The anomeric Pudovik rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.01.081

The O,O-dibenzyl-S-glycosyl phosphothioite derived from 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-α-d-glucopyranose rearranges under the influence of triethylborane and air to provide the corresponding 1-C-pyranosyl-O,O-dibenzylphosphonothioate, a new

Full text of DOI:10.1016/j.tetlet.2007.01.081

Tetrahedron Letters 48 (2007) 1945–1949
The anomeric Pudovik rearrangement
Spencer Knapp* and Kehinde Ajayi
Department of Chemistry and Chemical Biology, Rutgers—The State University of New Jersey,
610 Taylor Road, Piscataway, NJ 08854-8087, USA
Received 19 December 2006; revised 15 January 2007; accepted 16 January 2007
Available online 20 January 2007
Abstract—The O,O-dibenzyl-S-glycosyl phosphothioite derived from 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-a-D-glucopyra-
nose rearranges under the influence of triethylborane and air to provide the corresponding 1-C-pyranosyl-O,O-dibenzylphosphono-
thioate, a new type of carbohydrate derivative. The isomeric beta phosphothioite is compared, and evidence of a radical chain
mechanism for the Pudovik rearrangement is presented.
Ó 2007 Elsevier Ltd. All rights reserved.
O-GlcNAc transferase (OGT) is a biologically ubiqui-
tous enzyme that promotes the 2-acetamido-2-deoxy-b-
D-glucosylation of serine and threonine residues of a wide
variety of nuclear and cytoplasmic proteins (Fig. 1).1
Despite the importance of OGT in myriad biological
processes and disease states, there is a dearth of OGT
inhibitors for use as probes of its action and effects. As
a component of our search for OGT inhibitors, we exam-
ined the phosphorylation of 3,4,6-tri-O-acetyl-2-acetam-
ido-2-deoxy-1-thio-a-D-glucopyranose (1), and have
uncovered a new, anomeric, version of the Pudovik rear-
rangement of phosphothioites to phosphonothioates.
The reactions of 1 with O,O-dialkyl(N,N-diisopropyl)-
phosphoramidites under acidic activation with tetrazole
Figure 1. Glycosyl transfer to serine/threonine catalyzed by O-
GlcNAc transferase (OGT).
(Table 1), followed by oxidation with tert-butylhydro-
peroxide,2–5 gave good to poor yields of the desired
O,O-dialkyl-S-glycosylphosphothioates 2a–c, as a func-
tion of the O-alkyl substituent (allyl, methyl, or benzyl,
ucts 3a–c reflect a Pudovik rearrangement (Scheme 1),
wherein the phosphothioite S-substituent (here, gluco-
pyranosyl) has migrated to phosphorus. This reaction,
which may be viewed as a version of the Arbuzov
respectively). These products were characterized by their
1
mass, H NMR (JH-1/H-2 ꢀ 5 Hz), 13C NMR, and 31P
NMR (diagnostic signal near 24 ppm) spectra. In addi-
tion, 2 was accompanied by varying amounts of the
rearranged O,O-dialkyl-P-glycosyl-phosphonothioates
rearrangement, has been previously studied by Pudovik
and Pudovik and their co-workers,7–14 as well as by
3a–c (Table 1, entries 1–3). These products were charac-
others.15–18 The Arbuzov rearrangement19 itself encom-
1
terized by their mass, H NMR, 13C NMR, and 31P
passes a broad family of phosphite to phosphonate
NMR (diagnostic signal near 88 ppm) spectra. The
transformations initiated variously by alkylation, heat,
alpha configurations of 3 were indicated by their large
light, or radicals.
trans-diaxial H-2/P couplings (e.g., 31 Hz for 3c,
whereas the beta isomer should show ꢀ10 Hz).6 Prod-
Most prior examples of the Pudovik rearrangement
occur upon exposure of the phosphothioite to oxygen
or air, and are postulated to be radical processes.13
*
Corresponding author. Tel.: +1 732 445 2627; fax: +1 732 445
5312; e-mail: knapp@rutchem.rutgers.edu
Accordingly, the reaction of 1 with O,O-dibenzyl(N,
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.081

1946
S. Knapp, K. Ajayi / Tetrahedron Letters 48 (2007) 1945–1949
Table 1. S-Phosphorylations with O,O-dialkyl N,N-diisopropylphosphoramidites
Entry
R
Acid promoter
[O]
Yield of 2
Yield of 3
1
2
3
4
5
6
Allyl
Tetrazole
Tetrazole
Tetrazole
Tetrazole + BHT
Tetrazole, 0 °C
NMBÆHOTf
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
Et3B, air
m-CPBA
62% (2a)
5% (2b)
—
41% (2c)
<1%
—
Methyl
Benzyl
Benzyl
Benzyl
Benzyl
45% (3b)
48% (3c)
13% (3c)
79% (3c)
—
72% (2c)
The formation of phosphonothioates 3 can be accommo-
dated by the radical chain process shown in Scheme 3.
Initial S-phosphitylation of 1 to give the intermediate
phosphothioite 5 is followed, upon addition of initiator,
by a radical initiation step consisting of the removal of
the phosphothiyl fragment 7 and formation of the
3,4,5-O-triacetyl-2-acetamido-2-deoxy-D-glucopyranosyl
anomeric radical 6.22 Subsequent and analogous reaction
of 6 with 5 in a propagation step provides product 3 and
regenerates 6. The alpha anomeric stereochemistry of 3
reflects the tendency (with ample precedent) of D-gluco-
pyranosyl anomeric radicals such as 6 to react with
almost exclusive alpha stereoselectivity.23
Scheme 1. A prototypal Pudovik rearrangement.
N-diisopropyl)phosphoamidite was repeated, but with
the radical inhibitor 2,6-di-tert-butyl-4-methylphenol
(BHT) added during the oxidation step. The result
(entry 4) was an increase in the percentage of phospho-
thioate 2c, and less rearrangement to 3c. Very likely the
O-allyl substituents in entry 1 also inhibit radical prop-
agation, accounting for the preferred formation of 2a. In
contrast, the Pudovik rearrangement product 3c was
formed almost exclusively when the oxidation was
promoted by the radical initiator combination20 of
triethylborane and air (entry 5). Modifications in the
promoter21 and the oxidation conditions allowed the
isolation of the phosphorylation product 2c in good
yield to the exclusion of the rearrangement (entry 6,
NMB = N-methylbenzimidazole). The oxidant m-chloro-
perbenzoic acid probably operates by a polar mecha-
nism, minimizing the formation of 3c. Alternatively,
the S-glycosylphosphothioate product 4 was prepared
without oxidation by treating 1 directly with base and
diethyl chlorophosphate (Scheme 2). The latter reaction
failed in the O,O-dibenzyl version; instead, benzyl 3,4,
6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-a-D-gluco-
pyranoside was formed in 27% yield as the result of
thiolate S-benzylation.
A radical fragmentation/recombination mechanism has
been advanced for the Pudovik rearrangement;13 to
our knowledge the stereochemical consequences at the
migrating carbon have not previously been investigated.
Application of the reaction conditions of entry 5 to the
Scheme 3. Radical chain mechanism for the Pudovik rearrangement of
5.
Scheme 2. Direct phosphorylation of mercaptan 1.

S. Knapp, K. Ajayi / Tetrahedron Letters 48 (2007) 1945–1949
1947
phosphitylation/oxidation of the corresponding beta
anomeric mercaptan 8 led, after chromatography, to
the array of products shown in Scheme 4. The alpha
phosphothioate 3c matched the compound obtained
from 1. The corresponding beta phosphonothioate,
which if formed should have eluted near 3c, was neither
isolated nor detected by 31P or 1H NMR analysis of the
crude reaction mixture or chromatography fractions.
The beta phosphodithioate 9 was characterized by its
31
1H (with COSY analysis), 13C, P, and mass spectra.24
Its beta configuration was established by the large H-1/
H-2 coupling (10 Hz). The oxazoline 10 and 3,4,5-tri-
O-acetyl-2-acetamido-1,5-anhydro-2-deoxy-D-glucitol 11
were identified by spectroscopic comparison with the
known compounds.
Scheme 5 shows pathways that rationalize the formation
of 3c, 9, 10, and 11 from 8. Following phosphitylation of
8 analogous to that of 1, the phosphothioite 13 reacts
with the radical initiator to produce the same 3,4,5-O-tri-
acetyl-2-acetamido-2-deoxy-D-glucopyranosyl anomeric
radical 6. The analogous chain propagation step involv-
ing 6 and 13 likewise produces the alpha phosphonothio-
ate 3c (the Pudovik rearrangement product). To the
extent that starting mercaptan 8 remains, reaction of 6
with 8 gives thiyl radical 14 by hydrogen atom transfer,
and a chain propagation step involving 14 and 13 leads
to the phosphodithioate 9. Dithio products analogous
to 9 have been isolated previously from the Pudovik rear-
rangement reaction mixtures, particularly when excess
mercaptan is present.4,11 The other (reduced) product
from the latter process has not been reported, but in this
case can be isolated in the form of tri-O-acetyl-2-acet-
Scheme 5. Proposed pathways for the beta mercaptan phosphityla-
tion/oxidation.
amido-1,5-anhydro-2-deoxy-D-glucitol 11. While 9 can
come from unreacted 8, an additional reductive pathway
(e.g., 6 ! 11) is likely present to account for the fact that
there is formed more 11 than 9.
Some of the (P-oxidized) phosphothioate 12 probably
formed in competition with 3c, as has been noted in
other systems,4,11,18 and in the entries in Table 1.
Circumstantial evidence for 12 was found in the crude
reaction mixture: 31P NMR analysis showed a phospho-
thioate peak at 25.1 ppm (compare 2c at 24.4), and the
mass spectrum featured a prominent signal at m/z 646,
which corresponds to [M+Na]+ for 12. Instead of 12,
however, oxazoline 10 was isolated in significant
amounts, even though it was not present in the crude
product mixture (e.g., no H-4 of 10 at or near
4.81 ppm). Oxazoline 10 could be formed by acid-
promoted cyclization of 12 during chromatography.
The formation of 3c, independent of the stereochemistry
of the precursor phosphothioite (5 or 13) and to the
apparent exclusion of the beta stereoisomer, provides
strong evidence that the same anomeric radical (6) is
the intermediate in both reactions. Formation of the
reduction product 11 is also rationalized by invoking 6
as the intermediate.
The differences in the phosphitylation/oxidation reac-
tions of 1 and 8 merit comment. Although the reaction
Scheme 4. Phosphitylation/oxidation/rearrangement of the beta mer-
captan 8.

1948
S. Knapp, K. Ajayi / Tetrahedron Letters 48 (2007) 1945–1949
17. Despax, C.; Navech, J. Phosphorus Sulfur Silicon 1991, 56,
105–115.
18. Brill, W. K.-D.; Nielsen, J.; Caruthers, M. H. J. Am.
Chem. Soc. 1991, 113, 3972–3980.
19. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981,
81, 415–430.
20. Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415–
3434.
21. Hyodo, M.; Ando, H.; Nishitani, H.; Hattori, A.;
Hayakawa, H.; Kataoka, M.; Hayakawa, Y. Eur. J.
Org. Chem. 2005, 5216–5223.
22. Glucopyranosyl radicals similar to 6 are thought to
exist in a boat conformation: Sustmann, R.; Korth,
H.-G. J. Chem. Soc., Faraday Trans. 1 1987, 83, 95–
105.
23. Grant, L.; Liu, Y.; Walsh, K. E.; Walter, D. S.; Gallagher,
T. Org. Lett. 2002, 4, 4623–4625; Kahne, D.; Yang, D.;
Lim, J. J.; Miller, R.; Pasguaga, E. J. Am. Chem. Soc.
1988, 110, 8716–8717.
conditions are very similar, the relative rates of initial
phosphitylation differ, with alpha mercaptan 1 being
qualitatively more reactive according to TLC analysis.
The relative rates of conversion of the phosphothioites
5 and 13 to the anomeric radical 6 may also differ,
although the related 2,3,4,6-tetra-O-acetyl-D-glucopyr-
anosyl anomeric radical is formed from both the alpha
and beta anomeric chloride precursors at about the
same rate (Cl abstraction by tributyltin radical).25 Final-
ly, autooxidation at phosphorus26 of 5 and 13 to the
respective phosphothioates 2c and 12 (competing with
formation of 6) may occur at different rates. A faster
rate of oxidation of 13 would account for the formation
of more oxidized product 12 (and hence 10) compared
with 2c under these conditions.27
24. The formation of a related dithiophosphate has been
inferred by 31P NMR analysis: Kudelska, W.; Michalska,
M. Synthesis 1995, 1539–1544.
25. Giese, B.; Dupuis, J. Tetrahedron Lett. 1984, 25, 1349–
1352.
Acknowledgments
We are grateful to NIH (AI055760) for financial sup-
port. K.A. thanks the GAANN program for a graduate
fellowship.
26. Hwang, W.-S.; Yoke, J. T. J. Org. Chem. 1980, 45, 2088–
2091.
27. Experimental procedures and spectral data. Compound 3c:
Dibenzyl N,N-diisopropylphosphoramidite (0.09 mmol,
30.1 mg) was added to a solution of 1 (0.05 mmol,
18.6 mg) and tetrazole (0.15 mmol, 10.8 mg) in acetonitrile
(0.80 mL) at 0 °C. After 2 h at 23 °C, triethylborane (1 M
in hexanes, 0.052 mmol, 5.2 mg) was added, and a slow
stream of compressed air was bubbled through the
reaction for 15 min. Concentration and then chromatog-
raphy with 2:3 ethyl acetate/hexanes as the eluant
provided 24 mg of 3c: Rf 0.27 (1:1 ethyl acetate/hexanes);
1H NMR (400 MHz, CDCl3) (all d in ppm, then multi-
plicity, J in Hz, integral or assignments based on COSY
analysis) 7.31–7.35 (m, Ph–H’s), 5.96 (d, 8.4, –NHAc),
5.82 (dd, 8.4, 10.4, H-3), 5.12 (dd, 11.6, 13.2, –CHPh), 5.07
(app t, 11.2, –CHPh), 5.03 (app t, 11.6 –CHPh), 5.03 (t,
9.6, H-4), 4.93 (dd, 9.2, 11.2, –CHPh), 4.69 (dd, 6.8, 9.2,
H-1), 4.55 (dddd, 6.8, 8.4, 10.0, 31.2, H-2), 4.34 (dddd, 2.4,
5.2, 8.4, 9.6, H-5), 4.12 (dd, 5.2, 12.4, H-6), 3.98 (dd, 2.4,
12.4, H-60), 2.02 (s, 2 –COCH3). 2.01 (s, –COCH3), 1.57 (s,
–COCH3); 13C NMR (100 MHz) 171.2, 170.6, 170.2,
169.2, 135.5 (d, 6.1), 135.4 (d, 6.1), 128.8, 128.74 (3C’s),
128.68 (2C’s), 128.6 (2C’s), 128.4 (2C’s), 75.1 (d, 120.6),
72.8 (d, 2.3), 70.1, 69.2 (d, 7.6), 67.9, 67.7 (d, 7.6), 61.8,
50.3 (d, 2.3), 22.7, 20.7, 20.64, 20.62; 31P NMR (121 MHz)
88.24; ESI-MS m/z 630 MNa+. Compound 2c: A solution
of 1 (1.42 mmol, 514 mg) in dichloromethane (3.14 mL)
was added via a cannula to a solution of dibenzyl N,N-
diisopropylphosphoramidite (5.94 mmol, 2.05 g), 1-meth-
ylbenzimidazolium triflate (5.66 mmol, 1.60 g) and pow-
References and notes
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˚
dered, activated 4-A molecular sieves in 1:1
dichloromethane/acetonitrile (6.29 mL), held at ꢁ52 °C
during addition. After 5 h at ꢁ25 °C, the reaction was
cooled to ꢁ50 °C and m-CPBA (7.08 mmol, 1.22 g) was
added. The reaction was stirred for 1 h while warming to
23 °C. The mixture was filtered through Celite, diluted
with dichloromethane, washed sequentially with 20% aq
Na2SO3, 1 N aq HCl, and water, dried over MgSO4, and
then concentrated. Chromatography with 1:4 ethyl ace-
tate/dichloromethane as the eluant afforded 640 mg (72%)
of 2c as a sticky solid: Rf 0.36 (1:1 ethyl acetate/
dichloromethane); 1H NMR 7.36–7.34 (m, 10H), 6.01
(dd, 5.0, 11.6, H-1), 5.73 (d, 8.4, –NHAc), 5.16 (t, 9.6, H-
4), 5.14–5.09 (m, 4 –CHPh), 5.03 (dd, 10.8, 9.6, H-3), 4.56
16. Danchenko, M. N.; Sinitsa, A. D. J. Gen. Chem. USSR,
Engl. Transl. 1986, 56, 1567–1570.

S. Knapp, K. Ajayi / Tetrahedron Letters 48 (2007) 1945–1949
1949
(ddd, 10.8, 8.4, 4.8, H-2), 4.16 (dd, 13.6, 3.8, H-6), 4.19–
4.13 (m, H-5), 3.91 (dd, 13.6, 3.8, H-6), 2.04, 2.03. 1.98,
1.83 (s, 3H each, –COCH3); 13C NMR (assignments based
on HMQC analysis) 171.6, 170.5, 169.9, 169.1, 135.0,
134.8, 128.9 (2C’s), 128.7 (4C’s), 128.3 (2C’s), 128.2 (2C’s),
85.7 (d, 3.0, C-1), 70.9 (C-3), 70.6 (C-5), 69.7 (d, 6.7,
–CH2Ph), 69.5 (d, 6.7, –CH2Ph), 67.4 (C-4), 61.4 (C-6),
52.6 (d, 6.6, C-2), 23.0, 20.7, 20.6 (2C’s);31P NMR 24.44;
ESI-MS m/z 646 MNa+. Compound 4: Triethylamine
(0.55 mmol, 55.6 mg) was added to a solution of 1
(0.46 mmol, 166.1 mg) and diethyl chlorophosphate
(0.55 mmol, 94.7 mg) in acetonitrile (9.1 mL), held at
ꢁ40 °C during addition. After 4 h at 23 °C, the reaction
was diluted with ethyl acetate, washed with 10% aq
NaHCO3, dried, concentrated, and then chromatographed
with 7:3 ethyl acetate/dichloromethane as the eluant to
afford 161 mg (70%) of 4 as a white solid, mp 108–111 °C:
42.1 mg) in degassed acetonitrile (0.6 mL) was added to
a solution of tetrazole (0.42 mmol, 29.3 mg) and dibenzyl
N,N-diisopropylphosphoramidite (0.20 mmol, 68.0 mg) in
degassed acetonitrile (0.6 mL) at 0 °C. After 3 h at 23 °C,
triethylborane (1 M in hexanes, 0.12 mmol, 11.4 mg) was
added, and a slow stream of compressed air was bubbled
through the reaction for 20 min. The reaction was stirred
overnight, and then diluted with ethyl acetate, washed
with 5% aq NaHCO3, concentrated, and then chromato-
graphed with 2:3 ethyl acetate/hexanes, then ethyl acetate,
as the eluant, to give the following products in order of
elution. Compound 3c, 8.2 mg. Compound 9, 10.4 mg, Rf
0.22 (1:1 ethyl acetate/hexanes); 1H NMR 7.37–7.32 (m,
Ph–H), 5.50 (d, 9.5, –NHAc), 5.16 (dd, 11.5, 10.0,
–CHPh), 5.14–5.11 (m, 2 –CHPh), 5.09 (t, 10.0, H-4),
5.09 (dd, 11.5, 10.0, –CHPh), 5.06 (dd, 10.0, 9.5, H-3), 4.97
(dd, 14.0, 10.5, H-1), 4.35 (q, 10.0, H-2), 4.12 (dd, 12.5,
5.0, H-6), 4.04 (dd, 12.5, 2.0, H-60), 3.69 (ddd, 10.0, 5.0,
2.0, H-5), 2.03 (s, 2 –COCH3), 1.97 (s, –COCH3), 1.89 (s,
–COCH3); 13C NMR 171.1, 170.6, 170.0, 169.2, 135.4 (d,
9.3), 135.1 (d, 8.8), 128.7, 128.64, 128.61 (2C’s) 128.60
(2C’s), 128.2 (2C’s), 128.1 (2C’s), 87.4 (d, 3.3), 73.81,
73.80, 69.74 (d, 6.5), 69.69 (d, 6.4), 67.8, 61.9, 53.2 (d,
10.6), 23.1, 20.6 (3C’s); 31P NMR 94.99; ESI-MS m/z 662
MNa+. Compound 10, 12.5 mg, Rf 0.30 (ethyl acetate).
Compound 11, 11.2 mg, Rf 0.23 (ethyl acetate).
1
Rf 0.25 (1:19 methanol/dichloromethane); H NMR 5.89
(dd, 4.8, 12.0, 1H), 5.87 (d, 8.4, 1H), 5.15 (t, 9.6, 1H), 5.01
(dd, 10.8, 9.6, 1H), 4.53 (ddd, 11.1, 8.7, 5.1, 1H), 4.28–4.08
(m, 7H), 2.06 (s, 3H), 2.04 (s, 6H), 1.94 (s, 3H), 1.35 (ddd,
6.6, 3.3, 0.6, 6H); 13C NMR 171.7, 170.6, 170.0, 169.2,
85.7 (d, 3.4), 71.2, 70.8, 67.8, 64.6 (d, 6.3), 64.5 (d, 6.3),
61.9, 52.3 (d, 6.5), 23.5, 21.0 (2C’s), 20.9, 16.5 (d, 2.3), 16.4
(d, 2.3); 31P NMR 23.25; ESI-MS m/z 522 MNa+.
Phosphitylation of 8:
A solution of 8 (0.12 mmol,