quaternary derivatives C starting from common and easily
available precursors A. Being a free radical reaction, this
transformation should also enjoy mild reaction conditions
and should be compatible with a wide range of functional
groups. However, intermolecular radical addition onto
CdN double bonds proved to be difficult. Even for aldoimine
derivatives (other than formaldimines), efficiency has been
achieved only recently;8,9 for the more hindered ketoimines
A there has hitherto been no success at all. We report here
the first successful reaction of this type, which allows the
preparation of quaternary R-amino acids from R-alkoxycar-
bonyl ketoxime ethers.
Scheme 1
a Et3B (500 mol %), toluene, ∆. b A 450 W Hanovia medium-
pressure mercury lamp was employed. c Approximately one-third
of adduct 6 was partially transformed into the protected methylene
amino acetal 7 by reaction with formaldehyde generated in situ.
tions all failed, including those that worked well for its
aldoxime analogue 3 (Scheme 1). Addition did take place,
however, when we used the comparatively more nucleophilic
R-alkoxy carbon radicals. UV irradiation of a methanolic
solution of 5a in the presence of benzophenone afforded the
desired quaternary derivative 6 by addition of hydroxymethyl
radical.
Addition of a 1-hydroxy-1-methylethyl radical derived
from 2-propanol was also successful, giving the amino
alcohol derivative 8 (Table 1, entry 1). The formation of 8,
In keeping with the above antecedents, our attempts to
add primary, secondary, or tertiary alkyl radicals to methyl
2-(benzyloxyimino)propanoate (5a) under a variety of condi-
(5) For the biological significance of myriocin, see, for example: Chen,
J. K.; Lane, W. S.; Schreiber, S. L. Chem. Biol. 1999, 6, 221-235 and
references therein. For its total synthesis, see: (a) Banfi, L.; Beretta, M.
G.; Colombo, L.; Gennari, C.; Scolastico, C. J. Chem. Soc., Chem. Commun.
1982, 488-490. (b) Banfi, L.; Beretta, M. G.; Colombo, L.; Gennari, C.;
Scolastico, C. J. Chem. Soc., Perkin Trans. 1 1983, 1613-1619. (c)
Yosikawa, M.; Yokokawa, Y.; Okuno, Y.; Murakami, N. Chem Pharm.
Bull. 1994, 42, 994-996; Tetrahedron 1995, 51, 6209-6228. (d) Sano, S.;
Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama, S.; Fujita, T.;
Nagao, Y. Tetrahedron Lett. 1995, 36, 2097-2100. (e) Hatakeyama, S.;
Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawamoto, T.; Yamada,
H.; Nishizawa, M. Tetrahedron Lett. 1997, 38, 7887-7890. Formal
synthesis: (f) Rao, A. V. R.; Gurjar, M. K.; Devi, T. R.; Kumar, K. R.
Tetrahedron Lett. 1993, 34, 1653-1656. (g) Deloisy, S.; Thang, T. T.;
Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 4783-4786. (h)
Deloisy, S.; Thang, T. T.; Olesker, A.; Lukacs, G. Bull. Chem. Soc. 1996,
133, 581-585.
Table 1. Photoinduced Radical Addition onto Acyclic (5a) and
Cyclic (5b) Ketoxime Ethers
(6) Examples include the following. (a) (+)-Conagenin: Hatakeyama,
S.; Fukuyama, H.; Mukugi, Y.; Irie, H. Tetrahedron Lett. 1996, 37, 4047-
4050. Kova´cs-Kulyassa, A.; Herczegh, P.; Sztaricskai, F. Tetrahedron 1997,
53, 13883-13896. Enders, D.; Bartsch, M.; Runsink, J. Synthesis 1999,
243-248. (b) (+)-Lactacystin. For a recent critical review, including
synthetic contributions by E. J. Corey, J. E. Baldwin, H. Uno, N. Chida, S.
Omura, A. B. Smith, III, J. Adams, and J. S. Panek, see: Masse, C. E.;
Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513-
2528. For another recent review, see: Corey, E. J.; Li, W.-D. Z. Chem
Pharm. Bull. 1999, 47, 1-10. See also: Fenteany, G.; Standaert, R. F.;
Lane, W. S.; Choi, S.; Corey, E. J.; Schreiber, S. L. Science 1995, 268,
726-731. (c) Sphingofungines: Liu, D.-G.; Wang, B. Lin, G.-Q. J. Org.
Chem. 2000, 65, 9114-9119. Kobayashi, S.; Furuta, T.; Hayashi, T.;
Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908-919. Trost,
B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818-6819.
(7) For reviews, see: (a) Cativiella, C.; D´ıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517-3599. (b) Cativiella, C.; D´ıaz-
de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645-732. (c)
Seebach, D.; Hoffmann, M. Eur. J. Org. Chem. 1998, 1337-1351. (d) Wirth,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225-227. (e) Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708-2748.
(f) Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889-917.
(8) See: (a) Miyabe, H.; Ueda, M.; Naito, T. Chem. Commun. 2000,
2059-2060. (b) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.;
Perfetti, P. Tetrahedron 2000, 56, 3951-3961, and references therein. For
the use of sulfonyl-substituted oxime ethers as acylating agents, see: (c)
Jeon, G.-H.; Yoon, J.-Y.; Kim, S.; Kim, S. S. Synlett 2000, 128-130, and
references therein.
entry
5: R1, R2
product: R
yield (%)
1b
2c
3b
4c
5a : CH3, CH3
5a : CH3, CH3
5b: -CH2CH2-
5b: -CH2CH2-
8: -C(OH)(CH3)2
9: -CH(OCH2)2
10: -C(OH)(CH3)2
11: -CH(OCH2)2
58
74, 80,d 85e
73
73
a General Procedure. A 0.02 M solution of the ketoxime ether in the
appropriate solvent (see notes b and c), contained in a Pyrex vessel, was
deoxygenated by bubbling Ar for 10 min. Benzophenone (100 mol %) was
then added and the mixture was irradiated externally with a 450 W Hanovia
medium-pressure mercury lamp. Once the substrate was consumed (TLC),
the solvent was rotaevaporated and the adduct purified by flash chroma-
tography (the table lists isolated yields). b 2-Propanol was used as solvent.
1,3-Dioxolane was used as solvent. d ZnCl2 (50 mol %) was added after
c
deoxigenation. e p-TsOH (50 mol %) was added instead of ZnCl2.
which has two vicinal fully substituted carbon atoms,
illustrates the ability of the radical process to introduce
sterically demanding substituents at the quaternary center.
With 1,3-dioxolane as solvent, the product was 9, in which
a formyl group masked as an ethylene glycol acetal has been
efficiently introduced (74%).
(9) Despite recent advances, and with the exception of ethyl radical,
efficient intermolecular addition of unbranched carbon radicals to aldimine
derivatives has yet to be achieved.
1986
Org. Lett., Vol. 3, No. 13, 2001