Continuous flow photochemistry for the rapid and selective synthesis of 2′-deoxy and 2′,3′-dideoxynucleosides

Article abstract of DOI:10.1071/CH12426

A new photochemical flow reactor has been developed for the photo-induced electron-transfer deoxygenation reaction to produce 2′-deoxy and 2′,3′-dideoxynucleosides. The continuous flow format significantly improved both the efficiency and selectivity of the reaction, with the streamlined multi-step sequence directly furnishing the highly desired unprotected deoxynucleosides.

Full text of DOI:10.1071/CH12426

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 157–164
Full Paper
http://dx.doi.org/10.1071/CH12426
Continuous Flow Photochemistry for the Rapid
and Selective Synthesis of 2’-Deoxy
and 2’,3’-Dideoxynucleosides
A
A B
,
Bo Shen and Timothy F. Jamison
A
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, MA, 02139, USA.
B
Corresponding author. Email: tfj@mit.edu
A new photochemical flow reactor has been developed for the photo-induced electron-transfer deoxygenation reaction to
produce 20-deoxy and 20,30-dideoxynucleosides. The continuous flow format significantly improved both the efficiency
and selectivity of the reaction, with the streamlined multi-step sequence directly furnishing the highly desired unprotected
deoxynucleosides.
Manuscript received: 16 September 2012.
Manuscript accepted: 8 October 2012.
Published online: 19 November 2012.
Deoxynucleosides have demonstrated prominent antiviral and
antitumoral activities,[1] leading to the development of several
drugs, including but not limited to zidovudine, stavudine,
trifluridine, idoxuridine, cladribine, and didanosine (Fig. 1).
Extraction from natural sources and fermentation processes
can only provide a limited number of naturally-occurring
20-deoxynucleosides; therefore, synthetic approaches to the
preparation of deoxynucleosides are highly desired.[2] The most
common approach involves the direct SN2 reaction of metal salts
or silylated nitrogenous bases with 1-chloro-2-deoxyribose
derivatives (Scheme 1, Approach A). However, 1-chloro sugars
are expensive and unstable, and the substitution reaction often
generates a mixture of anomers that are difficult to separate.[2a]
Another method involves the radical deoxygenation reaction
of ribonucleosides when the C20-hydroxyl group is derivatized
as a phenoxythiocarbonyl ester.[3] Nevertheless, this method
is hampered by the use of a stoichiometric amount of toxic
reagent nBu3SnH, and is only applicable to naturally-occurring
ribonucleosides.
Rizzo and coworkers developed the two-step de novo syn-
thesis of 20-deoxynucleosides involving Lewis acid mediated
Vorbru¨ggen glycosylation[4] followed by selective C20-deox-
ygenation (Scheme 1, Approach B).[5] The C20-hydroxyl group
was derivatized as m-CF3-benzoate, which served as the
O
N
NH2
N
O
Me
I
N
NH
NH
HO
HO
HO
O
N
O
N
N
Cl
O
O
O
N3
OH
OH
Cladribine
Idoxuridine
Zidovudine
O
N
O
N
O
N
F3C
Et
N
NH
NH
NH
HO
HO
HO
O
O
N
O
O
O
OH
OH
Trifluridine
Edoxudine
Didanosine
Fig. 1. Selected deoxynucleoside drugs.
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

158
B. Shen and T. F. Jamison
(a) Direct approach
PO
PO
Base
O
O
Nitrogenous base
Cl
Glycosylation
OP
OP
P ϭ protecting group
• Labile glycosyl chloride
• Low diastereoselectivity
(b) Telescoped 2-step approach
BzO
BzO
BzO
Base
Base
Nitrogenous base
Photosensitizer
O
O
O
Lewis acid
hν
OBz
Glycosylation
Deoxygenation
O
O
O
OBz
O
OBz
F3C
OBz
F3C
• High diastereoselectivity
• Good chemoselectivity
• No intermediate purification
Scheme 1. Approaches toward 20-deoxynucleosides.
directing group for the glycosylation. This methodology allows
the installation of both natural and unnatural nitrogenous bases
with high diastereoselectivity favouring the b-anomer. The
20-m-CF3-benzoate moiety was then selectively removed
(deoxygenated) under photo-induced electron-transfer (PET)
conditions.[6] However, the photochemical step required rela-
tively long irradiation time (1.5–2.0 h), and over-deoxygenation
at the 30-position was often observed, leading to diminished
yields of the desired 20-deoxynucleosides.[5c,d]
Immersion well reactors are commonly used for photochem-
ical reactions using UV light irradiation in batch. Light intensity
significantly decreases as light travels through the reaction
solution (Beer-Lambert Law); therefore, only the area close to
the UV lamp absorbs enough light and the reaction often takes a
long time. When reaction scales change, poor reproducibility is
often encountered given the fact that photochemical reactions
are strongly dependent on the area of solution exposed to
irradiation. Additionally, due to the fixed reactor volume,
photochemical reactions are often very challenging to scale
up. Continuous flow chemistry has recently emerged as a
promising technology,[7] and demonstrated to be an efficient
tool for circumventing some of the limitations of traditional
batch photochemistry.[8] Larger scales can be achieved by
allowing more material to flow for longer periods of time (scale
out). The thin channel within the photochemical reactor allows
maximal light transmission and thus significantly increases
reactivity. In addition, since the product is continuously
removed from irradiation, over reaction and/or detrimental
side-reactions can be minimized.
quartz jacketed immersion well with tap water running through
to prevent overheating. Customized coils of quartz tubing (1 mm
i.d., 1.84 mL total volume) were placed around the immersion
well ,2 cm from the surface of the lamp (Fig. 2a). The quartz
tubing was extended with perfluoroalkoxy tubing, with the entry
connected to a peristaltic pump, and the exit connected to a
20 psi back pressure regulator and then a collection vial. The
apparatus described above was placed in a Pyrex cylinder
through which water was circulated with the aid of a water
pump immersed in a temperature controlled bath. The photo-
reactor (quartz tubing loops) was submerged in the water
flowing through the cylinder (Fig. 2b), allowing the reaction
temperature to be controlled from 0 to 508C by the bath.
9-Methylcarbazole was originally used as a photosensitizer
for the PET deoxygenation reaction.[6] 3,6-Dimethyl-9-
ethylcarbazole (2a) was later discovered as a more robust
photosensitizer which could be used in a catalytic amount.[5c,d]
With our flow system, we found that 20 mol-% photosensitizer
carbazole 2a catalyzed the PET deoxygenation reaction of
i
m-CF3-benzoate 1a in PrOH/H2O (9 : 1) to deliver protected
thymidine 3a in41 % yieldinonly10minat308C. Analuminium-
coated cylinder (mirror diameter¼ 11 cm, Fig. 2c) was employed
to increase the light intensity by using the reflection of UV
light,[10] and enabled an increase of the yield to 66 %. At this
stage, several new carbazoles were prepared and examined as
photosensitizers (Table 1). 3,6-Dimethoxy-9-ethylcarbazole
(2c) proved to be the best, affording 3a in 73 % yield (Table 1,
entry 4). This is likely attributed to the fact that the more
electron-rich substituents on 3- and 6- positions of the carbazole
could better stabilize the proposed radical cation interme-
diate.[11] Unfortunately, more electron-rich carbazoles 2d and
2e bearing the amino substituents decomposed when subjected
to UV light (Table 1, entries 5 and 6). When the reaction
temperature was raised to 458C, only 10 mol-% carbazole 2c
was needed to provide 3a in 84 % yield (Table 1, entry 7). The
additive Mg(ClO4)2 used in previous methods[5,6] was not
necessary in our system. Indeed, our unique photochemical
set-up substantially reduced the reaction time from 2 h in batch
to 10 min in flow. More significantly, performing the reaction in
the continuous flow fashion suppressed over deoxygenation,
We have recently developed a unique photochemical flow
reactor featuring quartz tubing, an aluminium mirror, and
temperature control, and used this set-up for the efficient
synthesis of 20-deoxy and 20,30-dideoxy-nucleosides in continu-
ous flow in high yields with good reproducibility.[9] In this
account, we disclose more details of our development and the
application of our flow photochemical set-up for the reaction
mechanism study as well as the multi-step synthesis of biologi-
cally interesting targets.
We used a 450 W medium pressure Hg lamp with a Pyrex
sleeve (280 nm cutoff) that was positioned in the centre of a

Continuous Flow Photochemistry
159
Reactor cabinet
H2O Out
H2O In
20
psi
Peristaltic
pump
Med-pressure Hg lamp
inlet
outlet
(a) Photoreactor (quartz tubing
coils) around the UV lamp
(b) Photoreactor in the
cylinder to hold water
for temperature control
(c) Photoreactor in
the cylinder coated
with aluminium
Fig. 2. Photochemical flow reactor featuring quartz tubing and an aluminium mirror.
Table 1. Screening of the photosensitizers
O
O
R
6
3 R
Me
Me
NH
hν
30ЊC
NH
N
BzO
BzO
N
O
O
N
Et
O
O
20 PSI
2a, R ϭ Me
Quartz tubing
photoreactor
(1.84 mL)
3Ј
OBz
2Ј
2b, R ϭ tBu
2c, R ϭ OMe
2d, R ϭ NMe2
2e, R ϭ piperidyl
OBz
1a
O
CF3
3a
tr ϭ 10 min
O
iPrOH/H2O (0.01 M)
EntryA
Photosensitizer
Yield [%]B
1
2a
2a
2b
2c
2d
2e
2c
41
66
49
73
0D
0D
84
2C
3C
4C
5C
6C
7C,E
AAll reactions were carried out at 308C using 20 mol-% photosensitizers unless otherwise noted.
BIsolated yield.
CAluminium mirror was used.
DCarbazole decomposed.
EReaction was carried out at 458C using 10 mol-% photosensitizer.

160
B. Shen and T. F. Jamison
Table 2. Screening of the solvents
O
N
O
Me
Me
NH
hν
45ЊC
NH
OMe
MeO
BzO
BzO
O
N
O
O
O
20 PSI
N
Quartz tubing
photoreactor
(1.84 mL)
Et
2c
OBz
O
OBz
3a
10 mol-%
CF3
1a
Solvent (0.01 M)
O
tr ϭ 10 min
Entry
Solvent
Yield [%]A
1
2
3
4
5
6
MeOH/H2O (9 : 1)
EtOH/H2O (9 : 1)
iPrOH/H2O (9 : 1)
iPrOH
18
63
84
76
CH2(OMe)2
,5
,5
CH(OMe)3
AIsolated yields.
BzO
hν
45ЊC
Base
MeO
OMe
BzO
O
Base
O
20 PSI
N
OBz
O
2Ј
Quartz tubing
photoreactor
(1.84 mL)
Et
CF3
OBz
2c
1
O
10 mol-%
iPrOH/H2O (0.01 M)
3
tr ϭ x min
O
O
N
O
N
Me
Et
NH
NH
NH
BzO
BzO
BzO
N
O
O
O
O
O
O
3a
3b
3c
OBz 10 min, 84 %
OBz 10 min, 80 %
OBz 10 min, 85 %
NH2
N
O
N
N
NHAc
NH
N
N
N
BzO
BzO
O
N
O
3e
3d
OBz 7 min, 75 %
OBz 9 min, 82 %
O
H
N
N
N
OMe
BzO
O
N
BzO
BzO
N
N
O
O
O
O
3f
3g
3h
OBz
7 min, 80 %
OBz 7 min, 85 %
OBz 5 min, 61 %
Scheme 2. Synthesis of 2’-deoxynucleosides in flow.
namely, the 20,30-dideoxy derivative was limited to only 2 %,
while it has been reported as 16 % in batch.[5c]
solvent also provided the desired product, although in a slightly
lower yield. We envisioned that CH2(OMe)2 and CH(OMe)3 are
better hydrogen radical donors as they would form more stable
radicals after hydrogen atom abstraction. However, they only
delivered a trace amount of the deoxygenation product, suggest-
ing that a protic solvent is essential for the reaction to proceed
(vide infra for mechanistic discussion).
i
A mixture of PrOH and H2O (9 : 1) has been used as the
solvent in Rizzo’s studies. Not only as a solvent component,
iPrOH was also proposed to be a hydrogen radical donor for the
deoxygenation reaction. We also evaluated other solvent sys-
tems (Table 2). Not surprisingly, MeOH/H2O and EtOH/H2O
generated lower yields (Table 2, entries 1–2), as they are weaker
hydrogen radical donors. Isopropanol solely (without water) as a
We investigated the scope of the deoxygenation reaction by
surveying a collection of ribonucleosides (Scheme 2). Taking

Continuous Flow Photochemistry
161
ArCO2
hν
45°C
Base
MeO
OMe
O
ArCO2
Base
4
O
N
20 PSI
ArCO2
Ar ϭ m-CF3C6H4
iPrOH/H2O (0.01 M)
O2CAr
Quartz tubing
photoreactor
(1.84 mL)
Et
2c
3Ј
2Ј
5
20 mol-%
tr ϭ 20 min
O
O
NH2
O
N
Me
NH
N
N
N
N
NH
N
NH
ArCO2
ArCO2
ArCO2
ArCO2
N
O
N
O
N
O
O
O
O
5a
5b
5c
5d
73 %
75 %
78 %
75 %
0.003 M, tr ϭ 15 min
Scheme 3. Synthesis of 2’,3’-dideoxynucleosides in flow.
10 eq
aq. NaOH
(2 M)
BzO
hν
45°C
Base
O
HO
50°C
Base
O
10 mol-%
20 PSI
O
20 PSI
OBz O2CAr
2c
Quartz
tubing
photoreactor
PFA
tubing
reactor
1
OH
6
Ar ϭ m-CF3Ph
iPrOH/H2O (0.01 M)
H
N
Me
NH
O
HO
HO
N
N
O
O
O
6a
6g
OH
OH
10 min ϩ 10 min
7 min ϩ 8 min
(81 %)
(85 %)
6 eq
aq. NaOH
(0.18 M)
ArCO2
hν
45°C
Base
O
30°C
HO
Base
O
20 PSI
20 PSI
20 mol-%
ArCO2 O2CAr
Quartz
tubing
photoreactor
PFA
4
2c
tubing
7
Ar ϭ m-CF3Ph
reactor
iPrOH/H2O (0.01 M)
tr ϭ 20 min
tr ϭ 8 min
NH2
O
N
N
N
N
NH
HO
HO
N
N
N
O
O
Didanosine
7c
76 %
7d
73 %
Scheme 4. One-flow two-step synthesis of deoxynucleosides.
advantage of the short reaction time under flow conditions, we
were able to rapidly optimize the residence time for each
substrate by changing flow rates to maximize yields.
Besides 1a, benzoyl-protected uridine (1c), adenosine (1d),
and N7-guanosine (1e) all generated the corresponding
20-deoxynucleosides (3c–3e) in high yields in no more than
10 min residence time.[12] Non-natural nucleosides containing
the ethyluracil (1b), triazole (1f), imidazolone (1g), and
pyridinone (1h) moieties were readily prepared by glycosylation
reaction of the protected ribose with the corresponding
nitrogenous bases, and they were also successfully deoxygenat-
ed with high efficiency. Over 80 % yields were obtained in most
cases, and the dideoxygenation by-products were often barely
detectable. The relatively low yield obtained in the case of 3h
was due to partial decomposition, which was minimized by
reducing the residence time to 5 min. Notably, compound 3b is
the precursor to the antiviral drug edoxudine, and compound 3c
is the precursor to the antiviral drug idoxuridine. Reactions in
flow were found to be highly reproducible regardless of the scale
in all cases.

162
B. Shen and T. F. Jamison
Me
BzO
O
ϩ
N
H
tBu
ϪOTf
OBz
tBu
1
OBz O2CAr
Ar ϭ m-CF3Ph
150ЊC
5
5 mol-%
CH3CN (0.4 M)
100 PSI
10 eq
aq. NaOH
(2 M)
120 μL PFA
O
OTMS
tubing reactor
R
8a, R ϭ Me
8b, R ϭ Et
CH3CN (0.44 M)
hν
R
NH
tr ϭ 30 min
45Њ
C
50ЊC
HO
N
O
OTMS
N
O
20 PSI
20 PSI
Quartz
tubing
photoreactor
PFA
tubing
reactor
OH
MeO
OMe
Thymidine 6a, R ϭ Me (72 %)
Edoxudine 6b, R ϭ Et (66 %)
tr ϭ 10 min
tr ϭ 10 min
N
Et
2c
iPrOH/H2O (1.5 mM)
Scheme 5. Three-step-in-one-flow synthesis of 2’-deoxynucleosides.
O
N
O
Me
Me
hν
45°C
NH
NH
BzO
BzO
O
N
O
20 mol-%
photosensitizer
O
O
20 PSI
2c
Quartz tubing
photoreactor
(1.84 mL)
Trans
OBz
OBz
D
O
9
CF3
iPrOD (d-8) (0.01 M)
1a
(84 %)
~5:1 dr
O
tr ϭ 25 min
No Deuterium incorporation when (CH3)2CHOD was used
Scheme 6. Synthesis of a deuterium-labelled 2’-deoxynucleoside.
is of particular interest, as it is the precursor to the anti-HIV
drug didanosine.
O
RO
Ar
Multi-step synthesis in flow has emerged as a very effective
strategy that saves cost and labour by circumventing the need for
purifying and isolating intermediate products.[13] However, the
development of multistep continuous-flow syntheses remains
challenging, as flow-rate synergy, solvent compatibility, and the
effect of by-products and impurities must be considered and
optimized in downstream reactions. We have demonstrated that
an aqueous solution of NaOH could be introduced via a T-mixer
to the exiting stream from the PET deoxygenation reaction, and
the deprotection occurred in 8–10 min. The photosensitizer
and the acid by-product from the first step did not affect the
second step. Both fully unprotected 20-deoxynucleosides and
20,30-dideoxynucleosides could be prepared using the two-step-
in-one-flow protocol in a very short time and high yields,
including the anti-HIV drug didanosine (7d) (Scheme 4).
We have recently developed a novel Brønsted acid-catalyzed
glycosylation reaction for the synthesis of ribonucleosides.[14]
This method precludes the use of a stoichiometric amount or
an excess of Lewis acids (most commonly SnCl4), and has
demonstrated to be a greener and more efficient process. Using
this method, we prepared compounds 1a and 1b and directly
used them for PET deoxygenation without purification in one
flow (Scheme 5). The use of CH3CN as the solvent in the
glycosylation step retarded the deoxygenation, presumably
due to its absorption of UV light. Therefore, more photosen-
sitizer (15 mol-%) was needed to maintain the reactivity.
The deoxygenation reaction was immediately followed by the
1
D ϭ photosensitizer 2
1
∗
D
OϪ
•
hν
Dϩ•
RO
Ar
10
11
Hϩ
D
O
Ϫ
Hϩ
OH
Me
Me
OH
•
OH
R
•
O
Ar
Me
Me
Me
Me
H
RH
3
R •
ArCO2H
Scheme 7. Proposed reaction mechanism.
We also examined the double deoxygenation reaction of
triesters 4, prepared directly from the corresponding nucleo-
sides. Differentiation of the 20- and 30-positions is unnecessary
in these cases. By increasing the catalyst (2c) loading to
20 mol-% and extending the residence time to 20 min, the
deoxygenation reaction afforded 20,30-dideoxynucleosides
5a–d selectively in high yields (Scheme 3). No 50-deoxy
derivative was observed in any case examined. Compound 5d

Continuous Flow Photochemistry
163
deprotection step. Thus, the three-step-in-one-flow protocol
(glycosylation-deoxygenation-deprotection)
team for stimulating discussions. Additional thanks to Edward Mitchell
(James Glass, Inc.) for fabricating the quartz tubing coils.
successfully
afforded thymidine (6a) and the anti-HIV drug edoxudine (6b)
in 72 % and 66 % yield, respectively. With the total residence
time less than 1 h, this telescoped procedure has demonstrated a
more efficient process for the synthesis of 20-deoxynucleosides.
Deuterium-labelled deoxynucleosides are useful for the
investigation of interactions of a sugar moiety in DNA with a
protein or a drug by NMR spectroscopy.[15] When we used [d8]
isopropanol as the solvent, 20-deoxy-[20-D]ribonucleoside 9 was
isolated in a good yield with ,5 : 1 dr at C-20, favouring the
C10-C20 trans diastereomer (Scheme 6). Similar substrate-
controlled diastereoselectivity has been observed in radical
deoxygenation[3b,16] or dehalogenation[17] using Bu3SnD; the
method described herein eschews this toxic and expensive
reagent. Deuterium atom transfer was substantially slower than
hydrogen atom transfer. The reaction in [d8]isopropanol
required the use of 20 mol-% carbazole 2a and 25 min to achieve
complete conversion (cf. 10 mol-% catalyst and 10 min in
iPrOH). Our flow photochemical set-up not only facilitates the
straightforward synthesis of deuterated deoxynucleoside 9, but
also provides a convenient means to investigate the mechanism
of the deoxygenation reaction using only a small amount of
the substrate and solvent. When (CH3)2CHOD was used as
the solvent, no deuterium incorporation was identified in the
product, and no kinetic isotope effect was observed, clearly
indicating that either a CH3 or CH group (likely the latter) of
iPrOH is the source of the hydrogen atom transferred to the
product.
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The PET deoxygenation mechanism has been discussed in
earlier reports (Scheme 7).[5c,6] Our studies provided further
understanding of the reaction mechanism in that: (1) a more
electron-rich carbazole photosensitizer facilitates the reaction as
it can better stabilize radical cation intermediate 10; (2) a protic
solvent is essential, as radical anion intermediate 11 needs to be
protonated to eliminate a carboxylic acid rather than a carbox-
ylate; and (3) the methine CH is most likely the source of
hydrogen that results in the deoxygenated product.
(c) D. R. Prudhomme, Z. W. Wang, C. J. Rizzo, J. Org. Chem. 1997,
62, 8257. doi:10.1021/JO971332Y
(d) Z. W. Wang, D. R. Prudhomme, J. R. Buck, M. Park, C. J. Rizzo,
J. Org. Chem. 2000, 65, 5969. doi:10.1021/JO0003652
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In conclusion, we have developed a unique flow photochem-
ical reactor featuring quartz tubing, an aluminium mirror, and
temperature control. With this setup, PET deoxygenation
reactions in flow afforded protected deoxynucleosides in high
yields and selectivity, in a short residence time. The new
electron-rich carbazole 2c further improves reactivity. Both
natural and non-natural deoxynucleosides were prepared with
high efficiency and reproducibility. The continuous multi-step,
one-flow sequence produced unprotected 20-deoxy and 20,30-
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provided further understanding of the reaction mechanism. We
believe that this contribution not only improves the synthesis of
deoxynucleosides, but will also incite further interest and
development of other photochemical transformations in flow.
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