A highly regio- and chemoselective reductive cleavage of benzylidene acetals with EtAlCl2-Et3SiH

Article abstract of DOI:10.1055/s-2004-817752

A highly regio- and chemoselective reductive cleavage of benzylidene acetals derived from 1,2- and 1,3-diols was achieved under mild conditions using EtAlCl₂-Et₃SiH reagent system in good to excellent yields. Labile protecting groups

Full text of DOI:10.1055/s-2004-817752

LETTER
647
A Highly Regio- and Chemoselective Reductive Cleavage of Benzylidene
Acetals with EtAlCl2–Et3SiH
R
eductive Cleava
g
i
e
of Be
j
nzylide
a
ne Acetalsy2 3
w
ith EtAlCl
a
–Et SiH krishnan Balakumar, Appu Aravind, Sundarababu Baskaran*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
Fax +91(44)22570545; E-mail: sbhaskar@iitm.ac.in
Received 5 December 2003
To explore the feasibility of the EtAlCl2–Et3SiH reagent
system in the regioselective reductive cleavage of ben-
zylidene acetal, the dioxolane A derived from styrene diol
was chosen as a model substrate (Scheme 1). A detailed
Abstract: A highly regio- and chemoselective reductive cleavage
of benzylidene acetals derived from 1,2- and 1,3-diols was achieved
under mild conditions using EtAlCl2–Et3SiH reagent system in
good to excellent yields. Labile protecting groups such as N-Boc, N-
Cbz and -OTBDMS are found to be stable under the reaction condi- study was carried out using different Lewis acids and the
tions.
results are shown in Table 1. Interestingly, EtAlCl2 was
found to be an excellent Lewis acid to bring about this
transformation in a highly regioselective manner and in
good yield. The formation of the primary alcohol can be
rationalized by the steric hindrance of the phenyl group,
which directs the coordination of the Lewis acid to the
dioxolane ring oxygen from the less hindered side.
Key words: regioselectivity, chemoselectivity, reductive cleavage,
benzylidene acetal, EtAlCl2, Et3SiH
Protection and deprotection of hydroxy group play a
prominent role in organic synthesis, especially com-
pounds containing more than one hydroxy group.1 Benz-
ylidene acetal is a widely used protecting group, due to its
tolerance to a wide variety of reagents as well as deprotec-
tion under mild conditions. The reductive cleavage of
benzylidene acetal is an important transformation as it
leads to synthetically useful mono-protected diols. The
reductive cleavage of benzylidene acetal to form primary
or secondary alcohols was achieved using various reduc-
ing agents. These include LiAlH4–AlCl3,2 DIBAL-H,3
NaBH3CN–HCl,4 CF3COOH–Et3SiH,5 BF3·OEt2–Et3SiH6
and others.7 However, many of these methods suffer from
one or more drawbacks such as excessive use of hydride
source, incongruity with other functional groups and mod-
erate yield. Interestingly, alkyl aluminum halides offer
many advantages over conventional Lewis acids such as
BF3, AlCl3, TiCl4 and InCl3. Alkyl aluminum halides min-
imize the hydrolysis of the acid sensitive functional
groups, as they would not allow the formation of any pro-
tic acid by virtue of their inherent ability to scavenge the
adventitious protons.8 It has been used effectively to cata-
lyze the intramolecular Diels–Alder reactions,9 Ene reac-
tions,10 Sakurai reactions11 and [2+2] cycloaddition
reactions.12 Furthermore, EtAlCl2 in combination with
Et3SiH has been used for the reductive elimination of al-
lylic acetates13 and deoxygenation of benzylic alcohols.14
Recently, we observed a highly stereoselective opening of
epoxide–azides with EtAlCl2, leading to azabicyclic
compounds.15 In this communication, we report a highly
regio- and chemoselective reductive cleavage of benz-
ylidene acetal using EtAlCl2 as a Lewis acid in combina-
tion with Et3SiH.
Ph
Lewis Acid
Ph
Ph
O
O
OH
OBn
+
Et3SiH, CH2Cl2
OBn
OH
Ph
C
B
A
Scheme 1
The regio- and chemoselective reductive cleavage of benz-
ylidene acetals bearing different functional groups were
studied with EtAlCl2–Et3SiH and the results are summa-
rized in Table 2. Benzylidene acetal, prepared from 2,2-
dimethyl-1,3-propane diol (entry 1), furnished the corre-
sponding mono benzylated product in excellent yield in a
shorter reaction time. Deprotection of N-Boc protective
group is often observed in the presence of Lewis acids,1,17
however under the reaction conditions, N-Boc protecting
group is found to be stable (entries 3–6). Moreover sensi-
tive functional groups like N-Cbz, -OTBDMS, -OMs and
-OAc are also found to be compatible under the reaction
conditions (entries 2, 5, 6, 7, 9, 11 and 12).
A high degree of chemoselectivity was observed in the
case of benzylidene acetal 17, where the dioxane ring
underwent a smooth reductive cleavage in preference to
the oxazolidine ring. Under similar reaction conditions
benzylidene acetal derived from (2R,4R)-pentanediol and
diethyl-L-tartarate (entries 8 and 10) furnished the corre-
sponding mono benzylated products in good yields with
high optical purity.18 The synthetic utility of this method-
ology was further exemplified in carbohydrate chemistry.
4,6-Di-O-benzylidene acetal derivative of glucose 21 was
smoothly reduced to the corresponding 6-O-Bn ether 22 in
excellent yield, demonstrating the complete regioselectiv-
ity of the reaction. In the case of 4,6-di-O-benzylidene
acetal derivative of mannose 23, 6-O-Bn ether 24 was
SYNLETT 2004, No. 4, pp 0647–0650
0
9.
0
3.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817752; Art ID: G34203ST
© Georg Thieme Verlag Stuttgart · New York

648
V. Balakumar et al.
LETTER
Table 1 Regioselective Reductive Cleavage of Benzylidene Acetal A with Various Lewis Acids
Entry
Lewis Acida
BF3·OEt2
CF3COOH
CF3SO3H
EtAlCl2
TiCl4
Temperature (°C)
Time (h)
% Yieldb (Conversion) Ratio (B/C)c
1
2
3
4
5
6
7
–78
0–25
–78
–78
–78
0–25
0
1
12 (40)d
19 (70)d
38 (48)
77 (100)
77 (100)
10 (58)d
70 (80)
6.5:1
1.5:1
7.5:1
10.1:1
2.4:1
6.0:1
1.6:1
4
1
0.5
0.5
5
InCl3
DIBAL-He
4
a 1.1 equiv of Lewis acid and 1.2 equiv of Et3SiH were used.
b Isolated yield.
c Based on NMR spectra of the purified product.
d Major process is acetal hydrolysis.
e See ref.16
observed as a major product. The formation of the 6-O-Bn the products in excellent yields under very mild condi-
ether in the case of glucose and mannose (entries 11 and tions. Labile protecting groups such as N-Cbz, N-Boc
12) is presumably due to chelation control.19 Interestingly, and -OTBDMS and sensitive functional groups such as
chemo- and regioselective reductive cleavage of isopro- -OMs and -OAc are found to be stable under the reaction
pylidene acetals was also realized in very good yields conditions. We believe this mild and efficient transforma-
under the reaction conditions (entries 13 and 14).
tion will find wide applications in organic synthesis.20
In summary, we have developed a highly regio- and
chemoselective reductive cleavage of benzylidene acetals
with EtAlCl2–Et3SiH. This reagent system furnished
Table 2 Regio- and Chemoselective Reductive Cleavage of Benzylidene Acetals with EtAlCl2–Et3SiH
Productb
Yield (%)c
89
a
Entry
1
Substrate
Equiv of EtAlCl2
Time (min)
30
1.1
H3C
O
H3C
OH
Ph
H3C
O
H3C
OBn
1
2
H3C
O
O
H3C
OH
Ph
R-HN
R-HN
OBn
2
3
3 R = Cbz
5 R = Boc
2.2
2.2
30
30
4 R = Cbz
6 R = Boc
78
76
BocHN
OH
BocHN
O
Ph
RO
OBn
RO
O
4
5
6
7 R = H
9 R = Ac
11 R = TBDMS
2.2
3.1
3.1
30
45
45
8 R = H
10 R = Ac
12 R = TBDMS
80
78
85
7
2.2
30
86
OBn
O
MsO
OH
MsO
Ph
O
13
14
8
1.1
30
70
Ph
OH OBn
O
O
16
15
Synlett 2004, No. 4, 647–650 © Thieme Stuttgart · New York

LETTER
Reductive Cleavage of Benzylidene Acetals with EtAlCl2–Et3SiH
649
Table 2 Regio- and Chemoselective Reductive Cleavage of Benzylidene Acetals with EtAlCl2–Et3SiH (continued)
Productb
Yield (%)c
98d
a
Entry
9
Substrate
Equiv of EtAlCl2
Time (min)
30
2.2
O
O
OH
O
O
Ph
N
Ph
N
OBn
Ph
Cbz
Cbz
17
18
10
3.1
30
86
O
O
O
HO
OEt
OEt
OEt
Ph
OEt
O
BnO
O
O
19
20
11
12
4.1
4.1
30
30
81
Ph
O
BnO
HO
O
O
O
AcO
AcO
AcO
AcO
OAc
OAc
OAc
21
22
91e
OAc
O
OAc
O
BnO
HO
AcO
Ph
O
O
AcO
OAc
24
23
13
14
3.1
1.1
30
30
85
O
O
O
O
HO
O
O
OEt
OEt
OEt
OEt
PriO
25
27
26
79f
HO
PriO
HO
OH
OH
O
PriO
OH
O
28a
28b
a 1.2 equiv of Et3SiH was used in all the cases.
b All the products were characterized by IR, 1H and 13C NMR spectroscopy.
c Yield of isolated product.
d 6:4 diastereomeric mixture.
e 6-O-Benzylated and 4-O-benzylated in 7:1 ratio.
f 28a and 28b in 8:1 ratio.
(5) Deninno, M. P.; Etienne, J. B.; Duplantier, K. C.
Acknowledgment
Tetrahedron Lett. 1995, 36, 669.
(6) Debenham, S. D.; Toone, E. J. Tetrahedron: Asymmetry
2000, 11, 385.
We thank CSIR and DST, New Delhi for the financial support. AA
(SRF) thanks CSIR, New Delhi for a fellowship.
(7) (a) Samuelsson, B.; Johanasson, R. J. Chem. Soc., Perkin
Trans. 1 1984, 2371. (b) Guindon, Y.; Girard, Y.;
References
Berthiaume, S.; Gorys, V.; Lemieux, R.; Yoakim, C. Can. J.
Chem. 1990, 68, 897. (c) Chan, T.-H.; Jiang, L. Tetrahedron
Lett. 1998, 39, 355. (d) Chandrasekar, S.; Reddy, Y. R.;
Reddy, C. R. Chem. Lett. 1998, 1273. (e) Sakagami, M.;
Hamana, H. Tetrahedron Lett. 2000, 41, 5547. (f) Wang,
C.-C.; Luo, S.-Y.; Shie, C.-R.; Hung, S.-C. Org. Lett. 2002,
4, 847. (g) Morelli, C. F.; Fornili, A.; Sironi, M.; Duri, L.;
Speranza, G.; Manittoa, P. Tetrahedron: Asymmetry 2002,
13, 2609. (h) Oikawa, M.; Liu, W.-C.; Nakai, Y.; Koshida,
S.; Fukase, K.; Kusumoto, S. Synlett 1996, 1179. (i) Seiki,
S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996, 231.
(8) Snider, B. B. Acc. Chem. Res. 1980, 13, 426.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(2) (a) Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975,
44, 1. (b) Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res.
1976, 52, 17. (c) Liptak, A.; Jodal, I.; Nanasi, P.
Tetrahedron 1982, 38, 3721.
(3) (a) Takano, S.; Akiyama, S.; Sato, S.; Ogasawara, K. Chem.
Lett. 1983, 1593. (b) Mikami, T.; Sasano, H.; Mitsunobu, O.
Chem. Lett. 1987, 2033. (c) Denmark, S. E.; Almstead, N.
G. J. Am. Chem. Soc. 1991, 113, 8089.
(4) (a) Garegg, J.; Hultberg, H.; Wallin, S. Carbohydr. Res.
1982, 108, 97. (b) Oleskar, A. G.; Cleophax, J.; Gero, S. D.
Tetrahedron Lett. 1986, 27, 41. (c) Kanie, O.; Takeda, T.;
Ogihara, Y. J. Carbohydr. Chem. 1990, 9, 159.
(9) (a) Smith, A. B.; Hale, K. J.; Laasko, L. M.; Chen, K.; Riera,
A. Tetrahedron Lett. 1989, 30, 6963. (b) Oppolzer, W.;
Dupuis, D. Tetrahedron Lett. 1985, 26, 5437.
Synlett 2004, No. 4, 647–650 © Thieme Stuttgart · New York

650
V. Balakumar et al.
LETTER
(10) (a) Snider, B. B.; Rodini, D. J.; Conn, R. S. E.; Sealfon, S. J.
Am. Chem. Soc. 1979, 101, 5283. (b) Snider, B. B.; Phillips,
G. B. J. Org. Chem. 1983, 48, 3685.
(11) (a) Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985,
50, 3615. (b) Majetich, G.; Khetani, V. Tetrahedron Lett.
1990, 31, 2243. (c) Schinzer, D. Synthesis 1988, 263.
(12) (a) Snider, B. B.; Spindell, D. K. J. Org. Chem. 1980, 45,
5017. (b) Snider, B. B.; Ron, E. J. Org. Chem. 1986, 51,
3643.
(13) Schreiber, S. L.; Kelly, S. E.; Porco, J. A. Jr.; Sammakia, T.;
Suh, E. M. J. Am. Chem. Soc. 1988, 110, 6210.
(14) Guanti, G.; Riva, R. Tetrahedron Lett. 1995, 36, 3933.
(15) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5,
583.
(16) Gautier, D. R. Jr.; Szumigala, R. H. Jr.; Armstrong, J. D.;
Volante, R. P. Tetrahedron Lett. 2001, 42, 7011.
(17) Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217.
(18) Compound 16 (see ref. 3c): [a]D25 = –53.6 (c = 1.14, CHCl3).
Compound 20 (see ref. 4b): [a]D25 = +72.8 (c = 1.35, CHCl3)
(19) (a) For a review on chelation and non-chelation controlled
reactions see: Reetz, M. T. Angew. Chem. Int. Ed. Engl.
1984, 23, 556. (b) Corcoran, R. C. Tetrahedron Lett. 1990,
31, 2101. (c) Zheng, B.-Z.; Yamauchi, M.; Dei, H.; Kusaka,
S.; Matsui, K.; Yonemitsu, O. Tetrahedron Lett. 2000, 41,
6441.
(20) Representative Experimental Procedure of Compound
14: To a stirred solution of benzylidene acetal 13 (103 mg,
0.40 mmol) in anhyd CH2Cl2 (5 mL) was added Et3SiH (56
mg, 0.48 mmol). The reaction mixture was cooled to –78 °C,
treated with EtAlCl2 (0.49 mL of 1.8 M solution in toluene,
0.88 mmol) dropwise, and the resultant mixture was stirred
at –78 °C for 30 min. After completion of the reaction, as
indicated by TLC, the reaction mixture was quenched with
sat. solution of NaHCO3 (10 mL) and extracted with CH2Cl2
(3 × 10 mL). The combined organic extracts were dried over
anhyd Na2SO4, filtered and concentrated under reduced
pressure to yield the crude compound, which was purified by
column chromatography on silica gel (gradient elution with
50–60% EtOAc in hexane) to afford pure compound 14
(89 mg, 86% yield) as a colorless liquid. IR (neat): 3504,
3040, 2944, 1452, 1340, 1171, 1104, 972, 924, 803, 736, 697
cm–1. 1H NMR (400 MHz, CDCl3): d = 2.70 (br s, 1 H), 3.08
(s, 3 H), 3.87–3.69 (m, 5 H), 4.83 (d, J = 12.2 Hz, 1 H), 4.89
(d, J = 12.2 Hz, 1 H), 7.39–7.28 (m, 5 H). 13C NMR (100
MHz, CDCl3): d = 38.4, 62.3, 69.2, 73.6, 127.8, 128.1,
128.4, 137.3.
Synlett 2004, No. 4, 647–650 © Thieme Stuttgart · New York