Functionalised tetrahydrofuran fragments from carbohydrates or sugar beet pulp biomass

Article abstract of DOI:10.1039/c9gc00448c

Carbohydrate biomass represents a potentially valuable sustainable source of raw materials for chemical synthesis, but for many applications, selective deoxygenation/dehydration of the sugars present is necessary to access compounds with useful chemical and physical properties. Selective dehydration of pentose sugars to give tetrahydrofurans can be achieved by treatment of the corresponding N,N-dimethylhydrazones under acidic or basic conditions, with the two approaches showing complementary stereoselectivity. The dehydration process is readily scalable and the THF hydrazones derived from arabinose, ribose, xylose and rhamnose were converted into a range of useful fragments containing primary alcohol, ketone, carboxylic acid or amine functional groups. These compounds have potentially useful physiochemical properties making them suitable for incorporation into fragment/lead generation libraries for medicinal chemistry. It was also shown that l-arabinose hydrazone could be obtained selectively from a crude sample of hydrolysed sugar beet pulp.

Full text of DOI:10.1039/c9gc00448c

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DOI: 10.1039/C9GC00448C
Green Chemistry
ARTICLE
Functionalised tetrahydrofuran fragments from carbohydrates or
sugar beet pulp biomass
Laure Benhamou,*a Robert W. Foster,a† David P. Ward,b Katherine Wheelhouse,c Lisa Sloan,c
Christopher J. Tame,c¥ Dejan-Krešimir Bučar,a Gary J. Lye,b Helen C. Hailes,*a and Tom D.
Sheppard*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Carbohydrate biomass represents a potentially valuable sustainable source of raw materials for chemical synthesis, but for
many applications, selective deoxygenation/dehydration of the sugars present is necessary to access compounds with useful
chemical and physical properties. Selective dehydration of pentose sugars to give tetrahydrofurans can be achieved by
treatment of the corresponding N,N-dimethylhydrazones under acidic or basic condiitions, with the two approaches showing
complementary stereoselectivity. The dehydration process is readily scalable and the THF hydrazones derived from
arabinose, ribose, xylose and rhamnose were converted into a range of useful fragments containing primary alcohol, ketone,
carboxylic acid or amine functional groups. These compounds have potentially useful physiochemical properties making
them suitable for incorporation into fragment/lead generation libraries for medicinal chemistry. It was also shown that L-
arabinose hydrazone could be obtained selectively from a crude sample of hydrolysed sugar beet pulp.
www.rsc.org/
with the exception of some partial reduction methods,6–8
carbohydrate biomass treatment often results in the loss of
functional groups and chiral information, and it remains very
challenging to selectively remove one or more hydroxyl groups
from a polyol, without resorting to extensive protecting group
manipulations.9,10 For this reason, the range of more complex
targets retaining stereochemical information from biomass
sugars prepared via succinct methods avoiding extensive
protection-deprotection steps has remained limited.
Introduction
The production of chemicals for medicinal chemistry relies
heavily on hydrocarbons from petrochemical sources to provide
small molecule synthons. Considering the inevitable exhaustion
of fossil fuels and the increased restriction of their use due to
concerns relating to climate change, the key to future chemical
processes will be the exploitation of renewable resources from
plant biomass.1 An important sustainable feedstock is sugar
beet, with a production cycle from seeds-to-seeds of only two
years. Cultivated predominantly in temperate regions for the
production of sucrose, the processing of the beet also generates
large quantities of pulp, which is considered as a low-value
waste product and is usually used as animal feed.2,3 This
material is highly enriched in carbohydrates, with the pulp being
composed of polymeric glucose (cellulose) and pectin (a co-
polymer of hexoses and pentoses). The latter fraction contains
a high proportion of L-arabinose as well as other sugars, which
could potentially be exploited as valuable chemical feedstocks,
but processing is required to release the monomeric sugars, and
strategies for this have been reported.4,5
Previous work (ref 12)
HO
OH
OH
O
1) H2NNMe2
2) [H+]
Me2NN
HO
OH
O
OH
L-Arabinose
67%, d.r. 75:25
This work
HO
OH
HO
OH
OH
HO
Pentoses
Me
HO2C
O
O
O
OH
NH2
A variety of transformations are now available to produce small
molecule building blocks from sugar monomers.4,5 However,
Chiral, 3D building blocks
- d.r. > 90:10 on gram scale
- Application to six pentoses
- Sustainable processes
Waste sugar
beet pulp
a. Department of Chemistry, University College London, Christopher Ingold
Laboratories, 20 Gordon St, London, WC1H 0AJ, UK; Email:
Scheme 1: Dehydration of pentose sugars for the synthesis of chiral building-
blocks
l.benhamou@ucl.ac.uk; h.c.hailes@ucl.ac.uk; tom.sheppard@ucl.ac.uk
b. Department of Biochemical Engineering, University College London, Bernard Katz
Building, London WC1E 6BT.
c. GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
Electronic Supplementary Information (ESI) available: Procedures for the
preparation of all compounds, together with characterisation data and X-Ray
crystallographic data. See DOI: 10.1039/x0xx00000x
Recently, some approaches have been developed which take
advantage of the intrinsic functionalities and chirality of
carbohydrates to develop novel methodology to access small
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3D-building-blocks.11,12 Indeed, we have recently developed a atmosphere (see ESI). Under these conditions, 3a was obtained
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DOI: 10.1039/C9GC00448C
selective method for the dehydration of pentose sugars to in 81% yield routinely on a 20 g scale. When these reaction
afford hydroxy-functionalised THFs without the need for conditions were applied to other pentose sugars, the yields
protecting groups.12 In this paper, we describe the optimisation were generally superior to the previously reported procedure,
of this chemistry on a multigram scale, the development of a with no significant difference in the diastereoselectivity
novel base-mediated cyclic dehydration of sugar hydrazones to observed (Scheme 3). THFs anti-3a and anti-3b derived from L-
access other stereoisomers, and the extension of this arabinose and D-ribose could be recrystallised from THF/Petrol
methodology to a range of pentoses. We also demonstrate the to give the pure anti-isomer in each case.
application of these dehydration reactions to the construction
under argon
of a small library of chiral THF fragments as useful building
OH
HO
OH
blocks for medicinal chemistry,13,14 via routes that offer
selectivity, scalability and sustainability. In addition, the direct
synthesis of one of our key starting materials directly from sugar
beet pulp is described, to demonstrate the feasibility of ‘up-
grading’ waste from biomass into complex chiral building
blocks.
20 mol% TFA
Me2NN
OH
Me2NN
iPrOH, 16 h
40 °C
O
OH
OH
anti-3a
81% (67%*)
dr 78:22
From L-arabinose
HO
OH
HO
OH
HO
OH
Me2NN
Me2NN
Me2NN
O
Results and discussion
Synthesis of chiral THFs from pentose sugars
O
O
anti-3b
68% (59%*)
dr 77:23
anti-3d
75% (69%*)
dr 60:40
(From L-rhamnose)
3c
66% (61%*)
55:45
dr
(From D-xylose)
The conversion of L-arabinose into 1a-3a was conducted
following the procedure described in our preliminary
communication for acid catalysed dehydration of pentoses.12
Hydrazone 1a was obtained quantitatively under acidic
conditions and subsequently cyclised using catalytic TFA
(Scheme 2). In our previous studies, this reaction had yielded
the THF in only moderate yield (67%), but the fate of the
remaining material was unclear. However, when the cyclisation
was performed on a larger scale (5–20 g), formation of two side-
products 4 and 5 in 22% and 5% yields respectively was
observed. The formation of methyl ether 4 could be rationalised
by the reaction of the vinyldiazenium intermediate 2a with
methanol. The formation of ketone 5 most likely results from
the aerobic oxidation of 1a at the C-2 position.
(From D-ribose)
Scheme 3: Optimised synthesis of chiral THFs anti-3a-anti-3d. *Yield obtained under
previous conditions.12
HO
OH
OH
1.5 eq DMC
2 eq. K2CO3
Me2NN
OH
Me2NN
O
MeOH, R.T.
1 eq. tBuOH
OH
OH
1a
3a, > 95%
dr 69:31
DMC = dimethylcarbonate
dr
Pentose
Product
Yield (%)
(syn:anti)
HO
OH
Me2NN
Me2NN
Me2NN
Me2NN
L-arabinose
D-ribose
> 95
87
69:31
O
syn-3a
HO
OH
OH
OH
OH
2 eq. H2NNMe2
Amberlyst 15
O
79:21
75:25
OH
Me2NN
syn-3b
O
HO
OH
1a, Quant.
OH
MeOH, 24 h, R.T.
HO
OH
OH
L-arabinose
D-xylose
> 95
O
syn-3c
HO
OH
HO
OH
Me2NN
20 mol% TFA
L-rhamnose
92
74:26
O
O
anti-3a, 68%, dr 78:22
MeOH, 16 h
syn-3d
40 °C
OH
HO
OH
Me2NN
Me2NN
L-xylose
D-lyxose
84
83:17
78:22
HO
OH
OH
Me2NN
O
syn-3e
via
OMe
OH
HO
OH
4, 22%, dr 57:43
HO
> 95
OH
N
2a
3c
Me2N
O
OH
Yields were determined by 1H NMR using tert-butanol as internal standard (1 eq.)
Table 1: Synthesis of chiral THFs syn-3a to syn-3e under basic conditions
Me2NN
O
OH
5, 5%
Scheme 2. Selective dehydration of L-arabinose and side-products formed
Investigations also established that the cyclisation of the sugar
hydrazones could be achieved to give THFs under basic
conditions, by activating the sugar-hydrazone 1a with
These issues were readily solved by running the cyclisation in a
less nucleophilic solvent (isopropanol) and under an argon
2 | J. Name., 2012, 00, 1-3
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dimethylcarbonate (DMC).15 The reaction occured at room
temperature and afforded the chiral THF syn-3a from arabinose
in excellent yield, with good diastereoselectivity. Importantly,
this provides a complementary approach to the acid-catalysed
cyclisation in terms of the THF isomer produced. These
conditions were also applied successfully to other pentoses,
with the major THF isomer in each case having syn-
stereochemistry at the THF carbons C-1 and C-2 (Table 1).
Full conversions were obtained after 4 hours and no change in
the diastereomeric ratio was noted during the course of the
cyclisation reaction. The presence of dimethylcarbonate and a
stoichiometric amount of base were essential for the reaction
to proceed in high yield. When a purified sample of the THF
anti-3a was submitted to the DMC/K2CO3 reaction conditions,
no epimerisation was observed after 24 hours suggesting that
there was no interconversion of the two isomers and that the
two products anti-3a and syn-3a were likely formed via two
different reaction pathways under the basic conditions. This is
in stark contrast to the acidic cyclisation conditions under which
the two products can rapidly interconvert, leading to
production of a thermodynamic mixture of products.
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DOI: 10.1039/C9GC00448C
O
OH
3
Me2NN
1
HO
OH
O
slow
OH
OH
OH
2
Me2NN
O
4
1a
O
OH
5
anti-3a
HO
Me2NN
From L-arabinose
O
6a
X
O
O
O
O
O
OH
HO
HO
OH
OH
OH
fast
fast
Me2NN
N
HO
8a
N
O
HO
7a
Me2NN
syn-3a
O
O
Me2NN
OH
O
1
OH
OH
OH
2
Me2NN
3
4
1b
O
5
OH
syn-3b
HO
6b
Me2NN
From D-ribose
X
O
O
O
HO
OH
OH
slow
Me2NN
HO
7b
O
Me2NN
anti-3b
Taking this into account, along with the observed
diastereomeric ratios of the products obtained from L-
arabinose, D-ribose, D-xylose and D-lyxose it is evident that
epimerisation of the the C-2 stereocentre must take place prior
to irreversible cyclisation, with the observed products resulting
from the relative rates of cyclisation of the two diastereomers.
Thus, arabinose hydrazone 1a must first be converted into cyclic
carbonate 6a (Scheme 4), which can only cyclise relatively
slowly to give anti-3a but can undergo epimerisation to 7a
which cyclises more rapidly to give syn-3a. Epimerisation may
take place via ring opening of the cyclic carbonate to generate
zwitterion 8a. In the case of D-ribose hydrazone 1b, the initially
formed carbonate 6b (the enantiomer of 7a) cyclises relatively
rapidly so less epimerisation to 7b (and subsequent cyclisation
Scheme 4: Proposed mechanism for the basic cyclisation of L-arabinose hydrazone
1a and D-ribose hydrazone 1b
O
(a)
MeO
O
Me2NN
HO
H
OMe
O
OH
O
O
OH
HO
Me2NN
HO
6a
(b)
HO
H
O
O
O
O
O
O
H
H
HO
OH
O
N
H
NMe2
O
O
to anti-3b) takes place leading to
a slightly higher
O
anti-3a
O
HO
6a
slow
Me2NN
H
diastereoselectivity in this reaction in comparison to the
formation of syn-3a. A similar rationale can be used to explain
the observed diastereoselectivities resulting from cyclisation of
D-xylose hydrazone 1c and D-lyxose hydrazone 1f. The selective
formation of the cyclic carbonate at C-2/C-3 could perhaps be
explained by involvement of the hydrazone group as a general
base that activates the C-2 alcohol towards reaction with
dimethyl carbonate (Scheme 5a). Furthermore, general base
assistance could also be invoked in the cyclisation reaction
(Scheme 5b), as in each case the cyclisation reaction which
proceeds fastest involves reaction of an intermediate in which
the hydrazone and nucleophilic primary alcohol are arranged on
the same face of the 5-membered carbonate ring. Cyclisation
with inversion at C-2 then leads to the THF ring in which the C-
3 alcohol and the hydrazone are on the same face of the newly
formed ring.
N
Me2N
HO
HO
O
O
NMe2
O
N
O
O
O
O
OH
H
NMe2
H
H
N
O
O
syn-3a
O
HO
7a
O
Me2NN
fast
H
H
Scheme 5: Base mediated a) cyclic carbonate 6a formation, b) cyclisation of 7a
Chiral functionalised THFs as 3D fragments for medicinal chemistry
The next objective of this study was to synthesise carefully
chosen targets for applications in medicinal chemistry, which
contained suitable functional groups for derivatisation in order
to prepare potential fragments and/or intermediates for
incorporation into lead-like molecules. Three families of
compounds were selected: (i) THF-triols 9, (ii) THF-carboxylic
acids 10 and (iii) THF-amines 11. It was envisioned that these
three compound classes would be ideal for generating libraries
for fragment-based lead discovery as they are of low molecular
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weight (Mw <150 g/mol), are highly soluble in water, and
contain a functional group ready for further elaboration
(primary alcohol, carboxylic acid, primary amine). In addition,
the targets could be used as strategic reagents16 for the final
derivatisation of core molecules so as to dramatically lower
logD by incorporation of the compact polyol moiety. Finally, by
using different pentose sugars, we aimed to prepare a range of
different stereoisomers, each with a diastereomeric ratio
>90:10, suitable for use in these applications.17
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DOI: 10.1039/C9GC00448C
HO
OH
6.8 g
3a, dr 78:22
(From L-arabinose)
Me2NN
O
CROP 1
CROP 2
Recrystallisation
2.4 g, anti-3a
1.4 g, 3a, dr 95:5
HO
OH
HO
OH
Amberlyst 15
HO
HO
HO
OH
HO
OH
HO
OH
Me2NN
O
H2O, R.T.
5 min
O
H2N
HO
O
Mother liquor
O
O
O
HO
2.5 g, 3a, dr 50:50
1.6 g, 12a, 77%
dr 80:20
9
11
Mw: 133
10
Scheme 7: Hydrolysis and increase in diastereoselectivity of 3a to 12a
Mw: 134
Mw: 148
CLogP: -1.747
CLogP: -1.211
CLogP: -1.268
The reduction of the hydrate using sodium borohydride
provided the alcohol 9a in excellent yield and without
significant change in the diastereomeric ratio (Scheme 8).
Figure 1: Selected targets and their calculated properties
The THF-hydrazone 3 is a versatile platform for accessing
several functionalities (e.g. aldehyde, alcohol, nitrile, protected-
amine, alkene).12 As previously reported the hydrazone can be
rapidly hydrolysed to the give the aldehyde hydrate 12 using an
acidic resin (Amberlyst 15). The reaction was easily scaled-up
(>10 g) and extended to the other pentoses (Scheme 6). The
reaction could safely be conducted on the mixture of
diastereomers obtained after cyclisation, as epimerisation takes
place under the acidic hydrolysis conditions. Remarkably, in the
case of L-rhamnose the hydrate was obtained with a higher
diastereoselectivity than the corresponding hydrazone.
HO
OH
HO
OH
1.5 eq. NaBH4
HO
HO
HO
MeOH, 24 h
0 °C - R.T.
O
O
12a
9a, 95%
dr 85:15
dr 80:20
(Recryst. anti only)
(From L-arabinose)
HO
OH
HO
OH
HO
OH
HO
HO
HO
O
O
O
HO
OH
HO
OH
9b, 74%
dr 90:10
(Recryst. 95:5)
(From D-ribose)
9c, 95%
dr. 60:40
(From D-xylose)
Amberlyst 15
9d, 95%
dr 65:35
(From L-rhamnose)
HO
HO
Me2NN
O
O
H2O, R.T.
5 min
Scheme 8: Synthesis of THF-triols 9
3a
12a, 77%
dr 80:20
(From L-arabinose)
Alcohols 9a and 9b, respectively derived from L-arabinose and
D-ribose could be recrystallised to afford the pure anti isomers
in high yield. The relative stereochemistry was confirmed
through an X-ray structure of ribose derivative 9b (Figure 2).
HO
OH
HO
OH
HO
OH
HO
HO
HO
HO
HO
HO
O
O
O
12b, 79%
dr 90:10
12c, 74%
dr 55:45
12d, 81%
dr 70:30
(From D-ribose)
(From D-xylose)
(From L-rhamnose)
Scheme 6: Synthesis of THF-hydrates 12
The epimerisation at C-2 during the hydrolysis of hydrazone 3a
to hydrate 12a offers an opportunity to maximise the value of
the material (Scheme 7). Thus, recrystallisation of 6.8 g of 3a
obtained directly from the acidic cyclisation (dr 78:22) yielded
2.4 g of anti-3a as a single isomer. A second crop of high purity
anti-3a was also obtained (1.4 g, dr 95:5), leaving the remaining
mother liquor as an equimolar mixture of diastereomers.
Submitting this material to the hydrolysis conditions led to an
increase in the diastereomeric ratio (dr 80:20) in the product
hydrate 12a, allowing efficient recycling of the mother liquor
from the recrystallisation of anti-3a (Scheme 7).
Figure 2: X-ray crystal structure of triol 9b. The thermal ellipsoids are shown at the
50% probability level, while hydrogen atoms are drawn as fixed spheres with a
‡
radius of 0.15 Å.
For the alcohols 9c and 9d obtained from the D-xylose and L-
rhamnose hydrates 12c and 12d respectively, the
diastereoselectivity was lower than required, and separation of
the two isomers was necessary. In order to discriminate
between the two species, formation of a benzylidene acetal on
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the 1,3-diol was performed as selectivity for the syn-diol should (Scheme 10a). The acetal-protected triol 17a was obtained in
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be expected.18 Indeed, the reaction of the D-xylose-triol 9c with high yield and was subsequently oxidised following a procedure
DOI: 10.1039/C9GC00448C
benzaldehyde in the presence of catalytic p-toluenesulfonic previously described for the oxidation of nucleosides.19 The
acid and a dehydrating agent resulted in the selective formation reaction proceeded at room temperature with a catalytic
of the acetal 13 along with unreacted anti-9c (Scheme 9a). The amount of TEMPO as primary oxidant, using PhI(OAc)2 as the
stereoselectivity of this acetal protection was confirmed by stoichiometric oxidant. The unprotected carboxylic acid 10a
single crystal X-ray crystallography of the analogous compound was then released under acidic conditions in moderate yields
13-Br.§ The triol anti-9c and acetal 13 were easily separated by over two steps and with high isomeric purity. The carboxylic
column chromatography. Finally, hydrolysis of 13 using acid was also accessible directly from the THF-hydrate 12a thus
Amberlyst 15 as a catalyst quantitatively afforded syn-9c. Acetal reducing the number of steps and the stoichiometry of oxidant
13 was also oxidised with a catalytic amount of TEMPO using required (Scheme 10b). Protection of the hydrate-THF 12b
PhI(OAc)2 as co-oxidant to afford the ketone 14 in high yield. resulted in a significant loss of diastereomeric purity. However,
This reaction sequence was also applied to L-rhamnose triol 9d after oxidation followed by deprotection, the carboxylic acid
allowing the separation of anti-9d and syn-9d via efficient 10a was isolated in moderate yield with a high diastereomeric
formation of the acetal 15 (Scheme 9b). Ketone 16 was similarly ratio in favour of the anti isomer. This rise in diastereomeric
obtained by oxidation of secondary alcohol 15.
ratio during the oxidation could be explained by a higher
reactivity of the anti-THF hydrate with the hindered oxidant
TEMPO in comparison to the syn-THF hydrate.
a) D-xylose triol
HO
OH
1) 0.2 eq. TEMPO
HO
OH
HO
OH
MeC(OMe)2Me
2.2 eq. PhI(OAc)2
CH3CN:H2O (1:1)
anti-9c
47% (75%)
anti only
O
O
HO
Ph
O
HO
OH
1 eq. PhCHO
1.1 eq. HC(OMe)3
O
Amberlyst 15
Acetone
2) Amberlyst 15
H2O, 100 °C
O
O
O
HO
HO
HO
R.T., 2 h
+
HO
O
pTSOH, THF
OH
O
10a, 65% (over 2 steps)
dr 93:7
9a, dr 95:5
17a, Quant., dr 95:5
9c 60:40 dr
13
O
32% (86%)
O
b) From hydrate 12a
Amberlyst 15
H2O, 100 °C
0.2 eq. TEMPO
1.1 eq. PhI(OAc)2
CH3CN:H2O, R.T.
1) 0.2 eq. TEMPO
1.2 eq. PhI(OAc)2
CH3CN:H2O (1:1)
HO
OH
O
O
HO
OH
Amberlyst 15
O
O
HO
HO
12a, dr 85:15
HO
OH
Ph
O
O
O
O
Acetone
50 °C, 2 h
O
2) Amberlyst 15
H2O, 100 °C
HO
HO
O
O
10a, 56%, (over 2 steps)
dr 95:5
18a, dr 63:37 (NMR)
O
syn-9c, Quant.
syn only
13-Br
14, 80%
Scheme 10: Synthesis of carboxylic acid 10a from a) triol 9a and b) hydrate 12a.
b) L-rhamnose triol
HO
OH
Finally, we sought an effective method for accessing the
THF-amine 11 by direct hydrogenation of the THF-hydrazones
3. Although the literature is quite rich in precedent for the
hydrogenation of hydrazones to hydrazines, the reduction of a
hydrazone directly to an amine is rare at low hydrogen
pressure.20 In our previous work, we presented a procedure to
prepare the THF-amine under 1 bar of hydrogen with Boc-
anhydride as an additive and Pd(OH)2/C as catalyst (Scheme
13).12 Reactions were initially conducted in CPME,21 but in
subsequent studies better reproducibility was achieved in a
mixture of isopropanol/water (2:1). The Boc-protected amine
20 was isolated in moderate yield on a small scale from the
hydrogenation of ribose-derived hydrazone 3b, and standard
deprotection using hydrochloric acid in methanol afforded the
hydrochloride salt 11a.HCl (Scheme 10). The scalability of the
hydrogenation proved to be problematic, however, with a
dramatic loss of yield and increased reaction time as the scale
was increased to gram quantities of material.
anti-9d
56% (86%)
anti only
HO
Ph
HO
OH
1 eq. PhCHO
1.1 eq. HC(OMe)3
O
HO
+
O
pTSOH, THF
OH
O
15
9d 65:35 dr
O
30% (84%)
O
HO
OH
Amberlyst 15
H2O, 100 °C
0.2 eq. TEMPO
1.1 eq. PhI(OAc)2
CH3CN:H2O, R.T.
HO
O
syn-9d, Quant.
syn only
Ph
O
O
O
16 76%
O
Scheme 9: Separation of the anti and syn isomers of a) D-xylose triol 9c and b) L-
rhamnose triol 9d; yields in parentheses are based on the quantity of the relevant
diastereoisomer present in the starting mixture; X-ray crystal structure of
compound 13-Br with the thermal ellipsoids shown at the 50% probability level,
‡
and hydrogen atoms drawn as fixed spheres with a radius of 0.15 Å.
Oxidation of triol 9a into the carboxylic acid-THF 10a
required a more conventional synthetic approach, using a
protecting group to allow selective oxidation of the primary
alcohol moiety. Protection of the syn 1,2-diol was performed
with 2,2-dimethoxypropane in the presence of Amberlyst 15
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ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C9GC00448C
HO
Boc
OH
Flow = 0.5 mL/min
Raney Nickel
H2 (90 bar)
HO
OH
HO
OH
HO
OH
HO
OH
20 mol% Pd(OH)2/C
H2 (1 atm.)
N
Me2NN
N
H2N
Me2NHN
Me2NN
O
2.5 eq. Boc2O
iPrOH:H2O (2:1)
R.T., 24 h
O
O
O
O
iPrOH:H2O, 80 °C
3b
11a, 89%
anti only
22a
3a, anti only
19, 12%
HO OH
dr 93:7
From L-arabinose
BocHN
HO
OH
HO
OH
HO
OH
Scalability - hydrogenation
100
O
H2N
H2N
H2N
20, 75%, dr 92:8
O
O
O
80
60
40
20
0
11d, 78%
dr 66:34
From L-rhamnose
11c, 68%
dr 55:45
From D-xylose
11b, 94%
anti only
From D-ribose
HCl, MeOH, 40 °C
HO
Scheme 12: Synthesis of amines 11 by reduction of the THF-hydrazones 3 using
flow chemistry
OH
ClH.H2N
0.05 0.25 0.50 1.00
COOH
O
THF 3b (g)
OH
OH
OH
OH
OH
11a.HCl, Quant., dr 92:8
O
O
O
1) Steam explosion
2) Acid hydrolysis
Sugar-beet
pulp
Scheme 11: Synthesis of Boc-protected amine 19 and scalability issues
HO
HO
HO
OH
OH
OH
OH
The drop in the conversion can probably be explained by a poor
gas-liquid-solid contact in the reaction mixture. Therefore,
subsequent reductions were attempted at higher pressures of
hydrogen (up to 5 bar) but did not lead to the desired amine,
and instead partial reduction to the hydrazine 19 was observed
(Scheme 11). Hydrogenation can present serious safety issues
in large scale batch reactions with high pressure, flammable
solvents and pyrophoric catalysts. We therefore moved to a
flow-chemistry set-up which offers several advantages in
comparison with more traditional hydrogenation procedures,
including the possibility to work at high pressure and
temperature with an encapsulated catalyst to reduce the
leaching of toxic metal into the reaction mixture.22–24 As a
starting point, iPrOH:H2O (2:1) was used as solvent and
Pd(OH)2/C as catalyst to remain close to the initial set of
reaction conditions. However even at high pressure (100 bar),
the transformation did not proceed to the amine at room
temperature with mostly the hydrazine 22a being formed.
Moreover, when the hydrazine 22a obtained was re-submitted
to a second hydrogenation-cycle, no amine product was
observed. The use of Boc-anhydride as additive did not solve the
issue, and as Pd(OH)2/C did not seem an efficient catalyst under
these conditions we moved to Raney Nickel which has been
reported previously as a good catalyst for the hydrogenation of
hydrazones.25 At room temperature and 100 bar of hydrogen,
only reduction of hydrazone 3a to the hydrazine 22a was
noticeable. However, at 80 °C, 3a was fully converted to the
amine 11a. Importantly no additives were required for this
transformation, and the amine was isolated in high yield directly
after evaporation of the solvent (Scheme 12). Moreover, no
erosion of the diastereoselectivity was observed compared to
the initial hydrazone 3a. This method was then applied to the
synthesis of amines 11b-11d in 68-94% yield. This direct
hydrogenation of the hydrazone provides an alternative route
for accessing the amines 11 to our recently reported
biocatalytic approach involving reaction of hydrates 12 with
transaminase enzymes.26
L-Arabinose
(12 g/L)
D-Rhamnose
(1 g/L)
D-Galacturonic acid
( 5 g/L)
HO
HO
Pulp composition after treatment
Na2SO4
OH
O
OH
O
L-arabinose
D-gaLac
HO
OH
HO
OH
OH
OH
D-galactose
L-rhamnose
D-glucose
D-Galactose
( 5 g/L)
D-Glucose
(1g/L)
OH
2 eq. H2NNMe2
OH
Me2NN
MeOH >1 M
24 h, R.T.
OH
1a, 30%
(Quant. from synthetic mixture)
OH
Scheme 13: Synthesis of L-arabinose hydrazone 1a from a solubilised sample of
sugar beet pulp
Synthesis of sugar hydrazones from sugar beet pulp
Sugar beet pulp contains significant quantities of L-arabinose,
so we were interested in its potential application as a feedstock
for the synthesis of these chiral THF building blocks. It was
therefore important to establish that hydrazone 1a could be
prepared from waste pulp material. To determine this, a
solubilised sample of sugar beet pulp after steam explosion and
acidic hydrolysis treatment was generated (Scheme 13).27–29
Analysis of the solution prepared in this way indicated it
contained sodium sulfate (80 g/L) and arabinose (12 g/L),
together with galacturonic acid (5 g/L), galactose (3 g/L),
rhamnose (1 g/L) and glucose (1 g/L) monomers. Initially, a
model synthetic mixture containing these components was
treated with N,N-dimethylhydrazine (2 eq. wrt arabinose).
Surprisingly, analysis of the crude product by NMR spectroscopy
revealed the selective formation of the hydrazone 1a derived
from L-arabinose under these conditions in quantitative yield,
with only traces of the rhamnose hydrazone present. This
selectivity could be explained by (i) the low solubility of
galacturonic acid in methanol and (ii) the much slower reaction
of hexose sugars with hydrazine compared to the pentoses.
Indeed, formation of the hydrazone from galactose was
6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
previously observed to require harsher conditions for an of a novel cyclisation procedure under basic conditions which
View Article Online
DOI: 10.1039/C9GC00448C
extended period of time (3 days) to reach only moderate preferentially provides THFs with syn stereochemistry at C-2/C-
conversion.12 Reaction of the heterogeneous mixture derived 3. These two complementary procedures offer access to a range
from sugar beet pulp under similar conditions also led to of chiral-THFs with varied stereochemistries. The THF-
selective formation of hydrazone 1a. The concentration (>1 M) hydrazones were subsequently transformed into THF-triols 9,
was found to be a crucial parameter for achieving high bicyclic ketones 14/16, THF-carboxylic acids 10 and THF-amines
conversion in this transformation, so concentration of the crude 11 to build a library of functionalised THFs (Figure 3) for
solution was necessary prior to reaction. After purification, the potential application in medicinal chemistry. Finally, we were
arabinose hydrazone 1a was isolated in high purity in 30% yield. able to prepare arabinose hydrazone 1a selectively from a pre-
The discrepancy in yield between the two experiments suggests treated sample of sugar beet pulp, thus demonstrating the
that partial decomposition of the sugars is taking place during feasibility of preparing many of these chiral THF building blocks
concentration of the crude starting material, and/or that from an abundant renewable feedstock.
impurities present in the pulp lead to loss of material during the
work-up and purification of hydrazone 1a.
Acknowledgements
From L-arabinose
We would like to thank the Engineering and Physical Sciences
HO
OH
HO
OH
HO
OH
Research Council (EPSRC) and the University College London
Impact Acceleration Account for providing PDRA funding to L.B.
(EP/K503745/1) for a collaboration with AstraZeneca and
GlaxoSmithKline. We would like to thank David Andrews
(AstraZeneca), Tony Dean and Rob Young (GlaxoSmithKline) for
their help and support on this project. We would also like to
thank GlaxoSmithKline for providing an EPSRC CASE studentship
for RWF. Finally, we thank Maciej Kucharski and Lee Edwards
(GlaxoSmithKline) for assistance with the flow hydrogenation
experiments.
O
HO
H2N
O
O
O
HO
11a
9a
10a
From D-ribose
HO
OH
HO
OH
HO
H2N
O
O
9b
11b
From D-xylose
Ph
HO
OH
OH
HO
OH
OH
O
Notes and references
O
HO
HO
†New address: AstraZeneca PLC, 2 Riverside, Milstein Building,
Granta Park, Cambridge, CB21 6GP, U.K.
O
O
O
anti-9c
syn-9c
13
¥New address: Benevolent AI, 4-8 Maple St, London, W1T 5HD,
U.K.
Ph
O
HO
O
O
‡Tables of selected crystallographic data for 9b and 13-Br can be
found in the supplementary information. CCDC 1877937 and
1877938 contain the supplementary crystallographic data for
compounds 9b and 13-Br respectively. The data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/structures.
H2N
O
O
11c
dr 55:45
14
From L-rhamnose
§The selectivity of the acetal protection was confirmed by
obtaining an X-Ray crystal structure of 13-Br,‡ an analogue of 13
prepared from 4-bromobenzaldehyde (see supplementary
information for full details).
Ph
OH
HO
OH
HO
OH
O
O
HO
HO
O
O
O
1
2
3
4
Y. Xu, M. A. Hanna, and L. Isom, Open Agric. J., 2008, 2, 54–
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anti-9d
syn-9c
15
Ph
O
O
HO
OH
O
H2N
O
O
11d
dr 66:34
16
5
6
Figure 3: Chiral THFs prepared in this work. All compounds shown above were
obtained in >95:5 dr (except 11c/11d).
7
8
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