A robust synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin

Article abstract of DOI:10.3762/bjoc.12.89

The biosynthetic precursor of redox cofactor F420, 7,8-didemethyl-8-hydroxy-5-deazariboflavin, was prepared in four steps from 6-chlorouracil, 2-chloro-4-hydroxybenzaldehyde and bis-isopropylidene protected D-ribose. The latter aldehyde was transformed to the corresponding protected ribitylamine via the oxime, which was submitted to reduction with LiAlH₄. Key advantage compared to previous syntheses is the utilization of a polyol-protective group which allowed the chromatographic purification of a key-intermediate product providing the target compound with high purity.

Full text of DOI:10.3762/bjoc.12.89

A robust synthesis of 7,8-didemethyl-8-hydroxy-
-deazariboflavin
5
Matthias Bender1, Henrik Mouritsen2,3 and Jens Christoffers*1
Full Research Paper
Open Access
Address:
Institut für Chemie, Universität Oldenburg, Carl von Ossietzky-Str.
–11, D-26129 Oldenburg, Germany, 2Institut für Biologie und
Beilstein J. Org. Chem. 2016, 12, 912–917.
1
doi:10.3762/bjoc.12.89
9
Umweltwissenschaften, Universität Oldenburg, D-26111 Oldenburg,
Germany and 3Centre for Neurosensory Sciences, University of
Oldenburg, D-26111 Oldenburg, Germany
Received: 09 March 2016
Accepted: 28 April 2016
Published: 06 May 2016
Email:
Associate Editor: S. Bräse
Jens Christoffers* - jens.christoffers@uni-oldenburg.de
©
2016 Bender et al; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
carbohydrates; heterocyclic compounds; protective groups; riboflavin
derivatives; ribose derivatives
Abstract
The biosynthetic precursor of redox cofactor F420, 7,8-didemethyl-8-hydroxy-5-deazariboflavin, was prepared in four steps from
6
-chlorouracil, 2-chloro-4-hydroxybenzaldehyde and bis-isopropylidene protected D-ribose. The latter aldehyde was transformed to
the corresponding protected ribitylamine via the oxime, which was submitted to reduction with LiAlH4. Key advantage compared
to previous syntheses is the utilization of a polyol-protective group which allowed the chromatographic purification of a key-inter-
mediate product providing the target compound with high purity.
Introduction
The deazariboflavin cofactor F420 plays an important role in turn [4-7] are very likely to be the primary magnetoreceptor
bacterial methanogenesis [1,2] and was – in contrast to other, molecules which enable migratory birds to perceive the
ubiquitous biological redox coenzymes like NAD+ or FAD – compass direction of the Earth’s magnetic field through a light-
discovered relatively late (in 1972) [3].
dependent, spin-based, radical-pair mechanism in the birds’
eyes [8-11]. A major challenge slowing down progress towards
Its biosynthetic precursor, 7,8-didemethyl-8-hydroxy-5-deaza- understanding the exact magnetoreceptive properties of avian
riboflavin (1, Scheme 1) without a phosphodiester extension is cryptochromes is that, so far, avian cryptochromes have been
called FO and came into our focus of interest because it was for very difficult to express recombinantly with their co-factors
instance suggested to function as an antenna pigment in several (most likely a FAD and a FO (1) or a FAD and a 5,10-
cryptochrome proteins [4]. One or more avian cryptochromes in methenyltetrahydrofolate (MTHF) still attached [4,12,13]).
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Beilstein J. Org. Chem. 2016, 12, 912–917.
Scheme 1: Target structure of this synthetic study and two previous approaches.
Consequently, no crystal structures of a functional avian cryp- they have published very recently a synthesis of compound 1 by
tochrome are known at present. While FAD and MTHF are a modified route [20] and achieve 34% yield over six steps
commercially available, FO (1) is not. However, this com- starting from D-ribose, 3-aminophenol and barbituric acid.
pound is potentially needed in order to reconstitute expressed Nevertheless, we would like to communicate herein our synthe-
apo-cryptochrome proteins to their functional state. Therefore, tic approach to compound FO (1), which finally turned out to
finding an efficient and reliable way to synthesize compound reliably yield the final product with high purity.
FO (1) is important.
Results and Discussion
Up to the year 2015 the preparation of compound FO (1) was Synthesis of aldehyde 9
reported in the literature twice, both utilized commercially We envisioned the reduction of an oxime to be the most conve-
available chlorouracil 3 as C-ring synthon. The first report by nient access to the doubly isopropylidene protected amine 10
Ashton et al. [14,15] used N-(D-ribityl)-3-hydroxyaniline (2) as [21,22]. Therefore, we prepared diisopropylidene ribose 9 ac-
A-ring fragment. The second report by Yoneda et al. [16-18] cording to a literature sequence of dithioacetalization, acetonide
employed 4-benzyloxy-2-chlorobenzaldehyde (4) as building formation and dithioacetal deprotection [23-25]. In particular,
block for the A-ring. Both syntheses suffer from several draw- we have chosen the conversion of D-ribose (6) with n-propyl-
backs; these are the limited stability of intermediate products thiol (Scheme 2), since the product 7 (57%) was crystalline
(
e.g., oxidation of compound 2) and low yields together with [26]. Diacetonide formation (product 8, 75%) proceeded as re-
low chemoselectivities. Major disadvantage in our hands turned ported for the di(ethylthio) congener [24]. Finally, the
out to be actually the high polarity and low solubility of inter- dithioacetyl was cleaved while the isopropylidene moieties
mediate products, which makes purification rather tedious. For were retained, but not with mercury salts, as in original publica-
example, the preparation of amine 5 by reduction of the oxime tions for the preparation of aldehyde 9 [27], but with the use of
and its conversion with chlorouracil 3 turned out to be impos- iodine (95% yield of product 9), as recommended by Ohlsson et
sible when following a literature protocol [19]. We therefore al. [28,29].
decided to develop a robust synthesis of a protected derivative
of amine 5 which could follow standard carbohydrate chem- Heterocyclic synthesis
istry and might then allow purification and characterization of From the aldehyde 9 the corresponding oxime was formed
intermediate products. While we were following the synthetic under buffered conditions [30] and the crude material was
approach by Yoneda et al. with a protected ribose derivative, directly submitted to reduction with LiAlH4 [31] to furnish
Foss and co-workers were obviously facing the same prepara- amine 10 as a practically pure compound (72%) (Scheme 3).
tive problem. To our surprise and delight (that we were not the The conversion of amine 10 with chlorouracil 3 proceeded with
only group struggling with the reports of Ashton and Yoneda), NEt3 as base in EtOH at elevated temperature. Now, the key
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Beilstein J. Org. Chem. 2016, 12, 912–917.
Scheme 2: Preparation of isopropylidene protected ribose 9 along a new, modified route. Reagents and conditions: (a) 2 equiv n-PrSH, conc. HCl/
H2O, 0 °C, 1.5 h; (b) 20 equiv 2,2-dimethoxypropane, 0.1 equiv p-TosOH·H2O, acetone, 2 h, 23 °C; (c) 3 equiv I2, 5.5 equiv NaHCO3, acetone/H2O
(10:1), 20 h, 23 °C.
Scheme 3: Final four steps of the synthesis. Reagents and conditions: (a) 1. 4.5 equiv NH2OH·HCl, 4 equiv NaHCO3, EtOH/H2O (10:1), 23 °C, 16 h;
. 5 equiv LiAlH4, THF, 67 °C, 4 h; (b) 1.2 equiv amine 10, 1.0 equiv chlorouracil 3, 2.0 equiv NEt3, EtOH, sealed reaction tube, 150 °C, 1.5 h (c) TFA/
2
H2O, 23 °C, 4 h; (d) 1 equiv aldehyde 13, 1.2 equiv NEt3, EtOH, 150 °C, 3 h.
advantage of using amine 10 with isopropylidene-protected groups into the ribose side chain, which allowed the chromato-
hydroxy functions came into the game, because product 11 graphic purification of key intermediate product 11. The se-
could be purified by column chromatography. We first investi- quence started with the preparation of literature-known bis-
gated the conversion of this material with aldehyde 13 to isopropylidene protected D-ribose 9, which required a
furnish the isopropylidene-protected annulation product. How- transitional protection of the aldehyde function as dithioacetal.
ever, subsequent deprotection gave compound 1 containing sig- With two deviations from the literature protocols (use of
nificant impurities. If compound 11 is first deprotected (prod- propyl- instead of ethylthiol and dithioacetal deprotection with
uct 12 was obtained in 99% yield without impurities) and then iodine instead of mercury compounds) we have improved the
converted with aldehyde 13, the final target compound 1 could synthesis of aldehyde 9. The latter compound was then trans-
be crystallized from EtOH and washed with EtOH to furnish a formed to the protected ribitylamine 10 via the oxime, which
pure, yellow crystalline material in 36% yield.
was reduced with LiAlH4. Primary amine 10 was then con-
verted with chlorouracil 3, which was actually the key innova-
tion of our new route, because the product 11 could be purified
Conclusion
We report on the new synthetic route to 7,8-didemethyl-8- by column chromatography prior to deprotection to compound
hydroxy-5-deazariboflavin (1), which is the biosynthetic precur- 12. The insufficient purity of compound 12 was the major draw-
sor compound to cofactor F420. In comparison with older back of one of the previously known syntheses. Conversion of
routes to this target compound, the key innovation of our proce- aminouracil 12 to the target compound 1 proceeded straightfor-
dures is the introduction of two isopropylidene protective wardly.
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Beilstein J. Org. Chem. 2016, 12, 912–917.
Experimental
(
500 MHz, CDCl3) δ 1.33 (s, 6H), 1.39 (s, 3H), 1.41 (s, 3H),
1
-Amino-1-deoxy-2,3:4,5-bis-O-(isopropyli-
3
.32–3.36 (m, 1H), 3.53 (dd, J = 13.9 Hz, J = 3.5 Hz, 1H),
3.84–3.91 (m, 1H), 4.02–4.16 (m, 3H), 4.41 (ddd, J = 9.0 Hz, J
Formation of the oxime: A solution of NaHCO3 (1.55 g, = 5.9 Hz, J = 3.6 Hz, 1H), 4.78 (s, 1H) 5.94 (s, 1H), 8.99 (brs,
8.4 mmol) and NH2OH·HCl (1.44 g, 20.7 mmol) in EtOH/ 1H), 10.40 (brs, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ
dene)-D-ribitol (10)
1
H2O (10:1) was stirred for 30 min at ambient temperature. A 25.28 (CH3), 25.30 (CH3), 26.7 (CH3), 27.8 (CH3), 42.2 (CH2),
solution of aldehyde 9 (1.06 g, 4.61 mmol) in EtOH (9 mL) was 69.0 (CH2), 73.0 (CH), 74.0 (CH), 75.0 (CH), 77.9 (CH), 109.5
then added, and the resulting mixture stirred for further 16 h at (C), 111.1 (C), 152.3 (C), 154.9 (C), 165.9 (C) ppm; IR (ATR):
ambient temperature. About half of the solvent was evaporated, 3360 (w), 3138 (w), 2987 (w), 2934 (w), 2881 (w), 1714 (s),
the residue extracted with Et2O (3 × 20 mL) and the combined 1626 (s), 1455 (m), 1381 (m), 1281 (m), 1212 (m), 1155 (m),
organic layers were dried (MgSO4) and evaporated after filtra- 1069 (s), 976 (w), 838 (s), 783 (s), 629 (m) cm−1; HRMS
tion to yield the crude oxime (985 mg, 4.00 mmol, 87%; mix- (ESI+): calcd for C15H23N3NaO6, 364.1479; found, 364.1480
ture of E/Z isomers, ratio ca. 3:1), which was submitted to [M + Na+].
reduction without further purification. HRMS (ESI+): calcd for
1-Deoxy-1-[(2,6-dioxo-1,2,3,6-tetrahydro-4-
C11H19NNaO5 268.1161, found 268.1157 [M + Na]+.
pyrimidinyl)amino]-D-ribitol (12)
Reduction to the amine 10: A solution of the above reported A solution of compound 11 (245 mg, 0.72 mmol) in TFA/H2O
oxime (985 mg, 4.00 mmol) in abs. THF (anhydrous, 20 mL) (2.2 mL, 10:1) was stirred for 4 h at 23 °C. Subsequently, all
was dropwise added to a cooled (ice/water bath) suspension of volatile materials were removed in vacuum, the residue was
LiAlH4 (760 mg, 20.0 mmol) in abs. THF (20 mL). The reac- suspended in Et2O (3 mL) and this suspension heated to reflux
tion mixture was heated for 4 h under reflux, then cooled with for 30 min. After cooling to ambient temperature, the precipi-
an ice/water bath and treated with MgSO4·7 H2O (20 g). The tate was collected on a glass frit, washed with EtOH (1 mL) and
suspension was stirred for 1 h at ambient temperature, then dried under vacuum to give the deprotected ribitol 12 (185 mg,
filtered through a short pad of MgSO4 and the residue washed 0.71 mmol, 99%) as a colorless solid; mp. 183–185 °C. [α]20D =
with MTBE (100 mL). The solvent was removed in vacuum to –16.7 (DMSO, 1 g/L); 1H NMR (500 MHz, DMSO-d6) δ 3.01
give amine 10 (771 mg, 3.33 mmol, 83%) as colorless oil; (ddd, J = 12.5 Hz, J = 8.0 Hz, J = 4.6 Hz, 1H), 3.17 (ddd, J =
[
α]20D = −40 (CH2Cl2, 1 g/L); 1H NMR (500 MHz, CDCl3) δ 12.8 Hz, J = 5.6 Hz, J = 3.2 Hz, 1H), 3.37–3.41 (m, 2H),
.32 (s, 6H), 1.38 (s, 3H), 1.39 (s, 3H), 2.74 (brs, 2H), 2.90 (dd, 3.48–3.51 (m, 1H), 3.57 (dd, J = 11.0 Hz, J = 3.3 Hz, 1H),
J = 13.2 Hz, J = 7.7 Hz, 1H), 3.03 (dd, J = 13.2 Hz, J = 5.4 Hz, 3.70–3.73 (m, 1H), 4.42 (s, 1H), 6.18 (s, 1H), 9.95 (brs, 1H),
H), 3.89 (dd, J = 8.1 Hz, J = 5.1 Hz, 1H), 3.98 (dd, J = 9.1 Hz, 10.15 (brs, 1H) ppm, signals for the four OH protons are not
1
1
J = 5.7 Hz, 1H), 4.03–4.11 (m, 2H), 4.19 (dt, J = 7.6 Hz, J = 5.5 resolved (broad singlet from 4.5–5.0 ppm); 13C{1H} NMR (125
Hz, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ 25.42 MHz, DMSO-d6) δ 43.9 (CH2), 63.2 (CH2), 69.5 (CH), 72.5
(
(
CH3), 25.43 (CH3), 26.7 (CH3), 28.1 (CH3), 41.2 (CH2), 68.0 (CH), 72.8 (CH), 73.0 (CH), 150.8 (C), 154.4 (C), 164.5 (C)
CH2), 73.2 (CH), 78.1 (CH), 79.2 (CH), 108.5 (C), 109.8 (C) ppm; IR (ATR): 3296 (br m), 3144 (m), 3133 (m), 2980 (m),
ppm; IR (ATR): 3385 (w), 2986 (m), 2961 (m), 2935 (m), 2875 2945 (m), 2889 (m), 1732 (m), 1709 (s), 1628 (s), 1603 (s),
(
(
(
w), 1571 (w), 1558 (w), 1481 (w), 1456 (m), 1400 (w), 1246 1556 (m), 1483 (w), 1462 (w), 1345 (w), 1203 (w), 1048 (m),
s), 1213 (s), 1156 (s), 1061 (s), 980 (m), 894 (w), 845 (s), 791 1024 (m), 1000 (m) cm−1. HRMS (ESI+): calcd for
w), 754 (m) cm−1; HRMS (ESI+): calcd for C11H22NO4, C9H16N3O6, 262.1039; found, 262.1040 [M + H+].
2
32.1543; found, 232.1539 [M + H+].
1-Deoxy-1-(8-hydroxy-2,4-dioxo-2,3,4,10-
1-Deoxy-1-[(1,2,3,6-tetrahydro-2,6-dioxo-
tetrahydropyrimido[4,5-b]quinoline-10-yl)-D-
pyrimidin-4 yl)amino]-2,3:4,5-bis-O-(iso-
propylidene)-D-ribitol (11)
ribitol (1)
A mixture of aldehyde 13 (90 mg, 0.57 mmol), aminouracil 12
A mixture of chlorouracil 3 (218 mg, 1.49 mmol), ribitylamine (150 mg, 0.57 mmol), NEt3 (0.10 mL, 0.68 mmol) and EtOH
0 (413 mg, 1.79 mmol), NEt3 (0.41 mL, 2.98 mmol) and EtOH (3 mL) was heated in a closed reaction vial at 150 °C for 3 h.
3 mL) was heated in a closed and sealed reaction vial at 150 °C After cooling to ambient temperature, the yellow precipitate
1
(
for 1.5 h. After cooling to ambient temperature the mixture was was collected by filtration and washed with EtOH (3 mL) to
concentrated in vacuum and the residue purified by column give deazariboflavin 1 (75 mg, 0.21 mmol, 36%) as yellow
chromatography (SiO2, MeOH/CH2Cl2 1:20, Rf 0.06) to give solid, mp 240–250 °C (decomposition). [α]20D = –6.7 (DMSO,
title compound 11 (350 mg, 1.03 mmol, 69%) as a colorless 1 g/L); 1H NMR (500 MHz, CDCl3) δ 3.44–3.66 (m, 4H),
solid; mp. 234–236 °C; [α]20D = –35 (MeOH, 1 g/L); 1H NMR 4.20–4.25 (m, 1H), 4.48 (brs, 1H), 4.64–4.83 (m, 3H),
915

Beilstein J. Org. Chem. 2016, 12, 912–917.
1
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.6 Hz, 1H), 7.39 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.87 (s, 1H),
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The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.12.89
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