Transformation of (+)-thiomicamine into a new ligand for the enantioselective addition of methyllithium to prochiral imines

Article abstract of DOI:10.1016/S0957-4166(99)00573-X

A new ligand 2 was prepared from (+)-thiomicamine 1 and o-methoxyphenol, and its activity as an external controller of stereochemistry in enantioselective additions of methyllithium to prochiral imines 8-10 tested. The non-racemic secondary amines 11-13 w

Full text of DOI:10.1016/S0957-4166(99)00573-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4791–4796
Transformation of (+)-thiomicamine into a new ligand for the
enantioselective addition of methyllithium to prochiral imines
Danuta Brózda, Maria Chrzanowska, Agata Głuszyn´ska and Maria D. Rozwadowska ∗
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
Received 9 November 1999; accepted 9 December 1999
Abstract
A new ligand 2 was prepared from (+)-thiomicamine 1 and o-methoxyphenol, and its activity as an external
controller of stereochemistry in enantioselective additions of methyllithium to prochiral imines 8–10 tested. The
non-racemic secondary amines 11–13 were prepared in 60–90% chemical yield with the enantioselectivity ranging
from 2 to 41%. 6,7-Dimethoxy-3,4-dihydroisoquinoline 8 was transformed into (+)-salsolidine 11 with an e.e. of
41%. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Racemic 2-amino-1-aryl-1,3-propanediols are intermediates in the industrial synthesis of amphenicol-
type antibiotics. After resolution only the (R,R)-enantiomers are further transformed into the therapeutic
drugs while the (S,S)-isomers are available for organic synthesis. They have found wide application as
enantiopure reagents and building blocks as well as chiral auxiliaries and ligands for stereoselective
transformations.
In an attempt to make use of the synthetic potential of the aminodiols we have undertaken experiments
aimed at transforming one of them, (+)-thiomicamine 1,1 into derivative 2, and testing its effectiveness
in the addition of organometallic reagents to prochiral imines. The structure of compound 2 bears a
pattern of complexing sites similar to those which may be found in the catalysts represented by structures
3–7 — having been proven to be effective asymmetry inductors in additions to imines.
Chiral ligand-mediated enantioselective additions of organometallic compounds to prochiral imines
as a method of synthesis of enantiomerically enriched amines has recently been studied extensively and
described in several review articles.2–5
The first report on the addition of organolithium reagents to N-methoxyphenyl imines performed in the
presence of an external chiral controller of stereochemistry was published by Tomioka and co-workers
∗
Corresponding author. E-mail: wzantk@main.amu.edu.pl
0957-4166/99/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00573-X
tetasy 3207

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in 1990.6 Among the various chiral ligands they applied, the tridentate amino ethers 3–5, prepared
from o-methoxyphenol and aminoalcohols derived from natural amino acids,6–14 provided high levels
of enantioselectivity with e.e. values up to 90% (Scheme 1).
Scheme 1.
Recently, North and co-workers15,16 have synthesized two other ligands of the same type, 6 and 7,
by coupling guaiacol with S-valine and S-proline derivatives, and used them in similar additions of
organolithiums to imines, however with less satisfactory results.
2. Results and discussion
As one of the approaches to the stereoselective synthesis of isoquinoline alkaloids we have considered
the enantioselective addition of organometallic reagents to imines 8–10 as the key step. In such a strategy
the C-1 stereogenic center could be created at an early stage of the synthesis. For example, optically
active salsolidine 11 could be prepared either directly from 3,4-dihydroisoquinoline by addition of
methyllithium or from acyclic imines 9 and 10 by further transformations of the addition products 12,
13.
In this paper we describe the synthesis of compound 2 and results of reactions between methyllithium
and imines 8–10 performed in the presence of 2. The prepared secondary amines 11–13 were obtained
in 60–90% chemical yield with the enantiomeric excess ranging from 2 to 41% (Scheme 2 and Table 1).
Scheme 2.
Ligand 2 was prepared from guaiacol and (+)-thiomicamine 1. Thus, (+)-thiomicamine 1 was con-
verted into oxazoline 1417 which was O-tosylated with tosyl chloride in pyridine to give tosylate 15.
Treatment of 15 with guaiacol sodium salt in DMF then gave compound 2 in 71% overall yield from 1.
(Scheme 3).

D. Brózda et al. / Tetrahedron: Asymmetry 10 (1999) 4791–4796
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Table 1
Addition of methyllithium to imines 8–10 in the presence of compound 2
Scheme 3. Reagents and conditions: (i) lit.;17 (ii) TsCl/PyH, 0°C, 48 h; (iii) o-CH3OC6H4O−Na+, DMF, 60°C
The starting imines were prepared according to the standard procedures: 6,7-dimethoxy-3,4-
dihydroisoquinoline 8 by the Bischler–Napieralski cyclization,18 imines 9 and 10 by condensation of
veratraldehyde with α-aminoacetaldehyde dimethylacetal19 and o-methoxybenzylamine,20 respectively.
Addition of methyllithium to imines 8–10 in the presence of ligand 2 was carried out following the
general reaction conditions described by Tomioka et al.:6–14 toluene (50 ml per mmol of imine) or THF
(40 ml per mmol of imine) were used as solvent and 2.5–3.0 equiv. of the organometallic reagent was
applied. The amount of catalyst 2 could not reach the optimum 2.6 equiv. because of solubility problems.
The best results in terms of the chemical yield and e.e. were achieved using 0.5 equiv. Due to its poor
solubility, 2 could be recovered from the reaction mixture simply by dissolving the crude products in
methanol from which it crystallized easily. The results of the experiments performed are shown in Table
1.
It is evident that the best enantioselectivity was achieved with imine 8. The enantiomeric excess
and (R)-configuration of the synthesized (+)-salsolidine were determined by comparison of the value
of specific rotation with that of the known (R)-enantiomer21 (41% e.e.) as well as by integration of the
1H NMR spectrum run in the presence of 2 equiv. of TADDOL22 (40% e.e.). The same solvating agent (3
equiv.) was used to determine the e.e. of amine 12, whose structure was also verified by converting it into
the known N-tosylate.23 The e.e. of amine 13 was established by HPLC with Chiracel OD-H column.

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3. Conclusion
The stereochemical result of the addition of methyllithium to imines carried out in the presence of
compound 2 was not as satisfactory as might be expected with a ligand incorporating two structural
fragments, oxazoline24 and amino ethers 3–7, both capable of high degree of asymmetric induction.
The usefulness of the above presented strategy for the synthesis of isoquinoline alkaloids seems
to be promising particularly in the case of additions to 3,4-dihydroisoquinoline. The stereogenic C-1
center could be created at an earlier stage of the synthesis with no covalently bound chiral auxiliary
being involved. Another example of utility of the enantiomerically pure and cheap 2-amino-1-aryl-1,3-
propanediol 1 in asymmetric synthesis has been demonstrated.
4. Experimental
4.1. General
Melting points: determined on a Koffler block and are not corrected. IR spectra: Perkin–Elmer 180 in
KBr pellets. NMR spectra: Varian Gemini 300, in CDCl3, with TMS as internal standard. Mass spectra
(EI): Joel D-100, 75 eV. Specific rotation: Perkin–Elmer polarimeter 243B at 20°C. Merck Kieselgel
60 (70–230 mesh) was used for column chromatography and Merck DC-Alufolien Kieselgel 60254 for
TLC. Analytical HPLC: Waters HPLC system with Mallinkrodt–Baker Chiracel OD-H column. (+)-
Thiomicamine was purchased from the Aldrich Chemical Co. and used as received.
4.2. Synthesis of ligand 2
4.2.1. (4S,5S)-5-Tosyloxymethyl-4-(4-methylthiophenyl)-2-phenyl-2-oxazoline 15
To a solution of oxazoline 1417 (2.99 g, 10 mmol) in pyridine (30 ml) p-toluenesulfonyl chloride (2.86
g, 15 mmol) was added portionwise at 0°C during 1.5 h with stirring. The mixture was kept at 0°C for 48
h, then poured onto ice (210 g) and after rt was reached the solid was removed by filtration, washed with
cold water (3×300 ml) and air-dried to give crude 15. It was then dissolved in CH2Cl2 and washed with
1% NaOH followed by 20% NH4Cl and dried; the solid precipitating during evaporation of solvent was
filtered off to give 4.2 g (92.6%) of TLC-pure 15, which was used in the next step of the synthesis without
further purification. For characterization, a sample was crystallized from methanol, m.p. 59–61°C; [α]D
+11.7 (c=0.98, ethanol). IR cm−1: 1647; 1H NMR δ: 2.43 (s, 3H, Ar-CH3), 2.48 (s, 3H, SCH3), 4.16–4.21
(m, 1H, H-5), 4.28–4.38 (m, 2H, CH2O), 5.45 (d, J=6.1 Hz, 1H, H-4), 7.19–7.95 (m, 13H, Ar-H); MS m/z
(%): 453 (25), 281 (70), 268 (50), 130 (85), 105 (100). Found: C, 63.60; H, 5.06; N, 3.10. C24H23NO4S2
(453.55) requires: C, 63.55; H, 5.11; N, 3.10.
4.2.2. (4S,5S)-5-(2-Methoxyphenoxymethyl)-4-(4-methylthiophenyl)-2-phenyl-2-oxazoline 2
A solution of tosylate 15 (4.53 g, 10 mmol) and sodium 2-methoxyphenolate (1.61 g, 11 mmol) in
DMF (40 ml) was kept at 60°C for 3 h under argon atmosphere, then left for 18 h at rt. The crystalline
solid was filtered off and washed with excess of methanol to deposit 3.35 g (82.7%) of pure 2. After
crystallization from CH2Cl2/methanol, m.p. 168–169°C, [α]D +17.3 (c=1, CHCl3). IR cm−1: 1648; 1H
NMR δ: 2.48 (s, 3H, SCH3), 3.85 (s, 3H, OCH3), 4.06 (t, J=8.7 Hz, 1H, CH2O), 4.47–4.60 (m, 2H, H-5,
CH2O), 5.70 (d, J=6.5 Hz, 1H, H-4), 6.88–8.06 (4m, 13 H, Ar-H). MS m/z (%): 405 (M+, 10), 375 (60),

D. Brózda et al. / Tetrahedron: Asymmetry 10 (1999) 4791–4796
4795
268 (10), 210 (20), 165 (30), 151 (13), 137 (18), 130 (80), 105 (100). Found: C, 71.01; H, 5.52; N, 3.17.
C24H23NO3S (405.49) requires: C, 71.08; H, 5.72; N, 3.45.
4.3. Synthesis of imines 9 and 10
Veratraldehyde (1.66 g, 10 mmol) was added to a solution of amine (1.1 ml, 10 mmol aminoacetalde-
hyde dimethyl acetal or 1.23 g, 10 mmol p-anisidine) in toluene (40 ml), and the reaction mixture was
refluxed for 3 h using a Dean–Stark trap. It was then concentrated under reduced pressure to give crude
product which was purified by recrystallization.
4.3.1. (3,4-Dimethoxybenzylidene)-(2,2-dimethoxyethyl)-amine 9
1
Colorless crystals (yield: 85%), m.p. 49–50°C (hexane–ether) (lit.19 m.p. 49°C). IR cm−1: 1642; H
NMR δ: 3.43 (s, 6H, OCH3), 3.76 (d, J=5.2 Hz, 2H, CH2), 3.92, 3.95 (2s, 3H each, OCH3), 4.68 (t, J=5.2
Hz, 1H, CH), 6.88 (d, J=8.2 Hz, 1H, Ar-H), 7.17 (dd, J=1.9, 8.2 Hz, 1H, Ar-H), 7.43 (s br., 1H, Ar-H),
8.20 (s, 1H, CH_N); MS m/z (%): 253 (M+,12), 178 (5), 151 (10), 92 (3), 75 (100). Found: C, 61.59; H,
7.89; N, 5.55. C13H19NO4 (253.13) requires: C, 61.68; H, 7.56; N, 5.53.
4.3.2. (3.4-Dimethoxybenzylidene)-(4-methoxyphenyl)-amine 10
Colorless crystals (yield: 88%), m.p. 131–132°C (hexane–ether) (lit.20 m.p. 126°C). IR cm−1: 1620;
1H NMR δ: 3.83, 3.95, 3.99 ( 3s, 3H each, OCH3), 6.93 (d, J=8,9 Hz, 2H, Ar-H), 7.21 (d, J=8.9 Hz, 2H,
Ar-H), 7.30–7.61 (m, 3H, Ar-H), 8.39 (s, 1H, CH=N); MS m/z (%): 271 (M+,100), 256 (64), 240 (12).
Found: C, 70.59; H, 6.26; N, 5.12. C16H17NO3 (271.32) requires: C, 70.83; H, 6.32; N, 5.16.
4.4. Addition of methyllithium to imines. General procedure
Ligand 2 (203 mg, 0.5 mmol) was dissolved in dry toluene (40 ml) or THF (30 ml) under an argon
atmosphere and cooled to the temperature indicated in Table 1. The imine (1 mmol) in dry toluene (10
ml) or THF (10 ml) was added and the reaction mixture was stirred vigorously for 30 min at the same
temperature, before MeLi (1.6 M solution in Et2O; 2.5 mmol or 3.0 mmol) was introduced. Stirring was
continued for 2 h, then quenched with 20% NH4Cl at the low temperature. Phases were separated at
rt and the aqueous one was extracted twice with ethyl ether (2× ca 50 ml). Combined organic extracts
were dried and the solvents were removed under reduced pressure. In the case of amines 12 and 13 the
residue was dissolved in methanol (ca. 20 ml) from which crystalline 2 was removed by filtration and the
filtrate was concentrated in vacuo. Amines 11 and 12 were purified by column chromatography (silica
gel, dichloromethane:methanol 50:1 for compound 11; toluene:ethyl ether 99:1 for compound 12) while
13 by crystallization.
4.4.1. (+)-Salsolidine 11
Oil, [α]D +24.0 (c=1.2, EtOH), 41% e.e. [lit.25 [α]D+59.9 (c=25, EtOH)], was identical with racemic
alkaloid in terms of spectral data26 as well as chromatographic (TLC) comparison.
4.4.2. (2,2-Dimethoxyethyl)-[1-(3,4-dimethoxyphenyl)ethyl]-amine 12
Oil,19 IR cm−1: 3430; 1H NMR δ: 1.35 (d, J=6.6 Hz, 3H, CH3), 1.57 (s, broad, N-H), 2.55 (dd, J=5.2,
12.1 Hz, 1H, CH), 2.63 (dd, J=5.5, 12.1 Hz, 1H, CH2), 3.31, 3.36 (2s, 3H each, OCH3), 3.71 (q, J=6.6
Hz, 1H, CH), 3.87, 3.89 (2s, 3H each, OCH3), 4.43 (t, J=5.2, 5.5 Hz, 1H, CH2), 6.82, 6.8, 6.89 (3s, Ar-H);
MS m/z (%): 269 (M+, 4), 254 (13), 206 (6), 165 (100), 121 (3), 75 (15).

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N-Tosylate: crystals, m.p. 95–96.5°C (methanol); IR cm−1: 1342, 1163; 1H NMR δ: 1.5 (d, J=7.14 Hz,
3H, CH3), 2.43 (s, 3H, Ar-CH3), 3.03 (dd, J=6.3, 15.4 Hz, 1H, CH2), 3.13 (dd, J=3.8, 15.4 Hz, 1H, CH2),
3.2, 3.33, 3.62, 3.84 (4s, 3H each, OCH3), 4.27 (dd, J=3.8, 6.3, 1H, CH), 5.03 (q, J=7 Hz, 1H, CH), 6.43,
6.73, 6.74 (3s, 3H, Ar-H), 7.32 (d, J=8.5 Hz, 2H, Ar-H), 7.80 (d, J=8.2 Hz, 2H, Ar-H); MS m/z (%): 423
(M+, 4), 360 (4), 268 (16), 165 (72), 75 (100). Found: C, 59.28; H, 7.17; N, 3.38. C21H29NO6S (423.17)
requires: C, 59.60; H, 6.91; N, 3.31.
4.4.3. (4-Methoxyphenyl)-[1-(3,4-dimethoxyphenyl)ethyl]-amine 13
Crystals, m.p. 81–82°C (ether). IR cm−1: 3400, 1520; 1H NMR δ: 1.49 (d, J=6.7 Hz, 3H, CH3), 1.57
(s, 1H, NH), 3.70, 3.87, 3.89 (3s, 3H each, OCH3), 4.35 (q, J=6.7 Hz, 1H, CH), 6.49 (d, J=8.9 Hz, 2H,
Ar-H), 6.70 (d, J=8.9 Hz, 2H, Ar-H), 6.82–6.92 (m, 3H, Ar-H); MS m/z (%): 287 (M+, 77), 165 (100),
150 (11), 123 (20). Found: C, 70.87; H, 7.37; N, 4.82. C17H21NO3 (287.28) requires: C, 71.06; H, 7.37;
N, 4.87.
Acknowledgements
This work was financially supported by KBN grant no. 3 T09A 027 17.
References
1. Coppi, L.; Giordano, C.; Longoni, A.; Panossian, S. Chirality in Industry II; John Wiley & Sons: Chichester, New York,
1997; pp. 353–362.
2. Denmark, S. E.; Nicaise, O. J.-C. J. Chem. Soc., Chem. Commun. 1996, 999–1004.
3. Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895–1946.
4. North, M. J. Chem. Soc., Perkin Trans. 1 1998, 2959–2971.
5. Bloch, R. Chem. Rev. 1998, 98, 1407–1438.
6. Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1990, 31, 6681–6684.
7. Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1991, 32, 3095–3098.
8. Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron: Asymmetry 1993, 4, 1603–1606.
9. Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron 1994, 50, 4429–4438.
10. Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K. Tetrahedron: Asymmetry 1995, 6, 2527–2533.
11. Taniyama, D.; Kanai, M.; Iida, A.; Tomioka, K. Chem. Pharm. Bull. 1997, 45, 1705–1707.
12. Taniyama, D.; Kanai, M.; Iida, A.; Tomioka, K. Heterocycles 1997, 46, 165–168.
13. Tomioka, K.; Satoh, M.; Taniyama, D.; Kanai, M.; Iida, A. Heterocycles 1998, 47, 77–80.
14. Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron: Asymmetry 1999, 10, 221–223.
15. Jones, C. A.; Jones, I. G.; North, M.; Pool, C. R. Tetrahedron Lett. 1995, 36, 7885–7888.
16. Jones, C. A.; Jones, I. G.; Mulla, M.; North, M.; Sartori, L. J. Chem. Soc., Perkin Trans. 1 1997, 2891–2896.
17. Rozwadowska, M. D. Tetrahedron: Asymmetry 1998, 9, 1615–1618.
18. Whaley, W. M.; Meadow, M. J. Chem. Soc. 1953, 1067–1070.
19. Lejay, P; Viel, C. Ann. Chim. (Paris) 1977, 2, 87–96; [C. A. 1977, 87, 117645b].
20. Rai, M.; Kaur, B.; Dhir, B. S. J. Indian Chem. Soc. 1982, 59, 416–417.
21. Battersby, A. R.; Edwards, T. P. J. Chem. Soc. 1960, 1214–1221.
22. Bussche-Hunnefeld, C.; Beck, A. K.; Seebach, D. Helvetica Chim. Acta 1992, 75, 438–441.
23. Ponzo, V. L.; Kaufman T. S. Tetrahedron Lett. 1995, 36, 9105–9108.
24. Gant, T. G.; Meyers, A. I. Tetrahedron 1997, 50, 2297–2360.
25. Spath, E.; Dengen F. Ber. 1938, 71, 113–119.
26. Menachery, M. D.; Lavanier G. L.; Wetherly, M. L.; Guinaudeau, H.; Shamma, M. J. Nat. Prod. 1986, 49, 745–778.