To circumvent the problem of migration of the oxycar-
bonyl moiety, the fluoride source must be applied in the
presence of a proton source. This would lead to a rapid
protonation of the released alkoxide preventing migration.
The use of TBAF/AcOH,9 TBAF/HF,10 triethylammonium
fluoride,11 and triethylamine trihydrofluoride are all known
reagents of which the latter was investigated in our labora-
tory. Starting from 2a-d, full conversion into 3a,c,d was
accomplished without any detectable formation of 4a,c,d.
In conclusion, we have demonstrated that desilylation of
pyroglutaminol 2a,b using TBAF not only provides the
expected free hydroxyl functionality (compound 3a) but also
promotes migration of the BOC group giving 4a. Our
findings were confirmed by an X-ray diffraction study, and
quantum chemical calculations provided support for mecha-
nistic interpretation of the results. In addition, we have proven
that this phenomenon can be extended to the Cbz and MOC
groups. We propose that this novel observation could explain
why TBAF, in some cases, has been reported not to be a
feasible reagent.2,11,12 For a 4-substituted pyroglutaminol
derivative, one group has suggested a rearrangement to give
the γ-lactone,9 but at least in the unsubstituted case inves-
tigated here, it is clear that migration of the oxycarbonyl
moiety is the favored process. However, in the case of
N-sulfonyl-protected pyroglutaminols the rearrangement to
the γ-lactone 7 is the favored process. As the general method
for desilylation of N-carbamate pyroglutaminols, we recom-
mend the use of an acidic fluoride source.
Scheme 3. Mechanism Leading to 7
level to the two tetrahedral intermediates 5 and 6,7 an energy
difference of 9.4 kJ/mol was obtained in favor of 5 which
leads to the observed product 4d (see Figure 2).
Figure 2. Application of a THF-solvation model at the B3LYP/
6-31+G* level to the two intermediates 5 and 6.7 An energy
difference of 9.4 kJ/mol was obtained in favor of 5, which leads to
the observed product 4d.
Supporting Information Available: X-ray structure
determination for compound 4a and H and 13C NMR data
for compounds 3a,c,d and 4a,c,d. This material is available
1
In comparison, when the carbamate group is exchanged
for an N-sulfonyl group, rearrangement to the γ-lactone is
favored.8 This can be explained on the basis of the low
tendency of sulfones to undergo nucleophilic attack.
OL0069397
(9) Herdeis, C.; Hubmann, H. P.; Lotter, H. Tetrahedron: Asymmetry
1994, 5, 351-354.
(7) Calculations were performed in Jaguar 4.0, Schrodinger, Inc.,
Portland, OR, 2000. Following the Hammond postulate the activation energy
of the rate-determining step is expected to correlate well with the energy
of the high energy intermediates 5 and 6. For reference, see: Hammond,
G. S. J. Am. Chem. Soc. 1955, 77, 334-338.
(10) Nakamura, H.; Oba, Y.; Murai, A. Tetrahedron Lett. 1993, 34,
2779-2782.
(11) Diaz, A.; Siro, J. G.; Garcia-Navio, J. L.; Vaquero, J. J.; Alvarez-
Builla, J. Synthesis 1997, 559-562.
(12) Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1992, 3,
1213-1221.
(8) Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron Lett. 1996, 37, 8173-
8174.
Org. Lett., Vol. 3, No. 3, 2001
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