Boronic acid-promoted site-selective Fischer esterifications of sugar alcohols

Article abstract of DOI:10.1039/c9gc00901a

A protocol for selective monoesterification of glycerol and pentose alcohols with fatty acids is described, using phenylboronic acid as a phase-transfer reagent. Formation of arylboronic ester intermediates serves both to increase the solubility of the alcohol substrate in nonpolar organic solvent and to selectively protect diol groups, allowing for efficient and selective condensation with the aliphatic carboxylic acid. A phase-switching workup with basic aqueous sorbitol solution is used to cleave the boronic ester groups and to separate the boronic acid from the monoester product. The method provides an operationally simple means of access to a class of bio-derived products that have been broadly applied as food additives, components of cosmetic products and pharmaceutical formations, plasticizers, and non-ionic surfactants.

Full text of DOI:10.1039/c9gc00901a

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Boronic acid-promoted site-selective Fischer
esterifications of sugar alcohols†
Cite this: DOI: 10.1039/c9gc00901a
Sanjay Manhas, Yu Chen Lin, Grace Wang, Luke T. Kyne and Mark S. Taylor
*
A protocol for selective monoesterification of glycerol and pentose alcohols with fatty acids is described,
using phenylboronic acid as a phase-transfer reagent. Formation of arylboronic ester intermediates serves
both to increase the solubility of the alcohol substrate in nonpolar organic solvent and to selectively
protect diol groups, allowing for efficient and selective condensation with the aliphatic carboxylic acid. A
phase-switching workup with basic aqueous sorbitol solution is used to cleave the boronic ester groups
and to separate the boronic acid from the monoester product. The method provides an operationally
simple means of access to a class of bio-derived products that have been broadly applied as food addi-
tives, components of cosmetic products and pharmaceutical formations, plasticizers, and non-ionic
surfactants.
Received 15th March 2019,
Accepted 25th August 2019
DOI: 10.1039/c9gc00901a
rsc.li/greenchem
not straightforward to achieve high levels of site-selectivity and
to suppress over-functionalization (formation of di- and trie-
Introduction
Carbohydrates and their derivatives (e.g., sugar alcohols, sugar ster products) in such condensations.18 Accordingly, chemists
acids) show great promise as sustainable feedstocks for the often resort to additional synthetic steps and protective group
production of organic molecules and polymers.1–3 Their highly manipulations. For example, condensation of 1,2-O-isopropyl-
functionalized nature represents an obstacle for these types of idene-protected glycerol with a carboxylic acid or acyl chloride
applications, and has motivated the development of new is
methods for the site-selective chemical modification of sugar- monoacylglycerols.19,20 Regioselective ring-opening of glycidol
derived compounds.4–11 by carboxylic acids is an alternative synthetic route.21–23 In
a typical approach to the controlled synthesis of
Long-chain, aliphatic monoesters of sugar alcohols are a general, the amount of protective group-derived waste pro-
class of bio-derived products of particular importance. They duced increases when these approaches are extended to acyla-
are applied broadly as food additives, components of cosmetic tions of higher sugar alcohols.24 Catalysis by lipase enzymes
products and pharmaceutical formulations, plasticizers, and provides another way to address the issue of selectivity in con-
as non-ionic surfactants in commercial and research densations of carboxylic acids with sugar alcohols.16,25–30
settings.12–15 The glycerolysis of fats, catalyzed by inorganic Challenges associated with this approach include the low solu-
bases or by lipases,16 is an important process for the manufac- bility of glycerol and other sugar alcohols in organic media,
ture of such compounds.17 Due to the heterogeneity of the modest levels of selectivity for monoacylation, and the limited
starting materials as well as selectivity issues, glycerolysis thermal stability of the enzyme catalysts.
results in mixtures of products that must be separated, for
Here, we report a method for the direct, site-selective coupling
example, by fractional distillation. To address this issue, of carboxylic acids with sugar alcohols by Fischer esterification in
methods based on condensation of aliphatic carboxylic acids the presence of phenylboronic acid. Under the optimized con-
with sugar alcohols have been developed. Although the use of ditions, arylboronic ester formation serves to transiently protect a
well-defined starting materials is an advantage of the latter diol motif31 while enhancing the solubility of the sugar alcohol
approach, the formation of mixtures remains a problem: it is substrate in the organic solvent. The protocol provides efficient
and selective access to monoesters of long-chain aliphatic car-
boxylic acids with glycerol, xylitol, ribitol and L-arabitol.
Department of Chemistry, University of Toronto, 80 St. George St., Toronto,
ON M5S 3H6, Canada. E-mail: mtaylor@chem.utoronto.ca
†Electronic supplementary information (ESI) available: Experimental and com-
Results and discussion
putational details, characterization data, copies of NMR spectra for products 2a–
f, 3a–b (PDF), X-ray crystal structure data for 2e (.cif). CCDC 1903546. For ESI
We have shown that arylboronic acids serve as phase-transfer
reagents for Fischer glycosidations in low-polarity organic sol-
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9gc00901a
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Table 1 Evaluation of reaction conditions for the condensation of
xylitol with decanoic acida
Entry
Solvent, T
Equiv. PhB(OH)2
Yield of 2a b
1
2
3
DCE, 85 °C
2.4
2.4
2.4
0
55%
<5%
60%
<5%
<5%
Dioxane, 110 °C
Toluene, 120 °C
Toluene, 120 °C
Toluene, 120 °C
4
Scheme 1 Boronic acid-mediated Fischer glycosidation and Fischer
esterification.
5c
2.4
a Reaction conditions: 1a (0.24 mmol, 1.2 equiv.), decanoic acid
(0.2 mmol, 1.0 equiv.), PhB(OH)2 (0.48 mmol, 2.4 equiv.), (S)-(+)-cam-
phorsulfonic acid ((S)-CSA, 0.05 mmol, 25 mol%), solvent (1.0 mL),
vents (Scheme 1, eqn (1)).32 In these transformations, the T °C, 24 h. b Yields of 2a were determined by 1H NMR spectroscopy of
unpurified reaction mixtures after workup with aqueous base, using
boronic acid influences both the rate (due to solubility
1,2,3-trimethoxybenzene as a quantitative internal standard. c Reaction
conducted without the addition of (S)-CSA.
enhancement33) and the selectivity (due to differences in the
stability of furanose- versus pyranose-derived boronic esters).
For example, in the case of mannose, the furanoside product
was generated selectively due to the favourable formation of
the 2,3,5,6-bis-boronic ester. A ‘phase-switching’ workup with
aqueous, basic sorbitol solution was used to cleave the
for such an intermediate (A and B, arising from condensations
with 1,3- and 1,2-diol groups, respectively) are depicted in
Fig. 1. To assess the relative stabilities of these two isomers,
product-derived boronic ester by transesterification while also
gas-phase computational modelling was conducted with
density functional theory, using the M06-2X functional41 and
facilitating the separation and recovery of the boronic acid
reagent.34,35 We reasoned that a similar principle could be
applied to achieve selective Fischer esterifications of sugar
alcohols (eqn (2)). In the case of a pentose alcohol, the for-
mation of a bis-boronic ester would increase the solubility of
the polar substrate in organic solvent36 while leaving a single
free OH group available for acid-mediated condensation with
the aliphatic carboxylic acid. Although boronic esters have
been employed as protective groups for acylations, silylations
and alkylations of glycerol,37 xylitol38 and mannitol,39,40 and
for lipase-catalyzed esterifications,27 we anticipated that the
ability to conduct direct condensations of sugar alcohols with
carboxylic acids in the presence of a boronic acid could form
the basis of a particularly efficient and operationally simple
protocol.
The coupling of xylitol (1a) with decanoic acid was studied
to evaluate the effect of phenylboronic acid on the Fischer
esterification of a sugar alcohol (Table 1). In the presence of
PhB(OH)2 (two equivalents relative to xylitol) and (S)-camphor-
sulfonic acid as catalyst ((S)-CSA, 25 mol%), condensation in
1,2-dichloroethane (DCE) solvent at 85 °C was accomplished in
55% yield after cleavage of the intermediate arylboronic ester
by workup with aqueous base. A similar yield was obtained in
toluene (oil bath temperature of 120 °C), whereas no product
was obtained in 1,4-dioxane, perhaps due to the relatively high
solubility of water in this solvent. Control reactions in toluene
conducted in the absence of the arylboronic acid or (S)-cam-
phorsulfonic acid showed no formation of the ester product.
Without the boronic acid, the xylitol substrate remained
largely insoluble under these reaction conditions.36
the 6-311+G(d,p) basis set.42 Isomer A was calculated to be the
more stable, consistent with the more favourable formation of
six-membered versus five-membered (trivalent) boronic
esters,43 and with previous observations related to threitol-
and mannitol-derived bis-boronates.40,44 It should be noted,
however, that Dahlhoff and co-workers obtained a mixture of
isomeric boronates upon condensation of xylitol with triethyl-
boroxine.38 At this stage, it is not fully clear whether the series
of condensations that generates 2a is under kinetic or thermo-
dynamic control, considering the reversible nature of both the
Fischer esterification and boronic ester formation; we note
that evidence for reversible glycoside formation was obtained
in our previous study of phenylboronic acid-mediated Fischer
glycosidation of mannose.32 Attempts to prepare the 3-O-acy-
lated isomer of 2a via the 1,2:4,5-bis-O-isopropylidene ketal (to
probe whether isomerization to 2a could take place under the
conditions of Table 1, entry 4) were thwarted by acyl group
migration under the acidic conditions used for hydrolysis of
the ketal groups. Subjecting a mixture of two monoacylated
Product 2a would be expected to arise from a bis-boronic
Fig. 1 Structures and calculated Gibbs free energies (gas phase, M06-
ester having a free primary OH group. Two possible structures 2X/6-311+G(d,p) of xylitol-derived bis-boronic esters A and B.
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sugar alcohol products to PhB(OH)2 and (S)-CSA under the sorbitol/Na2CO3 solution was then used to accomplish clea-
conditions of Table 1, entry 3 resulted in only 5% yield of the vage of the boronic ester groups by transesterification. The
intermolecular transesterification product, with recovery of the partitioning of the organoboron compound into the aqueous
starting esters and decomposition products accounting for the phase facilitated purification of the sugar alcohol-derived
remainder of the mass balance (see the ESI†). This observation monoester, while also allowing for recovery of PhB(OH)2 after
suggests that the arylboronic acid-promoted monoesterifica- acidification and extraction of the aqueous sorbitol solution.
tion reaction may not be under thermodynamic control, After the phase-switching workup, the monoester products
although further experiments should be undertaken to were isolated by recrystallization. Using this protocol, with 1.2
address this issue.
equivalents of PhB(OH)2, glycerol monocaprate and monostea-
Preparative esterifications of glycerol, xylitol, ribitol and rate (3a and 3b) were synthesized in 61% and 55% yield,
L-arabitol with decanoic acid and octadecanoic acid were con- respectively. For the pentose-derived sugar alcohols, 2.4
ducted in toluene on 2.0 mmol scale, using a Dean–Stark azeo- equivalents of PhB(OH)2 were used to ensure complexation of
tropic distillation apparatus to drive the condensations to com- two diol moieties. The yields of esterification of these sub-
pletion (Scheme 2). Liquid–liquid extraction with 1 M aqueous strates were more variable, with the formation of emulsions
during the phase-switching workup being an issue in certain
instances. The syntheses of 2a, 2c and 3a could be conducted
on 10.0 mmol scale with only minimal decreases in yield
(3–6%) from those obtained on 2.0 mmol scale (see the ESI†).
The yield of product 2b compares favorably to that obtained
for the coupling of xylitol and oleic acid catalysed by Novozym
435 (2-methyl-2-butanol solvent, 60 °C, reduced pressure:
98.2% conversion of oleic acid, 66.6% selectivity for mono-
acylation).28 Compound 2a has been synthesized in three steps
(formation of the bis-acetonide, esterification and hydrolysis
of the ketal groups) in 18% overall yield.24 A higher yield of 2a
(88% over three steps) has been obtained by protection of the
diol groups as ethylboronic esters.38 Relatively few methods for
the synthesis of monoesters derived from ribitol or arabitol
(products 2c–2f) have been reported; monoacylation of these
sugar alcohols with lauric acid was achieved in roughly 40%
yield using immobilized Candida antarctica lipase in acetone
at 50 °C.29 This protocol was also conducted in flow using a
packed bed reactor.29
For monoesterifications of L-arabitol (1c), mixtures of dia-
stereomers were generated using the phenylboronic acid-
mediated protocol: a 2.0 : 1 ratio of (S,S,S)-2e to (S,R,S)-2e′ was
obtained after phase-switching workup and prior to purifi-
cation. After recrystallization from ethanol, the (S,S,S)-isomer
was isolated in 38% yield, and its relative configuration was
established by single crystal X-ray diffraction analysis. It is con-
ceivable that the observed diastereoselectivity arises from a
(modest) thermodynamic preference for the formation of
trans-fused bis-boronate C over cis-fused D (Scheme 3). In any
case, the ability to access 2e and 2f in enantio- and diastereo-
merically enriched form is noteworthy. Opportunities may
exist to employ these compounds as chiral surfactants or
liquid crystals.24,38
As anticipated based on the proposal shown in Scheme 1,
six-carbon sugar alcohols (e.g., D-sorbitol 1d, D-mannitol 1e)
did not undergo selective esterification under the optimized
conditions. Partial boronate formation from such substrates is
known to be challenging: for example, treatment of D-mannitol
with two equivalents of PhB(OH)2 has been shown to result in
the exclusive formation of the tris-boronic ester.31
The phase-switching transesterification enables the
Scheme 2 Phenylboronic acid-mediated Fischer glycosidations.
straightforward separation and recovery of the arylboronic acid
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and the recovery of the phenylboronic acid promoter. New dia-
stereomerically and enantiomerically enriched monoesters of
L-arabitol have been synthesized using this method. The
results further illustrate the utility of organoboron compounds
as phase-transfer reagents for selective transformations of
polyhydroxylated compounds in organic solvents.
Conflicts of interest
There are no conflicts to declare.
Scheme 3 Diastereoselectivity in the esterification of 1c, and structures
of the proposed bis-boronic ester intermediates C and D.
Acknowledgements
This research was funded by NSERC (Discovery Grants and
Canada Research Chairs Programs), the Canada Foundation
for Innovation (Project No. 17545 and 19119) and the Province
of Ontario. Dr Alan Lough (University of Toronto) is acknowl-
edged for solving the X-ray crystal structure of 2e. Calculations
were carried out using resources and with support provided by
the Centre for Advanced Computing (CAC) at Queen’s
University in Kingston, Ontario. The CAC is funded by the
Canada Foundation for Innovation, the Government of
Ontario and Queen’s University.
Scheme 4 Boric acid-promoted monoacylation of glycerol.
promoter:32,34 after preparation of monoester 2a, PhB(OH)2
was recovered in 78% yield by acidification of the aqueous sor-
bitol fractions and extraction with ethyl acetate (see the ESI†).
Attempts were also made to develop a more cost-effective
monoesterification protocol using boric acid in place of PhB
(OH)2. Since the reaction of boric acid with diols can generate
spiro-borates via 2 : 1 complexation, a 0.5 : 1 B(OH)3 : diol ratio
(rather than 1 : 1, as was employed for the PhB(OH)2-mediated
reactions) was used. Under these conditions, monoacylation of
glycerol with decanoic acid was achieved in only slightly lower
(unoptimized) yield relative to that obtained using PhB(OH)2
(48% versus 61%: Scheme 4). Attempts to apply the boric acid-
mediated protocol to pentose alcohols were unsuccessful,
perhaps due to the potential for formation of several isomeric
spiro-borates from such substrates.
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