Synthesis of 6-formyluridine 5′-monophosphate: 6-Formyl-UMP

Article abstract of DOI:10.1081/NCN-100002478

A synthesis of 6-formyluridine 5′-monophosphate (6-formylUMP) in 6 steps starting from uridine is described. This approach should be applicable to the preparation of other O5′-phosphorylated 6-formylUrds such as 6-formylUDP and 6-formylUTP.

Full text of DOI:10.1081/NCN-100002478

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SYNTHESIS OF 6-FORMYLURIDINE 5′-
MONOPHOSPHATE: 6-FORMYL-UMP
Michael P. Groziak a
a Pharmaceutical Discovery Division , SRI International , Menlo Park, California,
94025-3493, U.S.A.
Published online: 07 Feb 2007.
To cite this article: Michael P. Groziak (2001) SYNTHESIS OF 6-FORMYLURIDINE 5′-MONOPHOSPHATE: 6-FORMYL-UMP,
Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1003-1006, DOI: 10.1081/NCN-100002478
To link to this article: http://dx.doi.org/10.1081/NCN-100002478
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1003–1006 (2001)
SYNTHESIS OF 6-FORMYLURIDINE
5ꢀ-MONOPHOSPHATE: 6-FORMYL-UMP
Michael P. Groziak
Pharmaceutical Discovery Division, SRI International,
Menlo Park, California 94025-3493
ABSTRACT
A synthesis of 6-formyluridine 5ꢀ-monophosphate (6-formylUMP) in 6 steps
starting from uridine is described. This approach should be applicable to the
preparation of other O5ꢀ-phosphorylated 6-formylUrds such as 6-formylUDP
and 6-formylUTP.
Previous investigations in my laboratory have demonstrated that the nucle-
osides 6-formyluridine (6-formylUrd), 6-formyl-2-deoxyuridine, and 6-formyl-1-
(β-D-arabinofuranosyl)uracil all possess the unusual carbohydrate-like property of
existing to some degree in transglycosidic cyclic hemiacetal form, even in aqueous
solution (1–6). This is a consequence of both the proximity of the formyl group
to certain carbohydrate hydroxyl groups and to the strong electron-withdrawing
force that the 1-alkyluracil-6-yl moiety exerts on the carboxaldehyde functionality.
For example, 6-formylUrd exists in water as a 2:1 mixture of the aldehyde hydrate
and the (7R)-O5ꢀ,7-intramolecular cyclic hemiacetal. In Me2SO, it exists as a 1:10
mixture of the aldehyde and the same hemiacetal diastereomer. Finally, it exists
as a 1:1 mixture of diastereomeric ethyl hemiacetals in EtOH, but 6-formylUrd
crystallizes out of this solvent exclusively as the (7R)-O5ꢀ,7-cyclic hemiacetal.
The task of preparing a 5ꢀ-nucleotide derivative of 6-formylUrd such as
6-formylUMP presents a unique obstacle to overcome: Any attempt to directly
O5ꢀ-phosphorylate an O5ꢀ-unprotected version of 6-formylUrd would surely fail
because of the overwhelming predominance of the transglycosidic hemiacetal form
that exists in anhydrous aprotic solvents. Thus, a less straightforward route—one
involving a masked aldehyde—is required for accessing 6-formylUMP or indeed
1003
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
1004
GROZIAK
O
H
N
O
HO
N H
O
O
- EtOH
+ EtOH
O
N
HO
N
O
O
OEt
HO
OH
99+% in EtOH
HO
HO
OH
100% in the solid state
any other O5ꢀ-phosphosphoryl derivatives that might be desired for investigations
with nucleotide-utilizing enzymes.
RESULTS AND DISCUSSION
A 6-formylUrd derivative in which the 2ꢀ-OH, 3ꢀ-OH, and 6-CHO groups are
all protected with acid-labile protecting groups might well be very useful in an effi-
cient and successful synthetic approach to 6-formylUMP. Using such a derivative,
a direct phosphorylation with, for instance, POCl3 would be assuredly regiospecific
for the 5ꢀ-OH group. Furthermore, the phosphorylation could be followed directly
by an in situ removal of all of the protecting groups in the last step of the synthesis,
taking advantage of the HCl that would be generated during an aqueous workup
procedure.
With these points in mind, an efficient 6-step synthesis of 6-formylUMP start-
ing from uridine was developed (Scheme 1). For its greater ease of removal com-
pared to that of an isopropylidene group, one of Reese’s 2ꢀ,3ꢀ-O-alkoxymethylidene
groups (7) was employed for the simultaneous protection of the 2ꢀ- and 3ꢀ-OH
groups in uridine. Its 5ꢀ-OH group was then protected with a TBDMS group,
giving nucleoside 1. A Miyasaka dianion (a uridine-3,6-diyldilithium species)

ORDER
REPRINTS
6-FORMYLURIDINE 5ꢀ-MONOPHOSPHATE
1005
H
N
O
H
O
O
N
N
O
O
(MeO)3CH TBDMS-Cl
1. 2.5 LDA
HO
N
TBDMSO
O
O
imidazole
(85-90%)
cat. pTsOH
2. HCO2Me
(95-97%)
HO
OH
O
1
OMe
O
H
O
H
N
N
O
O
(PhNHCH2)2
O
TBAF
THF
TBDMSO
N
TBDMSO
N
Ph
O
toluene
CHO
N
∆
N
Ph
O
(61-75%)
(96% based on
unrecovered S.M.)
O
O
O
(27%)
2
3
OMe
OMe
H
O
H O
N
N
N
1. POCl3,
PO(OEt)3
O
O
O
HO
N
H2O3PO
Ph
O
2. H2O
CHO
N
(in situ
deprotection)
3. NH4OH
N
Ph
O
HO
OH
5
O
4
(ammonium salt form)
OMe
(75%)
Scheme 1.
(8) was then generated from 1, and this was quenched with HCO2Me to give
the carbohydrate-protected 6-formylUrd 2 in an excellent yield. In our earliest
work with the 6-formylUrds, we found that their formyl group would undergo
acetalation only under forcing conditions, (1) and so for the present synthesis
of 6-formylUMP it instead was masked as a 1,3-diphenylimidazolidin-2-yl (DPI)
moiety as was found advantageous in our most recently completed investigation
(6).
This conversion of the 6-formyl group of 2 to the DPI one of 3 was the only
problematic step encountered. It was conducted without the aid of an acid catalyst
to avoid labilizing the acid-sensitive methoxymethylidene group. Perhaps due to a
steric hindrance provided by the carbohydrate fragment or a competing intramolec-
ular 5ꢀ-O-desilylation via silyl transfer to the hemiaminal intermediate, this conver-
sion (not optimized) proceeded in only a 27% yield. The 5ꢀ-O-TBDMS group in
3 was removed by exposure to TBAF, and the subsequent O5ꢀ-phosphorylation of
4 with POCl3 proceeded smoothly, as did the anticipated in situ removal of all the
protecting groups effected simply by the introduction of water after the phosphory-
lation was complete. The aqueous solution of 6-formylUMP (5) that this procedure
generated was promptly treated with NH4OH to convert 5 to its ammonium salt

ORDER
REPRINTS
1006
GROZIAK
form. Extraction with Et2O to remove the (PhNHCH2)2 and excess PO(OEt)3 was
followed by lyophilization, giving the target 6-formylUMP 5 as an anhydrous pow-
der ready for desalting (9).
CONCLUSIONS
With a careful consideration for the unusual carbohydrate-like properties of
6-formylUrd, a general route to its O5ꢀ-phosphorylated derivatives like 6-formyl-
UMP has now been developed. It should prove to be useful for the preparation
of 6-formylUDP, 6-formylUTP, and other similar 5ꢀ-phosphorylated 6-formylUrd
derivatives.
ACKNOWLEDGMENTS
Some of the intermediates were generated in connection with a separate in-
vestigation funded by a Shannon Award from NIH/NIGMS (grant GM56878).
REFERENCES
1. Groziak, M. P.; Koohang, A. J. Org. Chem. 1992, 57, 940–944.
2. Groziak, M. P.; Koohang, A.; Stevens, W. C.; Robinson, P. D. J. Org. Chem. 1993, 58,
4054–4060.
3. Groziak, M. P.; Lin, R.; Robinson, P. D. Acta Crystallogr. 1995, C51, 1204–1207.
4. Groziak, M. P.; Lin, R.; Stevens, W. C.; Wotring, L. L.; Townsend, L. B.; Balzarini, J.;
Witvrouw, M.; De Clercq, E. Nucleosides Nucleotides 1996, 15, 1041–1057.
5. Groziak, M. P.; Lin, R. ARKIVOC 2000, 1(1), 33–45.
6. Groziak, M. P.; Lin, R. Tetrahedron, submitted.
7. Griffin, B. E.; Jarman, M.; Reese, C. B.; Sulton, J. E. Tetrahedron 1967, 23, 2301–2313.
8. Tanaka, H.; Hayakawa, H.; Miyasaka, T. Tetrahedron 1982, 38, 2635–2642.
1
9. Preliminary characterization data obtained on un-desalted 5: H NMR (D2O) δ 6.07
(s, 1, H5), 5.97 (s, 1, CH(OD)2), 5.92 (d, J = 4Hz, 1, H1ꢀ), 4.40 (m, 1, H3ꢀ), 4.01 (m,
1, H4ꢀ), 3.87 (m, 2, 5ꢀ-CH2). 13C NMR (D2O) δ 166 (C4), 156 and 152 (C2/C6), 101
(C5), 92 (C1ꢀ), 86 (CH(OD)2), 82 (C4ꢀ), 72 (C2ꢀ), 69 (C3ꢀ), 64 (C5ꢀ). Low resolution
DCI (direct current ionization) mass spectrum, m/e: 213 (phosphoribosyl-H+H+).

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