Divergent regioselectivity in the base-promoted reactions of cyclic eight-membered α-ketols with activated halides

Article abstract of DOI:10.1021/ol027315z

(Matrix presented) Deprotonation of 2-hydroxycyclooctanone followed by exposure to an allylic or benzylic halide proceeds very selectively to give the product of C-alkylation. The effect of Δ^5,6-unsaturation is to promote instead the formation of the O-alkylated derivative. This crossover in kinetic preference is attributed to an inability of the olefinic system to attain a conformation conducive to proton abstraction at C-2.

Full text of DOI:10.1021/ol027315z

ORGANIC
LETTERS
2003
Vol. 5, No. 4
463-466
Divergent Regioselectivity in the
Base-Promoted Reactions of Cyclic
Eight-Membered r-Ketols with Activated
Halides
Leo A. Paquette,* Ivan Vilotijevic, David Hilmey, and Jiong Yang
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
Received November 20, 2002
ABSTRACT
Deprotonation of 2-hydroxycyclooctanone followed by exposure to an allylic or benzylic halide proceeds very selectively to give the product
of C-alkylation. The effect of ∆5,6-unsaturation is to promote instead the formation of the O-alkylated derivative. This crossover in kinetic
preference is attributed to an inability of the olefinic system to attain a conformation conducive to proton abstraction at C-2.
As a result of the application of several physical methods
including NMR analysis,1 X-ray diffraction,2 and molecular
mechanics calculations,3 functionalized eight-membered-ring
compounds are recognized to adopt essentially homogeneous
conformations in their ground state.4 The controlling features
include the minimization of angular strain, eclipsing interac-
tions, and nonbonded transannular repulsion.5 In combination,
these effects are influential in exerting profound conse-
quences on the stereochemical course of reactions involving
cyclooctanoid systems. The conversion of 1 to 2 and the
addition of lithium dimethylcuprate to 3 with generation of
4 constitute two examples of the level of effectiveness with
which remote asymmetric induction can be realized with
cyclic ketones of this class.4 The two π-surfaces in the
enolate ion 1- and in enone 3 are sterically very different.
The conformational bias provided by the resident methyl
substituent is presumably sufficient to guarantee the pre-
dominant generation of diastereomeric dimethyl products by
reagent capture from the less hindered direction.
(1) (a) Anet, F. A. L.; Hartman, J. S. J. Am. Chem. Soc. 1963, 85, 1204.
(b) Anet, F. A. L.; St. Jacques, M. J. Am. Chem. Soc. 1966, 88, 2585, 2586.
(c) Anet, F. A. L.; Cheng, A. K.; Krane, J. J. Am. Chem. Soc. 1973, 95,
7877.
(2) Dunitz, J. D. PerspectiVes in Structural Chemistry; Dunitz, J. D.,
Ibers, J. A., Eds.; Wiley: New York; 1968; Vol. 2, pp 1-70.
(3) (a) Wiberg, K. B. J. Am. Chem. Soc. 1965, 87, 1070. (b) Hendrickson,
J. B. J. Am. Chem. Soc. 1967, 89, 7036, 7043. (c) Engler, E. M.; Andose,
J. D.; Schleyer, P. v. R. J. Am. Chem. Soc. 1973, 95, 8005.
(4) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
(5) Dale, J. Stereochemistry and Conformational Analysis; Verlag
Chemie: Weinhein, Germany, 1978; pp 195-203.
10.1021/ol027315z CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/18/2003

Figure 1. The three lowest energy conformations of 5.
The experiments reported here demonstrate that pro-
nounced regioselectivity differences can accompany the
crossover from saturated to transannularly unsaturated eight-
membered R-ketols exemplified by 5 and 6. As shown in
The consequences of introducing an unsaturated linkage
as in 6 on the prevailing conformational topology is quite
dramatic (Figure 2). The lowest energy conformation can
expectedly be traced to the hydrogen-bonded structure D.
Intimately associated with the structural features of D is a
OdC-C-H dihedral angle of 164.0°. Like B, R-deproto-
nation from this arrangement is improbable since an E-
enolate would likely materialize. The dispositions of the
R-proton in structures E and F are similarly nonconducive
to enolate formation in light of the dihedral angles involved
(168.2° and -46.0°).
We rationalized A-F to reflect an unparalleled ability of
5 to experience C-alkylation when deprotonated with a
suitable base and exposed subsequently to an electrophilic
halide. We considered it reasonable to assume that the alkali
metal ion from the base would foster adoption of a
conformation akin to that present in A, where coordination
of M+ to both oxygens is conveniently accessible. At the
experimental level, treatment of 5 with sodium hydride (1.3
equiv) in DMF at -15 °C followed by an allylic or benzylic
halide resulted in smooth conversion to R-ketols 7 (Table
1). Processing 6 in an entirely comparable manner afforded
instead the R-alkoxy ketones 8 (Table 2).9 All reported yields
relate to material purified by chromatography on silica gel
and are not maximized. Control experiments have provided
Figure 1, 2-hydroxycyclooctanone (5) can adopt three low-
energy conformations as gauged by MM3 calculations.6 Of
these, the energy minimum possesses the hydrogen-bonded
arrangement A (21.1 kcal/mol). When viewed via a modified
Newman projection down the carbonyl-carbinol bond, the
OdC-C-H dihedral angle is seen to be 106.7°, a value
approaching that deemed to be ideal for maximum stereo-
electronic overlap.7 Moreover, the abstraction of this proton
would generate a low-energy Z-enolate.8 Release of the
hydrogen-bonding constraint leads to conformers B (22.5
kcal/mol) and C (23.2 kcal/mol), both of which are unat-
tractive candidates for R-deprotonation. Thus, B would serve
as a likely precursor to a highly strained E-enolate, and C
suffers from severe misalignment of the neighboring C-H
bond.
Figure 2. The three lowest energy conformations of 6.
464
Org. Lett., Vol. 5, No. 4, 2003

Table 1. Alkylation Products from 5
Table 2. Alkylation Products from 6
ing agent is bonded to saturated carbon in 7, it is linked to
oxygen in 8. Other differences such as the presence or
absence of the C-2 proton are equally evident. Remark-
ably, in no instance was cross-contamination of products
observed.
an indication that neither 5 nor 6 is completely stable under
the alkaline conditions applied here. In the absence of alkyl-
ating agent, only 75% of 5 and 90% of 6 could be recovered.
No byproduct was formed at a level sufficient to permit
possible isolation and characterization. In no instance was
evidence gained for the formation of that isomer where
alkylation may have occurred away from the R-hydroxyl
group. This impressive regiochemical control may be
traced to the mechanistic features of the process outlined
above.
Consequently, the conversion of tetrahedral carbon to
trigonal carbon at C-2 in 5 is particularly facile. While enolate
generation may be preceded by ionization of the geminal
hydroxyl, subsequent proton transfer from the adjoining C-H
bond operates smoothly via conformer A for the reasons
advanced above. The chelative assimilation of a larger
sodium ion into A is likely to be accompanied by a more
perfect dihedral angle alignment. On the basis of the
divergent chemical reactivity of 6, a geometry equivalently
favorable to R-deprotonation is obviously not populated as
readily. The ability of a transannularly disposed double bond
to provide conformational constraints such that adoption of
a different reaction pathway is directly impacted has not been
previously recognized. The consequences of this phenomenon
should be more far-reaching than the series of observations
recorded here.
The distinction between 7 and 8 is readily made on the
1
basis of H NMR. While the CH2 group from the alkylat-
(6) Allinger, N. L.; Yuh, Y. H.; Lii, J.-H. J. Am. Chem. Soc. 1989, 111,
8551.
(7) Sorrell, T. N. Organic Chemistry; University Science Books: Sau-
solito, CA, 1999; pp 987-988.
(8) Schreiber, S. L.; Smith, D. B. J. Org. Chem. 1989, 54, 5994.
(9) The bromide utilized in runs 8 and 16 was generated from the
carboxylic acid via a three-step sequence: (a) K2CO3, Me2SO4, acetone;
(b) LiAlH4; (c) PBr3. The carboxylic acid was prepared more than two
decades ago by Prof. Melvin S. Newman: Newman, M. S.; Kanakarajan,
K. J. Org. Chem. 1980, 45, 2301.
Org. Lett., Vol. 5, No. 4, 2003
465

Direct access to O-benzylated cyclooctanones such as 9
can be alternatively realized simply by making recourse to
acidic conditions such as those involving a trichloroacetimi-
date reagent. Informatively, the R-benzyloxycyclooctanone
9 does not undergo equilibration with 7 (R ) C6H5) when
treated with sodium hydride in DMF.10
Acknowledgment. This work was supported by grants
from the National Science Foundation and Aventis Pharma-
ceuticals, Inc.
Supporting Information Available: General experimen-
tal details and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL027315Z
(10) (a) Paquette, L. A.; Zeng, Q. Tetrahedron Lett. 1999, 40, 3823. (b)
Curtin, D. Y.; Leskowitz, S. J. Am. Chem. Soc. 1951, 73, 2633. (c) Curtin,
D. Y.; Proops, W. R. J. Am. Chem. Soc. 1954, 76, 494.
466
Org. Lett., Vol. 5, No. 4, 2003