Use of 1,2-dichloro 4,5-dicyanoquinone (DDQ) for cleavage of the 2- naphthylmethyl (NAP) group

Article abstract of DOI:10.1016/S0040-4039(99)02046-8

The 2-naphthylmethyl (NAP) group is a versatile group for protection of hydroxyl functions. It is stable to 4% TFA in CHCl₃, hot 80% HOAc-H₂O, SnCl₂-AgOTf and HCl-EtOH, but it can readily be removed with DDQ in CH₂Cl₂.

Full text of DOI:10.1016/S0040-4039(99)02046-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 169–173
Use of 1,2-dichloro 4,5-dicyanoquinone (DDQ) for cleavage of
the 2-naphthylmethyl (NAP) group
Jie Xia, Saeed A. Abbas, Robert D. Locke, Conrad F. Piskorz, James L. Alderfer and
Khushi L. Matta ∗
Molecular & Cellular Biophysics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
Received 6 August 1999; accepted 22 October 1999
Abstract
The 2-naphthylmethyl (NAP) group is a versatile group for protection of hydroxyl functions. It is stable to 4%
TFA in CHCl3, hot 80% HOAc–H2O, SnCl2–AgOTf and HCl–EtOH, but it can readily be removed with DDQ in
CH2Cl2. © 1999 Elsevier Science Ltd. All rights reserved.
Over the past decade, we have witnessed tremendous progress in the synthesis of complex
carbohydrates.1 A wide variety of glycosyl donors carrying different functionalities at their anomeric
6
centers, for example, thio,2 fluoride,3 imidate,4 sulfoxide,5 and pentenyl, together with an array of
highly efficient catalysts1 have proven to be the driving force behind such rapid and sustained progress
in saccharide synthesis. At the same time, the availability of diverse protection for hydroxy groups also
played an important role,7 particularly during sequential syntheses of both linear and branched higher
saccharides. Nonetheless, there is always the need for novel protecting groups for hydroxy functions that
are compatible with anticipated reaction conditions. The NAP group was recently introduced by Esko et
al.8a and Spencer et al.8b as a protecting group for polyhydroxy systems. Therefore, it was of interest
to further explore the utility of the NAP group in the synthesis of target oligosaccharide structures.
Interestingly, the NAP group, unlike its p-methoxybenzyl (PMB) counterpart which can be cleaved in
hot acetic acid9, was remarkably stable under those conditions usually employed for acetal cleavage.
Alkylation10 of diacetone glucose with naphthyl bromide (NAPBr) gave the 3-O-NAP derivative 1,
which upon treatment with HCl in ethanol11 provided 3-O-NAP glucose 2 in good yield. The latter
compound on acetylation gave 3. However, when 1,2:5,6-di-O-isopropylidene-3-O-PMB-α-D-glucose
was similarly treated, its PMB protecting group was partially cleaved. Similarly, compound 12 was
obtained by treatment of compound 11 with a 4% solution of TFA in CHCl3. By contrast, the PMB
protecting group was cleaved with a 0.5% solution of TFA in dichloromethane (Table 1).12,13
∗
Corresponding author.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02046-8
tetl 15974

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Table 1
Demonstration of NAP removal by DDQ
The NAP group readily undergoes oxidative cleavage under conditions analogous to those employed
for the removal of PMB.14 Removal of NAP from 3 provided the known11 1,2,4,6-tetra-O-acetyl-β-
D-glucopyranose 4. Example E represents a facile procedure for the preparation of methyl 2,4,6-tri-
O-benzyl-α-D-galactopyranoside 16. It is noteworthy that the NAP group was stable under glycosy-
lation conditions thus far examined by us. Recently, Wong and co-worker15 reported that the PMB
protecting group was cleaved in the presence of AgOTf. However, compound 17 was coupled with
phenyl 6-O-naphthylmethyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside 18 in the presence of
SnCl2–AgOTf as catalyst to give disaccharide 19 (Scheme 1). Similarly, phenyl 2,3,4,6-tetra-O-acetyl-1-
thio-galactopyranoside 20 on reaction with acceptor 7 provided the disaccharide derivative 21 (Scheme
2). Reaction of galactosaminide 22 with thioglycosyl donor 20 gave 23 in fairly good yield.
Scheme 1. (a) SnCl2–AgoTf/CH2Cl2–toluene, −15°C to 0°C, N2, 12 h, 74%
On removal of its anomeric NAP group, compound 23 gave 24 which has recently been reported as

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Scheme 2. (a) NIS–TfOH (cat)/CH2Cl2, 4A-MS, −40°C to 25°C, 1 h, 67%
a precursor for glycosyl donor 25 that was utilized for the synthesis of oligosaccharides containing the
Galβ1→3GalNAcβ-linkage (Scheme 3).16
Scheme 3. (a) NIS–TfOH/CH2Cl2, 4A-MS, −50°C, 2 h, 75%; (b) DDQ (3.0 equiv.)/CH2Cl2–MeOH (9:1), rt, 4 h, 76%; (c)
Cl3CN/DBU/CH2Cl2, rt, 3.5–4 h, 83%
The facile method for selective removal of the NAP group under such mild conditions is likely to
encourage the use of this protecting group in synthetic carbohydrate chemistry.
1. Experimental
Typical experiment: Compound 15 (15.3 g, 25.0 mmol) in dichloromethane–methanol (150 ml, 4:1)
was treated with DDQ (16.5 g, 73.3 mmol). The mixture was stirred at rt and the progress of reaction was
monitored by TLC. After 2 h, when TLC showed that only a trace of 15 was detectable, the mixture was
concentrated and the residue was taken up in dichloromethane. The solution was washed with aqueous
NaHCO3 (three times) and water, dried and concentrated. The concentrate was applied to a column of
silica gel and eluted with hexane:ethyl acetate (1:1) to give compound 16 (9.5 g, 80%) as an oil.
The selective physical data for 1, 3, 7, 15, 16, 18, 19 and 21. The structural assignment of 19 and 21
1
1
was based on 2D H–1H DQF-COSY and 2D ROESY spectroscopy. Compound 1: H NMR (CDCl3,
400 MHz) δ 7.83–7.79 (m, 4H, ArH), 7.48–7.45 (m, 3H, ArH), 5.93–5.92 (d, 1H, J1,2=3.7 Hz, H-1),
4.83–4.80 (dd, 2H, Jgem=12.1 Hz, OCH2C10H7, ABq), 4.63–4.61 (d, 1H, J=3.6 Hz), 4.51–4.35 (m, 1H),
4.20–4.00 (m, 4H), 1.49 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C
NMR (CDCl3, 100.6 MHz) δ 135.31, 133.46, 133.28, 128.40, 128.07, 127.90, 126.66, 126.35, 126.18,
125.84, 112.02, 109.24, 105.55 (C-1), 82.94, 81.90, 81.61, 72.76, 72.67, 67.67, 27.07 (CH3), 27.03
(CH3), 26.47 (CH3), 25.69 (CH3). Anal. calcd for C23H28O6: C, 68.98, H, 7.05. Found: C, 68.71, H,
1
6.93. Compound 3: (α+β): H NMR (CDCl3, 400 MHz) δ 7.82–7.80 (m, 6H, ArH), 7.72–7.68 (m,
2H, ArH), 7.52–7.44 (m, 4H, ArH), 7.40–7.32 (m, 2H, ArH), 6.33–6.32 (d, 1H, J 1,2=3.5 Hz, H-1, α-
form), 5.67–5.65 (d, 1H, J1,2=8.3 Hz, H-1, β-form), 5.25–5.09 (m, 4H), 4.88–4.78 (m, 3H, OCH2C10H7),
4.25–4.19 (m, 2H), 4.18–3.99 (m, 4H), 3.84–3.78 (t, 1H, J=8.9 Hz), 3.78–3.72 (dq, 1H), 2.16 (s, 3H,
Ac), 2.09 (s, 3H, Ac), 2.08 (s, 3H, Ac), 2.07 (s, 3H, Ac), 1.97 (s, 3H, Ac), 1.93 (s, 6H, 2Ac), 1.92
(s, 3H, Ac); 13C NMR (CDCl3, 100.6 MHz) δ 170.91 (C_O), 170.88 (C_O), 169.76 (C_O), 169.46
(C_O), 169.38 (C_O), 169.26 (C_O), 168.93 (C_O), 135.60, 135.22, 133.43, 133.41, 133.21, 128.45,

172
128.38, 128.09, 128.02, 127.86, 126.73, 126.47, 126.37, 126.31, 126.25, 125.82, 125.64, 92.22, 89.72,
80.20, 77.23, 74.99, 74.46, 73.23, 71.83, 71.77, 70.50, 69.34, (2C), 62.02 (2C), 21.05 (Ac), 21.03 (Ac),
20.89 (Ac), 20.85 (Ac), 20.77 (Ac). Anal. calcd for C25H28O10: C, 61.47, H, 5.78. Found: C, 61.43, H,
5.75. Compound 7: 1H NMR (CDCl3, 400 MHz) δ 7.90–7.70 (m, 8H, ArH), 7.50–7.20 (m, 11H, ArH),
5.20–5.10 (dd, 2H, OCH2Ar), 5.00–4.90 (m, 3H, OCH2Ar), 4.71–4.68 (d, 1H, Jgem=11.9 Hz, OCH2Ar),
4.59–4.57 (d, 1H, J1,2=7.0 Hz, H-1), 4.40–4.30 (m, 2H), 3.56–3.49 (m, 4H), 1.25 (s, 9H, t-Bu); 13C NMR
(CDCl3, 100.6 MHz) δ 174.30 (C_O), 136.06, 136.02, 128.71, 128.64, 128.34, 128.30, 128.15, 127.92,
127.89, 127.04, 127.02, 126.43, 126.35, 126.24, 126.19, 126.08, 126.03, 102.63 (C-1), 83.99, 82.07,
75.65, 75.61, 75.02, 73.89, 71.22, 70.61, 70.56, 63.66, 27.45 (CH3). Anal. calcd for C40H42O7: C, 75.69,
1
H, 6.67. Found: C, 75.52, H, 6.60. Compound 11: H NMR (CDCl3, 400 MHz) δ 7.90–7.70 (m, 4H,
ArH), 7.60–7.40 (m, 3H, ArH), 4.99–4.96 (d, 1H, Jgem=12.5 Hz, OCHAC10H7, ABq), 4.90–4.86 (d, 1H,
Jgem=13.2 Hz, OCHBC10H7, ABq), 4.65–4.64 (d, 1H, J1,2=3.9 Hz, H-1), 4.37–4.34 (dd, 1H), 4.11–4.00
(m, 3H), 3.57–3.55 (dd, 1H), 3.57 (s, 3H, OCH3), 1.38 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.31–1.29 (d,
3H, J=6.7 Hz, CH3); 13C NMR (CDCl3, 100.6 MHz) δ 135.57, 133.03, 132.89, 127.89, 127.93, 127.63,
127.45, 126.60, 125.85, 125.74, 125.63, 108.55 (ketal carbon), 98.21 (C-1), 76.12, 75.99, 75.91, 72.25,
1
62.67, 55.24, 28.00 (CH3), 26.21 (CH3), 16.06 (CH3). Compound 12: H NMR (CDCl3, 400 MHz) δ
7.88–7.80 (m, 4H, ArH), 7.56–7.40 (m, 3H, ArH), 5.00–4.70 (dd, 2H, OCH2C10H7), 4.63–4.62 (d, 1H,
J1,2=3.6 Hz, H-1), 4.00–3.80 (m, 4H), 3.80–3.65 (m, 2H), 3.33 (s, 3H, OCH3), 1.25–1.20 (d, 3H, J=6.7
Hz, CH3); 13C NMR (CDCl3, 100.6 MHz) δ 135.44, 133.00, 132.86, 127.95, 127.60, 127.35, 126.68,
125.90, 125.73, 125.71, 98.35, 76.31, 72.94, 71.80, 69.28, 65.33, 54.88, 15.65 (CH3). Compound 15:
1H NMR (CDCl3, 400 MHz) δ 7.81–7.61 (m, 7H, ArH), 7.52–7.20 (m, 15H, ArH), 5.00–4.94 (d, 1H,
Jgem=12.4 Hz, OCHAr), 4.94–4.80 (dd, 2H, OCH2Ar), 4.80–4.60 (dd, 2H, OCH2Ar), 4.56–4.50 (d, 1H,
Jgem=12.6 Hz, OCHAr), 4.50–4.44 (dd, 2H, OCH2Ar), 4.06–3.86 (m, 4H), 3.64–3.50 (m, 3H), 3.34 (s,
3H, OCH3); 13C NMR (CDCl3, 100.6 MHz) δ 133.50, 133.10, 128.55, 128.50, 128.38, 128.36, 128.25,
128.23, 128.08, 127.91, 127.85, 127.72, 126.30, 126.20, 126.11, 125.96, 125.87, 98.97, 79.21, 76.91,
75.50, 74.98, 73.69, 73.66, 73.56, 69.47, 69.29, 55.51. Anal calcd for C39H38O6: C, 77.45, H, 6.67.
1
Found: C, 77.37, H, 6.39. Compound 16: H NMR (CDCl3, 400 MHz) δ 7.40–7.20 (m, 15H, ArH),
4.86–4.76 (dd, 1H), 4.74–4.56 (m, 4H, 2OCH2Ph), 4.58–4.36 (dd, 2H, OCH2Ph), 4.10–4.00 (m, 1H),
4.00–3.90 (m, 2H), 3.85–3.75 (m, 1H), 3.60–3.50 (m, 2H), 3.34 (s, 3H, OCH3), 2.40–2.30 (br, 1H,
OH); 13C NMR (CDCl3, 100.6 MHz) δ 138.75, 138.39, 138.19, 128.69, 128.58, 128.55, 128.34, 128.32,
128.16, 127.90, 98.21 (C-1), 77.61, 76.90, 75.33, 73.65, 73.14, 70.48, 69.32, 69.26, 55.54. Compound
1
18: H NMR (CDCl3, 400 MHz) δ 7.85–7.75 (m, 4H, ArH), 7.37–7.35 (m, 5H, ArH), 7.25–7.24 (m,
7H, ArH), 5.64–5.61 (d, 1H, J1,2=10.4 Hz, H-1), 4.78–4.60 (d, 1H, Jgem=12.4 Hz, OCHC10H7, ABq),
4.60–4.54 (d, 1H, Jgem=12.6 Hz, OCHC10H7, ABq), 4.26–4.24 (t, 1H, J=8.4 Hz, H-3), 4.15–4.13 (t,
1H, J=10.8 Hz, H-2), 3.90–3.87 (dd, 1H, J=11.6, 3.6 Hz, H-6a,), 3.81–3.80 (dd, 1H, J=11.6, 3.6 Hz,
H-6b), 3.54–3.52 (m, 2H, H-4, H-5); 13C NMR (CDCl3, 100.6 MHz) δ 135.49, 134.27, 133.41, 133.16,
132.66, 132.32, 133.22, 131.72, 129.01, 128.91, 128.35, 128.10, 127.84, 126.63, 126.25, 126.03, 125.87,
83.73 (C-1), 78.96, 73.79, 72.92, 72.72, 70.10, 55.79. Anal. calcd for C31H27O6NS: C, 68.74, H, 5.02,
N, 2.59, S, 5.92. Found: C, 68.61, H, 5.11, N, 2.37, S, 6.08. Compound 19: 1H NMR (CDCl3, 400 MHz)
δ 7.86–7.80 (m, 6H, ArH), 7.68–7.64 (m, 2H, ArH), 7.52–7.40 (m, 5H, ArH), 7.28–7.16 (m, 3H, ArH),
5.65–5.63 (d, 1H, J1,2=10.4 Hz, H-1), 5.32–5.31 (d, 1H, J=2.0 Hz, H0-4), 5.20–5.16 (t, 1H, J=10.0, 8.8
Hz, H0-2), 4.94–4.90 (dd, 1H, H0-3), 4.89–4.86 (d, 1H, J=12.0 Hz, OCHAC10H7, ABq), 4.72–4.69 (d,
1H, J=12.0 Hz, OCHBC10H7, ABq), 4.53–4.51 (d, 1H, J=8.0 Hz), 4.47–4.42 (t, 1H), 4.05–4.03 (m, 4H),
3.87–3.71 (m, 4H), 2.14–2.10 (s, 3H, Ac), 1.96 (s, 3H, Ac), 1.94 (2s, 6H, 2Ac); 13C NMR (CDCl3, 100.6
Hz) δ 178.50 (C_O), 170.50 (C_O), 170.00 (C_O), 169.50 (C_O), 169.20 (C_O), 134.50, 132.75,
129.00, 128.50, 128.20, 128.00, 127.80, 126.58, 126.30, 126.00, 123.58, 123.50, 100.50, 83.50, 81.00,

173
79.20, 72.00, 70.80, 70.20 (2C), 69.50, 69.00, 68.50, 60.50, 58.50, 20.68 (Ac), 20.62 (Ac), 20.35 (Ac),
20.40 (Ac). Anal. calcd for C45H45O15NS: C, 68.54, H, 5.10, N, 2.59, S, 5.96. Found: C, 68.61, H, 5.11,
1
N, 2.37, S, 6.08. Compound 21: H NMR (CDCl3, 400 MHz) δ 7.82–6.80 (m, 19H, ArH), 5.28–5.27
(d, 1H, J=2.7 Hz, H0-4), 5.24–5.18 (dd, 1H, H0-2), 5.16–5.00 (m, 3H, OCH2Ph, OCHC10H7), 4.96–4.88
(d, 2H, H0-3, Jgem=12.4 Hz, OCHC10H7), 4.88–4.80 (d, 1H, Jgem=12.6 Hz, OCHC10H7), 4.76–4.72 (d,
1H, J1,2=7.5 Hz, H0-1), 4.68–4.64 (d, 1H, Jgem=12.2 Hz, OCHC10H7), 4.58–4.48 (m, 2H, H-1, H-6b),
4.60–4.50 (dd, 1H, H-6a), 4.20–3.98 (dd, 1H, H0-6b), 3.90–3.78 (m, 2H, H-4, H0-6a), 3.74–3.62 (m, 2H,
H-3, H0-5), 3.60–3.50 (m, 2H, H-5, H-2), 2.09 (s, 3H, Ac), 2.05 (s, 3H, Ac), 1.95 (s, 3H, Ac), 1.84 (s, 3H,
Ac), 1.25 (s, 9H, t-Bu); 13C NMR (CDCl3, 100.6 Hz) δ 179.11 (C_O), 171.31 (C_O), 171.22 (C_O),
171.19 (C_O), 170.63 (C_O), 137.63, 134.52, 131.45, 129.74, 129.70, 129.32, 129.30, 129.20, 129.18,
129.14, 128.94, 128.86, 128.49, 128.42, 127.84, 127.70, 127.46, 127.42, 127.40, 127.35, 127.28, 127.16,
127.02, 126.94, 126.88, 126.82, 102.16, 101.12, 83.74, 83.65, 79.46, 76.29, 76.05, 74.07, 72.35, 72.29,
72.16, 70.94, 68.03, 67.90, 61.93, 29.80, 28.53 (3CH3), 21.95 (Ac), 21.77 (Ac), 21.76 (Ac), 21.68 (Ac).
Acknowledgements
This work was supported by NIH grants CA35329 (K.L.M.) and CA16056 (RPCI). The authors would
like to thank the Chairman of our department, Dr. Sek Wen Hui, for his encouragement.
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