New Building Blocks for Tackling the Synthesis of Polyhydroxylated Piperidines: Expeditious Synthesis of Amino Derivatives in the 1-Deoxynojirimycin Series

Full text of DOI:10.1021/jo000434c

7208
J . Org. Chem. 2000, 65, 7208-7210
New Bu ild in g Block s for Ta ck lin g th e
Syn th esis of P olyh yd r oxyla ted
P ip er id in es: Exp ed itiou s Syn th esis of
Am in o Der iva tives in th e
1-Deoxyn ojir im ycin Ser ies
F igu r e 1.
Erwan Poupon,‡ Binh-Xuyen Luong,‡ Ange`le Chiaroni,†
Nicole Kunesch,*,‡ and Henri-Philippe Husson*,‡
and its straightforward transformation into the new
6-amino-1,6-dideoxy-5-epi-nojirimycin as a first applica-
tion.
UMR 8638 du CNRS Associe´e a` l’Universite´ Rene´ Descartes
(Paris V), Faculte´ des Sciences Pharmaceutiques, 4,
Avenue de l’Observatoire 75270 Paris, Cedex 06, France
The preparation of 1 parallels the double condensation
of R-(-)-phenylglycinol 3 as the nitrogen source, chirality
inducer, and iminium stabilizer,6 with glutaraldehyde
into building block 2.7 Taking advantage of carbohydrate
precursors to establish three of the five contiguous
stereogenic centers, our approach employed the meso-
trihydroxylated glutaraldehyde 4, easily prepared8 from
the commercialy available isopropylidene-R-D-glucofura-
nose by periodate oxidation and acidic deprotection
(Scheme 1).
Thus, condensation of 3 and 4 in the presence of
potassium cyanide in aqueous citric acid buffer afforded
a crude material which was equilibrated to the more
thermodynamically stable derivatives in the presence of
zinc bromide. After flash chromatography (yield: 45%),
compound 1 was crystallized from tetrahydrofuran while
its diastereomer 5 was obtained as a minor byproduct
(≈5-15%). Thus, two new stereogenic centers were
created at the same time and concomitant desymmetri-
zation of the “sugar moiety” included in the new structure
was achieved.
Careful NMR studies (2D-experiments: COSY, HET-
COR, and NOESY) of piperidine 1 established the
structure and stereochemistry as depicted in Scheme 1
(hexahydro-3-phenyl-6,7,8-trihydroxy-3R-[3R,5â,6â,7R,8â,-
8aâ]-5H-oxazolo[3,2-a]pyridine-5-carbonitrile). In par-
ticular, the coupling constant J H-6/H-5 ) 7.5 Hz was
significative of an axial relationship between H-6 and
H-5, while J H-2/H-3 ) 5.5 Hz was in favor of an equatorial/
axial relationship between H-2 and H-3. These results
were confirmed by H-6/H-8, H-6/H-4 as well as H-2/H-3
correlations in the NOESY spectrum.
husson@pharmacie.univ-paris5.fr
Received March 22, 2000
A remarkable range of polyhydroxylated piperidine and
indolizidine alkaloids isolated from living systems be-
longs to the important family of azasugars. Many of them
exhibit specific and potent inhibitory activity against
glycosidases, and as a consequence have a great potential
as drugs against diabetes, cancer, and viruses.1
Among them, 1-deoxynojirimycin2 and castanosper-
mine2c,3 have received much attention in recent years as
representatives of this class of compounds (Figure 1) and
led to an impressive number of review articles dealing
with their multistep syntheses.
Most of the numerous synthetic approaches in these
series are based upon carbohydrates as a predetermined
source of chirality for a given synthetic target.2a,4 The
heterocyclizations are achieved after introduction of an
amino group at the last stages of multistep routes.
The need for an easy access to this type of molecules
led us to conceive a new trihydroxylated chiral nonrace-
mic building block 1 (Figure 1) for the development of
our own approach based upon the general and versatile
CN(R,S) method.5,6
In this preliminary note, we disclose the facile synthe-
sis of 1 from commercially available starting materials
* Corresponding authors. e-mail for N. Kunesch: kunesch@
pharmacie.univ-paris5.fr.
† Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-
sur-Yvette, France.
The same NMR experiments performed on isomer 5
gave support for an axial position of the three hydroxyl
groups. This surprising feature was confirmed by a X-ray
study.
In principle, formation of eight configurationally dif-
ferent cyclization products was possible since selective
recognition of the aldehyde functions by phenylglycinol
was not expected.
It has been shown for the formation of 2 (85% yield)
in equilibrating conditions, that there is a stereoelectronic
preference for a trans-diaxial relationship for CN-addition
on iminium salts and the developing nitrogen lone pair
‡ Laboratoire de Chimie Therapeutique, Faculte´ des Sciences Phar-
maceutiques et Biologiques, 4, Avenue de l’Observatoire 75270 Paris
Cedex 06, France.
(1) (a) Nash, R. J .; Watson, A. A.; Asano, N. Polyhydroxylated
Alkaloids that Inhibit Glycosidases. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed., Elsevier Science Ltd.:
Oxford 1996, Vol. 10, p 345. (b) Sears, P.; Wong, C.-H. Angew. Chem.,
Int. Ed. 1999, 38, 2300-2324. (c) Elbein, A. D.; Molyneux, R. J .
Alkaloid Glycosidase Inhibitors, in Comprehensive Natural Products
Chemistry; Barton, D. H. R., Nakanishi, K., Eds.; Elsevier: New York,
Oxford, 1999; Vol. 3, pp 130-160.
(2) (a) Matos, C. C. R.; Lopes, R. S. C.; Lopes, C. L. Synthesis 1999,
571-573. For a review of published syntheses up to 1994, see (b)
Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994, 135-162 and
references therein. (c) Casighari, G.; Zanardi, F. Chem. Rev. 1995, 95,
1677-1716.
(3) (a) For a review of published syntheses up to 1992, see Burgess,
K.; Henderson, I. Tetrahedron 1992, 48, 4045-4066. (b) Denmark, S.
E.; Martinborough, E. A. J . Am. Chem. Soc. 1999, 121, 3046-3056
and references therein.
(4) (a) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1984, 25, 165-
168. (b) For recents carbohydrate-based approaches, see ref 2a and
Moutel, S.; Shipman, M. J . Chem. Soc., Perkin Trans. 1 1999, 1403-
1406. For a review of monosaccharide syntheses from non-carbohydrate
sources, see Hudlicky, T.; Entwistle, D. A.; Oitzer, K. K.; Thorpe, A. J .
Chem. Rev. 1996, 96, 1195-1220.
(5) For an overview on the CN(R,S) method, see Husson, H.-P.;
Royer, J . Advances in the Use of Synthons in Organic Chemistry:
Chemistry of Potential and Reversed Iminium Systems; Dondoni, A.,
Ed.; J AI Press: Greenwich, CT, 1995; Vol. 25, pp 1-168.
(6) Husson, H.-P.; Royer, J . Chem. Soc. Rev. 1999, 28, 383-394.
(7) Bonin, M.; Grierson, D. S.; Royer, J .; Husson, H.-P. Org. Synth.
1992, 70, 54-59.
(8) (a) Miculka, C. Synlett 1999, S1, 948-950. (b) Shankar, B. B.;
Kirkup, M. P.; McCombie, S. W.; Ganguly. A. K. Tetrahedron Lett.
1993, 34, 7171-7174.
10.1021/jo000434c CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7209
Sch em e 1. Syn th esis of Bu ild in g Block s 1 a n d 7
Sch em e 2. Syn th esis of 9 a n d 11
F igu r e 2. Preferred stereomers.
of electrons. Furthermore a trans relative stereochemis-
try between C-2 and C-6 substituents is observed.
Moreover, the absolute configuration of the C-2 stereo-
genic center is the result of a 1,3-transfer of chirality from
the phenyl substituent involving addition of CN- from
the upper face of ∆1-piperidinium chair transition state.
The four isomers wherein the cyano group is equatorial
can be disregarded because they do no profit from the
combined influence of a stabilizing anomeric effect be-
tween the nitrogen lone pair of electrons and the peri-
antiplanar cyano group.9 Since only two cyclization
products 1 and 5 were isolated (the remaining products
≈50% decompose during purification), mechanistic argu-
ments for their formation might be inspired from the
above-mentioned considerations. As far as the four
isomers with an axial cyano group are concerned (Figure
2), after equilibration to the more thermodynamically
stable trans-oxazolidines, one obtains compound 1 as the
major compound wherein the three hydroxyl groups are
equatorial and a themodynamically less-stable all-axial
compound 5.
Consequently, control of the configuration at these newly
created asymmetric centers would allow synthesis of
enantiomeric series.
(2) Access to indolizidines should be possible through
alkylation with suitable side chains and subsequent
cyclization on the nitrogen after elimination of the chiral
appendage.
(3) Compound 1 can be considered as a 1,4-dihydropy-
ridine equivalent since R-aminonitrile and R-aminoether
functions are both precursors of iminium salts and
tautomeric enamines.5 Thus, differentiated ketones could
be selectively generated â or â′ to the nitrogen, permitting
inversion of the configuration of hydroxyl groups or
introduction of new functions.
(4) In addition to reduction in a primary amine, the
nitrile itself could be hydrolyzed in acid or transformed
in aldehyde or alcohol under controlled reductions.
Interestingly, all this transformations should not re-
quire the protection of the hydroxyl groups.
One example of the numerous synthetic possibilities
of compound 1 is given by the easy preparation of a new
amino derivative (9) which is an isomer of the two amino
analogues of 1-deoxynojirimycin previously reported.10
Catalytic hydrogenation of 1 (Scheme 2) implying simul-
taneous reduction of the cyano group and hydrogenolysis
of the chiral appendage afforded 9 in a single operation
As expected, similar results were obtained by the
condensation of (S)-phenylglycinol 6 with glutaraldehyde,
leading to the enantiomer of 1 (7) as well as a minor
compound 8, enantiomeric with 5 (Scheme 1).
A general synthetic strategy for the preparation of the
polyhydroxylated piperidines and indolizidines from build-
ing block 1 would be very attractive acccording to the
following considerations:
(three steps, 40% overall yield, [R]20 ) -9.5 [c ) 1.5,
D
H2O, 2 HCl salt]). The relative configuration of 9 was
ascertained by NMR analysis in comparison with 6-amino-
1,5-imino-1,5,6-trideoxy-D-mannitol 10,10 and 6-amino-
(1) R or S phenylglycinols are the source of nitrogen
and chirality at R and R′ position of the nitrogen atom.
(9) Bonin, M.; Chiaroni, A.; Riche, C.; Belœil, J .-C.; Grierson, D. S.;
Husson, H.-P. J . Org. Chem. 1987, 52, 382.
(10) Kilonda, A., Compernolle, F.; Hoornaert, G. J . J . Org. Chem.
1995, 60, 5820-5824.

7210 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
phenylglycinol 3 (1.5 g, 11 mmol) was dissolved in 4% citric acid
buffer (50 mL). A solution of 4 (3 g, 20 mmol) in citric buffer (50
mL) was added followed by potassium cyanide (1 g, 15 mmol).
After stirring overnight, the reaction mixture was neutralized
with NaHCO3 and concentrated under reduced pressure. The
residue was dissolved in boiling MeOH, the resulting suspension
filtered over a pad of silica gel, and the filtrate evaporated. The
oily crude mixture was dissolved in MeOH and treated, under
vigorous stirring, with ZnBr2 (500 mg) for 3 h before being
evaporated in vacuo and submitted to a flash chromatography.
Elution with CH2Cl2/MeOH (95:5) gave 1.5 g (45%) of compound
1 and small amounts of diasteromer 5 (175 mg, 5%). Compound
F igu r e 3.
1,5-imino-1,5,6-trideoxy-D-glucitol 1111 (Figure 3). These
6-amino analogues of 1-deoxymannojirimycin and 1-deoxy-
nojirimycin were obtained in multistep syntheses. While
the δ values for C-2, C-3, C-5, C-6, and C-7 are very close
in the 13C NMR spectra of both 9 and 11, the shift
difference for C-4 (9: 69.3 ppm, 11: 77.4 ppm) is
suggestive of an 1,3-diaxial relationship between the
amino chain at C-2 and the proton attached at C-4 in
1 crystallized from THF: mp ) 182-185 °C; [R]25 _139 (c ) 1
D
1
in MeOH); H NMR (300 MHz, CDCl3/DMSO-d6 2:1, 25 °C): δ
3.5-3.6 (m, 1H), 3.66 (t, J ) 8 Hz, 1H), 3.76 (d, J ) 5.5 Hz, 1H),
3.88 (t, J ) 8 Hz, 1 H), 4.02 (d, J ) 7.5 Hz, 1H), 4.23 (t, J ) 8
Hz, 1H), 5.03 (d, J ) 3.5 Hz, 1H), 5.20 (d, J ) 4 Hz, 1H), 5.46
(d, J ) 4 Hz, 1H), 7.2-7.4 (m, 5H); 13C NMR (75 MHz, CD3OD,
25 °C) δ 51.7, 64.0, 71.1, 74.7, 75.1, 75.7, 92.9, 114.9, 128.4, 129.5,
129.8, 137.1; MS (CI, CH4) m/z 277 (M + 1)+; HRMS (CI, CH4)
m/z (M + 1)+; Calcd for C14H17N2O4: 277.1188, Found: 277.1176.
Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N,10.14. Found:
C, 60.70; H, 5.71; N, 10.20.
1
compound 9. Furthermore, a direct comparison of the H
NMR spectra of the HCl salts of 9 and 10 was very
informative. Indeed, the H-2 resonance at 3.75 ppm (3.46
ppm for 10)12 was a strong argument for an equatorial
proton as well as the coupling constants (td, J ) 6 and 3
Hz). The signal at 4.27 ppm for the equatorial proton H-5
in the spectrum of 9,11 was observed at 3.92 ppm for 9 as
a result of an axial position. This (2R,3S,4S,5R)-2-
(aminomethyl)piperidine-3,4,5-triol 9 obtained in a two-
step synthesis constitutes a new stereomer of the amino
analogue (11, (2R,3R,4R,5S)-2-(aminomethyl)piperidine-
1,3,5-triol)12 of natural 1-deoxynojirimycin (Figure 1).2
Finally, the same reaction was performed on the minor
compound 5 in order to synthesize the amino derivative
11 related to the parent azasugar deoxynojirymicine.2
Indeed, compound 11 was obtained quantitatively from
5 and showed identical physical data to those previously
reported.11b Although performed on a minor reaction
compound, this short synthesis favorably compares with
the already published method11b which needs 11 steps
for the same yield approximately.
Among the multiple ways for synthesizing polyhy-
droxylated piperidines alkaloids and analogues, the well-
established CN(R,S) method could provide a short and
efficient strategy toward the synthesis of a wide range
of azasugars. In this respect, the new building block 1
constitutes an ideal starting material for natural product
synthesis and design of new glycosidase inhibitors. The
potential flexibility of our approach is currently being
studied.
Hexah ydr o-3-ph en yl-6,7,8-tr ih ydr oxy-3R-[3r,5â,6r,7â,8r,-
8a â]-5H-oxa zolo[3,2-a ]p yr id in e-5-ca r bon itr ile (5): crystal-
lization from THF; mp ) 156-158 °C; [R]25 _155 (c ) 1 in
D
MeOH); 1H NMR (300 MHz, DMSO-d6, 25 °C): δ 3.63 (t, J )
7.5 Hz, 1H), 3.75-3.85m, 2H), 3.85-4.00 (m, 3H), 4.25 (t, J )
7.5 Hz, 1H), 4.49 (d, J ) 1 Hz, 1H), 4.80 (d, J ) 6 Hz, 1H), 5.09
(d, J ) 8 Hz, 1H), 5.46 (d, J ) 3.5 Hz, 1H), 7.2-7.4 (m, 5H); 13
C
NMR (75 MHz, CD3OD, 25 °C) δ 51.9, 64.3, 70.5, 71.8, 74.6, 89.2,
115.5, 129.0, 129.6, 130.0, 137.7; MS (CI, CH4) m/z 277 (M +
1)+.
Hexa h yd r o-3-p h en yl-6,7,8-tr ih yd r oxy-3S[3â,5r,6r,7â,8r,-
8a r]-5H-oxa zolo[3,2-a ]p yr id in e-5-ca r bon itr ile (7): identical
procedure as for 1. [R]25 +134 (c ) 1 in MeOH).
D
Hexa h yd r o-3-p h en yl-6,7,8-tr ih yd r oxy-3S[3â,5r,6â,7r,8â,-
8a r]-5H-oxa zolo[3,2-a ]p yr id in e-5-ca r bon itr ile (8): identical
procedure as for 5. [R]25 +150 (c ) 1 in MeOH); MS (CI) m/z
D
163 (M + 1)+; HRMS (FAB+, Na+) m/z (M + Na)+; calcd for
C6H15N2O3Na: 299.1007, found: 299.1001.
(2R ,3S ,4S ,5R )-2-(Am in om e t h yl)p ip e r id in e -3,4,5-t r iol
(9): a solution of 1 (100 mg, 0.36 mmol) in ethanol (18 mL) was
added to a 1 N HCl ethanolic solution (2 mL) and hydrogenated
at 10 bar over Pd/C/10% for 2 days. After filtration the mixture
was evaporated to dryness. The residue was triturated in THF/
Et2O (1:1) to remove phenylethanol.The remaining precipitate
was dried to give the hygroscopic hydrochloride salt of compound
9 (77 mg, 90%) as a yellowish powder: [R]20 _9.5 (c ) 1.5 in
D
H2O); 1H NMR (300 MHz, D2O, 25 °C): δ 3.15-3.45 (m, 4H),
3.75 (td, J ) 6, 3 Hz, 1H), 3.85-43.95 (m, 3H); 13C NMR (75
MHz, D2O, 25 °C) δ 40.4; 48.2, 54.8, 68.0, 69.3, 69.9; MS (CI)
m/z 163 (M + 1)+; HRMS (FAB+) m/z (M + 1)+; calcd for
C6H15N2O3: 163.1083, found: 163.1078.
(2R ,3R ,4R ,5S )-2-(Am in om e t h yl)p ip e r id in e -3,4,5-t r iol
(11): dichlorhydrate obtained by the same procedure as for
9: [R]25 +8 (c ) 1 in H2O); 1H NMR (400 MHz, D2O, 25 °C): δ
Exp er im en ta l Section
D
2.88 (t, J ) 11.5 Hz, 1H), 3.10-3.25 (m, 2H), 3.28 (m, 1H), 3.36
(m, 2H), 3.46 (t, J ) 10 Hz, 1H), 3.59 (ddd, J ) 5, 9, 11.5 Hz,
1H); 13C NMR (75 MHz, D2O, 25 °C) δ 42.40; 49.0, 57.9, 69.3,
73.8, 78.5; MS (CI) m/z 163 (M + 1)+; HRMS (FAB+) m/z (M +
1)+; calcd for C6H15N2O3: 163.1083, found: 163.1078.
All new compounds were characterized by 2D 1H and 13C NMR
as well as IR spectra, [R] values, simple and high-resolution mass
spectrometry, or elemental analysis.
Hexah ydr o-3-ph en yl-6,7,8-tr ih ydr oxy-3R-[3r,5â,6â,7r,8â,-
8a â]-5H-oxa zolo[3,2-a ]p yr id in e-5-ca r bon itr ile (1): (R)-(-)-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 1, 5, 7, 9,
11, and their NMR spectra viz. 1H, 13C, 2D experiments,
ORTEP plots, and X-ray data for 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) (a) Kilonda, A., Compernolle, F.; Toppet, S.; Hoornaert, G. J .
J . Chem. Soc. Chem. Commun. 1994, 2147. (b) Kilonda, A.; Comper-
nolle, F.; Peeters, K.; J oly, G. J .; Toppet, S.; Hoornaert, G. J .
Tetrahedron 2000, 56, 1005-1012.
(12) The numbering of compound 9 follows the usual nomenclature
while nojirimycin, mannojirimycin, and several analogues are num-
bered by some authors according to the sugar nomenclature.
J O000434C