Asymmetric synthesis of (S)-(-)-N-acetylcolchinol via Ullmann biaryl coupling

Article abstract of DOI:10.1016/j.tetlet.2007.04.103

A modified Ziegler Ullmann coupling process has been developed as the key step in an effective synthesis of (S)-(-)-N-acetylcolchinol, analogues of which are selective vascular targeting agents with potential importance in cancer chemotherapy. Asymmetric induction is achieved by enamide hydrogenation using FerroTANE catalysts.

Full text of DOI:10.1016/j.tetlet.2007.04.103

Tetrahedron Letters 48 (2007) 4627–4630
Asymmetric synthesis of (S)-(À)-N-acetylcolchinol via Ullmann
biaryl coupling
Simon D. Broady,a Michael D. Golden,a John Leonard,a,* James C. Muira and
Mickael Maudetb
aProcess R&D, AstraZeneca plc, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, UK
bAstraZeneca Pharma, Z.I. Pompelle, BP 1050, 51689 Reims, Cedex 2, France
Received 11 March 2007; revised 5 April 2007; accepted 19 April 2007
Available online 4 May 2007
Abstract—A modified Ziegler Ullmann coupling process has been developed as the key step in an effective synthesis of (S)-(À)-N-
acetylcolchinol, analogues of which are selective vascular targeting agents with potential importance in cancer chemotherapy. Asym-
metric induction is achieved by enamide hydrogenation using FerroTANE catalysts.
Ó 2007 Elsevier Ltd. All rights reserved.
The anti-tumour properties of colchicine 1 have been
known for several decades.1,2 It has also been established
that the biological activity stems from strong tubulin
binding, which leads to selective disruption of tumour
vasculature with consequent tumour necrosis. Colchicine
itself is much too toxic to have any therapeutic value in
this regard, but it has recently been recognised that deriv-
atives of N-acetylcolchinol 2 could be of value in cancer
therapy. A particular compound that has been in clinical
development at AstraZeneca is the phosphate pro-drug
of N-acetylcolchinol, known as ZD6126 33 (Fig. 1).
N-Acetylcolchinol was originally prepared in low yield
as a derivative of colchicine.5 The natural product is ex-
tracted commercially, predominantly for the treatment
of gout, from the lily Gloriosa superba, a native flower
of Northern India. However, reported yields of colchi-
nol derivatives from colchicine are low and the develop-
ment of an effective total synthesis was considered to be
a better option. In this communication we report an effi-
cient total synthesis of N-acetylcolchinol, which utilises
low temperature Ullmann coupling chemistry for the
construction of the core ring system.
OMe
For construction of the colchinol ring system, two strat-
egies were considered as shown in Figure 2. In both
OR
O
OMe
MeO
MeO
MeO
MeO
OH
OR
O
NHAc
NHAc
MeO
OMe
OMe
MeO
MeO
MeO
MeO
Colchicine, 1
R = H, N-Acetylcolchinol, 2
R = P(O)OH2, ZD6126, 3
NHAc
Figure 1.
We have been investigating a number of synthetic
approaches to N-acetylcolchinol as a key precursor to
ZD6126. In the first instance we needed a route that
could supply material for clinical trials, but ultimately
we were looking for a route that had the potential to
be developed for commercial manufacture of the drug.4
OR
Z
OR
O
OMe
MeO
X
MeO
MeO
MeO
Y
MeO
O
Intermediate B
Intermediate A
*
Corresponding author. Tel.: +44 1625 516405; fax: +44 1625
500780; e-mail: john.leonard@astrazeneca.com
Figure 2.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.103

4628
S. D. Broady et al. / Tetrahedron Letters 48 (2007) 4627–4630
approaches, the key step is formation of the bond
between the aromatic rings and range of
OR
OR
Z
a
OMe
MeO
MeO
X
appropriately substituted aromatic building blocks were
required to evaluate the routes. 3,4,5-Trimethoxybenz-
aldehyde 4 was selectively brominated or iodinated to
provide 5a/b, which were functionalised, as shown in
Scheme 1, to provide a range of potential A-ring
synthons 6a/b and 7.
MeO
MeO
Y
Z
MeO
12
13
R = H, TBDMS, OBn
Z = OH, OAc, NH2, NHAc
X, Y = H or Br
Scheme 3.
OMe
OMe
MeO
MeO
MeO
MeO
X
i) or ii)
Faced with the inefficiency of routes involving intramo-
lecular biaryl cyclisation of intermediates of type A, we
turned our attention to the alternative approach, start-
ing with an intermolecular biaryl coupling, to provide
intermediates of type B (Fig. 1), followed by subsequent
aldol cyclisation. The Suzuki reaction is perhaps the
most obvious choice for preparing biaryl systems and
we therefore prepared a broad range of boronic acid
and boronate derivatives from bromides 7 and 11. How-
ever, although we expended considerable efforts to find
palladium catalysts and procedures for coupling the
components, yields were always disappointing, Scheme
4.10
O
O
5a, X = Br
5b, X = I
4
iv)
iii)
OMe
OMe
MeO
MeO
X
MeO
MeO
Br
O
NCy
O
6a, X = Br
6b, X = I
7
Scheme 1. (i) NBS/MeCN/96%; (ii) NIS/MeCN/88%; (iii) cyclohexyl-
amine/toluene/88%, X = Br, 98% X = I; (iv) ethylene glycol/TsOH/
90%.
OR
O
OR
O
OMe
MeO
X
3-Hydroxyacetophenone was readily converted into a
range of C-ring precursors as shown in Scheme 2. Sev-
eral approaches were explored that involved cyclising
intermediates of type A, in Figure 2, to give the core tri-
cyclic ring system. Such strategies have literature prece-
dent,6–8 and the required precursors, such as 12, were
readily prepared from chalcone derivatives, formed by
reaction of aldehydes 4 or 5a with ketones 9 or 10.9
One report suggested that such compounds (where
X = Y = H) can be cyclised efficiently using thallium
trifluoroacetate,6 but we were unable to carry out such
a reaction in anything other than very low yields.7,8
Modest yields (34–60%) of a tricyclic product 13 were
provided when intermediate 12 (Y = Br, X = H,
Z = OAc) was treated with a catalytic amount of
Pd(OAc)2 (up to 1 equiv required) but the process was
not considered to be of practical utility (Scheme 3).9
MeO
MeO
MeO
MeO
Y
O
O
O
O
O
O
<10% yield
X = Br and Y = B(OH)2 or B(OAlk)2
or Y = Br and X = B(OH)2 or B(OAlk)2
Scheme 4.
The Ullmann reaction is an alternative biaryl coupling
reaction and Ziegler et al. devised an ambient tempera-
ture procedure that is useful for cross-coupling of aro-
matics with certain substitution patterns.11 The
aromatic systems that they were able to couple were
electron-rich iodides and bromides bearing ortho-sub-
stituents that are capable of co-ordinating to copper.
We therefore devised coupling components bearing sub-
stituents that would, in the first instance, be suitable for
co-ordinating to copper during an Ullmann reaction,
and could then be converted into residues that would
cyclise to form the central 7-membered colchinol ring.
OH
OBn
i)
O
OBn
O
O
9
8
Ziegler found that a thioacetal sulfur atom could be
used to co-ordinate the cuprate intermediate and in
our initial study we used thioacetal 11b as the key inter-
mediate. This was lithiated with n-BuLi in THF at
À78 °C, then treated with 1.5 equiv of CuIÆP(OEt)3 com-
plex, followed by 1.1 equiv of iodide 6b (X = I). The
mixture was then allowed to stir at room temperature
for 18 h. During work-up with aqueous AcOH the
cyclohexylimine was hydrolysed and aldehyde 14b was
isolated by chromatography in 70% yield. Unfortu-
ii)
OBn
iii) or iv)
Br
Br
10
O
X
11a, X = O
11b, X = S
Scheme 2. (i) BnCl/DMF/K2CO3, 90%; (ii) NBS/MeCN/70%; (iii)
HO(CH2)2OH/TsOH/Tol/93%; (iv) HS(CH2)2OH/TsOH/Tol/66%.

S. D. Broady et al. / Tetrahedron Letters 48 (2007) 4627–4630
4629
nately, the thioacetal protecting group proved difficult
to remove and heating in acetone with MeI (40 equiv)
was required. This did provide keto-aldehyde 15 in al-
most quantitative yield, which was efficiently cyclised
under basic conditions to give enone 16 (Scheme 5).
In the first instance the viability of replacing the iodides
with bromides was tested by repeating the procedure,
but with aryl bromide 6a as a reactant and CuBrÆ(OEt)3
as the copper source. Significantly, we observed very lit-
tle difference in the reaction profile and the yield of 14b
was unchanged. Next, using acetal 11a as the reaction
substrate instead of the thioacetal 11b tested the effect
of oxygen versus sulfur co-ordination. In this case the
rate of conversion to biaryl product 14a was consider-
ably reduced and we observed an increase in the level
of by-products formed. However, this problem was re-
solved by raising the reaction temperature slightly.
Thus, when the reaction was held at ambient tempera-
ture for 16 h, followed by 48 h at 45 °C the desired reac-
tion pathway was favoured and, following hydrolytic
work-up with 10% AcOH, the aldehyde product 14a
was isolated by crystallisation from ethanol in 77%
yield. The major advantages of using the acetal could
now be realised. Simple and quantitative hydrolysis of
14a was achieved using dil. HCl/EtOH, for 2 h at
65 °C and the resultant solution of aldehyde 15 was then
basified with K2CO3 and heated at 90 °C for 5 h, during
which time the enone 16 precipitated as yellow crystals,
which were isolated by filtration in 91% yield from 14a.
OBn
OBn
OMe
MeO
i), ii) or iii)
70-77%
O
O
Br
X
MeO
X
11a, X = O
11b, X = S
O
14a, X = O
14b, X = S
iv) or v)
OBn
OBn
OMe
OMe
vi)
MeO
MeO
MeO
MeO
91%
O
O
16
15
O
Scheme 5. (i) (a) n-BuLi/THF/À78 °C, (b) CuIÆP(OEt)3 (1.5 equiv), (c)
6b (1.1 equiv), (d) 18 h, rt, (e) aq AcOH (70%); (ii) (a) n-BuLi/THF/
À78 °C, (b) CuBrÆP(OEt)3 (1.5 equiv), (c) 6b (1.1 equiv), (d) 18 h, rt, (e)
aq AcOH (76%); (iii) (a) n-BuLi/THF/À78 °C, (b) CuBrÆP(OEt)3
(1.5 equiv), (c) 6a (1.1 equiv), (d) 18 h, rt, then 48 h, 45 °C (77%), (e)
10% aq AcOH (76%); (iv) MeI (40 equiv); (v) 10% HCl/EtOH; (vi)
K2CO3/90 °C/5 h (91% over two steps).
With the core ring system complete, asymmetric intro-
duction of the acetamide was the major remaining hur-
dle. Firstly, simultaneous hydrogenation of the enone
and hydrogenolysis of the benzyl ether, using Pd(OH)2,
was effected in THF containing 1% AcOH. Following
filtration of the mixture and evaporation of the solvent,
the ketone 19 was isolated by crystallisation from meth-
anol in 79% yield. This was converted into enamide 20
in a two-step procedure: the oxime of 19 was obtained
in 93% yield by treatment with hydroxylamine.HCl in
EtOH/pyridine, followed by filtration of the crystalline
product; this was converted into enamide 20, in 63%
yield, by treatment with Ac2O and Fe (powder) in
AcOH, followed by basic work-up and crystallisation
(Scheme 7).
This was the first high-yielding preparation of a colchi-
nol tricyclic unit that we achieved and as such the result
was very encouraging. However, two major issues com-
promised the efficiency of the route and challenged its
viability as a large scale manufacturing process. Firstly,
removal of the thioacetal unit was difficult and required
a large excess of methyl iodide. Secondly, the iodide res-
idues generated by the reaction are highly undesirable in
manufacturing waste streams. We therefore wanted to
establish whether or not this type of Ullmann coupling
could be effected with alternative functionalities, that
would greatly enhance the general synthetic utility of
this type of reaction. A crucial step in the mechanism
is thought to be the oxidative insertion of Cu into the
Ar–I bond in co-ordinated intermediate 17 (Scheme 6).
The key questions we had regarding the reaction inter-
mediates were: (i) would oxidative insertion into an
Ar–Br bond be effective, and (ii) could an acetal oxygen
co-ordinate effectively with the copper in place of the
thioacetal sulfur atom?
OBn
O
OH
O
OMe
OMe
a)
MeO
MeO
MeO
MeO
16
19
b), c)
OH
OH
OMe
OMe
d)
MeO
MeO
MeO
MeO
NHAc
NHAc
O
O
OBn
OBn
MeO
MeO
Z
3
20
Z
OMe
OMe
Cu
Scheme 7. (i) Pd(OH)2/THF/AcOH (79%); (ii) NH2OHÆHCl/pyridine/
EtOH (93%); (iii) Fe (powder)/Ac2O/AcOH (63%); (iv) (S)-iPrFerro-
TANE Ru(methallyl)2/H2/MeOH (ꢀ100%).
MeO
MeO
Cu
X
X
N
N
Cy
Cy
18
17
X = Br or I
Z = S or O
For the hydrogenation of enamide 20, a systematic study
Scheme 6.
of a wide variety of asymmetric rhodium, ruthenium

4630
S. D. Broady et al. / Tetrahedron Letters 48 (2007) 4627–4630
L.; Chaplin, D. J.; Hill, S. A. Cancer Res. 2002, 62, 7247–
7253; (h) Micheletti, G.; Poli, M.; Borsotti, P.; Martinelli,
M.; Imberti, B.; Taraboletti, G.; Giavazzi, R. Cancer Res.
2003, 63, 1534–1537; (i) McCarthy, M. F.; Takeda, A.;
Stoeltzing, O.; Liu, W.; Fan, F.; Reinmuth, N.; Akagi, M.;
Bucana, C.; Mansfield, P. F.; Ryan, A.; Ellis, L. M. Br. J.
Cancer 2004, 90, 705–711; (j) Taraboletti, G.; Micheletti,
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and iridium hydrogenation catalysts was carried out
and a full report of that study is presented in the
accompanying paper.12 FerroTANE derivatives were
the most effective catalysts screened. Reactions were
carried out in MeOH, with a 500–1000:1 substrate:
catalyst mole ratio, and were essentially quantitative.
(S)-iPrFerroTANE Ru(methallyl)2 gave (S)-(À)-N-acetyl-
colchinol 3 with an ee of 92% and [(S)-tBuFerroTANE
Rh(COD)]BF4 gave (R)-(À)-N-acetylcolchinol with an
ee of 94%. The hydrogenations were not fully optimised
and no attempt was made to enhance the enantiomeric
purity further.
4. (a) Broady, S. D.; Golden, M. D.; Leonard, J.; Muir, J. C.;
Billard, A.; Murray, K., PCT Int. Appl., 2006, WO
2006067411, CAN 145:63042; (b) Broady, S. D.; Martin,
D. M. G.; Lennon, I. C.; Ramsden, J. A.; Muir, J. C., PCT
Int. Appl., 2006, WO 2006067412, CAN 145:103874; (c)
Evans, M.; Leonard, J.; Lilley, T.; Whittall, J., PCT Int.
Appl., 2005, WO 2005061436, CAN 143:97179.
5. The literature synthesis of N-acetyl colchinol from colchi-
cine is low yielding: (a) Santavy, F. Collect. Czech. Chem.
Commun. 1949, 14, 532; A modified procedure involving
formaldehyde-O-oxide was evaluated, but considered to
be impractical on a manufacturing scale: (b) Dilger, U.;
Franz, B.; Roettele, H.; Schroeder, G.; Herges, R. J.
Prakt. Chem. 1998, 340, 468–471.
Conversion of (S)-(À)-N-acetylcolchinol into the drug
substance, ZD6126, was easily carried out by treatment
with excess POCl3 in THF/NEt3.13 The work described
here provides access to (S)-(À)-N-acetylcolchinol in a
short sequence of synthetic steps, starting from readily
available, simple aromatic precursors. All intermediates
were isolated by crystallisation and no chromatography
was required, making the route amenable to scale-up.
We have also demonstrated that low temperature Zeig-
ler–Ullmann couplings can be carried out using sub-
strates containing bromides instead of iodides and
acetals rather than thioacetals, which will increase their
synthetic utility.
6. Sawyer, J. S.; Macdonald, T. Tetrahedron Lett. 1988, 38,
4839–4942.
7. In a later, complimentary study improved cyclisation
conditions provided a moderate 47% yield of tricycle: (a)
Besong, G.; Jarowicki, K.; Kochienski, P. J.; Sliwinski, E.;
Boyle, T. F. Org. Biomol. Chem. 2006, 4, 2193–2207;
Other workers recently reported a 53% yield for this
cyclisation: (b) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8,
15–18.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.04.103.
8. Biaryl cyclisation appears to be more efficient in cases with
additional oxygenation in the phenol ring, see: Banwell,
M. G.; Farn, M.-A.; Gable, R. W.; Hamel, E. J. Chem.
Soc., Chem. Commun 1994, 2647–2649.
9. A wide range of intermediates of type 12 were prepared.
As an example compound 12 (R = Bn, X = H, Y = Br)
was prepared by the following sequence: (i) aldol conden-
sation between 4 and 10 in ethanol with catalytic EtONa
gave the corresponding chalcone (68%); (ii) the enone
function was reduced to a ketone with 9-BBN in CH2Cl2
(53%), (iii) the ketone was reduced with NaBH4 in IPA
and the resultant alcohol was acetylated with Ac2O in
CH2Cl2 (95%). Treatment of the intermediate ketone with
TFA in toluene removed the Bn group, allowing alterna-
tive phenol derivatives to be prepared. We thank David
Martin for work on this approach. More recently
References and notes
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a similar
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will be reported in a subsequent publication.