Double reductive amination and selective strecker reaction of a D-lyxaric aldehyde: Synthesis of diversely functionalized 3,4,5-trihydroxypiperidines

Article abstract of DOI:10.1002/ejoc.201200587

A D-mannose-derived aldehyde with the D-lyxo configuration is a versatile key intermediate to functionally and stereochemically diversified piperidines. It allowed the synthesis of natural 3,4,5-trihydroxypiperidines and new analogs through a double reductive amination strategy and the synthesis of novel 2-cyanotrihydroxypiperidines through a highly regio-and diastereoselective Strecker reaction.

Full text of DOI:10.1002/ejoc.201200587

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200587
Double Reductive Amination and Selective Strecker Reaction of a -Lyxaric
D
Aldehyde: Synthesis of Diversely Functionalized 3,4,5-Trihydroxypiperidines
Camilla Matassini,[a] Stefania Mirabella,[a] Andrea Goti,[a] and Francesca Cardona*[a]
Keywords: Total synthesis / Alkaloids / Azasugars / Amination / Strecker reaction
A
D
-mannose-derived aldehyde with the
D
-lyxo configura-
a double reductive amination strategy and the synthesis of
novel 2-cyanotrihydroxypiperidines through a highly regio-
and diastereoselective Strecker reaction.
tion is a versatile key intermediate to functionally and stereo-
chemically diversified piperidines. It allowed the synthesis of
natural 3,4,5-trihydroxypiperidines and new analogs through
We envisaged in “masked” dialdehyde 5, with the config-
uration of d-lyxose, a versatile building block for the syn-
thesis of trihydroxypiperidines and their unnatural conge-
ners (Scheme 1). In particular, the introduction of lipophilic
chains on the nitrogen atom was appealing to improve the
ability of the iminosugars to penetrate the cell membrane
and their chaperoning activity.[8] The most direct approach
conceivable for the synthesis of piperidines 6 was double
reductive amination with a primary amine. While many ex-
amples of this reaction have been reported starting from
diketones or ketoaldehyde derivatives,[9] the same approach
from dialdehydes has been less exploited, apart from Bols’
synthesis of isofagomine[10] and a few recent reports.[11] We
describe here the results obtained with aldehyde 5 that led
to the synthesis of natural 2, ent-1, and some new unnatural
N-alkylated piperidines. Preliminary results on the Strecker
reaction with 5 (and its debenzylated derivative) are also
reported.
Introduction
3,4,5-Trihydroxypiperidines 1–3 (Figure 1) were isolated
in 1995 from Eupatorium fortunei TURZ,[1] a plant used in
folk medicine for the treatment of several pathologies. They
have been synthesized by Ganem[2] and others either by the
“chiral pool” strategy[3] or by enantioselective syntheses[4]
and behave as selective inhibitors of glycosidases. These
molecules, also referred to as 1-N-iminosugars together
with their relative isofagomine (4), have shown potential
therapeutic applications for the treatment of several pathol-
ogies such as energy utilization diseases, viral infections,
and lysosomal storage disorders.[5] During our studies on
the synthesis of polyhydroxylated alkaloids and their unnat-
ural analogs,[6] our attention was drawn to aldehyde 5
(Scheme 1), whose synthesis from d-mannose has been re-
cently reported.[7]
Results and Discussion
Aldehyde 5 was synthesized in four steps from d-man-
nose, following a slight modification of the published pro-
cedure[7] (see the Supporting Information). We initially
sought to access piperidines 6 by one-pot double reductive
amination of 5 with hydrogen as the reducing agent, in view
of the required removal of the benzyl protecting group at
the anomeric position. Compound 5 was treated with ben-
zylamine (1 equiv.) in MeOH in the presence of 3 Å molecu-
lar sieves (Scheme 2). After 40 min, the imine was formed
Figure 1. Natural glycosidase inhibitor trihydroxypiperidine alka-
loids.
1
Scheme 1. Retrosynthetic strategy.
(as determined by H NMR spectroscopic analysis of the
crude reaction mixture), then Pd(OH)2/C was added, and
the mixture was stirred under an atmosphere of H2 (bal-
loon) for 25 h to afford compound 7[12a] in 69% yield.
Treatment of 7 with methanolic HCl followed by ion-ex-
change resin afforded unnatural ent-1,[12,4a,2,3b,3c] quantita-
tively. The spectroscopic data and physicochemical proper-
[a] Dipartimento di Chimica “Ugo Schiff”, Università di Firenze,
Via della Lastruccia 3-13, Polo Scientifico e Tecnologico,
50019 Sesto Fiorentino (FI), Italy
Fax: +39-055-457-3531
E-mail: francesca.cardona@unifi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200587.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Matassini, S. Mirabella, A. Goti, F. Cardona
SHORT COMMUNICATION
ties of ent-1 are in agreement with the literature data.[12b,4a] protected d-lyxaric aldehyde or as a 3,4-di-O-protected d-
Synthetic ent-1 showed a specific optical rotation {[α]D26
=
arabinaric aldehyde, could be a suitable substrate for the
–65.7 (c = 1.0, MeOH)} that was opposite to that reported double reductive amination reaction by using NaBH3CN as
for the natural sample {[α]D = +66.7 (c = 0.3, MeOH)}.[1] the reducing agent. This procedure would also allow the
This compound was shown to be a selective inhibitor of α- synthesis of N-benzyl-substituted piperidines. Martin and
l-fucosidase from human placenta.[12b] In order to access co-workers reported related examples on different carbo-
natural 2, the configuration at C5–OH in 7 had to be in- hydrate-derived aldehydes, and the yields varied from very
verted. However, the Mitsunobu reaction under standard low to excellent.[11b] While this work was in progress, Crich
conditions[13] failed both on 7 and on N-Boc-protected pip- and co-workers described the double reductive amination
eridine 8, which was obtained in 93% yield from 7 under of a 1,5-dialdehyde to afford isofagomine (4).[15] Our results
standard conditions. We then turned to an oxidation–re- on dialdehyde 12 are shown in Table 1.
duction procedure. In the final reduction, the expected fa-
vored axial attack of hydride to C=O at C-5 anti to the
Table 1. Double reductive amination of dialdehyde 12.
vicinal C–O bond according to a Felkin–Anh model would
install the desired all-cis relative configuration of the final
product. Oxidation of 8 with Dess–Martin periodinane[14]
gave ketone 9 in 98% yield, and subsequent reduction with
NaBH4 afforded stereoselectively alcohol 10, as expected,
in 76% yield. Final treatment with methanolic HCl fol-
lowed by ion-exchange resin afforded 2[3a,3c–3e,4a] in quanti-
tative yield (Scheme 2). The spectroscopic data and physico-
chemical properties of 2 were in agreement with those re-
ported in the literature.[3a,3e,4a] Compound 2 was shown to
inhibit β-glucosidase and α- and β-galactosidase.[3a,3d] The
double amination protocol on 5 employing butylamine and
octylamine afforded piperidines 11a and 11b in moderate
yields (Scheme 2). Obviously, N-benzyl-substituted piper-
idine could not be achieved through this catalytic hydrogen-
ation procedure.
Entry
RNH2
NaBH3CN Time
11/13[a]
Yield of
[equiv.]
[d]
11 [%][b]
1
2
3
4
BnNH2
BnNH2
BnNH2
C4H9NH2
BnNH2
C4H9NH2
C8H17NH2
3
3
2
2
3
3
3
3
2
5
5
3
7
7
2:1[c]
3.5:1[c]
6:1
23[d]
51[d]
32
43
93
3:1
5[e]
6[e]
7[e]
Ͼ98:2
Ͼ98:2
Ͼ98:2
48
56
[a] Determined by 1H NMR spectroscopic analysis of the crude
mixture. [b] Isolated yield after flash column chromatography.
[c] Determined after acetylation of the crude mixture. [d] Yield re-
fers to isolation of the acetate of 11. [e] Anhydrous MeOH, 3 Å
molecular sieves, R–NH2 (0.9 equiv.), AcOH (2 equiv.).
Initially, 12 was treated with benzylamine (1.2 equiv.) in
MeOH, and after 3 d, a 2:1 mixture of the desired 11c to-
gether with the unexpected amine 13c was recovered
(Table 1, Entry 1). Formation of cyano-substituted com-
pounds as byproducts during reductive amination reactions
under neutral or basic conditions has been occasionally re-
ported.[16] Remarkably, 2-cyano-substituted piperidine 13c
was formed completely regio- and stereoselectively. The
structure of 13c was assigned on the basis of 1D and 2D
NMR spectra of its acetate derivative, which showed for 3-
H a dd with J = 8.4 and 4.8 Hz, in agreement with an ax–
ax relationship with 4-H and an ax–eq relationship with 2-
H, respectively. Rationalization of the observed selectivity
is currently under investigation. The amount of 13c formed
could be reduced by shortening the reaction time (Table 1,
Entry 2 vs. 1) or by reducing the number of equivalents of
NaBH3CN (Table 1, Entry 3 vs. 1). The formation of 2-
cyanopiperidine 13a was also observed with the use of
Scheme 2. Synthesis of ent-1 and 2.
Alternatively, deprotection of the benzyl anomeric group BuNH2 (Table 1, Entry 4). By employing anhydrous MeOH
by catalytic hydrogenation afforded dialdehyde 12 in 100% and AcOH (2 equiv.),[11b] the formation of the 2-cyano ad-
yield (see the Supporting Information). This compound, duct was completely suppressed and N-alkyl piperidines
which can be viewed (in its open-chain form) as a 2,3-di-O- 11a–c were formed in good to excellent yields (Table 1, En-
2
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Synthesis of Diversely Functionalized 3,4,5-Trihydroxypiperidines
tries 5–7). Final treatment with methanolic HCl followed Table 2. Strecker reaction on aldehyde 5.
by ion-exchange resin afforded unnatural N-alkylated pip-
eridines 14a–c (Scheme 3) in quantitative yields.
Entry
RNH2/AcONH4
Solvent a/b[a]
Yield of a
[%][b]
Scheme 3. Synthesis of unnatural N-alkylated piperidines.
1
BnNH2
BuNH2
AcONH4
AcONH4
MeCN[c] Ͼ95:5
MeCN[c] Ͼ95:5
100[d] (80)[e]
2
100[d] (75)[e]
3[f]
4[f]
MeCN
EtOH
62:38
81:19
–
61
2-Cyanopiperidines 13 obtained as byproducts would be
valuable synthetic intermediates.[17] Thus, we reasoned that
such compounds could be obtained regioselectively by
Strecker reaction[18] of aldehyde 5, followed by deprotection
at the anomeric carbon atom and cyclization. The Strecker
reaction has been extensively used for the synthesis of α-
aminonitriles from aldehydes, also in its enantioselective
version,[17,19] and due to the chirality of 5, we envisaged
that a diastereoselective Strecker reaction could be ac-
complished. Aldehyde 5 was first treated with benzylamine
(1.0 equiv.) and TMSCN (1.0 equiv.) in dry acetonitrile with
the addition of 1.0 mol-% of Cu(OTf)2 as catalyst.[20] We
were delighted to observe that mainly one diastereoisomer
was formed, in remarkable diastereomeric excess (Ͼ95:5;
Table 2, Entry 1). A similar result was observed with
BuNH2 as the amine source (Table 2, Entry 2). However,
the presence of a Lewis acid catalyst was found unnecessary
(Table 2, Entries 1 and 2), with cleaner products obtained
under these conditions that did not require further purifica-
tion by flash column chromatography. By employing
10 equiv. of NH4OAc[21] as source of ammonia in acetoni-
trile (Table 2, Entry 3), adduct 17a was obtained in 62:38
diastereoselectivity. A change to EtOH led to an improve-
ment in the diastereoselectivity (81:19; Table 2, Entry 4) and
a quite good isolated yield (61%) of 17a was also achieved.
Configuration at the new stereocenter was assigned on the
basis of X-ray analysis of a single crystal of 17a (see the
Supporting Information).[22] The stereochemical outcome
of the reaction can be rationalized by considering the ap-
proach of the cyanide nucleophile through a Cram model
of a chelation-controlled transition state (Figure 2), where
the iminium proton is involved in a five-membered chelate
ring. According to this model, the cyanide ion would attack
from the less-hindered Si face of the double bond to give
diastereomers with the S absolute configuration at the
newly formed stereocenter as major products 15–17a. This
[a] Determined by 1H NMR spectroscopic analysis of the crude
mixture. [b] Isolated yield after flash column chromatography.
[c] Anhydrous solvent and 3 Å MS added. [d] Yield of the crude,
Ͼ95% purity as evaluated by H NMR spectroscopy. [e] Addition
of 1.0 mol-% of Cu(OTf)2. [f] 1.2 equiv. of TMSCN.
1
Figure 2. Cram chelate model for the Strecker reaction.
Supporting Information), which gave a sample identical to
the one formed during the reductive amination of 12
(Table 1). From this result, we may also infer that the regio-
and stereoselective formation of compounds 13 from 12
during the reductive amination is derived from a Strecker
reaction occurring at the more reactive aldehyde at C-5 fol-
lowed by intramolecular reductive amination at C-1.
Scheme 4. Regio- and stereoselective Strecker reaction.
Conclusions
In conclusion, we have reported ready access to valuable
stereochemical outcome is in agreement with the one re- 3,4,5-trihydroxypiperidines, including natural alkaloids and
cently reported for acyclic polyhydroxylated aldehydes.[21]
analogs, by reductive amination of a d-lyxaric/d-arabinaric
Even more intriguing, the direct Strecker reaction of dial- aldehyde derived from d-mannose. Highly regio- and
dehyde 12,[23] followed by cyclization and in situ reduction stereoselective Strecker reaction of the same key inter-
of the iminium ion intermediate by NaBH3CN afforded 2- mediate allowed access to 2-cyano-substituted piperidine
cyanopiperidine 13c with high regio- and stereoselectivity adducts. These latter are valuable intermediates for the syn-
(Scheme 4) in 50% yield after purification over silica gel.[24] thesis of pipecolic acid analogs and other natural com-
The structure of 13c was ascertained by acetylation (see the pounds.[25]
Eur. J. Org. Chem. 0000, 0–0
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C. Matassini, S. Mirabella, A. Goti, F. Cardona
SHORT COMMUNICATION
G. Horne, R. Storer, J. M. Tinsley, M. Jonathan, A. G. Geof-
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General Procedure for the Synthesis of N-Alkyl Piperidines 11a–c
by Double Reductive Amination: A solution of dialdehyde 12 (0.06 m
in dry MeOH) was stirred in the presence of powdered 3 Å mo-
lecular sieves for 15 min under a nitrogen atmosphere. Then,
NaBH3CN (3.0 equiv.) was added, and the reaction mixture was
cooled to 0 °C. Finally, RNH2 (R = Bn, Bu, octyl, 0.9 equiv.) and
AcOH (2.0 equiv.) were added, and the mixture was warmed to
room temperature and stirred for a total of 3–7 d under a nitrogen
atmosphere. The molecular sieves were removed by filtration
through Celite, and the filtrate was concentrated under vacuum.
The residue was purified by flash chromatography (CH2Cl2/MeOH
or CH2Cl2/MeOH/6% NH4OH) to afford 11a–c in 48–93% yield.
[7]
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General Strecker Reaction Procedure: A 0.2 m solution of com-
pound 5 and the appropriate amine source (BuNH2, BnNH2,
1.0 equiv., or NH4OAc, 10.0 equiv.) in dry CH3CN was stirred at
room temperature for 40 min and then trimethylsilyl cyanide (1.0
or 1.2 equiv.) was added. The resulting reaction mixture was stirred
at room temperature for 18 h, then diluted with EtOAc and washed
with water and brine. The organic layer was dried with anhydrous
Na2SO4 and concentrated under reduced pressure to give the crude
products, which were purified by flash chromatography (PE/
EtOAc) to afford major diastereoisomers 15–17a in 61–100% yield.
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1
X-ray structure of 17a, and copies of the H NMR and 13C NMR
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Full details will be given in a forthcoming Full Paper.
1
The H NMR spectrum of 12 showed the presence of a com-
plex mixture of different forms.
[24]
No other isomers were detectable in the crude mixture.
4
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Synthesis of Diversely Functionalized 3,4,5-Trihydroxypiperidines
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Received: May 4, 2012
Published Online: ᭿
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Job/Unit: O20587
/KAP1
Date: 14-06-12 16:52:39
Pages: 6
C. Matassini, S. Mirabella, A. Goti, F. Cardona
SHORT COMMUNICATION
Azasugars
C. Matassini, S. Mirabella, A. Goti,
F. Cardona* ...................................... 1–6
Double Reductive Amination and Selective
Strecker Reaction of a d-Lyxaric Aldehyde:
Synthesis of Diversely Functionalized
3,4,5-Trihydroxypiperidines
The synthesis of natural 3,4,5-trihydroxy-
piperidines and non-natural N-alkylated
derivatives from a dialdehyde possessing
the d-lyxo configuration is presented here-
in. The highly regio- and diastereoselec-
tive Strecker reaction on the same key alde-
hyde allowed access to important precur-
sors of pipecolic acids and diaminopiperid-
ine compounds.
Keywords: Total synthesis / Alkaloids /
Azasugars / Amination / Strecker reaction
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0