- Email: [email protected]
Polyoxygenated ketopinic-acid-derived γ-amino alcohols in the enantioselective diethylzinc addition to benzaldehyde
Tetrahedron: Asymmetry 20 (2009) 2655–2657
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Polyoxygenated ketopinic-acid-derived c-amino alcohols in the enantioselective diethylzinc addition to benzaldehyde Esther Márquez Sánchez-Carnerero, Tomás de las Casas Engel, Beatriz Lora Maroto, Santiago de la Moya Cerero * Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
a r t i c l e
i n f o
Article history: Received 20 October 2009 Accepted 13 November 2009 Available online 5 December 2009 Dedicated to Professor Antonio Garcia Martinez on the occasion of his last academic course.
a b s t r a c t Three N,N-dialkylated c-amino alcohols, specifically 10-(dialkylamino)isoborneols, with different grades of oxygenation in the nitrogen’s alkyl groups (alkoxyalkyl groups), have been obtained from commercial (+)-ketopinic acid and tested as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde, in order to evaluate the effect of polyoxygenation on the ligand’s catalytic activity. An interesting effect of the oxygen atoms on the ligand activity is observed. The observation is in agreement with two unique previous results on amino-acid-derived polyoxygenated b-amino alcohols. A noticeable dependence of the observed effect with the conformational flexibility of the polyoxygenated chains is also demonstrated. The effect is explained by a pincer role of the polyoxygenated dialkylamino moiety, activating and directing a diethylzinc molecule. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Chiral amino alcohols, especially N,N-dialkylated amino alcohols (e.g., Noyori’s DAIB 1, Fig. 1), are the main ligands for promoting the enantioselective addition of organozinc reagents to aldehydes.1 The reaction is one of the most important synthetic methods for the preparation of enantioenriched secondary alcohols, which are key intermediates in the preparation of valuable chiral molecules (e.g., biologically active natural products).1d,2 With the objective of finding more versatile ligands, new chiral architectures are being described as effective in promoting the enantioselective addition of organozinc reagents to aldehydes.3 In most cases, only the catalytic behaviour of the new ligand (chemical yield and ee) in the addition of diethylzinc to benzaldehyde (test reaction) is reported.1d Unfortunately, fewer studies have been directed to correlate the structural factors with catalytic activities, probably due to the high costs in the preparation of a large series of structurally related chiral ligands.4 However, this kind of studies are very important, since they can lead to the establishment of valuable rules for the rationalized design of improved new ligands. To date, the structure–activity correlation studies on N,N-dialkylated amino alcohols have mainly centred on the influence of the nitrogen’s alkyl substitution in the catalytic activity of easily obtainable amino alcohols (steric effects),1d whereas studies on the influence of other structural variables (e.g., electronic effects) are less common.4 * Corresponding author. Tel.: +34 91 394 5090; fax: +34 91 394 4103. E-mail address: [email protected] (S. de la Moya Cerero). 0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2009.11.010
On the other hand, the introduction of an oxygen atom in the dialkylamino group of certain amino alcohols is usually a successful structural modification for designing improved ligands (e.g., Nuggent’s MIB 2 vs Noyori’s DAIB 1, see Fig. 1).5 Moreover, oxygen has also been used as a convenient tool to link well-known chiral ligands to insoluble dendrimers and polymers (e.g., 3 in Fig. 1) with the aim of designing easily recyclable and reusable ligands, or supported ligands for flow chemistry.1d,6 O N
N
OH
OH
Ph Ph OH P
1
2
N
O 3
Figure 1. Some ligands for the enantioselective addition of organozinc reagents to aldehydes.
However, to the best of our knowledge and in spite of the importance of the introduction of oxygen atoms in the structure of amino-alcohol-based ligands, there are no rationalized studies on the influence of the oxygenation in the catalytic activity of the ligand. Only the work of Martens and Brunet, on the catalytic-activity variation caused by the introduction of oxygen atoms in the dialkylamino group of a set of related flexible b-amino alcohols derived from cysteine, methionine and leucine (from pro-R 92% ee to pro-S 11% ee) has been carried out.7 The authors concluded that additional factors, other than simple steric ones, should
2656
E. M. Sánchez-Carnerero et al. / Tetrahedron: Asymmetry 20 (2009) 2655–2657
be invoked to explain the observed variation of ee7b In this sense, the authors also concluded that the mechanism explaining the observed reversion of the enantioselection is still unclear.7b In relation to this and continuing with our previous work on the study and development of ketopinic-acid-derived chiral ligands for the enantioselective addition of organozinc reagents to aldehydes,8 we became interested in measuring the influence of the dialkylamino polyoxygenation on the catalytic activity of 10-(diakylamino)isoborneols, in order to test the possible extension of the effect found by Martens and Brunet to another amino-alcohol type, and attempt to give a reasonable explanation for such effect on the basis of our experience in structure–activity relationships for the catalyzed enantioselective addition of diethylzinc to benzaldehyde.8,9 2. Results and discussion For our purpose, we chose three related oxygenated ligands 4–6 (Fig. 2) and the addition of diethylzinc to benzaldehyde as the test reaction. These three ligands are obtained from commercially available structurally related secondary amines based on 2alkoxyethylamine.
OH N
OH
OH O
N
N
O
O
O
O 4
O 5
6
Figure 2. Differently oxygenated ketopinic-acid-derived 10-(dialkylamino)isoborneols.
The preparation and catalytic activity of 4 have previously been reported by Aoyama.10 Aoyama’s work also compares the catalytic activity of morpholine-based 4 (74% ee, pro-R) with its piperidinebased analogue (77% ee, pro-R). The similar measured activities demonstrate that no effect is exerted by the heterocyclic oxygen of 4 in its catalytic activity.10 Ligands 4,11 512 and 613 can be obtained from commercial (1S)ketopinic acid in two steps: amidation by EDC activation,14 followed by stereoselective reduction of the ketoamides obtained with lithium and aluminium hydride.15 The three ligands were tested under the same standard test-reaction conditions,16 to make the later comparisons possible. The measured catalytic activities (chemical yield, ee and dominant configuration for the obtained alcohol) are shown in Table 1.
Substitution of the morpholine moiety in ligand 4 by the trioxygenated aza-12-crown-4 moiety in ligand 6 leads to a noticeable loss in enantioselectivity (20 points in ee, see Table 1). The same effect, although more intensive (up to 97 points in ee), was observed by Martens and Brunet in a series of cysteine-based b-amino alcohols with the same structural variations.7 A larger decrease in enantioselectivity (98 points in ee, see Table 1), even with reversion of the enantioselection sense (from pro-R to pro-S), was observed when the morpholine moiety of 4 was substituted by the dioxygenated open-chained bis(2-methoxyethyl)amino moiety in 5. Since ligand 5 exhibits a stronger effect than 6, the known affinity of Zn2+ for macrocycles of four heteroatoms17 must not be the unique possible cause for the observed effect, as previously suggested by Marteens and Brunet.7b,18 On the other hand, Aoyama explained the sense of the stereodifferentiation exhibited by morpholine-based ligand 4 (pro-R) and other related 10-(dialkylamino)isoborneols on the basis of 7 as the most stable transition state [i.e., the less-hindered diastereomer (endo-anti-anti TS)19 from a set of eight possible competing diastereomeric TSs]. It was demonstrated that in the controlling-TS model, there was not any appreciable coordinative interaction between the oxygen atom of the morpholino group and the catalytic zinc.10,8a Therefore, it was concluded that the substituents at nitrogen must be removed from the sterically congested reaction site in the most stable conformation of 7. Continuing with this reasoning, it is expected that the structural variations of ligands 5 and 6, regarding ligand 4 (see Fig. 2), will not produce any changes in the catalytic behaviour, at least due to steric effects, since the same 2-oxyethylamino moiety is present in the three cases. We did observe a noticeable effect on the catalytic behaviour (see Table 1), and for this we think that this effect must be electronic and must be caused by the polyoxygenation of the dialkyalmino group. As an explanation for the observed effect, we propose that the two oxygen atoms conveniently located at the dialkylamino group of the 10-(dialkylamino)isoborneol, but not one alone (morpholine-based case), could be able to activate synergically a diethylzinc molecule, directing it to the Si face of benzaldehyde (see TS 8 in Fig. 4).20,21 Thus, for ligands 5 and 6, but not for ligand 4 (see Fig. 2), the competitive pro-S TS 8 (Fig. 4) would be acting together with pro-R TS 7 (Fig. 3), which would explain the observed enantioselectivity loss for the polyoxygenated ligands 5 and 6 (Table 1).
R N R
O Et Zn Et O
Zn
Et H (R)
Table 1 Enantioselective addition of diethylzinc to benzaldehyde in the presence of oxygenated amino alcohols 4–6 Ligand
4 5 6
1-Phenylpropan-1-ol Yield (%)
ee (%)
99 99 99
72 36 52
7
Ph
Figure 3. Proposed controlling TS for 4 (–NR2 = morpholin-1-yl) and related 10(dialkylamino)isoborneols. Catalytic chelate in red. Reacting activated molecules in black.
Dominant configuration (R) (S) (R)
The measured activity of our ligand 4 (72% ee, pro-R) agrees with the activity determined previously by Aoyama for the same ligand.10
According to this hypothesis, competitive TS 8 must be the controlling TS in the case of ligand 5 (note the pro-S sense of the stereodifferentiation for such ligand in Table 1), which indicates a higher capacity of the dioxygenated open-chained bis(2-methoxyethyl)amino group of 5 to activate a diethylzinc molecule, when compared to the trioxygenated cyclic aza-12-crown-4 moiety of 6. This higher capacity can be explained on the basis of a higher
E. M. Sánchez-Carnerero et al. / Tetrahedron: Asymmetry 20 (2009) 2655–2657
8.
O Et
N
Zn
O R R
O
9.
O Zn
Et
Et Ph
H (S)
8 Figure 4. Proposed competitive TS for ligands 5 and 6. Catalytic chelate in red. Reacting activated molecules in black.
conformational flexibility for the group, favouring its pincer capacity.
bis(2-methoxyethyl)amino
10. 11. 12.
3. Conclusion In conclusion, the polyoxygenation of the dialkylamino group, at least when such oxygenation is located at the b-position to the nitrogen atom, produces the same effect in amino-acid-derived b-amino alcohols (a seminal observation of Martens and Brunet) and in ketopinic-acid-derived c-amino alcohols. Since both kinds of amino alcohols are very different (not only concerning to the relative positions of the amino and hydroxyl groups, but also in the conformational flexibility of the supporting hydrocarbonated chiral skeletons), it seems reasonable to think that this effect should be general for all amino-alcohol-based ligands. The effect consists of a modulation of the catalytic activity of the ligand by enhancing the formation of the opposite enantiomer. The effect is higher in b-amino alcohols than in c-amino alcohols, probably due to the lower conformational flexibility of the five-membered zinc-chelate catalyst for b-amino alcohols, when compared to the six-membered one for c-amino alcohols (note the flexibility of the sixmembered zinc-chelate in Fig. 3). We have explained this effect by a competitive pincer activation of diethylzinc in the case of the polyoxygenated ligands, proposing a TS model for such behaviour. We have also demonstrated that the observed effect is sensitive to the flexibility of the pincer, being higher for the more flexible open-chained bis(2-methoxyethyl)amino pincer, when compared to the cyclic aza-12-crown-4.
13.
14.
15.
16.
Acknowledgements We thank MEC (CTQ2007-67103-C02/BQU), UCM-CM (910107) and Santander-UCM (PR34/07-15782 and 910107) for supporting this work. References 1. Some reviews are: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49–69; (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856; (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824; (d) Pu, L. Tetrahedron 2003, 59, 9873–9886; (e) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763–2793; (f) Zhu, H.-J.; Jiang, J.-X.; Ren, J.; Yan, Y.-M.; Pitmann, C. U. Curr. Org. Synth. 2005, 2, 547–587. 2. For example see: Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774– 3776. 3. SciFinder (copyright 2009, CAS; licensed to UCM) finds ca. 1500 references by crossing the topics ‘diethylzinc’ and ‘enantioselective’. 4. For example see: Scarpi, D.; Occhiato, E. G.; Guarna, A. Tetrahedron: Asymmetry 2009, 20, 340–350. 5. (a) Chen, Y. K.; Jeon, S. J.; Walsh, P. J.; Nuggent, W. A. Org. Synth. 2005, 82, 87; an additional recent example is: (b) Wu, Z.-L.; Wu, H.-L.; Wu, p.-Y.; Uang, B.-J. Tetrahedron: Asymmetry 2009, 20, 1556–1560. 6. Chai, L.-T.; Wang, Q.-R.; Tao, F.-G. J. Mol. Catal. A: Chem. 2007, 276, 137–142. 7. (a) Kossemjans, M.; Pennemann, H.; Martens, J.; Juanes, O.; Rodríguez-Ubis, J. C.; Brunet, E. Tetrahedron: Asymmetry 1998, 9, 4123–4125; (b) Juanes, O.;
17. 18.
19.
20.
21.
2657
Rodríguez-Ubis, J. C.; Brunet, E.; Pennemann, H.; Kossemjans, M.; Martens, J. Eur. J. Org. Chem. 1999, 3323–3333. (a) de las Casas Engel, T.; Lora Maroto, B.; García Martínez, A.; de la Moya Cerero, S. Tetrahedron: Asymmetry 2008, 19, 269–272; (b) de lasCasas Engel, T.; Lora Maroto, B.; García Martínez, A.; de la Moya Cerero, S. Tetrahedron: Asymmetry 2008, 19, 646–650; (c) de lasCasas Engel, T.; Lora Maroto, B.; García Martínez, A.; de la Moya Cerero, S. Tetrahedron: Asymmetry 2008, 19, 2003–2006. (a) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P.; Chicharro Villas, P. Tetrahedron: Asymmetry 2002, 13, 1–4; (b) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P. Tetrahedron: Asymmetry 2002, 13, 1457–1460; (c) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2003, 14, 1959–1963; (d) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2004, 15, 753–756; (e) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron 2005, 61, 3055–3064; (f) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P.; Diaz Morillo, C. Tetrahedron: Asymmetry 2007, 18, 742–749. Hari, Y.; Aoyama, T. Synthesis 2005, 583–587. Characterization data agree with the previous data reported by Aoayama (see Ref. 10). 1 Colorless oil. ½a20 D ¼ 115:4 (c 0.065, CHCl3). H NMR, (CDCl3, 300 MHz), d: 437 (br s, 1H), 3.92 (dd. J = 7.8 Hz, J = 3.8 Hz, 1H), 3.56–3.36 (m, 4H), 3.33 (s, 6H), 2.96–2.87 (m, 3H), 2.58–2.52 (m, 2H), 2.39 (d, J = 13.3 Hz, 1H), 1.81–1.63 (m, 4H), 1.59–1.49 (m, 1H), 1.39–1.28 (m, 1H), 1.13 (s, 3H), 1.08–1.00 (m, 1H), 0.79 (s, 3H) ppm. 13C NMR, (CDC13, 75 MHz), d: 77.5 (CH), 70.6 (CH2), 58.7 (CH3), 55.8 (CH2), 54.0 (CH2), 51.4 (C), 47.9 (C), 44.7 (CH), 39.0 (CH2), 33.6 (CH2), 22.8 (CH2), 20.6 (CH3), 20.2 (CH3), ppm. FTIR, m: 3441 (br, weak), 2927 (str), 1120 (str) cm1. EM, m/z (%): 286 (100), 287 (19). HRMS (FTMS-ESI): 286.23786 (calcd for C16H32NO3 286.23767). 1 Pale yellow liquid. ½a20 D ¼ 55:1 (c 0.675, CHCl3). H NMR (CDCl3, 300 MHz), d: 5.11 (br s, 1H), 4.05 (dd, J = 8.1 Hz, J = 4.1 Hz, 1H), 3.83 (t, J = 9.6 Hz, 2H), 3.67– 3.56 (m, 10H), 3.09–2.87 (m, 3H), 2.45–2.21(m, 3H), 1.84–1.35 (m, 6H), 1.15 (s, 3H), 1.08–0.99 (m, 1H), 0.79 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz), d: 77.2 (CH), 71.7 (CH2), 71.6 (CH2), 70.0 (CH2), 69.4 (CH2), 56.4 (CH2), 55.4 (CH2), 51.1 (C), 48.1 (C), 44.7 (CH), 39.1 (CH2), 33.9 (CH2), 27.8 (CH2), 20.5 (CH3), 20.3 (CH3) ppm. FTIR, m: 3439 (br, weak), 1185 (str), 1127 (str) cm1. MS (ESI), m/z (%): 350 (30), 329 (14), 328 (100). HRMS (FTMS-ESI): 328.24778 (calcd for C18H34NO4 328.24824). Over a solution of (1S)-ketopinic acid (1.6 mmol) in CH2Cl2 at rt were added N-3-[(dimethylamino)propyl]-N0 -ethylcarbodiimide hydrochloride (EDCHCl, 1.8 mmol), 4-(dimethylamino)pyridine (DMAP, 1.8 mmol) and the corresponding secondary amine (morpholine, bis(2-methoxyethyl)amine or aza-12-crown-4, 1.8 mmol). The reaction mixture was stirred for 24 h. Then, CH2Cl2 (3 mL) and H2O (3 mL) were added to the mixture and the obtained phases were separated. The organic phase was washed with 10% HCl (1 3 mL), water (1 3 mL), 10% NaOH (2 3 mL), water (1 3 mL) and brine (1 3 mL), and dried over MgSO4. After filtration and solvent elimination, the corresponding pure ketoamide was obtained (morpholine-based ketoamide: 85% yield; bis(2-methoxyethyl)amine-based ketoamide: 77% yield; aza-12-crown-4-based ketoamide: 83% yield). Characterization data agree with the corresponding structures. Morpholine-based ketoamide was previously described by Aoyama (see Ref. 10). Standard LiAlH4 reduction in refluxing THF (see Ref. 10). Yield: 89% for 4 (characterisation data in Ref. 10), 75% for 5 (characterisation data in Ref. 12), and 77% for 6 (characterisation data in Ref. 13). Under argon, diethylzinc (1.0 M in hexanes, 2 mL, 2.0 mmol) was added to the corresponding ligand (0.050 mmol) in anhydrous hexane (1 mL) and the mixture was stirred for 1 h at rt. After that freshly distilled benzaldehyde (1.0 mmol) was slowly added and the resulting mixture was stirred for 5 h at rt. Final treatment with 1 N HCl and standard work-up (e.g., see Ref. 10) yielded the resulting enantioenriched mixture of 1-phenylpropan-1-ol. The yield was determined by GC (SGL-1). The ee was determined by chiral HPLC (Chiralpak IC). The dominant configuration was also determined by chiral HPLC (the absolute configurations for the enantiomeric elution peaks were previously assigned by chiral HPLC analysis of a known mixture of enantiomers). Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L. Chem. Rev. 1991, 91, 1721–2085. Anyway, the ability of four-heteroatom macrocycles for coordinating a Zn2+ cation should not be compared with the ability for coordinating a Et2Zn molecule. Endo vs exo indicates the face on which reacting species coordinates to the Zn– O bond of the norbornane-based catalyst. Syn vs anti indicates the relative position of both zinc ethyl groups. Re vs Si indicates the carbonyl face on which the ethyl transfer occurs. Kozlowski and Wang have, respectively, proposed similar directing effects exerted by an unique neighboring amino group in piperidine-substituted bis(hydroxyimines) and pyridine-substituted amino alcohols: (a) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668–12669; (b) Kang, Y. F.; Liu, L.; Wang, R.; Yan, W. J.; Zhou, Y. F. Tetrahedron: Asymmetry 2004, 15, 3155–3159. Pentacoordinated Zn(II) complexes are well known and many examples can be found in the literature (inclusively supported by X-ray diffractograms). Moreover, related pentacoordinated-zinc-based TSs has been previously proposed (e.g., see: Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645–5648. See also Ref. 8a).
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Polyoxygenated ketopinic-acid-derived c-amino alcohols in the enantioselective diethylzinc addition to benzaldehyde Esther Márquez Sánchez-Carnerero, Tomás de las Casas Engel, Beatriz Lora Maroto, Santiago de la Moya Cerero * Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
a r t i c l e
i n f o
Article history: Received 20 October 2009 Accepted 13 November 2009 Available online 5 December 2009 Dedicated to Professor Antonio Garcia Martinez on the occasion of his last academic course.
a b s t r a c t Three N,N-dialkylated c-amino alcohols, specifically 10-(dialkylamino)isoborneols, with different grades of oxygenation in the nitrogen’s alkyl groups (alkoxyalkyl groups), have been obtained from commercial (+)-ketopinic acid and tested as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde, in order to evaluate the effect of polyoxygenation on the ligand’s catalytic activity. An interesting effect of the oxygen atoms on the ligand activity is observed. The observation is in agreement with two unique previous results on amino-acid-derived polyoxygenated b-amino alcohols. A noticeable dependence of the observed effect with the conformational flexibility of the polyoxygenated chains is also demonstrated. The effect is explained by a pincer role of the polyoxygenated dialkylamino moiety, activating and directing a diethylzinc molecule. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Chiral amino alcohols, especially N,N-dialkylated amino alcohols (e.g., Noyori’s DAIB 1, Fig. 1), are the main ligands for promoting the enantioselective addition of organozinc reagents to aldehydes.1 The reaction is one of the most important synthetic methods for the preparation of enantioenriched secondary alcohols, which are key intermediates in the preparation of valuable chiral molecules (e.g., biologically active natural products).1d,2 With the objective of finding more versatile ligands, new chiral architectures are being described as effective in promoting the enantioselective addition of organozinc reagents to aldehydes.3 In most cases, only the catalytic behaviour of the new ligand (chemical yield and ee) in the addition of diethylzinc to benzaldehyde (test reaction) is reported.1d Unfortunately, fewer studies have been directed to correlate the structural factors with catalytic activities, probably due to the high costs in the preparation of a large series of structurally related chiral ligands.4 However, this kind of studies are very important, since they can lead to the establishment of valuable rules for the rationalized design of improved new ligands. To date, the structure–activity correlation studies on N,N-dialkylated amino alcohols have mainly centred on the influence of the nitrogen’s alkyl substitution in the catalytic activity of easily obtainable amino alcohols (steric effects),1d whereas studies on the influence of other structural variables (e.g., electronic effects) are less common.4 * Corresponding author. Tel.: +34 91 394 5090; fax: +34 91 394 4103. E-mail address: [email protected] (S. de la Moya Cerero). 0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2009.11.010
On the other hand, the introduction of an oxygen atom in the dialkylamino group of certain amino alcohols is usually a successful structural modification for designing improved ligands (e.g., Nuggent’s MIB 2 vs Noyori’s DAIB 1, see Fig. 1).5 Moreover, oxygen has also been used as a convenient tool to link well-known chiral ligands to insoluble dendrimers and polymers (e.g., 3 in Fig. 1) with the aim of designing easily recyclable and reusable ligands, or supported ligands for flow chemistry.1d,6 O N
N
OH
OH
Ph Ph OH P
1
2
N
O 3
Figure 1. Some ligands for the enantioselective addition of organozinc reagents to aldehydes.
However, to the best of our knowledge and in spite of the importance of the introduction of oxygen atoms in the structure of amino-alcohol-based ligands, there are no rationalized studies on the influence of the oxygenation in the catalytic activity of the ligand. Only the work of Martens and Brunet, on the catalytic-activity variation caused by the introduction of oxygen atoms in the dialkylamino group of a set of related flexible b-amino alcohols derived from cysteine, methionine and leucine (from pro-R 92% ee to pro-S 11% ee) has been carried out.7 The authors concluded that additional factors, other than simple steric ones, should
2656
E. M. Sánchez-Carnerero et al. / Tetrahedron: Asymmetry 20 (2009) 2655–2657
be invoked to explain the observed variation of ee7b In this sense, the authors also concluded that the mechanism explaining the observed reversion of the enantioselection is still unclear.7b In relation to this and continuing with our previous work on the study and development of ketopinic-acid-derived chiral ligands for the enantioselective addition of organozinc reagents to aldehydes,8 we became interested in measuring the influence of the dialkylamino polyoxygenation on the catalytic activity of 10-(diakylamino)isoborneols, in order to test the possible extension of the effect found by Martens and Brunet to another amino-alcohol type, and attempt to give a reasonable explanation for such effect on the basis of our experience in structure–activity relationships for the catalyzed enantioselective addition of diethylzinc to benzaldehyde.8,9 2. Results and discussion For our purpose, we chose three related oxygenated ligands 4–6 (Fig. 2) and the addition of diethylzinc to benzaldehyde as the test reaction. These three ligands are obtained from commercially available structurally related secondary amines based on 2alkoxyethylamine.
OH N
OH
OH O
N
N
O
O
O
O 4
O 5
6
Figure 2. Differently oxygenated ketopinic-acid-derived 10-(dialkylamino)isoborneols.
The preparation and catalytic activity of 4 have previously been reported by Aoyama.10 Aoyama’s work also compares the catalytic activity of morpholine-based 4 (74% ee, pro-R) with its piperidinebased analogue (77% ee, pro-R). The similar measured activities demonstrate that no effect is exerted by the heterocyclic oxygen of 4 in its catalytic activity.10 Ligands 4,11 512 and 613 can be obtained from commercial (1S)ketopinic acid in two steps: amidation by EDC activation,14 followed by stereoselective reduction of the ketoamides obtained with lithium and aluminium hydride.15 The three ligands were tested under the same standard test-reaction conditions,16 to make the later comparisons possible. The measured catalytic activities (chemical yield, ee and dominant configuration for the obtained alcohol) are shown in Table 1.
Substitution of the morpholine moiety in ligand 4 by the trioxygenated aza-12-crown-4 moiety in ligand 6 leads to a noticeable loss in enantioselectivity (20 points in ee, see Table 1). The same effect, although more intensive (up to 97 points in ee), was observed by Martens and Brunet in a series of cysteine-based b-amino alcohols with the same structural variations.7 A larger decrease in enantioselectivity (98 points in ee, see Table 1), even with reversion of the enantioselection sense (from pro-R to pro-S), was observed when the morpholine moiety of 4 was substituted by the dioxygenated open-chained bis(2-methoxyethyl)amino moiety in 5. Since ligand 5 exhibits a stronger effect than 6, the known affinity of Zn2+ for macrocycles of four heteroatoms17 must not be the unique possible cause for the observed effect, as previously suggested by Marteens and Brunet.7b,18 On the other hand, Aoyama explained the sense of the stereodifferentiation exhibited by morpholine-based ligand 4 (pro-R) and other related 10-(dialkylamino)isoborneols on the basis of 7 as the most stable transition state [i.e., the less-hindered diastereomer (endo-anti-anti TS)19 from a set of eight possible competing diastereomeric TSs]. It was demonstrated that in the controlling-TS model, there was not any appreciable coordinative interaction between the oxygen atom of the morpholino group and the catalytic zinc.10,8a Therefore, it was concluded that the substituents at nitrogen must be removed from the sterically congested reaction site in the most stable conformation of 7. Continuing with this reasoning, it is expected that the structural variations of ligands 5 and 6, regarding ligand 4 (see Fig. 2), will not produce any changes in the catalytic behaviour, at least due to steric effects, since the same 2-oxyethylamino moiety is present in the three cases. We did observe a noticeable effect on the catalytic behaviour (see Table 1), and for this we think that this effect must be electronic and must be caused by the polyoxygenation of the dialkyalmino group. As an explanation for the observed effect, we propose that the two oxygen atoms conveniently located at the dialkylamino group of the 10-(dialkylamino)isoborneol, but not one alone (morpholine-based case), could be able to activate synergically a diethylzinc molecule, directing it to the Si face of benzaldehyde (see TS 8 in Fig. 4).20,21 Thus, for ligands 5 and 6, but not for ligand 4 (see Fig. 2), the competitive pro-S TS 8 (Fig. 4) would be acting together with pro-R TS 7 (Fig. 3), which would explain the observed enantioselectivity loss for the polyoxygenated ligands 5 and 6 (Table 1).
R N R
O Et Zn Et O
Zn
Et H (R)
Table 1 Enantioselective addition of diethylzinc to benzaldehyde in the presence of oxygenated amino alcohols 4–6 Ligand
4 5 6
1-Phenylpropan-1-ol Yield (%)
ee (%)
99 99 99
72 36 52
7
Ph
Figure 3. Proposed controlling TS for 4 (–NR2 = morpholin-1-yl) and related 10(dialkylamino)isoborneols. Catalytic chelate in red. Reacting activated molecules in black.
Dominant configuration (R) (S) (R)
The measured activity of our ligand 4 (72% ee, pro-R) agrees with the activity determined previously by Aoyama for the same ligand.10
According to this hypothesis, competitive TS 8 must be the controlling TS in the case of ligand 5 (note the pro-S sense of the stereodifferentiation for such ligand in Table 1), which indicates a higher capacity of the dioxygenated open-chained bis(2-methoxyethyl)amino group of 5 to activate a diethylzinc molecule, when compared to the trioxygenated cyclic aza-12-crown-4 moiety of 6. This higher capacity can be explained on the basis of a higher
E. M. Sánchez-Carnerero et al. / Tetrahedron: Asymmetry 20 (2009) 2655–2657
8.
O Et
N
Zn
O R R
O
9.
O Zn
Et
Et Ph
H (S)
8 Figure 4. Proposed competitive TS for ligands 5 and 6. Catalytic chelate in red. Reacting activated molecules in black.
conformational flexibility for the group, favouring its pincer capacity.
bis(2-methoxyethyl)amino
10. 11. 12.
3. Conclusion In conclusion, the polyoxygenation of the dialkylamino group, at least when such oxygenation is located at the b-position to the nitrogen atom, produces the same effect in amino-acid-derived b-amino alcohols (a seminal observation of Martens and Brunet) and in ketopinic-acid-derived c-amino alcohols. Since both kinds of amino alcohols are very different (not only concerning to the relative positions of the amino and hydroxyl groups, but also in the conformational flexibility of the supporting hydrocarbonated chiral skeletons), it seems reasonable to think that this effect should be general for all amino-alcohol-based ligands. The effect consists of a modulation of the catalytic activity of the ligand by enhancing the formation of the opposite enantiomer. The effect is higher in b-amino alcohols than in c-amino alcohols, probably due to the lower conformational flexibility of the five-membered zinc-chelate catalyst for b-amino alcohols, when compared to the six-membered one for c-amino alcohols (note the flexibility of the sixmembered zinc-chelate in Fig. 3). We have explained this effect by a competitive pincer activation of diethylzinc in the case of the polyoxygenated ligands, proposing a TS model for such behaviour. We have also demonstrated that the observed effect is sensitive to the flexibility of the pincer, being higher for the more flexible open-chained bis(2-methoxyethyl)amino pincer, when compared to the cyclic aza-12-crown-4.
13.
14.
15.
16.
Acknowledgements We thank MEC (CTQ2007-67103-C02/BQU), UCM-CM (910107) and Santander-UCM (PR34/07-15782 and 910107) for supporting this work. References 1. Some reviews are: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49–69; (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856; (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824; (d) Pu, L. Tetrahedron 2003, 59, 9873–9886; (e) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763–2793; (f) Zhu, H.-J.; Jiang, J.-X.; Ren, J.; Yan, Y.-M.; Pitmann, C. U. Curr. Org. Synth. 2005, 2, 547–587. 2. For example see: Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774– 3776. 3. SciFinder (copyright 2009, CAS; licensed to UCM) finds ca. 1500 references by crossing the topics ‘diethylzinc’ and ‘enantioselective’. 4. For example see: Scarpi, D.; Occhiato, E. G.; Guarna, A. Tetrahedron: Asymmetry 2009, 20, 340–350. 5. (a) Chen, Y. K.; Jeon, S. J.; Walsh, P. J.; Nuggent, W. A. Org. Synth. 2005, 82, 87; an additional recent example is: (b) Wu, Z.-L.; Wu, H.-L.; Wu, p.-Y.; Uang, B.-J. Tetrahedron: Asymmetry 2009, 20, 1556–1560. 6. Chai, L.-T.; Wang, Q.-R.; Tao, F.-G. J. Mol. Catal. A: Chem. 2007, 276, 137–142. 7. (a) Kossemjans, M.; Pennemann, H.; Martens, J.; Juanes, O.; Rodríguez-Ubis, J. C.; Brunet, E. Tetrahedron: Asymmetry 1998, 9, 4123–4125; (b) Juanes, O.;
17. 18.
19.
20.
21.
2657
Rodríguez-Ubis, J. C.; Brunet, E.; Pennemann, H.; Kossemjans, M.; Martens, J. Eur. J. Org. Chem. 1999, 3323–3333. (a) de las Casas Engel, T.; Lora Maroto, B.; García Martínez, A.; de la Moya Cerero, S. Tetrahedron: Asymmetry 2008, 19, 269–272; (b) de lasCasas Engel, T.; Lora Maroto, B.; García Martínez, A.; de la Moya Cerero, S. Tetrahedron: Asymmetry 2008, 19, 646–650; (c) de lasCasas Engel, T.; Lora Maroto, B.; García Martínez, A.; de la Moya Cerero, S. Tetrahedron: Asymmetry 2008, 19, 2003–2006. (a) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P.; Chicharro Villas, P. Tetrahedron: Asymmetry 2002, 13, 1–4; (b) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P. Tetrahedron: Asymmetry 2002, 13, 1457–1460; (c) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2003, 14, 1959–1963; (d) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2004, 15, 753–756; (e) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron 2005, 61, 3055–3064; (f) García Martínez, A.; Teso Vilar, E.; García Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P.; Diaz Morillo, C. Tetrahedron: Asymmetry 2007, 18, 742–749. Hari, Y.; Aoyama, T. Synthesis 2005, 583–587. Characterization data agree with the previous data reported by Aoayama (see Ref. 10). 1 Colorless oil. ½a20 D ¼ 115:4 (c 0.065, CHCl3). H NMR, (CDCl3, 300 MHz), d: 437 (br s, 1H), 3.92 (dd. J = 7.8 Hz, J = 3.8 Hz, 1H), 3.56–3.36 (m, 4H), 3.33 (s, 6H), 2.96–2.87 (m, 3H), 2.58–2.52 (m, 2H), 2.39 (d, J = 13.3 Hz, 1H), 1.81–1.63 (m, 4H), 1.59–1.49 (m, 1H), 1.39–1.28 (m, 1H), 1.13 (s, 3H), 1.08–1.00 (m, 1H), 0.79 (s, 3H) ppm. 13C NMR, (CDC13, 75 MHz), d: 77.5 (CH), 70.6 (CH2), 58.7 (CH3), 55.8 (CH2), 54.0 (CH2), 51.4 (C), 47.9 (C), 44.7 (CH), 39.0 (CH2), 33.6 (CH2), 22.8 (CH2), 20.6 (CH3), 20.2 (CH3), ppm. FTIR, m: 3441 (br, weak), 2927 (str), 1120 (str) cm1. EM, m/z (%): 286 (100), 287 (19). HRMS (FTMS-ESI): 286.23786 (calcd for C16H32NO3 286.23767). 1 Pale yellow liquid. ½a20 D ¼ 55:1 (c 0.675, CHCl3). H NMR (CDCl3, 300 MHz), d: 5.11 (br s, 1H), 4.05 (dd, J = 8.1 Hz, J = 4.1 Hz, 1H), 3.83 (t, J = 9.6 Hz, 2H), 3.67– 3.56 (m, 10H), 3.09–2.87 (m, 3H), 2.45–2.21(m, 3H), 1.84–1.35 (m, 6H), 1.15 (s, 3H), 1.08–0.99 (m, 1H), 0.79 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz), d: 77.2 (CH), 71.7 (CH2), 71.6 (CH2), 70.0 (CH2), 69.4 (CH2), 56.4 (CH2), 55.4 (CH2), 51.1 (C), 48.1 (C), 44.7 (CH), 39.1 (CH2), 33.9 (CH2), 27.8 (CH2), 20.5 (CH3), 20.3 (CH3) ppm. FTIR, m: 3439 (br, weak), 1185 (str), 1127 (str) cm1. MS (ESI), m/z (%): 350 (30), 329 (14), 328 (100). HRMS (FTMS-ESI): 328.24778 (calcd for C18H34NO4 328.24824). Over a solution of (1S)-ketopinic acid (1.6 mmol) in CH2Cl2 at rt were added N-3-[(dimethylamino)propyl]-N0 -ethylcarbodiimide hydrochloride (EDCHCl, 1.8 mmol), 4-(dimethylamino)pyridine (DMAP, 1.8 mmol) and the corresponding secondary amine (morpholine, bis(2-methoxyethyl)amine or aza-12-crown-4, 1.8 mmol). The reaction mixture was stirred for 24 h. Then, CH2Cl2 (3 mL) and H2O (3 mL) were added to the mixture and the obtained phases were separated. The organic phase was washed with 10% HCl (1 3 mL), water (1 3 mL), 10% NaOH (2 3 mL), water (1 3 mL) and brine (1 3 mL), and dried over MgSO4. After filtration and solvent elimination, the corresponding pure ketoamide was obtained (morpholine-based ketoamide: 85% yield; bis(2-methoxyethyl)amine-based ketoamide: 77% yield; aza-12-crown-4-based ketoamide: 83% yield). Characterization data agree with the corresponding structures. Morpholine-based ketoamide was previously described by Aoyama (see Ref. 10). Standard LiAlH4 reduction in refluxing THF (see Ref. 10). Yield: 89% for 4 (characterisation data in Ref. 10), 75% for 5 (characterisation data in Ref. 12), and 77% for 6 (characterisation data in Ref. 13). Under argon, diethylzinc (1.0 M in hexanes, 2 mL, 2.0 mmol) was added to the corresponding ligand (0.050 mmol) in anhydrous hexane (1 mL) and the mixture was stirred for 1 h at rt. After that freshly distilled benzaldehyde (1.0 mmol) was slowly added and the resulting mixture was stirred for 5 h at rt. Final treatment with 1 N HCl and standard work-up (e.g., see Ref. 10) yielded the resulting enantioenriched mixture of 1-phenylpropan-1-ol. The yield was determined by GC (SGL-1). The ee was determined by chiral HPLC (Chiralpak IC). The dominant configuration was also determined by chiral HPLC (the absolute configurations for the enantiomeric elution peaks were previously assigned by chiral HPLC analysis of a known mixture of enantiomers). Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L. Chem. Rev. 1991, 91, 1721–2085. Anyway, the ability of four-heteroatom macrocycles for coordinating a Zn2+ cation should not be compared with the ability for coordinating a Et2Zn molecule. Endo vs exo indicates the face on which reacting species coordinates to the Zn– O bond of the norbornane-based catalyst. Syn vs anti indicates the relative position of both zinc ethyl groups. Re vs Si indicates the carbonyl face on which the ethyl transfer occurs. Kozlowski and Wang have, respectively, proposed similar directing effects exerted by an unique neighboring amino group in piperidine-substituted bis(hydroxyimines) and pyridine-substituted amino alcohols: (a) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002, 124, 12668–12669; (b) Kang, Y. F.; Liu, L.; Wang, R.; Yan, W. J.; Zhou, Y. F. Tetrahedron: Asymmetry 2004, 15, 3155–3159. Pentacoordinated Zn(II) complexes are well known and many examples can be found in the literature (inclusively supported by X-ray diffractograms). Moreover, related pentacoordinated-zinc-based TSs has been previously proposed (e.g., see: Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645–5648. See also Ref. 8a).