A convenient synthesis of N-substituted trihydroxypiperidines from bis- epoxides: Nucleophilic opening of 1,2:4,5-dianhydropentitols

Article abstract of DOI:10.1055/s-2000-6499

Synthesis of a number of N-substituted trihydroxypiperidine and trihydroxypyrrolidines is described via the nucleophilic opening and cyclisation of suitable bis-epoxides. Reaction conditions to maximise the yield of the trihydroxypiperidine products forme

Full text of DOI:10.1055/s-2000-6499

LETTER
193
A Convenient Synthesis of N-substituted Trihydroxypiperidines from
Bis-Epoxides: Nucleophilic Opening of 1,2:4,5-Dianhydropentitols
Rachel D. Smith, Neil R. Thomas*
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
E-mail: Neil.Thomas@Nottingham.ac.uk
Received 12 November 1999
OH
OH
HO
HO
HO
N
Abstract: Synthesis of a number of N-substituted trihydroxypiperi-
dine and trihydroxypyrrolidines is described via the nucleophilic
opening and cyclisation of suitable bis-epoxides. Reaction condi-
tions to maximise the yield of the trihydroxypiperidine products
formed by a 6-endo-tet cyclisation process are provided.
HO
HO
HO
OH
N
H
N
X
OH
OH
Isofagomine 1
HO
HO
HO
HO
X = CH2CH2, 2
X = CH2, 3
Key words: aza-sugar, imino sugar, bis-epoxide, glycosidase inhib-
itor, isofagomine
O
O
OCH3
OH
OH
OH
OH
OH
N
The synthesis and biological evaluation of ‘aza-sugars’
has been an area of intense research over the past decade,
as the importance of glycosidase-mediated processes in
disease states such as viral or bacterial infections, diabetes
and cancer metastasis has become apparent.1 One impor-
tant recent discovery has been the fact that monosaccha-
ride analogues with a nitrogen introduced into the
anomeric carbon position, rather than the more usual ring
oxygen position gives potent glycosidase inhibitors i.e
isofagomine (1, Ki = 0.11 mM, b-D-glucosidase from
sweet almonds).2,3 However, a significant deterrent to the
use of azasugars as therapeutics is the fact that they often
inhibit a broad range of glycosidases leading to detrimen-
tal side effects. Recent research has shown that the affinity
of an aza-sugar can be dramatically increased by inclusion
of an appropriate aglycon moiety.4-6 This is seen in the
case of methyl-6,7-dideoxy-7-[(3R,3R,5R)-3,4-dihy-
droxy-5-hydroxymethyl-piperidinyl]-a-D-glucoheptopyr-
anoside (2) which has a much higher affinity for
glucoamylase from Aspergillus awamori (Ki = 0.063
mM), than its parent azasugar, isofagomine (1, Ki = 3.7
mM),4 and the Merrell Dow compound MDL 73945 (3)
which is a potent inhibitor of sucrase, maltase, glucomal-
tase and isomaltase.6 In an effort to produce a ‘second
generation’ of inhibitors with increased specificity for se-
lected glycosidases we wished to explore the preferences
of the aglycon binding site within a range of glycosidases
as this is currently very poorly defined.7 To achieve this a
synthetic route which would allow the rapid preparation
of a considerable number of N-substituted aza sugars was
required. To observe any positive contributions made by
the aglycon of an N-substituted aza sugar to binding, we
targeted the 1,5-dideoxy-1,5-imino-D-pentitols 4-7 which
are known to have moderate binding affinity for a broad
range of glycosidases (1,5-dideoxy-1,5-imino-D-xylitol
HO
OH
OH HO
HO
OH HO
OH
N
H
N
H
N
6
7
5
4
H
H
from human placenta10). Simple affinity measurements
would allow us to identify any increased selectivity
caused by the inclusion of an aglycon substituent. A num-
ber of routes to 3,4,5-trihydroxy piperidines have been re-
ported in the literature.11-13 However, these routes either
required a large number of steps, or the early introduction
of the amine which could significantly restrict the nitro-
gen substituent that could be incorporated. We have de-
signed an alternative synthesis based on the use of 1,2:4,5-
dianhydropentitols 8a-d as key intermediates (Scheme 1).
These have previously been used in the preparation of
pentitol derivatives from divinyl methanol;14 as potential
DNA crosslinking agents;15 for the synthesis of a 3,4,5-tri-
hydroxy-tetrahydrothiopyran;16 in the preparation of a C2-
symmetric HIV protease inhibitor;17 and in the synthesis
of the immunosuppressant FK506,18 their use in the prep-
aration of polysubstituted piperidines has yet to be report-
ed.
X
X
OH
HO
OH
HO
HO
OH
OH
RNH2
O
O
N
R
(4), Ki = 430 mM, b-D-glucosidase from sweet almonds8; Scheme 1
1,5-dideoxy-1,5-imino-adonitol Ki = 40 mM (5) a-D-ga-
lactosidase from green coffee beans;9 and 1,5-dideoxy-
1,5-imino-D-arabitol (6), Ki = 2.2 mM a-L-fucosidase
Synlett 2000, No. 2, 193–196 ISSN 0936-5214 © Thieme Stuttgart · New York

194
R. D. Smith, N. R. Thomas
LETTER
Literature precedence for the nucleophilic opening/ami-
nocyclisation of bis-epoxides to give heterocyclic amines
has been established by Depezay and coworkers,19 who
have prepared 7-membered ring polyhydroxyazepanes
from the appropriate bis-epoxide.
OH
OBn
OH
HO
OH
HO
HO
OH
OH
ii
i
O
O
42%
75%
8c
TsO
OTs
(i) TsCl (2 eq.), pyr., 0 °C, 30 min. (ii) NaH (3.3 eq.), THF, 0 °C;
BnBr (1.1 eq.), 0 °C to RT, 16 h.
The overall strategy for our synthesis is shown in Scheme
1. This route allows the incorporation of any suitable pri-
mary amine in the penultimate step in the synthesis per-
mitting the rapid generation of a library of potential
inhibitors.20 The route also allows functional group inter-
conversion of the C-4 hydroxyl of the trihydroxypiperi-
dine which complements the substitution of the C-3 and
C-5 hydroxyl positions which is possible using a route de-
scribed by Kim et al.21. Conversion of the C-4 hydroxyl to
its epimeric amine has been performed to give rapid ac-
cess to the sialidase inhibitors, trans,trans-3,5-dihydroxy-
4-acetamido-piperidines originally reported by Parr and
Horenstein (Scheme 2).22
Scheme 3
Altenbach and Merhof16 have shown that 3-acetyl-
1,2:4,5-dianhydro-D-arabitol generated in situ from 2,3,4-
tri-O-acetyl-1,5-dichloro-1,5-dideoxy-D-arabitol can be
cyclised in the presence of sodium sulfide in methanol to
form a 3,4,5-trihydroxy-tetrahydrothiopyran in 35% yield
together with 10% of a mixture of two thiofuranoses. This
is the only report in the literature on the preparation of het-
erocycles from a 1,2:4,5-dianhydropentitol.
OH
OH
Ac
Ac
NH
N
NH
OH
O
O
O
O
HO
HO
OH
OH
i
ii
HO
OH
O
O
O
O
81%
85%
O
O
NH2
OMe
OBn
OBn
OBn
OMe
R
R
HO
HO
OH
O
O
O
O
O
iii
85%
iv
O
O
O
54%
8b
OH
Scheme 2
(i) Dimethoxypropane, acetone, TsOH, DMF, RT, 16 h. (ii) NaH (1.1.
eq.), BnBr (1.2 eq.), THF, 0 °C to RT, 16 h. (iii) 75% AcOH, 50 °C,
2 h. (iv) DIAD (2.3 eq.), PPh3 (2.3 eq.), PhCH3, 130 °C, 4 h.
Several syntheses of 1,2:4,5-dianhydropentitols have ap-
peared in the literature.14-18 The most reproducible route to
3-benzyl-1,2:4,5-dianhydroarabitol was found to be that
reported by Dreyer et al.17 in which D-arabitol was treated
with two equivalents of p-toluenesulfonyl chloride in py-
ridine to give the ditosylate in 75% yield. The ditosylate
was then taken up in THF at 0 °C and treated with three
equivalents of sodium hydride followed by benzyl bro-
mide to give 3-benzyl-1,2:4,5-dianhydro-D-arabitol (8c)
in 42% yield (31% over 2 steps) (Scheme 3). Repeating
this approach we obtained similar yields of 3-benzyl-
1,2:4,5-dianhydropentitols from L-arabitol (8d) and xy-
litol (8a). However this approach failed to yield the dito-
sylated compound in the case of adonitol even when the
3-hydroxyl functionality of this pentitol was protected as
its benzyl ether. In this case a slightly longer route
(Scheme 4) was used in which the 1,2 and 4,5 hydroxyls
were first protected as their acetonides using dimethox-
ypropane, acetone and a catalytic amount of tosyl chloride
in anhydrous DMF. Following alkylation of the 3-hydrox-
yl with benzyl bromide and removal of the isopropylidene
protecting groups using 75% acetic acid, the diepoxides
were generated via a Mitsunobu reaction on the two termi-
nal hydroxyl groups to yield 3-benzyl-1,2:4,5-dianhy-
droadonitol (8b) in 32% yield over 4 steps from adonitol.
Scheme 4
A number of reaction conditions were investigated in the
nucleophilic opening and aminocyclisation of the bis-ep-
oxides to maximise the yield of the piperidine (Scheme 5,
route a), in preference to the pyrrolidine products (route
b). Depezay has reported a number of examples of re-
giospecific ring opening/aminocyclisation of bis-ep-
oxides derived from D-mannitol19 leading to poly-
hydroxy-piperidines and/or azepanes via 6-exo-tet or 7-
OBn
OBn
OBn
HO
HO
OH
b
a
O
O
O
a
+
N
NH
R
10
NH2
R
R
b
PhCH2 or
R =
H2C
O
O
OBn
O
HO
OH
O
N
R
12
11
O
+ enantiomer
Scheme 5
Synlett 2000, No. 2, 193–196 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Nucleophilic Opening of 1,2:4,5-Dianhydropentitols
195
endo-tet processes. He found that reactions conducted
with benzylamine in an aprotic medium such as chloro-
form favoured the 6-exo-tet ring closure, whereas use of a
protic medium (water/HClO4), or a Lewis acid in an apro-
tic medium favoured the formation of the polyhy-
droxyazepane via a 7-endo-tet ring closure. We have
investigated a number of different reaction conditions (re-
fluxing the diepoxide and amine in methanol; stirring with
AlCl3 in DCM; stirring with silica in chloroform) and
found that for small amines such as benzylamine, the slow
addition of 6 eq. of perchloric acid and 12 eq. of the amine
followed by stirring for 2 hours at 0 °C, and for 16 hrs at
room temperature favoured the 6-endo-tet cyclisation to
the trihydroxypiperidine 10a-d, in preference to a 5-exo-
tet cyclisation to the related pyrrolidines 11a-d. The pipe-
ridine:pyrrolidine ratio was approximately 3:1 under
these conditions, although only the piperidine product
could be isolated from the cyclisation of 3-aminobenzyl-
3-deoxy-1,2:4,5-dianhydroxylitol 8e with benzylamine
(Table). For sterically hindered amines such as 6-amino-
6-deoxy-1,2-3,4-bis-O-isopropylidene-D-galactose 12,24
Acknowledgement
We thank the EPSRC for a studentship to RDS, and The Royal So-
ciety for a University Research Fellowship to NRT.
References and Notes
(1) Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Stütz, A.E., Ed.; Wiley-VCH: Weinheim, 1999.
(2) Bols, M. Acc. Chem. Res. 1998, 31, 1; Legler, G. in Ref. 1 p
41.
(3) Ishikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am.
Chem. Soc. 1998, 120, 3007.
(4) Dong, W.; Jesperson, T.; Bols, M.; Skrydstrup, T.; Sierks,
M.R. Biochemistry 1996, 35, 2788.
(5) Sun, L.; Li, P.; Amankulor, N.; Tang, W.; Landry, D.W.;
Zhao, K. J. Org.Chem. 1998, 63, 6472.
(6) Robinson, K.M.; Begovic, M.E.; Rhinehart, B.L.; Heinke,
E.W.; Ducep, J.-B.; Kastner, P.R.; Marshall, F.N.; Danzin, C.
Diabetes 1991, 40, 825.
(7) G. Legler in Ref. 1. p 56-59.
(8) Lehman, J.; Rob, B. Carbohydrate Res. 1995, 272, C11.
(9) Igarashi, Y.; Ichikawa, M.; Ichikawa, Y. Bioorg. Med. Chem.
Lett. 1996, 6, 553.
these conditions led to the formation of tetrahydrofurans (10) Legler, G.; Stütz, A. E.; Immrich, H. Carbohydrate Res. 1995,
272, 17.
via an intramolecular cyclisation. This is in agreement
(11) Paulsen, H.; Steinert, G. Chem. Ber. 1967, 100, 2467.
(12) Bernotas, R.C.; Papandreou, G.; Urbach, J.; Ganem, B.
Tetrahedron Lett. 1990, 31, 3393.
(13) Godskesen, M.; Lundt, I.; Madsen, R.; Winchester, B. Bioorg.
with the observations of Capon and Barrow on stepped
epoxides.23 The reaction conditions which led to the best
yield of trihydroxypiperidines from 1,2:4,5-dianhydro-
pentitols with bulky amines such as 12 was found to be
simply to heat the compounds together in water at 50 °C
for 24 h. This again gave an approximate 3:1 ratio of pip-
eridine to pyrrolidine products. Repeating the reaction un-
der aprotic conditions, such as DMF (120 °C, 24 h) gave
only 25% yield of the N-substituted trihydroxypiperidine.
The results for these transformations are summarised in
the Table. The benzyl protecting groups were removed by
hydrogenation, and the acetonides by treatment with
aqueous hydrochloric acid. The deprotected aza-disaccha-
ride products were then purified using ion exchange col-
umn chromatography. Spectroscopic data on the xylitol
family of compounds is given below. Biological testing of
the trihydroxypiperidine and pyrrolidine compounds re-
ported in this paper is currently underway.
Med. Chem. 1996, 4, 1857.
(14) Holland, D.; Stoddart, J.F. Carbohydrate Res. 1982, 100, 207.
(15) Vidra, I.; Institóris, L.; Simon, K.; Czugler, M.; Csöregh, I.
Carbohydrate Res. 1983, 111, 215.
(16) Altenbach, H.J.; Merhof, G.F. Tetrahedron: Asymmetry 1996
7, 3087.
(17) Chenera, B.; Boehm, J.C.; Dreyer, G.B. Bioorg. Med. Chem.
Lett 1991, 1, 219.
(18) Schreiber, S.L.; Sammakia, T.; Uehling, D.E. J. Org. Chem.
1989, 54, 15.
(19) Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett.
1994, 35, 3293; Depezay, J.-C. In Carbohydrate Mimics:
Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH:
Weinheim 1998; chap. 16.
(20) A first combinatorial library of azasugar glycosidase
inhibitors based on 1-azafagomine has recently been reported;
Lohse, A.; Jensen, K.B.; Bols, M. Tetrahedron Lett. 1999, 40,
3033.
(21) Kim, D.-K.; Kim, G.; Kim, Y.-W. J. Chem. Soc., Perkin
Trans. 1. 1996, 803.
Table 1
(22) Parr, I.B.; Horenstein, B.A. J. Org. Chem. 1997, 62, 7489.
(23) Capon R.J.; Barrow, R.A. J. Org. Chem. 1998, 63, 75.
(24) For the synthesis of 6-amino-6-deoxy-1,2-3,4-bis-O-
isopropylidene-D-galactose see J.M. Garcia Fernandez, C.O.
Mellet, J. Fuentes J. Org. Chem. 1993, 58, 5192.
(25) Selected spectroscopic data:
N-Benzyl-3-benzyl-3,4,5-trans,trans-trihydroxy-
piperidine (9a)
1H NMR (400 MHz/CDCl3) 2.28 (dd, 2H, H1b, H5b), 2.87
(dd, 2 H, J=11.4 and 3.4 Hz, H1b, H5b), 3.28 (t, 1H, J=7.2 Hz,
H3), 3.58 (s, 2H, NCH2Ph), 3.79 (dt, 2H, J=11.4 and 7.2 Hz,
H2, H4), 4.79 (s, 2H, OCH2Ph), 7.38-7.25 (m, 10H, Ar).
13C NMR (100 MHz/CDCl3) 57.0 (CH2, C1, C5), 62.0 (CH2,
NCH2Ph), 69.8 (CH, C2, C4), 73.8 (CH2, OCH2Ph), 84.3 (CH,
C3), 127.2, 127.7, 127.9, 128.3, 128.6, 129.0 (all CH, Ar),
137.7, 138.6 (C, Ar).
Reaction conditions
A) 6 eq. 60% HClO4, 12 eq. amine, 2 h at 0 °C, then 16 h at RT.
B) 0.9 eq. amine, H2O, 50 °C, 24 h (at 0.1 mM concentration).
RNH2 = 6-amino-6-deoxy-1,2-3,4-bis-O-isopropylidene-D-galactose
Synlett 2000, No. 2, 193–196 ISSN 0936-5214 © Thieme Stuttgart · New York

196
R. D. Smith, N. R. Thomas
LETTER
N-(6’-Deoxy-1’,2’-3’,4’-bis-O-isopropylidene-D-
3,4,5-trans,trans-Trihydroxypiperidine (4)
1H NMR (400 MHz/D2O) 2.26 (dd, 2H, J=10.5 and 12.6 Hz,
H1b, H5b), 2.94 (dd, 2H, J=4.9, 12.6 Hz, H1a,H5a), 3.11 (t,
J=9.1 Hz, H3), 3.31 (ddd, 2H, J=4.9, 9.1 and 10.5 Hz, H2,
H4). 13C NMR (67.80 MHz/D2O) 49.6 (CH2, C1, C5), 71.1
(CH, C2, C4), 78. 6 (CH, C3).
galactosyl)-3,4,5-trans,trans-trihydroxypiperidine
1H NMR (400 MHz, CDCl3) 1.32 (s, 6H, C(CH3)2), 1.44 (s,
3H, C9CH3)2), 1.55 (s, 3H, C(CH3)2), 2.09 (m, 2H, H2b, H6b),
2.56-2.7 (m, 2H, H6’), 3.03 (m, 2H, H2a, H6a), 3.24 (t, 1H,
J=8.6 Hz, H4), 3.64 (m, 2H, H3, H5), 3.92, (m, 1H, H5’), 4.16
(app. d, 1H, H4’), 4.29 (dd, 1H, J=2.3 and 5.0 Hz, H2’), 4.5
(dd, 1H, J=2.3 and 7.9 Hz, H3’), 5.54 (d, 1H, J=5 Hz, H1’).
13C NMR (67.80 MHz/CDCl3) 25.3 (CH3, C(CH3)2), 24.4
(CH3, C(CH3)2), 24.9 (CH3, C(CH3)2), 26.0 (CH3, C(CH3)2),
26.1 (CH3, C(CH3)2), 57.2 (CH2, C2, C6), 57.9 (CH2, C6’),
65.1 (CH, C5’), 69.9, (CH, C4), 70.0 (CH, C3, C5), 70.4 (CH,
C2’), 70.8 (CH, C3’), 72.3 (CH, C4’), 96.4 (CH, C1’), 108.7
(C, C(CH3)2), 109.3, (C, C(CH3)2).
N-(6’-Deoxy-1’,2’-3’,4’-bis-O-isopropylidene-D-
galactosyl)-3-benzyl-3,4,5-trans,trans-trihydroxy-
piperidine (10a)
1H NMR (400 MHz, CDCl3) 1.34 (s, 6H, C(CH3)2), 1.45 (s,
3H, C9CH3)2), 1.54 (s, 3H, C(CH3)2), 2.39-2.49 (m, 2H, H2b,
H6b), 2.61-2.78 (m, 2H, H6’), 2.96 (m, 2H, H2a, H6a), 3.31
(t, 1H, J=6.5 Hz, H4), 3.80 (m, 2H, H3, H5), 3.94, (m, 1H,
H5’), 4.20 (dd, 1H, J=2 and 8 Hz, H4’), 4.30 (dd, 1H, J=2 and
5 Hz, H2’), 4.59 (dd, 1H, J=2 and 8 Hz, H3’), 4.76 (s, 2H,
CH2Ph), 5.54, (d, 1H, J=5 Hz, H1’), 7.36 (m, 5H, Ar). 13
C
NMR (67.80 MHz/CDCl3) 25.3 (CH3, C(CH3)2), 26.4 (CH3,
C(CH3)2), 26.5 (CH3, C(CH3)2), 57.5 (CH2, C2, C6), 57.6
(CH2, C6’), 66.0 (CH, C5’), 69.9, (CH, C3, C5), 70.9 (CH,
C2’), 71.3 (CH, C3’), 73.0 (CH, C4’), 74.2 (CH2, CH2Ph),
83.1 (CH, C4), 97.0 (CH, C1’), 109.0 (C, C(CH3)2), 110.0, (C,
C(CH3)2), 128.1, 128.3, 129.0 (all CH, Ar), 138.0 (C, Ar).
HRMS (EI): m/z found: 465.2343; C24H35NO8 requires
465.2363.
Article Identifier:
1437-2096,E;2000,0,02,0193,0196,ftx,en;L21699ST.pdf
Synlett 2000, No. 2, 193–196 ISSN 0936-5214 © Thieme Stuttgart · New York