The synthesis of the 2, 3-difluorobutan-1, 4-diol diastereomers

Article abstract of DOI:10.3762/bjoc.13.280

The diastereoselective synthesis of fluorinated building blocks that contain chiral fluorine substituents is of interest. Here we describe optimisation efforts in the synthesis of anti-2, 3-difluorobutane-1, 4-diol, as well as the synthesis of the corresponding syn-diastereomer. Both targets were synthesised using an epoxide opening strategy.

Full text of DOI:10.3762/bjoc.13.280

The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers
Robert Szpera, Nadia Kovalenko, Kalaiselvi Natarajan, Nina Paillard and Bruno Linclau*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2883–2887.
Chemistry, University of Southampton, Highfield, Southampton SO17
doi:10.3762/bjoc.13.280
1BJ, United Kingdom
Received: 05 October 2017
Accepted: 13 December 2017
Published: 27 December 2017
Email:
Bruno Linclau* - bruno.linclau@soton.ac.uk
*
Corresponding author
This article is part of the Thematic Series "Organo-fluorine chemistry IV".
Guest Editor: D. O'Hagan
Keywords:
acetal isomerization; deoxyfluorination; epoxide opening; fluorinated
building block; vicinal difluoride
© 2017 Szpera et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The diastereoselective synthesis of fluorinated building blocks that contain chiral fluorine substituents is of interest. Here we
describe optimisation efforts in the synthesis of anti-2,3-difluorobutane-1,4-diol, as well as the synthesis of the corresponding syn-
diastereomer. Both targets were synthesised using an epoxide opening strategy.
Introduction
The introduction of fluorine in organic compounds usually on a multigram scale. Interestingly, the majority of currently
results in the modification of a range of chemical, physical and commercially available fluorinated building blocks do not
biological properties [1]. Fluorine incorporation is therefore a contain stereogenic C–F bonds.
common strategy to optimise the properties of drugs/agrochemi-
cals, as well as materials [2-6].
The vicinal-difluoride motif is known to exert conformational
control through the fluorine gauche effect [14,15], and so build-
Many methods exist for the stereoselective introduction of the ing blocks containing this motif are of interest [16,17]. We have
C–F group [7-11]. An alternative and often time-efficient ap- previously reported on the gram-scale synthesis of meso-2,3-
proach is the use of fluorinated building blocks, where fluorine difluorobutane-1,4-diol (anti-5) starting from commercially
is introduced as part of a carbon containing fragment, some- available cis-but-2-ene-1,4-diol (Scheme 1) [17]. The vicinal-
times also bearing other functionality [12,13]. The develop- difluoride group was introduced by a two-step sequence, with
ment of novel fluorinated building blocks is therefore of initial nucleophilic epoxide [18] opening by a fluoride source
interest, particularly those that can be synthesised conveniently [19], followed by nucleophilic deoxyfluorination [9-11].
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Beilstein J. Org. Chem. 2017, 13, 2883–2887.
Scheme 1: The synthesis of anti-2,3-difluorobutan-1,4-diol (anti-5) [17].
In this contribution, we report on work directed at the further opening with the recently described TBAF/KHF2 [22] was also
optimisation of the synthesis of anti-5, as well as on a gram- possible, but in lower yield (75%, not shown). Incidentally, it
scale synthesis of its diastereomer (±)-syn-5, a novel compound. was also found that the subsequent deoxofluorination reaction
was somewhat higher yielding when DAST was added at rt over
Results and Discussion
just 5 min, immediately followed by the addition of pyridine
Optimisation of the synthesis of anti-5
and heating at 70 °C.
While the synthesis of anti-5 as described in Scheme 1 was
high-yielding [17], two disadvantages were apparent. First, the It should be noted that DAST is known to undergo decomposi-
epoxide opening takes 2.5 days at 115 °C and uses an expen- tion at temperatures above 90 °C [23]. Here we use DAST in
sive fluoride source (Landini’s reagent [18]: Bu4NH2F3). It was solution. The initial mixing is at room temperature, and heating
found that Bu4NH2F3 made in-house gave significantly reduced doesn’t exceed 70 °C, and therefore, the procedure is deemed to
yields. Second, the use of the benzyl ether protecting group have low risk. Nonetheless, care must be taken and the reaction
resulted in a significant increase in mass, and therefore, chro- was run with the protection of a blast shield.
matographic purification of the protected intermediates upon
scale-up was inconvenient.
In order to reduce the relative contribution of the protecting
group to the overall weight of the intermediates, the use of an
As previously reported [17], epoxide opening of cis-2 with acetonide was explored. Given the starting alkene was cis-con-
Olah’s reagent (HF·py) led to an 80% yield of the fluorohydrin figured, its introduction was possible from the start (Scheme 3).
after just three hours, however, the product was obtained as a
mixture of both the syn- and anti-diastereomers. Whilst no Hence, following literature procedures [24-26], the reaction of
mechanistic studies were conducted, it is possible that cis-1 with 2,2-dimethoxypropane and subsequent epoxidation
competing SN1 and/or anchimeric assistance by the benzyloxy led to 7. However, epoxide opening with Et3N·3HF was accom-
group occurred. Work by Schlosser has shown that 1,2-disubsti- panied by acetonide rearrangement to afford fluorohydrin (±)-9,
tuted epoxide opening with Et3N·3HF proceeds with excellent containing the thermodynamically favoured five-membered ring
diastereoselectivity [19]. Et3N·3HF is less acidic than Olah’s [24]. This is clearly indicated by the appearance of a doublet of
reagent, disfavouring SN1 and rearrangement pathways [20,21]. doublets for the primary alcohol OH proton. DAST-mediated
Indeed, the use of this reagent for the epoxide opening of cis-2 deoxofluorination then led to (±)-10, in which an alkyl fluoride
led to (±)-syn-3 in excellent yield (Scheme 2), with no signifi- signal at −232 ppm confirmed the presence of a primary fluo-
cant isomerisation (see Supporting Information File 1). Epoxide ride.
Scheme 2: Improved epoxide opening and deoxofluorination conditions.
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Beilstein J. Org. Chem. 2017, 13, 2883–2887.
Scheme 3: Attempted synthesis of anti-5 via acetonide protection.
Hence, non-acidic epoxide opening conditions were investigat- immediately subjected to acid hydrolysis to give anti-5.
ed to circumvent the rearrangement (Scheme 4). Both the Unfortunately, the yield for this two-step process was only
use of Bu4NH2F3 [18] and of the TBAF/KHF2 reagent combi- moderate (30%).
nation [22] were successful (56% and 64%, respectively).
While subsequent fluorination using PyFluor only led to Synthesis of (±)-syn-5
the formation of the 2-pyridinesulfonate intermediate (±)-12, The synthesis of (±)-syn-5 (Scheme 5) was achieved starting
the use of DAST at 60 °C proved successful. The difluoride from the trans-configured but-2-ene-1,4-diol (1), which is not
meso-11 was not isolated due to its low boiling point, but was commercially available in geometrically pure form.
Scheme 4: Completion of the synthesis of anti-5.
Scheme 5: Synthesis of (±)-syn-5.
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Beilstein J. Org. Chem. 2017, 13, 2883–2887.
Hence, according to literature procedures, reduction of 1,4- protocols provided will be of use for the large-scale synthesis of
butynediol (13) by LiAlH4 to give trans-1 [27] was followed by both syn- and anti-2,3-difluorobutan-1,4-diol building blocks.
benzylation [28] and epoxidation with m-CPBA to give
(
±)-trans-2 [28]. When the reaction was performed on a small
Supporting Information
scale, excess m-CPBA and the byproduct 3-chlorobenzoic acid
were removed by extraction with a saturated Na2S2O3 solution.
However, on scale-up this proved inconvenient due to the large
volumes of solvent required, and so these impurities were pre-
cipitated out the reaction mixture by cooling to 0 °C and
collected by filtration through Celite. After work-up, the ob-
tained epoxide was of high purity and no additional chromato-
Supporting Information File 1
Experimental part and NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-280-S1.pdf]
graphic purification was required, which was convenient on Acknowledgements
scale. The reaction of (±)-trans-2 with neat Et3N·3HF at 120 °C We thank the University of Southampton and the EPSRC (core
for 16 h led, after aqueous work-up, to (±)-anti-3 in high dia- capability EP/K039466/1) for funding.
stereomeric purity (see Supporting Information File 1). The 19F
shift of −195.3 ppm is different compared to that of (±)-syn-3 ORCID® iDs
(
−204.4 ppm) [17]. Upon scale-up of the reaction to 10 g of
Robert Szpera - https://orcid.org/0000-0003-1351-1750
Nina Paillard - https://orcid.org/0000-0003-0109-5403
Bruno Linclau - https://orcid.org/0000-0001-8762-0170
(
±)-trans-2, a similarly high yield of 90% (crude) was obtained,
which again could be used directly in the next step without
purification. Conversion of fluorohydrin (±)-anti-3 to difluo-
ride (±)-syn-4 under the same conditions as shown in Scheme 2 References
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