The synthesis of possible transition state analogue inhibitors of thymidine phosphorylase

Article abstract of DOI:10.1016/j.tetlet.2014.11.113

The synthetically challenging S_N2 transition state mimic for thymidine phosphorylase, along with its phosphonate analogue, were synthesised via a modified Corey-Link reaction in good overall yields and ensuring the correct stereochemical outcome.

Full text of DOI:10.1016/j.tetlet.2014.11.113

Tetrahedron Letters 56 (2015) 406–409
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis of possible transition state analogue inhibitors
of thymidine phosphorylase
b
c
a
Gary B. Evans a, , Graeme J. Gainsford , Vern L. Schramm , Peter C. Tyler
⇑
a Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand
b Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA
c Callaghan Innovation Ltd, Gracefield Rd., PO Box 31-310, Lower Hutt 5040, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthetically challenging SN2 transition state mimic for thymidine phosphorylase, along with its
phosphonate analogue, were synthesised via a modified Corey–Link reaction in good overall yields and
ensuring the correct stereochemical outcome.
Received 31 August 2014
Revised 17 October 2014
Accepted 25 November 2014
Available online 29 November 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Thymidine phosphorylase
Enzyme
Transition state analogue
Cancer
Corey–Link
Enzymes comprise one of the major categories of drug targets
pursued by the pharmaceutical and biotechnology industries.1 His-
torically, small molecule inhibitors of enzyme function have affor-
ded a significant proportion of FDA approved drugs.2 Enzymes have
been optimised by Nature to make and break covalent chemical
bonds as opposed to ligand binding.1 The methodology used to
design enzyme inhibitors has progressed markedly over the past
quarter of a century and shares many aspects of ligand design in
general.3 These design aspects can include knowledge of the natu-
ral ligand or substrate of the target of interest or of another com-
pound already known to interact with the target of interest,
screening of both random and biased libraries against a target,
fragment-based screening (which can involve a variety of physical
methods of analysis but mostly centre around X-ray crystallogra-
phy and NMR).3a
As an alternative to these ground state methods of inhibitor
design, transition state affinity4 of enzymes and the design of tran-
sition state analogs should be considered as the preeminent
method by which to afford both potent and selective inhibitors
of enzymes.1,3a,5 Pauling first posited that enzymes had evolved
or were designed to recognise the activated state of reactants. This
premise was restated by Leinhard5b and Wolfenden4 that the tran-
sition state binds more tightly than the substrate(s) and so
accounts for catalysis. Schramm6 has developed methods that
can ‘‘image’’ the activated state of reactants or the transition state,
on-enzyme, and we can then develop a blueprint for the design of
selective tight binding inhibitors. Some of these inhibitor designs
have been realised over the past two decades7 and have been
shown to possess the advantages of covalently bound inhibitors
without the off-site activity that sometimes impacts on the utility
of this class of enzyme inhibitor.8
Thymidine phosphorylase (TP) is an enzyme that catalyses the
reversible phosphorolysis of thymidine into thymine and 20-
deoxy-D-ribose 1-phosphate. TP is an enzyme important in the sal-
vage of pyrimidine nucleosides, and to promote angiogenesis.9
Improved vasculature is necessary for the growth of solid tumours
and the expression of this enzyme in many solid tumours corre-
lates with the aggressiveness and invasiveness of the cancer.9c,f,10
TP inhibitors affect the production of 20-deoxy-
D-ribose, and in
turn suppress tumour growth. Consequently, inhibitors of TP are
expected to be useful as anti-cancer compounds.11
Schramm’s initial design blueprint for a transition state ana-
logue inhibitor of human TP, was derived using an enzyme con-
struct with purification tags, and suggested an SN2-like transition
state, with a bond order of 0.5 to the leaving group and 0.33 to
the attacking oxygen nucleophile of the phosphate, which was
unprecedented for N-ribosyl transferase. This transition state sup-
ports continuous electron density extending from N1 through C1 to
the phosphate oxygen as expected for an SN2 transition state, that
is, with equal participation of both the incoming phosphate
⇑
Corresponding author. Tel.: +64 4 463 0048; fax: +64 4 931 3055.
E-mail address: gary.evans@vuw.ac.nz (G.B. Evans).
http://dx.doi.org/10.1016/j.tetlet.2014.11.113
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

G. B. Evans et al. / Tetrahedron Letters 56 (2015) 406–409
407
O
N
RO
RO
N3
NH
O
COOMe
O
HO
OR
OR
1
2-
CH2-OPO3
A
B
OH
TARGET 15
Figure 1. Retrosynthetic analysis of the transition state analogue target.
nucleophile and pyrimidine leaving group with little or no charge
at the reaction centre of the ribosyl moiety.12 With this back-
ground, we embarked on the synthesis of analogs geometrically
and electronically similar to the SN2 transition state. The novel
chemistry of their synthesis is described here. They were not sig-
nificant inhibitors of the enzyme, supporting a different transition
state for TP.
characteristics of alkene 1 were the same as those reported in
the literature and it was benzylated to yield compound 2 and then
hydroborated using borane to afford a mixture of alcohols 3 and 4,
which could be separated by chromatography.17 Oxidation of the
alcohol 3 using PDC afforded the key ketone intermediate, com-
pound 5,17 in good overall yield from cyclopentadiene.
Consideration was now given to the stereochemical outcome of
methods appropriate for installing the nitrogen and carbon func-
tionalities C10, where the nitrogen required to construct the thy-
mine moiety is above the ring plane and the carbon, which will
provide the methylene ‘spacer’ between the ring and the phos-
phate moiety, is below. We were influenced by the stereochemical
analysis of Stick and co-workers on a carbohydrate ketone in their
study and the likely outcomes of a Strecker reaction18 versus that
of a modified Corey–Link reaction.19 Corey and Link first described
Subsequent hydrolytic13 and arsenolytic6d transition state anal-
ysis with native human TP, and without the protein-modifying
purification tags, supported a transition state with ribocationic
character with little or no participation of the incoming nucleo-
phile in an ANDN mechanism.
Regardless of these latter results, incorporating both a thymine
or thymine mimic and a phosphate or phosphate mimic at a single
carbon of a cyclopentane ring, with a methylene group between
the phosphate and the ring as a ‘spacer’ provided a real synthetic
challenge (Fig. 1). The resulting compounds proved useful in elim-
inating the earlier SN2 transition state proposal for TP. The present
chemistry provides a useful precedent for the synthesis of similar
compounds for related enzyme chemistry.
the synthesis of a-amino acids via the reaction of a trichlorometh-
ylcarbinol with NaOH and NaN3 in 1992.20 This was followed by a
modification of this procedure by Domínguez et al., exemplified in
a ring system not dissimilar to our own, using DBU and MeOH to
afford the desired a
-azido methyl ester.21 Further literature prece-
Ludek and Meier14 previously described the synthesis of a car-
bocyclic thymidine analogue, and so we investigated ways in
which this procedure could be modified to afford our desired target
compound. The core cyclopentane structure could be realised via
the alkene intermediate 1, which utilised an enantioselective hyd-
roboration of cyclopentadiene first described by Biggadike et al.,15
and inspired by Partridge et al. (Scheme 1).16 The physical
dent21,22 demonstrated the utility of the modified Corey–Link reac-
tion and so we were keen to adopt this approach in the setting
described above. We considered that the addition of a sterically,
and hence, stereochemically demanding trichloromethylcarbanion
would occur predominantly from the least hindered b face of the
cyclopentanone ring and therefore, where the Corey–Link reaction
with azide, base and the intermediate gem-dichlorooxirane
BnO
OH BnO
+
BnO
a, b, c, d
f, c, d
Na
OH
BnO
BnO
RO
sodium cyclopentadienylide
3
77%
g
4
10%
R = H, 45%
1
e
2
R = Bn, 75%
BnO
BnO
CCl3
OH
BnO
OH
h
O
+
CCl3
BnO
BnO
major
BnO
5
82%
minor
6
47%
7
15%
i
BnO
N3
BnO
k
NH2
j
CO2Et
89%
CH2OR
R = H,
BnO
BnO
8
9
100%
10
R = TBDMS,
64%
Scheme 1. Reagents and conditions: (a) BOMCl, THF –60 °C ? ꢀ20 °C; (b) (–)-diisopinan-3-yl borane, THF, ꢀ60 °C ? –20 °C; (c) 3 M NaOH, 0 °C; (d) 30% H2O2, THF, 0 °C ? rt;
(e) BnBr, NaH, DMF, 0 °C ? rt; (f) 9-BBN, THF, 0 °C ? rt; (g) PDC, Ac2O, CH2Cl2, rt; (h) CHCl3, LHMDS, THF, ꢀ78 °C ? rt; (i) NaN3, DBU, EtOH, 50 °C; (j) LAH, THF, 0 °C ? rt; (k)
TBDMSCl, imidazole, DMF, rt.

408
G. B. Evans et al. / Tetrahedron Letters 56 (2015) 406–409
Installation of the thymine moiety was achieved via amine 10,
which was reacted with 3-methoxy-2-methylacryloyl isocyanate23
to afford intermediate compound 11 and then cyclisation and desi-
lylation with HCl proceeded in good yield to afford thymine ana-
logue 12 in excellent yield over the two steps. Debenzylation of
12 gave compound 13 and this compound was put aside to be
assayed against TP as a potential inhibitor. Compound 13 was sub-
sequently investigated as a source of the target phosphate 15.
Treatment of alcohol 13 with dibenzyl diisopropylphosphorami-
dite yielded the tetrabenzyl compound 14 in good yield which,
on hydrogenolysis, afforded the putative transition state analogue
target phosphate 15 (see Scheme 2).24
We also proposed that the phosphonate analogue 21 of phos-
phate 15 would also afford a putative inhibitor of TP. Compound
13 was used as a starting point for its construction. We began by
N-protection of 13 with BOMCl followed by oxidation of the result-
ing alcohol 16 with Dess Martin periodinane to afford aldehyde 17
in good overall yield. The anion of diethyl phosphate was gener-
ated in situ with sodium hydride25 and added to aldehyde 17,
and the intermediate alcohol was converted into the protected
phosphonate 19 using a Barton–McCombie deoxygenation proce-
dure.26 Sequential deprotection of compound 19 using TMSBr
and then BBr3 yielded the required phosphonate 2127 in excellent
overall yield.
Figure 2. XRD of compound 7.
In summary, we have realised for the first time a carbocyclic
proceeds with complete stereochemical inversion,20 our nitrogen,
in the form of an azide, would ultimately be installed on the
desired b face and the carbon functionality on the
thymidine analogue with a pendant
a-carbon at the C1 position
in order to incorporate either a methylene group linked to a phos-
phate or phosphonate group. The design was based on the premise
that the transition state of thymidine phosphorylase had SN2, but
no ribocation character, and the key synthetic steps involved a
modified Corey–Link reaction which ultimately yielded the target
compounds in good overall yields.
a
face of C10.
Initial addition of the trichloromethylcarbanion yielded com-
pounds 6 (47%) and 7 (15%), the X-ray crystal structure of the
minor product 7 (Fig. 2) confirming the stereochemistry of both
isomers. As expected attack of the trichloromethylcarbanion
occurred predominantly from the b face of the cyclopentane ring.
Treatment of 6 with NaN3 and DBU in ethanol afforded the
desired azido ethyl ester 8 in excellent yield. Concomitant reduc-
tion of both the azido and ester moieties of 8 using LAH gave the
amino alcohol 9 and presumably due to the lability of any silylated
amine, treatment of 9 with TBDMSCl, under standard conditions,
yielded only the desired silyl ether 10 in good overall yield.
Acknowledgments
This work was supported by funds from the NIH GM 41916
(VLS) and the New Zealand Foundation for Research, Science, and
Technology.
O
O
N
O
N
MeO
BnO
NH
NH
NH
a
b
d
10
HN
O
RO
c
O
RO
O
CH2OTBDMS
CH2OH
CH2OPO(OR)2
BnO
OR
OR
14
11 85%
12 R = Bn,
79%
86%
R = Bn,79%
R = H,86%
c
13
R = H,
15
e
O
N
O
N
O
N
NH
NBOM
NBOM
j
g
RO
O
BnO
O
BnO
O
R
PO(OH)2
PO(OEt)2
OR
OBn
18 R = OH
R
OBn
20
R = Bn,78%
R = H,90%
16
R = CH OH,
72%
2
k
h,i
f
19
R = H,
21
51% over 2 steps
17
R = CHO,
80%
Scheme 2. Reagents and conditions: (a) MeOCH = C(CH3)CONCO, MeCN, rt; (b) 10% HCl, 1,4-dioxane, reflux; (c) H2 (1 atm), Pd/C, EtOH, rt; (d) dibenzyl diisopropylphosph-
oramidite, tetrazole, CH2Cl2, rt; (e) BOMCl, DBU, DMF, rt; (f) Dess Martin periodinane, CH2Cl2, rt; (g) diethyl phosphate, NaH, THF, 0 °C ? rt; (h) CS2, NaH, MeI, DMF, rt; (i)
nBu3SnH, benzene, reflux; (j) TMSBr, Et3N, CH2Cl2, rt; (k) BBr3, CH2Cl2, Ar, ꢀ78 °C.

G. B. Evans et al. / Tetrahedron Letters 56 (2015) 406–409
409
Shin, Y. K.; Kim, K. Y.; Rha, S. Y.; Noh, S. H.; Chung, H. C.; Jeung, H. C. Pathology
2014, 46, 316.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11.
113.
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2.58 (m, 2H), 2.23 (m, 1H), 2.14 (m, 1H), 1.84 (s, 3H), 1.77 (t, J = 12.1 Hz, 1H);
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(t, J = 11.7 Hz, 1H); 13C NMR (75 MHz, D2O): d 167.3, 152.5, 142.4, 108.9, 72.3,
68.0 (d, JCP = 5.9 Hz), 63.4, 48.6 (d, JCP = 9.4 Hz), 47.8, 39.6, 35.3 (d, JCP = 132 Hz),
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