Hydride-Promoted Ring Expansion of 2-Azaspiropyrrolinium Salts: An Approach Towards the Synthesis of (-)-Nitramine

Abstract

An enantioselective approach toward the synthesis of the spiroalkaloid (-)-nitramine was achieved by electrophile-induced cyclization of a suitably substituted and protected chiral α-allylcyclohexanecarboxaldimine. Its hydride-promoted ring expansion after spirocyclization gave rise to the competitive formation of isomeric spiropyrrolidines and a spiropiperidine, the latter being further transformed into (-)-nitramine.

alkaloids - cyclizations - ring expansion - spiro compounds

References

1

Present address: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium

2 Smolanoff J. Kluge AF. Meinwald J. McPhail A. Miller RW. Hicks K. Eisner T. Science  1975,  188:  734 

3 Sugahara T. Komatsu Y. Takano S. J. Chem. Soc., Chem. Commun.  1984,  214 

4 Chemical Ecology   Sondheimer E. Simeone JB. Academic Press; New York: 1970.  p.157 

5 Smolanoff JR. inventors; U.S. Patent  4400512.  ; Chem. Abstr. 1983, 98, 198045

6 Osmanov Z. Ibragimov AA. Yunusov SYu. Khim. Prir. Soedin.  1982,  126 

7 Ibragimov AA. Osmanov Z. Tashkhodzhaev B. Adbullaev ND. Yagudaev MR. Yunusov SYu. Khim. Prir. Soedin.  1981,  623 

8 Tashkhozhaev B. Khim. Prir. Soedin.  1982,  75 

9 Wanner JW. Koomen GJ. In Studies in Natural Products Chemistry: Stereoselectivity in Synthesis and Biosynthesis of Lupine and Nitraria Alkaloids   . Elsevier; Amsterdam: 1994.  p.731 ; and references therein

10a Snider BB. Cartaya-Marin CP. J. Org. Chem.  1984,  49:  1688 

10b Mieckzowski JB. Bull. Pol. Acad. Sci., Chem.  1985,  33:  13 

10c Kozikowski AP. Yuen PW. J. Chem. Soc., Chem. Commun.  1985,  847 

10d Hellberg LH. Beeson C. Somanathan R. De Graduados C. Tetrahedron Lett.  1986,  27:  3955 

10e Carruthers W. Moses RC. J. Chem. Soc., Chem. Commun.  1987,  509 

10f Carruthers W. Moses RC. J. Chem. Soc., Perkin Trans. 1  1988,  2255 

10g Tanner D. He HM. Bergdahl M. Tetrahedron Lett.  1988,  29:  6493 

10h Wanner MJ. Koomen GJ. Tetrahedron Lett.  1989,  30:  2301 

10i Kim D. Kim HS. Yoo JY. Tetrahedron Lett.  1991,  32:  1577 

10j Fujii M. Kawaguchi K. Nakamura K. Ohno A. Chem. Lett.  1992,  1493 

10k Wanner MJ. Koomen GJ. Tetrahedron  1992,  48:  3935 

10l Keppens M. De Kimpe N. Synlett  1994,  285 

10m Wanner MJ. Koomen GJ. Pure Appl. Chem.  1994,  66:  2239 

10n Senboku H. Hatazawa M. Orito K. Tokuda M. Heterocycles  1997,  46:  413 

10o Deyine A. Poirier JM. Duhamel L. Duhamel P. Tetrahedron Lett.  2005,  46:  2491 

11 Daly JW. In Progress in the Chemistry of Organic Natural Products   Herz W. Griesebach H. Kirby GW. Springer-Verlag; Berlin: 1982.  p.205 

12a McCloskey PJ. Schultz AG. Heterocycles  1987,  25:  437 

12b Quirion JC. Grierson DS. Royer J. Husson HP. Tetrahedron Lett.  1988,  29:  3311 

12c Tanner D. He HM. Tetrahedron  1989,  45:  4309 

12d Imanishi T. Kurumada T. Maezaki N. Sugiyama K. Iwata C. J. Chem. Soc., Chem. Commun.  1991,  1409 

12e Westermann B. Scharmann G. Kortmann J. Tetrahedron: Asymmetry  1993,  4:  2119 

12f Keppens M. De Kimpe N. J. Org. Chem.  1995,  60:  3916 

12g Kim D. Choi WJ. Hong JY. Park IY. Kim YB. Tetrahedron Lett.  1996,  37:  1433 

12h Yamane T. Ogasawara K. Synlett  1996,  925 

12i Trost BM. Radinov R. Grenzer EM. J. Am. Chem. Soc.  1997,  119:  7879 

12j Francois D. Lallemand MC. Selkti M. Tomas A. Kunesch N. Husson HP. Angew. Chem. Int. Ed.  1998,  37:  104 

12k Koreeda M. Wang Y. Zhang L. Org. Lett.  2002,  4:  3329 

13 De Kimpe N. Boelens M. J. Chem. Soc., Chem. Commun.  1993,  916 

14 De Kimpe N. Boelens M. Piqueur J. Baele J. Tetrahedron Lett.  1994,  35:  1925 

15 Alderdice M. Sum FW. Weiler L. Org. Synth. Coll. Vol. VII   Wiley and Sons; New York: 1990.  p.351 

16 Deol BS. Ridley DD. Simpson GW. Aust. J. Chem.  1976,  29:  2459 

17 Fráter G. Helv. Chim. Acta  1980,  63:  1383 

18 Fráter G. Müller U. Günther W. Tetrahedron  1984,  40:  1269 

19 Kocienski PJ. In Protecting Groups   Enders D. Noyori R. Trost BM. Georg Thieme Verlag; New York: 1994.  p.83 

20 Greene TW. Wuts PG. Protective Groups in Organic Synthesis   John Wiley; New York: 1991.  p.31 

21

Experimental Conditions.
A solution of 470 mg (2.9 mmol) of bromine in 10 mL of CH₂Cl₂ was slowly added to 1.0 g (2.93 mmol) of imine 16a in 10 mL of dry CH₂Cl₂ at 0 °C. After 20 min of vigorous stirring at 0 °C, the solvent was evaporated in vacuo under gentle warming, resulting in 17a as a syrupy ocher mass which decomposed after standing at r.t.

22

Spectral data of (6R,7S)-2-benzyl-2-azaspiro[5.5]-undecan-7-ol (19a): ¹H NMR (270 MHz, CDCl₃): δ = 1.04-1.80 [12 H, m, (CH₂)₆], 1.93-2.03 and 2.22-2.28 (1 H each, each m, NCH₂CH₂), 2.88 (1 H, br d, J _AX = 11.5 Hz, C_spiroHCHN), 3.24 (1 H, d, J _AX = 11.5 Hz, C_spiroHCHN), 3.40-3.49 (1 H, m, CHOH), 3.38-3.48 (1 H each, each d, J _AB = 12.9 Hz, CH₂C₆H₅), 5.32 (1 H, br s, OH), 7.17-7.39 (5 H, m, C₆H₅). ¹³C NMR (68 MHz, C₆D₆): δ = 21.35, 23.93, 24.60, 32.95, 37.25 and 38.40 [(CH₂)₄ and (CH₂)₂], 37.64 (C_spiro), 54.75 (NCH₂CH₂), 59.15 (C_spiroCH₂N), 63.80 (NCH₂C₆H₅), 78.40 (CHOH), 127.56, 128.66, 129.32 and 138.40 (C₆H₅). MS (70 eV): m/z (%) = 259 (8) [M⁺], 258 (4), 231 (5), 174 (12), 168 (14), 148 (5), 146 (8), 140 (5), 134 (29), 133 (14), 132 (5), 121 (6), 120 (33), 106 (5), 92 (10), 91 (100), 67 (6), 65 (9), 55 (8), 44 (13), 43 (5), 42 (9), 41 (10). IR (NaCl): 3160-3435 (O-H) cm^-1. Rf = 0.33 (CHCl₃-MeOH, 95:5); [α]_D ²² +15 (c 1.12, CHCl₃).

23

Synthesized nitramine: [α]_D ²³ -21.5 (c 1.51, CH₂Cl₂). Lit. [12a] [α]_D ²⁵ +23 (c 1.58, CH₂Cl₂). Enantiomeric excess values for all succeeding compounds were 91-93%.

24 Greene TW. Wuts PG. Protective Groups in Organic Synthesis   John Wiley; New York: 1991.  p.77 

25 Braish TF. Fuchs PL. Synth. Commun.  1986,  16:  111 

26 De Vries EFJ. Brussee J. Van der Gen A. J. Org. Chem.  1994,  59:  7133 

27 Omura K. Swern D. Tetrahedron  1978,  34:  1651 

28 Ley SV. Norman J. Griffith WP. Marsden SP. Synthesis  1994,  639 

29 Corey EJ. Suggs JW. Tetrahedron Lett.  1975,  2647 

30 Corey EJ. Schmidt G. Tetrahedron Lett.  1979,  399