Organoiridium complexes: Efficient catalysts for the formation of sugar acetals and ketals

Article abstract of DOI:10.1016/j.carres.2011.05.008

[Cp*IrCl₂]₂ is used as an efficient promoter for the synthesis of sugar acetals and ketals with good to excellent yields. The catalyst is found to be general for a wide range of sugars.

Full text of DOI:10.1016/j.carres.2011.05.008

Carbohydrate Research 346 (2011) 2007–2010
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Organoiridium complexes: efficient catalysts for the formation of sugar
acetals and ketals
⇑
⇑
Soumik Mandal , Prashant Ranjan Verma , Balaram Mukhopadhyay , Parna Gupta
Indian Institute of Science Education and Research-Kolkata (IISER-K), Mohanpur Campus, PO BCKV Campus Main Office, Mohanpur, Nadia, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
[Cp⁄IrCl2]2 is used as an efficient promoter for the synthesis of sugar acetals and ketals with good to excel-
lent yields. The catalyst is found to be general for a wide range of sugars.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 8 April 2011
Received in revised form 8 May 2011
Accepted 10 May 2011
Available online 14 May 2011
Keywords:
Organoiridium
Sugar acetals
Catalysis
Protecting group manipulations are the key to the success of oli-
gosaccharide synthesis. With the ever-increasing growth in the
demand for the medicinally relevant sugar molecules to determine
their applications in elucidating various biological pathways and
designing of future drugs or delivery agents,1 development of smar-
ter synthetic techniques is of constant requirement. Formation of
acetals and ketals for the protection of cis-diols is very common
and extremely useful for making building blocks for oligosaccharide
synthesis.2 Depending on the position of the cis-diols, acceptors can
be synthesized by the formation of acetals/ketals. Moreover, cyclic
ketals of sugars are often medicinally relevant, for example,
(BDMS),14 tetrabutylammonium tribromide (TBATB),15 heteroge-
neous catalysts like montmorillonite clay, Zeolite-HY, supported
catalysts like H2SO4 immobilized on silica,16 polymer bound PPh3
and I2.17 However, several drawbacks, such as harsh reaction condi-
tions, extensive purification, requirement of inert atmosphere, and
eventual loss in yields limit the use of the catalysts. Therefore, there
is a clear need of a simple but versatile technique to make these
important compounds in large scale.
Transition metal catalysts are often advantageous especially for
acid-labile substrates and substrates with multiple functionalities
where a mixture of products is possible. Thus, various complexes
of platinum,18 rhodium,19 iridium,20 ruthenium19,20, and palla-
dium18 are employed as catalysts for different organic reactions
including the synthesis of acetals. Recently, Crotti et al.21 reported
the use of [Cp⁄IrCl2]2 as the catalyst for the synthesis of glycerol
acetals and ketals with a range of aldehydes and ketones. To the
best of our knowledge, there is no report on the use of transition
metal catalysts for the synthesis of sugar acetals/ketals. The pres-
ent report describes the results obtained from the [Ir(cod)Cl]2
and [Cp⁄IrCl2]2-catalyzed sugar acetal/ketal formation reactions.
1,2:5,6-di-O-isopropylidene-D
-glucofuranose3 is known for its anti-
pyretic and anti-inflammatory activities with low toxicity. Due to
the wide applications of cyclic acetals/ketals of sugars, considerable
effort has been paid to develop strategies for the synthesis of these
molecules in large quantities.
The most traditional method uses dry acetone in the presence of
an acid for example, concd H2SO4,4 HClO4, or anhydrous ZnCl2.5 The
corresponding dimethyl acetals,6 ketals7, or enol-ethers8 have
earned their applications owing to its better reactivity. However,
the use of strong acids limits the scope of the application in the pres-
ence of other protecting groups. Therefore, several modifications are
made to increase the compatibility with commonly used protecting
groups. Literature evidences suggest a long list of catalysts that in-
cludes FeCl3,9 AlCl3,10 CuSO4,11 cerium(IV) ammonium nitrate
(CAN),12 VO(OTf)2ꢀxH2O,13 bromodimethylsulfonium bromide
To start with, commercially available D-glucose (1 mmol) was
suspended in dry acetone (2 mL) in a Schlenk flask. After flashing
the system with nitrogen, the catalyst (0.03 mmol) was introduced
and the reaction mixture was allowed to stir at 40 °C and the pro-
gress of the reaction was monitored by TLC. With [Ir(cod)Cl]2 as the
catalyst, the reaction took 8 h to complete whereas in the presence
of [Cp⁄IrCl2]2, TLC showed complete conversion within 2 h. Purifi-
cation of the product by flash chromatography using n-hexane–
EtOAc (3:1) and characterization of the product by spectroscopic
⇑
Corresponding authors.
E-mail addresses: sugarnet73@hotmail.com (B. Mukhopadhyay), parna.gupta@
gmail.com (P. Gupta).
means revealed that 1,2:5,6-di-O-isopropylidene-D-glucofuranose
is the only product in both reactions, however, the yields are 53%
Authors contributed equally.
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.05.008

2008
S. Mandal et al. / Carbohydrate Research 346 (2011) 2007–2010
and 89%, respectively (Scheme 1). Hence, [Cp⁄IrCl2]2 was chosen as
O
the preferred catalyst to study further. Replacing acetone with
more reactive 2,2-dimethoxypropane (2 equiv) in acetonitrile
resulted in a faster reaction (45 min) without any significant
change in the product yield.
O
O
dry acetone
40 o
O
D-glucose
C
1
O
HO
2
Once the conditions are optimized [Cp⁄IrCl2]2 was used for the
[Cp*IrCl2]2: 89%
[Ir(cod)Cl]2: 53%
acetonation of other hexoses:
D-galactose and
D
-mannose; pen-
toses:
L
-arabinose,
D
-xylose and
D-ribose; 6-deoxy hexoses:
Scheme 1. Organoiridium catalyzed synthesis of sugar acetonides.
L-rhamnose and the results are summarized in Table 1. The yields
Table 1
[Cp⁄IrCl2]2 catalyzed synthesis of isopropylidene and benzylidene derivatives of sugars and glycosides
No.
Starting materiala
Product
Method
Time (min)
Yieldb (%)
Ref.
22
O
O
O
A
B
120
45
89
90
D-Glucose
O
1
1
O
HO
2
O
OH
O
O
A
B
120
60
85
87
D
-Galactose
2
3
4
22
17
22
O
3
O
4
O
O
OH
O
D-Mannose
A
A
120
90
81
82
5
O
O
O
6
O
O
L-Arabinose
O
7
O
8
O
O
O
D
-Xylose
5
6
A
A
90
90
82
85
14
17
O
9
O
10
O
OH
HO
HO
D-Ribose
O
O
O
O
11
12
O
OH
L-Rhamnose
7
8
A
B
60
60
87
91
23
13
14
OMP
OMP
Me
HO
Me
HO
O
O
24
25
HO
O
OH
O
15
16
HO
HO
O
O
O
OMP
OMP
OMP
9
B
B
60
60
89
86
O
OH
OH
18
17
HO
HO
O
O
O
10
OMP
O
OH
OH
19
20

S. Mandal et al. / Carbohydrate Research 346 (2011) 2007–2010
2009
Table 1 (continued)
No.
Starting materiala
Product
Method
B
Time (min)
90
Yieldb (%)
83
Ref.
HO
HO
HO
O
OTBDPS
O
OTBDPS
O
11
OMP
OMP
O
OH
O
OH
21
22
O
Ph
Ph
O
HO
O
O
O
HO
HO
12
13
C
C
90
90
81
85
26
27
OH
OH
23
24
HO
O
O
O
HO
O
OMP
OMP
HO
HO
OH
OH
26
25
HO
O
Ph
O
O
HO
O
O
O
HO
HO
14
C
90
84
NPhTh
27
NPhTh
28
a
MP = p-methoxyphenyl, PhTh = phthalimido.
Yields are those obtained after chromatographic purification.
b
are good in all cases. The glycosides of different sugars also ended
up with the expected isopropylidene derivatives in good yields
when subjected to [Cp⁄IrCl2]2 catalyzed reaction (Table 1, entries
8–11).
The success with the isopropylidene formation triggered our
attention to envisage the scope of the catalyst for the synthesis of
benzylidene derivatives, another important and to some extent
inevitable protecting group in oligosaccharide syntheses. To our sat-
idium catalyst (0.03 mmol) was added and the mixture was
allowed to stir at 40 °C under argon atmosphere till the TLC (n-
hexane–EtOAc 2:1) showed complete conversion of the starting
material. The work-up and purification of the product was as
above.
1.1.3. Method C
To a suspension of the sugar/glycoside (1 mmol) in dry acetoni-
trile (3 mL) and a,a-dimethoxytoluene (2 mmol), the organoiridium
catalyst (0.03 mmol) was added and the mixture was allowed to stir
at 40 °C under argon atmosphere till the TLC (n-hexane–EtOAc 2:1)
showed complete conversion of the starting material. The work-up
and purification of the product were same as Method A.
isfaction, the reaction of propargyl b-
benzaldehyde dimethylacetal in the presence of [Cp⁄IrCl2]2 in dry
CH3CN afforded propargyl 4,6-O-benzylidene-b- -glucopyranoside
D-glucopyranoside (23) and
D
(24) in 81% yield. Similarly, derivatives of galactose and mannose
gave the desired benzylidene derivatives (Table 1, entries 12–14).
In conclusion, [Cp⁄IrCl2]2 is an efficient organometallic catalyst
for the syntheses of sugar isopropylidene and benzylidene deriva-
tives in mild condition. It is potentially an effective alternative of
the reported catalysts that require harsh reaction conditions and
extra precautions.
1.2. Spectroscopic data of new compounds
1.2.1. p-Methoxyphenyl 3,4-O-isopropylidene-a-L-arabino
pyranoside (20)
½
a 2D5 +102 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) d: 6.93 (d,
ꢁ
1. Experimental section
2H, J 9.0 Hz, C6H4OCH3), 6.77 (d, 2H, J 9.0 Hz, C6H4OCH3), 4.73 (d,
1H, J 7.2 Hz, H-1), 4.29–4.26 (m, 1H, H-4), 4.10 (dd, 1H, J 7.2 Hz,
H-2), 4.08 (dd, 1H, J 4.5 Hz, 7.2 Hz, H-3), 3.86 (dd, 1H, J 2.1 Hz,
12.9 Hz, H-5a), 3.82 (dd,1H, J 4.2 Hz, 12.9 Hz, H-5b), 3.75 (s, 3H,
C6H4OCH3), 2.94 (br s, 1H, OH), 1.54 (s, 3H, isopropylidene-CH3),
1.36 (s, 3H, isopropylidene-CH3). 13C NMR (75 MHz, CDCl3) d:
148.8, 136.7, 118.7 (2 ꢂ C), 114.7 (2 ꢂ C), (ArC), 110.2 (isopropyli-
dene-C), 101.5 (C-1), 77.9, 72.9, 72.4, 62.7 (C-5), 55.5 (C6H4OCH3),
27.8 (isopropylidene-CH3), 25.8 (isopropylidene-CH3). HRMS calcd
for C15H24O6N [M+NH4]+: 314.1604; found 314.1601.
1.1. General procedure for reactions
[Ir(cod)Cl]228 and [Cp⁄IrCl2]229 were prepared by following liter-
ature procedures and used directly for the reactions. Following
appropriate literature procedure the solvents were dried prior to
use in the reactions. All reactions were carried out in Schlenk appa-
ratus under argon atmosphere. Following are the methods applied
for the experiments described.
1.1.1. Method A
1.2.2. p-Methoxyphenyl 6-O-tert-butyldiphenylsilyl-3,4-O-
To a suspension of the sugar/glycoside (1 mmol) in dry acetone
(2 mL), the organoiridium catalyst (0.03 mmol) was added and the
mixture was allowed to stir at 40 °C under argon atmosphere till
the TLC (n-hexane–EtOAc 2:1) showed complete conversion of
the starting material. The mixture was evaporated in vacuo, the
residue was dissolved in CH2Cl2 (5 mL) and washed with brine
(5 mL). The organic layer was separated, dried (Na2SO4), filtered,
and evaporated to afford the crude product that was further puri-
fied by flash chromatography using n-hexane–EtOAc 2:1 as the
eluent.
isopropylidene-b-
D-galactopyranoside (22)
½ ꢁ
a 2D5
+122 (c 1.1, CHCl3). 1H NMR (CDCl3, 300 MHz) d: 7.59–7.19
(m, 10H, ArH), 6.91 (d, 2H, J 9.0 Hz, C6H4OCH3), 6.67 (d, 2H, J 9.0 Hz,
C6H4OCH3), 4.53 (d, 1H, J 8.1 Hz, H-1), 4.15 (br d, 1H, J 5.4 Hz, H-4),
4.04 (m, 1H, H-3), 3.87 (m, 3H, H-5, H-6ª, H-6b), 3.71 (dd, 1H, J
8.1 Hz, 9.3 Hz, H-2), 3.67 (s, 3H, C6H4OCH3), 2.62 (br s, 1H, OH),
1.43, 1.28 (2s, 6H, 2 ꢂ isopropylidene CH3), 1.01 (s, 9H, SiC(CH3)3).
13C NMR (CDCl3, 75 MHz) d: 155.5, 151.3, 135.7 (5 ꢂ C), 133.3,
129.8 (2 ꢂ C), 127.7 (4 ꢂ C), 118.7 (2 ꢂ C), 114.5 (2 ꢂ C) (ArC),
110.2 (C(CH3)2), 102.0 (C-1), 79.0, 74.2, 73.5, 73.4, 63.0 (C-6),
55.4 (C6H4OCH3), 28.3, 26.5 (2 ꢂ isopropylidene CH3), 27.0 (3 ꢂ C)
(SiC(CH3)3), 19.4 (SiC(CH3)3). HRMS calcd for C32H40O7SiNa
[M+Na]+: 587.2441; found 587.2439.
1.1.2. Method B
To a suspension of the sugar/glycoside (1 mmol) in dry aceto-
nitrile (3 mL) and 2,2-dimethoxypropane (2 mmol), the organoir-

2010
S. Mandal et al. / Carbohydrate Research 346 (2011) 2007–2010
4. (a) Stevens, J. D. Chem. Commun. 1969, 1140–1141; (b) Hughes, N. A.;
Speakman, P. R. H. Carbohydr. Res. 1965, 1, 171–175.
5. Wood, H. B., Jr.; Diehl, H. W.; Fletcher, H. G., Jr. J. Am. Chem. Soc. 1957, 79, 1986–
1988.
6. Kihlberg, J.; Frejd, T.; Jansson, K.; Magnusson, G. Carbohydr. Res. 1986, 152, 113–
130.
7. Barili, P. L.; Berti, G.; Catelani, G.; Colonna, F.; Marra, A. Tetrahedron Lett. 1986,
27, 2307–2310.
8. Hung, S.-C.; Chen, C.-S. J. Chin. Chem. Soc. 2000, 47, 1257–1262.
9. Singh, P. P.; Gharia, M. M.; Dasgupta, F.; Srivastava, H. C. Tetrahedron Lett. 1977,
439–440.
10. Lal, B.; Gidwani, R. M.; Rupp, R. H. Synthesis 1989, 711–713.
11. (a) Morgenlie, S. Acta Chem. Scand. 1973, 27, 3609–3610; (b) Morgenlie, S. Acta
Chem. Scand. Ser. B 1975, 29, 367–372.
12. Manzo, E.; Barone, G.; Parrilli, M. Synlett 2000, 887–889.
13. Lin, C.-C.; Jan, M.-D.; Weng, S.-S.; Lin, C.-C.; Chen, C.-T. Carbohydr. Res. 2006,
341, 1948–1953.
1.2.3. Propargyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-b-D-
glucopyranoside (28)
½
a 2D5 +93 (c 1.1, CHCl3). 1H NMR (500 MHz, CDCl3) d: 7.87–7.72
ꢁ
(m, 9H, ArH), 5.58 (s, 1H, CHPh), 5.50 (d, 1H, J 8.5 Hz, H-1), 4.72 (dd,
1H, J 8.5 Hz, 10.5 Hz, H-2), 4.40 (dd, 1H, J 5.0 Hz, 10.5 Hz, H-6a),
4.33, 4.28 (2dd, 2H, J 2.5 Hz, 16.0 Hz, CH2–C„CH), 4.26 (dd, 1H, J
2.5 Hz, 10.5 Hz, H-6b), 3.84 (t, 1H, J 10.5 Hz, H-3), 3.68 (m, 1H,
H-5), 3.63 (t, 1H, J 10.5 Hz, H-4), 2.25 (t, 1H, J 1.5 Hz, CH2–C„CH).
13C NMR (125 MHz, CDCl3) d: 167.5, 167.6 (2 ꢂ phthalimido C@O),
137.2, 135.9 (2 ꢂ C), 133.1 (2 ꢂ C), 130.8, 128.4 (3 ꢂ C), 127.4,
123.4, 123.2 (ArC), 101.0 (CHPh), 95.8 (C-1), 81.1, 74.3, 67.6, 67.4,
65.2, 55.3, 21.7 (CH2–C„CH), 21.7 (CH2–C„CH). HRMS calcd for
C
24H21O7NNa [M+Na]+: 458.1216; found 458.1211.
14. Khan, A. T.; Khan, M. M. Carbohydr. Res. 2010, 345, 154–159.
15. Khan, A. T.; Khan, M. M.; Adhikary, A. Carbohydr. Res. 2011, 346, 673–677.
16. Rajput, V. K.; Mukhopadhyay, B. Tetrahedron Lett. 2006, 47, 5939–5941.
17. Silvana, P.; Annalisa, G.; Daniele, D.; Mauro, D. N.; Giovanni, P. Synthesis 2006,
305–308.
Acknowledgments
18. Cataldo, M.; Nieddu, E.; Gavagnin, R.; Pinna, F.; Strukul, G. J. Mol. Catal. A: Chem.
1999, 142, 305–316.
19. Barbaro, P.; Bianchini, C.; Oberhauser, W.; Togni, A. J. Mol. Catal. A: Chem. 1999,
145, 139–146.
20. Sulu, M.; Venanzi, L. M. Helv. Chim.Acta 2001, 84, 898–907.
21. Crotti, C.; Farnetti, E.; Guidolin, N. Green Chem. 2010, 12, 2225–2231.
22. Rauter, A. P.; Ramôa-Ribeiro, F.; Fernandes, A. C.; Figueiredo, J. A. Tetrahedron
1995, 51, 6529–6540.
S.M. is thankful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, India for fellowship and P.R.V is thank-
ful to IISER-Kolkata for fellowship. The work is funded by the
Department of Science and Technology (DST), New Delhi, India
through a SERC Fast-Track Grant SR/S1/OC-67/2009.
23. Haines, A. H. Carbohydr. Res. 1965, 1, 214–217.
References
24. (a) Werz, D. B.; Seeberger, P. H. Angew. Chem., Int. Ed. 2005, 44, 6315–6318; (b)
Sarkar, K.; Mukherjee, I.; Roy, N. J. Carbohydr. Chem. 2003, 22, 95–108.
25. Roy, B.; Pramanik, K.; Mukhopadhyay, B. Glycoconjugate J. 2008, 25, 157–166.
26. Minoru, I.; Koichi, F.; Shoichi, K. Synlett 2002, 1409–1416.
27. (a) Nitz, M.; Bundle, D. R. J. Org. Chem. 2000, 65, 3064–3073; (b) Meijer, A.;
Ellervik, U. J. Org. Chem. 2004, 69, 6249–6256.
1. (a) Mansour, H. M.; Xu, Z.; Hickey, A. J. J. Pharm. Sci. 2010, 99, 3430–3441; (b)
Chen, G.; Amajjahe, S.; Stenzel, M. H. Chem. Commun. 2009, 1198–1200; (c)
Sears, P.; Wong, C.-H. Science 2001, 291, 2344.
2. (a) Mukherjee, D.; Shah, B. A.; Gupta, P.; Taneja, S. C. J. Org. Chem. 2007, 72,
8965–8968; (b) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-W.;
Lee, C.-C.; Chang, K.-L.; Hung, S.-C. Nature 2007, 446, 896–899.
3. Goi, A.; Bruzzese, T.; Notarianni, A. F.; Riva, M.; Ronchini, A. Arzneim.-Forsch./
Drug Res. 1979, 29, 986–990.
28. Herde, J. L.; Lambert, J. C.; Senoff, C. V. Inorg. Synth. 1974, 15, 18–20.
29. White, C.; Yates, A.; Maitlis, P. M. Inorg. Synth. 1992, 29, 228–234.