C O M M U N I C A T I O N S
the enhanced selectivity of the methyl/phenyl case (i.e., by reaction
rate acceleration through a gem-dialkyl effect9).
The exploration of this rearrangement reaction has uncovered
two noteworthy effects that contribute to its stereoselectivity: the
enhancement of selectivity by using a linker containing a quaternary
carbon and electronic tuning of a through-space π-cation interac-
tion. In addition to their interest from a fundamental perspective,
both effects have the potential for broader application in a variety
of stereoselective transformations. This work, along with further
computational and experimental studies, is underway in this
laboratory.
Figure 1. Proposed π-cation interaction in intermediates leading to iso-
mers b.
Scheme 2
Acknowledgment. We thank the National Institutes of Health
(GM-49093) for support of this work, Douglas Powell for X-ray
crystallographic analyses (the X-ray apparatus was acquired through
NSF CHE-0079282), and Richard Givens for helpful discussions.
Supporting Information Available: Hammett plots, solvent stud-
ies, experimental procedures (PDF). CIF files for X-ray determinations.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Diels-Alder: (a) Wilson, S. R.; Mao, D. T. J. Am. Chem. Soc. 1978,
100, 6289-6291. (b) Roush, W. R.; Kageyama, M.; Riva, R.; Brown, B.
B.; Warmus, J. S.; Moriarty, K. J. J. Org. Chem. 1991, 56, 1192-1210.
(c) Jung, M. E.; Huang, A.; Johnson, T. W. Org. Lett. 2000, 2, 1835-
1837. (d) Tantillo, D. J.; Houk, K. N.; Jung, M. E. J. Org. Chem. 2001,
66, 1938-1940. Radical cyclization: (e) Winkler, J. D.; Hershberger, P.
M.; Springer, J. P. Tetrahedron Lett. 1986, 27, 5177-5180. (f) RajanBabu,
T. V. J. Am. Chem. Soc. 1987, 109, 609-611. (g) Winkler, J. D.; Hey, J.
P.; Hannon, F. J.; Williard, P. G. Heterocycles 1987, 25, 55-60. (h)
RajanBabu, T. V. Acc. Chem. Res. 1991, 24, 139-145. Other reactions:
(i) Lee, C. B.; Wu, Z.; Zhang, F.; Chappell, M. D.; Stachel, S. J.; Chou,
T.-C.; Guan, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 5249-
5259. (j) Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int. Ed.
2003, 42, 1734-1737.
model suggests that the ability of the aromatic ring to pivot is
necessary to both maximize stabilizing through-space electronic
interactions and to minimize steric interactions with the hydrogen
atom on the same carbon. This point was addressed through the
experiments shown in Scheme 2.
(2) (a) Gracias, V.; Milligan, G. L.; Aube´, J. J. Am. Chem. Soc. 1995, 117,
8047-8048. For a detailed mechanistic discussion, see: (b) Sahasrabudhe,
K.; Gracias, V.; Furness, K.; Smith, B. T.; Katz, C. E.; Reddy, D. S.;
Aube´, J. J. Am. Chem. Soc. 2003, 125, 7914-7922.
Remarkably, when 3-azido-2-methyl-2-phenylpropanol was made
to react with 4-tert-butylcyclohexanone, product lactam 15 was
isolated with g19:1 selectiVitysby far the most lopsided of any
encountered in this study. Strikingly, the controlling center is a
quaternary carbon, whereas conventional wisdom dictates that such
centers ought to be ineffective purveyors of stereocontrol because
of the need to place one group in an ostensibly disfavored axial
position. Further, the intermediate leading to the major isomer places
the phenyl group in an axial position and the methyl group
equatorial. It is likely that the aromatic group adopts the axial
position partially because it can minimize steric interactions through
rotation and that this conformation is further favored by minimiza-
tion of steric interactions between the ortho hydrogen and the methyl
group (R ) Me in Figure 1).6
To address this point, we synthesized conformationally con-
strained hydroxyalkyl azide 16 and subjected it to the reaction
conditions. Here, a lower (ca. 3:1) ratio of lactams 17a,b was
obtained, favoring the intermediate with an equatorial phenyl group.
This clearly establishes (1) that the conformational mobility of the
phenyl group is key to the selectivity of these reactions and (2)
that having a quaternary center per se is not solely responsible for
(3) A values: Me (1.74), i-Pr (2.21), and Ph (2.8): Eliel, E. L.; Wilen, S. H.;
Mander, L. N. Stereochemistry of Organic Compounds; Wiley-Inter-
science: New York, 1994; pp 696-697 and references cited therein.
(4) For lead references: (a) Dougherty, D. A. Science (Washington, DC) 1996,
271, 163-168. (b) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97,
1303-1324.
(5) For an example in the related Beckmann rearrangement: (a) Prager, R.
H.; Tippett, J. M.; Ward, A. D. Aus. J. Chem. 1978, 31, 1989-2001. (b)
Neda, I.; Sakhaii, P.; Wassmann, A.; Niemeyer, U.; Gunther, E.; Engel,
J. Synthesis 1999, 1625-1632. (c) Lakshminarasimhan, P.; Sunoj, R. B.;
Chandrasekhar, J.; Ramamurthy, V. J. Am. Chem. Soc. 2000, 122, 4815-
4816. (d) Rensing, S.; Arendt, M.; Springer, A.; Grawe, T.; Schrader, T.
J. Org. Chem. 2001, 66, 5814-5821. (e) Yamada, S.; Saitoh, M.; Misono,
T. Tetrahedron Lett. 2002, 43, 5853-5857. (f) Yamada, S.; Morita, C. J.
Am. Chem. Soc. 2002, 124, 8184-8185.
(6) Hodgson, D. J.; Ryclewska, U.; Eliel, E. L.; Manoharan, M.; Knox, D.
E.; Olefirowicz, E. M. J. Org. Chem. 1985, 50, 4838-4843.
(7) Most reactions were carried out in racemic form but are depicted in a
single enantiomeric series to allow easy comparison between examples.
Selectivities were determined by NMR and chromatography of the crude
reaction mixture. Most of the structures were determined by X-ray analysis
of one of the diastereomers. See Supporting Information.
(8) See Supporting Information for the plotted values. (a) Adcock, W.; Cotton,
J.; Trout, N. A. J. Org. Chem. 1994, 59, 1867-1876. (b) Gallivan, J. P.;
Dougherty, D. A. J. Am. Chem. Soc. 2000, 122, 870-874. (c) A modest
solvent effect was also observed, with ethereal solvents affording lower
a/b ratios than either hydrocarbon or halocarbon solvents.
(9) Jung, M. E. Synlett 1999, 843-846.
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