Stereochemical reversal of nucleophilic substitution reactions depending upon substituent: Reactions of heteroatom-substituted six-membered-ring oxocarbenium ions through pseudoaxial conformers

Full text of DOI:10.1021/ja993366o

168
J. Am. Chem. Soc. 2000, 122, 168-169
tions will be strongly influenced by effects that stabilize the
ground state conformations, since the transition structures for
nucleophilic attack should be early and thus reactant-like. The
C-glycosylation13,14 of an anomeric acetate with allyltrimethyl-
silane, which likely proceeds via an oxocarbenium ion,15 is an
excellent probe for determining reactive conformations since
attack of this carbon nucleophile is irreversible and high-yielding.
The nucleophilic substitution of 4-substituted tetrahydropyran
acetals 3 proceeded with opposite stereochemistry depending upon
the substituent (eq 2). Alkyl-substituted acetals 3a and 3c provided
Stereochemical Reversal of Nucleophilic Substitution
Reactions Depending upon Substituent: Reactions of
Heteroatom-Substituted Six-Membered-Ring
Oxocarbenium Ions through Pseudoaxial Conformers
Jan Antoinette C. Romero, Sarah A. Tabacco, and
K. A. Woerpel*
Department of Chemistry, UniVersity of California
IrVine, California 92697-2025
ReceiVed September 16, 1999
Although conformational preferences of neutral six-membered-
ring systems are dominated by steric effects,1 recent computational
studies suggest that electronic effects exert a profound influence
on the conformations of six-membered-ring oxocarbenium ions.
In the process of analyzing rates of glycoside hydrolysis, Bowen
and co-workers reported molecular mechanics calculations indi-
cating that hydroxyl groups at C-4 and C-3 of a six-membered
oxocarbenium ion2 assume pseudoaxial positions in the half-chair
conformation (eq 1).3,4 The pseudoaxial preference has been
the 1,4-cis products 4a,c whereas the presence of a benzyloxy
group at C-4 in 3b led to selective formation of the 1,4-trans
product 5b.16,17
The stereoselectivity observed for nucleophilic substitution of
3b (eq 2) indicates that the alkoxy-substituted oxocarbenium ion
intermediate18 reacts through the pseudoaxial conformer 7 (eq 3),8
attributed to a stabilizing electrostatic attraction between the
partially negatively charged hydroxyl oxygen atom and the
carbocationic carbon,5 which are positioned closer together in a
pseudoaxial conformer than in a pseudoequatorial conformer.3,4
This phenomenon would have significant impact on bioorganic
and synthetic chemistry if it could be confirmed by solution-phase
experiments. For example, the mannosyl cation is believed to
adopt a conformation in which alkoxy groups at C-3 and C-4
reside in pseudoaxial orientations.6,7 The preference for pseudo-
axial positions in oxocarbenium ions could also provide a means
to control the stereochemical courses of synthetic transforma-
tions.8,9 In this paper, we report evidence that oxocarbenium ions
bearing electronegative substituents at C-3 and C-4 react through
pseudoaxial conformers.
since stereoelectronic effects11,12 require that the 1,4-trans product
arises from nucleophilic attack on this conformer of the cation.
This conformational preference is in accord with computationally
determined conformational preferences for substituted tetrahy-
dropyran cations in their ground states.3,4 The results also indicate
that the alkyl-substituted oxocarbenium ions react through the
pseudoequatorial conformer 6.3 Alternative explanations for these
stereoselectivities do not account for the experimental data.
To investigate the influence of alkoxy groups on the conforma-
tions of oxocarbenium ions, we compared nucleophilic substitution
reactions of analogous alkyl- and alkoxy-substituted acetals
bearing a single substituent at various positions on the ring.2,10
Because nucleophiles attack oxocarbenium and iminium ions
along axial trajectories through chairlike transition structures,11,12
the stereochemistries of the products reveal the reactive confor-
mations of the oxocarbenium cations. These reactive conforma-
(10) Acetals with alkyl substituents at C-5 undergo nucleophilic substitution
with high anti selectivity. See, for example: Brown, D. S.; Ley, S. V.; Bruno,
M. Heterocycles 1989, 28, 773-777.
(11) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032-
7035.
(12) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983; pp 209-221.
(13) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
FL, 1995.
(14) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon:
Tarrytown, NY, 1995; Vol. 13.
(1) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp 686-740.
(15) Reactions of acetals with carbon nucleophiles have been shown to
proceed via carbocation intermediates. 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. Other reactions of acetals do not appear to involve free
cations. See, for example: (c) Denmark, S. E.; Almstead, N. G. J. Am. Chem.
Soc. 1991, 113, 8089-8110.
(16) In all cases, stereoselectivities were determined by GC or GCMS
analysis of unpurified reaction mixtures. These selectivities were corroborated
by 1H and 13C NMR spectroscopy. The relative stereochemistries of the
products were determined using combinations of 1H NMR coupling constant
data and NOE measurements. The yields are reported for purified products.
(17) The addition of the enoxysilane derived from acetophenone to 3b in
the presence of BF3‚OEt2 provided the corresponding ketone with 93:7
diastereoselectivity, favoring the 1,4-trans isomer. This preference for 3b to
form the 1,4-trans product does not change ((3%) as a function of solvent
(CH2Cl2, toluene, EtNO2, EtCN) or Lewis acid (SnBr4).
(2) The numbering used in this paper considers the carbocationic carbon
as C-1.
(3) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992,
114, 859-864.
(4) Other calculations (HF/6-31G*) indicate that oxocarbenium ion 2 (R
) Me) is favored over 1 by 4.1 kcal/mol: Miljkovic, M.; Yeagley, D.;
Deslongchamps, P.; Dory, Y. L. J. Org. Chem. 1997, 62, 7597-7604.
(5) Dudley, T. J.; Smoliakova, I. P.; Hoffmann, M. R. J. Org. Chem. 1999,
64, 1247-1253.
(6) Winkler, D. A.; Holan, G. J. Med. Chem. 1989, 32, 2084-2089.
(7) Ble´riot, Y.; Genre-Grandpierre, A.; Imberty, A.; Tellier, C. J. Carbohydr.
Chem. 1996, 15, 985-1000.
(8) This counter-intuitive conformational preference has been invoked to
explain stereoselective reactions of acetoxy-substituted vinyloxocarbenium
ions: Hosokawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron Lett. 1998, 39,
1917-1920.
(18) Except for 13a (which is prepared as only the cis isomer), mixtures
of anomeric acetates were employed. For the acetate 18 (eq 8), the two anomers
of starting material are separable. Control experiments indicate that both
anomers give the same product with the same degree of selectivity.
(9) Roush has proposed pseudoaxially substituted oxocarbenium ions as
reactive intermediates in highly stereoselective glycosidation reactions: Roush,
W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53, 8837-8852.
10.1021/ja993366o CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/21/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 1, 2000 169
Substituents at C-4 are too far away from the cationic carbon
atom to impede approach of the nucleophile. Anchimeric as-
sistance from the benzyloxy group can be discounted by examina-
tion of selectivities exhibited for other substitution patterns (vide
infra). Because both methyl-substituted acetal 3a and phenethyl-
substituted acetal 3c undergo substitution with 1,4-cis selectivity,
participation by the phenyl group on the benzyloxy substituent
cannot be responsible for the reversal of selectivity.19
The reversal of selectivity exhibited by C-4 substituted acetals
was also observed for C-3 substituted systems. Nucleophilic
substitution on methyl-substituted acetal 8a provided the 1,3-trans
product 10a with high selectivity,20 and the alkoxy-substituted
analogue 8b provided 1,3-cis product 9b (eq 4).
modestly favored for the 2-methyl oxocarbenium ion 16 (X )
Me),3,24 this conformer is less reactive than the axial conformer
17 (X ) Me) since approach of the nucleophile to 16 must occur
along a trajectory over the methyl group. The low selectivity
observed for this substrate indicates that steric inhibition of
nucleophilic attack opposes conformational control. These forces
are not balanced for the alkoxy-substituted oxocarbenium ion,
however. Alkoxy substituents exhibit a larger preference for the
pseudoequatorial conformer than the alkyl-substituted cation,24
likely due to hyperconjugation between the electron-donating
C-H bond and the 2p orbital on the electrophilic carbon atom.5
Because an alkoxy group is less sterically demanding than an
alkyl group, the nucleophile can approach from the same face as
the substituent to provide predominantly the 1,2-cis product 14b.
As with the 3-substituted oxocarbenium ion, cis selectivity is
inconsistent with anchimeric assistance.
The selectivities observed for 3-substituted acetals 8 (eq 4) are
consistent with calculations of ground-state conformations of
oxocarbenium ions in which an alkyl group at C-3 favors
pseudoequatorial conformer 11, while an alkoxy group favors
pseudoaxial conformer 12 (eq 5).3,21 Unlike the C-4 substituted
The preference for C-4 substituted oxocarbenium ions to react
with alkoxy groups in pseudoaxial orientations extends to other
electronegative heteroatom substituents. Nucleophilic substitution
on 4-chloro acetal 18 provided the 1,4-trans product 19 prefer-
entially (eq 8). This result may be understood by considering
nucleophilic attack on the pseudoaxially substituted oxocarbenium
ion 7 (X ) Cl, eq 3).25
systems, the pseudoaxial substituent at C-3 of 12 is close enough
to inhibit approach of the nucleophile. Evidently, the alkoxy
substituent is not large enough to force the reaction to occur via
the less stable conformer 11 (X ) OBn). The stereochemistry
observed for the alkoxy-substituted acetal 8b demonstrates that
anchimeric assistance by the alkoxy group does not occur. If this
group were to participate in this way, the 1,3-trans product would
be formed from 8b, contrary to the experimental result (eq 4).
To complete our studies, we examined the influence of
substitution adjacent to the acetal carbon. An alkyl substituent
confers little stereochemical differentiation between the two sides
of the intermediate oxocarbenium ion (eq 6), consistent with
In conclusion, the stereoselective reactions of tetrahydropyran
acetals with nucleophiles demonstrate that oxocarbenium ions
bearing electronegative substituents at C-3 and C-4 react through
pseudoaxial conformers. These experiments show that for sub-
stitution at both C-3 and C-4, alkyl- and alkoxy-substituted
oxocarbenium ions provide products with opposite stereochem-
istries. In these cases, the conformer of the intermediate that
undergoes nucleophilic attack is the lower energy conformer as
determined using computational methods. The preference for
heteroatom-substituted oxocarbenium ions to react through pseudo-
axial conformers likely operates in other carbocationic systems
such as N-acyliminium ions.26
Acknowledgment. This research was supported by the Research
Corporation in the form of a Cottrell Scholar Award to K.A.W. J.A.C.R.
is a recipient of a Presidential Undergraduate Fellowship from UCI.
K.A.W. thanks the American Cancer Society, AstraZeneca, the Camille
and Henry Dreyfus Foundation, and Glaxo-Wellcome for awards to
support research. Dr. John Greaves and Dr. John Mudd are acknowledged
for mass spectrometric data.
observations on 2-methyl-substituted tetrahydrofuran acetals.22 The
reaction of the 2-alkoxy acetal 13b, on the other hand, was cis-
selective.23
Supporting Information Available: Complete experimental proce-
dures, product characterization, and stereochemical proofs (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
The selectivities shown in eq 6 are the result of conformational
bias and steric approach control working in opposition to each
other. Although the pseudoequatorial conformer should be
JA993366O
(23) The use of BF3‚OEt2 resulted in lower selectivity (66:34, 85% yield).
Using TMSOTf as the Lewis acid with the corresponding methyl acetal results
in no stereoselectivity: Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Kim,
B. H.; Ogilvie, W. W.; Yiannikouros, G.; Prasad, C. V. C.; Veale, C. A.;
Hark, R. R. J. Am. Chem. Soc. 1990, 112, 6263-6276.
(19) Ichikawa, Y.-i.; Kubota, H.; Fujita, K.; Okauchi, T.; Narasaka, K. Bull.
Chem. Soc. Jpn. 1989, 62, 845-852.
(20) This selectivity is reminiscent of chelation-controlled additions to
â-alkoxy aldehydes. See, for example: Chen, K.; Goetz, E. H.; Prasad, K.;
Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155-158.
(21) Calculations (B3LYP/6-31G*//HF/6-31G*) indicate that the methoxy-
substituted cation prefers the pseudoaxial conformer by 2.8 kcal/mol, and the
methyl-substituted cation favors the pseudoequatorial conformer by 1.4 kcal/
mol.
(24) Calculations (B3LYP/6-31G*//HF/6-31G*) show that conformer 16
is favored by only 0.5 kcal/mol when X ) Me, but is preferred by 1.6 kcal/
mol for X ) OMe.
(25) Ab initio calculations (HF/3-21G*) show that the pseudoaxial oxo-
carbenium 7 (X ) Cl) is favored over the pseudoequatorial cation 6 by 2.5
kcal/mol.
(22) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40-42.
(26) Herdeis, C.; Engel, W. Tetrahedron: Asymmetry 1991, 2, 945-948.