Synthesis of β-C-GlcNAc ser from β-C-Glc ser

Article abstract of DOI:10.1021/jo401044x

The glycosylation of proteins, specifically installation of O-GlcNAc on Ser/Thr residues, is a dynamic control element for transcription repression, protein degradation, and nutrient sensing. To provide homogeneous and stable structures with this motif, the synthesis of a C-linked mimic, C-GlcNAc Ser, has been prepared from the C-Glc Ser by a double inversion strategy using azide to insert the C-2 nitrogen functionality. The C-Glc Ser was available by a ring-closing metathesis and hydroalkoxylation route.

Full text of DOI:10.1021/jo401044x

Note
pubs.acs.org/joc
Synthesis of β‑C‑GlcNAc Ser from β‑C‑Glc Ser
Ernest G. Nolen,* Leyan Li, and Kristopher V. Waynant
Department of Chemistry, Colgate University, Hamilton, New York 13346, United States
S
* Supporting Information
ABSTRACT: The glycosylation of proteins, specifically installation of O-GlcNAc on Ser/Thr residues, is a dynamic control
element for transcription repression, protein degradation, and nutrient sensing. To provide homogeneous and stable structures
with this motif, the synthesis of a C-linked mimic, C-GlcNAc Ser, has been prepared from the C-Glc Ser by a double inversion
strategy using azide to insert the C-2 nitrogen functionality. The C-Glc Ser was available by a ring-closing metathesis and
hydroalkoxylation route.
he syntheses of biochemically robust glycosyl amino acids
that may be incorporated into peptide constructs are
Our initial strategy to forge an all-carbon linkage was developed
around an olefin cross-metathesis (CM) approach,12 but C-
vinyl glycosides have low reactivity with vinyl glycines,13
although related CMs have been successful.14,15 We then
envisioned a repositioning of the alkene to allow for greater
metathesis reactivity, as found in the heptenitol 2 (Scheme 1).
T
important for the development of tools to assist in
glycobiological studies. Because protein glycosylation is a
post-translational event and thus beyond the direct governance
of DNA control, and because some glycosylations are highly
dynamic, access to pure and stable glycopeptides has been of
synthetic interest since 19751 and a review of artificial
glycopeptides by Dondoni in 20002 generated considerable
attention.
Scheme 1. Retrosynthetic Analysis of β-C-GlcNAc Ser via β-
C-Glc Ser
One of the most common glycoprotein motifs is a β-O-
GlcNAc Ser/Thr linkage found on a wide variety of nuclear and
cytoplasmic proteins.3,4 This single carbohydrate modification
exhibits a reciprocal relationship with phosphorylation for the
regulation of protein activity and degradation, and nutrient
sensing.5−7 In view of these biochemical activities, the
misregulation of O-GlcNAc has been implicated in cancer,
neurodegenerative disorders, and type-II diabetes.
Although the interplay between phosphorylation and O-
GlcNAc-ylation has been established, it is surprising that
phosphorylation is mediated by over 650 enzymes,8 while O-
GlcNAc is maintained by only two: O-GlcNAc transferase and
O-GlcNAc-ase. Due to the widespread deployment of these
enzymes with multiple physiological roles, inhibition of the O-
GlcNAc enzymes, while illustrative, is of limited therapeutic use
due to likely side effects. Therefore, the development of more
localized downstream mimetics, such as targeted mimics of O-
GlcNAc modified peptides, may prove useful. For this reason,
we have directed our attention to the synthesis of the
metabolically more stable β-C-GlcNAc Ser 1.
Thus, our retrosynthetic plan derives the β-C-GlcNAc Ser 1
from a double inversion with the C-2 acetamido introduced
onto β-C-Man Ser as the azide. The axial hydroxyl of the
manno-isomer would itself be the product of an inversion of the
C-2 equatorial hydroxyl of β-C-Glc Ser 3. Structure 3
represents a stable mimic of β-O-Glc Ser, a core carbohydrate
Three previous syntheses of β-C-GlcNAc Ser 1 have been
reported and all began with a C-2 nitrogen (glycoside
numbering) functionality in place prior to the elaboration of
the carbon-linkage to the amino acid moiety by a Wittig,9 a
Received: May 16, 2013
Ramberg−Backlund rearrangement,10 and an ethynylation.11
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© XXXX American Chemical Society
A
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Note
Scheme 2. Synthesis of β-C-Glc Ser
Scheme 3. Synthesis of β-C-GlcNAc Ser
found in the epidermal growth factor (EGF)-like domain
associated with blood clotting factors, in fetal antigen-1, and in
Notch1;16,17 also, stability issues of β-O-Glc Ser peptides have
been reported to be troublesome.18 The β-C-Glc Ser 3 was
prepared according to our previously reported method19 via an
intramolecular mercury-mediated hydroalkoxylation on the
(Z)-alkene 4 obtained from esterification and RCM, by way
of the heptenitol 2 and (S)-allyl glycine 5.
chemical preference met with failure. So, we turned our
attention to a double-inversion strategy to introduce the C-2
acetamido group (Scheme 3). Toward that end, the β-C-Glc
Ser 3 was oxidized with Dess-Martin periodane, and following
workup it was reduced directly with NaBH4 to give β-C-Man
Ser 10 with complete stereocontrol.25 Reducing agents such as
L-selectride, known to add by an equatorial approach also
worked, but care had to be taken not to reduce the methyl ester
as well. Although purification of the intermediate ketone was
possible, this carbonyl had a tendency to hydrate and form the
gem-diol during chromatography unnecessarily complicating its
purification, so this material was telescoped into the reduction
step.
Activation of the axial C-2 hydroxyl was required to allow for
an inversion by azide. Unfortunately, triflic anhydride led to loss
of the N-Boc protecting group either directly26 or by
advantageous acid, and formation of the mesylate gave
incomplete reactions. Gratifyingly the diphenylphosphoryl
azide under Mitsunobu condtions27 gave a clean reaction
leading to a 73% yield of the azide 11. Global deprotection of
the benzyl ethers with concomitant reduction of the azide was
initially problematic even when taking care to acetylate the
catalyst-poisoning amine at an early stage of the process before
attempting the exhaustive hydrogenolysis.10 Use of methanol as
a solvent or cosolvent in the initial reduction of the azide led to
small amounts of N-methylation easily observed by MALDI
analysis of the crude reaction mixture. Optimized conditions
required initial hydrogenation using 10% Pd/C in pyridine to
selectively reduce the azide only.28 Partial acetylation of the
newly generated amine and subsequent hydrogenolysis using
20% Pd(OH)2/C Degussa type in tBuOH/H2O led overnight
to complete debenzylation. Following acetylation in pyridine,
the target β-C-GlcNAc Ser 1 was formed in 65% yield over the
four steps. It is important to note the ability to selectively
Following our earlier report (Scheme 2), the readily available
Glc-configured heptenitol 2 was esterified with N-Boc-allyl
glycine 5 to give a nonselective esterification, along with ∼6%
diester formation. The monoesters 6 and 7, taken as a mixture,
were treated with 5 mol % of the Grubbs second generation
catalyst to afford the ring-closing metathesis products in 89−
94% yield. The resulting lactone mixture, 8 and 9, underwent
methanolysis to converge on the identical Z-alkene 4 in 88%
yield, as we had reported previously. The stereoselective
cyclization to the pyran was accomplished with mercury(II)
trifluoroacetate, followed by in situ demercuration using
20
LiBH4 and BEt3.21 These improved conditions consistently
furnished consistent results (>80% yields) by avoiding workup
of the organomercury intermediate and the procedural
simplicity of adding LiBH4 as a solution versus our previous
attempts to add solid NaBH4 to a −78 °C reaction mixture.
The stereochemical outcome is driven by allylic 1,3-strain from
the Z-alkene and overrides the inside-alkoxy effect commonly
observed in electrophilic cyclizations with an allylic hydrox-
yl.19,22
With β-C-Glc Ser 3 in hand, we explored an oxime route to
introduce the nitrogen functionality. Oxidation of the C-2
hydroxyl and benzyloxime formation went smoothly, but
23,24
reduction with NaCNBH3 and BF3·OEt2
gave the axial
benzyloxyamine product with the mannose-configuration.
Other attempts to overcome this substrate-controlled stereo-
B
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Note
= 8.8 Hz, 1H, H-3), 3.89 (t, J = 9.2 Hz, 1H, H-4), 3.84 (m, 1H, H-1),
3.8−3.7 (m, 3H), 3.74 (s, 3H, OMe), 1.95 (bm, 2H), 1.80 (bm, 2H),
1.46 (s, 9H, tBu). 13C NMR (CDCl3) δ 202.7, 173.1, 155.5, 137.9,
137.8, 137.6, 129.0−127.7, 86.6, 80.0, 79.9, 79.8, 79.1, 75.0, 73.8, 73.5,
68.9, 53.0, 52.3, 28.3, 28.0, 24.3. IR 3438, 1740, 1710 cm−1. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C37H45NO9Na 670.2992; found
670.2988.
reduce the azide in the presence of the benzyl ethers so as to
afford the opportunity to acylate the amino at this point.
Several groups have successfully produced labeled variants of
O-GlcNAc for biochemical assays through alternative acylations
on the C-2 amine;29,30 hence, this work allows the opportunity
to tag the amine of our more robust C-linked isostere.
4
1
The C-linked GlcNAc-β-Ser clearly resides in the C1 chair
β-C-Man Ser 10. [α]D +1.6 (c 2.5, CHCl3). H NMR (CDCl3) δ
conformation like its O-linked counterpart judged by triplet
coupling patterns for H-3 and H-4 due to axial−axial couplings
with neighboring protons. Most interestingly, H-2 is an
apparent quartet (J = 9.8 Hz) due to the axial couplings and
to the approximate 180°-dihedral relation to the NH of the
acetamide. Conformational work, both NMR31,32 and X-ray,33
on O-GlcNAc all highlight this general orientation of the
acetamide, which may be a key presentation mode for this
carbohydrate. A recent report on the X-ray structure of OGT as
a binary and ternary complex with UDP and a peptide is
noteworthy, but therein the authors regret that no complex
with O-GlcNAc was achieved due to hydrolysis of the
substrate.34
7.5−7.2 (m, 15H, 3 × Bn), 5.12 (bd, J = 8.3 Hz, 1H, NH), 4.86 (d, J =
10.8 Hz, 1H, Bn), 4.75 (d, J = 11.6 Hz, 1H, Bn), 4.69 (d, J = 11.6 Hz,
1H, Bn), 4.63 (d, J = 12.2 Hz, 1H, Bn), 4.56 (d, J = 12.2 Hz, 1H, Bn),
4.54 (d, J = 10.8 Hz, 1H, Bn), 4.34 (m, 1H, H-α), 3.90 (m, 1H, H-2),
3.85−3.66 (m, 3H), 3.74 (s, 3H, OMe), 3.61 (dd, J = 3.3, 9.1 Hz, 1H,
H-3), 3.40 (ddd, J = 1.9, 4.96, 9.8 Hz, 1H, H-5), 3.36 (m, 1H, H-1),
2.39 (bs, 1H, OH), 1.93 (m, 3H), 1.64 (m, 1H), 1.46 (s, 9H, tBu). 13C
NMR (CDCl3) δ 173.2, 155.4, 138.2, 138.2, 137.7, 128.5−127.5, 83.3,
79.8, 79.1, 77.1, 75.1, 74.6, 73.4, 71.6, 69.3, 68.3, 53.1, 52.3, 28.9, 28.3,
26.7. IR 3566, 3440, 1736, 1710 cm−1. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C37H47NO9Na 672.3148; found 672.3150.
(S)-Methyl 4-((2S,3S,4R,5S,6R)-3-azido-4,5-bis(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2yl)-2-((tert-butoxy-
carbonyl)amino)butanoate, 11. At rt, diphenylphosphoryl azide (178
μL, 0.82 mmol) was added over 15 min to a solution of the alcohol 10
(162 mg, 0.25 mmol), DEAD (131 μL, 0.82 mmol), triphenylphos-
phine (215 mg, 0.82 mmol) in THF (3.5 mL) and stirred 26 h. The
reaction mixture was concentrated onto SiO2 and flash chromato-
graphed (10 to 30% EtOAc/hexanes) to yield 119 mg (73%) as a
cloudy oil. [α]D −26 (c 2.5, CHCl3). 1H NMR (CDCl3) δ 7.5−7.2 (m,
15H, 3 × Bn), 5.12 (d, J = 8.4 Hz, 1H, NH), 4.91 (d, J = 10.7 Hz, 1H,
Bn), 4.87 (d, J = 10.7 Hz, 1H, Bn), 4.81 (d, J = 10.9 Hz, 1H, Bn), 4.62
(d, J = 12.2 Hz, 1H, Bn), 4.59 (d, J = 10.9 Hz, 1H, Bn), 4.54 (d, J =
12.2 Hz, 1H, Bn), 4.37 (m, 1H, H-α), 3.75 (s, 3H, OMe), 3.75−3.62
(m, 2H, H-6), 3.66 (t, J = 9.4 Hz, 1H, H-4), 3.57 (t, J = 9.1 Hz, 1H, H-
3), 3.37 (dt, J = 3.0, 9.7 Hz, 1H, H-5), 3.22 (t, J = 9.5 Hz, 1H, H-2),
3.09 (bdd, J = 8.3, 9.5 Hz, 1H, H-1), 1.91 (m, 3H), 1.59 (m, 1H), 1.47
(s, 9H, tBu). 13C NMR (CDCl3) δ 173.2, 155.4, 138.1, 137.9, 137.8,
128.5−127.7, 85.4, 79.9, 79.0, 78.3, 77.3, 75.6, 74.9, 73.5, 68.7, 66.5,
53.1, 52.3, 28.3, 28.3. IR 3440, 2110, 1740, 1710 cm−1. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C37H46N4O8Na 697.3213; found
697.3214.
(2R,3S,4R,5S,6S)-5-Acetamido-2-(acetoxymethyl)-6-((S)-3-((tert-
butoxycarbonyl)amino)-4-methoxy-4-oxobutyl)tetrahydro-2H-
pyran-3,4-diyl diacetate, 1. The catalyst Pd/C (10%, 1 × weight of
the starting material) was added to a solution of the tri-O-benzyl azido
C-glucoside 11 (24 mg, 0.034 mmol) in pyridine (3.5 mL) under Ar.
The reaction flask was evacuated and saturated with H2 (by means of a
H2-filled balloon) three times. The suspension was rapidly stirred for 2
h. MALDI analysis indicated complete consumption of the azide. The
mixture was filtered through a polytetrafluoroethene (PTFE) syringe
filter (25 mm diameter, 0.2 μm pore size) and washed with pyridine.
The solvent was coevaporated with toluene and dried in vacuo for
several hours. The residue was stirred with Ac2O (0.5 mL) for 1 h and
then concentrated. The mixture was placed back under hydrogenation
conditions as above, but with Pd(OH)2/C (20%, 1 × weight of the
starting material) in tBuOH:H2O (6:1, 2.8 mL) and left to stir 18 h.
MALDI analysis confirmed the loss of all benzyl protecting groups.
The mixture was filtered through a PTFE syringe filter and washed.
Solvents were coevaporated with toluene and dried in vacuo. A
solution of the crude product in Ac2O (0.4 mL) and pyridine (0.8 mL)
was stirred 12 h. This mixture was concentrated onto SiO2 and
chromatographed (75% EtOAc/hexanes to 100% EtOAc) to give a 12
mg (65%) as a white solid. Mp = 177−180 °C. [α]D −23 (c 1.9,
CHCl3). 1H NMR (CDCl3) δ 5.49 (bd, J = 9.5 Hz, 1H, NHAc), 5.21
(bd, J = 8.3 Hz, 1H, NHBoc), 5.08 (t, J = 9.5 Hz, 1H, H-4), 5.02 (t, J =
9.5 Hz, 1H, H-3), 4.23 (dd, J = 5.2, 12.2 Hz, 1H, H-6a), 4.22 (m, 1H,
H-α), 4.11 (dd, J = 2.3, 12.2 Hz, 1H, H-6b), 4.05 (q, J = 9.8 Hz, 1 H,
H-2), 3.76 (s, 3H, OMe), 3.61 (m, 1H, H-5), 3.42 (bdd, J = 7.9, 8.4
Hz, 1H, H-1), 2.11 (s, 3H, OAc), 2.05 (bs, 6H, 2 × OAc), 2.01 (m,
1H, H-βa),1.96 (s, 3H, NHAc), 1.76 (m, 2H, H-βb and H-γa), 1.60
(m, 1H, H-γb), 1.46 (s, 9H, tBu). 13C NMR (CDCl3) δ 173.2, 171.6,
In conclusion, we have demonstrated that the ring-closing
metathesis and pyran cyclization approach can take advantage
of the free C-2 hydroxyl for the synthesis of a C-linked
analogue of the biochemically important O-GlcNAc and that
initial NMR indications corroborate it as a true isosteric mimic.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were carried out
under an argon atmosphere using oven-dried glassware. Anhydrous
THF, toluene, and dichloromethane were obtained from activated
commercial columns. Thin-layer chromatography was performed using
commercially prepared 60-mesh silica gel plates, and visualization was
achieved with UV light (254 nm) and an acidic phosphomolybdic acid,
cerium(IV) sulfate stain. Preparative chromatographic separations
were performed on silica gel (0.040−0.063 mm). Optical rotations
were measured using a polarimeter at ambient temperature in
chloroform in a 0.25 dm cell and are reported in 10−1 deg cm2 g−1.
Infrared (IR) spectra were recorded as a chloroform solution. All
NMR spectral assignments were determined by H (400 MHz), 13C
1
(100 MHz) attached proton tests, COSY, and HMQC 2D techniques
in CDCl3. Peaks were referenced to residual chloroform signals (δH
7.26 ppm, or δC 77.0 ppm). High resolution mass spectra were
recorded on an ESI-TOF instrument.
(S)-Methyl 4-((2S,3S,4R,5R,6R)-4,5-di(benzyloxy)-6-((benzyloxy)-
methyl)-3-hydroxytetrahydro-2H-pyran-2yl)-2-((tert-butoxy-
carbonyl)amino)butanoate, 10. To a solution of alcohol 319 (666
mg, 1.03 mmol) in 10 mL DCM was added Dess-Martin Periodinane
(873 mg, 2.05 mmol) and the mixture was stirred under Ar at rt for 12
h. Then a 1:1:0.5 solution of aqueous saturated NaHCO3, aqueous
saturated Na2S2O3 and DI H2O (20 mL) was added. This biphasic
mixture was stirred for an additional 30 m. After separation, the
aqueous phase was extracted with DCM (2 × 10 mL); the combined
organics were washed with saturated aqueous NaHCO3, water, and
brine and then dried over Na2SO4. Flash chromatography using 20%
EtOAc/hexanes provided 550 mg of a colorless solid, 83% or the crude
material could be carried through to the next step.
To a solution of crude ketone (96 mg, 0.15 mmol) in methanol (3.7
mL) at −10 °C was added solid NaBH4 (11 mg, 0.29 mmol). After 1
h, the reaction was quenched with a small amount of acetic acid and
concentrated. The residue was taken up in DCM and washed with
water, brine, and dried over Na2SO4. Flash chromatography with 20 to
30% EtOAc/hexanes afforded 77 mg (80%) of an oily residue of 10,
giving a 66% yield over two steps.
Intermediate Ketone. Mp = 103−105 °C. [α]D −26 (c 2.5,
CHCl3). 1H NMR (CDCl3) δ 7.5−7.2 (m, 15H, 3 × Bn), 5.12 (bd, J =
8.8 Hz, 1H, NH), 5.01 (d, J = 11.3 Hz, 1H, Bn), 4.86 (d, J = 10.9 Hz,
1H, Bn), 4.68−4.52 (4 × d, 4H, 2 × Bn), 4.33 (m, 1H, H-α), 4.19 (d, J
C
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Note
170.8, 170.1, 169.3, 155.8, 79.8, 77.7, 75.7, 74.5, 68.5, 62.5, 53.2, 52.6,
52.3, 28.4, 27.8, 27.0, 23.3, 20.7, 20.7, 20.6. IR 3427, 1742, 1708 cm−1.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C24H38N2O12Na
569.2322; found 569.2332.
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59, 6728−6734.
(26) Schuler, P.; Fischer, S. N.; Marsch, M.; Oberthur, M. Synthesis
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2013, 45, 27−39.
(27) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
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ASSOCIATED CONTENT
■
(28) Venot, A.; Swayze, E. E.; Griffey, R. H.; Boons, G. J.
ChemBioChem 2004, 5, 1228−1236.
S
* Supporting Information
1H and 13C NMR spectra for new and title compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(29) Gross, B. J.; Kraybill, B. C.; Walker, S. J. Am. Chem. Soc. 2005,
127, 14588−14589.
(30) Witte, M. D.; Florea, B. I.; Verdoes, M.; Adeyanju, O.; Van der
Marel, G. A.; Overkleeft, H. S. J. Am. Chem. Soc. 2009, 131, 12064−
12065.
AUTHOR INFORMATION
Corresponding Author
*E-mail: enolen@colgate.edu.
■
(31) Mobli, M.; Almond, A. Org. Biolmol. Chem. 2007, 5, 2243−2251.
(32) Fernandez-Tejada, A.; Corzana, F.; Busto, J. H.; Jimenez-Oses,
G.; Jimenez-Barbero, J.; Avenzoa, A.; Peregrina, J. M. Chem.Eur. J.
2009, 15, 7297−7301.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (R15 GM83261-1).
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