Practical one-pot stereospecific preparation of vicinal and 1,3-diols

Article abstract of DOI:10.1016/j.tetlet.2016.11.101

A facile one-pot synthesis providing vicinal diols and 1,3-diols in >95% stereoisomeric purity from commercially available enantiopure hydroxy esters has been developed. The esters were reduced with DIBALH and alkylated in situ with 4-pentenylmagnesium br

Full text of DOI:10.1016/j.tetlet.2016.11.101

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical one-pot stereospecific preparation of vicinal and 1,3-diols
a
b
Bjorn Bohman a,b, , Gavin R. Flematti , C. Rikard Unelius
⇑
a School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia
b Department of Chemistry and Biomedical Sciences, Linnaeus University, SE-391 82 Kalmar, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile one-pot synthesis providing vicinal diols and 1,3-diols in >95% stereoisomeric purity from com-
mercially available enantiopure hydroxy esters has been developed. The esters were reduced with
DIBALH and alkylated in situ with 4-pentenylmagnesium bromide, which after workup generated the title
diols as diastereomeric pairs. These pairs were easily separated by preparative chromatography, affording
products with retained stereoisomeric purity from the starting materials. This method represents an
expedient preparation of many common natural products, such as cerambycid beetle pheromones and
intermediates towards bicyclic acetal bark beetle pheromones.
Received 2 November 2016
Revised 21 November 2016
Accepted 23 November 2016
Available online xxxx
Keywords:
Diols
DIBALH
Grignard
Acetals
Ó 2016 Elsevier Ltd. All rights reserved.
Pheromone
Vicinal diols are widespread natural products that have been
identified as pheromones in several species of cerambycid beetles,1
and have also been found in diverse groups of animals such as fruit
flies2 and rodents.3 Furthermore, vicinal diols and 1,3-diols are key
intermediates in the synthesis of monocyclic and bicyclic acetals,
which comprise important and distinct groups of natural products
found in triatomine bugs4 and bark beetles.5 Research on the
chemical ecology of bark beetles is of utmost importance in order
to manage forests infested with these pests both in North America
and in Europe. In order to fully understand the chemical communi-
cation between bark beetles, infested trees, and microorganisms,6
it is important to obtain easy access to all stereoisomers of identi-
fied semiochemicals. New research programs investigating the
complex relationships between the bark beetles and the tree-kill-
ing symbiotic fungi that they convey into the phloem require easy
access to all stereoisomers in order to achieve a detailed under-
standing of the specific compounds used by each organism.7
Many of the cyclic acetals identified to date can be prepared
from 1,2- and 1,3-diol precursors via Wacker type cyclisations.8
For example, 1,3-dimethyl-2,9-dioxabicyclo[3.3.1]nonane and
7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane have been suc-
cessfully synthesized using this approach in order to confirm their
role as semiochemicals in a number of bark beetle species.8
Several synthetic routes have been described to prepare bioac-
tive diols and cyclic acetals over the last few decades.8–21 However,
these methods have several disadvantages including requiring
many steps,16 advanced protocols,8 non-commercially available
reagents11,14,21 or biocatalytic systems,14,15,18 or being limited to
specific stereoisomers of the products.9,10,14,17–19
In our previous work22 we utilized a modified method from
Lacey and co-workers.23 to prepare all stereoisomers of 2,3-pen-
tanediol from the two enantiomers of methyl lactate. Herein, we
present an improved one-pot method involving an in situ Grignard
reaction on an aldehyde intermediate formed by DIBALH reduction
of an
a- or b-hydroxy ester starting material. This method is pre-
dicted to be generally applicable to the synthesis of a wide range
of vicinal diols and 1,3-diols in one-pot reactions. This method
offers many advantages: the enantiomerically pure hydroxy esters
employed are commercially available, no protection is necessary,
the configuration of the chiral precursors is retained, and the
product diastereomers can be easily separated using column
chromatography or preparative HPLC. Further, in cases where
enantiomerically pure
a-hydroxyesters are not commercially
available, amino acids can easily be subjected to diazotization
and esterification24 to provide an extended range of starting
materials.
We have exemplified the synthesis by preparing all isomers of
non-8-ene-2,4-diol 3a–d and non-8-ene-3,4-diol 4a–d in one-pot
reactions from methyl (2R)-hydroxybutanoate (1a), methyl (2S)-
hydroxybutanoate (1b), methyl (3R)-hydroxybutanoate (2a) and
methyl (3S)-hydroxybutanoate (2b) (Scheme 1). The hydroxy
esters were subjected to DIBALH reduction in toluene at À78 °C,
and subsequently treated in the same pot with 4-pentenylmagne-
sium bromide in THF at the same temperature, forming the diols
⇑
Corresponding author at: School of Chemistry and Biochemistry, The University
of Western Australia, Crawley, WA 6009, Australia.
E-mail address: bjorn.bohman@uwa.edu.au (B. Bohman).
http://dx.doi.org/10.1016/j.tetlet.2016.11.101
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Bohman B., et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.11.101

2
B. Bohman et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Scheme 1. Synthetic route to all stereoisomers of non-8-ene-2,4-diol (3a–d) and non-8-ene-3,4-diol (4a–d).
after standard workup. In order to separate the formed pair of
diastereoisomers, either column chromatography on silica gel
(3a–d) or preparative HPLC (4a–d) was performed.
Centre for Microscopy, Characterisation & Analysis, The University
of Western Australia, a facility funded by the University, State and
Commonwealth Governments.
The yields ranged from 24 to 47% (combined isolated yield per
pair of diastereoisomers, >95% stereoisomeric purity). Since the
configuration of the first stereocenter was retained from the
hydroxy ester precursor the absolute configuration of all products
could easily be determined by comparing NMR spectra, which
were clearly distinguishable between the syn and anti diols.15,21
The stereoisomeric purities of the products were identical to that
of the purchased hydroxy ester precursors, which were confirmed
by enantioselective GC analysis. The diastereomers of 4 were also
separated on a non-polar GC column, further validating the
diastereomeric purity of the isolated products. Following a litera-
ture procedure,25 the diols were converted into all possible
stereoisomers of the bicyclic acetals 1,3-dimethyl-2,9-dioxabicy-
clo[3.3.1]nonane and 7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]oc-
tane (brevicomin) for use in subsequent ongoing bark beetle
chemical ecology projects (data not shown).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.11.101.
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In conclusion, we have developed a quick and facile method to
prepare all stereoisomers of vicinal and 1,3-diols in excellent pur-
ity from commercially available starting materials and reagents.
Acknowledgments
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This study was supported by Linnaeus University, Kalmar,
Sweden. GRF gratefully acknowledges the Australian Research
Council for funding (FT110100304). The authors acknowledge
the facilities, and the scientific and technical assistance of the
Australian Microscopy & Microanalysis Research Facility at the
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