Catalytic asymmetric acyl halide-aldehyde cyclocondensations. A strategy for enantioselective catalyzed cross aldol reactions [11]

Journal of the American Chemical Society

Volumn 121, Issue 41, 1999, Pages 9742-9743

  Nelson, Scott G ^a   Peelen, Timothy J ^a   Wan, Zhonghui ^a  

^a UNIVERSITY OF PITTSBURGH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACID HALIDE; ALDEHYDE DERIVATIVE; ALUMINUM DERIVATIVE; LACTONE DERIVATIVE;

CARBON NUCLEAR MAGNETIC RESONANCE; CATALYSIS; CHEMICAL BOND; COMPLEX FORMATION; ENANTIOMER; LETTER; PROTON NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; SYNTHESIS;

EID: 0032704431     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja992369y     Document Type: Letter

References (32)

1. For recent asymmetric catalyzed additions of latent enolates, see: (a) Krüger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838. (b) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032-10039. (c) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685 and references therein. (d) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699 and references therein. For a review, see: (e) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
2. For recent asymmetric catalyzed additions of latent enolates, see: (a) Krüger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838. (b) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032-10039. (c) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685 and references therein. (d) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699 and references therein. For a review, see: (e) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
3. For recent asymmetric catalyzed additions of latent enolates, see: (a) Krüger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838. (b) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032-10039. (c) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685 and references therein. (d) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699 and references therein. For a review, see: (e) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
4. For recent asymmetric catalyzed additions of latent enolates, see: (a) Krüger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838. (b) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032-10039. (c) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685 and references therein. (d) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699 and references therein. For a review, see: (e) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
5. For recent asymmetric catalyzed additions of latent enolates, see: (a) Krüger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838. (b) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032-10039. (c) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669-685 and references therein. (d) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-699 and references therein. For a review, see: (e) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
6. For highly enantioselective catalyzed aldol addition reactions involving commercially available reagents, see: Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649-3650.
7. For a recent example of catalyzed asymmetric intermolecular aldol reactions, see: (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178. For other examples of catalytic aldol-type reactions, see: (b) Shibasaki, M.; Sasi, H.; Aral, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256 and references therein. (c) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405- 6406.
8. For a recent example of catalyzed asymmetric intermolecular aldol reactions, see: (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178. For other examples of catalytic aldol-type reactions, see: (b) Shibasaki, M.; Sasi, H.; Aral, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256 and references therein. (c) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405- 6406.
9. For a recent example of catalyzed asymmetric intermolecular aldol reactions, see: (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168-4178. For other examples of catalytic aldol-type reactions, see: (b) Shibasaki, M.; Sasi, H.; Aral, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1256 and references therein. (c) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405-6406.
10. Optically active 4-methylene-2-oxetanones have been developed as propionate aldol synthons, see: Calter, M. A.; Guo, X. J. Org. Chem. 1998, 63, 5308-5309.
11. For the utility of aldol adducts as precursors to β-lactones, see: (a) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185. (b) Yang, H. W.; Romo, D. J. Org. Chem. 1997, 62, 4-5. (c) Wedler, C.; Ludwig, R.; Schick, H. Pure Appl. Chem. 1997, 69, 605-608. (d) Yang, H. W.; Romo, D. J. Org. Chem. 1998, 63, 1344-1345.
12. For the utility of aldol adducts as precursors to β-lactones, see: (a) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185. (b) Yang, H. W.; Romo, D. J. Org. Chem. 1997, 62, 4-5. (c) Wedler, C.; Ludwig, R.; Schick, H. Pure Appl. Chem. 1997, 69, 605-608. (d) Yang, H. W.; Romo, D. J. Org. Chem. 1998, 63, 1344-1345.
13. For the utility of aldol adducts as precursors to β-lactones, see: (a) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185. (b) Yang, H. W.; Romo, D. J. Org. Chem. 1997, 62, 4-5. (c) Wedler, C.; Ludwig, R.; Schick, H. Pure Appl. Chem. 1997, 69, 605-608. (d) Yang, H. W.; Romo, D. J. Org. Chem. 1998, 63, 1344-1345.
14. For the utility of aldol adducts as precursors to β-lactones, see: (a) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185. (b) Yang, H. W.; Romo, D. J. Org. Chem. 1997, 62, 4-5. (c) Wedler, C.; Ludwig, R.; Schick, H. Pure Appl. Chem. 1997, 69, 605-608. (d) Yang, H. W.; Romo, D. J. Org. Chem. 1998, 63, 1344-1345.
15. Nelson, S. G.; Wan, Z.; Peelen, T. J.; Spencer, K. L. Tetrahedron Lett. 1999, 40, 6535-6539.
16. Nelson, S. G.; Peelen, T. J.; Wan, Z. Tetrahedron Lett. 1999, 40, 6541-6543.
17. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166-168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
18. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
19. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
20. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
21. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
22. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
23. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
24. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
25. Asymmetric catalyzed ketene additions to chloral and related aldehydes: (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166- 168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-1979. Asymmetric ketene-aldehyde additions: (c) Tamai, Y.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 1994, 1549-1550. (d) Tamai, Y.; Yoshiwara, H.; Someya, M.; Fukumoto, J.; Miyano, S. J. Chem. Soc., Chem. Commun. 1994, 2281-2282. Asymmetric catalyzed cycloadditions using trimethylsilylketene: (e) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. J. Chem. Soc., Chem. Commun. 1996, 1053-1054. (f) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.; Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998, 6, 1255-1272 and references therein. (g) Yang, H. W.; Romo, D. Tetrahedron Lett. 1998, 39, 2877-2880. (h) Dymock, B. W.; Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655-1661. For catalyzed asymmetric ketene dimerization, see: (i) Calter, M. A. J. Org. Chem. 1996, 61, 8006-8007.
26. For a comprehensive review of syntheses of optically active β-lactones, see: Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403-6434.
27. Triamine 4 was prepared according to the published procedure: Cernerud, M.; Skrinning, A.; Bérgère, I.; Moberg, C. Tetrahedron: Asymmetry 1997, 8, 3437-3441.
28. For structural investigations of related Al(III)-triamine complexes, see: (a) Emig, N.; Réau, R.; Krautscheid, H.; Fenske, D.; Bertrand, G. J. Am. Chem. Soc. 1996, 118, 5822-5823. (b) Jegire, J. A.; Atwood, D. A. Inorg. Chem. 1997, 36, 2034-2039.
29. For structural investigations of related Al(III)-triamine complexes, see: (a) Emig, N.; Réau, R.; Krautscheid, H.; Fenske, D.; Bertrand, G. J. Am. Chem. Soc. 1996, 118, 5822-5823. (b) Jegire, J. A.; Atwood, D. A. Inorg. Chem. 1997, 36, 2034-2039.
30. 2, and the filtrate was concentrated in vacuo. If necessary, crude reaction mixtures were purified by flash chromatography (hexanes:ethyl acetate). For an experimental procedure using preformed Al(III) complex 5a, see the Supporting Information.
31. 2O, 0 °C) and correlation of their optical rotation to those of authentic samples of known configuration; see the Supporting Information for full procedural details. The configuration of the remaining β-lactones (3c-h) was assigned by analogy to these determinations.
32. As part of synthesis studies underway in our laboratories, the enantiomeric form of lactone 3a was required. Thus, this large-scale reaction was conducted with the enantiomer of catalyst 5a.