1,3:4,6-Di-O-benzylidene-D-mannitol as a source for novel chiral intermediates through regioselective reductive cleavage

Article abstract of DOI:10.1016/j.tetlet.2004.12.036

Synthetically useful chiral intermediates have been synthesized starting from 1,3:4,6-di-O-benzylidene-D-mannitol by regioselective reductive cleavage using BF₃?Et₂O and Et₃SiH in high yields.

Full text of DOI:10.1016/j.tetlet.2004.12.036

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 743–745
1,3:4,6-Di-O-benzylidene-D-mannitol as a source for novel
chiral intermediates through regioselective reductive cleavage
Appu Aravind and Sundarababu Baskaran*
Department of Chemistry, Indian Institute of Technology-Madras, Chennai 600 036, India
Received 17 October 2004; revised 1 December 2004; accepted 8 December 2004
Abstract—Synthetically useful chiral intermediates have been synthesized starting from 1,3:4,6-di-O-benzylidene-D-mannitol by
regioselective reductive cleavage using BF
2004 Elsevier Ltd. All rights reserved.
3 2 3
ÆEt O and Et SiH in high yields.
ꢀ
Development of C symmetric chiral ligands has played
2
Ph
a significant role in transition metal-catalyzed asymmet-
1
1
1
R O
O
O
R O
OH OBn
OH OR2
ric synthesis and has attracted much attention from
synthetic chemists. D-Mannitol and its derivatives are
3 2 3
BF .Et O/Et SiH
0 oC, DCM
widely used as C symmetric chiral reagents as well as
2
O
O
OR2
BnO
2
chiral auxiliaries. In addition, mannitol, an inexpensive
Ph
Scheme 1. Reductive cleavage using BF ÆEt O/Et SiH.
chiral pool hexitol with four asymmetric centres, is rec-
ognized as the most easily available starting material for
many organic transformations leading to biologically
3
2
3
3
active and pharmaceutically important products. Suc-
cessful synthesis of these chiral intermediates relies heav-
ily on the selective protection and deprotection of
Thus, treatment of 1,3:4,6-di-O-benzylidene-D-mannitol
withBF ÆEt O (3.2 equiv) in combination withEt SiH
2.2 equiv) at 0 ꢁC gave the corresponding dibenzyl
ether as the only isolable product in good yield and with
high regioselectivity (Scheme 1).
4
3
2
3
hydroxyl functional groups. The regioselective reduc-
7
(
tive cleavage of the bis-benzylidene acetal of D-mannitol
would lead to the selective formation of synthetically
useful di-protected tetrols. Recently we reported the reg-
ioselective reductive cleavage of various benzylidene
The generality of this methodology was further exam-
ined with1,3:4,6-di- O-benzylidene-D-mannitol deriva-
tives withdifferent sensitive functional groups and the
results are shown in Table 1. In all cases the benzylidene
acetals underwent smoothreductive cleavage under very
mild conditions to the corresponding primary dibenzyl
ethers in good yields. The regioselectivity can be ratio-
nalized by chelation-controlled cleavage of the bis-benz-
5
acetals using EtAlCl /Et SiH as a novel reagent system.
2
3
In this communication, we report our approach to the
generation of chiral intermediates through regioselective
reductive cleavage of 1,3:4,6-di-O-benzylidene-D-manni-
tol derivatives withBF ÆEt O/Et SiH.
3
2
3
The reductive cleavage of benzylidene acetals to form
monoprotected diols can be achieved using various re-
6l
ylidene acetal. Labile functional groups suchas
6
agent systems. We anticipated that the regioselective
OTBDPS, OMs, OBn, OAc and OTs were found to be
stable under these reaction conditions. The benzylidene
acetal of dimesylate 1 was smoothly cleaved to the diol
2, which was isolated as the corresponding acetonide
using DMP and CSA in acetone. Similarly, the
benzylidene acetals of diacetate 3 and the dibenzyl ether
also underwent reductive cleavage and yielded the
diols 4 and 6, respectively, in a highly regioselective
manner. Diol 6 is a known non-nitrogen containing
reductive cleavage of bis-benzylidene acetals derived
from D-mannitol would lead to highly functionalized
chiral intermediates under mild reaction conditions.
Keywords: Regioselective; Reductive cleavage; Chiral intermediates;
Chemoselective; Benzylidene acetals.
5
*
Corresponding author. Tel.: +91 44 2257 8260; fax: +91 44 2257
545; e-mail: sbhaskar@iitm.ac.in
0
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.036

744
A. Aravind, S. Baskaran / Tetrahedron Letters 46 (2005) 743–745
a
Table 1. Regioselective reductive cleavage using BF
3
ÆEt
2
O/Et
3
SiH
6), reductive cleavage of unsymmetrical compounds (en-
tries 4, 5 and 7) was also achieved in good yields and
with high regioselectivity. Furthermore, the compounds
b
Entry Substrate
Product
Yield
%)
(
8
, 10 and 14 are also unsymmetrical and thus could have
Ph
9
importance in enantiospecific syntheses. Under the
reaction conditions, the reductive cleavage of benzylid-
ene acetal derivative of TBDPS ethers (entries 4, 5 and
6) gave the corresponding diols in good yields. The acid
labile TBDPS ethers were stable under these conditions.
MsO
OH OBn
OMs
MsO
O
O
O
c
1
2
3
4
5
6
70
88
86
90
84
72
BnO HO
O
O
O
OMs
2
Ph
1
Ph
O
In a typical procedure, to a solution of 1,3:4,6-di-O-benz-
ylidene-D-mannitol 3 (500 mg, 1.13 mmol) in dry
CH Cl (25 mL) at 0 ꢁC was added Et SiH (397 lL,
AcO
OH OBn
OAc
AcO
O
O
2
2
3
2
.48 mmol) followed by BF ÆEt O (454 lL, 3.61 mmol).
3 2
BnO HO
OAc
4
After stirring the reaction mixture at 0 ꢁC for 30 min, it
3
was quenched with saturated NaHCO solution (15 mL)
and extracted withCH Cl (2 · 25 mL). The organic
Ph
3
2
2
Ph
O
layer was dried over anhydrous Na SO , concentrated
2
4
BnO
OH OBn
OBn
BnO
O
O
under reduced pressure and the crude product was puri-
fied by column chromatography over silica gel using a
20–50% EtOAc–hexane solvent gradient to yield the
pure compound 4 (443 mg, 88%) as a colourless liquid.
BnO HO
OBn
6
5
Ph
Ph
In conclusion, we have developed an efficient and novel
method for the regioselective reductive cleavage of
1
TBDPSO
OH OBn
TBDPSO
O
O
O
,3:4,6-di-benzylidene-D-mannitol derivatives using
BF ÆEt O and Et SiH. We strongly believe that our
3
2
3
BnO HO
OH
O
O
O
OH
chemoselective reductive cleavage methodology leading
0
8
1
7
to highly functionalized chiral intermediates will find
wide application in enantiospecific syntheses.
Ph
Ph
TBDPSO
OH OBn
OMs
TBDPSO
O
O
O
Acknowledgements
BnO HO
OMs
10
We thank CSIR and DST, New Delhi for Financial
support. A.A. (SRF) thanks CSIR, New Delhi for a
fellowship.
9
Ph
Ph
O
TBDPSO
OH OBn
TBDPSO
O
O
References and notes
BnO HO
OTBDPS
OTBDPS
12
1
. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1994; (b) Lin, G.-Q.;
Li, Y.-M.; Chan, A. S. C. Principles and Applications
11
Ph
Ph
of Asymmetric Synthesis; John Wiley
&
Sons:
TsO
OH OBn
TsO
O
O
O
New York, 2001; (c) Comprehensive Asymmetric Catalysis
(1st Supplement); Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: New York, 2003.
c
72
7
BnO HO
OBn
O
OBn
1
4
2. (a) Masaki, Y.; Arasaki, H.; Itoh, A. Tetrahedron Lett.
1999, 40, 4829–4832; (b) Chen, Y.; Li, X.; Tong, S.-K.;
Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett. 1999, 40,
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Depezay, J. C. Synlett 1998, 402–404; (g) Byung, T. C.;
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1
3
Ph
a
b
c
3.2 equiv BF
Isolated yield.
3
2 3
ÆEt O and 2.2 equiv Et SiH were used for the reaction.
The crude diol after reductive cleavage was isolated as the corre-
sponding acetonide.
8
HIV-protease inhibitor. Diols 2, 4, 6 and 12 are highly
functionalized C2 symmetric intermediates and have
considerable scope for further functional group manipu-
lations to produce novel chiral synthons. Moreover,
these diols are key intermediates in the stereoselective
3
. (a) Chandrasekhar, M.; Chandra, K. L.; Singh, V. K. J.
Org. Chem. 2003, 68, 4039–4045; (b) Chakraborty, T. K.;
Srinivasu, P.; Kiran Kumar, S.; Kunwar, A. C. J. Org.
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T. Tetrahedron Lett. 2002, 43, 6983–6985; (e) Poitout, L.;
2
f,3e
synthesis of glycosidase inhibitors. Apart from the
C symmetric benzylidene acetals (entries 1, 2, 3 and
2

A. Aravind, S. Baskaran / Tetrahedron Letters 46 (2005) 743–745
745
ꢁ
1
1
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1.0, CHCl
(400 MHz, CDCl
2H), 3.74–3.81 (m, 6H), 4.54 (AB quartet, J = 12.0 Hz,
3
); IR (neat): 3472, 1724 cm
;
H NMR
3
3
) d 2.03 (s, 6H), 3.10 (d, J = 6.6 Hz,
4
5
6
1
3
4H), 5.01 (m, 2H), 7.25–7.35 (m, 10H); C (100 MHz,
CDCl ) d 21.1, 68.2, 68.7, 72.0, 73.4, 127.7, 127.8, 128.4,
3
6
. (a) LiAlH –AlCl : (i) Liptak, A.; Jodal, I.; Nanasi, P.
Carbohydr. Res. 1975, 44, 1–11; (ii) Liptak, A.; Jodal, I.;
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47–650.
137.6, 171.0; HRMS (ESI) calcd for
(M+Na) : 469.1838, found: 469.1845.
C
24
H
30
O
8
Na
+
4
3
3
0
Compound 6 ½aꢀ ꢁ15.1 (c 1.0, CHCl
3
); IR (neat): 3472,
; H NMR (400 MHz, CDCl ) d
D
2912, 2864, 1452 cm
ꢁ1
1
3
3.13 (br s, 2H), 3.71 (dd, J = 10.1, 5.3 Hz, 2H), 3.79 (m,
4H), 4.03 (d, J = 5.9 Hz, 2H), 4.59 (s, 4H), 4.65 (AB
1
982, 38, 3721–3727; (b) DiBAL-H: (i) Takano, S.;
Akiyama, S.; Sato, S.; Ogasawara, K. Chem. Lett. 1983,
593–1596; (ii) Mikami, T.; Sasano, H.; Mitsunobu, O.
1
3
quartet, J = 11.4 Hz, 4H), 7.31–7.37 (m, 20H);
(100 MHz, CDCl ) d 69.9, 70.2, 73.0, 73.5, 79.1, 127.6,
127.6, 127.7, 127.9, 128.05, 128.4, 138.0, 138.1; HRMS
C
1
3
Chem. Lett. 1987, 2033–2036; (iii) Denmark, S. E.;
Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089–
+
(ESI) calcd for C34
565.2549.
38 6
H O Na (M+Na) : 565.2566, found:
8
3
110; (c) NaBH CN–HCl: (i) Garegg, J.; Hultberg, H.;
3
0
Wallin, S. Carbohydr. Res. 1982, 108, 97–101; (ii) Oleskar,
A. G.; Cleophax, J.; Gero, S. D. Tetrahedron Lett. 1986,
Compound 8. ½aꢀ ꢁ23.9 (c 1.0, CHCl
3
); IR (neat): 3440,
D
ꢁ
1
1
2944, 1107 cm ; H NMR (400 MHz, CDCl ) d 1.05 (s,
3
2
Carbohydr. Chem. 1990, 9, 159–165; (d) CF COOH–
Et SiH: DeNinno, M. P.; Etienne, J. B.; Duplantier, K.
3
7, 41–44; (iii) Kanie, O.; Takeda, T.; Ogihara, Y. J.
9H), 3.42 (dd, J = 10.0, 4.0 Hz, 1H), 3.51 (dd, J = 10.0,
6.0 Hz, 1H), 3.61–3.68 (m, 2H), 3.82–3.90 (m, 2H), 3.99–
4.03 (m, 2H), 4.21 (AB quartet, J = 11.6 Hz, 2H), 4.53 (s,
2H), 7.09–7.11 (m, 2H), 7.24–7.42 (m, 14H), 7.66–7.69 (m,
3
C. Tetrahedron Lett. 1995, 36, 669–672; (e) NaBH CN–
3
1
3
TMSCl, NaBH
anasson, R. J. Chem. Soc., Perkin Trans. 1 1984, 2371–
374; (f) R BBr–BH ÆTHF: Guindone, Y.; Girard, Y.;
3
CN–CF
3
COOH: Samuelsson, B.; Joh-
3
4H); C (100 MHz, CDCl )d 19.4, 27.0, 70.3, 71.1, 71.4,
71.6, 72.0, 73.1, 73.3, 73.4, 127.6, 127.7, 127.8, 127.9,
128.3, 128.4, 129.7, 130.0, 132.7, 133.8, 135.8 136.0, 137.4,
2
2
3
+
SiNa (M+Na) :
Berthiaume, S.; Gorys, V.; Lemieux, R.; Yoakim, C. Can.
J. Chem. 1990, 68, 897–902; (g) Bu B(OTf)–BH ÆTHF:
Jiang, L.; Chan, T.-H. Tetrahedron Lett. 1998, 39, 355–
58; (h) AlCl –PMHS: Chandrasekar, S.; Reddy, Y. R.;
137.9; HRMS (ESI) calcd for C36
623.2805, found: 623.2805.
H
44
O
6
2
3
3
0
Compound 10. ½aꢀ ꢁ16.0 (c 1.0, CHCl
3
); IR (neat): 3472,
2928 cm ; H NMR (400 MHz, CDCl ) d 1.05 (s, 9H),
D
ꢁ1 1
3
3
3
Reddy, C. R. Chem. Lett. 1998, 1273–1274; (i) PhBCl
Et SiH: Sakagami, M.; Hamana, H. Tetrahedron Lett.
000, 41, 5547–5551; (j) M(OTf) –BH ÆTHF: (i) Wang, C.-
2
–
2.99 (d, J = 6.3 Hz, 1H), 3.02 (s, 3H), 3.08 (d, J = 4.0 Hz,
1H), 3.42 (dd, J = 9.9, 4.0 Hz, 1H), 3.50 (dd, J = 9.9,
5.6 Hz, 1H), 3.78 (dd, J = 11.2, 6.4 Hz, 1H), 3.94 (dd,
J = 11.2, 2.5 Hz, 1H), 3.96–3.99 (m, 2H), 4.07–4.17 (m,
1H), 4.23 (AB quartet, J = 11.7 Hz, 2H), 4.54 (AB quartet,
J = 11.7 Hz, 2H), 4.76–4.80 (m, 1H), 7.09–7.13 (m, 2H),
3
2
3
3
C.; Luo, S.-Y.; Shie, C.-R.; Hung, S.-C. Org. Lett. 2002, 4,
47–849; Morelli, C. F.; Fornili, A.; Sironi, M.; Duri, L.;
Speranza, G.; Manitto, P. Tetrahedron: Asymmetry 2002,
3, 2609–2618; (k) BH Me NH–BF ÆEt O: Oikawa, M.;
8
1
3
1
7.27–7.36 (m, 14H), 7.65–7.68 (m, 4H);
C NMR
3
2
3
2
Liu, W.-C.; Nakai, Y.; Koshida, S.; Fukase, K.; Kusum-
oto, S. Synlett 1996, 1179–1180; (l) BH ÆS(CH
BF ÆEt O: Seiki, S.; Kuroda, A.; Tanaka, K.; Kimura,
R. Synlett 1996, 231–233; (m) Bu SnH–MgBr : Zheng, B.-
Z.; Yamauchi, M.; Dei, H.; Kusaka, S.-I.; Matsui, K.;
Yonemitsui, O. Tetrahedron Lett. 2000, 41, 6441–6445.
(100 MHz, CDCl ) d 19.3, 26.9, 38.4, 69.0, 69.6, 70.3,
3
3
3
)
2
–
71.3, 72.6, 73.1, 73.5, 80.5, 127.5, 127.6, 127.7, 127.7,
127.8, 128.3, 128.4, 129.7, 129.9, 132.4, 133.6, 135.7, 136.0,
137.4, 137.5; HRMS (ESI) calcd for C H O SSiNa
3
2
3
2
37 46
8
+
(M+Na) : 701.2580, found: 701.2588.
3
0
Compound 12. ½aꢀ ꢁ18.7 (c 1.0, CHCl
3
); IR (neat): 3472,
) d 1.04 (s, 18H),
D
2928 cm ; H NMR (400 MHz, CDCl
ꢁ1 1
7
. (a) BF
3
ÆEt
2
O–Et
3
SiH: Debenham, S. D.; Toone, E. J.
3
Tetrahedron: Asymmetry 2000, 11, 385–387; (b) Watan-
abe, S.; Sueyoshi, T.; Ichihara, M.; Uehara, C.; Iwamura,
M. Org. Lett. 2001, 3, 255–257; (c) Al-Mughaid, H.;
Grindley, T. B.; Robertson, K. N.; Cameron, T. S. Can. J.
Chem. 2003, 81, 505–516.
2.94 (d, J = 5.4 Hz, 2H), 3.43–3.44 (m, 4H), 4.01 (dd,
J = 10.6, 4.4 Hz, 2H), 4.15–4.20 (m, 6H), 7.07–7.09 (m,
4H), 7.22–7.25 (m, 8H), 7.29–7.34 (m, 8H), 7.38–7.41 (m,
1
3
2H), 7.69–7.71 (m, 8H); C NMR (100 MHz, CDCl ) d
3
19.4, 27.0, 70.7, 71.5, 72.9, 73.3, 127.3, 127.4, 127.4, 127.6,
128.1, 129.5, 129.7, 132.8, 134.3, 135.8, 136.1, 138.0; ESI-
8
. Bouzide, A.; Sauve, G.; Seviguy, G.; Yelle, J. Bioorg. Med.
Chem. 2003, 13, 3601–3605.
+
Na (M+Na) : 861.3983; Anal. Calcd for
MS: C52
H
62
O
Si
6 2
9
. (a) Bouzide, A.; Sauve, G. Org. Lett. 2002, 14, 2329–2332;
(b) Chakraborty, T. K.; Ghosh, S.; Jayaprakash, S.;
Sharma, J. A. R. P.; Ravikanth, V.; Diwan, P. V.;
C H O Si : C, 74.42; H, 7.45%. Found: C, 74.39; H,
52 62 6 2
7.49%.
3
0
Compound 14. (acetonide derivative) ½aꢀ +10.9 (c 1.0,
D
H NMR (400 MHz,
ꢁ
1
;
1
Nagaraj, R.; Kunwar, A. C. J. Org. Chem. 2000, 65, 6441–
6
CHCl
3
); IR (neat): 3472 cm
457.
CDCl ) d 1.35 (s, 6H), 2.31 (s, 3H), 3.56–3.60 (m, 2H),
3
2
5
1
0. Compound 2 (acetonide derivative) ½aꢀ +28.6 (c 1.0,
3.67 (dd, J = 11.2, 3.6 Hz, 1H), 3.70 (dt, J = 5.6, 3.2 Hz,
1H), 3.77 (dd, J = 10.5, 3.2 Hz, 1H), 4.12 (t, J = 6.8 Hz,
1H), 4.23 (s, 2H), 4.38 (dd, J = 7.2, 4.0 Hz, 1H), 4.53 (s,
2H), 4.64 (d, J = 11.6 Hz, 1H), 4.77(d, J = 11.6 Hz, 1H),
4.90 (dt, J = 5.4, 3.2 Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H),
7.08–7.11 (m, 4H), 7.24–7.35 (m, 11H), 7.63 (d, J = 8.2 Hz,
D
); IR (neat): 1356, 1177 cm ; H NMR (400 MHz,
ꢁ
1 1
CHCl
3
CDCl ) d 1.33 (s, 6H), 2.98 (s, 6H), 3.65 (dd, J = 7.3,
3
1
J = 4.8 Hz, 2H), 4.47 (AB quartet, J = 11.7 Hz, 4H), 4.78–
1.2 Hz, 2H), 3.79 (dd, J = 3.4, 11.7 Hz, 2H), 4.27 (d,
1
.82 (m, 2H), 7.18–7.28 (m, 10H); C NMR (100 MHz,
3
4
1
3
CDCl ) d 27.0, 38.5, 68.6, 73.2, 76.4, 80.2, 111.0, 127.6,
2H); C NMR (100 MHz, CDCl ) d 21.5, 27.0, 67.9, 70.1,
3
3
1
(
27.7, 128.3, 137.1; MS (EI) m/z (relative intensity %) 558
32) (M+), 557 (10), 467 (23), 379 (15), 181 (100), 111 (20),
72.6, 72.9, 73.4, 76.7, 78.7, 79.1, 80.7, 110.2, 127.5, 127.5,
127.5, 127.6, 128.0, 128.0, 128.1, 128.2, 128.2, 128.3, 129.4,
134.0, 137.6, 138.2, 138.3, 144.3; HRMS (ESI) calcd for
+
9
5
34 10 2
1 (60); HRMS (ESI) calcd for C25H O S Na (M+Na) :
3
0
+
81.1491, found: 581.1489.Compound 4. ½aꢀ ꢁ20.4 (c
C H O SNa (M+Na) : 669.2498, found: 669.2485.
37 42
D
8