Continuous flow photocatalysis enhanced using an aluminum mirror: Rapid and selective synthesis of 2′-deoxy and 2′,3′-dideoxynucleosides

Article abstract of DOI:10.1039/c2cc33356b

A unique photochemical flow reactor featuring quartz tubing, an aluminum mirror and temperature control has been developed for the photo-induced electron-transfer deoxygenation reaction to produce 2′-deoxy and 2′,3′-dideoxynucleosides. The continuous flow format significantly increased the efficiency and selectivity of the reaction.

Full text of DOI:10.1039/c2cc33356b

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COMMUNICATION
Continuous flow photocatalysis enhanced using an aluminum mirror:
rapid and selective synthesis of 20-deoxy and 20,30-dideoxynucleosidesw
Bo Shen, Matthew W. Bedore, Adam Sniady and Timothy F. Jamison*
Received 9th May 2012, Accepted 6th June 2012
DOI: 10.1039/c2cc33356b
A unique photochemical flow reactor featuring quartz tubing, an
aluminum mirror and temperature control has been developed for the
photo-induced electron-transfer deoxygenation reaction to produce
20-deoxy and 20,30-dideoxynucleosides. The continuous flow format
Scheme 1 Synthesis of 20-deoxynucleosides via photo-induced
significantly increased the efficiency and selectivity of the reaction.
deoxygenation.
Many deoxynucleosides have potent effects against viruses and
tumors.1 Several have been approved as antiviral and/or
anti-cancer drugs, including zidovudine, stavudine, trifluridine,
idoxuridine, cladribine and didanosine (Fig. 1). Extraction from
natural sources and fermentation processes provide only a limited
number of naturally occurring 20-deoxynucleosides; therefore,
chemical approaches for the general synthesis of deoxynucleosides
are highly desired.2 A common strategy is the direct SN2 reaction
between a 1-chloro-2-deoxyribose derivative and a metalated or
silylated nitrogenous base. Drawbacks of this strategy are the
costs and stereochemical lability of 1-chloro sugars. Furthmore,
the substitution reaction tends to generate a mixture of anomers
that are difficult to separate.2a,3
nitrogenous bases with high diastereoselectivity while favoring the
b-anomer. The 20-m-CF3-benzoate was then selectively removed
(deoxygenated) under photo-induced electron-transfer (PET)
conditions.6 Nevertheless, the synthesis of 20-deoxynucleosides
required relatively long irradiation time (1.5–2.0 h), and
over-deoxygenation (30-position) was often observed, leading to
diminished yields of the desired 20-deoxynucleosides.5c,d
Photochemical reactions are commonly performed in immer-
sion well reactors with fixed volume; therefore, the reactions are
often troublesome to scale up. Additionally, poor reproduci-
bility is often encountered given the fact that photochemical
efficiency depends directly upon the pathlength of the incident
light (Beer–Lambert Law). Continuous flow synthetic chemistry
has recently emerged as a promising technology,7 and demon-
strated to be an efficient tool for circumventing many 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 photo-
chemical 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.
Herein, we report the efficient photochemical synthesis of two
important classes of deoxynucleosides in continuous flow. We also
introduce a novel photochemical reactor design in which an
aluminum mirror enhances the reactivity and efficiency by reflection
of UV light. Other features of this method include high selectivity,
high chemical yield, and short reaction (residence) times (r10 min
for 20-deoxynucleosides; r20 min for 20,30-dideoxynucleosides).
Rizzo and co-workers reported the synthesis of 20-deoxy-
nucleosides involving Lewis acid mediated Vorbruggen glyco-
¨
sylation4 followed by selective C20-deoxygenation (Scheme 1).5
The C20-hydroxyl group was derivatized as m-CF3-benzoate
For our studies we used a 450 W medium pressure Hg lamp
with a Pyrex sleeve (280 nm cutoff) that was positioned in the
center of a 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 approximately 2 cm from the surface
of the lamp (Fig. 2a). The quartz tubing was extended with PFA
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
photoreactor (quartz tubing loops) was submerged in the water
flowing through the cylinder (Fig. 2b), allowing the reaction
temperature to be controlled from 0 to 50 1C by the bath.
which served as the directing group for Vorbruggen glycosylation,
¨
allowing the installation of both natural and non-natural
Fig. 1 Selected deoxynucleoside drugs.
Department of Chemistry, Massachusetts Institute of Technology,
77 Massachusetts Ave., Cambridge, MA 02139, USA.
E-mail: tfj@mit.edu; Fax: (+)1 617-324-0253
w Electronic supplementary information (ESI) available: Experimental
details and copies of NMR spectra. See DOI: 10.1039/c2cc33356b
c
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substituents decomposed when subjected to UV light (Table 1,
entries 5 & 6). When the reaction temperature was raised to
45 1C, only 10 mol% carbazole 2c was needed to provide 3a in
84% yield (Table 1, entry 7). The additive Mg(ClO4)2 used in
other reports5,6 was not necessary in our system.
The use of 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 reaction, namely, the 20,30-dideoxy
derivative was limited to only 2%, while it has been reported
as 16% in batch.5c
We investigated the scope of the deoxygenation reaction by
surveying a collection of ribonucleosides (Scheme 2). Taking
the advantage of the short reaction time under the flow condi-
tions, we were able to rapidly optimize the residence time for
each substrate by changing flow rates to maximize yields.
Benzoyl-protected uridine (1b), adenosine (1c), N7-guanosine
(1d) all generated the corresponding 20-deoxynucleosides (3b–3d)
in high yields in no more than 10 min.11 Notably, compound 3b is
the precursor to the antiviral drug idoxuridine. Non-natural
nucleosides containing the triazole (1e), imidazolone (1f) and
pyridinone (1g) moieties were readily prepared by glycosylation
reaction of the protected ribose with corresponding nitrogenous
bases, and they were also successfully deoxygenated with high
efficiency. Over 80% yields were obtained in most cases, and the
dideoxygenation products were barely detectable. The relatively
low yield in the case of 3g was due to partial decomposition,
which was limited to the minimal extent by reducing the residence
time to 5 min. Reactions in flow were found to be highly
reproducible regardless of the scale in all cases.
Fig. 2 Photochemical flow reactor featuring quartz tubing and an
aluminum mirror.
Using our flow system, we found that 20 mol% photosensi-
tizer carbazole 2a9 catalyzed the PET deoxygenation reaction
of m-CF3-benzoate 1a to deliver protected thymidine 3a in
41% yield in only 10 min at 30 1C. We hypothesized that a
UV-reflecting mirror would increase the effective light intensity
and thus enhance the efficiency and throughput of photochemical
reactions in flow. Therefore, the cylinder was coated with aluminum
(mirror diameter = 11 cm, Fig. 2c), which is best for UV reflection
(480%). Gratifyingly, this improved set-up increased the yield of
3a to 66% under the aforementioned conditions.
We also examined the double deoxygenation reaction of
triesters 4, prepared directly from the corresponding nucleosides.
That is, 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 is of particular interest, as it is
the precursor to the anti-HIV drug didanosine.
We next investigated the effect of structure of the carbazoles
photosensitizer (Table 1), and 3,6-dimethoxy-9-ethylcarbazole
(2c) proved to be the best, affording 3a in 73% yield (Table 1,
entry 4). This improvement is attributable to the electron-rich
substituents on 3- and 6- positions of the carbazole, which
stabilize the proposed radical cation intermediate better than
the H atoms at the same positions in 2a.10 Unfortunately,
more electron-rich carbazoles 2d and 2e bearing the amino
Deuterium-labeled deoxynucleosides are useful for the
investigation of intermolecular interaction of a sugar moiety
in a DNA complex with a protein or a drug by NMR
Table 1 Screening of the photosensitizersa
i
spectroscopy.12 When we used PrOD (d-8) as the solvent,
Entry
Photosensitizer
Yieldb (%)
1
2a
2a
2b
2c
2d
2e
2c
41
66
49
73
0d
2c
3c
4c
5c
6c
7c,e
0d
84
a
All reactions were carried out at 30 1C using 20 mol% photosensitizers
unless otherwise noted. Isolated yield. Aluminum mirror was used.
b
c
d
e
Carbazole decomposed. Reaction was carrid out at 45 1C using
10 mol% photosensitizer.
Scheme 2 Synthesis of 20-deoxynucleosides in flow.
Chem. Commun., 2012, 48, 7444–7446 7445
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This work was supported by the Novartis-MIT Center for
Continuous Manufacturing. The authors thank the members of
the Novartis team for stimulating discussions and Edward
Mitchell (James Glass, Inc.) for making the quartz tubing coils.
Notes and references
1 (a) E. Ichikawa and K. Kato, Curr. Med. Chem., 2001, 8, 385–423;
(b) Nucleosides and Nucleotides as Antitumor and Antiviral Agents,
ed. C. K. Chu and D. C. Baker, Plenum Press, New York, 1993;
(c) G. J. Peters, Deoxynucleoside Analogs in Cancer Therapy,
Humana Press, Totowa, NJ, 2006; (d) P. Herdwijn, Modified
Nucleosides: in Biochemistry, Biotechnology and Medicine,
Wiley-VCH, Weinheim, 2008; (e) C. Perigaud, G. Gosselin and
J. L. Imbach, Nucleosides Nucleotides, 1992, 11, 903–945.
Scheme 3 Synthesis of 20,30-dideoxynucleosides in flow.
2 (a) H. Vorbruggen and C. Ruh-Pohlenz, Handbook of Nucleoside
&
¨
Synthesis, John Wiley
Sons, Inc., 2001, pp. 51–60;
(b) D. M. Huryn and M. Okabe, Chem. Rev., 1992, 92, 1745–1768.
3 Another method involves the radical deoxygenation reaction of
ribonucleosides when the C20-hydroxyl group is derivatized as a
phenoxythiocarbonyl ester. However, this method is undesirable as
it requires the use of a stoichiometric amount of toxic reagent
nBu3SnH, and is only applicable to naturally-occurring
ribonucleosides.(a) M. J. Robins and J. S. Wilson, J. Am. Chem.
Soc., 1981, 103, 932–933; (b) M. J. Robins, J. S. Wilson and
F. Hansske, J. Am. Chem. Soc., 1983, 105, 4059–4065.
4 (a) U. Niedball and H. Vorbruggen, Angew. Chem., Int. Ed. Engl.,
¨
Chem., Int. Ed. Engl., 1975, 14, 421–422; (c) H. Vorbruggen,
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1970, 9, 461–462; (b) H. Vorbruggen and K. Krolikiewicz, Angew.
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K. Krolikiewicz and B. Bennua, Chem. Ber., 1981, 114, 1234–1255.
5 (a) M. Park and C. J. Rizzo, J. Org. Chem., 1996, 61, 6092–6093;
(b) Z. W. Wang and C. J. Rizzo, Tetrahedron Lett., 1997, 38,
8177–8180; (c) D. R. Prudhomme, Z. W. Wang and C. J. Rizzo,
J. Org. Chem., 1997, 62, 8257–8260; (d) Z. W. Wang,
D. R. Prudhomme, J. R. Buck, M. Park and C. J. Rizzo, J. Org.
Chem., 2000, 65, 5969–5985.
Scheme 4 One-flow two-step synthesis of deoxynucleosides.
20-deoxy-[20-D]ribonucleoside (6) was isolated in 84% yield with
about 5 : 1 dr at C-20, favoring the C10–C20 trans diastereomer.
We then turned our attention to the preparation of unprotected
deoxynucleosides. Multi-step synthesis in flow has emerged as a
very effective strategy that saves cost and labor by circumventing
the need for purifying and isolating intermediate products.13 Thus,
a continuous one-flow, two-step setup was assembled as depicted
in Scheme 4. An aqueous solution of NaOH was introduced via a
T-mixer to the exiting stream from the PET deoxygenation
reaction, and the deprotection occurred in 8–10 min to furnish
the fully unprotected 20-deoxynucleosides. The photosensitizer
and the acid by-product from the first step did not affect the
second step. Thymidine (7a) was produced in high yield in no
more than 20 min in total, as well as the non-natural nucleoside 7f.
In a similar fashion, the two-step sequence also smoothly deliv-
ered 20,30-dideoxynucleosides efficiently, including 20,30-dideoxya-
denosine (8c) and the anti-HIV drug didanosine (8d).
6 I. Saito, H. Ikehira, R. Kasatani, M. Watanabe and T. Matsuura,
J. Am. Chem. Soc., 1986, 108, 3115–3117.
7 For recent general reviews on continuous flow chemistry see:
(a) R. L. Hartman, J. P. McMullen and K. F. Jensen, Angew. Chem.,
Int. Ed., 2011, 50, 7502–7519; (b) R. L. Hartman and K. F. Jensen,
Lab Chip, 2009, 9, 2495–2507; (c) K. Geyer, T. Gustafsson and
P. H. Seeberger, Synlett, 2009, 2382–2391; (d) T. Wirth, Micro-
reactors in organic synthesis and catalysis, Wiley-VCH, Weinheim,
2008; (e) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan
and D. T. McQuade, Chem. Rev., 2007, 107, 2300–2318;
(f) A. Kirschning, W. Solodenko and K. Mennecke, Chem.–Eur. J.,
2006, 12, 5972–5990; (g) K. Jahnisch, V. Hessel, H. Lowe and
M. Baerns, Angew. Chem., Int. Ed., 2004, 43, 406–446.
8 For recent reviews on photochemistry in flow, see: (a) M. Oelgemoller
and O. Shvydkiv, Molecules, 2011, 16, 7522–7550; (b) E. E. Coyle and
M. Oelgemoller, Photochem. Photobiol. Sci., 2008, 7, 1313–1322;
(c) Y. Matsushita, T. Ichimura, N. Ohba, S. Kumada, K. Sakeda,
T. Suzuki, H. Tanibata and T. Murata, Pure Appl. Chem., 2007, 79,
1959–1968; For a seminal publication on photochemistry in flow, see:
B. D. A. Hook, W. Dohle, P. R. Hirst, M. Pickworth, M. B. Berry
and K. I. Booker-Milburn, J. Org. Chem., 2005, 70, 7558–7564.
9 9-Methylcarbazole was commonly used as a photosensitizer for the
PET deoxygenation reaction. 3,6-Dimethyl-9-ethyl-carbazole (2a)
was later developed as a more robust photosensitizer which could
be used in a catalytic amount. See ref. 5c,d. Michler’s ketone was
also tested, but no reaction occurred.
10 J. F. Ambrose, L. L. Carpenter and R. F. Nelson, J. Electrochem.
Soc., 1975, 122, 876–894.
11 Described as capricious by Rizzo (ref. 5d), the cytidine derivative
failed in the deoxygenation reaction, which is consistent with
previous studies by Benner. Z. Huang, K. C. Schneider and
S. A. Benner, J. Org. Chem., 1991, 56, 3869–3882.
12 (a) K. Wuthrich, NMR of Proteins and Nucleic Acids, John Wiley
& Sons, Inc., New York, 1986; (b) C. Kojima, E. Kawashima,
T. Sekine, Y. Ishido, A. Ono, M. Kainosho and Y. Kyogoku,
J. Biomol. NMR, 2001, 19, 19–31.
13 For a review, see: D. Webb and T. F. Jamison, Chem. Sci., 2010, 1,
675–680.
In conclusion, we have developed a unique flow photo-
chemical reactor featuring quartz tubing, an aluminum mirror,
and temperature control. With this setup, PET deoxygenation
reactions were performed for the first time in flow and 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 deoxynucleo-
sides were prepared with high efficiency and reproducibility. The
continuous two-step, one-flow sequence circumvented the need
of purifying and isolating the intermediate product and produced
unprotected 20-deoxy and 20,30-dideoxy ribonucleosides in a
streamlined manner. We believe that this contribution not only
improves the synthesis of deoxynucleosides, but will also incite
further interest and development of other photochemical trans-
formations in flow.
c
7446 Chem. Commun., 2012, 48, 7444–7446
This journal is The Royal Society of Chemistry 2012