Investigations into the role of ion pairing in reactions of heteroatom-substituted cyclic oxocarbenium ions

Article abstract of DOI:10.1021/ol0500620

(Chemical Equation Presented) The O-to-C rearrangement of vinyl acetals is used to demonstrate that tight ion pairing is not involved in the stereoselective nucleophilic addition reactions of alkoxy-substituted cyclic oxocarbenium ions.

Full text of DOI:10.1021/ol0500620

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1157-1160
Investigations into the Role of Ion
Pairing in Reactions of
Heteroatom-Substituted Cyclic
Oxocarbenium Ions
Siddhartha R. Shenoy and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine,
IrVine, California 92697-2025
kwoerpel@uci.edu
Received January 12, 2005
ABSTRACT
The O-to-C rearrangement of vinyl acetals is used to demonstrate that tight ion pairing is not involved in the stereoselective nucleophilic
addition reactions of alkoxy-substituted cyclic oxocarbenium ions.
Although it is generally accepted that many organic trans-
formations proceed via oxocarbenium ion intermediates,1-4
the details of oxocarbenium ion reactivity continue to garner
tremendous interest in both bioorganic5-9 and synthetic
organic chemistry.10,11 For example, the rates of glycoside
hydrolysis12 and the high diastereoselectivities observed in
the nucleophilic substitution reactions of 1,3-dioxanes10 are
attributed to the stability and conformational preferences of
these ionic intermediates. We recently reported that tetrahy-
dropyran acetals bearing alkoxy substituents undergo sub-
stitution reactions with opposite diastereoselectivities to those
observed for pyrans bearing alkyl groups.13,14 We attributed
these results to the electronic preference15,16 of heteroatom
substituents to adopt pseudoaxial positions in the half-chair
conformations of the incipient cyclic oxocarbenium ion
intermediates.17,18
(1) Dixon, D. J.; Ley, S. V.; Tate, E. W. Synlett 1998, 1093-1095.
(2) Molander, G. A.; Cameron, K. O. J. Org. Chem. 1993, 58, 5931-
5943.
(3) Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143-
7157.
(4) Sammakia, T.; Berliner, M. A. J. Org. Chem. 1995, 60, 6652-
6653.
(5) Banait, N. S.; Jencks, W. P. J. Am. Chem. Soc. 1991, 113, 7951-
7958.
(6) Lee, J. K.; Bain, A. D.; Berti, P. J. J. Am. Chem. Soc. 2004, 126,
3769-3776.
(7) Unrau, P. J.; Bartel, D. P. Proc. Natl. Acad. Sci. U.S.A. 2003, 100,
15393-15397.
(8) Werner, R. M.; Stivers, J. T. Biochemistry 2000, 39, 14054-14064.
(9) Zhu, J.; Bennet, A. J. J. Am. Chem. Soc. 1998, 120, 3887-3893.
(10) See, for example: (a) Sammakia, T.; Smith, R. S. J. Am. Chem.
Soc. 1994, 116, 7915-7916. (b) Matsutani, H.; Ichikawa, S.; Yaruva, J.;
Kusumoto, T.; Hiyama, T. J. Am. Chem. Soc. 1997, 119, 4541-4542. Some
reactions of acetals do not appear to involve free cations: (c) Denmark, S.
E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089-8110
(11) For a review on the nucleophilic substitution reactions of five-
membered ring acetals, see: Harmange, J.-C.; Figadere, B. Tetrahedron:
Asymmetry 1993, 4, 1711-1754.
Recently, an intriguing report from Rovis and co-workers
described an O-to-C vinyl acetal rearrangement in alkyl-
(12) Jensen, H. H.; Bols, M. Org. Lett. 2003, 5, 3419-3421.
(13) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168-169.
(14) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521-15528.
(15) Miljkovic, M.; Yeagley, D.; Deslongchamps, P.; Dory, Y. L. J. Org.
Chem. 1997, 62, 7597-7604.
(16) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc.
1992, 114, 859-864.
(17) Other research groups have also reported nucleophilic addition to
oxocarbenium ions with pseudoaxial alkoxy groups: (a) Chong, P. Y.;
Roush, W. R. Org. Lett. 2002, 4, 4523-4526. (b) Saeeng, R.; Isobe, M.
Tetrahedron Lett. 1999, 40, 1911-1914. (c) Hosokawa, S.; Kirschbaum,
B.; Isobe, M. Tetrahedron Lett. 1998, 39, 1917-1920. (d) Roush, W. R.;
Sebesta, D. P.; Bennet, C. E. Tetrahedron 1997, 53, 8825-8836.
10.1021/ol0500620 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/19/2005

substituted pyrans in which the selectivity of the rearrange-
ment was controlled by contact ion pairs.19 In light of these
results, we examined the role of ion-pairing in the reactions
of heteroatom-substituted six-membered ring oxocarbenium
ions with nucleophiles. In this paper, we document the use
of the O-to-C vinyl acetal rearrangement as a mechanistic
probe to prove conclusively that ion pairing is not a factor
controlling the high selectivity of nucleophilic additions to
heteroatom-substituted tetrahydropyran oxocarbenium ions.
We employed the six-membered-ring oxocarbenium ion
bearing a single substituent at C-4 as a model system to study
the role of ion pairing.20 The C-4-substituted system was
appealing due to the simplicity in its reactivity with nucleo-
philes. Oxocarbenium ions bearing a C-4-substituent can
adopt two diastereomeric half-chair conformations (1eq and
1ax, Scheme 1).21,22 Heteroatom-substituted oxocarbenium
oxocarbenium ion precursor. In principle, the existence of
ion pairing should affect the diastereoselectivity of nucleo-
philic additions to these oxocarbenium ion intermediates. Ion
pairing has been suggested to explain the unique selectivities
observed in the substitution reactions of nucleophiles with
glycosides and other six-membered ring oxocarbenium
ions.23,24
In this paper, we use a modified version of the Winstein
ion pair mechanism25 for the analysis of ion pair intermedi-
ates (Scheme 2).26 In this scheme, the leaving group forms
Scheme 2
Scheme 1
a contact ion pair with the carbenium ion (5).27 The limiting
SN2 pathway (a) is considered to be unlikely.28 If ion pairing
is involved, nucleophilic attack prior to ion pair disassocia-
tion requires the nucleophile to approach the carbenium
ion stereospecifically from the side opposite the ion pair
complex, leading to products with inversion of stereochem-
istry at the cationic center (pathway b). If ion pairing is not
involved, the carbenium would be solvated and nucleophilic
attack could occur from either face of the solvent-equilibrated
carbenium ion 6 (pathway c).
To study the involvement of ion-pairing in the nucleophilic
substitution reactions of heteroatom-substituted oxocarbe-
nium ions, we first considered a case in which a nucleophile
could attack the oxocarbenium ion irreversibly prior to the
leaving group escaping the solvent cage (pathway b).19 The
formation of oxocarbenium ions 8eq and 8ax occur with the
departure of the Lewis acid-bound vinyl ethers from cis-7
and trans-7, respectively (Scheme 3). If these interme-
diates exist as contact ion pairs, the O-to-C vinyl acetal
rearrangement should lead to cis- and trans-9 by stereospe-
cific recombination to the same face of the oxocarbenium
ion from which they left.19 Thus, the ratio of cis- to trans-9
should be identical to the initial anomeric ratio of starting
acetal 7.19
ions favor the pseudoaxial conformer by about 4 kcal/mol
due to stabilizing electrostatic interactions between the
partially negatively charged atom of the substituent and the
positively charged carbon (Scheme 1).15,16 As a consequence,
nucleophilic addition to an oxocarbenium ion bearing a C-4
alkoxy substituent results in 1,4-trans selectivity (pyran 2),
while opposite diastereoselectivities are observed in additions
to oxocarbenium ions bearing C-4 alkyl substituents (pyran
3).21,22 In both cases, the approaching nucleophile does not
develop unfavorable steric interactions with the C-4 ring
substituent, and consequently, the activation energies for the
reactions of 1ax and 1eq are comparable.
Two assumptions are implicit in the analysis of the
oxocarbenium ion reactivity depicted above. First, it is
presumed that nucleophilic attack is slower than the con-
formational interconversion between the two half-chair
conformers. Second, it is assumed that the cations 1ax and
1eq are fully disassociated from the leaving group of the
(23) Bennet, A. J.; Kitos, T. E. J. Chem. Soc., Perkin Trans. 2 2002,
1207-1222.
(24) Huang, X.; Surry, C.; Hiebert, T.; Bennet, A. J. J. Am. Chem. Soc.
1995, 117, 10614-10621.
(25) Winstein, S.; Klinedinst, P. E., Jr.; Robinson, G. C. J. Am. Chem.
Soc. 1961, 83, 885-895.
(18) For an example of the electronic effects of axial hydroxyl groups
on the rates of glycoside hydrolysis, see: Jensen, H. H.; Bols, M. Org.
Lett. 2003, 5, 3419-3421.
(26) Since the separation of the cation and leaving group by solvent would
allow for the equilibration of the oxocarbenium ion intermediate, the
“solvent-separated ion pair” intermediate in the Winstein scheme has been
combined with the “dissociated carbenium ion” and deemed a “solvent-
equilibrated cation.” See: Shiner, V. J., Jr.; Dowd, W. J. Am. Chem. Soc.
1969, 91, 6528-6529.
(19) Zhang, Y.; Reynolds, N. T.; Manju, K.; Rovis, T. J. Am. Chem.
Soc. 2002, 124, 9720-9721.
(20) The numbering used in this paper considers the carbocationic carbon
as C-1.
(27) Since a Lewis acid would be required to activate 4 for solvolysis,
the actual counterion involved in an ion pairing mechanism may involve a
leaving group-Lewis acid complex.
(21) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983; pp 209-221.
(22) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289-296.
(28) Eliel, E. L.; Ro, R. S. J. Am. Chem. Soc. 1957, 79, 5995-6000.
1158
Org. Lett., Vol. 7, No. 6, 2005

2). Treating acetate 14 with the exogenous silyl enol ethers
15 and 16 in the presence of BF3‚OEt2 afforded the respective
ketones 12 and 13 with comparable 1,4-trans selectivities to
the intramolecular vinyl acetal rearrangements of 10 and 11
(Scheme 5).31 These stereoselectivities indicate that the
Scheme 3
Scheme 5
We tested this hypothesis by subjecting an anomeric
mixture of vinyl acetals 10 and 11 to the reaction conditions
outlined by Rovis et al. for generating contact ion pairs in
the analogous alkyl-substituted pyran systems19 and to the
optimized conditions we generally use for nucleophilic
substitution reactions to six-membered ring oxocarbenium
ions.14 Under both conditions, 1,4-trans selectivity was
observed for both 10 and 11, irrespective of the anomeric
ratios of the starting vinyl acetals (Scheme 4).29 The O-to-C
benzyloxy-substituted oxocarbenium ion intermediate reacts
through the solvent-equilibrated pseudoaxial conformer 8ax
(Scheme 3).
A crossover experiment provided conclusive evidence that
the substitution reactions of C-4 alkoxy-substituted six-
membered ring oxocarbenium ions proceed through fully
solvent-equilibrated ionic intermediates. We used the C-4
benzyloxy vinyl acetal 10 and the C-4 p-xylyloxy vinyl acetal
17 shown in Scheme 6. If conformational interconversion
Scheme 4 a
Scheme 6 a
a Typical reaction conditions: (A) BF3‚OEt2 (1.3 equiv), -78
to 25 °C, 30 min. (B) AlMe3 (4.0 equiv), BF3‚OEt2 (1.1 equiv),
-78 °C, 30 min. bMeasured by GC analysis of unpurified reaction
a p-Xyl ) (4-Me)C6H4CH2
c
mixture. Reported yields based on purified products.
and recombination were faster than the dissociation of an
ion pair, C-4 benzyloxy vinyl acetal 10 should give methyl
ketone product 12 and C-4 p-xylyloxy vinyl acetal 17 should
give n-propyl ketone product 18 exclusively, and the
crossover products 19 and 20 should not be observed.
vinyl acetal rearrangement appears to occur slower than the
conformational interconversion of the cation intermediate;
thus, the diastereoselectivities of the products represent the
relative ground-state populations of the two half-chair con-
formers (8eq and 8ax) as described by the Curtin-Hammet/
Winstein-Holness concepts.30
The 1,4-trans stereoselectivities obtained in the vinyl acetal
rearrangements above indicate that nucleophilic attack occurs
stereoselectively on the pseudoaxial conformer of a solvent-
equilibrated oxocarbenium intermediate (pathway c, Scheme
(29) Rovis and co-workers (ref 19) have shown that optimal selectivities
for C-4-substituted oxocarbenium ions are observed when the reactions are
performed at -25 °C. Performing the rearrangement reaction on the C-4
benzyloxy-substituted oxocarbenium ions at -25 °C or slowly warming
the reaction mixture from -78 to -25 °C did not affect the diastereose-
lectivity of the reaction.
(30) Seeman, J. I. Chem. ReV. 1983, 83, 83-134.
Org. Lett., Vol. 7, No. 6, 2005
1159

Upon treating a 1:1 mixture of vinyl acetals 10 and 17
with BF3‚OEt2, all four ketone products were produced as
detected by GC-MS and H NMR analysis. In addition, all
the stereoelectronic effects of C-4 alkoxy-substituted oxo-
carbenium ions dominated the stereochemical course of nu-
cleophilic addition to these cations. The results of the cross-
over experiment confirm that ion pairing is not a factor
controlling the high selectivity of nucleophilic additions to
C-4 alkoxy-substituted oxocarbenium ion intermediates.
1
four ketone products were produced with 1,4-trans selectivity
(Scheme 6). The observation of rearrangement products 19
and 20 conclusively indicated that the reaction proceeds
through solvent-equilibrated oxocarbenium ion intermedi-
ates.32
In conclusion, our experiments indicate that ion pairing
is not involved in the nucleophilic substitution reactions of
alkoxy-substituted six-membered ring oxocarbenium ions.
The analysis of product diastereoselectivities indicated that
Acknowledgment. This research was supported by the
National Institute of General Medical Sciences of the
National Institutes of Health (GM61006). K.A.W. thanks
Merck Research Laboratories and Johnson & Johnson for
awards to support research. We thank Dr. Phil Dennison for
assistance with NMR spectrometry and Dr. John Greaves
and Dr. John Mudd for mass spectrometry.
(31) For all experiments, stereoselectivities were determined by GC and
1H NMR spectroscopic analysis of unpurified reaction mixtures. The
reported yields are based on purified products (see Supporting Information
for further details).
(32) Performing the crossover experiment using the reaction conditions
outlined by Rovis et al. (ref 19) for generating contact ion pairs in the
analogous alkyl-substituted pyran systems also provided all four ketone
products. The details of this crossover experiment are included in Supporting
Information.
Supporting Information Available: Complete experi-
mental procedures and product characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0500620
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