Modular synthesis of dihydroxyacetone monoalkyl ethers and isosteric 1-hydroxy-2-alkanones

Article abstract of DOI:10.1002/ejoc.201403695

Straightforward methods for the efficient, systematic preparation of libraries of the title compound classes have been evaluated. A general and efficient modular route to dihydroxyacetone monoethers was developed based on trityl glycidol, which, through epoxide opening, oxidation, and deprotection, provided variously alkylated ethers by three routine operations in good overall yields (eight examples, 24-59 %). The preparation of structurally related 1-hydroxyalkanones depends on the availability of the most economic starting materials and on their physicochemical properties. Thus, the most practical one-step approaches consisted of the sec-selective oxidation of short-chain 1,2-diols (≤ C₆) using NaOCl, and the direct ketohydroxylation of 1-alkenes (≥ C₆) using buffered stoichiometric KMnO₄ or catalytic RuO₄ with reoxidation by oxone, for which mostly good overall yields were achieved on a multigram scale (nine examples, 15-78 %).

Full text of DOI:10.1002/ejoc.201403695

FULL PAPER
DOI: 10.1002/ejoc.201403695
Modular Synthesis of Dihydroxyacetone Monoalkyl Ethers and Isosteric
1-Hydroxy-2-alkanones
Deniz Güclü,[a] Madhura Rale,[a,b] and Wolf-Dieter Fessner*[a]
Keywords: Synthetic methods / Oxygenation / Hydroxylation / Oxidation / Alkylation / Regioselectivity / Ketones
Straightforward methods for the efficient, systematic prepa- starting materials and on their physicochemical properties.
ration of libraries of the title compound classes have been
evaluated. A general and efficient modular route to di-
hydroxyacetone monoethers was developed based on trityl
glycidol, which, through epoxide opening, oxidation, and de-
protection, provided variously alkylated ethers by three rou-
tine operations in good overall yields (eight examples, 24–
Thus, the most practical one-step approaches consisted of the
sec-selective oxidation of short-chain 1,2-diols (Յ C6) using
NaOCl, and the direct ketohydroxylation of 1-alkenes (Ն C6)
using buffered stoichiometric KMnO4 or catalytic RuO4 with
reoxidation by oxone, for which mostly good overall yields
were achieved on a multigram scale (nine examples, 15–
59%). The preparation of structurally related 1-hydroxyalk- 78%).
anones depends on the availability of the most economic
were in need of practical methods that were of sufficient
Introduction
scope to serve in the routine preparation of the correspond-
ing arrays of compound types 3 and 4. Here, we report on
practical methods that were found to deliver these struc-
tures reliably, including linear and appropriately branched
isomers, cost-effectively on the laboratory scale.
Asymmetric carbon–carbon bond formation by enzyme-
catalyzed aldol reactions is a highly versatile method for
the synthesis of diastereoisomeric sets of carbohydrates and
structurally related polyoxygenated building blocks.[1] Re-
cently, we have reported on the complementary aldol donor
and broad acceptor substrate promiscuity of two carbo-
ligation enzymes from E. coli, the fructose 6-phosphate ald-
olase (FSA) and engineered variants of transaldolase B
(TalBF178Y), which together allowed the convenient prepa-
ration of a deoxysugar library.[2] Particularly, FSA is un-
usual among known aldolases in its ability to convert a
range of aldol donor components such as dihydroxyacetone
(1), monohydroxyacetone, and 1-hydroxybutanone (2) with
similar activity (Figure 1).[3] For subsequent studies to fur-
ther widen the substrate scope of the enzymes towards
novel specificities by protein engineering, we needed struc-
tural analogues of 1 and 2, such as monoether derivatives
3 and higher homologous ketols 4 in multigram quantities
for systematic screening purposes and subsequent prepara-
tive applications. Unfortunately, none of these were com-
mercially available, and only a very limited number of ex-
amples among these compound categories had been pre-
viously synthesized by using different approaches. Thus, we
Figure 1. Bioisosteric substrate pair 1 and 2, which can be con-
verted by FSA to yield deoxysugars,[2] and target compound fami-
lies having extended structures (3 and 4).
Results and Discussion
[a] Institut für Organische Chemie und Biochemie, Technische
Universität Darmstadt,
Dihydroxyacetone monoethers 3, mostly the benzyl de-
rivative, have been described for studies of stereoselective
biochemical reductions,[4–7] but derivatives containing aro-
matic or larger organic groups have also been prepared for
use as pharmaceutical building blocks and in cosmetic ap-
plications.[8,9] Starting materials for the known synthetic
routes (Figure 2) were either the acetal-protected di-
Alarich-Weiss-Str. 4, 64287 Darmstadt, Germany
E-mail: fessner@tu-darmstadt.de
http://www.chemie.tu-darmstadt.de/fessner/
[b] Division of Biochemical Sciences, National Chemical
Laboratory,
Pune-411008, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403695.
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Dihydroxyacetone Monoalkyl Ethers
hydroxyacetone monomer 5[4,10] or the dimer 6 (each three duction and deprotection of the trityl group under compati-
steps overall from 1),[8,11] whereas others started from epi- ble conditions, its steric bulk (which was expected to sup-
chlorohydrin 7 (five steps)[6] or acrolein acetal via 8 (four port the regioselectivity for terminal epoxide opening), and
steps).[7,12]
its hydrophobicity (which was expected to improve the
handling of otherwise highly polar compounds). Indeed,
epoxide opening of 10 with sodium alkoxides proceeded
with practically quantitative yields of ethers 11 (90–97%).
A shorter route is available for commercial glycerol ethers
13d–f (or their glycidol precursors) containing iPr, tBu and
allyl moieties, which were converted directly into the trityl
protected ethers 11 (61–85%). 3-Buten-2-ol and prenyl
alcohol, which turned out to be more sensitive under stan-
dard etherification conditions, were preferentially reacted
with the more reactive epichlorohydrin,[15] and the resulting
epoxide ring was opened by neutral hydrolysis in boiling
water,[16] followed by tritylation (68 and 40% overall,
respectively).
Figure 2. Starting materials utilized for syntheses of ether com-
pounds 3.
In principle, starting from the correct level of oxygen-
ation present in both 5 and 6 is highly appealing, because
this only involves an O-alkylation using inexpensive alkyl
halides as electrophiles followed by simple acid-catalyzed
acetal hydrolysis. However, because we were interested in a
broad structural variety of ethers not limited to primary
but also including secondary and tertiary alkyl residues, the
need for selective monoalkylation of 5 and the steric bulk
around the OH functions of 6 appeared problematic. Simi-
larly, an approach for sequential substitution of 1,3-di-
haloacetone was dismissed after considering potential prob-
lems regarding regioselectivity.[9,13] Epoxides 7 and 8 were
both unattractive as starting materials because of their tox-
icity and high cost, respectively. On the other hand, inex-
pensive glycidol (9) offered easy handling combined with
the option for immediate introduction of a temporary pro-
tection on the free hydroxyl end followed by regioselective
nucleophilic epoxide opening on the other end to introduce
the alkyl ether functionality (Scheme 1).
Mildly basic pyridinium dichromate (PDC) in CH2Cl2
proved to be the most effective reagent for oxidation of the
sterically shielded secondary alcohols 11 to the correspond-
ing ketones 12, with generally good to excellent yields (55–
88%). Reactions using 2-iodoxybenzoic acid (IBX) or
KMnO4/MnO2 proceeded more sluggishly and returned sig-
nificantly lower yields because of partial loss of the protec-
tive group and other side reactions. Unfortunately, ether
cleavage was observed during attempts to oxidize 11h,
which has so far precluded access to 3h.
Final deprotection was tested under a range of aqueous-
acidic conditions. Particularly with smaller alkyl ether moi-
eties, isolation from aqueous solution is difficult, which sug-
gests that acids must be volatile or solid supported for easy
removal. Dilute mineral acids (e.g., HCl) failed to bring
about detritylation, whereas pTsOH, 80% acetic acid, and
DOWEX-H+ required extended reaction times and deliv-
ered moderate to poor yields only. Deprotection with neat
trifluoroacetic acid proceeded smoothly at room tempera-
ture and gave near quantitative yields by lyophilization (59–
96%). It proved to be particularly important to remove
traces of acid after workup by neutralization with solid
NaHCO3 to prevent decomposition of the ketol ethers with
time to give methylglyoxal (Scheme 2). Although the use of
a trityl protection group is not atom economical, it can be
recycled with high efficiency, thereby much improving its
relative mass balance. Indeed, trityl alcohol could be easily
recovered by crystallization in high yield for reuse, making
the synthesis more effective. When low selectivity was ob-
served upon final detritylation of tBu ether 12e, which
mostly yielded 1, the sequence was repeated with mono-
methoxytrityl ether protection instead, from which 3e could
be isolated after smooth deprotection in 80% acetic acid
without concomitant dealkylation (49%).
Scheme 1. Synthesis of dihydroxyacetone monoalkyl ethers 3.
Anticipating the chemical reactivity of the highly func-
tionalized target ketones, preference was given to trityl pro-
Scheme 2. Proposed decomposition pathway for enediol tautomers
tection of glycidol (10)[14] because of the efficiency for intro- of ketol ethers 3 under acidic conditions.
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D. Güclü, M. Rale, W.-D. Fessner
FULL PAPER
Hydroxy ketones 3 contain both a reactive electrophilic of over-oxidation.[18b] Indeed, this method proved to reli-
and a nucleophilic group and thus could form oligomers ably generate the desired ketols with high selectivity
upon removal of solvent.[17] According to NMR analysis, (Scheme 4), and low effort, particularly for alkenes having
hydroxy ketones 3 indeed become partially hydrated in low volatility. Ketohydroxylation of both simple alkenes
aqueous solution, particularly for the smaller alkyl ethers. and tritylated hydroxyalkenes proceeded rapidly and un-
Therefore, protected ketones 12 are preferred for storage in eventfully. Product isolation was relatively straightforward,
solid form as the immediate precursors to 3, which can be although isolated yields were only low to moderate (15–
generated in aqueous solution for immediate use as poten- 78%), and became more efficient only with increasing chain
tial enzymatic substrates in aldol reactions.
length and lower volatility of the precursors. Commercial
For the synthesis of the corresponding isosteric 1- availability of various olefinic and hydroxyalkene precur-
hydroxyalkanones 4, no modular synthesis with similar sors make it the method of choice for a convenient single-
flexibility is applicable. Although many methods have been step synthesis of the corresponding ketols.
investigated (Scheme 3),[18–23] to our knowledge, no system-
atic studies have been performed to evaluate synthetic meth-
ods for their scope in generating a larger variety of consti-
tutional members among the family of terminal aliphatic
ketols.
Scheme 4. Synthesis of a set of linear and branched-chain 1-
hydroxyalkanones by ketohydroxylation of the corresponding alk-
enes.
The RuO4-catalyzed alkene ketohydroxylation in combi-
nation with oxone as re-oxidant is a promising alternative
to the KMnO4 method.[18g,18h] Indeed, RuCl3 was particu-
larly efficient in providing small quantities of ketols,
whereas scale-up became cumbersome because of the re-
quired excess stoichiometry of the co-oxidant (oxone/
NaHCO3). Furthermore, addition of oxone en masse led to
a loss in temperature control, thus limiting the use of vola-
Scheme 3. Summary of synthetic methodology developed for the
tile starting compounds. Despite serving as an attractive
preparation of terminal ketols from readily available classes of pre-
single-step methodology for ketohydroxylation of both alk-
enes and hydroxyalkenes, the RuO4 method poses some dif-
cursor compounds containing a lower level of oxygenation.
In selecting the most suitable laboratory method, regio- ficulty with respect to challenges in temperature control and
selective oxidation of 1,2-diols 16 by using inexpensive handling of large quantities of co-oxidant.
NaOCl in acetic acid[20a] was attractive because of its low
In the case of ketol 4e, an alternative to the handling of
environmental impact given the nontoxic nature of the gaseous isopentene for catalytic oxidation was sought.
spent oxidant. Moreover, the reaction is fast, allows easy Thus, selective cross-acyloin condensation[23] of the easier
scale-up, and involves simple setup and workup procedures. to handle isobutyraldehyde and formaldehyde also fur-
Selective sec-oxidation of the commercially available and nished ketol 4e in moderate yield (42%). However, when
synthesized C4–C7 diols 16 by the hypochlorite reagent isolation of the desired product from other reaction compo-
provided the corresponding hydroxy ketones in 44–75% nents proved rather tedious, further development of the
yield, which improved with increasing chain length. How- method was finally abandoned.
ever, this method is limited by the commercial availability
of compounds 16, and could not be applied to ether-derived zation and had to be purified either by distillation or col-
diols 13. umn chromatography. Although distillation of ketols 4 was
The synthesized ketols defied all attempts at crystalli-
The ketohydroxylation of alkenes 14 by stoichiometric generally preferred over chromatographic separations, ketol
quantities of KMnO4 in aqueous acetone under acidic con- ethers 3 decomposed during distillation and had to be puri-
ditions is the oldest methodology,[18a] but the oxidant re- fied by column chromatography. The acid sensitivity of such
mains attractive even at the industrial scale because of its compounds meant that they were best stored below –20 °C.
low cost, tolerance to wet media, and environmentally be- On the other hand, once distilled, hydroxyalkanones 4 had
nign character.[24] Recent optimization studies indicate that long shelf-lives and could be stored at room temperature
pH control is the key to reaction selectivity for suppression for several months.
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Eur. J. Org. Chem. 2015, 2960–2964

Dihydroxyacetone Monoalkyl Ethers
Epoxide Substitution: The trityl-protected epoxide 10 (15.8 mmol)
was dissolved in anhydrous alcohol (50 mL). To this was added the
sodium salt (31.6 mmol) of the alcohol that served as a nucleophile.
Conclusions
The synthesis of two complementary substrate families
was achieved, including a systematic structural variation of The suspension was heated to reflux for 15 h, diluted with a small
volume of H2O, and the resulting mixture was extracted with
CH2Cl2. The organic layer was separated, dried with MgSO4, fil-
tered, and the solvents evaporated. The crude product was purified
by column chromatography to furnish the ethers 11.
steric bulk that will be important for the screening of ald-
olases to determine their substrate promiscuity.
Nine alkylated ketol ethers 3 were synthesized by a
straightforward modular route starting from readily avail-
able trityl glycidol by nucleophilic epoxide opening, oxid- Oxidation: A suspension of 11 (1 mol equiv.), PDC (2 mol equiv.),
and 4 Å molecular sieves (1 g per mmol of alcohol) in anhydrous
CH2Cl2 (2.5 mL per mmol of alcohol) was stirred vigorously at
room temp. Upon complete consumption of the alcohol, the reac-
tion mixture was worked up by adding three volumes of Et2O. The
solution was decanted, filtered through a glass frit and then
through a short pad of Celite. The combined filtrates were concen-
trated and the residue was purified by column chromatography to
furnish the protected ketones 12.
ation of the secondary alcohol, followed by detritylation in
good overall yields. The isosteric structurally related 1-
hydroxyalkanones 4 were prepared from relevant commer-
cially available precursors and the synthesis depended
heavily on their physicochemical properties. Among these,
selective 2°-oxidation of the 1,2-diols (Յ C6) using NaOCl
and the direct ketohydroxylation of 1-alkenes (Ն C6) by
using buffered stoichiometric KMnO4 or catalytic RuO4
with reoxidation by oxone, were found to be the most prac-
tical one-step approaches for which mostly good overall
yields were achieved on a multigram scale.
Deprotection: The tritylated ketone 12 (10.0 mmol) was deprotected
by dissolving in TFA (15 mL) at room temp. Upon complete con-
version, the reaction was diluted with H2O (15 mL) and the mix-
ture was extracted with Et2O (3ϫ 15 mL). The combined aqueous
phases were evaporated to dryness, and the residue was taken up
in anhydrous MeOH (5 mL) and neutralized by addition of solid
NaHCO3. The crude product 3 was purified by column chromatog-
From a preliminary substrate screening, only 4a and
none of the higher homologous ketols, and only the small-
est ether compound 3a and none of the larger alkyl deriva-
tives could be converted by wild-type FSA. Application of raphy.
these compounds to the protein engineering of novel ald-
Supporting Information (see footnote on the first page of this arti-
olase specificities is underway and the results will be re-
ported in due course.
cle): Experimental section, including complete experimental pro-
cedures and copies of the 1H and 13C NMR spectra of all described
compounds.
Experimental Section
Acknowledgments
General Procedures for Synthesis of Diols (GP1)
This work was supported by the German Bundesministerium für
Bildung und Forschung (BMBF) (grant to W. D. F., 0315775B PT-
J) within the transnational Eurotrans-Bio framework, as well as
by student exchange funds from DAAD (grant to W. D. F., PPP-
50749958). The authors gratefully acknowledge Sebastian Adler
and Andreas Baumruck for their help in preliminary experiments
and Dr. Anna Szekrenyi and Prof. Pere Clapés (IQAC Barcelona)
for fruitful discussions.
Alkoxide Substitution: A mixture of 40% aq. NaOH (50 mL),
epichlorohydrin 7 (120 mmol) and tetrabutylammonium bromide
(1.5 mmol) was stirred vigorously at 0 °C. To this mixture was
added the respective alcohol (30 mmol) over 30 min at a controlled
rate so that temperature was maintained below room temp. Reac-
tion progress was monitored by TLC. Upon completion, the mix-
ture was diluted with water (50 mL) and extracted with Et2O (3ϫ
25 mL). The organic phase was dried with MgSO4 and evaporated
to give the corresponding epoxides, which were purified by column
chromatography.
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stirring until complete consumption of epoxide. The reaction mix-
ture was concentrated to provide the pure diols 13, which could be
used without further purification unless otherwise indicated.
General Procedure for Synthesis of Dihydroxyacetone Monoethers
(GP2)
Tritylation: Trityl chloride (5 g, 18.1 mmol), NEt3 (2.52 mL,
18.1 mmol) and DMAP (0.1 g, 0.7 mmol) were added with stirring
to a solution of the alcohol (15 mmol; glycidol 9 or 1,2-diols 13)
in anhydrous CH2Cl2 (25 mL) under an argon atmosphere at 0 °C.
The mixture was warmed to room temp. and the reaction was mon-
itored by TLC. Upon complete consumption of the starting mate-
rial, the reaction was quenched with saturated Na2CO3 (15 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ 25 mL), and
the combined organic extracts were dried, evaporated, and purified
by column chromatography to afford the corresponding tritylated
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Received: December 29, 2014
Published Online: March 17, 2015
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