Synthesis of polymeric chiral l -prolinol derivatives and its applications on the asymmetric Michael addition

Reactive & Functional Polymers 49 (2001) 173–178 www.elsevier.com / locate / react

Synthesis of polymeric chiral L-prolinol derivatives and its applications on the asymmetric Michael addition Jinxia Huang*, Yan Li, Jun Ren, Yuanyuan Zhou, Junli Hou Faculty of Chemical and Material Science, Hubei University, Wuhan 430062, PR China Received 18 January 2001; received in revised form 7 June 2001; accepted 14 June 2001

Abstract N-acylation of L-prolinol (2) with enoyl chloride provided L-cinnamoylprolinol (3a) and L-crotonylprolinol (3b), respectively. The attachment of (3a) or (3b) to Merrifield resin and the utilization of such a system for asymmetric Michael additions of Grignard reagents to a,b-unsaturated carbonyl compounds were studied. The stereoselectivities have been increased compared with those observed for the same reactions in solution. On the other hand, it has been proved by the FT-IR difference spectrum of the Merrifield resin and polymer-supported chiral auxiliary that L-prolinol derivatives have been coupled to the resin.  2001 Elsevier Science B.V. All rights reserved. Keywords: Polymer-supported L-prolinol derivatives; Chiral auxiliary; Asymmetric Michael addition; Difference spectrum

1. Introduction Reactive and functional polymers have recently found widespread applications in combinatorial chemistry based on the advantages of the functional groups and properties of the polymeric molecule, and the enormous growth in solid phase organic synthesis has re-stimulated interest in the area of asymmetric solidphase reactions. Over recent years some chiral auxiliaries (esp. Evans’ auxiliary) which showed excellent asymmetric induction in solution reactions were bound to polymers and used in

*Corresponding author. E-mail address: [email protected] (J. Huang).

alkylation reactions [1], aldol reactions [2], Diels–Alder reactions [3] and conjugated additions. L-Prolinol derivatives have been utilized in alkylation, iodination reactions [4,5] and conjugate addition [6] as good chiral auxiliaries. On the other hand, polymer-supported L-prolinol derivatives in solid phase organic synthesis have been reported. Kurth [7] employed a polymersupported pyrrolidine chiral auxiliary in the preparation of a nonracemic g-butyrolactone using L-prolinol as the source of chirality and he also developed a so-called second generation polymer-supported chiral auxiliary, based on a C 2 -symmetric pyrrolidine, for use in enantioselective synthesis. And most recently Hodge [8] used a polymer-supported L-prolinol as a catalyst for asymmetric alkylation of aldehydes.

1381-5148 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S1381-5148( 01 )00076-1

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Here we have prepared polymer-supported N-enoylprolinol (4) from L-prolinol (2) by the attachment of N-enoylprolinol (3) to Merrifield resin and used the system for asymmetric Michael additions of Grignard reagents to a,bunsaturated carbonyl compounds for the first time (Scheme 1). The structure of resin (4) was characterized by the analysis of the FT-IR difference spectrum of the Merrifield resin and resin (4). In order to determine the enantiomeric excess of acids (1), they were converted to N-acylbornane-10,2-sultam [9,10] using D-(2)-bornane10,2-sultam, then the diastereomeric compositions were determined by HPLC and the stereoselectivities have been increased remarkably compared with those observed for the same reactions in solution.

2. Experimental

2.1. Materials and instruments The chloromethylated styrene–divinylbenzene beads were purchased from Aldrich Chemical Company (2–2.5 meq. Cl / g, 200–400 mesh). IR spectra were run on a Shimadzu IR-440 Spectrometer and PE spectrum One (version 3.01). 1 H NMR spectra were recorded on a Brucker AC-80 and ARX-500 spectrometer in CDCl 3 using TMS as internal standard. The elemental analyses were made using a PE-2400 Analyzer. The optical rotations were measured on a WZZ-T1 polarimeter produced at Physical Instrument Plant, Shanghai, China. L-Prolinol (2) was prepared according to the literature method [11].

Scheme 1.

J. Huang et al. / Reactive & Functional Polymers 49 (2001) 173 – 178

2.2. Synthesis of polymer-supported L-prolinol derivatives 2.2.1. Synthesis of N-enoylprolinol (3) Thirty ml of 1.0 mol / l aqueous NaOH were added to a mixture of L-prolinol (2) (2.28 g, 22.6 mmol) and water (20 ml). The mixture was cooled in an ice-bath and enoyl chloride (23.2 mmol) in ether (30 ml) was added. The mixture was stirred at room temperature for 3 h and extracted with ethyl acetate; the extract was then dried (MgSO 4 ), and evaporated under reduced pressure. Purification of the residue by silica gel column chromatography afforded (3). L-Cinnamoylprolinol (3a) was prepared by use of the procedure described above with 85% yield. 1 H NMR (CDCl 3 ) d ppm 1.50–2.40 (m; 4H; 2 3 –CH 2 ), 3.40–3.80 (m; 4H; N–CH 2 , –CH 2 –O), 4.00–4.70 (m, 1H, N–CH), 5.10– 5.50 (m, 1H, –OH) and 6.55–8.10 (m, 7H; C 6 H 5 –, –CH=CH–); m.p. 84–868C, [lit. [6], 84.5–85.58C]; [a ] 20 2 34.18 (c 5 2.1, CHCl 3 ) D [lit. [6], [a ] 20 2 33.08 (c 5 2.0, CHCl 3 )]; FTD IR(KBr) ymax : 3350, 2950, 2380, 1650, 1580, 21 1430, 1260, 1200, 1050, 980, 860, 680 cm . Calculated for C 14 H 17 NO 2 : C 72.70%, H 7.41%, N 6.06%; found: C 72.53%, H 7.52%, N 6.14%. L-Crotonylprolinol (3b) was prepared by use of the procedure described above with 80% yield. 1 H NMR (CDCl 3 ) d ppm 1.60–2.20 (m; 4H; 2 3 –CH 2 ), 1.86 (d, 3H, J 5 7.0 Hz, C=C– CH 3 ), 3.35–3.75 (m; 5H; N–CH 2 , –CH 2 –O, –OH), 4.00–4.40 (m; 1H; N–CH), 6.10 (dq; 1H; J 5 16.5, 2.0 Hz, C=CH–CO) and 6.96 (dq; 1H; J 5 16.5, 7.0 Hz, C–CH=C); FT-IR(KBr) ymax : 3390, 2954, 2878, 1660, 1593, 1454, 1193, 1050, 901, 827 cm 21 . Calculated for C 9 H 15 NO 2 : C 63.88%, H 8.93%, N 8.28%; found: C 63.78%, H 8.75%, N 8.33%. 2.2.2. Synthesis of polymer-supported Nenoylprolinol (4) [12] Potassium hydride (1.35 g, 33.75 mmol) was added to a three-neck flask under Ar flow, and

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washed three times by 20 ml petroleum ether per time, then cooled in an ice-bath and the solution of N-enoylprolinol (3) (22.5 mmol) in dry DMF (50 ml) was added dropwise. After 2 h, DMF-swollen Merrifield resins (6 g, 15 mmol) and 18-Crown-6 ether (0.12 g, 0.45 mmol) were added. The mixture was heated to 808C and stirred for 5 days. The beads were filtered off, rinsed with water, DMF and MeOH before being extracted in a Soxhlet (THF) for at least 48 h. The beads were finally dried in a vacuum oven (608C / 5 mmHg) for 48 h. Polymer-supported L-cinnamoylprolinol (4a) was prepared according to the procedure described above, yielding 5.9 g. Nitrogen content of 4a was about 1.71 mmol / g. FT-IR(KBr) ymax : 3056, 2918, 1944, 1870, 1803, 1749, 1650, 1599, 1510, 1492, 1450, 1194, 973, 760, 696 cm 21 . Polymer-supported L-crotonylprolinol (4b) was prepared according to the procedure described above, yielding 6.0 g. Nitrogen content of 4b was about 1.85 mmol / g. FT-IR(KBr) ymax : 3057, 2912, 1942, 1870, 1799, 1680, 1601, 21 1509, 1492, 1452, 1018, 758, 698 cm .

2.3. Asymmetric Michael addition of polymersupported N-enoylprolinol (4) At 2 208C, alkylmagnesium bromide (25 mmol) in Et 2 O was added dropwise to resin (4) (10–11 mmol) in THF. The mixture was stirred at 2 208C for 24 h and then stirred at room temperature for 72 h. The beads were filtered off, rinsed with aqueous HCl, water, THF before being extracted in a Soxhlet (THF) for at least 48 h. The beads were finally dried in a vacuum oven (608C / 5 mmHg) for 48 h.

2.3.1. Conjugate addition of nbutylmagnesium bromide (5 a) Resin (4a) (6.0 g, 10 mmol) and n-BuMgBr were treated to give resin (5a). FT-IR(KBr) ymax : 3641, 3082, 3024, 3058, 2913, 2847, 1939, 21 1873, 1801, 1653, 1492, 1180, 1067 cm .

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2.3.2. Conjugate addition of nbutylmagnesium bromide (5 b) Resin (4b) (6.0 g, 11 mmol) and n-BuMgBr were treated to give resin (5b). FT-IR(KBr) ymax : 3641, 3070, 3010, 3000, 2847, 1939, 1873, 1801, 1655, 1490, 1180, 1060 cm 21 .

(S)-3-Methyl-5-hexenoic acid (1c) yield 79% (0.92 g); 1 H NMR (CDCl 3 ): 0.95 (t, J 5 7.0 Hz, 3H, CH 3 –C), 1.80–2.10 (m, 3H, 3 –CH, 4 –CH 2 ), 2.41 (d, J 5 7.0 Hz, 2H, CH 2 CO), 4.90–5.10 (m, 2H, CH 2 =CH–), 5.80 (m, 1H, CH=C), 11.8 (s, 1H, COOH).

2.3.3. Conjugate addition of allylmagnesium bromide (5 c) Resin (4b) (6.0 g, 11 mmol) and allylmagnesium bromide were treated to give resin (5c). FT-IR(KBr) ymax : 3641, 3080, 3020, 3000, 2850, 1939, 1873, 1801, 1657, 1490, 1180, 1060 cm 21 .

2.5. Recyclation of resin (4)

2.4. Preparation of chiral acids (1) by nondestructive removal of auxiliary groups of resin (5) Resin (5) (5.8 g, 10 mmol) was added to a suspension of LiOH ? H 2 O (4.1 g, 100 mmol), THF (20 ml) and water (10 ml). The mixture was stirred at 408C for 48 h. The beads were filtered off, rinsed with aqueous HCl, water, THF before being extracted in a Soxhlet (THF) for at least 48 h. The beads were finally dried in a vacuum oven (608C / 5 mmHg) for 48 h to produce resin (6). FT-IR(KBr) ymax : 3297, 1943, 1869, 1750, 1601, 1492, 1432, 813, 759, 699 cm 21 . The aqueous layer from the original filtrate was extracted with Et 2 O, the extract was then dried (Na 2 SO 4 ) and vaporated under reduced pressure. Purification of the residue by silica gel column flash chromatography afforded acids (1). (S)-3-Phenylheptanoic acid (1a) yield 80% (1.65 g); 1 H NMR (CDCl 3 ): 0.70–1.93 (m, 9H), 2.40–3.20 (m, 3H), 6.90–7.42 (m, 5H), 11.53–11.76 (s, 1H). (S)-3-Methylheptanoic acid (1b) yield 78% (1.12 g); 1 H NMR (CDCl 3 ): 0.80 (d, J 5 7.5 Hz, 3H), 0.90 (d, J 5 7.5 Hz, 3H), 1.22–1.49 (m, 6H), 1.95 (m, 1H), 2.30 (d, J 5 6.8 Hz, 2H), 11.5 (s, 1H).

Resin (6) (10 mmol) was swollen with dry THF (20 ml) in a dry N 2 -flushed three-necked flask. At 2 788C n-BuLi (15 ml, 2.0 M in hexane) was added dropwise over a period of | 1 h to the stirred mixture, then the excess reagents were drained away. The second batch of THF and n-BuLi was treated with the same procedure described above. After draining the second batch of n-BuLi, the resin was resuspended in 20 ml THF and enoyl chloride (100 mmol) was added dropwise at 2 788C. The mixture was stirred at this temperature for 6 h. The cooling bath was then removed, allowing a gradual warming to room temperature. The reaction was left stirring for 24 h and filtered. The polymer beads were washed with MeOH and THF before being dried in a vacuum oven (608C / 5 mmHg) for 48 h. Nitrogen content of resin 4a was about 1.50 mmol / g. Nitrogen content of resin 4b was about 1.62 mmol / g.

3. Results and discussion

3.1. Preparation of polymer-supported Nenoylprolinol The general procedure of alcohol being coupled to Merrifield resin is as follows: potassium hydride reacted with alcohol to yield potassium alkoxide which attacked the C–Cl bond of the Merrifield resin as a nucleophilic reagent in the presence of 18-Crown-6 ether to produce polymer-supported alcohol. But the results are not satisfactory when sodium hydride is used, be-

J. Huang et al. / Reactive & Functional Polymers 49 (2001) 173 – 178

cause the ring size of 18-Crown-6 may be not just fit to the ionic radius of Na 1 . We also investigated the influence of reaction time and reaction temperature in an attempt to find conditions under which the best results could be achieved (Table 1). The reaction temperature plays an important role in polymer-supported reaction. At a relatively higher temperature, the resins are well swollen so that little molecules could enter the resin, thereby the yield is raised. Moreover, the increase of temperature, accelerating the movement of molecules, makes the reaction sufficient. But if the temperature is too high, the resin may be crushed. We discover that, when the reaction is carried out at 808C for 5 days, the obtained resin seems not to be damaged and the yield is remarkably improved. Table 1 Influence of reaction time and reaction temperature Alcohol

Solvent

Temperature (8C)

Time (days)

Nitrogen content

3a 3a 3a 3a

DMF DMF DMF DMF

60 70 80 85

7 7 5 5

1.10 1.20 1.71 1.72

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3.2. Analysis of polymer-supported products (4) by FT-IR spectra N-enoylprolinol (3) is coupled to the Merrifield resin with good yield by elemental analysis. A strong C=O (1650 cm 21 ) band in the FT-IR spectra of resin (4) also confirms this. As the peak of the C=C band is covered by the peak of the benzene ring of the resin, we designed the difference spectrum (Fig. 1). Difference spectrum 5 (spectrum of polymer-supported resin (4)) 2 (spectrum of Merrifield resin) 3 Factor 1 c. Here the parameter Factor enables us to multiply the spectrum so that we can subtract it from the former spectrum. And c is a constant that is calculated by spectra to minimize baseline shift in the difference spectrum. Instead of defining the Factor, we choose to have it calculated automatically by software. The automatic calculation could eliminate the effect of different concentrations or sample thickness for the two spectra and perform a least squares fit of the two spectra. We subtracted the background spectrum of the Merrifield resin and could see C=C (1585 cm 21 ) band from the difference spectrum. All of these facts prove that coupling has been performed successfully.

Fig. 1. The IR spectra of 4a (1), Merrifield resin (2) and difference of 4a and Merrifield resin (3).

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3.3. Study on asymmetric Michael addition Asymmetric Michael addition is performed by the reaction of polymer-supported Nenoylprolinol (4) with alkyl Grignard reagents. Addition product (5) is characterized by disappearance of the C=C (1585 cm 21 ) band and shift of the C=O (1650 cm 21 ) band. Analysis of the FT-IR of resin (5) reveals that the peak of C=O has shifted to higher wave number (from 1650 to 1657 cm 21 ). It may be due to the disappearance of the p–p conjugate system between C=O bond and C=C bond. The 1 H NMR data of the expected acids (1) also confirm that Michael addition is performed successfully. Furthermore, the extent of cleavage could be roughly estimated from the FT-IR spectra, mainly from the decrease or disappearance of the carbonyl peak by comparison with that of addition product (5). Obviously, the cleavage of the resin (5) has been performed well, because only a small amount of the carbonyl peak remains. Another expected product (6) of base-catalyzed hydrolysis could be re-used satisfactorily at least three times with only a little loss of content.

3.4. Enantioselectivity of Michael addition In order to determine the enantiomeric excess of acids (1), they are converted to N-acylbornane-10,2-sultam [9,10] using D-(2)-bornane10,2-sultam. The diastereomeric compositions are determined by HPLC spectroscopy to be about 60:40, accordingly the enantiomeric excess is about 20%. Soai [6] has reported that when (3) reacted with Grignard reagents, the enantiomeric excess was from 69 to 89% in solution reactions. However when the corresponding ether instead of the alcohol (3) was used, the optical yields

were low (4–14% e.e). Therefore, the hydroxyl group is considered to play an important role in asymmetric induction. Although we want to utilize the steric bulk of the polymer chain of the resin to affect the enantiomeric selectivity and increase optical yield, it seems not to work satisfactorily. But the stereoselectivities have been increased remarkably compared with those observed for the same reactions in solution [6]. So the best way to increase yield might be to optimize the molecular structure of Nenoylprolinol (3). Further study is in progress. Acknowledgements We wish to thankfully acknowledge the support of the National Natural Science Foundation of China (contract no. 29872012) and the Foundation of Hubei Province Key Lab of Polymer Materials, Hubei University (Wuhan). References [1] H.S. Moon, N.E. Schore, M.J. Kurth, Tetrahedron Lett. 35 (1994) 8915–8918. [2] D.A. Evans, E.P. Ng, J.S. Clark, Tetrahedron 48 (1992) 2127–2142. [3] D.A. Evans, K.T. Chapman, J. Bisaha, J. Am. Chem. Soc. 110 (1988) 1238–1256. [4] H. Kawa, N. Ishikawa, J. Org. Chem. 45 (1980) 3137–3139. [5] S. Terashima, S. Yamada, Chem. Pharm. Bull. 25 (1977) 29–40. [6] K. Soai, H. Machida, N. Yakota, J. Am. Chem. Soc. Perkin Trans. I 9 (1987) 1909–1914. [7] H. Moon, N.E. Schore, M.J. Kurth, J. Org. Chem. 57 (1992) 6088–6090. [8] P. Hodge, R.J. Kell, J. Ma et al., Austria J. Chem (1999) 1041–1046. [9] J.X. Huang, Y. Li, X.Q. Ma et al., Chem. Res. Chin. Univ. 15 (1999) 23–28. [10] W. Oppolzer, G. Poli, A.J. Kingma et al., Helv. Chim. Acta 70 (1987) 2201–2215. [11] J. Meckennon, A.I. Meyers, J. Org. Chem. 58 (1993) 3568– 3571. [12] S.M. Allin, S.J. Shuttleworth, Tetrahedron Lett. 44 (1996) 8023–8026.