Oxoammonium salts. Part 8: Oxidations in base: Oxidation of O-1 unprotected monosaccharides to lactones using 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate

Article abstract of DOI:10.1016/S0040-4039(01)01950-5

The oxidant, 4-acetylamino-2,2,6,6-tetramethylpiperidine-oxoammonium tetrafluoroborate in pyridine/CH₂Cl₂, is reported to be an excellent reagent for the conversion of hemiacetals to lactones. Specifically, the conversion of 1-O unprotected sugars to their corresponding aldonolactones is achieved in high yields. The basic reaction conditions partially overcome some disadvantages reported for oxoammonium-type oxidants, namely the inability to run the reaction in the presence of acid-labile groups and in the presence of β-oxygens.

Full text of DOI:10.1016/S0040-4039(01)01950-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8793–8796
Oxoammonium salts. Part 8: Oxidations in base: oxidation of
O-1 unprotected monosaccharides to lactones using
4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium
tetrafluoroborate†
Nabyl Merbouh, James M. Bobbitt and Christian Bru¨ckner*
Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, USA
Received 1 August 2001; accepted 16 October 2001
Abstract—The oxidant, 4-acetylamino-2,2,6,6-tetramethylpiperidine-oxoammonium tetrafluoroborate in pyridine/CH2Cl2, is
reported to be an excellent reagent for the conversion of hemiacetals to lactones. Specifically, the conversion of 1-O unprotected
sugars to their corresponding aldonolactones is achieved in high yields. The basic reaction conditions partially overcome some
disadvantages reported for oxoammonium-type oxidants, namely the inability to run the reaction in the presence of acid-labile
groups and in the presence of b-oxygens. © 2001 Elsevier Science Ltd. All rights reserved.
We described in a previous paper,1b the oxidations of
alcohols to the corresponding aldehydes or ketones
with an oxoammonium salt, specifically 4-acetylamino-
2,2,6,6-tetramethylpiperidineoxo-ammonium perchlo-
rate. However, there are limitations to that method:
most seriously, the perchlorate salt turned out to be
explosive.2 Secondly, a limitation noted by us and
others was that a b-oxygen or b-nitrogen inhibited the
reaction.3 For instance, the oxidation of 2-phen-
oxyethanol proceeded to only 7% conversion over 72
h.1b Thirdly, the oxidations were carried out in a mildly
acidic medium (CH2Cl2/silica gel catalysis), meaning
that the method was not applicable to substrates carry-
ing acid labile protecting groups such as most silyl and
acetal groups. Lastly, trisubstituted double bonds
reacted appreciably with the oxidant to form uniden-
tified side products.1b
sized using oxidants such as AgCO3 on Celite, PCC, or
involved multi-step procedures with photochemical key
steps, Swern or Dess–Martin oxidations.8–13
The explosion hazard of the perchlorate salt can be
eliminated by using the tetrafluoroborate salt which
possesses identical oxidizing properties.1b,2,4 The key to
overcoming some of the limitations posed by the origi-
nal reaction conditions and the choice of substrates was
performing the oxidation in the presence of base. Reac-
tion of a hemiacetal with 2 equiv. of oxoammonium salt
in CH2Cl2 in the presence of 2 equiv. of pyridine at
room temperature furnishes the corresponding lactones
overnight in excellent yields (see Table 1). We are not
aware of any report describing the use of oxammonium
salts as stoichiometric oxidants in the presence of base.
Endo and co-worker, however, demonstrated the oxida-
tion of simple cyclic five- and six-membered hemi-
acetals, formed in situ by oxidation of 1,v-diols, to the
corresponding lactones using an oxoammonium chlo-
ride (in the absence of base).5
In this paper, we will describe a method overcoming
some of these limitations, thereby expanding the appli-
cability of the mild, heavy metal-free, convenient and
clean oxoammonium oxidant. We will demonstrate that
the method is an excellent, high yielding and simple way
to prepare aldonolactones from their corresponding O-1
unprotected aldose derivatives. Aldonolactones are key
intermediates in the synthesis of a number of sugar
derivatives of current interest. They have been synthe-
The use of base changes the course of the reaction
compared to that of the acidic counterpart. 2 Equiv. of
oxidant are used (instead of one under acidic condi-
tions) and the oxidant is reduced to a nitroxide (and
not a hydroxyl amine). Thus, its mechanism appears to
be similar to nitroxide catalyzed oxidations using ClO−
as terminal oxidant.6 Scheme 1 shows the overall reac-
tion scheme.
* Corresponding author.
† For Parts 6 and 7, see: Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01950-5

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N. Merbouh et al. / Tetrahedron Letters 42 (2001) 8793–8796
Table 1.
Entry
Substrate
Producta
Isolated yield (%)
Ref.
8
1
95
2,3,4,6-Tetra-O-methyl-D
-glucopyranosee
2
3
4
5
94
97
94
91
9
2,3,4,6-Tetra-O-acetyl-D
-glucopyranosee
10
11
12f
2,3,4,6-Tetra-O-benzyl-D
-glucopyranosee
2,3,5,6-Diisopropylidene-
D
-mannofuranosee
4,6-Benzylidene-2-deoxy-
D
-glucopyranosee
6
80
13
3,4,6-Tri-O-benzyl-D
-glucopyranosee
7
TBMS-O-(CH2)4CH2OH
TBMS-O-(CH2)4CHO
97
14
d
8
9
+aldol product
Incomplete (ꢀ90%)
conversionb,c,d

N. Merbouh et al. / Tetrahedron Letters 42 (2001) 8793–8796
8795
Table 1. (Continued)
Entry
Substrate
Producta
Isolated yield (%)
Ref.
10
–
No reaction after
24 h
1,2,5,6-Diisopropylidene-a-
D
-glucofuranose
11
Product in complex
mixtureb,c,d
1,2,3,4-Diisopropylidene-a-
D
-galactopyranose
a General procedure: About 2 mmol of substrate was dissolved in CH2Cl2 (20 mL) and 2.05 equiv. of pyridine was added, followed by 2.05 equiv.
of 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate. The mixture was stirred overnight, filtered to remove the
precipitated pyridinium tetrafluoroborate, and evaporated to dryness under reduced pressure. The residue was suspended in dry diethyl ether.
Filtration of the suspension recovers almost all of the nitroxide. The filtrate was concentrated to a small volume and passed over a short (ꢀ5×1
cm) column of silica gel. Using diethyl ether as eluent, the product eluted ahead of the orange nitroxide band in all cases investigated.
Evaporation of the main fraction yielded product which was identified by 1H and 13C NMR. The purity of the compounds was assessed by 1H
NMR or GC (GC-MS).
b By 1H NMR.
c By GC.
d By GC–MS.
e Mixture of the a- and b-epimers.
f Compound data for the product, 4,6-benzylidene-2-deoxy-g-gluconolactone have not been reported in Ref. 12: white crystal; mp 156–157°C; 1H
NMR (400 MHz, CDCl3): l 7.54–7.44 (m, 5H, phenyl), 5.64 (s, 1H, H7), 4.49 (dd, 1H, H6), 4.29 (m, 1H, H3), 4.14 (m, 1H, H5), 3.87 (t, 1H,
H6), 3.78 (broad t, 1H, H4), 3.24 (dd, 1H, H2), 2.72 (dd, 1H, H2); 13C NMR (100 MHz, CDCl3): l 168 (C1), 136.4, 129.6, 128.5, 126.3 (phenyl),
102.1 (C7), 80.7 (C4), 68.1, 68.0, 66.5 (C3, C5, C6), 37.7 (C2).
Scheme 1.
Since sugar derivatives are the quintessential b-oxy-
genated compounds, they are ideal substrates to test the
superiority of our novel methodology over our origi-
nally reported protocols. In addition, we have also
tested our new method with compounds that did not
undergo satisfactory reactions in our original work.7
The results are listed in Table 1. All of the products are
known.
sugar hemiacetals are not oxidized under the original
acidic oxidation conditions (as demonstrated by a failed
oxidation attempt of the glucose derivative of entry
1).1b,15 Hence, this oxidation method represents a good
alternative to other methods for the synthesis of aldo-
lactones.8–13 Some features of this oxidation are note-
worthy. Isolated secondary hydroxyl groups in the
sugar ring are not (or very slowly) oxidized and do not
interfere with (fast) hemiacetal oxidations (entries 5, 6,
10). Sugars carrying acid-labile protecting groups can
be oxidized without inadvertent deprotection (entries 4,
5). As well, and in direct contrast to our earlier paper,1b
the TBDMS group is stable under the basic oxidation
conditions (entry 7).
Several conclusions can be drawn from the data com-
piled in Table 1. Fully or partially protected sugar
acetals can be oxidized to the corresponding lactones in
high yields with utmost simplicity (entries 1–6). Thus,
b-oxygens do not inhibit the hemiacetal reactions. Such

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N. Merbouh et al. / Tetrahedron Letters 42 (2001) 8793–8796
Entries 8–11 delineate the limits of the reaction: com-
pounds such as phenoxyethanol oxidize readily but
undergo an aldol condensation (entry 8). Hence, the
reaction conditions are too basic for carbonyls under-
going facile aldolization. Unlike using the acidic proto-
col,1b trisubstituted olefins are not (or are very slowly)
attacked by the oxidant under basic conditions. For
instance, the oxidation of citronellol produces the cor-
responding aldehyde, but the reaction is retarded and
up to 10% of the starting material remained in the
reaction mixture after 24 h reaction time (entry 9). The
oxidation of a primary hydroxyl groups in sugars takes
place, albeit slowly, but does not give a clean product
(entry 11). The effect of b-oxygens on the oxidation
cannot be clearly delineated.
glycols, see: Banwell, M. G.; Bridges, V. S.; Dupuche, J.
R.; Richards, S. L.; Walter, J. M. J. Org. Chem. 1994, 59,
6338–6343.
4. A slightly improved procedure for the making of the
tetrafluoroborate salt is available by contacting J.M.B. by
mail or e-mail: bobbitt@nucleus.chem.uconn.edu.
5. Miyazawa, T.; Endo, T. J. Org. Chem. 1985, 50, 3930–
3931.
6. (a) Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetra-
hedron Lett. 1992, 33, 5029–5032; (b) Review article: de
Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthe-
sis 1996, 1153–1174.
7. Certain oxidations, such as the decanol to decanal, gave
identical results using the acidic as well as the basic
protocol and are not further discussed here.
8. Bihovski, R.; Selick, C.; Giusti, I. J. Org. Chem. 1988, 53,
4026–4031.
9. (a) Binkley, R. W. J. Org. Chem. 1977, 42, 1216–1221; (b)
Senni, D.; Praly, J.-P. Synth. Commun. 1998, 28, 433–441.
10. Brunckova, J.; Crich, D. Tetrahedron 1995, 51, 11945–
11952.
In conclusion, we have demonstrated the applicability
of an oxoammonium salt as an oxidant for the mild
and high yielding conversion of sugar hemiacetals to
their corresponding lactones under mildly basic condi-
tions. This oxidation method was particularly success-
fully applied to the synthesis of aldolactones by
oxidation of O-1 unprotected sugars.
11. Moore, B. S.; Cho, H.; Casati, R.; Kennedy, E.;
Reynolds, K. A.; Mocek, U.; Beale, J. M.; Floss, H. G. J.
Am. Chem. Soc. 1993, 115, 5254–5266.
12. Horigome, M.; Watanabe, H.; Kitahara, T. Tennen Yuki
Kagobutsu Toronkai Koen Yoshishu 1999, 41, 73–78.
(Chem. Abstr. 1999, 132, 279088).
13. Takahashi, T.; Ebata, S.; Yamada, H. Synlett 1998, 4,
381–382.
14. Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.; Villa, M.
Tetrahedron 1999, 55, 8103–8110.
15. This implies that, using the acidic conditions, other oxi-
dizable portions can be oxidized without protection of
the hemiacetal functionality.
References
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