Truly catalytic and chemoselective cleavage of benzylidene acetal with phosphomolybdic acid supported on silica gel

Article abstract of DOI:10.1002/ejoc.200800963

Phosphomolybdic acid supported on silica gel provides a truly catalytic method for the chemoselective cleavage of benzylidene acetals having sensitive functional groups under mild conditions. It is easy to perform on large scale owing to minimal catalyst loading (0.5 mol-%). Several sensitive functional groups such as TBDPS ether, -OMs, -OAc, allyl ether, N-Boc, N-Fmoc and N-Cbz are stable under the reaction conditions. In addition, benzylidene acetal is selectively cleaved in the presence of isopropylidene ketal. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800963

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800963
Truly Catalytic and Chemoselective Cleavage of Benzylidene Acetal with
Phosphomolybdic Acid Supported on Silica Gel
Ponminor Senthil Kumar,[a] Gaddale Devanna Kishore Kumar,[a] and
Sundarababu Baskaran*[a]
Keywords: Chemoselectivity / Heterogeneous catalysis / Protecting groups / Supported catalysts
Phosphomolybdic acid supported on silica gel provides a
truly catalytic method for the chemoselective cleavage of
benzylidene acetals having sensitive functional groups under
mild conditions. It is easy to perform on large scale owing to
minimal catalyst loading (0.5 mol-%). Several sensitive func-
tional groups such as TBDPS ether, -OMs, -OAc, allyl ether,
N-Boc, N-Fmoc and N-Cbz are stable under the reaction con-
ditions. In addition, benzylidene acetal is selectively cleaved
in the presence of isopropylidene ketal.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
reagents such as FeCl3/SiO2,[8a] HClO4/SiO2,[8b] NaHSO4/
Introduction
[8c]
SiO2
and potassium peroxymonosulfate (Oxone) sup-
ported on neutral alumina[8d] have also been employed for
the deprotection of benzylidene acetals. Most of these
methods are difficult to perform on large scale due to the
usage of excess amounts of reagent, harsh reaction condi-
tions/reagents, tedious aqueous workup procedure or lack
of selectivity.
One of the foremost challenges currently facing synthetic
organic chemistry is the demand for alternative methods
that are simple, environmentally friendly, highly chemo- and
regioselective and also more convenient for industrial appli-
cations. The key to waste minimization in fine chemical syn-
thesis is the widespread substitution of classical organic re-
actions employing stoichiometric amounts of reagents with
cleaner and catalytic alternatives. Whereas many supported
reagents are stoichiometric in nature, the successful devel-
opment of “truly catalytic” supported reagents will greatly
enhance their application in green synthesis. Recently, het-
eropoly acids (HPAs) have gained considerable attention in
organic synthesis and numerous environmentally benign
chemical transformations have been reported.[1] HPAs are
environmentally friendly and economically feasible solid ac-
ids exhibiting higher catalytic behaviour, unique selectivi-
ties, cleaner reaction profiles and well-known bifunctional
(acid and redox) catalysts.[2,3] Because bulk HPAs have low
specific surfaces, supported heteropoly acids are more
widely used than typical solid acids.[1a] In particular, phos-
phomolybdic acid supported on silica gel (PMA/SiO2) is
found to be an excellent catalyst for various environmen-
tally benign organic transformations.[4,5]
Results and Discussion
In this communication, we report a truly catalytic, non-
aqueous and efficient method for the chemoselective cleav-
age of benzylidene acetals by using PMA supported on sil-
ica gel as a catalyst under mild conditions (Scheme 1). Pre-
liminary studies revealed selective cleavage of six-membered
benzylidene acetal 1 with PMA (0.1 mol-%) in CH3CN un-
der homogeneous conditions.
Scheme 1. Catalytic chemoselective cleavage of benzylidene acetals
with PMA supported on silica gel.
In order to improve the efficacy of the reaction, we inves-
tigated several variables, and the results are summarized in
Table 1. After much experimentation, it was found that
0.5 mol-% of PMA/SiO2 effectively catalyzed the cleavage
of benzylidene acetal 1 under heterogeneous (dichlorometh-
ane, DCM) as well as under homogeneous conditions
(CH3CN) at room temperature to give the corresponding
diol 2 in good yield. This reaction worked equally well in
other organic solvents such as ethyl acetate, THF and hex-
ane, albeit at a slower rate.
Chemoselective deprotection of benzylidene acetal is one
of the most important transformations in carbohydrate
chemistry. Various reagent systems are known for the de-
protection of benzylidene acetals.[6,7] In addition, supported
[a] Department of Chemistry, Indian Institute of Technology,
Madras, Chennai – 36, India
Fax: +91-44-22570545
E-mail: sbhaskar@iitm.ac.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 6063–6067
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6063

P. S. Kumar, G. D. K. Kumar, S. Baskaran
SHORT COMMUNICATION
Table 1. The effect of solvent on the cleavage of benzylidene acetal
1 catalyzed by PMA/SiO2.
Table 2. PMA/SiO2 catalyzed cleavage of benzylidene acetals de-
rived from carbohydrates.[a]
Yield [%]
Entry
PMA/SiO2 loading
Solvent
Time [h]
[a]
1
2
3
4
5
6
0.1 mol-%
0.1 mol-%
0.5 mol-%
0.5 mol-%
THF
CH3CN
CH3CN
DCM
DCM
DCM
10
12
3
4.5
2
61
52
76
76[b]
74
1 mol-%
0.5 mol-% (1st cycle)
0.5 mol-% (2nd cy-
cle)
4.5
76
7
8
DCM
DCM
4.5
4.5
76
75
0.5 mol-% (3rd cycle)
[a] Yield refers to pure isolated product. [b] TON = 152; TOF =
34 h–1.
Because this method requires only 0.5 mol-% of the cata-
lyst, it can be readily implemented on large scale. In ad-
dition, the catalyst can be readily recovered and recycled.
The efficiency (turnover frequency, TOF = 34 h–1) and sta-
bility (turnover number, TON = 152) of the catalyst were
found to be very good even after three cycles. HRTEM
studies before and after the reactions of the supported cata-
lyst revealed that the catalyst is uniformly dispersed over
the silica support and there is no significant change in the
morphology of the catalyst even after three cycles (Fig-
ure 1).
Figure 1. HRTEM studies of the supported catalyst (a) before and
(b) after the reaction (three cycles).
Encouraged by these findings, detailed studies towards
the deprotection of benzylidene acetals were undertaken,
and the results are summarized in Table 2. Labile functional
groups such as TBDPS ether, -OMs, -OAc, allyl ether, io-
dide and azide were found to be stable under the reaction
condition. The reactions were usually performed on a
multigram scale and the catalyst was readily recovered and
recycled.
[a] Reaction was carried out in DCM under heterogeneous condi-
tions. [b] Yield refers to pure isolated product. [c] Reaction was car-
ried out in CH3CN under homogeneous conditions.
During these studies, we also observed that compounds from carbohydrate molecules (Table 3). A high degree of
13, 15 and 15a underwent smooth deprotection of benzyl- chemoselectivity was observed in these reactions, and the
idene acetal followed by in situ lactonization mediated by results are summarized in Table 3. Sensitive functional
PMA/SiO2 to give the corresponding functionalized chiral groups such as isopropylidene ketals, -OAc and -OMs were
lactones 14, 16 and 16a, respectively, in good yields found to be stable under the reaction conditions. Intrigu-
(Table 2, entries 7 and 8). These functionalized chiral lac- ingly, benzylidene acetal was selectively deprotected in the
tones are important intermediates in the synthesis of vari- presence of acid-labile isopropylidene ketal under hetero-
ous natural products.[9]
geneous conditions (Table 3, entries 1–3).[10] Furthermore,
Further, the efficiency of the catalytic system was also methyl-2,3,4,6-di-O-benzylidene-α--mannopyranoside (25)
investigated in the cleavage of benzylidene acetals derived having both five- and six-membered benzylidene acetals, re-
6064
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6063–6067

Truly Catalytic and Chemoselective Cleavage of Benzylidene Acetal
acted readily in a chemoselective manner to give the corre- Table 4. PMA/SiO2 catalyzed cleavage of benzylidene acetals.[a]
sponding methyl-4,6-O-benzylidene-α--mannopyranoside
(26) in good yield (Table 3, entry 5).
Table 3. PMA/SiO2 catalyzed cleavage of N-protected-2-phenyl-1,3-
oxazolidines.[a]
[a] Reaction was carried out in DCM under heterogeneous condi-
tions. [b] Yield refers to pure isolated product. [c] Reaction was car-
ried out in CH3CN under homogeneous conditions.
The synthetic utility of our novel catalytic system was
further explored in the synthesis of 2-hydroxymethyl-3-pip-
eridinol (2-epi-4-deoxyfagomine, 41), which is an important
intermediate in the synthesis of several biologically active
and pharmaceutically important piperidine alkaloids
(Scheme 3).[12] The structure and the relative stereochemis-
try of 2-epi-4-deoxyfagomine (41) were unambiguously con-
firmed by single-crystal X-ray analysis (Figure 2).[13]
[a] Reaction was carried out in DCM with PMA/SiO2 (0.5 mol-%)
under heterogeneous conditions. [b] Yield refers to pure isolated
product.
Similarly, the reactivity of N-protected-2-phenyl-1,3-ox-
azolidines towards PMA/SiO2 were examined (Scheme 2).
As expected, under the reaction conditions 2-phenyl-1,3-ox-
azolidines underwent smooth cleavage to give the corre-
sponding synthetically useful N-protected chiral vicinal
amino alcohols in good yields (Table 4).[11] Interestingly,
protecting groups such as N-Boc, N-Fmoc and N-Cbz were
found to be stable under the reaction conditions.
Scheme 3. Synthesis of 2-epi-4-deoxyfagomine (41).
The wide-ranging application of this methodology was
further extended towards the synthesis of the δ-lactam de-
rivative of 2-epi-4-deoxyfagomine (42; Scheme 4), which has
Scheme 2. PMA/SiO2 catalyzed cleavage of N-Boc protected 2-
phenyl-1,3-oxazolidine.
Eur. J. Org. Chem. 2008, 6063–6067
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6065

P. S. Kumar, G. D. K. Kumar, S. Baskaran
SHORT COMMUNICATION
(m, 2 H), 3.61–3.59 (m, 1 H), 3.3 (br. s, 1 H), 2.65–2.62 (m, 1 H),
2.59–2.50 (m, 1 H), 2.38–2.36 (m, 1 H), 2.20–2.18 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 177.14, 78.8, 65.6, 61.9, 28.0,
24.5 ppm. HRMS (ESI): calcd. for C6H9N3O3Na [M + Na]+
194.0542; found 194.0546.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and full spectroscopic data.
Acknowledgments
This work was financially supported by the Council of Scientific
and Industrial Research (CSIR), New Delhi. The authors thank
the Department of Science & Technology (DST), New Delhi, for
NMR and HRTEM facilities. P. S. K thanks the Council of Scien-
tific and Industrial Research (CSIR), New Delhi, for a research
fellowship.
Figure 2. ORTEP diagram of 2-epi-4-deoxyfagomine (41).
[1] a) I. V. Kozhevnikov, Chem. Rev. 1998, 98, 171–198; b) N. Mi-
zuno, M. Misono, Chem. Rev. 1998, 98, 199–218; c) J. Masam-
oto, K. Hamanaka, K. Yoshida, H. Nagahara, K. Kagawa, T.
Iwaisako, H. Komai, Angew. Chem. Int. Ed. 2000, 39, 2102–
2104; d) I. V. Kozhevnikov, S. M. Kulikov, N. G. Chukaeva,
A. T. Kirsanov, A. B. Letunova, V. I. Blinova, React. Kinet. Ca-
tal. Lett. 1992, 47, 59–64; e) Y. Ishii, K. Yamawaki, T. Ura, H.
Yamada, T. Yoshida, M. Ogawa, J. Org. Chem. 1988, 53, 3587–
3593; f) Y. Izumi, K. Hayashi, Chem. Lett. 1980, 787–790; g)
Y. Izumi, R. Hasebe, K. Urabe, J. Catal. 1983, 84, 402–409.
[2] a) H. Hamamoto, Y. Shiozaki, H. Nambu, K. Hata, H. Tohma,
Y. Kita, Chem. Eur. J. 2004, 10, 4977–4982; b) G. Smitha, B.
Miriyala, J. S. Williamson, Synlett 2005, 5, 839–841; c) K. Na-
gaiah, D. Sreenu, R. S. Rao, G. Vashishta, J. S. Yadav, Tetrahe-
dron Lett. 2006, 47, 4409–4413; d) E. Rafiee, F. Tork, M. Josh-
aghani, Bioorg. Med. Chem. Lett. 2006, 16, 1221–1226.
[3] a) M. Misono, I. Ono, G. Koyano, A. Aoshima, Pure Appl.
Chem. 2000, 72, 1305–1311; b) K. Wilson, J. H. Clark, Pure
Appl. Chem. 2000, 72, 1313–1319; c) J. Kaur, I. V. Kozhevnikov,
Chem. Commun. 2002, 21, 2508–2509; d) N. Azizi, L. Torkiyan,
M. R. Saidi, Org. Lett. 2006, 8, 2079–2082; e) N. Azizi, M. R.
Saidi, Tetrahedron 2007, 63, 888–891; f) E. Rafiee, H. Jafari,
Bioorg. Med. Chem. Lett. 2006, 16, 2463–2466.
also been found to be an important intermediate in the
synthesis of various biologically active 2,3,6-trisubstituted
piperidine alkaloids.[15]
Scheme 4. Synthesis of (5S,6S)-5-hydroxy-6-(hydroxymethyl)piper-
idin-2-one (42).
Conclusions
We developed a simple and an efficient method for the
chemoselective cleavage of benzylidene acetal and 2-phenyl-
1,3-oxazolidine by using PMA/SiO2 (0.5 mol-%) as a cata-
lyst under heterogeneous conditions. The remarkable fea-
tures of our method are mild and clean reaction conditions,
simplicity in operation even on large scale and, finally, the
active catalyst can be readily recovered and recycled with-
out any loss of activity. The chemoselective nature of the
PMA/SiO2 reagent system was exploited in the stereoselec-
tive synthesis of 2-epi-4-deoxyfagomine and its analogues.
We believe that this truly catalytic method for the selective
deprotection of benzylidene acetal will find practical appli-
cation in organic synthesis.
[4] a) G. D. Kishore Kumar, S. Baskaran, J. Org. Chem. 2005, 70,
4520–4523; b) G. D. Kishore Kumar, S. Baskaran, Synlett
2004, 10, 1719–1722; c) G. D. Kishore Kumar, S. Baskaran,
Chem. Commun. 2004, 8, 1026–1027.
[5] a) J. S. Yadav, S. Raghavendra, M. Satyanarayana, E. Balanar-
saiah, Synlett 2005, 16, 2461–2464; b) J. S. Yadav, M. Satyana-
rayana, E. Balanarsaiah, S. Raghavendra, Tetrahedron Lett.
2006, 47, 6095–6098; c) J. S. Yadav, B. V. S. Reddy, T. Pandur-
angam, K. V. R. Rao, K. Praneeth, G. G. K. S. N. Kumar, C.
Madavi, A. C. Kunwar, Tetrahedron Lett. 2008, 49, 4296–4301;
d) M. M. M. A. El-Wahab, A. A. Said, J. Mol. Catal. A 2005,
240, 109–118; e) P. L. Majumder, M. Basak, Tetrahedron 1991,
47, 8601–8610; f) J. S. Yadav, B. V. S. Reddy, A. S. Reddy, J.
Mol. Catal. A 2008, 280, 219–223; g) J. S. Yadav, B. V. S. Reddy,
T. Pandurangam, Y. J. Reddy, M. K. Gupta, Catal. Commun.
2008, 9, 1297–1301; h) J. S. Yadav, B. V. S. Reddy, T. S. Rao, R.
Narender, M. K. Gupta, J. Mol. Catal. A 2007, 278, 42–46.
[6] a) T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 1999; b) J. P. Kocien´-
ski, Protecting Groups, Thieme, New York, 1994; c) B. Capon,
W. G. Overend, M. Sobell, Tetrahedron 1961, 16, 106–112; d)
G. Barone, E. Bedini, A. Iadonisi, E. Manzo, M. Parrilli, Syn-
lett 2002, 10, 1645–1648; e) Y. Ming-Chung, C. Yeng-Nan, W.
Huan-Ting, L. Chang-Ching, C. Chien-Tien, L. Chun-Cheng,
J. Org. Chem. 2007, 72, 299–302; f) A. Procopio, R. Dalpozzo,
A. D. Nino, L. Maiuolo, M. Nardi, G. Romeo, Org. Biomol.
Chem. 2005, 3, 4129–4133.
Experimental Section
General Procedure: A mixture of benzylidene acetal 13 (2 g,
6.56 mmol) and PMA/SiO2 (740 mg, 0.0327 mmol based on PMA)
in DCM (25 mL) was stirred at room temperature for 4 h. After
completion of the reaction, as indicated by TLC, the reaction mix-
ture was filtered to recover the catalyst and the filtrate was concen-
trated under reduced pressure. The crude product was purified by
column chromatography (silica gel; 30–50% EtOAc in hexane) to
give the corresponding chiral lactone 14 in good yield (0.998 g,
89%). Physical data for 14: [α]2D6 = +49.8 (c = 1, CHCl3). IR (neat):
ν = 3395, 2925, 2100, 1758, 1268, 1182, 1156, 1060, 916, 809 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 4.69–4.66 (m, 1 H), 3.87–3.86
6066
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6063–6067

Truly Catalytic and Chemoselective Cleavage of Benzylidene Acetal
[7] a) P. Meresse, C. Monneret, E. Bertounesque, Tetrahedron
2004, 60, 2657–2671; b) W. A. Szarek, A. Zamojski, K. N. Ti-
wari, E. R. Ison, Tetrahedron Lett. 1986, 27, 3827–3830; c) T.
Bieg, W. Szeja, Synthesis 1986, 317–318; d) L. Shi, W. J. Xia,
F. M. Zhang, Y. Q. Tu, Synlett 2002, 1505–1507; e) A. Zak-
arian, A. Batch, R. A. Holton, J. Am. Chem. Soc. 2003, 125,
7822–7824.
[8] a) K. S. Kim, Y. H. Song, B. H. Lee, C. S. Hahn, J. Org. Chem.
1986, 51, 404–407; b) A. Geetanjali, A. K. Misra, Tetrahedron
Lett. 2006, 47, 3653–3658; c) Y. Niu, N. Wang, X. Cao, X.-S.
Ye, Synlett 2007, 13, 2116–2120; d) S. Bose, B. Jayalakshmi,
A. V. Narsaiah, Synthesis 2000, 67–68.
[9] a) M. B. Angela, F. Angelo, P. P. Pier, S. Francesco, Org. Lett.
2003, 5, 2923–2926; b) H. K. Sung, T. K. Geun, Tetrahedron
Lett. 1995, 36, 5049–5052; c) P. C. Subhash, P. Cherukupally,
S. Pallavi, U. R. Kalkote, Tetrahedron Lett. 2005, 46, 439–441;
d) P. Velimir, K. Ivana, P. Mirjana, S. Bojana, B. Goran, K.
Vesna, B. Gordana, Tetrahedron 2006, 62, 11044–11053; e) W.
Zhi-Min, Z. Xiu-Lian, K. B. Sharpless, S. C. Sinhaa, A. S.
Bagchia, E. Keina, Tetrahedron Lett. 1992, 33, 6407–6410; f)
P. C. Subhash, P. Cherukupally, Tetrahedron Lett. 2004, 45,
421–423.
[12]
[13]
a) I. S. Kim, J. S. Oh, O. P. Zee, Y. H. Jung, Tetrahedron 2007,
63, 2622–2633; b) H. Takahata, Y. Banba, H. Ouchi, H. Nem-
oto, A. Kato, I. Adachi, J. Org. Chem. 2003, 68, 3603–3607; c)
Y. Banba, C. Abe, H. Nemoto, A. Kato, I. Adachi, H. Takah-
ata, Tetrahedron: Asymmetry 2001, 12, 817–819.
CCDC-664806 (for 41) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[14] U. R. Jong, I. B. Brian, T. V. RajanBabu, J. Am. Chem. Soc.
2003, 125, 1492–1493.
[15] a) S. D. Koulocheri, M. Prokopios, S. A. Haroutounian, J. Org.
Chem. 2001, 66, 7915–7918; b) C. Bo-Fong, T. Min-Ruei, Y.
Cheng-Yu, C. Jung-Kai, C. Nein-Chen, Tetrahedron 2004, 60,
10223–10231; c) T. Naoki, Y. Yasuko, Y. Yasuhito, M. Takef-
umi, J. Org. Chem. 1999, 64, 4914–4919; d) W. Bang-Guo, C.
Jie, H. Pei-Qiang, Tetrahedron 2006, 62, 190–198; e) S. D. Koul-
ocheri, M. Prokopios, S. Alexios-Leandros, S. A. Haroutoun-
ian, Tetrahedron 2002, 58, 6665–6671; f) T. Naoki, Y. Yasuko,
M. Takefumi, Tetrahedron Lett. 1995, 36, 3715–3718; g) K. L.
Hyeon, S. C. Jong, S. P. Chwang, Tetrahedron Lett. 2001, 42,
3483–3486; h) K. L. Hyeon, S. C. Jong, S. P. Chwang, Tetrahe-
dron 2003, 59, 6445–6454.
[10] The hydrolysis of isopropylidene ketal with PMA has been re-
ported under homogeneous conditions.[4a]
Received: October 1, 2008
Published Online: November 12, 2008
[11] E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Comprehensive
Asymmetric Catalysis, Springer, Heidelberg, 1999.
Eur. J. Org. Chem. 2008, 6063–6067
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6067