Regioselective and diastereoselective amination of polybenzyl ethers using chlorosulfonyl isocyanate: Total syntheses of 1,4-dideoxy-1,4-imino-D-arabinitol and (-)-lentiginosine

Article abstract of DOI:10.1021/ol061614x

The total syntheses of DAB1 (1) and (-)-lentiginosine (2) were concisely accomplished from D-lyxose via regioselective and diastereoselective NHCbz introduction using CSI, chemoselective removal of the Cbz protection, and ring-closing metathesis as key steps.

Full text of DOI:10.1021/ol061614x

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4101-4104
Regioselective and Diastereoselective
Amination of Polybenzyl Ethers Using
Chlorosulfonyl Isocyanate: Total
Syntheses of
1,4-Dideoxy-1,4-imino-
)-Lentiginosine
D-arabinitol and
(−
In Su Kim, Ok Pyo Zee, and Young Hoon Jung*
College of Pharmacy, Sungkyunkwan UniVersity, Suwon 440-746, Korea
yhjung@skku.ac.kr
Received June 30, 2006
ABSTRACT
The total syntheses of DAB1 (1) and (
−)-lentiginosine (2) were concisely accomplished from
D-lyxose via regioselective and diastereoselective
NHCbz introduction using CSI, chemoselective removal of the Cbz protection, and ring-closing metathesis as key steps.
We recently reported a novel regioselective and diastereo-
selective amination of anti-1,2-dimethyl ether with chloro-
sulfonyl isocyanate (CSI) and its application to the synthesis
of (-)-cytoxazone.1 As a part of our research program aimed
at developing polyhydroxylated alkaloids, we extended the
CSI reaction to the syntheses of pyrrolidine alkaloid 1,4-
dideoxy-1,4-imino-D-arabinitol (DAB1) (1), isolated in 1985
from Angylocalyx boutiqueanu2 and Arachniodes standishii,3
and indolizidine alkaloid (-)-lentiginosine (2), isolated in
1990 from the leaves of Astragalus lentiginosus.4 These
polyhydroxylated alkaloids are receiving increasing attention
as potential medical agents due to their many pharmacologi-
cal properties.5 (-)-Lentiginosine is particularly intriguing
because of its potent and selective inhibition of amyloglu-
cosidases that hydrolyze 1,4- and 1,6-R-glucosidic linkages.4,6
Because of their potent bioactivities and relatively simple
structures, numerous ways of synthesizing 1, 2, and their
isomers have recently been reported,7 and these studies
confirmed their absolute configurations. This paper describes
(5) For some leading references, see: (a) Junge, B.; Matzke, M.;
Stoltefuss, J. In Handbook of Experimental Pharmacology; Kuhlmann, J.,
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N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645. (e) McCarter, J. D.; Withers, S. G. Curr. Opin. Struct.
Biol. 1994, 4, 885. (f) Ly, H. D.; Withers, S. G. Annu. ReV. Biochem. 1999,
68, 487.
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2005, 7, 4025.
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Tetrahedron Lett. 1985, 26, 3127.
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1985, 24, 593.
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10.1021/ol061614x CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/01/2006

our synthetic approach to 1 and 2 utilizing the regioselective
and diastereoselective CSI reaction.8
Our retrosynthetic analyses of 1 and 2 are outlined in
Scheme 1. The common intermediate 4 would be prepared
Table 1. Diastereoselective CSI Reaction of Cinnamyl
Polybenzyl Ether 6 in Various Solvents and at Different
Temperatures
Scheme 1. Retrosynthetic Analysis of 1 and 2
entry solvent T (°C) time (h) yielda (%) ratiob (5a/5b)
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
CCl4
Et2O
hexane
toluene
0
0
0
0
0
14
14
20
18
24
24
72
168
80
78
84
82
62
84
57 (35)c
51 (45)c
14:1
14:1
16:1
17:1
18:1
26:1
40:1
73:1
0
-40
-78
a Isolated yield of pure materials. b Isomer ratio determined by 1H NMR
spectroscopy. c Recovery yield of starting materials.
As solvent polarity or the reaction temperature was
reduced, the diastereoselectivity increased gradually. In
particular, reaction in toluene at low temperature produced
the desired product 5a in high yield (∼84%) with a
remarkable increase of diastereoselectivity (26:1-73:1). This
result reveals that the stereochemistry is retained more so in
nonpolar solvents and at low temperature. Regioselective
substitution at the cinnamylic position is expected because
regioselectivity is controlled by the stability of the carbo-
cation intermediate, i.e., the cinnamylic carbocation is more
by intramolecular cyclization of bromide 5a, which, in turn,
would come from the regioselective and diastereoselective
installation of an NHCbz group into cinnamyl polybenzyl
ether 6 using CSI.
In initial studies, we examined the regioselectivity and
diastereoselectivity of the reaction of anti-1,2-diether 6 with
CSI. Treatment of 6 with CSI afforded the anti-1,2-amino
alcohol 5a as the major product. The ratio of anti-1,2-amino
alcohol 5a and syn-1,2-amino alcohol 5b depended on
solvent and temperature, as shown in Table 1.
9
stable than the corresponding secondary carbocation.
Consistent with these observations, we investigated the
diastereoselectivity of the CSI reactions of the cinnamyl
polybenzyl ethers 6-9, which were prepared from com-
mercially available D-sugars (D-lyxose, D-ribose, D-arabinose,
and D-xylose), to afford the corresponding allylic amine
products 5a and 10-12 (Table 2).
(7) For the syntheses of 1,4-dideoxy-1,4-imino-D-arabinitol, see: (a) Fleet,
G. W. J.; Smith, P. W. Tetrahedron 1986, 42, 5685. (b) Ikota, N.; Hanaki,
A. Chem. Pharm. Bull. 1987, 35, 2140. (c) Fleet, G. W. J.; Witty, D. R.
Tetrahedron: Asymmetry 1990, 1, 119. (d) Kim, Y. J.; Kido, M.; Bando,
M.; Kitahara, T. Tetrahedron 1997, 53, 7501. (e) Hulme, A. N.; Mont-
gomery, C. H.; Henderson, D. K. J. Chem. Soc., Perkin Trans. 1 2000,
1837. (f) Lombardo, M.; Fabbroni, S.; Trombini, C. J. Org. Chem. 2001,
66, 1264. For the syntheses of (-)-lentiginosine and its enantiomer, see:
(g) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron:
Asymmetry 1993, 4, 1455. (h) Cordero, F. M.; Cicchi, S.; Goti, A.; Brandi,
A. Tetrahedron Lett. 1994, 35, 949. (i) Gurjar, M. K.; Ghosh, L.; Syamala,
M.; Jayasree, V. Tetrahedron Lett. 1994, 35, 8871. (j) Nukui, S.; Sodeoka,
M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 398. (k) Giovannini,
R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1995, 60, 5706. (l) McCaig,
A. E.; Meldrum, K. P.; Wightman, R. H. Tetrahedron 1998, 54, 9429. (m)
Ha, D.-C.; Yun, C.-S.; Lee, Y.-J. J. Org. Chem. 2000, 65, 621. (n) Yoda,
H.; Katoh, H.; Ujihara, Y.; Takabe, K. Tetrahedron Lett. 2001, 42, 2509.
(o) Rasmussen, M. O.; Delair, P.; Greene, A. E. J. Org. Chem. 2001, 66,
5438. (p) El-Nezhawy, A. O. H.; El-Diwani, H. I.; Schmidt, R. R. Eur. J.
Org. Chem. 2002, 4137. (q) Rabiczko, J.; Urbanczyk-Lipkowska, Z.;
Chmielewski, M. Tetrahedron 2002, 58, 1433. (r) Chandra, K. L.;
Chandrasekhar, M.; Singh, V. K. J. Org. Chem. 2002, 67, 4630. (s) Feng,
Z.-X.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 497. (t) Ichikawa, Y.; Ito,
T.; Nishiyama, T.; Isobe, M. Synlett 2003, 1034. (u) Ayad, T.; Ge´nisson,
Y.; Baltas, M.; Gorrichon, L. Chem. Commun. 2003, 582. (v) Raghavan,
S.; Sreekanth, T. Tetrahedron: Asymmetry 2004, 15, 565. (w) Cardona,
F.; Moreno, G.; Guarna, F.; Vogel, P.; Schuetz, C.; Merino, P.; Goti, A. J.
Org. Chem. 2005, 70, 6552.
Table 2. Diastereoselective CSI Reactions of Cinnamyl
Polybenzyl Ethers 6-9
a Isolated yield of pure materials. b Isomer ratio determined by 1H NMR
spectroscopy.
(8) (a) Kim, J. D.; Lee, M. H.; Lee, M. J.; Jung, Y. H. Tetrahedron Lett.
2000, 41, 5073. (b) Kim, J. D.; Lee, M. H.; Han, G.; Park, H.-J.; Zee, O.
P.; Jung, Y. H. Tetrahedron 2001, 57, 8257. (c) Kim, J. D.; Zee, O. P.;
Jung, Y. H. J. Org. Chem. 2003, 68, 3721. (d) Kim, J. D.; Kim, I. S.; Jin,
C. H.; Zee, O. P.; Jung, Y. H. Tetrahedron Lett. 2005, 46, 1097.
As shown in entries 3 and 4, the syn-1,2-diethers 8 and 9
in toluene at 0 °C afforded the corresponding syn-1,2-amino
4102
Org. Lett., Vol. 8, No. 18, 2006

alcohols 11 and 12 as an inseparable mixture of diastereo-
isomers in moderate yield with a low diastereoselectivity of
4:1 and 3:1 in favor of the syn-isomer. However, CSI
reactions of the anti-1,2-diethers 6 and 7 afforded exclusively
the anti-1,2-amino alcohols 5a and 10 as the major products
with significantly increased diastereoselectivity of 1:26 and
1:15, respectively. Table 1 shows that the stereochemistries
of major products were the same as those of the starting
materials, even though the CSI reaction of cinnamyl benzyl
ether progresses via a carbocation intermediate.
Scheme 2. Total Synthesis of DAB1 (1)
The diastereoselectivity of these reactions can be explained
by the neighboring group effect,10 in which the NHCbz group
orientation retains the original configuration in benzyl ether
via a double inversion of the configuration, as shown in
Figure 1. The reduced diastereoselectivities of 8 and 9 may
in 94% yield. The hydroxyl moiety of 14 was then converted
to bromide 6 with carbon tetrabromide, triphenylphosphine,
and triethylamine in 89% yield.13
The CSI reaction was carried out on cinnamyl tribenzyl
ether 6 in toluene solution at 0 °C for 24 h, followed by
desulfonylation using an aqueous solution of 25% sodium
sulfite to give the allylic amine product 5a with a high
diastereoselectivity (syn/anti ) 1:26, 96% ds) in 84% yield.
Treatment of 5a with potassium tert-butoxide provided the
pyrrolidine 4. Ozonolysis of the CHdCH bond of 4 and
subsequent reduction of the resulting aldehyde gave the
alcohol 15.7f Finally, the benzyl and N-Cbz protecting groups
of 15 were removed by palladium-catalyzed hydrogenolysis
to give DAB1 (1) in 98% yield. Spectroscopic data and the
specific rotation of 1 were found to be in full agreement
with the reported literature values.7a-e
To further explore the synthetic utility of the CSI reaction,
we envisioned that the selective removal of the Cbz protec-
tion of 4 could potentially provide the most direct approach
to (-)-lentiginosine via a three-step synthesis (Scheme 3).
After several failed attempts (e.g., BBr3,14 hydrogenations,
and KOH15), chemoselective removal of the Cbz protection
of 4 was achieved under palladium-catalyzed N-deprotection
conditions16 (Et3SiH, Pd(OAc)2, triethylamine, CH2Cl2, re-
flux) to give the secondary amine 16 concomitant with
isomerization of the cis/trans olefin mixtures 4 to produce
exclusively the cis-olefin.17 Direct introduction of the 3-bute-
nyl moiety into 16 was carried out using 3-butenyl trifluo-
romethanesulfonate18 and Proton Sponge to afford 3 in 75%
yield.
Figure 1. Proposed reaction mechanism of cinnamyl polybenzyl
ethers 6 and 9 with CSI.
have been caused by the increased steric repulsion between
the two bulky substituents in transition state B.
On the basis of the above results, we planned to utilize
cheap and commercially available D-lyxose as the starting
material for the total synthesis of DAB1 (1) and (-)-
lentiginosine (2). The synthesis of 1 began with the benzyl-
protected lactol 13, prepared from D-lyxose, by the known
procedure according to the literature11 (Scheme 2).
Wittig olefination of 13 with DMSO anion12 in THF at
45 °C afforded 14 as a ca. 3.1:1 mixture of cis/trans isomers
(9) Kim, J. D.; Han, G.; Jeong, L. S.; Park, H.-J.; Zee, O. P.; Jung, Y.
H. Tetrahedron 2002, 58, 4395.
(10) (a) Allred, E. L.; Winstein, S. J. Am. Chem. Soc. 1967, 89, 3991.
(b) Allred, E. L.; Winstein, S. J. Am. Chem. Soc. 1967, 89, 3998. (c) Roberts,
D. D. J. Org. Chem. 1997, 62, 1857. (d) Krow, G. R.; Yuan, J.; Lin, G.;
Sonnet, P. E. Org. Lett. 2002, 4, 1259.
(11) Nadein, O. N.; Kornienko, A. Org. Lett. 2004, 6, 831
(12) For a recent review, see: Maryanoff, B. E.; Reitz, A. B. Chem.
ReV. 1989, 89, 863.
(13) (a) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem.
Soc. 1991, 113, 4252. (b) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org.
Chem. 1994, 59, 1358. (c) Kashem, A.; Anisuzzaman, M.; Whistler, R. L.
Carbohydr. Res. 1978, 61, 511.
(14) Pless, P.; Bauer, W. Angew. Chem., Int. Ed. Engl. 1973, 12, 147.
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(16) (a) Sakatani, M.; Kurokawa, N.; Ohfune, Y. Tetrahedron Lett. 1986,
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Org. Lett., Vol. 8, No. 18, 2006
4103

ride was employed; however, the reaction required 60 h to
go to completion. The best result was realized when 3 was
exposed to second-generation Grubbs catalyst in toluene,
which provided the bicyclic compound 17 in high yield
(86%) within 8 h.19 The final deprotection of benzyl groups
and hydrogenation of the double bond afforded (-)-lentigi-
nosine (2) as a crystalline form: mp 105-106 °C (CHCl3/
hexane) [lit.7l mp 106-107 °C]; [R]25D -3.1 (c 0.8, MeOH)
[lit.7l [R]25D -3.05 (c 1.0, MeOH)]. Moreover, 2 had spectral
properties (1H and 13C NMR) in full agreement with the
reported literature values.7g-w
Scheme 3. Total Synthesis of (-)-Lentiginosine (2)
In conclusion, we described a newly developed method
for the regioselective and diastereoselective introduction of
an NHCbz group into cinnamyl polybenzyl ethers using
chlorosulfonyl isocyanate (CSI). Moreover, we have dem-
onstrated the application of this methodology to the total
syntheses of DAB1 and (-)-lentiginosine. We believe that
this synthetic protocol will be useful for the preparation of
stereodefined hydroxyl amino alcohols and hydroxyl amino
acids, and for the preparation of pyrrolidine, piperidine,
pyrrolizidine, and indolizidine alkaloids; important compo-
nents of various glycosidase inhibitors.
Acknowledgment. This work was supported by a Korea
Research Foundation Grant (KRF-2003-015-E00232) and
partially by the Brain Korea 21 Program.
To obtain the indolizidine framework, several conditions
were investigated. Treatment of 3 with first-generation
Grubbs catalyst in methylene chloride at reflux provided 17
in low yield (∼10%). The yield of 17 was improved to 56%
when second-generation Grubbs catalyst in methylene chlo-
Supporting Information Available: Experimental pro-
cedure and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061614X
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