Toward preparative resolution of chiral alcohols by an organic chemical method

Article abstract of DOI:10.1039/b9nj00768g

Asymmetric alcohols were resolved as 1-α-O-alkyl-2,3-unsaturated hexosides. After separation of diastereoisomers, the auxiliary and the enantiomeric alcohol were recovered by transglycosidation. Potential applications include resolution of labile secondary and tertiary alcohols, difficult by existing techniques, and enhancement of ees of chiral alcohols produced enzymatically or by synthetic catalytic methods. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010.

Full text of DOI:10.1039/b9nj00768g

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LETTER
www.rsc.org/njc | New Journal of Chemistry
Toward preparative resolution of chiral alcohols by an organic
chemical methodw
Nino Malic,a Cornelis Moorhoff,a Valerie Sage,a Dilek Saylik,a Euneace Teoh,a
Janet L. Scottb and Christopher R. Strauss*c
Received (in Montpellier, France) 17th December 2009, Accepted 28th December 2009
First published as an Advance Article on the web 25th January 2010
DOI: 10.1039/b9nj00768g
Asymmetric alcohols were resolved as 1-a-O-alkyl-2,3-unsaturated
hexosides. After separation of diastereoisomers, the auxiliary and
the enantiomeric alcohol were recovered by transglycosidation.
Potential applications include resolution of labile secondary and
tertiary alcohols, difficult by existing techniques, and enhancement
of ees of chiral alcohols produced enzymatically or by synthetic
catalytic methods.
toxicity, and chemically stable, as well as easy to apply and to
remove by reversible, efficient, non-hazardous methods.
Ferrier reaction7 of glycals with racemic alcohols has
already been employed to produce 2,3-unsaturated glycosides
of optically active alcohols.1j,k Separation of the respective
diastereoisomers and acid hydrolysis can afford individual
enantiomers of the alcohol. A major drawback is that loss of
the auxiliary sugar after successive chemical transformations
renders the method wasteful and impractical for general use.
Acid hydrolysis employed to cleave the glycosides also has the
potential to affect the enantiomeric purity and to degrade
some alcohols.
Organic chemical methods for resolving racemic mixtures
of alcohols have proven difficult to develop, somewhat
cumbersome to use and they appear to have limited scope.1
Consequently, bio-organic approaches, commonly involving
enantioselective enzymatic hydrolysis of racemic esters or
stereoselective reduction of ketones, have gained favour.2a,b
Their disadvantages, however, can include needs for high
dilution, low throughputs of substrate, lengthy reaction times,
low reactivity of sterically crowded molecules and difficulties
with isolation.2c–f Encouragingly though, reports indicating
early signs of progress in the resolution of sterically crowded
molecules including tertiary alcohols, by enzymatic means,
have appeared.3
In this work, we have investigated a potential low-waste
process that would not require strong acid and that involves
the use and recycling of 2,3-unsaturated hexosides, e.g. 1
(Scheme 1) of low molecular weight alcohols such as MeOH
and EtOH, as chiral auxiliaries. The aim was to attach and
detach the chiral alcohol from such auxiliaries under mild
conditions, by Lewis acid-catalysed transacetalisation pro-
cesses that would afford optically enriched alcohols and enable
the glycosidic moiety to be recycled.
It was hypothesised that attack by the chiral alcohol
(i.e. that to be resolved) at the anomeric centre of the auxiliary
would not proceed by nucleophilic substitution of 1, but
rather through a cationic intermediate such as 2 (Scheme 1),
by a pathway analogous to that proposed for the Ferrier
rearrangement and Ferrier glycosylation of 1,2-glycals.8
If that premise were to hold, literature reports suggested
that, owing to a strong anomeric effect, a-epimers would
predominate.9 Hence, racemic alcohols possessing one asym-
metric centre would be expected to give essentially two major
diastereoisomers instead of four. Somewhat surprisingly,
literature precedents for transacetalisation of an O-glycoside
of a 2,3-unsaturated hexose are rare.10 Searches did not reveal
any examples concerned with alcohol resolution.
With regard to synthetic approaches, a strategy involving
thermal retro Diels–Alder reactions was recently disclosed.4a
Most commonly, however, enantiospecific syntheses of
asymmetric alcohols utilise precursor aldehydes, but such
processes tend not to afford uniformly high ees with any one
particular catalyst.4b,c Consequently, enantiomeric alcohols
that are not readily accessible through the chiral pool5 tend
to be available in limited quantities and at premium prices.
We now report preliminary studies toward a novel and
green organic chemical approach for the preparative resolution
of alcohols. It was considered that a chiral auxiliary could
satisfy commercial requirements, including objectives of green
chemistry,6 if it had broad applicability and was effective,
readily accessible, of relatively low molecular weight and low
The present process, outlined in Scheme 2 with racemic
alcohol R3R4R5COH, contains three key steps: (1) trans-
acetalisation of resolving agents such as 1 by the racemic
a Centre for Green Chemistry and School of Chemistry,
Monash University, Wellington Rd, Clayton, VIC 3800, Australia
b JLS ChemConsult Ltd, 31 Oakley Rd, Reading, UK RG4 7RN.
E-mail: JanetScott@JLSChemConsult.com;
Tel: +44 (0)118 9463901
c Queen’s University Ionic Liquids Research Laboratories,
David Keir Building, Stranmillis Rd, Belfast, Northern Ireland,
UK BT9 5AG. E-mail: chris.strauss@qub.ac.uk;
Fax: +44 (0)28 9066 5297; Tel: +44 (0)28 9097 5420
w Electronic supplementary information (ESI) available: Experimental
methods, procedures and characterisation data of all new compounds.
See DOI: 10.1039/b9nj00768g
Scheme 1 Pathway proposed for transacetalisation of 2,3-unsaturated
hexosides.
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398 | New J. Chem., 2010, 34, 398–402

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Table 1 Transacetalisation of auxiliary 4 with alcohols 5–14
Isolated
yield (%)
Entry
1
Alcohol
Product
45
58
85 : 15
2
3
4
72
67
Scheme 2 Cycle of alcohol resolution via transacetalisation.
5
6
57
alcohol to afford a mixture of diastereoisomeric glycosides 3 of
(R) and (S)-alcohols, with loss of R1OH (typically MeOH or
EtOH), (2) isolation and separation of diastereoisomeric
glycosides 3a and 3b and (3) reverse transacetalisation of 3a
or 3b with R1OH to release the (R) or (S)-alcohol and to
re-form the resolving agent 1.
53 : 43 : 4
41 (10a)
4 (10b)
The relative stereochemistries about the asymmetric centres
of auxiliaries 1 are depicted by way of illustration only, in
Schemes 1 and 2. A wide array of auxiliaries analogous to 1 is
possible, for example via O-derivatisation at the C4 and C6
positions as well as through the use of glycals obtained from
various sugars or by total synthesis.11 Such variations can
influence properties such as polarity and crystallinity of the
auxiliaries and their derivatives. Herein, the principle has been
demonstrated through examples with novel auxiliary 4 derived
from glucose. Auxiliary 4 was readily produced. It occurred
predominantly as the a-anomer and was crystalline. This latter
property was advantageous for preparative applications, but
was somewhat offset by a tendency to sublime, behaviour that
would militate against industrial applicability of 4.
71 : 29
56 : 44
7
8
40
61
71 : 23 : 6
39 (13a)
12 (13b)
9
78 : 22
57 : 43
Regarding Step 1 (Scheme 2), glycosylation of racemic
chiral alcohols was carried out in solvents of relatively low
polarity. Toluene was preferred from the standpoint of green
chemistry. K10 Montmorillonite clay or BF3ÁOEt2 were
employed as catalysts. Temperatures ranged from ambient to
80 1C depending upon the stability of the components under
the conditions applied. The forward reaction was promoted by
removal of MeOH or EtOH under partial vacuum (ca.
20 mmHg pressure) or, with MeOH, by 4 A molecular sieves.
The efficacy of K10 Montmorillonite as a catalyst appeared to
vary with individual batches. Acid-treated clay gave higher
conversions in shorter times. Significantly, during this step the
isomeric ratio of products did not appear to be affected by
reaction time or temperature.
10
15b, 51c
a
b
Stereochemistries were not determined. Partially isolated as a single
c
anomer. Remainder of eluted adduct was a mixture of anomers.
(13) and rac-3-methyl-1-pentyn-3-ol (14) underwent substantial
or complete conversion.
The use of enantiomerically enriched alcohols (ee 4 98%)
in transacetalisations (entries 1–4, Table 1) established that
epimerisation about the asymmetric centre was negligible under
the conditions used. Furthermore, all of the (R)-alcohols
investigated gave a-anomers exclusively. (S)-Alcohols tended
to afford a-anomers predominantly, but unfortunately, not
exclusively. Nonetheless, the stereoselectivity was usually
around 4 : 1 and strongly favoured the a-anomer (see entries
1 and 5 in Table 1). This result was consistent with findings
reported for Ferrier glycosylation of alkynols by Schreiber
et al.12 Significantly, in some cases, the transglycosylation step
As shown in Table 1, transacetalisation with different classes
of alcohols was carried out with the methylene bridged
auxiliary 4 and K10 Montmorillonite as catalyst, at tempera-
tures of 50–80 1C. Alcohols including (S)-1-phenylethanol (5),
(R)-3-hydroxytetrahydrofuran (6), (R), (S) and rac-2-butanols
(7, 8 and 9), rac-pantolactone (10), rac-a-methyl cyclo-
propanemethanol (11), rac-1-pentyn-3-ol (12), rac-1-octyn-3-ol
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New J. Chem., 2010, 34, 398–402 | 399

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itself displayed enantioselectivity. Indeed, more than 70% of the
(R)-a adduct was obtained from rac-pantolactone (10), rac-
1-pentyn-3-ol (12) and rac-1-octyn-3-ol (13) (entries 6, 8 and 9).
Of particular interest, the transacetalisation of a racemic
tertiary alcohol, 3-methyl-1-pentyn-3-ol (14), also showed
enantioselectivity. Analysis of the isolated adduct 14a
(Table 1, entry 10) by 13C NMR and GC showed an enantio-
meric ratio of 4 : 3 for derivatised alcohol 14. Although the
absolute stereochemistries were not determined, the enantio-
meric ratio was preserved in the liberated alcohol 14 after
reverse transacetalisation. This indicated that racemisation
about the tertiary centre did not occur during the process
and confirmed the applicability of the approach to tertiary
alcohols, which otherwise can be reactive under acidic
conditions.
Scheme 3 Decomposition of auxiliary 4 during transglycosylation.
Table 2 Release of chiral alcohols from adducts 10a and 13b
Chiral
alcohol
Isolated yield (%)
4 : alcohol : 15
Cyclopropylcarbinols also are acid labile, affording ring
expansion and ring opening13 and 1-phenylethanol (5) readily
undergoes acid-catalysed dehydration which can lead to the
formation of bis(a-methylbenzyl)ether.14 In a literature example,
the success of Ferrier glycosylation with acid-sensitive alcohols
was dependent upon the Lewis acid catalyst used.15 Herein,
the stability of auxiliary 4, together with the relatively mild
conditions required for transacetalisation at C1, precluded
decomposition of all labile alcohols investigated. Successful
transacetalisation with rac-a-methylcyclopropanemethanol
(11), rac-1-pentyn-3-ol (12), and rac-1-octyn-3-ol (13) demon-
strated the feasibility of the process regarding that aspect.
Differences in polarity between the reactants and the
products were exploited where possible, to facilitate isolation
and separation of the components. In Step 1 (Scheme 2), a
relatively non-polar auxiliary is attacked by a polar racemic
alcohol to afford a relatively non-polar diastereoisomeric
mixture of derivatised chiral alcohols. A volatile, polar alcohol
of low MW is liberated. As mentioned, the leaving alcohol
(shown as R1OH) can be removed under reduced pressure or,
in some cases, with molecular sieves, leaving a mixture of
derivatised and underivatised chiral alcohols. In some cases
the mixture could be class-separated by solvent partition with
pentane and a mixture of MeOH–saturated aqueous NaHCO3
(1 : 1). The glycosides were partitioned into the hydrocarbon
solvent and the unreacted alcohol dissolved in the aqueous
phase. The isolated glycosides may be separated chromato-
graphically if necessary or, preferably, by crystallisation, as
illustrated for 10a.
Entry
1
Adduct
% eea
10a
18 : 35 : 13
23 : 38 : 22
499
2
13b
499
a
Assessed by chiral GC.
of acid washed K10 Montmorillonite catalyst and a longer
reaction time than did the forward reaction (Step 1, Scheme 2).
Chiral alcohols 10c and 13c were recovered in reasonable
yields and with high ee, as determined by chiral GC
(Table 2). Auxiliary 4 was not fully recovered, owing to ring
opening to the acetal 15. The ultimate objective, establishment
of industrially viable methodology, will depend upon the use
of auxiliaries that are more stable under the conditions of
transacetalisation.
To summarise, in this preliminary study, proof of principle
has been demonstrated for a novel organic chemical approach
toward resolution of chiral alcohols. A proposed reaction
cycle involving three steps and the use of glycosides of 2,3-
unsaturated hexoses has been validated experimentally, but
yields and recoveries are not yet satisfactory. Non-enzymatic
resolution of chiral tertiary alcohols has been addressed
apparently for the first time. Although auxiliary 4 was the
illustrative resolving agent employed herein, it could not be
recovered quantitatively for future use, so its potential for
industrial scale applications appears to be limited. However,
given the wide array of naturally occurring sugars and scope
for their derivatisation, there are ample opportunities for
preparing robust auxiliaries. Apart from tertiary alcohols,
the methodology was applied to secondary alcohols including
those with additional reactive functionality. Such alcohols can
be difficult to resolve by existing alternative techniques. After
refinement of the technique, potential applications could
include separation of racemic mixtures as well as enrichment
of optically active alcohols produced enzymatically or by
synthetic catalytic methods that do not afford high enantio-
meric excesses in the reactive step. We acknowledge the ARC
for funding this work.
Forward reactions (Step 1, Scheme 2) usually proceeded
readily. Not surprisingly then, the positions of equilibrium
often disfavoured reverse reactions. In those cases, Step 3
required more forcing conditions than did Step 1. It was
carried out with either MeOH or EtOH, depending upon
the regenerated auxiliary desired, but typically with a higher
loading of K10 Montmorillonite than for the forward process.
Temperatures exceeding 50 1C tended to promote decomposition
of the auxiliary, typically through ring opening of the pyran
to afford an acetal, 15, and/or an enal, 1616 (Scheme 3 and
Table 2).
Reverse transacetalisation (depicted as Step 3, Scheme 2)
was carried out on (R)-a-pantolactone adduct 10a and (R)-a-
1-octyn-3-ol adduct 13b as shown in Table 2. Here also, release
of (R)-a-1-octyn-3-ol required a substantially higher loading
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400 | New J. Chem., 2010, 34, 398–402

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69.1, 64.5, 40.5, 23.5, 19.5. Mass spectrum (ESI+, MeOH) m/z
calculated [C13H18O6Na]+ 293.1001, found 293.0990.
Experimental
Full experimental details are provided as ESI.w Representative
procedures for the preparation of auxiliary 4, formation of the
adducts of pantolactone (10) with this auxiliary and recovery
of one enantiomer of the resolved alcohol and auxiliary follow.
Resolved alcohol and auxiliary recovery: (R)-a adduct 10a
(160 mg, 0.59 mmol) was dissolved in dry methanol (20 mL)
followed by the addition of acid-treated K10 Montmorillonite
(1.28 g, 800 wt%). The reaction mixture was heated to 40 1C
for 8 h, clay removed by filtration and the solvent evaporated
to give a yellow oil containing no 10a. GC analysis revealed
auxiliary 4 and acetal 15 (ring-opened by-product) in a 60 : 40
ratio. After column chromatography on a silica column eluting
with ethyl acetate–hexane (1 : 2), methyl-2,3-dideoxy-4,6-O-
methylene-a-D-erythro-hex-2-enopyranoside (4) (31 mg, 18%),
(R)-pantolactone (10c) (45 mg, 35%) and the acetal by-product
16 (26 mg, 13%) were recovered. The enantiomeric excess of
recovered (R)-pantolactone was determined to be 499% by
chiral GC (temperature program: initial column temperature
was 110 1C for 10 min, then heated to 200 1C at 20 1C minÀ1
and maintained at 200 1C for 5 min).
Auxiliary preparation
Methyl-2,3-dideoxy-4,6-O-methylene-a-D-erythro-hex-2-eno-
pyranoside (4) was prepared by a method adapted from the
procedure of Lipta
´
k et al.17 To a solution of methyl-2,3-
dideoxy-a-D-erythro-hex-2-enopyranoside (1.00 g, 6.24 mmol)
in DMSO (6 mL) was added NaOH (1.00 g, 24.96 mmol) as a
powder. This mixture was stirred at 60 1C for 30 min under N2
prior to the addition of CH2Br2 (1.14 g, 6.55 mmol). After
1.5 h at 60 1C the mixture was poured into water (20 mL) and
extracted with diethyl ether (3 Â 20 mL). The organic layer
was dried (MgSO4), filtered and the solvent removed in vacuo
to give a yellow oil, which, after chromatographic purification
(silica column eluting with diethyl ether–pentane = 7 : 2),
yielded 4 as a white crystalline solid (0.46 g, 43%), mp
85.5–85.9 1C. IR (Nujol) n cmÀ1 2893, 2463, 1737, 1711,
1150, 1107, 1061, 1022, 998, 968, 940, 916, 893, 722, 670.
1H NMR (CDCl3, 300 MHz) d 6.07 (m, 1H), 5.71 (ddd, J =
2.3, 2.5, 10.3 Hz, 1H), 5.06 (d, J = 6.2 Hz, 1H), 4.85 (m, 1H),
4.67 (d, J = 6.2 Hz, 1H), 4.18 (m, 1H), 3.86 (m, 1H), 3.73
(m, 1H), 3.54 (t, J = 10.3, 1H), 3.44 (s, 3H). 13C NMR
(CDCl3, 75 MHz) d 130.7, 126.9, 96.1 (anomeric-C), 94.1,
75.3, 69.4, 64.2, 56.1. Mass spectrum (ESI+, MeOH) m/z
calculated for [C8H12O4Na]+ 195.0629, found 195.0633.
Notes and references
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rac-Pantolactone (10) (450 mg, 3.49 mmol) and methyl-2,3-di-
deoxy-4,6-O-methylene-a-D-erythro-hex-2-enopyranoside (4)
(200 mg, 1.16 mmol) were dissolved in dry toluene (5 mL)
and acid-treated K10 Montmorillonite (60 mg, 30 wt%) and
4 A molecular sieves added. After heating at 75 1C for 20 h the
clay and molecular sieves were removed by filtration and the
solvent evaporated to give a yellow oil. GC analysis indicated
93% conversion to product with a ratio of (R)-a adduct 10a :
(S)-a adduct 10b = 71 : 29. Upon trituration with methanol
the (R)-a adduct 10a crystallised as a white solid (126 mg,
41%), mp 192.4–194.6 1C. 1H NMR (CDCl3, 300 MHz) d
6.12 (d, J = 10.8 Hz, 1H), 5.85 (m, 1H), 5.44 (br s, 1H), 5.07
(d, J = 6.2 Hz, 1H), 4.69 (d, J = 6.2 Hz, 1H), 4.16 (s, 1H),
4.12 (dd, J = 4.7, 10.3 Hz, 1H), 4.03 (d, J = 8.8 Hz, 1H), 3.94
(d, J = 8.9 Hz, 1H), 3.89 (br s, 1H), 3.77 (m, 1H), 3.56
(m, 1H), 1.20 (s, 3H), 1.11 (s, 3H). 13C NMR (CDCl3,
75 MHz) d 175.2, 130.9, 126.5, 94.1, 93.9, 78.6, 76.4, 75.1,
69.1, 64.5, 40.1, 22.9, 19.6. Mass spectrum (ESI+, MeOH) m/z
calculated for [C13H18O6Na]+ 293.1001, found 293.0997.
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yellow oil post column chromatography and partition (12 mg,
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This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010
402 | New J. Chem., 2010, 34, 398–402