Stereochemistry of Nucleophilic Substitution Reactions
A R T I C L E S
6-31G**) on C-4 alkoxy-substituted oxocarbenium ions reported
by Miljkovic et al.,27 who concluded that a through-space effect,
but not anchimeric assistance (vide infra), stabilizes the axial
conformation 7 (X ) OMe) by about 4 kcal/mol relative to the
equatorial conformer 8 (eq 2).27
2. In all cases, studies were carried out using oxocarbenium
ion precursors rather than iminium ion precursors, since the
stereoselective reactions of iminium ions are frequently con-
trolled by allylic strain.39
3. Anomeric acetates were employed as oxocarbenium ion
precursors in all cases because the reactions proceeded in higher
yields than if methoxy groups were employed. In several cases,
substitution using methyl acetals showed selectivities that were
comparable to the reactions with acetates. When a highly
electron-withdrawing substituent such as a fluoro or nitro group
was present, however, the reactions of the methyl acetals
proceeded to provide ring-opened products instead.
4. Allyltrimethylsilane was generally employed as the nu-
cleophile because the reactions are high-yielding and irrevers-
ible,40 and the product cannot epimerize (as has been observed
when silyl enol ethers,28,41 oxygen nucleophiles,42 or nitrogen
nucleophiles are employed43,44). In addition, steric approach
considerations are minimized with this small nucleophile,45 and
the allyl group can be manipulated easily to facilitate analysis
of product stereochemistry.
5. The stereochemistry of the products was assigned by
analysis of 1H NMR coupling constants and NOE measurements
on the products or their derivatives. These techniques provided
reliable assignments because the 2-alkyltetrahydropyran products
adopt chair conformers.46
Reactions of C-4 Substituted Tetrahydropyran Oxocar-
benium Ions. A series of three experiments demonstrated that
the computational studies of Bowen16 and Miljkovic27 (vide
supra) could be employed to predict the stereoselective reactions
of C-4 substituted oxocarbenium ions (eq 3). Acetals 9a-c were
treated with BF3‚OEt2 and allyltrimethylsilane to provide
allylated products 10 and 11. Whereas the two alkyl-substituted
systems 9a,b provided preferentially the 1,4-cis products 10a,b,
the alkoxy-substituted acetal provided almost exclusively the
1,4-trans product 11c. Similar selectivities were observed when
SnBr4 was employed as the Lewis acid. Because the methyl-
substituted acetal 9a and the phenethyl compound 9b provided
the same selectivity, it was concluded that the phenyl ring of
the alkoxy group could not be the origin of the reversal of
stereochemistry exhibited for 9c.41
The conclusions of Bowen16 and Miljkovic27 regarding the
unusual conformers of heteroatom-substituted oxocarbenium
ions suggested that these systems might exhibit unusual ste-
reoselectivities upon reactions with nucleophiles. Several re-
search groups have noted that their results are consistent with
the reactions of oxocarbenium and iminium ions with pseudo-
axial heteroatom substituents.17,28-34 Oxocarbenium ions with
pseudoaxial alkoxy groups have also been described for
biologically relevant carbohydrate systems.35,36 In other cases,
the unusual conformational preferences of cations were not
invoked. For example, reactions of six-membered-ring iminium
ions substituted at C-4 with oxygen-containing groups provided
high 1,4-trans selectivity comparable to our observations with
oxocarbenium ions,17 but these results were not explained at
the time.37,38
In this paper, we detail our studies of the stereoselective
reactions of six-membered-ring oxocarbenium ions.17 A series
of acetoxytetrahydropyrans were prepared and subjected to
nucleophilic substitution reactions in the presence of Lewis
acids, reactions which are believed to proceed via oxocarbenium
ion intermediates.7 These experiments illustrate the dramatic
difference in diastereoselectivity between alkyl- and heteroatom-
substituted systems. Studies with halogen-substituted acetals are
consistent with the electrostatic argument proposed by Bowen16
and Miljkovic.27
Results and Discussion
Details of the Experimental Approach. Several specific
details of the experimental approach deserve comment:
1. The acetal substrates employed for this study were
prepared, typically as mixtures of anomers, in several steps;
the details of these syntheses are provided as Supporting
Information.
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C-4 substituted six-membered-ring acetals (9a-c) can be
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