Direct one step mono-functionalisation of symmetrical 1,2-diols

Article abstract of DOI:10.1016/S0040-4039(00)00224-0

The mono-functionalisation of meso- and C₂-symmetric diols has been achieved via the use of a new lanthanide(III) chloride catalysed acylation reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00224-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2687–2690
Direct one step mono-functionalisation of symmetrical 1,2-diols
Paul A. Clarke,a,∗ Robert A. Holton b and Nadim E. Kayaleh b
aSchool of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
bDittmer Laboratory Of Chemistry, Florida State University, Tallahassee, FL 32306, USA
Received 17 December 1999; accepted 3 February 2000
Abstract
The mono-functionalisation of meso- and C2-symmetric diols has been achieved via the use of a new lantha-
nide(III) chloride catalysed acylation reaction. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: acylation; lanthanides; diols; desymmetrisation.
The mono-functionalisation of diols is an important challenge in organic synthesis. While sterically or
electronically different hydroxyls may be selectively modified, methods for the mono-functionalisation
of similar hydroxyl groups are virtually unknown. The problem is that both hydroxyl groups react at a
similar, if not the same, rate and thus even with one equivalent of reagent, a statistical mixture of starting
diol and mono-/bis-functionalised products are formed (Scheme 1). This problem, to date, is still very
much unsolved.
Scheme 1.
Traditionally, the acylation of hydroxyl groups has been carried out using either an acyl halide or
anhydride in the presence of a base and a nucleophilic activating agent. A fundamentally different
approach is the use of a Lewis acid to activate the acylating agent towards nucleophilic attack by the
hydroxyl group. In these systems the simple alcohols reported are acylated in good to high yields,1 but
when molecules containing several hydroxyl functions are employed, multiple acylations occur.2 We are
unaware of any procedure to date that can selectivity acylate one of two similar hydroxyl groups.
We now wish to report that lanthanide(III) chlorides can be used in conjunction with carboxylic acid
anhydrides to mono-acylate meso- and C2-symmetric 1,2-diols with very high levels of selectivity. While
it is not surprising that lanthanide salts catalyse acylation reactions,3,4 it is surprising that they do so
with such high levels of mono-selectivity. Our preliminary investigations to find the optimum conditions
∗
Corresponding author. E-mail: paul.clarke@nottingham.ac.uk (P. A. Clarke)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00224-0
tetl 16504

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focused on the mono-acylation of meso-hydrobenzoin. As can be seen from Table 1, the optimum
conditions (entry 4) involved the use of 10 mol% CeCl3 and 10 equiv. Ac2O. A slight improvement
in the selectivity was seen if the reaction was initially run at a lower temperature. The concentration of
the reaction can be seen to be important (entries 3, 6 and 7) with the reaction proceeding sluggishly in
the absence of THF and at concentrations other than 0.366 M. It is also important to note the remarkable
acceleration induced by CeCl3: in the absence of CeCl3 the reaction is only 16% complete after 44 h
(entry 1).
Table 1
With conditions in hand for the selective mono-functionalisation of meso-hydrobenzoin, we decided
to see if this methodology could be extended to other symmetrical 1,2 diol systems. We selected 3 diols
for our initial study, meso-hydrobenzoin, 1,2-cis-cyclohexanediol (4) and meso-2,3 butanediol (5). In the
case of (4) we found that the reaction was very slow, and in the case of (5) it did not proceed at all over
a useful period of time. We discovered, however, that by changing the lanthanide from Ce to one of a
higher atomic number (Dy or Yb) the rate of the reaction increased. The best results were obtained using
YbCl3 as the catalyst and are summarised in Table 2.
Table 2
Armed with these conditions we expanded our investigation to include a more varied selection of
1,2-diols. A summary of this study appears in Table 3. As can be seen from Tables 2 and 3, both
meso- and C2-symmetric diols can be mono-functionalised by use of this procedure. In general C2-

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symmetrical diols were acylated at a faster rate than the meso-diols. It is possible that this has to do with
the preferred conformational/steric requirements for the coordination of the diol to the lanthanide salt,
although we do not have sufficient data to draw firm mechanistic conclusions at this time. Cyclic diols
of various ring sizes all react to give good to excellent yields of the mono-acylated product. Acyclic
diols are also mono-acylated in excellent yields. Diols with heteroatoms on adjacent carbons undergo
the reaction selectively and at an enhanced rate. We have also extended this reaction to include the use
of other carboxylic acid anhydrides (10 equiv.) further enhancing the utility of the process. In these
cases 1 was functionalised to yield 91% of the mono-propionate and 45% of the mono-benzoate (at
45% conversion). 1,4-Anhydroerythritol was converted exclusively to the mono-benzoate (100%) and
1,2-trans-cyclopentanediol provided the mono-benzoate with 80% selectivity.
Table 3
While the two hydroxyl groups of a C2-symmetric diol are homotopic, those of a meso-diol are
enantiotopic. The procedure at present does not discriminate between two enantiotopic sites, it thus
generates a racemic product. We decided to investigate the use of this methodology in the desymme-
terisation of meso-1,2-diols (i.e. the formation of a non-racemic product). To date we have two examples
of this process from our laboratories, which encourages further investigation. Chiral anhydride 6 was
prepared from its commercially available parent acid and acid chloride in toluene with an equivalent of
pyridine. meso-Hydrobenzoin was treated with 6 under our standard reaction conditions and produced
a 3:1 ratio of diastereomeric products (Scheme 2). Racemic hydrobenzoin was also acylated under
these conditions with 6 (2 equiv.) and this provided two diastereomeric products in a 3:1 ratio. The
configurations of the major products in either of these reactions were not determined. When the major
diastereomer was resubmitted to the reaction conditions in the absence of carboxylic acid anhydride no
loss of diastereomeric purity was observed, i.e. there was no acyl transfer between hydroxyl groups.
Scheme 2.

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While the levels of diastereoselection are only modest, we believe that this is an important proof of
concept and it encourages further investigation. A more efficient process, however, would be the use of
a chiral lanthanide(III) complex to desymmeterise meso- or resolve racemic systems. Investigations into
this possibility are currently underway.
Acknowledgements
We would like to thank the University of Nottingham and Florida State University for financial support
of this work.
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