7-aza-7,8-dihydrolimonenes, 2-azabornanes, 2-azacam-
phanes, and azatricyclenes.9 In this paper we report the
preparation and characterization of the enantiomeric
2-azapinanes (5 and ent-5, Figure 1),10 potential inhibitors
and active site probes for the pinene synthases.
Scheme 1
Scheme 2
cyclizations of the endo,anti conformations (e.g., 2b)
followed by π-cyclizations of the enantiomeric R-terpinyl
carbocations generate the bicyclic pinyl ions (C and ent-
C), which undergo proton eliminations to form the pinene
isomers (Scheme 1 and Figure 1).
The synthesis of [1R, 5S]-2-azapinane (5)11 (Scheme 2)
was accomplished in four steps (ca. 46-50% overall yield)
starting from known acetamide 8,12 which wasavailable via
Beckmann rearrangement (H2NOSO3H, AcOH, reflux,
77-81%) of (-)-cis-pinonic acid (6)12,13 ([R]D = -94.1°
(c 0.63, CHCl3) [lit.13c -93.7 (c 4.60, CHCl3), lit.14 -94.2
(c 5-10, CHCl3)] obtained by KMnO4 oxidation of (-)-R-
pinene.13 The optical purity of the starting (-)-cis-pinonic
acid was estimated to be 99.0% assuming that the highest
absolute value of specific rotation ([R]D = þ95° (CH-
Cl3))13b,15,16 reported for (þ)- and (-)-cis-pinonic acids
corresponds to 100% optically pure dextrorotatory
enantiomer. An identical synthesis of the enantiomeric
[1S, 5R]-2-azapinane (ent-5) was carried out in parallel
Figure 1. Enantiomeric 2-azapinane salts (5 Hþ and ent-5 Hþ),
aza analogues of the pinyl carbocation intermediates (C and ent-
C) in pinene biosynthesis.
3
3
(9) (a) Szabo, C. M.; Matsumura, Y.; Fukura, S.; Martin, M. B.;
Sanders, J. M.; Sengupta, S.; Cieslak, J. A.; Loftus, T. C.; Lea, C. R.;
Lee, H.-J.; Koohang, A.; Coates, R. M.; Sagami, H.; Oldfield, E. J. Med.
Chem. 2002, 45, 2185–2196. (b) McGeady, P.; Pyun, H.-J.; Coates,
R. M.; Croteau, R. Arch. Biochem. Biophys. 1992, 299, 63–72. (c)
Whittington, D. A.; Wise, M. L.; Urbansky, M.; Coates, R. M.; Croteau,
R. B.; Christianson, D. W. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
15375–15380. (d) Faraldos, J. A.; Coates, R. M., unpublished results. (e)
Hu, H.; Faraldos, J. A.; Coates, R. M.. J. Am. Chem. Soc. 2009, 131,
11998–12006.
(10) The systematic names and absolute stereochemistry of azapi-
nanes 5 and ent-5 are [1R, 5S]- and [1S, 5R]-2,7,7-trimethyl-2-
azabicyclo[3.1.1]heptane derived from (-)- and (þ)-R-pinene, respec-
tively.
(11) For a summary of a synthesis of the isomeric 3-azapinane, see:
Gannon, M.; Postlewhite, A.; McElhinney, R. S. J. Chem Res., Synop.
1979, 12, 393.
Terpene synthase inhibitors which bind tightly in the
active sites of these enzymes afford mechanistic insights,
and in some instances, serve as useful aids for crystal-
lization of the proteins yielding valuable three-dimen-
sional structural data by X-ray diffraction analysis.7 Aza
analogues of high-energy carbocation intermediates have
found applications as mechanism-based inhibitors and
active site probes for terpene synthases.7,8 For the pur-
pose of characterizing monoterpene synthases, we have
carried out the synthesis, characterization, and applications
of 3-aza-2,3-dihydrogeranyl diphosphate, the enantiomeric
(12) Borges, J. R.; Fernandez, F.; Garcia, X.; Huergueta, A. R.;
Lopez, C. Org. Prep. Proc. Int. 1997, 29, 303–307.
(13) (a) Delepine, M. Bull. Soc. Chim. Fr. 1936, 1369–1382. (b) Wolk,
J. L.; Goldschmidt, Z.; Dunkelblum, E. Synthesis 1986, 347–348. For
purification of cis-pinonic acid see:(c) Muscio, O. J., Jr.; Poulter, C. D. J.
Org. Chem. 1974, 39, 3288–3291.
(14) Thoi, L. V. Ann. Chim. (Paris) 1955, 10, 35–91.
(15) Barbier, P.; Grignard, V. Bull. Soc. Chim. Fr. 1910, 548–557.
(16) Harispe, M.; Mea, D. Bull. Soc. Chim. Fr. 1962, 1340–1343.
(7) Christianson, D. W. Chem. Rev. 2006, 106, 3412–3442.
(8) For reviews and leading references, see: (a) Narula, A. S; Rahier,
A.; Benveniste, P.; Schuber, F. J. Am. Chem. Soc. 1981, 103, 2408–2409.
(b) Rahier, A.; Taton, M.; Benveniste, P. Biochem. Soc. Trans. 1990, 48–
52. (c) Poulter, C. D. Acc. Chem. Res. 1990, 23, 70–77. (d) Abe, I.;
Tomesch, J. C.; Wattanasin, S.; Prestwich, G. D. Nat. Prod. Rep. 1994,
11, 279–302. (e) Rahier, A.; Taton, M.; Bouviernave, P.; Schmitt, P.;
Beneviste, P.; Schuber, F.; Narula, A. S.; Cattel, L.; Anding, C.; Place, P.
Lipids 1986, 21, 52–62.
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