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
aDepartment of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon St, London, WC1H 0AJ, UK. E-mail: l.benhamou@ucl.ac.uk; h.c.hailes@ucl.ac.uk; tom.sheppard@ucl.ac.uk
bDepartment of Biochemical Engineering, University College London, Bernard Katz Building, London WC1E 6BT, UK
cGSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
First published on 14th March 2019
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.
A variety of transformations are now available to produce small molecule building blocks from sugar monomers.4,5 However, 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.
Recently, some approaches have been developed which take advantage of the intrinsic functionalities and chirality of carbohydrates to develop novel methodology to access small 3D-building-blocks.11,12 Indeed, we have recently developed a selective method for the dehydration of pentose sugars to afford hydroxy-functionalised THFs without the need for protecting groups (Scheme 1).12 In this paper, we describe the optimisation of this chemistry on a multigram scale, the development of a novel base-mediated cyclic dehydration of sugar hydrazones to access other stereoisomers, and the extension of this methodology to a range of pentoses. We also demonstrate the application of these dehydration reactions to the construction of a small library of chiral THF fragments as useful building blocks for medicinal chemistry,13,14via 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.
These issues were readily solved by running the cyclisation in a less nucleophilic solvent (isopropanol) and under an argon atmosphere (see ESI†). Under these conditions, 3a was obtained in 81% yield routinely on a 20 g scale. When these reaction conditions were applied to other pentose sugars, the yields were generally superior to the previously reported procedure, with no significant difference in the diastereoselectivity observed (Scheme 3). THFs anti-3a and anti-3b derived from L-arabinose and D-ribose could be recrystallised from THF/Petrol to give the pure anti-isomer in each case.
Scheme 3 Optimised synthesis of chiral THFs anti-3a–anti-3d. *Yield obtained under previous conditions.12 |
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 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.
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 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 to anti-3b) takes place leading to a slightly higher 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.
Scheme 4 Proposed mechanism for the basic cyclisation of L-arabinose hydrazone 1a and D-ribose hydrazone 1b. |
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 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.
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).
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). 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 (Fig. 2).
Fig. 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 the 1,3-diol was performed as selectivity for the syn-diol should be expected.18 Indeed, the reaction of the D-xylose-triol 9c with benzaldehyde in the presence of catalytic p-toluenesulfonic acid and a dehydrating agent resulted in the selective formation of the acetal 13 along with unreacted anti-9c (Scheme 9a). The stereoselectivity of this acetal protection was confirmed by single crystal X-ray crystallography of the analogous compound 13-Br.|| The triol anti-9c and acetal 13 were easily separated by column chromatography. Finally, hydrolysis of 13 using Amberlyst 15 as a catalyst quantitatively afforded syn-9c. Acetal 13 was also oxidised with a catalytic amount of TEMPO using PhI(OAc)2 as co-oxidant to afford the ketone 14 in high yield. This reaction sequence was also applied to L-rhamnose triol 9d allowing the separation of anti-9d and syn-9dvia efficient formation of the acetal 15 (Scheme 9b). Ketone 16 was similarly obtained by oxidation of secondary alcohol 15.
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 (Scheme 10a). The acetal-protected triol 17a was obtained in high yield and was subsequently oxidised following a procedure previously described for the oxidation of nucleosides.19 The reaction proceeded at room temperature with a catalytic amount of TEMPO as primary oxidant, using PhI(OAc)2 as the stoichiometric oxidant. The unprotected carboxylic acid 10a was then released under acidic conditions in moderate yield over two steps and with high isomeric purity. The carboxylic acid was also accessible directly from the THF-hydrate 12a thus reducing the number of steps and the stoichiometry of oxidant required (Scheme 10b). Protection of the hydrate-THF 12b resulted in a significant loss of diastereomeric purity. However, after oxidation followed by deprotection, the carboxylic acid 10a was isolated in moderate yield with a high diastereomeric ratio in favour of the anti isomer. This rise in diastereomeric 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.
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 11).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 11). 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. 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 (Scheme 12).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 21a being formed. Moreover, when the hydrazine 21a 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 21a 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
Fig. 3 Chiral THFs prepared in this work. All compounds shown above were obtained in >95:5 dr (except 11c/11d). |
Footnotes |
† Electronic supplementary information (ESI) available: Procedures for the preparation of all compounds, together with characterisation data and X-ray crystallographic data. CCDC 1877937 and 1877938. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9gc00448c |
‡ New address: AstraZeneca PLC, 2 Riverside, Milstein Building, Granta Park, Cambridge, CB21 6GP, UK. |
§ New address: Benevolent AI, 4-8 Maple St, London, W1T 5HD, UK. |
¶ Tables of selected crystallographic data for 9b and 13-Br can be found in the ESI.† CCDC 1877937 and 1877938 contain the supplementary crystallographic data for compounds 9b and 13-Br respectively. |
|| 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 ESI† for full details). |
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