Tandem nucleophilic addition/cyclization reaction in the synthesis of ketimine-type iminosugars

Article abstract of DOI:10.1021/jo702616x

(Chemical Equation Presented) The biological activity of unsaturated iminosugars has not yet been extensively studied because of a lack of general synthetic methods. A practical synthesis of these cyclic ketimine sugars was developed, which was based on a tandem addition-cyclization reaction of a Grignard reagent to a ω-methanesulfonylglycononitrile.

Full text of DOI:10.1021/jo702616x

Tandem Nucleophilic Addition/Cyclization
Reaction in the Synthesis of Ketimine-Type
Iminosugars
Jean-Bernard Behr,* Adel Kalla, Dominique Harakat, and
Richard Plantier-Royon
Institut de Chimie Moléculaire de Reims (ICMR), UFR
Sciences, CNRS, BP 1039, 51687 Reims Cedex 2, France
jb.behr@uniV-reims.fr
ReceiVed December 7, 2007
FIGURE 1. Structures of unsaturated iminosugars.
ketimine moiety have been isolated from the branches of
Broussonetia kazinoki.6 Broussonetines U and U1 (Figure 1)
might belong to the sixth class of iminosugars, i.e., the
polyhydroxypyrrolines.7 Broussonetines are 18-carbon chain
alkaloids featuring a 13-carbon substituent at the 2-alkyl position
of the 5-membered ring. Because broussonetines appear to be
biosynthesized through intermediates related to sphingosines,
which play important roles in biological processes, the synthesis
and biological evaluation of these alkaloids and related ana-
logues is of great interest.8 There has been enormous effort
expended in the search for synthetic methods toward the
standard iminosugars. Nevertheless, the development of a
general approach to polyhydroxyketimines remains challenging.
A first example of such an approach has been described
recently,9 which involved an exo-imino- to endo-iminocyclitol
rearrangement as the key step, occurring in 25–42% yield.
However, the introduction of the C-2 substituent appeared at
an early stage of the synthetic sequence, limiting the versatility
required for the synthesis of a library of analogues. Herein, we
describe a new synthesis of novel cyclic ketimines sugars 1a-h
The biological activity of unsaturated iminosugars has not
yet been extensively studied because of a lack of general
synthetic methods. A practical synthesis of these cyclic
ketimine sugars was developed, which was based on a
tandem addition-cyclization reaction of a Grignard reagent
to a ω-methanesulfonylglycononitrile.
Iminosugars are naturally occurring sugar mimics displaying
well-documented glycosidase1 or glycosyltransferase2 inhibition
potencies. Recent years have seen an increasing interest in
natural or synthetic iminosugars as biological tools or potential
therapeutics in the treatment of various infections,3 cancer,4 and
certain genetic disorders.5 Iminosugars are usually classified into
five structural classes: the polyhydroxylated pyrrolidines, pyr-
rolizidines, piperidines, indolizidines, and nortropanes. Recently,
two polyhydroxylated alkaloids featuring an unprecedented
(1) Iminosugars as glycosidase inhibitors: Nojirimycin and beyond; Stütz,
A. E., Ed.; Wiley-VCH: Weinheim, Germany, 1999.
(6) (a) Tsukamoto, D.; Shibano, M.; Okamoto, R.; Kusano, G. Chem. Pharm.
Bull. 2001, 49, 492. (b) Tsukamoto, D.; Shibano, M.; Kusano, G. Chem. Pharm.
Bull. 2001, 49, 1487.
(2) (a) Gautier-Lefebvre, I.; Behr, J.-B.; Guillerm, G.; Muzard, M. Eur.
J. Med. Chem. 2005, 40, 1255. (b) Djebaili, M.; Behr, J.-B. J. Enzyme Inhib.
Med. Chem. 2005, 20, 123. (c) Compain, P.; Martin, O. R. Curr. Top. Med.
Chem. 2003, 3, 525. (d) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001,
9, 3077.
(7) Nectrisine, the cyclic imine nominally derived from dehydration of
4-amino-4-deoxy-D-arabinose, is an example of naturally occurring aldimine-
type 5-membered iminosugar and might be classified into the pyrroline-derived
iminosugars as well. In opposition to ketimines, numerous syntheses of nectrisine
and other cyclic sugar aldimines have appeared in the literature, which use, for
instance, a chlorination/elimination strategy from the corresponding pyrrolidine.
For an example, see: Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem.
Eur. J. 2003, 9, 3397.
(3) (a) Bosco, M.; Bisseret, P.; Constant, P.; Eustache, J. Tetrahedron Lett.
2007, 48, 153. (b) Steet, R.; Chung, S.; Lee, W.-S.; Pine, C. W.; Do, H.; Kornfeld,
S. Biochem. Pharmacol. 2007, 73, 1376. (c) Liautard, V.; Christina, A. E.;
Desvergnes, V.; Martin, O. R. J. Org. Chem. 2006, 71, 7337. (d) Behr, J.-B.;
Gainvors-Claisse, A.; Belarbi, A. Nat. Prod. Res. 2006, 20, 1308. (e) Robina,
I.; Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab. 2004,
5, 329. (f) Behr, J.-B. Curr. Med. Chem. (Anti InfectiVe Agents) 2003, 2, 173.
(4) (a) Moreno-Vargas, A. J.; Carmona, A. T.; Mora, F.; Vogel, P.; Robina,
I. Chem. Commun. 2005, 4949. (b) Fiaux, H.; Popowycz, F.; Favre, S.; Schütz,
C.; Vogel, P.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L. J. Med. Chem. 2005,
48, 4237. (c) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575. (d) Barchi,
J. J. Curr. Pharm. Des. 2000, 6, 485.
(8) Shibano, M.; Tsukamoto, D.; Kusano, G. Heterocycles 2002, 57, 1539.
(9) Only one example of a general synthesis of ketimine-type iminosugars
has been reported so far; see: Moriarty, R. M.; Mitan, C. I.; Branza-Nichita, N.;
Phares, K. R.; Parrish, D. Org. Lett. 2006, 8, 3465. Some other unsaturated
iminosugars have been obtained by specific transformations; see: (a) Izquierdo,
I.; Plaza, M. T.; Rodríguez, M.; Franco, F.; Martos, A. Tetrahedron 2005, 61,
11697. (b) Davis, B. G.; Maughan, M. A.; Chapman, T. M.; Villard, R.; Courtney,
S. Org. Lett. 2002, 4, 103. (c) Yokoyama, M.; Ikenogami, T.; Togo, H. J. Chem.
Soc., Perkin Trans. l 2000, 2067. (d) Schuster, M.; Blechert, S. Tetrahedron:
Asymmetry 1999, 10, 3139. (e) Bouix, C.; Bisseret, P.; Eustache, J. Tetrahedron
Lett. 1998, 39, 825. (f) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siuzdak,
G.; Wong, C.-H. J. Am. Chem. Soc. 1997, 119, 8146.
(5) (a) Yu, Z.; Sawkar, A. R.; Whalen, L. J.; Wong, C.-H.; Kelly, J. W.
J. Med. Chem. 2007, 50, 94. (b) Wennekes, T.; van den Berg, R. J.; Donker,
W.; van der Marel, G. A.; Strijland, A.; Aerts, J. M.; Overkleeft, H. S. J. Org.
Chem. 2007, 72, 1088. (c) Faugeroux, V.; Génisson, Y.; Andrieu-Abadie, N.;
Colie´, S.; Levade, T.; Baltas, M. Org. Biomol. Chem. 2006, 4, 4437.
3612 J. Org. Chem. 2008, 73, 3612–3615
10.1021/jo702616x CCC: $40.75 2008 American Chemical Society
Published on Web 03/22/2008

TABLE 1. Screening of Various Conditions for the Addition of Organometallics to Nitrile Mesyl Ester 2
entry
[R-M]a
T (°C)
solvent
additive
CuId
time (h)
conversionb (%)
yieldc (%)
1
2
3
4
5
6
7
8
CH3-MgBr
CH3-MgBr
CH3-MgBr
CH3-MgBr
CH3-MgBr
CH3-MgBr
CH3-MgBr
CH3-MgBr
CH3-Li
20
20
20
20
20
20
70
70
70
70
70
70
THF
THF
Et2O
Et2O
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
24
24
24
24
24
24
1.5
1.5
1.5
1.5
1.5
1.5
<5
<5
<5
<5
30
60
100
35
100
100
100
100
a
LiClO4
a
LiClO4
1a (10)
1a (55)
THFe
9
1a (26)
1b (61)
1c (56)
1d (38)
10
11
12
C6H5-MgBr
nC4H9-MgBr
nC10H21-MgBr
b
a 1.5 equiv was added. The amount of remaining starting material was determined by H NMR analysis of the crude reaction mixtures. c Yields refer
to isolated, purified (SiO2) product. d 10 mol % of catalyst was used. e A 3 M solution of CH3MgBr in THF was used as the reagent, giving rise to a
reaction mixture that contained 5% THF in toluene as the solvent.
1
which is based on the tandem addition/cyclization reaction of
Grignard reagents to easily available ω-methanesulfonylgly-
cononitriles.
under these conditions, and the starting material was entirely
recovered. Efforts to overcome the lack of reactivity observed
in these coordinating solvents by increasing the reaction
temperature failed. Alternatively, the addition of copper iodide,
known to accelerate drastically the addition of Grignard reagents
to nitriles,15 was unsuccessful (entry 2). In a same manner, the
use of lithium perchlorate as an activating agent failed (entry
4).16
Among the various syntheses of cyclic ketimines,10 the
reaction of ω-halonitriles with organometallic reagents allows
a rapid access to simple C-2-substituted pyrrolines and tetrahy-
dropyridines.11 Nevertheless, this transformation has not found
widespread applications since unwanted R-deprotonation com-
petes with nucleophilic addition to the nitrile functionality,12
leading to non-negligible amounts of side products. Neverthe-
less, we wished to explore the application of this reaction to
polyhydroxycyano compounds, such as glycononitriles, in an
attempt to prepare the target unsaturated iminosugars.
The 5- or 6-O-methanesulfonylglycononitriles are readily
available building blocks, which are obtained from suitably
protected carbohydrates by a two-step sequence involving the
reaction of the free hemiacetal function with hydroxylamine
followed by a dehydration/mesylation procedure with an excess
of methanesulfonyl chloride. A series of such activated gly-
cononitriles has been recently exploited for the synthesis of
spirocyclopropyliminosugars.13 In this work, we used 4-O-
methanesulfonyl-2,3,5-tri-O-benzyl-D-arabinononitrile 214 as the
model substrate to experiment the feasibility of the method and
to establish the most adequate reaction conditions.
In some cases, nonpolar solvents have been reported to
increase the reactivity of organometallics toward nitriles by
modulating the solvation of the nucleophile.17 When the reaction
of 2 with methylmagnesium bromide was conducted in toluene
at room temperature, TLC monitoring revealed the formation
of a more polar product. NMR analysis of the crude mixture
after workup (addition of a saturated ammonium chloride
solution and extraction with Et2O) revealed a 30% conversion
after 24 h (Table 1, entry 5), and unreacted 2 could be separated
after chromatography. As expected, the newly formed compound
was the imine 1a, resulting from a tandem addition/cyclization
process (Scheme 1). Basically, the structure of 1a was assessed
1
by H NMR (δ, 2.13, CH3), 13C NMR (δ, 175.8, C-2; δ, 18.4,
CH3), IR (1646 cm-1, CdN), and HRMS. The configuration at
C-5 in 1a might be the opposite of that in the starting material,
since analogous intramolecular displacements have proven of
the SN2 type.18 This was firmly established by NOE experi-
ments: the cis relationship between H-3 and the exocyclic H-6a,b
in the proposed structure 1a was assessed by a 5.1% nuclear
Overhauser effect (Scheme 1). Compound 1a was stable at -20
°C for weeks and turned brown with little decomposition by
standing several days in air at room temperature.
In a first set of experiments, 2 was reacted with CH3MgBr
(1.5 equiv from a 3 M ethereal solution) at room temperature
in diethyl ether or THF for 24 h (Table 1, entries 1 and 3). No
evolution of the reaction could be detected (TLC monitoring)
(10) (a) Liang, Y.; Dong, D.; Liu, Y.; Wang, Y.; Pan, W.; Choi, Y.; Liu, Q.
Synthesis 2006, 3301. (b) Savoia, D.; Alvaro, G.; Di Fabio, R.; Gualandi, A.;
Fiorelli, C. J. Org. Chem. 2006, 71, 9373. (c) Lee, M. J.; Lee, K. Y.; Park,
D. Y.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1281. (d) Kondo, T.; Okada,
T.; Titsudo, T.-A. J. Am. Chem. Soc. 2002, 124, 186. (e) Giovannini, A.; Savoia,
D.; Umani-Ronchi, A. J. Org. Chem. 1989, 54, 228.
Having established the feasibility of the expected transforma-
tion, we sought to improve the reaction efficiency. In toluene,
the addition of 1 equiv of LiClO4 clearly accelerates the addition
of CH3MgBr to the nitrile 2 (entry 6). However, in this case, a
(11) (a) Fry, D. F.; Brown, M.; McDonald, J. C.; Dieter, R. K. Tetrahedron
Lett. 1996, 37, 6227. (b) Gallulo, V.; Diams, L.; Zezza, C. A.; Smith, M. B.
Org. Prep. Proc. Int. 1989, 21, 297. (c) Larchevêque, M.; Debal, A.; Cuvigny,
T. Bull. Soc. Chim. Fr. 1974, n/a, 1710.
(15) Taber, D. F.; Yu, H. J. Org. Chem. 1997, 62, 1687.
(16) Chastrette, M.; Amouroux, R.; Subit, M. J. Organomet. Chem. 1975,
99, C41.
(12) Fleming, F. F.; Wei, Y.; Liu, W.; Zhang, Z. Org. Lett. 2007, 9, 2733.
(13) Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.; Schütz, C.; Vogel,
P.; Plantier-Royon, R. Bioorg. Med. Chem. 2006, 14, 4047.
(17) (a) Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994, n/a, 836. (b)
Cannone, P.; Foscolos, G. B.; Lemay, G. Tetrahedron Lett. 1980, 21, 155.
(18) Laroche, C.; Plantier-Royon, R.; Szymoniak, J.; Bertus, P.; Behr, J.-B.
Synlett 2006, n/a, 233.
(14) Buchanan, G. J.; Lumbard, K. W.; Sturgeon, R. J.; Thompson, D. K.;
Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 1990, n/a, 699.
J. Org. Chem. Vol. 73, No. 9, 2008 3613

SCHEME 1. Tandem Addition/Cyclization Reaction
Strategy for the Synthesis of 1a
SCHEME 2. Synthesis of Unsaturated Iminosugars 1e-h
mixture of products was obtained, and 1a was isolated in only
10% yield. The major product of the reaction was the meth-
anesulfonyl ketone 3, resulting from hydrolysis of the intermedi-
ate ketimine salt during the workup (Scheme 1). We assumed
that strong chelation of the ketimine salt with lithium certainly
hampers an efficient ring closure. Nevertheless, when the
reaction of 2 with CH3MgBr was performed in toluene at 70
°C without any additive, a complete transformation of the
starting material occurred after 1.5 h and imine 1a could be
isolated in 55% yield after silica gel chromatography (entry 7).
Interestingly, when a 3 M solution of CH3MgBr in THF was
used instead of the ethereal solution (150 µL of the reagent in
3 mL of toluene), only 35% conversion was reached after 1.5 h
at 70 °C (entry 8), which underlines the strong solvent sensitivity
of this reaction, as outlined above. It was previously reported
that organolithium reagents are significantly more reactive
toward nitriles than the corresponding Grignard reagents.11b,19
However, reaction of 2 with CH3Li (entry 9) in the conditions
described by Zezza et al. led to a sluggish reaction mixture and
a marked reduction in the yield of target imine 1a.
The scope of this transformation was investigated next by
reacting 2 with PhMgBr, n-BuMgBr, and CH3(CH2)9MgBr
under the conditions stated above (1.5 equiv of the organome-
tallic species, toluene as the solvent, 1.5 h, 70 °C). The 2-phenyl-
or 2-butyl-∆-pyrrolines 1b and 1c were isolated in 61% and
56% yield, respectively (Table 1). A lower yield (38%) was
obtained for the decyl-substituted ketimine 1d as the result of
a tedious separation from Würtz-type compound present in the
freshly prepared Grignard reagent. In each case, TLC monitoring
of the reaction as well as NMR analysis of the crude reaction
mixture showed no remaining starting material (100% conver-
sion). However, the presence of byproduct could be observed
in most of the cases, and some of the ketimine sugars proved
to be moderately stable over silica gel, which account for the
50–60% isolated yields.
the corresponding oxime and dehydration/mesylation with
methanesulfonylchloride, Scheme 2), whereas compound 8 was
prepared as described in a previous paper.13 Thus, the protected
ribononitrile 6 was successfully reacted with methyl- or phe-
nylmagnesium bromide under the conditions developed above
(Scheme 2) to give rise to the desired compounds 1e and 1f in
45% and 53% yield, respectively. Interestingly, the trityl lyxose
7 underwent the addition/cyclization procedure with CH3MgBr
with the greatest efficiency to afford 1g in a very good yield
(88%). In stark contrast to the reaction with other substrates,
initial experiments with L-xylono-derived nitrile 8 showed that
the conditions stated above failed to give the desired ketimine.
In this case, it appeared that the cyclization was not spontaneous,
giving rise to secondary products during the workup. The
addition of BF3 ·OEt2 in the reaction mixture was not sufficient
to induce the expected ring formation since only 8% imine could
be isolated. These results prompted us to choose another
protocol. On the basis of a successful procedure utilizing THF
to promote analogous cyclization,17a compound 8 was reacted
first with PhMgBr in toluene at 70 °C for 1.5 h, THF was then
added, and the reaction mixture was allowed to stir overnight
at room temperature. This procedure afforded imine 1h in greatly
improved yield (50%).
One of our longer term goals is to develop a series of
deprotected unsaturated iminosugars to screen their therapeutic
potential. Thus, it is important to explore the viability of the
subsequent deprotection step, in particular when O-Bn groups
were used.
In this study, we experimented with boron trichloride as the
debenzylating agent to prevent hydrogenation of the ketimine
(Scheme 3). Gratifyingly, the reaction of 1a with BCl3 for 6 h
at -60 °C afforded the deprotected cyclic imine 9 cleanly,22
without the imino group being affected. Compound 9 was
isolated in its iminium chloride form as a consequence of in
To investigate the method further, we expanded the array of
sugar substrates (D-ribo 6, D-lyxo 7, and L-xylo 8) focusing on
the protecting groups tolerance (O-TBS, O-Tr, O-isopropy-
lidene). Glycononitriles 6 and 7 were prepared from the known
precursors 420 and 521 by the standard procedure (formation of
(21) Fan, G.-T.; Pan, Y.-S.; Lu, K.-C.; Cheng, Y.-P.; Lin, W.-C.; Lin, S.;
Lin, C.-H.; Wong, C.-H.; Fang, J.-M.; Lin, C.-C. Tetrahedron 2005, 61, 1855.
(22) As determined by the 1H and 13C NMR spectra of the crude material.
(23) Movassaghi, M.; Chen, B. Despite their low basicity, ketimines are
known to form stable iminium salts by reaction with strong acids. Angew. Chem.,
Int. Ed. 2007, 46, 565.
(19) Zezza, C. A.; Smith, M. B.; Ross, B. A.; Arhin, A.; Cronin, P. L. J.
Org. Chem. 1984, 49, 4397.
(20) Choi, W. J.; Moon, H. R.; Kim, H. O.; Yoo, B. N.; Lee, J. A.; Shin,
D. H.; Jeong, L. S. J. Org. Chem. 2004, 69, 2634.
3614 J. Org. Chem. Vol. 73, No. 9, 2008

SCHEME 3. Debenzylation of Compound 1a
under argon was heated at 70 °C, and the Grignard reagent (1.5
equiv) was added dropwise. The solution was stirred at 70 °C for
1.5 h and cooled to rt. Diethyl ether (20 mL) and a saturated solution
of NH4Cl (20 mL) were successively added, and the resulting
solution was extracted. The aqueous phase was extracted with Et2O
(2 × 20 mL), and the organic layers were washed with brine, dried
(MgSO4), and evaporated. The crude sample of 1 was purified by
silica gel chromatography to yield the pure compound. Data of
selected example (3R,4R,5S)-3,4-dibenzyloxy-5-benzyloxymethyl-
2-methyl-1-pyrroline 1a: colorless oil (55%); Rf ) 0.50 (PE/EtOAc
situ reaction with HCl generated during the procedure.23 The
13C NMR spectrum of 9 showed δ 197.9 ppm for C-2, which
is consistent with protonation at nitrogen as observed for
2-methyl-∆-pyrroline hydrochloride (δ 196.4).24 Purification of
9 was performed by chromatography on a hydrophobic HP20
support by elution with 1 mM HCl.
In summary, we have successfully developed a simple
reaction for the direct formation of unsaturated iminosugars,
starting from readily accessible ω-methanesulfonylglycononi-
triles. Since only a few preparative methods are available for
such compounds, the reaction described herein would provide
a new convenient route. Furthermore, variation of the Grignard
reagent in the tandem nucleophilic addition/cyclization reaction
allows for a range of different side chains to be introduced
easily, with the goal of generating libraries of broussonetine
analogues.
6:4); [R]20 ) -67.1 (c 1.1, CHCl3); IR (film) 3063, 3030, 2920,
D
2861, 1646, 1496, 1454, 1363 cm-1; 1H NMR (500 MHz; CDCl3)
δ 2.13 (3 H, s), 3.80 (2 H, d, J ) 4.2 Hz), 4.22–4.35 (2 H, m),
4.59 (1 H, m), 4.55–4.72 (6 H, m), 7.25–7.45 (15 H, m, Ar-H);
13C NMR (62.5 MHz; CDCl3) δ 18.4 (CH3), 68.8 (CH2), 70.8 (CH),
73.0 (CH2), 73.1 (CH2), 73.8 (CH2), 84.4 (CH), 89.4 (CH),
127.8–128.9 (Ar-CH), 138.3 (Ar-C), 138.4 (Ar-C), 138.9 (Ar-C),
175.8 (C); ESI-HRMS calcd for C27H30NO3 [M + H]+ 416.2226,
found 416.2219.
Acknowledgment. We gratefully acknowledge H. Baillia and
S. Lanthony for technical assistance. We also thank G. Lejeune
and A. Ronsin (undergraduate students) for their participation
in some aspects of this project.
Supporting Information Available: General details as well
as experimental procedures for the preparation of new nitriles
6 and 7 and for the deprotection of 1a. Characterization data
and copies of NMR spectra (1H, 13C) for compounds 1a-h, 6,
7, 9, 2-methylpyrroline hydrochloride, and 2-methylpyrroline.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
General Procedure for the Synthesis of Cyclic Ketimine
Sugars. A solution of glycononitrile (0.40 mmol) in toluene (7 mL)
(24) 2-Methyl-∆-pyrroline hydrochloride was prepared from commercial
2-methyl-∆-pyrroline (δ 181.0 for C-2) by stirring in 1 M HCl for 0.5 h and
evaporation of the solvents. The NMR spectra of both compounds can be found
in the Supporting Information.
JO702616X
J. Org. Chem. Vol. 73, No. 9, 2008 3615