Modular continuous flow synthesis of orthogonally protected 6-deoxy glucose glycals

Article abstract of DOI:10.1039/d0ob00522c

An efficient, modular continuous flow process towards accessing two orthogonally protected glycals is described with the development of reaction conditions for several common protecting group additions in flow, including the addition of benzyl, naphthylme

Full text of DOI:10.1039/d0ob00522c

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DOI: 10.1039/D0OB00522C
COMMUNICATION
Modular Continuous Flow Synthesis of Orthogonally
Protected 6-Deoxy Glucose Glycals
Subbarao Yalamanchili a, Tu-Anh V. Nguyen a, Nicola L. B. Pohl *b, and Clay S. Bennett *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An efficient, modular continuous flow process towards natural product synthesis to the generation of novel
accessing two orthogonally protected glycals is structural motifs, glycals are versatile building blocks.7 In
described with the development of reaction conditions for carbohydrate chemistry, glycals can be directly used as
several common protecting group additions in flow, donors in chemical glycosylation18 by a variety of different
including the addition of benzyl, naphthylmethyl and tert- activation conditions.19-26 Glycals also serve as important
butyldimethylsilyl ethers.
The process affords the intermediates in the construction of glycosyl donors, as
desired target compounds in 57-74% overall yield in just they can readily be made into hemiacetals27,28 or
21-37 minutes of flow time. Furthermore, unlike batch thiogylcosides.29-33
conditions, the flow processes avoided the need for
active cooling to prevent unwanted exotherms and
required shorter reaction times.
O
O
BnO
BnO
Recently, continuous flow processes have been
adapted by many groups in the synthesis of different
natural products1 and active pharmaceutical ingredients
(APIs).2,3 Flow chemistry can provide many benefits,4–6
including the ability to run continuous processes enabling
large scale production7 of material and increased reaction
efficiencies8 as compared to batch processes. Reactions
can be more efficiently heated and cooled and highly
reactive intermediates can be made transiently to avoid
the safety hazards of larger scale production.
ONap
OTBS
1
2
O
HO
O
O
HO
O
OH
O
O
HO
O
O
O
HO
Landomycin D
Landomycin E
O
O
OH
Landomycin B
Landomycin A
OH
O
The design of efficient flow reactions requires
O
O
HO
O
consideration
of
several
parameters.
Although
O
microfluidic systems require careful consideration of
parameters to get reproducible temperature transfers and
mixing efficiencies,9 larger tubing-based systems flow
systems can be easier to implement. The benefits of
microfluidic and larger flow systems have seen
applications to chemical glycosylation,10-15 but almost
none of the necessary glycosyl donors and acceptors
needed for glycosylation reactions have been produced
with the development of continuous flow processes.16
Glycals—1,2-unsaturated monosaccharide derivatives
—have a wide variety of uses in organic synthesis. From
O
HO
O
O
O
OH
Saquayamicin Z
Figure 1. Oligosaccharide portions of angucycline natural products
containing 2-6-dideoxy glucose (blue).
A major hurdle in carbohydrate chemistry remains the
ability to quickly and efficiently access multiple donor and
acceptor building blocks.34 Our solution to this problem is
to take advantage of the faster timescales of continuous
flow processes. In continued studies on deoxy-sugar
oligosaccharide synthesis, we had need for large
quantities of glycal precursors. In an effort to circumvent
issues associated with batch synthesis (time consuming
reaction sequences, limited scale, potential exotherms,
etc.), we chose to examine if these substrates could be
a.62 Talbot Ave, Medford, MA, 02145.
b.212 S. Hawthorne Dr, Bloomington, IN 47405
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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produced in a continuous flow system. As an initial foray auxiliary base such 4-dimethylaminepyridine (DMAP)
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DOI: 10.1039/D0OB00522C
into this chemistry, we chose the synthesis of which is known to have improved rates of silylation
orthogonally protected L
-rhamnals 1 and 2, which serve relative to imidazole.40 Using 1.5 equivalents (0.89 M in
as precursors for many of the deoxy-sugars found in DMF) of DMAP, we were able to get complete conversion
natural products, such as those in the anthracycline35 and of diol 4 to corresponding silyl ether 5 in 88% yield in 10
angucycline36-38 families of antibiotics (Figure 1).
minutes of total retention time (Table 2, entry 5). After
The synthesis of glycals 1 and 2 commenced with increasing the scale of the reaction to 2.97 g of diol 4, we
translating Zemplén deacetylation that we had were able to achieve regioselective protection of the
a
previously run in batch reaction conditions28 into a flow allylic alcohol at a rate of 29.4 g/h. These conditions are
process. As is the case with converting manual to an improvement to traditional TBS silylation conditions
automated batch process,29 the conversion of batch to that typically use a large excess of base to increase the
flow processes is not trivial. Ideally, solvents are found in rate of reaction. Interestingly, we also found that the
which all reagents and reactants are soluble and no reaction could be run at ambient temperature and it was
products or byproducts precipitate during the course of not necessary to cool the reaction down to 0 ˚C in order
the reaction. We started with 0.4 equivalents (0.24 M in to selectively protect the C3 position.
MeOH) of sodium methoxide (Table 1, entry 1). While the
O
desired diol 4 was formed in 76% yield, the reaction did
not go to completion. By an increase in the amount of
OH
sodium methoxide (NaOMe) to 0.8 equivalents (0.48 M in
1 mL/min
MeOH), compound 3 was completely consumed and the
formation of the desired product 4 was affected in 98%
yield (Table 1, entry 2). Importantly, we were able to run
the deacetylation on a five gram scale of 3, at a rate that
could produce 35.8 g/h of diol 4.
HO
O
4
HO
in DMF (0.6 M)
OTBS
Static
Mixer
TBSCl + base
in DMF
5
1 mL/min
Table 2. Optimization of Regioselective TBS Protection in Flow
O
Entry
Base
Eq. of
Base in
DMF
Flow
Total Tr
Yieldb
(%)
Rate in
(min)
AcO
O
Main
OAc
2 mL/min
Reaction
3
HO
in MeOH (0.6 M)
Tube
OH
Static
Mixer
NaOMe in
MeOH
(mL/min)
4
1a
2a
3a
4a
5a
Imidazole
Imidazole
Imidazole
4-DMAP
4-DMAP
1.1
1.5
1.5
1.1
1.5
2
2
2
2
2
40
40
10
10
10
83
91
49
64
88
2 mL/min
Table 1. Optimization of Zemplén Deacetylation in Flow
Entry
Eq. of
NaOMe
in MeOH
Flow Rate in
Main
Total Tr (min)
Yieldb (%)
a. Run at Ambient Temperature, b. Isolated Weight
Reaction
Tube
(mL/min)
4
1a
2a
0.4
0.8
5
5
76
98
With the allylic alcohol successfully protected, we next
chose to protect the C4 alcohol with an orthogonal
protecting group such as an alkyl ether. Recently, the
Pohl lab has demonstrated continuous flow benzylation,
acetylation, and thioglycoside formation in the synthesis
of protected levoglucosan and glucose.16 While
acetylation and thioglycoside formation proceeded
smoothly, the use of BaO packed bed reactors had issues
with pressure buildup and possibly product absorption to
the solid phase that warranted a reenvisioning of this
reaction.41 In our case, only a single hydroxyl group was
free for protection, which expanded the choice of solvents
and conditions that could be considered for the
benzylation reaction.
4
a. Run at Ambient Temperature, b. Isolated Weight
With 4 in hand, we next sought to convert the
traditional Corey silylation conditions39 to a flow process
by regioselectively protecting the allylic alcohol as a tert-
butyldimethylsilyl (TBS) ether. Following optimization, we
found that using 1.1 equivalents of TBSCl (0.66 M in
DMF) and 1.5 equivalents of imidazole (0.89 M in DMF)
was sufficient to selectively protect the C3 alcohol over
the C4 position in 40 minutes of retention time to afford 5
in 91% yield (Table 2, entry 2). Efforts to reduce the
retention time by increasing flow rate resulted in formation
of product in 49% yield with recovery of unreacted
starting material (Table 2, entry 3). In order to increase
the rate of the reaction, we looked into using a different
To address this, we chose to examine the use of
alternative bases in the reaction. Typical Williamson ether
conditions include sodium hydride, which is incompatible
with flow-based setups due to it being a heterogeneous
2 | J. Name., 2012, 00, 1-3
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solution. However, benzylation has successfully been fluoride (TBAF, 1.0 M in THF) to afford 7 in 93% yield in
View Article Online
DOI: 10.1039/D0OB00522C
demonstrated under
a
variety of homogeneous 10 minutes of total retention time (Figure 2). Upon scale
conditions, such as LiHMDS/BnBr/TBAI42 or benzyl up to 1.7 g of 1, we were able to produce 6 at a rate of
trichloroacetimidate/TfOH.43 To this end, we pictured 6.4 g/h. Importantly, while typical silyl ether removals are
glycal 5 first going through a deprotonation sequence with run in THF, we found that it was possible to run this
KHMDS, followed by treatment with BnBr and TBAI to reaction in DMF, which was used for the previous two
achieve benzylation (Table 3, entry 1). Through reactions in this sequence. This use of the same solvent
optimizations, we found that TBAI was unnecessary in the opens up the future possibility of telescoping these
reaction, perhaps due to the high reaction concentration reactions into a single step if only a particular product is
leading to fast rates of reaction (Table 3, entry 2). Further needed.
optimization of the reaction led to finding that 5.0
O
equivalents of BnBr (1.8 M in DMF) was optimal for
BnO
benzylation, affording 1 in 86% yield without any
OTBS
O
observed migration of the silyl ether (Table 3, entry 5).
With a total retention time of only 6 minutes, this is a large
improvement to traditional batch Williamson ether
1 mL/min
1
in DMF (0.5 M)
BnO
Static
Mixer
TBAF in
THF (1.0 M)
OH
Tr = 10 min
conditions that we have observed in our previous work
where benzylations can take between 3-16 hours.44–46
Increasing the scale of the reaction to 2.7 grams of 5
enabled production of target glycal 1 at a rate of 31.6 g/h.
Importantly, to prevent clogging due to the formation of
insoluble salts that was observed through the course of
the reaction, we chose to exclude a static mixer at the T-
junction between the deprotonated glycal and solution of
benzyl bromide. Furthermore, the reaction proceeded
smoothly at ambient temperature, thus avoiding a cooling
bath for another reaction that is typically run at 0 ˚C.
6
1 mL/min
Figure 2. Silyl ether removal using TBAF.
To finish the synthesis of
L
-olivose glycal 2, we
protected the C3 hydroxyl with naphthylmethyl ether
following similar conditions as we did with the benzyl
ether alkylation. Gratifyingly, naphthylmethyl ether
synthesis proceeded smoothly to afford 2 in 82% yield in
6 minutes of total retention time (Figure 3). Scaling up to
1.1 g of 6 proceeded without incident, allowing for
production of 2 at a rate of 14.4 g/h. Similar to the
benzylation, we found that this reaction could be run at
ambient temperatures and did not require cooling to 0 ˚C.
Table 3. Optimization of Benzylation in Flow
O
O
HO
O
1 mL/min
1 mL/min
OTBS
No
BnO
5
O
Static Mixer
BnO
OH
1 mL/min
1 mL/min
in DMF (0.6 M)
No
Static
Mixer
OTBS
6
KHMDS in
THF (1.0 M)
Static Mixer
T
r = 1 min
Tr = 5 min
BnO
in DMF (0.6 M)
1
Static
Mixer
ONap
KHMDS in
THF (1.0 M)
Tr = 1 min
Tr = 5 min
2
BnBr in
DMF
2 mL/min
5.0 eq. of
NapBr in
DMF
Entry
Additive
Eq. of
Flow
Total Tr
Yieldba
(%)
2 mL/min
BnBr
Rate in
(min)
Figure 3. Naphthylmethyl ether installation.
in DMF
Main
Reaction
Tube
Conclusions
(mL/min)
1a
2a
3a
4a
5a
TBAI
none
none
none
none
neat
neat
1.0
4
4
4
4
4
6
6
6
6
6
79
81
52
65
86
In summary, we have demonstrated the first modular
syntheses of two orthogonally protected glycals of the
2,6-dideoxy glucose
L
-olivose using only continuous flow
was
3.0
processes for each reaction step. Glycal
1
5.0
synthesized in 74% overall yield over three steps with a
total retention time of 21 minutes. Similarly, glycal 2 was
synthesized in 57% overall yield in 5 steps in 37 minutes
of total retention time. These processes are in stark
contrast to batch approaches to these molecules, which
in our experience can take over 1 week.44–46 All of the
reactions in question are run at ambient temperature and
most are in the same solvent (DMF), again in contrast to
batch approaches to these molecules. Through increased
a. Run at Ambient Temperature, b. Isolated Weight
We chose to next investigate replacing the silyl ether
with a naphthylmethyl (Nap) ether47 to further illustrate the
general applicability of this method. Following similar
reaction conditions as Corey,39 TBS removal proceeded
smoothly with 2.0 equivalents of tetra-butylammonium
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reaction concentration, all reactions were able to be run in (10)
less than 10 minutes of total retention time. Furthermore,
due to the efficient heat transfer enabled by the flow
processes, both TBS silyl protection and alkyl ether (11)
installations could be run at ambient temperatures rather
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
C.S.B and N.L.B.P. both thank the U.S. National Institutes
of Health Common Fund in Glycosciences (5U01GM116248
and 5U01-GM120414) for partial support of this work and to
allow S.Y. to work in Bloomington. N.L.B.P. is grateful to the
Joan and Marvin Carmack Chair funds for partial support of
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the U. S. National Science Foundation (NSF CHE-1566233)
for additional support. We are also thankful to Zachary
Wooke, Ashley DeYoung, and Gavin Stamper, for their
assistance in setting up the initial flow systems.
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The use of continuous flow platform for the rapid and highly efficient construction
of differentially protected glycals from commercial sources is described.