20 -20 -20 -20 -20 -40 -20 -40 -20 -40 -40 -40
6 6 6 20 8 21 48 48 5 12 6 12 4.5 3.5
4a 4a 4a 4a 4a 4d 4e 4e 4f 4g 4h 4h 4i 4j
yield configuration, (%)a erb 99 99 99 99 99 99 70 45 99 99 99 99 99 99
(R) >99/1 (S) >99/1 (R) >99/1 (R) >99/1 (S) 98/2 (R) >99/1 (R) 85/15 (R) 89/11 (R) 88/12 (R) 96/4 (R) 91/9 (S) >99/1 (S) 94/6 (S) 83/17
a Isolated yields of the cyanohydrin after acidic hydrolysis. b Enantiomeric ratios were determined by chiral HPLC analysis (Chiralcel OD-H and Chiralpak AD and AS). c Reaction was performed with recovered ligand by extractive workup and recrystallization.
the preparation of cyanohydrins (S)-4. In all studied cases, the reaction conversions and chemical yields were both very high, the title alcohol 4 being obtained after acidic treatment. From the experimental viewpoint two noticeable aspects need to be remarked, especially when compared with the procedure reported by Shibasaki et al.7 First, the procedure is extremely simple as reagents can be added at once (no slow pump addition is needed); reaction times are short; and the temperature of operation is quite high. In addition, the process can be scaled-up without appreciable differences in chemical and stereochemical yields. Thus, when the cyanation of benzaldehyde was carried out in a 2.5 mmol scale, a 98% isolated yield of cyanohydrin was obtained, after 12 h at -20 °C, in a 98.5:1.5 er. Moreover, enantiomerically pure (S)-BINOLAM was almost quantitatively (>95% yield) recovered after a simple acid-base workup and purification and reused without a loss of efficiency (Table 2, entry 3). The cyanation of the aldehyde containing a thiazole moiety deserved special attention,7b,20 as this asymmetric reaction constitutes one of the key steps in the synthesis of epothilone A.21 Previously, compound (S)-4k was prepared at -40 °C in 48 h by adding 1.5 equiv of TMSCN very slowly (syringe pump).7b,21 In our case, slow addition of 2 equiv of TMSCN was not productive (Table 3, entry 3) because residual unreacted 4k was observed in the crude reaction mixture. Fortunately, when the reaction was carried out at -20 °C and excess TMSCN (9 equiv) added in one portion, (20) (a) Sawada, D.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 209-213. (b) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 43, 10521-10532. (21) (a) Nicolaou, K. C.; Hepworth, D.; King, N. P.; Finlay, M. R. V.; Scarpelli, R.; Pereira, M. M. A.; Bollbuck, B.; Bigot, A.; Werschkun, B.; Winssinger, N. Chem. Eur. J. 2000, 6, 2783-2800. (b) Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410-6424. 2591
Our catalyst has an efficiency similar to that of Shibasaki’s LALB phosphine oxide catalyst while allowing work to be performed at higher temperatures and with an easier setup. In addition, we have demonstrated that chiral ligand (S)BINOLAM 2 can be easily recovered at the end of the reaction and recycled, thus suggesting the possible application of this methodology in large-scale processes. Experimental and theoretical studies are currently underway in order to clarify the mechanistic details of this reaction.
Table 3. Synthesis of Cyanohydrin (S)-4k
run
TMSCN (equiv)
T (°C)
t (h)
4k (%)a
er (%)b
1 2 3 4 5
3 1.5 + 1.5c 2d 9 9
-20 -20 -20 -20 -40
22 48 24 36 48
33 52 0 >98 >98
96/4 88/12
Acknowledgment. This work has been supported by the DGES of the Spanish Ministerio de Educacio´n y Cultura (MEC) (PB96-0203, PB97-0123, and BQU2001-0724).
96/4 96/4
OL0262338
a Isolated yields given refer to the cyanohydrin obtained after acidic hydrolysis. b Enantiomeric ratios were determined by chiral HPLC analysis (Chiralcel OD-H). c Second 1.5 equiv of TMSCN was added after 1 day. d Slow (syringe pump) addition over 24 h.
the reaction was completed in 36 h in excellent chemical yield and very good er (Table 3, entry 4). Lowering the working temperature to -40 °C did not improve the enantiomeric ratio of the product (Table 3, entry 5). In summary, we have shown that our BINOLAM-derived catalyst is more efficient that the otherwise simpler LA catalysts in the enantioselective cyanation of aldehydes.22
2592
(22) Typical Experimental Procedure. To a suspension of enantiopure (S)-BINOLAM 2 (0.025 mmol, 11.4 mg), triphenylphosphane oxide (0.1 mmol, 28 mg), and 4 Å MS (0.25 mg/mmol, previously dried at 120 °C for 4 h) in dry toluene (1 mL), under an inert atmosphere (argon), was added dimethylaluminum chloride (1 M solution in hexanes, 0.025 mmol, 25 µL), and the resulting suspension was stirred at room temperature for 1 h. This mixture was cooled at -20 or -40 °C (see Table 2), and then freshly distilled aldehyde (0.25 mmol) and TMSCN (0.75 mmol, 100 µL) were added in one portion. The reaction was monitored by 1H NMR spectroscopy, and when it was judged to be complete, a 2 M aqueous solution of hydrochloric acid (2 mL) and ethyl acetate (2 mL) were added; the resulting mixture was stirred vigorously for 1 h. The emulsion was filtered through a Celite pad, and the organic layer was separated, dried (MgSO4), and evaporated, affording a residue that was purified by flash chromatography to obtain pure cyanohydrins 4.
Org. Lett., Vol. 4, No. 15, 2002
