Sustainable Synthesis of Chiral Tetrahydrofurans through the Selective Dehydration of Pentoses

Article abstract of DOI:10.1002/chem.201503510

L-Arabinose is an abundant resource available as a waste product of the sugar beet industry. Through use of a hydrazone-based strategy, L-arabinose was selectively dehydrated to form a chiral tetrahydrofuran on a multi-gram scale without the need for protecting groups. This approach was extended to other biomass-derived reducing sugars and the mechanism of the key cyclization investigated. This methodology was applied to the synthesis of a range of functionalized chiral tetrahydrofurans, as well as a formal synthesis of 3R-3-hydroxymuscarine.

Full text of DOI:10.1002/chem.201503510

DOI: 10.1002/chem.201503510
Communication
&
Cyclization
Sustainable Synthesis of Chiral Tetrahydrofurans through the
Selective Dehydration of Pentoses
[a]
[b]
[a]
[a]
ˇ
ˇ
Robert W. Foster, Christopher J. Tame, Dejan-Kresimir Bucar, Helen C. Hailes,* and
Tom D. Sheppard*[a]
Abstract: l-Arabinose is an abundant resource available
as a waste product of the sugar beet industry. Through
use of a hydrazone-based strategy, l-arabinose was selec-
tively dehydrated to form a chiral tetrahydrofuran on
a multi-gram scale without the need for protecting
groups. This approach was extended to other biomass-de-
rived reducing sugars and the mechanism of the key cycli-
zation investigated. This methodology was applied to the
synthesis of a range of functionalized chiral tetrahydrofu-
rans, as well as a formal synthesis of 3R-3-hydroxymuscar-
ine.
The effective use of biomass, and in particular that generated
as waste,[1] is essential to reduce the global dependence on
petrochemical resources for the manufacture of valuable com-
pounds, fuels and materials.[2] The majority of biomass is made
Scheme 1. The preparation of furfural and THFs from biomass feedstock.
up of carbohydrates, which are an abundant source of pento-
ses and hexoses.[3] For example, the refinement of sugar beet
troduction of stereocenters using asymmetric catalysis[8] or res-
generates beet pulp as a major waste product, and this is
a rich source of l-arabinose.[4] A variety of techniques has been
developed to convert these biomass resources into valuable
small molecules, such as the dehydration of pentoses under
forcing acidic conditions to give furfural (Scheme 1), which can
then be converted into various alcohols, alkenes, and heterocy-
cles.[5] However, the majority of compounds prepared from
pentoses and hexoses in this fashion are either achiral[6] or rac-
emic mixtures where the stereochemistry of the chiral precur-
sors is lost.[7] Using these products as intermediates in the syn-
thesis of more complex targets may therefore require the rein-
olutions.[9]
The tetrahydrofuran (THF) is a privileged scaffold within me-
dicinal chemistry[10] and the stereoselective synthesis of chiral
THFs has been a major area of recent research.[11] An attractive
approach is to utilize the inherent chirality present in single
isomer biomass-derived carbohydrates.[12] However, existing
methods often require the selective conversion of a primary al-
cohol into an alkyl sulfonate or halide[13] and/or the use of pro-
tecting groups,[14] both of which are detrimental to the econo-
my of a synthetic route.[15] Herein we describe the application
of N,N-dimethylhydrazine[16] for the selective dehydration of
biomass-derived reducing sugars to prepare chiral THFs under
mildly acidic conditions (Scheme 1).[17]
ˇ
[a] R. W. Foster, Dr. D.-K. Bucar, Prof. H. C. Hailes, Dr. T. D. Sheppard
Department of Chemistry, University College London
Christopher Ingold Laboratories
20 Gordon Street, London, WC1H 0AJ (UK)
E-mail: h.c.hailes@ucl.ac.uk
tom.sheppard@chem.ucl.ac.uk
Homepage: http://www.tomsheppard.eu
Treating l-arabinose 1a with N,N-dimethylhydrazine and
Amberlystꢀ 15 acidic resin in methanol at room temperature
gave hydrazone 2a in 99% yield (Table 1, entry 1). Stirring hy-
drazone 2a in methanol at 408C for 16 h with 20 mol% TFA re-
1
sulted in 100% conversion of 2a. Analysis of the crude H NMR
[b] Dr. C. J. Tame
spectrum indicated the formation of THF 3a as a 75:25 mix-
ture of diastereoisomers and purification by flash column chro-
matography gave a mixture of the two stereoisomers in 67%
yield. The reaction was scaled up from a 6.7 mmol scale to
a 104 mmol scale without any significant drop in yield, giving
11.9 g of THF 3a. The major diastereoisomer was isolated by
recrystallization and the stereochemistry was confirmed by
GlaxoSmithKline, Medicines Research Centre
Gunnels Wood Road, Stevenage, Herts, SG1 2NY (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503510.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
tribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
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Communication
single-crystal X-ray diffraction
(Figure 1). Both steps were con-
Table 1. Two-step synthesis of THFs 3 from sugars 1.
ducted in
a sustainable sol-
vent[18] (methanol) without the
need for either pre-drying of the
solvent or for a drying agent in
the reaction.
Entry
Sugar 1
Step 1
THF 3[b]
Step 2
d.r.[c]
yield [%]
yield [%]
The same reaction conditions
were used to prepare the enan-
tiomeric THF ent-3a from d-
ribose (Table 1, entry 2) in a 58%
yield over two steps. It is note-
worthy that the diastereoselec-
tivity of this reaction was com-
parable with that observed for
the cyclization of arabinose-de-
rived hydrazone 2a. The meth-
odology was also extended to d-
lyxose (Table 1, entry 3), with the
corresponding hydrazone pre-
pared in 98% yield. The TFA-
mediated cyclization step gave
THF 3b in 66% yield as a 55:45
mixture of diastereoisomers. THF
3b could also be prepared from
d-xylose in 61% yield over two
steps, again as a 55:45 mixture
of diastereoisomers (entry 4).
This is a particularly important
result as d-xylose is one of the
major components of biomass.[3]
Xylose is naturally available in
both enantiomers and using l-
xylose it was possible to access
ent-3b in a comparable yield
(entry 5). The methodology was
extended to deoxy sugar l-
rhamnose, another constituent
of sugar beet pulp, to give THF
3c in 69% yield as a 60:40
mixture of diastereoisomers
(entry 6).
1
99
67 (66)[d]
75:25
2
3
4
5
98
59
75:25
55:45
55:45
55:45
98
66
not isolated
not isolated
61[e]
57[e]
6
99
69
60:40
[a] Reagents and Conditions: NH2NMe2 (2.0 equiv), Amberlystꢀ 15, MeOH, 24 h, RT. [b] Reaction conducted on
a 6.0–6.7 mmol scale unless otherwise stated. [c] Determined by analysis of the crude H NMR spectra. [d] Reac-
1
tion conducted using 20.0 g (104 mmol) of hydrazone 2a. [e] Yield over two steps from xylose.
Recrystallization of hydrazone 3a yielded the major anti-dia-
stereoisomer in high purity. Reducing hydrazone anti-3a using
hydrogen, a palladium catalyst and Boc2O gave carbamate 4 in
60% yield as a single stereoisomer (Scheme 2).
Treatment of THF 3a (d.r.=75:25) with Amberlystꢀ 15 acidic
resin in water at room temperature resulted in rapid hydrolysis
of the hydrazone to give hydrolyzed product 5 (Scheme 3).[20]
Figure 1. ORTEP of the asymmetric unit in the crystal structure of hydrazone
anti-3a. The thermal ellipsoids are shown at a 50% probability level. Only
hydrogen atoms belonging to the cyclic core are shown for clarity.[19]
Scheme 2. Reduction of hydrazone anti-3a.
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Communication
Scheme 4. Postulated mechanism and mechanistic studies.
the adjacent hydroxyl to give vinyldiazenium intermediate
13.[22] Cyclization of this intermediate would give THF 3a as
either an anti- or syn-diastereoisomer. Resubmission of an iso-
merically pure sample of anti-3a to the reaction conditions re-
sulted in the same 75:25 mixture of anti- and syn-diastereoiso-
mers that was observed in the original reaction, which sug-
gests that the diastereoselectivity is under thermodynamic
control. Conducting the reaction in [D4]MeOH did not result in
detectable incorporation of deuterium adjacent to the hydra-
zone, indicating that epimerization occurs through a reversible
ring closure rather than via a vinylhydrazine intermediate. The
proposed mechanism is also consistent with the observation
that hydrazones 2a and 2b converge to THF 3a and ent-3a
with the same diastereoselectivity (Table 1, entries 1 and 2), as
the two reactions would proceed through enantiomeric vinyl-
diazenium intermediates. Without TFA present no cyclization
of 1a was observed.
Scheme 3. Hydrolysis of hydrazones 3 and transformation into a range of
THFs. Reagents and conditions; i) Amberlystꢀ 15, H2O, 5 min, RT; ii) NaBH4,
MeOH, 1 h, 08C; iii) nBuNH2, AcOH, H2 (1 atm.), 10% Pd/C, MeOH, 4 h, RT,
then Boc2O, cyclopentyl methyl ether (CPME), 16 h, RT; iv) trimethyl phos-
phonoacetate, K2CO3, MeOH, 4 h 08C; v) Amberlystꢀ 15, MeOH, 48 h, RT.
Reduction of compound 5 with NaBH4 in methanol gave triol 6
as an 85:15 mixture of diastereoisomers in 98% yield over two
steps from hydrazone 3a. Reductive amination of intermediate
5 using n-butylamine, acetic acid, and hydrogen/palladium, fol-
lowed by trapping of the intermediate amine with Boc2O, gave
carbamate 7 in 65% yield from hydrazone 3a as an 80:20 mix-
ture of diastereoisomers. Compound 5 was also converted to
alkene 8 using trimethyl phosphonoacetate in 73% yield over
two steps with excellent E-selectivity. Finally, treating com-
pound 5 with Amberlystꢀ 15 in methanol resulted in the forma-
tion of dimethyl acetal 9 in 74% yield over two steps from 3a
as a 65:35 mixture of stereoisomers.
In a preliminary study, the extension of this approach to
hexoses was explored (Scheme 5). Hydrazone 14, formed from
d-galactose, was subjected to the TFA-mediated cyclization
conditions. This gave a 60:40 mixture of THF 15 and tetrahy-
dropyran 16 in 53% isolated yield, with both heterocycles
formed as single stereoisomers.
The hydrolysis/reduction sequence was also applied to the
hydrazones 3b and 3c, which gave the corresponding triols
10 and 11 in 90% and 93% yield respectively. l-Rhamnose-de-
rived triol 11 is a late-stage intermediate in Fleet’s synthesis of
3R-3-hydroxymuscarine 12.[21] Triol 11 was previously prepared
from l-rhamnose using stoichiometric bromine, trifluorometha-
nesulfonic anhydride, and lithium aluminium hydride, so our
route represents a less hazardous and more sustainable alter-
native.
A plausible reaction mechanism for the cyclization of hydra-
zone 2a is proposed in Scheme 4. The N,N-dialkylhydrazone
group of 2a could promote the acid-mediated elimination of
Scheme 5. Extending the methodology to d-galactose.
Chem. Eur. J. 2015, 21, 15947 – 15950
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Communication
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Experimental Section
1
Experimental procedures, H and 13C NMR spectra, characterization
data for all compounds and crystallographic data for anti-3a are
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anti-3a: Isolated as a single stereoisomer following recrystallization
from boiling CPME; white crystalline solid; m.p.=65–678C; Rf =
0.33 (1:1 acetone:hexane); nmax (film/cmÀ1
) 3415 s br. 2875 s,
1586 s, 1467 s, 1445 s; 1H NMR (600 MHz; [D4]MeOH) 6.51 (1H, d,
J=6.6, N=CH), 4.23–4.18 (2H, m, N=CHCH, CH2CH), 4.08 (1H, dd,
J=9.6, 4.9, OCHH’), 4.02 (1H, dd, J=7.3, 5.1, N=CHCHCH), 3.76–
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Keywords: arabinose · biomass · hydrazines · cyclization ·
tetrahydrofurans
[19] CCDC 1411520 contains the supplementary crystallographic data for
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Received: September 3, 2015
Published online on September 25, 2015
Chem. Eur. J. 2015, 21, 15947 – 15950
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15950 ꢁ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim