First example of the carbon-Ferrier rearrangement of glycals with isocyanides: a novel synthesis of C-glycosyl amides

Article abstract of DOI:10.1016/j.tetlet.2008.10.090

Glycals undergo smooth carbon-Ferrier rearrangement with isocyanides in the presence of a catalytic amount of FeCl₃ under mild reaction conditions to provide C-glycosyl amides in good yields with high α-selectivity. The use of FeCl₃

Full text of DOI:10.1016/j.tetlet.2008.10.090

Tetrahedron Letters 50 (2009) 81–84
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First example of the carbon-Ferrier rearrangement of glycals
with isocyanides: a novel synthesis of C-glycosyl amides
*
J. S. Yadav , B. V. Subba Reddy, D. Narasimha Chary, C. Madavi, A. C. Kunwar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2008
Revised 10 October 2008
Accepted 21 October 2008
Available online 1 November 2008
Glycals undergo smooth carbon-Ferrier rearrangement with isocyanides in the presence of a catalytic
amount of FeCl3 under mild reaction conditions to provide C-glycosyl amides in good yields with high
a
-selectivity. The use of FeCl3 makes this method simple, convenient and cost-effective. This is the first
report on carbon-Ferrier rearrangement using isonitriles as nucleophiles.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Ferrier rearrangement
Glucal
Isocyanides
C-Glycosyl amides
C-Glycosidation is an important tool for the synthesis of opti-
cally active compounds, since it allows the introduction of carbon
chains to sugar chirons and the use of sugar nuclei as chiral pool
reagents as well as carbon sources.1 C-Glycosides are versatile
chiral building blocks for the synthesis of many biologically inter-
esting natural products such as palytoxin, spongistatin, halichon-
drin, and many others.2 The discovery of naturally occurring
C-nucleosides with important pharmacological properties gave
impetus to synthetic efforts for preparing active carbohydrate
analogs.3 In addition, C-glycosides are potential inhibitors of carbo-
hydrate-processing enzymes, and they are stable analogs of
glycans involved in important intra- and inter-cellular processes.4
Of these C-glycosides, 2,3-unsaturated glycosides (pseudoglycals)
are versatile synthetic intermediates and also constitute the struc-
tural units of several antibiotics.5 Pseudoglycals are traditionally
obtained by an acid-catalyzed allylic rearrangement of glycals in
the presence of nucleophiles, a reaction known as the Ferrier rear-
rangement.6 Lewis acids are known to promote C-glycosidation
with various nucleophiles such as allyltrimethylsilane, tri-
methylsilylcyanide, and alkynylsilanes.7–9 However, there have
been no reports on the allylic nucleophilic substitution of glycals
(SN20) with isocyanides to produce C-glycosyl amides.10
produce x-hydroxy carboxamides. Surprisingly, we observed the
formation of glycosyl amides instead of open-chain hydroxyl
amides. This provided incentive for an extensive study. Initially,
we examined the reaction of 3,4,6-tri-O-acetyl-D-glucal (1) with
tosylmethylisocyanide (2, Tosmic) in the presence of 10 mol % of
FeCl3. The reaction was complete within 30 min, and the desired
product was obtained in 92% yield as a mixture of
anomers in a 9:1 ratio favoring -anomer 3a (Scheme 1).
Similarly, various other -glucal derivatives such as 3,4,6-tri-O-
benzoyl-, 3,4,6-tri-O-benzyl-, 3,4,6-tri-O-methyl-, and 3,4,6-tri-O-
allyl- -glucal reacted effectively with isonitriles to produce the
corresponding C-glycosides in good yields (Table 1, entries b–k).
The reaction was also effective with the TBS derivative of -glucal
a-3a and b-3b
a
D
D
D
without affecting the TBS functionality (Table 1, entries l and m).
This method is applicable for both ester and ether derivatives of
D
-glucal. In each case, the a-anomer was obtained predominantly.
The ratio of anomers was determined by 1H NMR spectroscopy of
O
O
NHCH2Ts
NHCH2Ts
AcO
AcO
In continuation of our interest on glycosidation, we disclose a
versatile approach for the preparation of C-glycosyl amides from
glucal and isonitriles by means of a carbon-Ferrier rearrangement.
Initially, we attempted the Passerini-type coupling of an isonitrile,
a carboxylic acid, and a glycal instead of a carbonyl compound to
O
3a
10 mol% FeCl3
CH2Cl2 , r.t.
AcO
AcO
CN-CH2Ts
+
O
OAc
O
AcO
AcO
1
2
3a1
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.090

82
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 81–84
Table 1
FeCl3-catalyzed Ferrier rearrangement of glycals with isocyanides
Entry
a
Glucal
Isonitrile
Producta
Time (min)
30
Yieldb (%)
92
Ratioc
9:1
(a:b)
O
O
O
AcO
AcO
O
O
Tosmic
NHCH2Ts
AcO
AcO
OAc
O
NC
AcO
AcO
b
30
85
9:1
N
H
AcO
AcO
OAc
O
O
O
AcO
AcO
O
O
N
H
c
d
e
f
50
35
45
56
30
45
25
75
90
85
70
85
80
90
9:1
9:1
6:1
9:1
9:1
9:1
9:1
AcO
AcO
NC
OAc
O
BnO
BnO
NHCH2Ts
Tosmic
BnO
BnO
OBn
O
O
O
NC
BnO
BnO
O
O
N
H
BnO
BnO
OBn
O
BnO
BnO
N
H
BnO
BnO
NC
OBn
O
O
BzO
BzO
O
NHCH2Ts
g
h
i
Tosmic
BzO
BzO
OBz
O
O
O
NC
BzO
BzO
O
O
N
H
BzO
BzO
OBz
O
MeO
MeO
NHCH2Ts
Tosmic
MeO
MeO
OMe
O
O
NC
MeO
MeO
O
j
30
45
50
85
75
70
6:1
9:1
9:1
N
H
MeO
MeO
OMe
O
O
O
O
NHCH2Ts
k
l
Tosmic
O
O
O
O
O
O
TBSO
O
NHCH2Ts
Tosmic
TBSO
TBSO
TBSO
OTBS
O
O
NC
TBSO
TBSO
O
m
40
30
65
89
7:1
—
N
H
TBSO
TBSO
OTBS
O
O
O
NHCH2Ts
n
Tosmic
AcO
OAc
AcO
a
All products were characterized by NMR, IR, and the mass spectrometry.
Yield refers to pure products after chromatography.
b
c
Ratio was determined from the 1H NMR spectrum of crude product.

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 81–84
83
7
the crude products obtained in the C-glycosidation. The predomi-
nant formation of the -anomer may be explained by electronic
CH3
Ts
a
HN
effects on the oxocarbenium intermediate involved in this trans-
formation. Kinetically preferred axial addition of the carbon nucleo-
phile was observed in most cases.11 The structures of 3a and 3a0
were thoroughly studied by various NMR techniques including
1D 1H NMR, homo-nuclear decoupling, double quantum filtered
correlation spectroscopy (DQFCOSY), and nuclear Overhauser
effect spectroscopy (NOESY). The spectral assignments were
obtained from DQFCOSY experiments. Since the configurations at
C2 and C3 are fixed, for the major isomer 3a, the coupling constant
between protons H2 and H3 (3JH2–H3 = 5.9 Hz) supports the equato-
rial disposition of H2 and H3, thereby implying axial orientation of
the substituents at C2 and C3. The presence of NOE correlations
between H1–H3 and H1–H6 suggest that all these three protons
lie on the same side of the C3–C4–C5–C6 plane. These observations
in turn indicate that the substituent at C6 is on the other side of
this plane, which is additionally supported by the NOE correlation
between NH and H2. The characteristic NOE’s and energy-mini-
mized structure of 3a are shown in Figure 1.
O
H
O
O
O
3
4
O
6
5
1
O
2
H3C
H
H
For the minor isomer, a large coupling constant (3JH2–H3
=
Figure 2. Characteristic NOE’s and energy-minimized structure of 3a0.
9.2 Hz) between protons H2 and H3 indicates that they occupy
axial positions in the six-membered ring. Further, the presence of
a strong NOE correlation between H2 and H6 indicates that these
protons occupy 1,3-diaxial positions, which in turn provides sup-
port for the equatorial orientation of all the three substituents on
the ring. The characteristic NOE’s and energy-minimized structure
of 3a0 are shown in Figure 2.
NOE’s and energy-minimized structure of 3n are shown in Figure
3.
The products were characterized by 1H, 13C NMR, and IR spectra
and by mass spectrometry. In the absence of catalyst, no reaction
was observed even after an extended reaction time (12 h). As
solvent, Dichloro methane gave the best results. In all the cases,
the reactions proceeded rapidly at room temperature under mild
conditions. The reactions were clean, and no side products were
detected under these conditions as determined from the NMR
spectra of the crude products. There are several advantages in
the use of FeCl3 as catalyst for this transformation, which include
Similarly, di-O-acetyl-L-arabinal also underwent the Ferrier-
type rearrangement to produce C-glycosyl amide 3n with a-selec-
tivity.12 The presence of strong correlations between H10/H5 and
H1/H2 and of medium correlations between H10/H2 protons and
3
3
0
the coupling constants JH1–H2 = 5.2 and JH1 –H2 = 7.4 Hz provides
ample support for the structure shown in Figure 3, with substitu-
ents at C4 trans to the O-acetyl group at C1. The characteristic
high conversions, short reaction times and high
a-selectivity. In
addition, this method avoids the use of expensive reagents, and
does not require any additives or stringent reaction conditions.
This method is quite simple and convenient, affording the desired
products in good yields.
The efficacy of various metal halides such as FeCl3, InBr3, InCl3,
GaCl3, YCl3, and YbCl3 was studied for this transformation. Of these
catalysts, FeCl3 was found to be more effective in terms of conver-
sion. For example, treatment of 3,4,6-tri-O-acetyl-D-glucal with
Tosmic in the presence of 10 mol % FeCl3 and 10 mol % InCl3 over
30 min afforded 92% and 75% yields, respectively.
'
H
H3C
H
O
H
1
2
H
H
H
O
O
5
4
H
6
O
3
O
O
H
N
7
CH3
Ts
'
H
1
H
O
H
H3C
H
4
5
Ts
N
2
3
6
O
H
O
O
Figure 1. Characteristic NOE’s and energy-minimized structure of 3a.
Figure 3. Characteristic NOE’s and energy-minimized structure of 3n.

84
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 81–84
..
O
+
O
AcO
AcO
O
AcO
FeCl3
−
AcO
AcO
CN-CH2Ts
AcO
CH2Cl2 , r.t.
+
O
OAc
O
Fe(III)
H2O
O
+
O
O
NCH2Ts
AcO
AcO
NHCH2Ts
AcO
AcO
Scheme 2. A plausible reaction mechanism.
12. For C-glycosides derived from di-O-acetyl-L-arabinal, the a-configuration
The scope and generality of this process are illustrated with re-
corresponds to a trans relationship between the substituents at C1 and C4
(Table 1).
spect to various glucal derivatives and isonitriles, and the results
are presented in Table 1.13 Mechanistically, the reaction proceeds
via an oxocarbenium ion intermediate by a Ferrier rearrangement.
Subsequent axial attack of the isonitrile on the oxocarbenium ion
would give a carbimminium intermediate which is probably
hydrolyzed to the product amide (Scheme 2).
In summary, we have described a novel method for the synthe-
sis of C-pseudoglycals from glycals and isonitriles using a catalytic
amount of FeCl3 under mild reaction conditions. This method
provides high yields of C-glycosyl amides in short reaction times
with high anomeric selectivity, which makes it a useful process
for carbon–carbon bond formation at the anomeric position of
sugars.
13. Experimental procedure: To a stirred solution of glucal triacetate (0.5 mmol) in
Dichloro methane (2 mL) were added Tosmic (0.6 mmol) and FeCl3 (10 mol %).
The resulting mixture was stirred at room temperature for 30 min. After
complete conversion as indicated by TLC, the reaction mixture was diluted
with water and extracted with Dichloro methane (3 ꢀ 10 mL), and the
combined organics were dried over anhydrous Na2SO4. Removal of the
solvent in vacuo, followed by purification on silica gel using hexane–ethyl
acetate (3:1), afforded the pure C-glycosyl amide. Spectral data for selected
products: Major isomer 3a: ½a D27
ꢁ
11.6 (c 2.5, chloroform); IR (KBr): mmax: 3393,
2924, 2853, 1740, 1694, 1597, 1513, 1453, 1372, 1322, 1232, 1143, 1084, 1045,
758 cmꢂ1 1H NMR (300 MHz, CDCl3): d 7.72 (m, 2H, Ar), 7.27 (t, J = 6.9 Hz, 1H,
.
NH), 7.31 (m, 2H, Ar), 5.98 (ddd, J = 10.5, 3.0, 1.7 Hz, 1H, H4), 5.86 (dt, J = 10.4,
ꢃ2.9 Hz, 1H, H5), 5.06 (ddt, J = 5.9, 1.7, ꢃ3.0 Hz, 1H, H3), 4.70 (dd, J = 13.9,
7.4 Hz, 1H, H7), 4.54 (q, J = ꢃ2.8 Hz, 1H, H6), 4.51 (dd, J = 13.9, 6.4 Hz, 1H, H70),
4.21 (dd, J = 11.9, 3.7 Hz, 1H, H1), 4.17 (dd, J = 11.9, 7.5 Hz, 1H, H10), 3.90 (ddd,
J = 7.5, 5.9, 3.7 Hz, 1H, H2), 2.46 (s, 3H, Me), 2.19 (s, 3H, OAc), 2.14 (s, 3H, OAc).
13C NMR (75 MHz, CDCl3): d 170.8, 170.1, 168.2, 145.5, 133.5, 129.9, 128.8,
127.6, 124.8, 72.8, 71.9, 64.0, 62.6, 59.6, 21.6, 20.8, 20.6. LC–MS: m/z: 448.0
(M+Na). HRMS calcd for C19H23NO8NaS: 448.1015; found: 448.1012.
Minor isomer 3a0: 1H NMR (500 MHz, CDCl3): d 7.72 (m, 2H, Ar), 7.31 (m, 2H,
Ar), 7.23 (t, J = 6.6 Hz, 1H, NH), 5.80 (dt, J = 10.5, ꢃ1.6 Hz, 1H, H4), 5.76 (dt,
J = 10.5, ꢃ1.6 Hz, 1H, H5), 5.28 (ddd, J = 9.2, 3.3, 1.6 Hz, 1H, H3), 4.73 (dd,
J = 13.9, 7.4 Hz, 1H, H7), 4.56 (dt, J = 3.3, ꢃ1.6 Hz, 1H, H6), 4.44 (dd, J = 13.9,
5.7 Hz, 1H, H70), 4.31 (dd, J = 12.4, 2.6 Hz, 1H, H1), 4.25 (dd, J = 12.4, 5.2 Hz, 1H,
H10), 3.76 (ddd, J = 9.2, 5.2, 2.5 Hz, 1H, H2), 2.46 (s, 3H, Me), 2.17 (s, 3H, OAc),
2.10 (s, 3H, OAc).
Acknowledgement
D.N.C. thanks UGC, New Delhi, for the award of fellowship.
References and notes
1. (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545; (b) Hanessian, S. C. Total
Synthesis of Natural Products: The Chiron Approach; Pergamon Press: Oxford,
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2. (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976; (b)
Paterson, L.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727; (c) Horita, K.;
Sakurai, Y.; Nagasawa, M.; Hachiya, S.; Yonemistu, O. Synlett 1994, 43.
3. Suhadolnik, R. J. Nucleoside Antibiotics; Wiley-Interscience: New York, 1970.
4. Weatherman, R. V.; Mortell, K. H.; Chervenak, M.; Kiessling, L. L.; Toone, E. J.
Biochemistry 1996, 35, 3619.
5. Williams, N. R.; Wander, J. D. In The Carbohydrates. Chemistry and Biochemistry;
Academic Press: New York, 1980; pp 761–798.
6. (a) Ferrier, R. J. J. Chem. Soc. (C) 1964, 5443; (b) Ferrier, R. J.; Ciment, D. M. J.
Chem. Soc. (C) 1966, 441; (c) Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 570.
For a recent review on the Ferrier rearrangement, see: (d) Ferrier, R. J. Top. Curr.
Chem. 2001, 215, 153.
7. (a) Danishefsky, S. J.; Denin, S.; Lartey, P. J. Am. Chem. Soc. 1987, 109, 2082; (b)
De Raadt, A.; Griegl, H.; Klempic, N.; Stutz, A. E. J. Org. Chem. 1993, 58, 3179; (c)
De-Las Heras, F. G.; Felix, A. S.; Ferdanzandez-Risa, P. Tetrahedron 1983, 39,
1617; (d) Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M. Chem. Lett. 1993,
2013; (e) Toshima, K.; Miyamito, N.; Matsuo, G.; Nakata, M.; Matsumura, S. J.
Chem. Soc., Chem. Commun. 1996, 1379.
8. (a) Dawe, R. D.; Fraser-Reid, B. J. Chem. Soc., Chem. Commun. 1981, 1180; (b)
Hayashi, M.; Kawabata, H.; Inoue, K. Carbohydr. Res. 2000, 325, 68; (c) Takhi, M.;
Adel, A.-H. A. R.; Schimdt, R. R. Tetrahedron Lett. 2001, 42, 4053; (d) Yadav, J. S.;
Reddy, B. V. S.; Chand, P. K. Tetrahedron Lett. 2001, 42, 4057; (e) Danishefsky, S.
J.; Keerwin, J. F. J. Org. Chem. 1982, 47, 3803.
Major isomer 3b: ½a D27
ꢁ
49.8 (c 1.0, chloroform); IR (KBr)
m
max: 3408, 2929, 1715,
.
1656, 1515, 1455, 1374, 1346, 1177, 1068, 986, 759 cmꢂ1
1H NMR (300 MHz,
CDCl3): d 6.55 (d, J = 8.2 Hz, 1H), 5.92–5.81 (m, 2H), 5.12–5.05 (m. 1H), 4.63–
4.59 (m, 1H), 4.22–4.10 (m, 2H), 3.95–3.85 (m, 1H), 2.16 (s, 3H), 2.10 (s, 3H),
1.98–1.10 (m, 11H). 13C NMR (75 MHz, CDCl3): d 170.8, 170.2, 169.9, 145.0,
133.1, 73.0, 71.6, 64.3, 62.2, 47.0, 32.9, 25.3, 24.6, 20.8, 20.6. LC–MS: m/z: 362.0
(M+Na). HRMS calcd for C17H25NO6 Na: 362.1579; found: 362.1591.
Major isomer 3d: ½a D20
ꢁ
ꢂ7.7 (c 1.13, chloroform); IR (KBr)
m
max: 3132, 2929,
2856, 2657, 1630, 1510, 1384, 1255, 1086, 835, 773, 699, 624 cmꢂ1
.
1H NMR
(300 MHz, CDCl3): d 7.79–7.67 (m, 3H), 7.38–7.18 (m, 12H), 5.98–5.84 (m, 2H),
4.62–4.39 (m, 7H), 3.80–3.63 (m, 3H), 3.49 (dd, J = 9.8, 7.5 Hz, 1H), 2.37 (s, 3H).
13C NMR (75 MHz, CDCl3): d 169.2, 144.9, 137.5, 133.6, 129.6, 128.6, 128.3,
128.2, 127.6, 127.5, 127.3, 125.9, 125.3, 74.5, 73.3, 72.7, 70.6, 69.2, 68.7, 59.6,
21.4. LC–MS: m/z: 544.2 (M+Na). HRMS calcd for C29H31NO6NaS: 544.1769;
found: 544.1761.
Major isomer 3i: ½a D20
ꢁ
ꢂ28.4 (c 1.15, chloroform) IR (KBr)
m
max: 3350, 2989,
2930, 2826, 1693, 1596, 1514, 1456, 1396, 1322, 1144, 1087, 753 cmꢂ1
.
1H
NMR (300 MHz, CDCl3): d 7.75–7.70 (m, 3H), 7.30 (d, J = 8.3 Hz, 2H), 5.87–6.60
(m, 2H), 4.54–4.67 (m, 2H), 4.40–4.44 (m, 1H), 3.52–3.71 (m, 2H), 3.46 (s, 3H),
3.38 (s, 3H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3): d 169.4, 145.5, 133.4, 129.7,
128.7, 126.9, 125.4, 74.2, 72.6, 71.4, 71.2, 59.8, 59.2, 56.1, 21.5. LC–MS: m/z:
392.1 (M+Na). HRMS calcd for C17H23NO6NaS: 392.1143; found: 392.1154.
Compound 3n: ½a 2D0
ꢂ136.7 (c 0.6 in chloroform); IR (KBr) m(max): 3344, 2927,
ꢁ
2857, 1734, 1693, 1596, 1515, 1372, 1322, 1238, 1144, 1086, 954, 815,
752 cmꢂ1 1H NMR (500 MHz, CDCl3): d 7.75 (m, 2H, Ar), 7.33 (m, 2H, Ar), 7.31
.
9. (a) Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1992, 33, 7911; (b) Huang, G.;
Isobe, M. Tetrahedron 2001, 57, 10241; (c) Tsukiyama, T.; Peters, S. C.; Isobe, M.
Synlett 1993, 413; (d) Hosokawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron Lett.
1998, 39, 1917.
(t, J = 7.0 Hz, 1H, NH), 5.93 (dt, J = 10.5, ꢃ1.7 Hz, 1H, H3), 5.76 (dt, J = 10.5,
ꢃ2.3 Hz, 1H, H4), 5.27(m, 1H, H2), 4.71 (dd, J = 14.2, 7.3 Hz, 1H, H6), 4.60 (dd,
J = 14.2, 6.8 Hz, 1H, H70), 4.50 (q, J ꢃ 2.3 Hz, 1H, H6), 4.17 (dd, J = 11.2, 5.2 Hz,
1H, H1), 3.60 (dd, J = 11.2, 7.4 Hz, 1H, H10), 2.44 (s, 3H, Me), 2.09 (s, 3H, OAc).
13C NMR (75 MHz, CDCl3): d 170.3, 168.6, 145.4, 133.4, 129.9, 128.8, 128.1,
125.8, 73.7, 65.3, 63.6, 59.4, 21.6, 20.8. LC–MS: m/z: 376 (M+Na). HRMS calcd
for C16H19NO6NaS: 376.0830; found, 376.0828.
10. Nicotra, F. Top. Curr. Chem. 1997, 187, 55.
11. (a) McMillan, K. G.; Tackett, M. N.; Dawson, A.; Fordyce, E.; Paton, R. M.
Carbohydr. Res. 2006, 341, 41; (b) Smith, M. D.; Long, D. D.; Marquess, D. G.;
Claridge, T. D. W.; Fleet, G. W. J. Chem. Commun. 1998, 2039.