Quantifying Electronic Effects of Common Carbohydrate Protecting Groups
FULL PAPER
H1), 3.91 (dd, J=8.5, 5.3 Hz, 1H, H6), 3.77–3.63 (m, 1H, H5), 3.60 (dd,
J=3.4, 1.9 Hz, 1H, H2), 2.88 (dd, J=14.2, 1.9 Hz, 1H, H1), 2.14–1.99 (m,
1H, H3), 1.99–1.78 (m, 1H, H4), 1.65–1.47 ppm (m, 2H, H3, H4);
13C NMR (75 MHz, CDCl3) d=157.8 (C=O), 138.2, 128.4, 127.7, 127.5
(Ar), 70.1 (C6), 69.5 (C2), 68.1 (C6), 53.9 (C5), 43.2 (C1), 27.5 (C3),
24.5 ppm (C4); elemental analysis calcd (%) for C 68.00, H 6.93, N 5.66;
found: C 67.89, H 6.86, N 5.60. Compound 8 (0.065 g, 11%): 1H NMR
(300 MHz, CDCl3) d=7.52–7.09 (m, 5H), 4.59 (d, J=11.7 Hz, 1H,
PhCH2), 4.54 (d, J=11.7 Hz, 1H, PhCH2), 4.37 (t, J=8.4 Hz, 1H, H6),
4.15 (ddd, J=12.6, 5.2, 1.7 Hz, 1H, H1), 3.85 (dd, J=8.6, 5.8 Hz, 1H,
H6), 3.67–3.50 (m, 1H, H5), 3.47–3.30 (m, 1H, H2), 2.67 (dd, J=12.6,
10.3 Hz, 1H, H1), 2.29–2.14 (m, 1H, H3), 1.95–1.79 (m, 1H, H4), 1.53–
1.25 ppm (m, 2H, H3, H4); 13C NMR (75 MHz, CDCl3) d=156.9 (C=O),
138.0, 128.5, 127.8, 127.6 (Ar), 72.5 (C2), 70.9 (PhCH2), 67.7 (C6), 53.7
(C5), 45.5 (C1), 29.5 (C3), 29.1 ppm (C4); HRMS: m/z: calcd for
C14H17NO3Na: 270.1106; found: 270.1106.
138.45, 128.39, 128.34, 127.71, 127.58, 127.54, 127.41 (Ar), 74.4 (C6), 73.2
(PhCH2), 71.1 (C2), 69.9 (PhCH2), 55.8 (C5), 49.3 (C1), 27.8 (C3), 24.1
(C4); HRMS: m/z: calcd for C20H26NO2: 312.1964; found: 312.1970.
Compound
13:
(2R,5S),ACTHNGUETRNNU(G 2S,5R)-N-Boc-2,6-dibenzoyloxopiperidine
(0.116 g, 0.378 mmol) was dissolved in CH2Cl2 and an excess of TFA was
added. When the reaction was finished (TLC) the mixture was evaporat-
ed to dryness to give the product (0.120 g, 100%). Elemental analysis
calcd (%): C 70.78, H 6.24, N 4.1; found: C 70.70, H 6.78, N 3.79. Free
amine: 1H NMR (300 MHz, CDCl3) d=8.11–7.99 (m, 4H, Ar), 7.64–7.38
(m, 6H, Ar), 5.07–4.90 (m, 1H, H2), 4.40 (dd, J=11.1, 4.1 Hz, 1H, H6),
4.22 (dd, J=11.1, 7.2 Hz, 1H, H6), 3.45 (ddd, J=11.2, 4.5, 1.8 Hz, 1H,
H1), 3.07–2.97 (m, 1H, H5), 2.75 (dd, J=11.2, 10.4 Hz, H1), 2.57 (s, 1H),
2.37–2.23 (m, 1H, H3), 1.90 (dd, J=12.5, 3.2 Hz, 1H, H4), 1.57 ppm (m,
2H, H3, H4); 13C NMR (75 MHz, CDCl3) d=166.5 (C=O), 165.9 (C=O),
133.3, 133.1, 130.5, 130.0, 129.8, 129.7, 128.6, 128.5 (Ar), 70.7 (C2), 68.2
(C6), 54.7 (C5), 49.8 (C2), 29.9 (C3), 27.6 ppm (C2).
Compounds 9 and 10: N-Boc-6-(hydroxymethyl)piperidine-3-ol (0.293 g,
1.26 mmol) was dissolved in benzyl bromide (7 mL) and tetrabutylammo-
nium iodide (TBAI) (48 mg, 0.13 mmol) was added. The mixture was
stirred for 20 min followed by the addition of freshly prepared Ag2O
(1.17 g, 5.1 mmol). The reaction mixture was stirred for 12 h followed by
the addition of DMF (5 mL) and NaOH (aq, 50%, 5 mL) and then stir-
ring for another 12 h. The reaction mixture was then filtered through
Celite, diluted with 50 mL of water, and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried (MgSO4), and
evaporated. The crude products were carefully separated by dry column
chromatography with heptane as eluent with a gradient of ethyl acetate
Compound
14:
(2R,5S),ACTHNGUETRNNU(G 2S,5R)-N-Boc-2,6-dibenzyloxopiperidine
(0.061 g, 0.148 mmol) was dissolved in CH2Cl2 and an excess of TFA was
added. The reaction was stirred until it was finished (TLC) and then
evaporated to dryness. The compound was then dissolved in CH2Cl2 and
extracted with 1m NaOH. The organic layer was dried (MgSO4) and
evaporated to dryness to give the product (0.045 g, 98%). 1H NMR
(300 MHz, CDCl3) d=7.71–6.88 (m, 10H, Ar), 4.56 (s, 2H, PhCH2), 4.50
(s, 2H, PhCH2), 3.51–3.39 (m, 2H, H2, H6), 3.39–3.31 (m, 1H, H1), 3.27
(t, J=8.7 Hz, 1H, H6), 2.80–2.69 (m, 1H, H5), 2.49 (dd, J=10.2, 9.8 Hz,
1H, H1), 2.16 (d, J=12.3 Hz, 2H, NH, H3), 1.63 (dd, J=12.8, 2.9 Hz,
1H, H4), 1.48–1.30 (m, 1H, H3), 1.25–1.06 ppm (m, 1H, H4); 13C NMR
(75 MHz, CDCl3) d=138.9, 138.3, 128.6, 128.5, 127.9, 127.8, 127.7, 127.7
(Ar), 75.3 (C2), 74.7 (C6), 73.6 (PhCH2), 70.6 (PhCH2), 55.8 (C5), 51.1
(C1), 31.0 (C3), 27.5 ppm (C4); HRMS: m/z: calcd for C20H26NO2:
312.1964; found: 312.1960.
1
to give each product. Compound 10 (0.061 g, 11%): H NMR (300 MHz,
CDCl3) d=7.50–7.16 (m, 10H, Ar), 4.71–4.40 (m, 5H, PhCH2, H5), 4.34
(d, J=14.4 Hz, 1H, H1), 3.61–3.49 (m, 2H, H2, H6), 2.84 (d, J=14.5 Hz,
1H, H1), 2.16–1.97 (m, 1H, H4), 1.85–1.53 (m, 3H, H3, H4), 1.50–
1.41 ppm (m, 9H, Boc); 13C NMR (75 MHz, CDCl3) d=155.6
ACTHNUTRGNE(NUG C=O),
Compound 17: A solution of tetra-O-benzyl-1-deoxynojirimycin (1.491 g,
2.85 mmol) in CH2Cl2 was cooled to 08C and one equivalent of triethyl-
AHCTUNGTRENNaGUN mine was added. Then a solution of Boc anhydride in CH2Cl2 was
added. The solution was stirred at 08C for 0.5 h and then allowed to
reach room temperature over 2 h. The solution was washed with 1m HCl,
138.9, 138.5, 128.5, 128.4, 127.7, 127.6, 127.5 (Ar), 79.6 (C-Boc), 73.0
(PhCH2), 70.8 (C2), 69.8 (PhCH2), 68.5 (C6), 49.2 (C5), 41.7 (C1), 28.6
(CH3-Boc), 24.7 (C3), 19.9 (C4); HRMS: m/z: calcd for C25H33NO4Na:
434.2307; found: 434.2321. Compound
9
(0.166 g, 32%): 1H NMR
(300 MHz, CDCl3) d=7.57–7.09 (m, 10H, Ar), 4.58 (s, 2H, PhCH2), 4.53
(s, 2H, PhCH2), 4.51–4.01 (m, 2H, H1, H5), 3.54 (d, J=6.9 Hz, 2H, H6),
3.37 (s, 1H, H2), 2.59 (s, 1H, H1), 2.06–1.79 (m, 2H, H3, H4), 1.73–1.50
(m, 2H, H3, H4), 1.45 ppm (s, 9H); 13C NMR (75 MHz, CDCl3) d=155.2
(C=O), 138.5, 138.4, 128.5, 128.5, 127.7, 127.6 (Ar), 79.9 (C-Boc), 74.1
(C2), 73.0, 70.7 (PhCH2), 67.7 (C6), 49.6, 47.9 (C5), 44.6, 43.4 (C1), 28.5
(CH3-Boc), 26.41, 23.77 (C3, C4); HRMS: m/z: calcd for C25H33NO4Na:
434.2307; found: 434.2326.
a
saturated aqueous solution of bicarbonate, brine, and dried over
MgSO4. The organic layer was evaporated and the crude compound was
purified by flash column chromatography. The eluent was pentane with a
gradient of ethyl acetate (1.35 g, 81%). [a]RDT =12.88 (c=1.0, CHCl3);
1H NMR (300 MHz, CDCl3) d=7.3 (20H, Ar), 4.7–4.4 (8H, PhCH2), 4.1
(m, 2H, H1, H5), 3.9 (t, J=6.4 Hz, 1H, H4), 3.7 (1H, H3), 3.6 (m, 4H,
H2, H6), 3.3 (dd, J=3.3, 14.2 Hz, 1H, H1), 1.4 ppm (s, 9H, Boc);
13C NMR (75 MHz, CDCl3) d=155.3 (C=O), 138.4 (Ar-C), 128.7–127.3
(Ar), 82.7 (C-Boc), 80.0 (C3), 78.2 (C2), 76.8 (C4), 73.1–72.9 (PhCH2),
68.9 (C6), 55.6 (C5), 41.0 (C1), 28.6 ppm (CH3-Boc); HRMS: m/z: calcd
for C39H45NO6Na: 646.3145; found: 646.3127.
Compound
11:
(2S,5S),ACTHNGUETRNNU(G 2R,5R)-N-Boc-2,6-dibenzoyloxopiperidine
(0.383 g, 0.871 mmol) was dissolved in CH2Cl2 and an excess of TFA was
added. When the reaction was finished the mixture was evaporated to
dryness to give the product (0.422 g, quantitative yield, with small excess
of TFA). 1H NMR (300 MHz, CDCl3) d=10.06–9.76 (brm, 2H, NH),
8.16 (d, J=7.7 Hz, 2H, Ar), 7.97 (d, J=7.7 Hz, 2H Ar), 7.55 (t, J=
7.4 Hz, 2H, Ar), 7.46 (t, J=7.4 Hz, 2H, Ar), 7.39 (t, J=7.7 Hz, 2H, Ar),
7.30 (t, J=7.6 Hz, 2H, Ar), 5.29 (s, 1H, H2), 4.53 (ddd, J=15.1, 12.4,
5.0 Hz, 2H, H6), 3.61–3.44 (s, 1H, H5), 3.42 (d, J=13.5 Hz, 1H, H1),
3.13 (d, J=13.5 Hz, 1H, H1), 2.31 À1.79 ppm (m, 4H, H3, H4);
13C NMR (75 MHz, CDCl3) d=166.1 (C=O), 165.5 (C=O), 133.7, 133.5,
130.2, 130.0, 129.1, 128.9, 128.6, 128.5 (Ar), 64.4 (C2), 64.1 (C6), 55.3
(C5), 46.9 (C1), 26.4, 20.5 ppm (C1, C2); HRMS: m/z: calcd 340.1549;
found: 340.1545.
Compound
18:
N-Boc-tetra-O-benzyl-1-deoxynojirimycin
(1.31 g,
2.1 mmol) was dissolved in 1:1 mixture of methanol and ethyl acetate
(20 mL) and Pd/C was added (10%, 0.2 g), the flask was flushed with hy-
drogen and the solution was then stirred overnight. The reaction mixture
was filtered and evaporated to give the product (0.553 g, 100%). [a]DRT
=
À15.98 (c=1.0, MeOH); 1H NMR (300 MHz, CDCl3) d=4.15 (m, 1H,
H5), 3.9 (d, 1H, J=13.9 Hz, H1), 3.85–3.82 (m, 2H, H6), 3.79 (m, 1H,
H4), 3.70 (m, 2H, H2, H3), 3.40 (dd, 1H, J=3,4, 13,8 Hz, H1), 1.51 (s,
9H, Boc); 13C NMR (75 MHz, CD3OD) d=156.9 (C=O), 80.1 (C-Boc),
71.0, 70.1, 69.2, 60.2, 59.8, 43.0, 27.5 (CH3-Boc); HRMS: m/z: calcd for
C11H21NO6Na: 286.1267; found: 286.1268.
Compound
12:
(2S,5S),ACTHNGUETRNNU(G 2R,5R)-N-Boc-2,6-dibenzyloxopiperidine
Compound 20: Pyridine (1 mL) and acetic acid anhydride (1 mL) were
added to N-Boc-1-deoxynojirimycin (0.157 g, 0.596 mmol). The reaction
mixture was stirred for 24 h and the solvents were removed by co-evapo-
ration with toluene. The crude product was purified by flash chromatog-
raphy with pentane as the eluent with a gradient of ethyl acetate to give
the product (0.247 g, 96%). [a]RDT =1.98 (c=1.0, CHCl3); 1H NMR
(300 MHz, CDCl3) d=4.97 (t, J=3.8 Hz, 1H, H3), 4.84 (t, J=3.8 Hz,
1H, H4), 4.70 (d, J=2.9 Hz, 1H, H2), 4.50 (m, 1H, H5), 4.30–4.17 (m,
3H, H6, H1), 3.22 (dd, J=15.4, 2.1 Hz, 1H), 2.03–1.99 (m, 12H, Ac),
1.39 ppm (s, 12 H CH3-Boc); 13C NMR (75 MHz, CDCl3) d=170.4, 169.6,
(0.166 g, 0.403 mmol) was dissolved in CH2Cl2 and an excess of TFA was
added. The reaction was stirred until finished (TLC) and then evaporated
to dryness. The compound was then dissolved in CH2Cl2 and extracted
with 1m NaOH. The organic layer was dried (MgSO4) and evaporated to
dryness to give the product (0.123 g, 98%). 1H NMR (300 MHz, CDCl3)
d=7.50–7.15 (m, 10H, Ar), 4.67–4.37 (m, 4H, PhCH2), 3.51–3.39 (m, 3H,
H6, H2), 3.20 (dt, J=13.2, 2.3 Hz, 1H, H1), 2.88–2.78 (m, 1H, H5), 2.74
(dd, J=13.2, 1.8 Hz, 1H, H1), 2.11 (s, 1H, NH), 2.09–1.98 (m, 1H, H3),
1.72–1.39 ppm (m, 3H, H3, H4); 13C NMR (75 MHz, CDCl3) d=139.06,
Chem. Eur. J. 2010, 16, 13982 – 13994
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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