An efficient stereoselective synthesis of (+)-deoxoprosophylline

Article abstract of DOI:10.1016/j.tetlet.2007.07.034

An efficient stereoselective synthesis of (+)-deoxoprosophylline from readily available p-anisaldehyde is described. Key steps in the synthesis include the stereoselective amination of anti-1,2-dibenzyl ether using chlorosulfonyl isocyanate, intermolecula

Full text of DOI:10.1016/j.tetlet.2007.07.034

Tetrahedron Letters 48 (2007) 6258–6261
An efficient stereoselective synthesis of (+)-deoxoprosophylline
In Su Kim, Chae Baek Ryu, Qing Ri Li, Ok Pyo Zee and Young Hoon Jung*
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Received 20 June 2007; revised 5 July 2007; accepted 6 July 2007
Available online 30 July 2007
Abstract—An efficient stereoselective synthesis of (+)-deoxoprosophylline from readily available p-anisaldehyde is described. Key
steps in the synthesis include the stereoselective amination of anti-1,2-dibenzyl ether using chlorosulfonyl isocyanate, intermolecular
olefination, and Pd-catalyzed intramolecular cyclization.
Ó 2007 Elsevier Ltd. All rights reserved.
A large number of polyhydroxylated piperidine alkal-
oids have been found in nature, and have been reported
to have valuable biological and pharmacological proper-
ties.1 Among these, 2,6-disubstituted piperidine-3-ols,
such as, Prosopis alkaloids 1–4 and Cassia alkaloids 5
and 6 have received much recent attention as potential
medical agents, due to their varied pharmacological
properties, which include anesthetic, analgesic, and anti-
biotic activities (Fig. 1).2
hydrophobic aliphatic tail. The polar piperidine ring
core of these alkaloids is known to be essentially
required for the inhibition of various glycosidases, and
to have therapeutic potential for the treatment of dis-
eases such as diabetes, viral infections, and cancer.4
On the other hand, the lipophilic aliphatic tail serves
to facilitate transfer across lipid membranes.5 However,
although many studies have been conducted on glycosi-
dase inhibitors, their structural and inhibitory activity
relationships are not well understood.
In particular, (+)-deoxoprosophylline 1, the reduced
adduct of (+)-prosophylline 2 isolated from the leaves
of Prosopis africana Taub,3 has attracted considerable
interest as an important synthetic target molecule
because of its potent biological activities and interesting
structural features involving a polar head group and a
Several methods for synthesizing (+)- and (ꢀ)-deoxo-
prosophyllines have been reported,6–8 and the majority
of these methods have relied upon the chiral starting
materials, like sugars6 and amino acids;7 however, meth-
ods of asymmetric syntheses are rather scarce.8 As a
HO
HO
HO
HO
N
N
8
8
H
H
X
(+)-Deoxoprosopinine (3, X = H)
(+)-Prosopinine (4, X = O)
X
(+)-Deoxoprosophylline (1, X = H)
(+)-Prosophylline (2, X = O)
HO
HO
O
O
N
N
7
10
H
H
(+)-Prosafrinine (6)
(+)-Spectaline (5)
Figure 1. Structure of Prosopis alkaloids and Cassia alkaloids.
Keywords: Deoxoprosophylline; Intermolecular olefination; Intramolecular cyclization; Chlorosulfonyl isocyanate.
*
Corresponding author. Tel.: +82 31 290 7711; fax: +82 31 290 7773; e-mail: yhjung@skku.ac.kr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.034

I. S. Kim et al. / Tetrahedron Letters 48 (2007) 6258–6261
6259
result of our previous studies on the stereoselective
amination of various allylic ethers using chlorosulfonyl
isocyanate (CSI),9 and on the application of this method
to the total synthesis of polyhydroxylated alkaloids,10
we became interested in developing an efficient synthetic
route to (+)-deoxoprosophylline. Herein, we describe
the novel total synthesis of 1 via the stereoselective
amination of anti-1,2-dibenzyl ether using CSI, intermo-
lecular olefination, and Pd-catalyzed intramolecular
cyclization.
Grubbs catalyst followed by the oxidation of the p-meth-
oxyphenyl moiety and Pd-catalyzed intramolecular cycli-
zation. The anti-amino alcohol 9 was synthesized via the
regioselective and diastereoselective introduction of the
NHCbz group into anti-1,2-dibenzyl ether 10 using CSI.
The total synthesis of 1 began with the commercially
available p-anisaldehyde, which was converted into
anti-1,2-diol 11 with high enantioselectivity (95% ee)
according to the literature (Scheme 2).10c,d Treatment
of the diol 11 with benzyl bromide and sodium hydride
in the presence of DMF and THF gave anti-1,2-dibenzyl
ether 10 in quantitative yield. The regioselective and
diastereoselective CSI reaction of 10 was carried out in
The retrosynthetic analysis of 1 is outlined in Scheme 1.
Piperidine 7 was prepared from anti-1,2-amino alcohol 9
by intermolecular olefination using Hoveyda 2nd
BzO
NHCbz
O
1
H3CO
C11H23
C12H25
N
H
OBn
O
H3CO
8
7
Intramolecular
olefination
NHCbz
O
OBn
CSI
H
OBn
OBn
H3CO
H3CO
H3CO
9
10
p-anisaldehyde
Scheme 1. Retrosynthetic analysis.
OR
O
NHCbz
b
c
ref. 6
H
OR
11 (R = H)
90%
88%
OBn
H3CO
H3CO
H3CO
9
a
10 (R = Bn)
100%
NHCbz
O
NHCbz
O
d
e
C12H25
C12H25
OBn
OBn
70%
73%
H3CO
H3CO
H3CO
8
12
HO
HO
BzO
H3CO
NHCbz
O
g
f
C11H23
C11H23
C12H25
N
H
N
H
83%
63%
O
OBz
O
1
7
13
N
N
Mes
Mes
O
Cl
Ru
O
Mes =
C12H25
Cl
14
15
Scheme 2. Reagents and conditions: (a) NaH, BnBr, THF/DMF (1:1), 11 h; (b) (i) CSI, Na2CO3, toluene, ꢀ78 °C, 24 h; (ii) 25% Na2SO3, 24 h; (c)
14, 15, toluene, 80 °C, 48 h; (d) PtO2, H2, EtOAc, 2 h; (e) (i) cat. RuCl3, NaIO4, H2O/CH3CN/EtOAc (2:1:1), 4 h; (ii) CH2N2, Et2O, 0 °C, 1 h; (f) 10%
Pd/C, H2, MeOH, 24 h; (g) (i) LAH, THF, 12 h; (ii) 8 N KOH, MeOH, reflux, 10 h.

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I. S. Kim et al. / Tetrahedron Letters 48 (2007) 6258–6261
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toluene solution at ꢀ78 °C for 24 h, followed by desulf-
onylation with aqueous 25% sodium sulfite solution to
give the desired anti-1,2-amino alcohol 9 with high dia-
stereoselectivity (anti:syn = 49:1, 98% ds) in 90% yield.
The diastereoselectivity of 9 can be explained by the
neighboring group effect, whereby the NHCbz group
orientation retains its original configuration in benzyl
ether via a double inversion of the configuration.10c,d
Cross-metathesis of 9 with pentadec-1-en-3-one (14)11
using Hoveyda 2nd Grubbs catalyst 15 in toluene at
80 °C provided (E)-a,b-unsaturated ketone 8,12 which
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Oxidation of 12 with RuCl3 (0.15 equiv) and NaIO4
(17 equiv) in H2O/CH3CN/EtOAc (2:1:1)13 gave the
intermediate carboxylic acid, in which the benzyl group
had been oxidized to benzoate.14 Treatment of the crude
carboxylic acid with diazomethane gave the desired
methyl ester 13. Removal of the Cbz group by palla-
dium-catalyzed hydrogenolysis and simultaneous intra-
molecular cyclization afforded piperidine 7 in 83%
yield. From observations of vicinal coupling constants
and NOE correlations, the cyclization of 13 provided 7
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of the cyclic iminium intermediate.7d,15 Finally, reduc-
tion of ester 7 with LiAlH4 in THF and removal of
the benzoate group using 8 N KOH in MeOH furnished
(+)-deoxoprosophylline 1 with specific rotation and
spectral data (1H and 13C NMR) identical to those
reported in the literature.16
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In conclusion, we describe the stereoselective total syn-
thesis of (+)-deoxoprosophylline via the stereoselective
amination of anti-1,2-dibenzyl ether using CSI, inter-
molecular olefination, and Pd-catalyzed intramolecular
cyclization as key transformations. It is evident that this
synthetic route can be applied to the preparation of var-
ious polyhydroxylated piperidine alkaloids or other nat-
ural products containing a nitrogen atom in the ring.
9. (a) Kim, J. D.; Kim, I. S.; Hua, J. C.; Zee, O. P.; Jung, Y.
H. Tetrahedron Lett. 2005, 46, 1079; (b) Jung, Y. H.; Kim,
J. D. Arch. Pharm. Res. 2005, 28, 382; (c) Kim, J. D.; Zee,
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Acknowledgments
This work was supported by the Korean Research
Foundation Grant funded by the Korean Government
(MOEHRD) (KRF-2006-311-E00613) and by the Brain
Korea 21 Program.
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Zee, O. P.; Jung, Y. H. Synlett 2007, 1711; (b) Kim, I. S.;
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
07.034.
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25 24
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