Unprecedented migration of N-alkoxycarbonyl groups in protected pyroglutaminol.

Article abstract of DOI:10.1021/ol0069397

[figure: see text] Cleavage of an O-silyl ether in an N-BOC-protected pyroglutaminol using TBAF led to an unprecedented migration of the BOC group. An investigation of the mechanism, based on experimental data and quantum mechanical calculations, is presented. Similar migration was observed for N-Cbz and N-methoxycarbonyl groups.

Full text of DOI:10.1021/ol0069397

ORGANIC
LETTERS
2001
Vol. 3, No. 3
433-435
Unprecedented Migration of
N-Alkoxycarbonyl Groups in Protected
Pyroglutaminol
Lennart Bunch, Per-Ola Norrby, Karla Frydenvang, Povl Krogsgaard-Larsen, and
Ulf Madsen*
Center for Drug Design and Transport, Department of Medicinal Chemistry,
The Royal Danish School of Pharmacy, UniVersitetsparken 2,
DK-2100 Copenhagen, Denmark
um@dfh.dk
Received November 30, 2000
ABSTRACT
Cleavage of an O-silyl ether in an N-BOC-protected pyroglutaminol using TBAF led to an unprecedented migration of the BOC group. An
investigation of the mechanism, based on experimental data and quantum mechanical calculations, is presented. Similar migration was observed
for N-Cbz and N-methoxycarbonyl groups.
(S)-Pyroglutaminol (1), derived from (S)-glutamic acid in
two steps, serves as an important building block in synthetic
Scheme 1. Reaction Pathway to 3 and 4
organic chemistry.1 In an approach to synthesize a novel
potentially CNS active glutamic acid analogue, selective
cleavage of the TBDMS ether in 2a with TBAF was expected
to proceed in high yield on the basis of a previously reported
synthesis.2 However, instead of obtaining the expected free
hydroxyl functionality in compound 3a, migration of the
BOC group led to the lactam-carbonate derivative 4a as the
only product observed (Scheme 1). An X-ray diffraction
study of 4a confirmed the structure (Figure 1). In general,
migration of the oxycarbonyl moiety in N-carbamates is a
known but rarely observed rearrangement reaction and only
favorable if an additional anion stabilizing group is present
(1) For an extensive review, see: Na´jera, C.; Yus, M. Tetrahedron:
Asymmetry 1999, 10, 2245-2303.
(2) Ikota, N. Chem. Pharm. Bull. 1992, 40, 1925-1927
(3) Valentekovich, R. J.; Schreiber, S. L. J. Am. Chem. Soc. 1995, 117,
9069-9070
(4) Johnson, C. K. ORTEPII. Report ORNL-5138; Oak Ridge Laboratory,
Tennessee, 1976.
(5) Experimental procedure: To 0.30 mmol of 2a-d in dry THF (0.5
mL) was added 0.9-1.6 equiv of a 1 M solution of TBAF‚3H2O in THF
(Aldrich). The reaction mixture was stirred for 5 or 30 min at rt and then
diluted with EtOAc and quenched by addition of H2O. The organic layer
was separated and washed with brine, dried over Na2SO4, and evaporated.
1
Ratios of products determined from H NMR.
10.1021/ol0069397 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/06/2001

complexes is presumably due to the difference in steric bulk
around the silane. According to experimental results, the rate
of migration for the TBDMS ether shows a higher depen-
dency on the TBAF concentration. This may be a result of
the prolonged lifetime of the pentacoordinate TBDMS ether
which is then susceptible to attack by a second fluoride anion,
followed by a rapid release of the alkoxide.6 The proposed
general mechanism is illustrated for 2a in Scheme 2.
Scheme 2. Proposed Mechanism for the Formation of 4a
Figure 1. Molecular structure (ORTEPII)4 of compound 4a as
determined from an X-ray diffraction analysis (see Supporting
Information).
on the nitrogen.3 Here we wish to report an investigation of
this so far overlooked problem in pyroglutaminol chemistry.
In the area of pyroglutaminol chemistry, the most com-
monly used O-protective groups are the TBDMS and TBDPS
ethers. Thus, 2a and 2b were included in this investigation.
To investigate the structural generality of this N-oxycarbonyl
group migration, the benzyloxycarbonyl 2c and methoxy-
carbonyl (MOC) 2d groups were also included in this study.
At first, the influence of the amount of TBAF and the
reaction time on the percentage of migration were investi-
gated, see Table 1.5
Table 1. Deprotection of 2a and 2b with TBAF
2a (R ) TBDMS)
2b (R ) TBDPS)
TBAF
t
(equiv) (min) % 2a
% 3a
% 4a
% 2b
% 3a
% 4a
1.6
1.6
1.2
1.2
0.9
0.9
30
5
30
5
30
5
0
0
0
0
0
0
39
20
60
53
75
100
61
80
40
47
20
0
0
0
0
0
0
12
14
23
33
45
100
88
86
77
67
55
<5
<5
To investigate the generality of this migration, 2c,d were
threated with 1.2 or 1.6 equiv of TBAF for 5 or 30 min,
respectively (Table 2). In both cases the migration proved
It is well established that the cleavage of an O-silyl ether
with fluoride anions proceeds through an initially formed
pentacoordinate silicate which then collapses either sponta-
neously or upon the following aqueous workup.
Table 2. Deprotection of 2c and 2d with TBAF5
Addition of two fluoride anions to form a hexacoordinate
silicate is also known and may facilitate the following
collapse of the Si-O bond, setting free the alkoxide. It has
also been shown that nucleophilic attack on a pentacoordinate
silicate is a faster process than attack on the starting
tetracoordinate silane.6
2c (R ) Cbz)
2d (R ) MOC)
TBAF
t
(equiv) (min) % 2c
% 3c
% 4c
% 2d
% 3d
% 4d
1.6
1.2
30
5
0
0
0
0
100
100
0
0
0
0
100
100
From Table 1 it is clear that the ratio of 3a and 4a is
dependent on both time and the amount of TBAF added. It
can be concluded that the stability of the pentacoordinate
TBDMS ether compared to that of the TBDPS ether is
higher, thus giving rise to the lower tendency of migration.
This difference in stability of the pentacoordinate silane
to be a much faster process compared to that of 2a. This
may be attributed to the lower steric bulk of the benzyl and
methyl group compared to the tert-butyl group.
To address the question of why oxycarbonyl migration is
favored over rearrangement to the N-protected γ-amino
lactone 7 (see Scheme 3), a quantum mechanical investiga-
tion was carried out.
(6) Chult, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. ReV. 1993,
93, 1371-1448.
Applying a THF-solvation model at the B3LYP/6-31+G*
434
Org. Lett., Vol. 3, No. 3, 2001

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
free of charge via the Internet at http://pubs.acs.org.
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.
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