Synthesis of acetal protected building blocks using flow chemistry with flow I.R. analysis: Preparation of butane-2,3-diacetal tartrates

Article abstract of DOI:10.1039/b917289k

The syntheses of butane-2,3-diacetal protected tartrate derivatives are described using continuous flow processing techniques with in-line purification and I.R. analytical protocols.

Full text of DOI:10.1039/b917289k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of acetal protected building blocks using flow chemistry with flow
I.R. analysis: preparation of butane-2,3-diacetal tartrates†
a
a
a
b
a
Catherine F. Carter, Ian R. Baxendale, Matthew O’Brien, John B. J. Pavey and Steven V. Ley*
Received 21st August 2009, Accepted 4th September 2009
First published as an Advance Article on the web 28th September 2009
DOI: 10.1039/b917289k
The syntheses of butane-2,3-diacetal protected tartrate
derivatives are described using continuous flow processing
techniques with in-line purification and I.R. analytical proto-
cols.
The production of starting materials for use in complex synthesis
programmes often entails repetitive experiments and routine
reaction optimisation, especially when using conventional batch-
mode approaches. Furthermore, extensive unit operations are
required to deliver pure products when chromatography or
other labour intensive methods are used. Additionally, because
of the repetitive nature of these experiments, there is little to
be gained in terms of acquiring new knowledge. We believe
a better approach in these circumstances is to employ more
machine assisted synthesis techniques of which flow chemistry
and related continuous processing concepts are of particular
1,2
value. A good case in point is the preparation of butane-
3
,4
2
,3-diacetal (BDA) protected tartrates since our group and
5
others have used these widely as starting materials for the
syntheses of various natural products such as muricatetrocin
Fig. 1 Natural products derived from BDA protected building blocks.
6
7
8
9
C, 10-hydroxyasimicin, didemniserinolipid B, (+)-aspicillin,
10
11
12
antascomicin B, epipyriculol, (+)-nephrosteranic acid and
13
(
+)-O-methylpiscidic acid dimethylester (Fig. 1).
These embedded diol motifs are introduced via the condensation
of dimethyl-L-tartrate with butanedione to give an enantiopure
14-16
BDA building block 1.
The particularly useful and spatially
differentiated meso derivative 3 is also accessed via oxidation of 1
to the dehydro species 2, followed by stereospecific introduction
17
of hydrogen. While in the past we have scaled up these processes
by application of the conventional batch methods, these are time
consuming and often wasteful of materials, particularly during
the necessary recrystallisations to yield high quality products
Scheme 1 Batch synthesis of butane-2,3-diacetal protected tartrate
derivatives.
(
Scheme 1).
As a platform to carry out the flow synthesis of BDA protected
tartrate 1 we selected the Uniqsis FlowSyn system, comprising
In this new work we describe a method suitable for automation
18
and scale-up using commercially available flow chemistry equip-
ment in combination with packed tubes containing appropriate
solid-supported reagents and scavengers. We also report the use
of flow I.R. equipment to monitor reaction pathways in-situ
to provide important mechanistic information concerning the
reaction progress in real-time.
of two HPLC pumps and fitted with a 14 mL PTFE coil
and a column heater suitable for heating OmnifitꢀR columns
of 10 ¥ 100 mm dimensions. A back pressure regulator (BPR)
at the end of the flow stream allows for the superheating of
solvents above their standard boiling point. In the first instance
we envisaged solutions of dimethyl-L-tartrate, butanedione and
trimethyl orthoformate being pumped through an OmnifitꢀR
column packed with Quadrapure sulfonic acid resin (QP-SA), to
mimic the use of DL-camphorsulfonic acid (CSA) in the batch
synthesis (Scheme 2). This set-up was expected to eliminate the
need for a traditional reaction work-up step.
a
Department of Chemistry, Innovative Technology Centre, University
of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. E-mail:
svl1000@cam.ac.uk
b
AstraZeneca, Bakewell Road, Loughborough, Leics, LE11 5RH, UK
Unfortunately, low yields of product were obtained from this
arrangement, despite attempted optimisation of flow rates, stoi-
chiometries and temperatures. To investigate this process further
†
Electronic supplementary information (ESI) available: Full experimental
data for compounds 1–6 and details of the I.R. experiments are available.
See DOI: 10.1039/b917289k
4
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rather increases the activity of the diol by forming an orthoester
in-situ. In addition, QP-SA was not a strong enough acid to carry
this intermediate through to product 1. Although we did not
generate the desired product, these experiments show the value of
being able to monitor a reaction in-line. Despite running similar
experiments in batch mode many times, we had not observed these
intermediates previously.
Scheme 2 Attempted flow synthesis of 1 with in-line I.R. monitoring.
we attached a recently devised flow cell containing an FTIR
Consequently it was decided to return to the use of CSA as
a heterogeneous acid catalyst (Scheme 4). Optimisation of the
process conducted in flow revealed the best conditions for the
reaction to be flowing a 2 M stock solution of the reagents into
19
diamond probe to monitor the progress of the reaction in-line
20
(
Fig. 2).
◦
a 14 mL PTFE flow coil held at 90 C with a residence time
of 2 h. This gave the product in 78% yield, which constituted a
consistent 8% improvement on the batch process. In order to purify
the product in-line a column packed with a benzylamine resin
(
QP-BZA) was introduced into the flow stream to scavenge out the
acid catalyst and also to trap out any unreacted butanedione as the
imine species. Subsequently, passing the flow stream over periodate
resin 5 removed any unreacted diol. Immobilised reagent 5 was
freshly prepared by stirring commercially available quaternary
ammonium chloride ion exchange resin (A-900) with sodium
21
periodate in water, and effects a glycol cleavage to yield volatile
byproducts. After passing the flow stream through these clean-up
columns solvent evaporation is the only manual operation required
to yield elementally pure BDA tartrate 1.
Fig. 2 A React IR 45 m. B Fibre optic cable. C Flow cell.
By obtaining the I.R. reference spectra of the reagents and
monitoring the intensity in peak height over time, the consumption
of reagents and formation of products can be readily monitored in
real-time, along with any unexpected byproducts being generated.
As can be seen in Fig. 3, butanedione and trimethyl orthoformate
are immediately consumed to form a new intermediate, which was
later identified to be the tetramethoxyacetal of butanedione.
Fig. 3 Relative trends from peak height analysis.
In order to investigate the effect of methanol on this process the
reaction was carried out using 1:1 MeOH:MeCN as the solvent
system. Surprisingly, the reaction afforded only the orthoester
4
(Scheme 3). This suggests that the role of the trimethyl
orthoformate is not to simply act as a dehydrating agent but
Scheme 4 Continuous flow synthesis of 1 with the Uniqsis FlowSyn.
One of the many advantages of flow chemistry is the ease of scale
up, with minimal change to the reaction set-up. To demonstrate
this principle the same reaction was carried out on a 200 mmol
scale and 40 g of elementally pure product was obtained in just
Scheme 3 Production of orthoester 4.
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1
0 h of processing time with no manual purification required. The
been carried out in-line with solid-supported reagents. These new
processes allow large amounts of material to be generated in a less
labour-intensive fashion. In this work we have also demonstrated
the utility of a flow I.R. system in the monitoring of intermediates
which we believe will find more general application than using
other I.R. probe devices.
only change was doubling of the flow rate to 0.30 mL/min to
increase the throughput with only a corresponding drop in yield.
With a process for the preparation of the enantiopure BDA
tartrate 1 established we turned our attention to the precursor for
the meso BDA protected tartrate 3, namely oxidised product 2
(
Scheme 5). The optimum conditions for preparing this building
block involved mixing equimolar solutions of the bis-enolate in
THF with iodine in THF, both held at -78 C, in a T-piece
◦
Acknowledgements
and allowing the reaction to warm to room temperature by
passage through a 14 mL PTFE coil. The combined flow rate
for this process was 1.0 mL/min, allowing for a high throughput
of material. The in-line purification process for the work-up of
this reaction involved three stages: firstly, the reaction mixture
was passed through a column of sulfonic acid resin (QP-SA)
to scavenge the diisopropylamine, then through a column of
thiosulfate resin 6 to remove any excess iodine and finally through
a short plug of silica gel to trap any inorganic lithium salts. This
overall sequence yielded compound 2 in 65% yield, which was an
improvement over the batch process since no manual work-up or
purification procedures were required.
We would like to acknowledge AstraZeneca (CFC), the BP
1
702 Chemistry Professorship (SVL), EPSRC (MOB), and the
Royal Society (IRB) for funding. We would also like to thank
Dr Jon Goode and Nigel Gaunt from Mettler Toledo for their
collaboration with the I.R. flow cell device.
22
Notes and references
1
For reviews in the area see I. R. Baxendale, J. J. Hayward, S. Lanners,
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Catalysis, ed. T. Wirth, Wiley-VCH, Weinheim, 2008, ch. 4.2, pp. 84–
1
22; I. R. Baxendale and S. V. Ley, in New Avenues to Efficient Chemical
Synthesis - Emerging Technologies, eds. P. H. Seeberger and T. Blume,
Springer, Berlin Heidelberg, 2007, vol. 1, pp. 151–185; N. G. Anderson,
Org. Proc. Res. Dev., 2001, 5, 613–621; A. Kirschning, W. Solodenko
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Egberink, D. N. Reinhoudt and W. Verboom, Tetrahedron, 2008, 64,
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0023–10040.
2
For recent examples from our laboratories see I. R. Baxendale, S. V.
Ley, A. C. Mansfield and C. D. Smith, Angew. Chem., Int. Ed., 2009,
Scheme 5 Continuous flow synthesis of BDA derivative 2.
4
8, 4017–4021; M. Baumann, I. R. Baxendale and S. V. Ley, Synlett,
008, 14, 2111–2114; M. Baumann, I. R. Baxendale, S. V. Ley, N.
2
The final step to produce synthetically useful quantities of meso
tartrate 3 required a flow hydrogenation procedure (Scheme 6).
Nikbin, C. D. Smith and J. P. Tierney, Org. Biomol. Chem., 2008, 6,
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577–1586; M. Baumann, I. R. Baxendale, S. V. Ley, C. D. Smith and
23
Using the H-CubeꢀR reactor and a Rh/Al
catalyst, 1 mmol of oxidised substrate 2 was dissolved in 5 mL
methanol and recycled through the machine at 60 bar of H for
h to obtain full conversion to spatially desymmetrised BDA
O
cartridge as the
G. K. Tranmer, Org. Lett., 2006, 8, 5231–5234; I. R. Baxendale, J.
Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby and G. K. Tranmer,
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2
3
2
4
protected meso tartrate 3 in 100% yield. This represents a vast
improvement on the batch procedure which required five days of
3
4
stirring at 80 bar of H in a pressurised reactor vessel, which carries
2
S. V. Ley, D. K. Baeschlin, D. J. Dixon, A. C. Foster, S. J. Ince, H. W.
Priepke and D. J. Reynolds, Chem. Rev., 2001, 101, 53–80.
with it many safety concerns, particularly on a large scale.
5
6
7
8
9
E. Lence, L. Castedo and C. Gonzalez-Bello, Chem. Soc. Rev., 2008,
3
7, 1689–1708.
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Scheme 6 Continuous flow synthesis of BDA derivative 3.
1
1
0 D. E. A. Brittain, C. M. Griffiths-Jones, M. R. Linder, M. D. Smith, C.
McCusker, J. S. Barlow, R. Akiyama, K. Yasuda and S. V. Ley, Angew.
Chem., Int. Ed., 2005, 44, 2732–2737.
TM
Using the commercially available H-Cube Midi , a preparative
version of the H-CubeꢀR , the reaction was performed on a 13 mmol
scale at an increased flow rate of 5 mL/min, giving 3.8 g of pure
product in just 2 h with no further purification necessary. As this
valuable motif is not commercially available our reproducible route
to large amounts of pure material is particularly attractive.
In conclusion, we have reported the syntheses of three BDA
protected derivatives for use in total synthesis programmes using
continuous flow processing technology, giving higher yields than
the corresponding batch processes. All purification steps have
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9 Prototype flow cell shown, currently under development by Mettler
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23 www.thalesnano.com.
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