Studies on the niobium pentachloride-mediated nucleophilic additions to an enantiopure cyclic N-acyliminium ion derived from (S)-malic acid

ARTICLE

Studies on the niobium pentachloride-mediated nucleophilic additions to an enantiopure cyclic N-acyliminium ion derived from (S)-malic acid

Carlos Kleber Z. Andrade^I,*; Rafael O. Rocha^I; Dennis Russowsky^II; Marla N. Godoy^II

^IInstituto de Química, Universidade de Brasília, CP 4478, 70910-970 Brasília-DF, Brazil

^IIInstituto de Química, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre-RS, Brazil

ABSTRACT

The nucleophilic addition of several nucleophiles (allyltrimethylsilane, silyl enol ether from acetophenone, indole and N-sulfonylindole) to the enantiopure cyclic N-acyliminium ion 1a, derived from (S)-malic acid, promoted by niobium pentachloride is described. The products were obtained in good yields and in variable diastereoselectivities depending on the steric bulkiness of the nucleophile. The best results were obtained with the addition of indoles.

Keywords:N-acyliminium ions, niobium pentachloride, nucleophilic additions, diastereoselectivity

RESUMO

A adição nucleofílica de vários nucleófilos (alilsilano, silil enol éter da acetofenona, indol e N-sulfonilindol) ao íon N-acilimínio enantiopuro 1a, derivado do ácido (S)-málico, promovida por pentacloreto de nióbio é descrita. Os produtos foram obtidos em bons rendimentos e em diastereosseletividades variáveis dependendo do volume estérico do nucleófilo. Os melhores resultados foram obtidos com a adição de indóis.

Introduction

The search for new Lewis acids that effectively promote the formation of N-acyliminium ions has been the subject of many studies.¹ These ions are very important in organic synthesis since they are reactive intermediates involved in the synthesis of many compounds with interesting biological properties, especially alkaloids.^2,3

Recently, the use of niobium pentachloride as a novel and efficient Lewis acid in nucleophilic additions to cyclic N-acyliminium ions was reported by us.^4,5 Now we wish to report our preliminary results on the diastereoselectivity control in these reactions.⁶

The enantiomerically pure substrate 1 was prepared in 3 steps, as a diastereomeric mixture, from commercially available (S)-malic acid, according to a known procedure.^3,7 In the presence of 0.6 equiv. of NbCl₅ in CH₂Cl₂, at 0ºC, the presumed N-acyliminium ion 1a was formed in 20 min (Scheme 1), as evidenced by the consumption of 1 by TLC. Next, the nucleophiles were added and the reactions were followed by TLC, affording the respective compounds 5-7 (Scheme 1).

Three classes of nucleophiles were investigated: allyltrimethylsilane (2), silyl enol ether (from acetophenone) (3), and indoles (indole 4a and N-sulfonylindole 4b).

The addition of allylsilane 2 (Scheme 2) was used as a model and the results are summarized in Table 1.

The reaction did not work with a 25 mol % amount of NbCl₅ (entry 1). On the other hand, a substoichiometric amount of NbCl₅ (0.6 equiv) was enough to generate the N-acyliminium ion from substrate 1.

A mixture of compounds 5 trans and 5 cis were obtained in better yields when 3 equiv. of the allylsilane were used (entries 5 and 6) in a relative ratio of 2:1 favoring the 5 trans isomer and this ratio remained unchanged regardless of the experimental conditions used. The ratio of isomers and their relative stereochemistry were determined by ¹H-NMR integration of the hydrogen attached to the a-nitrogen carbon and by its chemical shift, respectively, comparing to literature data for similar compounds.^3,8,9

Although the N-acyliminium ion 1a can be generated at –78 ºC, the reactions did not proceed at this temperature (even after 2 h the products could not be detected by TLC). However, when the reaction was warmed up to room temperature the products were obtained in good yields after stirring for 13-16h (entries 4 and 5).

A similar level of diastereoselectivity was obtained in the addition of the silyl enol ether of acetophenone 3 (2 equiv.) to the cation 1a. The 2:1 mixture of compounds 6 trans and 6 cis, respectively, was obtained in 81% yield (Scheme 3). The ratio of isomers and their relative stereochemistry were determined as above comparing with literature data for the same compounds.⁸

This low diastereoselectivity was unexpected in view of the better results with other Lewis acids such as InCl₃ which gave a trans:cis ratio of 10:1.⁸

Next, we investigated the indole compounds 4a and 4b as nucleophiles, which are not so commonly used in nucleophilic additions to N-acyliminium ions (Scheme 4).¹⁰ The results obtained were noteworthy and are summarized in Table 2.

The addition of indole 4a to the N-acyliminium ion 1a gave a mixture of compounds 7a trans and 7a cis (80-90% yield) in a 7a trans: 7a cis = 6:1 ratio (entries 1 and 2). As expected, the major isomer showed a trans configuration. This was confirmed by the analysis of the ¹H-NMR spectrum of 7a trans and 7a cis. The hydrogen attached to the a-nitrogen carbon of the major 7a trans isomer appears as a doublet with a small coupling constant (J 1.4 Hz) at 4.76 ppm whereas the same proton of the 7a cis isomer appears also as a doublet at 5.03 ppm but with a larger coupling constant (J 6.2 Hz). This difference in J values is in agreement with the reported data for the trans and cis isomers in similar compounds.^3,8,9 The ratio of isomers was measured by ¹H-NMR integration of these signals.

The reaction of the bulkier N-sulfonylindole 4b showed a high level of diastereoselectivity with a ratio of 94:6, favouring the 7b trans isomer in 75% isolated yield (entry 3).

On the other hand, probably due to the strongly electron withdrawing sulfonyl group attached to the indole nitrogen, the reaction with compound 4b was slower as compared to indole 4a (see entries 2 and 3).

The stereochemistry of the isomers was once more assigned based on spectroscopic data. Similar to the data for compounds 7a trans and 7a cis , the hydrogen attached to the a-nitrogen carbon of the major isomer in compound 7b trans appears at 4.61 ppm (broad singlet) whereas in the cis isomer 7b it appears at 4.90 ppm (doublet, J 7.0 Hz).

The preference for anti addition can be rationalized by previously reported antiperiplanar and synclinal models shown in Figure 1 in which the preferential approach of the nucleophile occurs at the opposite face of the acetoxy group in the cyclic N-acyliminium ion.⁸ This explains the increase in the diastereoselectivity with an increase in the steric bulkiness of the nucleophile when indoles 4a and 4b were used.

Although the selectivities shown in this work are not superior to other common Lewis acids such as InCl₃ and TMSOTf some advantages associated with this methodology must be considered: NbCl₅ is solid and if handled and stored properly can be used without the need of purification; a substoichiometric amount of NbCl₅ is enough to generate the N-acyliminium ions; NbCl₅ is abundant in Brazil (Brazil accounts for 86% of total niobium production) and is less expensive than InCl₃ and TMSOTf (Aldrich catalog); and the reaction can be run in non-cryogenic temperatures. Besides, the results with indoles are promising and can be addressed in a future work.

In summary, NbCl₅ has proved to be an efficient Lewis acid in the formation of enantiopure N-acyliminium ions broadening even more the scope of this versatile reagent in organic synthesis.

The diastereoselectivity of this reaction proved to be dependent on the steric bulkiness of the nucleophile, at least in the case of indoles. Studies towards the intramolecular version of this reaction are under investigation.

Experimental

All reactions involving Lewis acids were performed under argon in a flame-dried flask. CH₂Cl₂ was distilled from CaH₂ prior to use. NbCl₅ was supplied by Companhia Brasileira de Mineração e Metalurgia (CBMM). (S)-Malic acid was purchased from Aldrich.

IR spectra were recorded on a BOMEM Hartman & Braun – Michelson MB series 100 LASER FT-IR. NMR spectra were recorded on a Varian Mercury Plus 300 spectrometer. Chemical shifts are reported in ppm from tetramethylsilane as internal reference. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet of doublets of doublets, m = multiplet, etc), coupling constant and integration.

Column chromatography was performed on silica gel (70-230 mesh).

General procedure for the nucleophilic attack to the N-acyliminium ions

To a NbCl₅ (0.6 mmol) suspension in CH₂Cl₂ (3 cm³) at 0 ºC, under an argon atmosphere, was added substrate 1 (1.0 mmol), diluted in CH₂Cl₂ (2 cm³). After 20 min, the nucleophile (2.0 or 3.0 mmol) was added. After the time specified in the Tables, the reaction was quenched with sat. NaHCO₃ (4 cm³), extracted with CH₂Cl₂ (2 x 10 cm³), dried over Na₂SO₄ and concentrated at reduced pressure to furnish the crude products 5-7, which were purified by silica gel chromatography (20% EtOAc in hexanes). The cis and trans isomers of compounds 5-7 were not separated during the chromatographic purification.

(2RS,3S)-2-Allyl-1-benzyl-5-oxopyrrolidin-3-yl acetate (5, mixture of cis and trans isomers)

5 trans. IR (film) n_max/cm^-1: 3065, 3030, 2931, 1740, 1694, 1443, 1237, 1033, 703; ¹H-NMR (300 MHz, CDCl₃): d 1.98 (s, 3H), 2.20-2.40 (m, 2H), 2.44 (dd, J 18.0, 1.2 Hz, 1H), 2.87 (dd, J 18.0, 6.0 Hz, 1H), 3.45 (dd, J 6.6, 4.5 Hz, 1H), 3.98 (d, J 15.0 Hz, 1H), 5.00-5.20 (m, 2H), 5.25-5.40 (m, 2H), 5.51-5.60 (m, 1H), 7.22-7.40 (m, 5H); ¹³C-NMR (75 MHz, CDCl₃): d 20.9, 34.7, 37.7, 44.2, 62.3, 71.1, 119.7, 127.7, 127.8, 128.1, 132.0, 136.0, 170.3, 172.0.

5 cis. IR (film) n_max/cm^-1: 3065, 3030, 2931, 1740, 1694, 1443, 1237, 1033, 703; ¹H-NMR (300 MHz, CDCl₃): d 2.05 (s, 3H), 2.20-2.80 (m, 4H), 3.58 (dd, J 13.5, 6.0 Hz, 1H), 3.88 (d, J 15.0 Hz, 1H), 5.00-5.20 (m, 2H), 5.25-5.40 (m, 2H), 5.51-5.60 (m, 1H), 7.22-7.40 (m, 5H); ¹³C-NMR (75 MHz, CDCl₃): d 20.9, 32.0, 37.9, 44.2, 59.0, 68.2, 118.7, 127.7, 127.8, 128.1, 133.0, 136.0, 170.1, 172.0.

(2RS,3S)-1-Benzyl-5-oxo-2-(2-oxo-2-phenylethyl) pyrrolidin-3-yl acetate (6, mixture of cis and trans isomers)

6 trans. IR (film) n_max/cm^-1: 3072, 3029, 2935, 1738, 1692, 1677, 1448, 1240, 1033, 703; ¹H-NMR (300 MHz, CDCl₃): d 2.02 (s, 3H), 2.53 (dd, J 18.0, 1.5 Hz, 1H), 3.10 (ddd, J 18.0, 6.9, 0.8 Hz, 1H), 3.15 (dd, J 17.5, 6.4 Hz, 1H), 3.27 (dd, J 17.5, 4.9 Hz, 1H), 4.00 (ddd, J 6.3, 4.9, 1.2 Hz, 1H), 4.18 (d, J 15.2 Hz, 1H), 4.75 (d, J 15.2 Hz, 1H), 5.12 (dt, Jd 6.73 Hz, Jt 1.5 Hz, 1H), 7.10-7.80 (m, 10H). ¹³C-NMR (75MHz, CDCl₃): d 20.9, 36.9, 39.3, 44.8, 61.0, 72.1, 127.6, 127.9, 128.6, 128.7, 133.5, 136.1, 136.2, 170.5, 172.4, 196.4.

6 cis. IR (film) n_max/cm^-1: 3072, 3029, 2935, 1738, 1692, 1677, 1448, 1240, 1033, 703; ¹H-NMR (300 MHz, CDCl₃): d 2.02 (s, 3H), 2.41 (dd, J 18.0, 2.1 Hz, 1H), 2.83-2.91 (m, 1H), 2.97 (dd, J 7.0, 1.1 Hz, 1H), 3.03 (dd, J 7.0, 0.8 Hz, 1H), 4.16-4.22 (m, 1H), 4.17 (d, J 15.5 Hz, 1H), 4.92 (d, J 15.5 Hz, 1H), 5.0 (ddd, J 7.0, 2.06, 0.96 Hz, 1H), 7.10-7.80 (m, 10H). ¹³C-NMR (75 MHz, CDCl₃): d 20.9, 35.9, 39.3, 43.4, 61.0, 73.8, 127.6, 127.9, 128.6, 128.7, 133.6, 136.1, 136.2, 170.5, 172.2, 196.4.

(2R,3S)-1-Benzyl-2-(1-H-indol-3-yl)-5-oxopyrrolidin-3-yl acetate (7a, mixture of cis and trans isomers)

7a trans. IR (film) n_max/cm^-1: 3227, 2927, 1745, 1689, 1442, 1366, 1340, 1233, 1030, 744, 703. ¹H-NMR (300 MHz, CDCl₃): d 2.03 (s, 3H), 2.56 (dd, J 17.6 and 1.8 Hz, 1H), 3.05 (ddd, J 17.6, 6.3 and 1.0 Hz, 1H), 3.73 (d, J 16.0 Hz, 1H), 4.76 (d, J 1.4 Hz, 1H), 5.19-5.23 (m, 1H), 5.25 (d, J 16.0 Hz, 1H), 7.01 (d, J 2.3 Hz, 1H), 7.10-7.35 (m, 7H), 7.40 (d, J 8.1 Hz, 1H), 7.65 (d, J 7.5 Hz, 1H); ¹³C-NMR (75 MHz, CDCl₃): d 20.9, 36.7, 44.1, 61.1, 73.5, 111.4, 111.7, 118.8, 120.1, 122.5, 125.0, 127.5, 127.8, 128.4, 136.0, 136.5, 170.4, 172.3.

7a cis. IR (film) n_max/cm^-1 3227, 2927, 1745, 1689, 1442, 1366, 1340, 1233, 1030, 744, 703. ¹H-NMR (300 MHz, CDCl₃): d 2.03 (s, 3H), 2.78 (ddd, J 17.6, 4.3 and 0.9 Hz,1H), 3.05 (dd, J 17.6 and 7.4 Hz, 1H), 3.55 (d, J 14.3 Hz, 1H), 5.03 (d, J 6.2 Hz), 5.17 (d, J 14.3 Hz, 1H), 5.56 (ddd, J 7.4, 6.2 and 4.3 Hz, 1H), 7.01 (d, J 2.3 Hz, 1H), 7.10-7.35 (m, 7H), 7.40 (d, J 8.1 Hz, 1H), 7.54 (d, J 8.0 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): d 20.3, 37.2, 44.4, 59.0, 69.0, 108.3, 111.4, 111.7, 118.8, 120.1, 122.5, 125.0, 127.5, 127.8, 128.4, 136.0, 136.5, 170.2, 172.1.

(2R,3S)-1-Benzyl-2-(1-sulfonyl-indol-3-yl)-5-oxopyrrolidin-3-yl acetate (7b trans)

IR (film) n_max/cm^-1: 3010, 2925, 1742, 1698, 1448, 1374, 1237, 1177, 1095, 1035, 977, 756, 727. ¹H-NMR (300 MHz, CDCl₃): d 2.01 (s, 3H), 2.54 (dd, J 17.7 and 1.9 Hz, 1H), 2.94 (ddd, J 17.7, 6.3 and 1.0 Hz, 1H), 3.64 (d, J 15.0 Hz, 1H), 4.61 (s br, 1H), 5.12 (dt, J 6.2 and 1.9Hz, 1H), 5.25 (d, J 15.0 Hz, 1H), 7.01 (d, J 2.3 Hz, 1H), 7.10-7.35 (m, 7H), 7.40 (d, J 8.1 Hz, 1H), 7.65 (d, J 7.5 Hz, 1H). ¹³C-NMR (75 MHz, CDCl₃): d 20.8, 36.3, 44.4, 60.3, 72.4, 113.9, 118.3, 119.9, 123.9, 125.6, 126.8, 127.8, 128.6, 129.4, 134.1, 135.5, 135.8, 137.9, 170.3, 172.0. [a]_D = -21.7 (c 0.15, CHCl₃).

Acknowledgments

The authors thank the Instituto de Química, Universidade de Brasília and Finatec, for financial support, FINEP-CT INFRA nº 0970/01 and CBMM for NbCl₅ samples. We also thank Prof. Inês S. Resck for recording the high field NMR spectra. R. O. R. acknowledges CAPES and CNPq/PIBIC for fellowships.

References

1. Speckamp, W. N.; Moolenaar, M. J.; Tetrahedron 2000, 56, 3827.

2. See, for example: Pilli, R. A.; Dias, L. C.; Maldaner, A. O.; J. Org. Chem. 1995, 60, 717; Dhimane, H.; Vanucci, C.; Lhommet, G.; Tetrahedron Lett. 1997, 38, 1415; Bennet, D. J.; Blake, A. J.; Cooke, P. A.; Godfrey, C. R. A.; Pickering, P. L.; Simpkins, N. S.; Walker, M. D.; Wilson, C.; Tetrahedron 2004, 60, 4491; Osante, I.; Lete, E.; Sotomayor, N.; Tetrahedron Lett. 2004, 45, 1253. See also ref. 3.

3. Pilli, R. A.; Russowsky, D.; J. Org. Chem. 1996, 61, 3187.

4. Andrade, C. K. Z.; Matos, R. A. F.; Synlett 2003, 1189.

5. For other examples from our laboratory on the use of NbCl₅ as Lewis acid, see: Andrade, C. K. Z.; Azevedo, N. R.; Oliveira, G. R.; Synthesis 2002, 928; Andrade, C. K. Z.; Azevedo, N. R.; Tetrahedron Lett. 2001, 42, 6473; Andrade, C. K. Z.; Oliveira, G. R.; Tetrahedron Lett. 2002, 43, 1935; Andrade, C. K. Z.; Kalil, P. P.; Rocha, R. O.; Alves, L. M.; Panisset, C. M. A.; Lett. Org. Chem. 2004, 1, 109. See also ref. 4. For a review on NbCl₅ applications in Organic Synthesis, see: Andrade, C. K. Z.; Curr. Org. Synth. 2004, 1, 333.

6. This work was presented at the X Brazilian Meeting on Organic Synthesis (BMOS): Andrade, C. K. Z.; Rocha, R. O.; Russowsky, D. August, 2003, São Pedro, SP, Brazil.

7. Koot, W. -J.; van Ginkel, R.; Kranenburg, M.; Hiemstra, H.; Louwrier, S.; Moolenaar, M. J.; Speckamp, W. N. Tetrahedron Lett. 1991, 32, 401.

8. Russowsky, D.; Petersen, R. Z.; Godoi, M. N.; Pilli, R. A.; Tetrahedron Lett. 2000, 41, 9939.

9. Thaning, M.; Wistrand, L. G.; J. Org. Chem. 1990, 55, 1406; Koot, W. -J.; Van Ginkel, R.; Kranenburg, M.; Hiemstra, H.; Lonwrier, S.; Moolenaar, M. J.; Speckamp, W. N.; Tetrahedron Lett. 1991, 32, 401; Lennartz, M.; Sadakane, M.; Steckhan, E.; Tetrahedron 1999, 55, 14407; Klitzke, C. F.; Pilli, R. A.; Tetrahedron Lett. 2001, 42, 5605.

10. For an example, see: Ollero, L.; Mentink, G.; Rutjes, F. P. J. T; Speckamp, W. N.; Hiemstra, H.; Org. Lett. 1999, 1, 1331. See also ref. 4.

Received: June 4, 2004

Published on the web: March 9, 2005

Publication Dates

• Publication in this collection
  09 Aug 2005
• Date of issue
  June 2005

History

• Accepted
  09 Mar 2005
• Received
  04 June 2004