3
17. Kunitake, M.; Oshima, T.; Konoki, K.; Ebine, M.; Torikai, K.;
Murata, M.; and Oishi, T. J. Org. Chem. 2014, 79, 4948−4962.
in THF to deprotonate the diol. Subsequent two-step oxidation of
the monoprotected alcohol provides carboxylic acid 11 in 88%
yield. Activation of 11 sets the stage for nucleophilic addition of
(S)-(+)-4-phenyl-2-oxazolidinone to furnish the oxazolidinone 9 in
95% yield.
18. Williams, D. R.; Mullins, R. J.; and Miller, N. A. Chem. Commun.,
2003, 2220–2221.
19. Wilding, E. E.; Gregg, J. J.; Mullins, R. J. Synlett 2010, 793–795.
20. (a) Faveau, C.; Mondon, M.; Gesson, J.-P.; Mahnke, T.; Gebhardt,
S.; Koert, U. Tetrahedron Lett. 2006, 8305–8308. (b) Azuma, M.;
Yoshikawa, T.; Kogure, N.; Kitajima, M.; Takayama, H. J. Am.
Chem. Soc. 2014, 136, 11618–11621. (c) McLeod, M. C.; Wilson,
Z. E.; Brimble, M. A. J. Org. Chem. 2012, 77, 400–416. (d)
Kaneko, H.; Takahashi, S.; Kogure, N.; Kitajima, M.; Taayama, H.
J. Org. Chem. 2019, 84, 5645–5654. (e) Nakayama, A.; Kogure, N.;
Kitajima, M.; Takayama, H. Org. Lett. 2009, 11, 5554–5557. (f)
Kumar, S. M.; Prasad, K. R. Chem. Asian J. 2014, 9, 3431–3439.
21. (a) Gerrard, A. W. Pharm. J. 1875, 5, 86. (b) Hardy, E. Bull. Soc.
Chim. Fr. 1875, 24, 497.
22. Bárány, E. H. Investigative Ophthalmology & Visual Science, 1962,
1, 712–727.
23. Flocks, M. and Zweng, H. C. Am. J. Ophthalmology, 1957, 44(5),
380–388.
24. Kaneyuki, H., Mitsuno, S., Nishida, T., Yamada, M. Neurology,
1998, 50 (3), 802–804.
At this point in the synthesis, the two enantiomers diverge in
the conjugate addition step. To access (+)-pilosinine, 9 undergoes
an asymmetric 1,4-conjugate addition with allylstannane in the
presence of zirconium chloride to give 7 in 90% yield and 10:1 d.r.
(Scheme 2). Deprotection of
7 with TBAF resulted in
intramolecular ring closure to afford lactone 12 in 98% yield.
Lactone 12 is then subjected to ozonoylsis to provide the
homopilosinic aldehyde 5 in 99% yield. Finally, 5 is treated with
methylamine in the presence of potassium carbonate to form the
precursor imine in situ, followed by imidazole formation upon
treatment with TosMIC to furnish (+)-pilosinine (2) in 55% yield.
25. Compagnone, R. and Rapoport, H. J. Org. Chem., 1986, 51, 1713–
1719.
26. Dener, J.; Hua Zhang, L.; and Rapoport, H. J. Org. Chem., 1993,
58, 1159–1166.
27. Home, D. A.; Fugmann, B.; Yakushijin, K.; and Buchi, G. J. Org.
Chem. 1993, 58, 62–64.
28. Wang, Z.; Lu, X. Tetrahedron Lett, 1997, 38 (29), 5213–5216.
29. Davies, S.; Roberts, P. M; Stephenson, P. T.; Storr, H.; and
Thomson, J. Tetrahedron, 2009, 65, 8283–8289.
Alternatively, to access ( ̶)-pilosinine, 9 is subjected to
allylmagnesium bromide in the presence of copper (I) bromide-
dimethyl sulfide complex to deliver 8 (Scheme 2) as the major
diastereomer (confirmed by 1H NMR) in 79% yield. Deprotection
of 8 with TBAF once again resulted in intramolecular ring closure
to afford lactone 13 in 95% yield. Based on the reactions described
above for the synthesis of (+)-pilosinine, the preparation of lactone
13 represents a formal synthesis of ( )-pilosinine.
30. Davies, S.; Roberts, P. M.; Stephenson, P. T.; and Thomson, J.
Tetrahedron Lett, 2009, 50, 3509–3512.
Conclusion
Acknowledgments
In conclusion, using stereodivergent conjugate addition
reactions, we have completed the total synthesis of (+)-pilosinine
in 7 steps and 26% overall yield, and by extension, a formal
synthesis of ( )-pilosinine. This work conclusively demonstrates
the ability to utilize the reversal of selectivity observed in
allylstannane conjugate addition reactions for synthesis of
enantiomeric products using a single chiral auxiliary. Furthermore,
this approach enables access to different stereoisomers without
altering the overall synthetic route and permits the expeditious
production of analogs from a common precursor.
The authors gratefully acknowledge the Arthur C. Cope
Scholar Fund and the Borcer fund at Xavier University for their
support of undergraduate research.
Supplementary Material
Supplementary material for this article, including
experimental design and spectral analysis, can be found online at
<insert link>.
References
1.
Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series, Pergamon: Oxford, 1992;
No. 9.
2.
3.
Rossiter, B. E. and Swingle, N. M. Chem. Rev, 1992, 92, 771–806.
Nicolas, E.; Russell, K. C.; and Hruby, V. J. J. Org. Chem. 1993,
58 (3), 766–770.
4.
5.
6.
Li, G.; Jaronsinski, M. A.; and Hruby, V .J. Tetrahedron Lett.,
1993, 34, 2561.
Liao, S.; Han, Y.; Qui, W.; Bruck, M.; and Hruby, V. J. Tetrahedron
Lett., 1996, 37, 7917.
7.
8.
Han, Y. and Hruby, V. J. Tetrahedron Lett., 1997, 38, 7317.
Williams, D. R. and Kissel, W. S. J. Am. Chem. Soc., 1998, 120,
11198–11199.
9.
Davies, S. G.; Sanganee, H. J.; and Szolcsanyi, P. Tetrahedron,
1999, 55, 3337–3354.
10. Chen, C. and Reamer, R. A. Org. Lett., 1999, 1 (2), 293–294.
11. Williams, D. R.; Patnaik, S.; and Plummer, S. V. Org. Lett., 2003,
5 (26) 5035-5038.
12. Williams, D. R. and Shamim, K. Org. Lett., 2005, 7 (19), 4161–
4164.
13. Morita, M.; Ishiyama, S.; Koshino, H.; and Nakata, T. Org. Lett.,
2008, 10 (9), 1675–1678.
14. Umezawa, T.; Sueda, M.; Kamura, T.; Kawahara, T.; Han, X.;
Okino, T.; and Matsuda, F. J. Org. Chem. 2012, 77, 357−370.
15. Hethcox, J. C.; Shanahan, C.S.; and Martin, S.F. Tet. Lett. 2013, 54,
2074–2076.
16. Yadav, J. S.; Chary, D. N.; Yadav, N. N.; Sengupta, S.; and Subbaꢀ
Reddy, B. V. Helvetica Chimica Acta, 2013, 96, 1968–1977.