Stereospecific anionically promoted transannular hydride shifts in medium-ring hydroxy ketones. Probe of their reversibility and the potential for regiocontrol.

Article abstract of DOI:10.1021/ol0100733

Examples are provided of stereospecific transannular oxidation-reduction processes involving the conjugate bases of delta-hydroxy ketones in a nine-membered ring setting. The ability to control the direction of these equilibria by proper modulation of the

Full text of DOI:10.1021/ol0100733

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1777-1780
Stereospecific Anionically Promoted
Transannular Hydride Shifts in
Medium-Ring Hydroxy Ketones. Probe
of Their Reversibility and the Potential
for Regiocontrol
John E. Hofferberth, Ho Yin Lo, and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received April 16, 2001
ABSTRACT
Examples are provided of stereospecific transannular oxidation−reduction processes involving the conjugate bases of δ-hydroxy ketones in
a nine-membered ring setting. The ability to control the direction of these equilibria by proper modulation of the solvent environment and level
of hydroxyl group protection is demonstrated. MM3-derived steric energies of the isomer pairs suggest that the equilibrium distributions are
the outcome of the extent to which intramolecular hydrogen bonding forces are disrupted by polar solvent molecules when present.
The transannular migration of hydride ions has long been
recognized to be a fundamental and important reactivity
feature of cyclic and bicyclic carbocations of medium-ring
size.1,2 One of the most advanced and elegant applications
of this phenomenon is the preparation of stable carbenium
ions containing symmetrical three-center, two-electron
C-H-C bonds.3,4 As extensive as these past studies have
been, considerably less attention has been accorded to anionic
counterparts. From among several possible lines of investiga-
tion,5 that involving the conjugate bases of hydroxy ketones
such as 1 and 2 holds significant attraction.6 However, two
limitations might be construed to restrict practical exploita-
tion of these potentially useful processes. Hemiacetal forma-
tion is often readily accommodated in the neutral precursors,
thereby depleting the equilibrium of the desired reactant. Two
representative examples are given by 37 and 4.8 Beyond this,
these reactions feature concurrent Oppenauer oxidation9 and
(1) Cope, A. C.; Martin, M. M.; McKervey, M. A. Q. ReV. 1966, 20,
119.
(2) For examples, see: (a) Appleton, R. A.; Dixon, J. R.; Evans, J. M.;
Graham, S. H. Tetrahedron 1967, 23, 805. (b) Eakin, M. A.; Martin, J.;
Parker, W. Chem. Commun. 1968, 298. (c) Prelog, V.; Troxler, E.; Westen,
H. H. HelV. Chim. Acta 1968, 51, 1678. (d) Ourrison, G.; Stehelin, L.;
Lhomme, J. J. Am. Chem. Soc. 1971, 93, 1650. (e) Traynham, J. G.; Foster,
A. W. J. Am. Chem. Soc. 1971, 93, 6216. (f) Doyle, M.; Parker, W. J.
Chem. Soc., Perkin Trans. 1 1977, 858. (g) Whalen, D. L.; Cooper, J. D.
J. Org. Chem. 1978, 43, 432. (h) Schneider, H. J.; Heiske, D. J. Am. Chem.
Soc. 1981, 103, 3501. (i) Momose, T.; Itooka, T.; Nishi, T.; Uchimoto, M.;
Ohnishi, K.; Muraoka, O. Tetrahedron 1987, 43, 3713.
(4) McMurry, J. E.; Lectka, T.; Hodge, C. N. J. Am. Chem. Soc. 1989,
111, 8867.
(5) The reaction of 3 with a primary amine constitutes an interesting
variant: (a) Wiseman, J. R.; Lee, S. Y. J. Org. Chem. 1986, 51, 2485. (b)
Aggarwal, V. K.; Humphries, P. S.; Fenwick, A. Angew. Chem., Int. Ed.
1999, 38, 1985.
(6) The parent degenerate reaction has been reported: Parker, W.;
Stevenson, J. R. J. Chem. Soc. D 1969, 1289.
(7) Hemiketal 3 shows no carbonyl band in the infrared [Quinn, C. B.;
Wiseman, J. R. J. Am. Chem. Soc. 1973, 95, 1342]. Nevertheless, both
tautomers can be brought into reaction depending upon the specific
transformation in question: (a) Braish, T. F.; Fuchs, P. L. Synth. Commun.
(3) Kirchen, R. P.; Ranganayakulu, K.; Rauk, A.; Singh, B. P.; Sorensen,
T. S. J. Am. Chem. Soc. 1981, 103, 588.
10.1021/ol0100733 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/05/2001

Meerwein-Ponndorf-Verley reduction steps,10 but practical
means for driving a given process to the left or right at will
as is possible for the classical reactions11 have been intimated
to be unavailable.12
was noted to result in very efficient conversion to a 6:1
mixture of 6 and 7 (Scheme 1). Aldol cyclization to construct
Scheme 1
Herein we report the results of the first coordinated
experimental and theoretical study of nondegenerate, an-
ionically driven, transannular hydride migratability in a
medium-ring setting. The present investigation sheds light
on the fundamental manner in which hydrogen bonding can
contribute in a useful manner to the thermodynamic control
of these equilibria. In addition, the impressive extent to which
these effects can be outweighed by solvation influences is
illustrated. In the examples that follow, the MM3-derived
steric energies that are provided were obtained on the actual
molecules carrying the bulky p-methoxyphenoxy and tert-
butyldimethylsilyloxy substituents. Simplification by alterna-
tive substitution with methoxy and trimethylsilyloxy, re-
spectively, in an attempt to place added emphasis on the
contributions of the other structural sectors did not affect
the outcome of the computational results. All equilibrium
ratios were determined by integration of high-field 1H NMR
spectra. The number of runs made for each experiment varied
from 2 to >10, and the error limits in Schemes 1-3 are
considered to be no greater than (5%.
the six-membered ring is recognized to be more rapid than
hydrolysis of the cyclic carbonate functionality since the
unprotected diol undergoes hemiacetal formation exclusively
under the same conditions. Our structural assignments to 6
and 7 were corroborated by single-crystal X-ray diffraction
methods (Figures 1 and 2, respectively). Attention is called
In an initial experiment, treatment of keto aldehyde 5 with
0.5 N NaOH in MeOH/THF (2:3:1 v:v) for 12 h at 20 °C
1986, 16, 111. (b) Kobayashi, K.; Sasaki, A.; Kanno, Y.; Suginome, H.
Tetrahedron 1991, 47, 7245. (c) Zhao, S.; Mehta, G.; Helquist, P.
Tetrahedron Lett. 1991, 32, 5753. (d) Molander, G. A.; McKie, J. A. J.
Org. Chem. 1993, 58, 7216.
(8) 6-Hydroxycyclodecanone exists in the hemiacetal form to the extent
of 39-77% depending upon solvent [Mijs, W. J.; De Vries, K. S.; Westra,
J. G.; Gaur, H. A. A.; Smidt, J.; Vriend, J. Recl. TraV. Chim. Pays-Bas
1968, 87, 580]. For representative reactions of this substance, consult: (a)
Thies, R. W.; Yue, S. T. J. Org. Chem. 1982, 47, 2681. (b) McMurry, J.
E.; Hodge, C. N. J. Am. Chem. Soc. 1984, 106, 6450. (c) Hamon, D. P. G.;
Krippner, G. Y. J. Org. Chem. 1992, 57, 7109.
(9) Djerassi, C. Org. React. 1951, 6, 207.
(10) Wilds, A. L. Org. React. 1944, 2, 178.
(11) In the intramolecular variants, neither of the two functional groups
is present in excess and no volatile byproduct is generated as reaction
progresses.
(12) For example, see: (a) Berner, H.; Vyplel, H.; Schulz, G. Monatsh.
Chem. 1983, 114, 501. (b) Paquette, L. A.; Huber, S. K.; Thompson, R. C.
J. Org. Chem. 1993, 58, 6874. (c) Paquette, L. A.; Bailey, S. J. Org. Chem.
1995, 60, 7849. (d) Paquette, L. A.; Zeng, Q.; Tsui, H.-C.; Johnston, J. N.
J. Org. Chem. 1998, 63, 8491. (e) Magnus, P.; Booth, J.; Diorazio, L.;
Donohoe, T.; Lynch, V.; Magnus, N.; Mendoza, J.; Pye, P.; Tarrant, J.
Tetrahedron 1996, 52, 14103. (f) Appendino, G.; Fenoglio, I.; Vander Velde,
D. G. J. Nat. Prod. 1997, 60, 464. (g) Magnus, P.; Ujjainwalla, F.;
Westwood, N.; Lynch, V. Tetrahedron 1998, 54, 3069.
Figure 1. Molecular structure of 6‚C6H6 in the solid state.
to the adventitious placement of the migratory hydrogen in
the central cavity of this pair of isomers (see arrows). The
subsequent equilibration experiments, approached from either
1778
Org. Lett., Vol. 3, No. 11, 2001

connectivity between the stabilization derived from intramo-
lecular hydrogen bonds and solvent effects. The more polar
the medium, the more 8 is favored. This trend parallels that
seen earlier in the 6/7 series, except that a greater displace-
ment toward 8 is now operative.
The disilylated analogue 10 presents an equally striking
distribution profile (Scheme 3). Despite an appreciable gas-
Scheme 3
Figure 2. Molecular structure of 7‚CH3OH in the solid state.
direction, demonstrate that interruption of the internal
hydrogen bonding pattern by dissolution in a protic solvent
favors 6. To form 7 completely, one needs to simulate gas-
phase conditions as much as possible in order to maximize
the effects of intramolecular hydrogen bonding as recognized
by the molecular mechanics software package. Evidently,
benzene solvent serves well in this capacity. Since we have
not been able to produce 6 totally free of 7, the energetics
do not appear to be completely reversed by external
influences.
Regioselective silylation of 7 gives rise to 9 wherein one
of the hydrogen bonding opportunities available to the
progenitor triol is now deleted.13 This feature is seen to
narrow substantially the strain energy gap separating 8 and
9. Scheme 2 summarizes the equilibration ratios determined
phase bias favoring 11, the formation of even low concentra-
tions of this isomer has not been observed. These results, in
combination with the behavior exhibited by isotaxanes 6-9,
suggests that hydrogen bonding along the northern rim of
these molecules is more sensitive to solvent interruption
relative to those control mechanisms at play along the leading
edge. These differing sensitivities conform in degree and
direction to the pharmacophore model most widely accepted
for the ability of paclitaxel and related bioactive molecules
to stabilize microtubules along their more accessible leading
edge14 (note also Figures 1 and 2).
Our results are entirely consistent with the basic notion
of solvent competition with intramolecular hydrogen bond-
ing. The effect is envisioned as a preempting of stabilizing
internal interactions by solvents containing polar functional
groups, particularly ones with a known capacity for strong
coordination. Such a process may operate by several mech-
anisms, not only by making sites unavailable for internal
substrate interactions. Alternatively, steric interactions prob-
ably develop as well by adding bulk to those sites most
available for solvent interaction. It is possible that the
preference of 10 over 11 in the range of media examined is
directly attributable to increased congestion along the already
crowded northern ridge of 11.
Scheme 2
The test reported herein has been designed to enable
regiocontrol in proper structural contexts under suitable
experimental conditions. Indeed, an important preparative
method has been uncovered whose merits in the context of
total synthesis will be illustrated in future reports.
(13) At ordinary temperatures, 9 is constituted of a mixture of two
atropisomers in which the carbonyl group is projected in either an upward
or downward direction.
(14) Ojima, I.; Chakravarty, S.; Inoue, T.; Lin, S.; He, L.; Horwitz, S.
B.; Kuduk, S. D.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U.S.A. 1999,
96, 4256.
for the 8/9 isomeric pair at 20 °C. Our inability to detect the
presence of 9 in the MeOH/THF experiments and the general
tendency to minimize the proportion of 9 suggests a reduced
Org. Lett., Vol. 3, No. 11, 2001
1779

Acknowledgment. This work is financially supported by
a grant from the National Cancer Institute (CA-83830). J.E.H.
is a trainee in the NIH Chemistry/Biology Interface Program.
We are grateful for Dr. Judith Gallucci for the X-ray
crystallographic analyses.
Supporting Information Available: Illustrative equili-
bration experimental conditions and X-ray crystallographic
details for 6‚C6H6 and 7‚CH3OH. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0100733
1780
Org. Lett., Vol. 3, No. 11, 2001