A synthesis of (aR,7S)-(-)-N-acetylcolchinol and its conjugate with a cyclic RGD peptide

Article abstract of DOI:10.1016/j.tet.2008.01.130

An asymmetric synthesis of (-)-N-acetylcolchinol is described based on a Suzuki-Miyaura coupling to generate the biaryl pharmacophore. The sole asymmetric centre was introduced by an asymmetric reduction of a dibenzosuberone derivative 24 using lithium bo

Full text of DOI:10.1016/j.tet.2008.01.130

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4700e4710
www.elsevier.com/locate/tet
A synthesis of (aR,7S)-(ꢀ)-N-acetylcolchinol and its conjugate
with a cyclic RGD peptide
a
Gilbert Besong a, Denis Billen a, Indu Dager a, Philip Kocienski a, , Eric Sliwinski ,
*
Lik Ren Tai a, F. Thomas Boyle b,y
a School of Chemistry and Institute of Process Research and Development, Leeds University, Leeds LS2 9JT, UK
b AstraZeneca Pharmaceuticals, Mereside, Alderley Edge, Cheshire SK10 4TG, UK
Received 25 September 2007; received in revised form 25 October 2007; accepted 27 October 2007
Available online 6 February 2008
Abstract
An asymmetric synthesis of (ꢀ)-N-acetylcolchinol is described based on a SuzukieMiyaura coupling to generate the biaryl pharmacophore.
The sole asymmetric centre was introduced by an asymmetric reduction of a dibenzosuberone derivative 24 using lithium borohydride in the
presence of stoichiometric amounts of a chiral Lewis acid (TarBeNO2). A conjugate between an aVb3 integrin-binding cyclic peptide c[RGDfK]
and colchinol (adipoyl linker) was synthesised with an aim to deliver colchinol to solid tumours selectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Colchicine; SuzukieMiyaura cross-coupling; Biaryl; Asymmetric reduction; RGD peptide
1. Introduction
drug ZD6126 (3), selectively induces tumour vascular damage
and tumour necrosis at well-tolerated doses in animal models.7
Like colchicine, N-acetylcolchinol (NAC) arrests mitosis by
inhibiting tubulin polymerisation.8
The highly toxic nature of extracts of the meadow saffron
(Colchicum autumnale) was first recorded by the Greek physi-
cian Dioscorides (A.D. 78) in his seminal De Materia
Medica.1 The active principle, colchicine (1), was isolated in
pure form by Pelletier and Caventou in 1820 and the structure
was finally determined in 1945 by Dewar after a protracted
struggle involving many contributors.2,9 Low doses of colchi-
cine have been used since the 16th century for the treatment of
gout but reports by Dustin (1934),3 Lits (1934)4 and Amoroso
(1935)4 that colchicine induces metaphase arrest in mouse tu-
mour cells with consequent tumour regression excited much
interest.5 Unfortunately, near lethal doses of colchicine are
required and subsequent efforts have focused on the search
for colchicine analogues with an improved therapeutic index.
One promising lead to emerge is (aR,7S)-N-acetylcolchinol
(2)6 which, in the form of its water-soluble phosphate pro-
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
NHAc
NHAc
NHAc
OH
P
HO
MeO
HO
O
O
O
(–)-colchicine (1)
(–)-N-acetylcolchinol (2)
ZD6126 (3)
Until recently, the commercial demand for NAC has been
supplied by degradation of colchicine. The venerable proce-
dure by Windaus9 (Scheme 1), recently revived in a patent,10
generates NAC by reaction of colchicine with sodium hypoio-
dite to give first N-acetyliodocolchinol (4) which is then
reduced by treatment with zinc. A related oxidative ring con-
traction of colchiceine (5)11ditself a hydrolysis product of
colchicinedwith basic hydrogen peroxide at 60 ꢁC12 delivers
NAC in 24% yield. Scheme 2 shows two further approaches.
* Corresponding author. Fax: þ44 (0)113 343 6401.
E-mail address: p.j.kocienski@leeds.ac.uk (P. Kocienski).
y
Deceased on 5th July, 2006.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.130

G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
MeO
4701
MeO
Diazotisation of 8 followed by heating then generated NAC
but the yield for both steps was poor. A recent patent15 has
described a modern rendition of an old phenol synthesis as
an efficient route to NAC. The tertiary alcohol 9 generated
by reaction of allocolchicine with methyllithium gave the
hydroperoxide intermediate 10 on treatment with hydrogen
peroxide in the presence of methanesulfonic acid. The hydro-
peroxide rearranged under the acidic conditions to give NAC
in 90% yield.
MeO
MeO
0.1 N HCl
Δ, 1.75 h
80-86%
MeO
MeO
NHAc
NHAc
MeO
HO
O
O
(aR,7S)-(–)-colchicine (1)
(aR,7S)-colchiceine (5)
0.1 N NaOH, 30% H2O2 (1:1)
60 °C, 2 h
NaOH, I2, NaI
95%
24%
0-5 °C, 1 h
The need for more scalable and economic supplies of NAC
has stimulated interest in its total synthesis. The first synthesis
of (ꢂ)-NAC by Sawyer and Macdonald16 achieved the simul-
taneous construction of the seven-membered B-ring and the
biaryl by an intramolecular non-phenolic oxidative coupling
reaction of a 1,3-diarylpropane (11) mediated by thallium(III)
trifluoroacetate (Scheme 3). This oxidant was later used by Wu
and Chong17 in an asymmetric synthesis of (ꢀ)-NAC but the
yield (53%) was lower than that reported by Sawyer and Mac-
donald (71%) whereas we could only muster an exiguous 31%
for the identical transformation.18 With phenyliodonium bis-
(trifluoroacetate), oxidative cyclisation of 11 was accomplished
reproducibly in ca. 50% yield.19 Banwell and co-workers re-
ported the related intramolecular phenolic oxidative coupling
of 12 using lead(IV) acetate in their synthesis of colchicine.20
MeO
MeO
MeO
MeO
Zn, HOAc, Δ , 1 h
MeO
MeO
83%
NHAc
I
NHAc
HO
HO
(aR,7S)-(–)-N-acetylcolchinol (2)
N-acetyliodocolchinol (4)
Scheme 1.
Reaction of colchicine with sodium methoxide or sodium
hydroxide in refluxing methanol generates allocolchicine (6)
and allocolchiceine (7), respectively,13,14 both of which have
been converted to NAC. A Schmidt reaction on allocolchiceine
was used by Fernholz14 to generate the aniline derivative 8.
MeO
MeO
MeO
MeO
Tl(OCOCF3)3
(31-71%)
MeO
MeO
(–)-colchicine (1)
MeO
MeO
or
MeO
MeO
PhI(OCOCF3)2
(45%)
non-phenolic
NHAc
NHAc
NaOMe NaOH
MeO
MeO
MeOH, Δ MeOH, Δ
TBSO
11
HO
oxidative
100%
100%
(–)-N-acetylcolchinol (2)
NHAc
NHAc
coupling
MeO
MeO
MeO
O
O
OMe
(–)-allocolchicine (6)
OH
allocolchiceine (7)
MeO
Pb(OAc)4
(42%)
NaN3, H2SO4
CHCl3, 40-45 °C
85%
22%
MeLi, THF, –5 °C, 1 h
MeO
MeO
MeO
phenolic
oxidative
coupling
OH
OH
MeO
MeO
MeO
MeO
MeO
MeO
MeO
HO
12
HO
13
Scheme 3.
NHAc
OH
NHAc
NH2
Recently a process development group at AstraZeneca
described a short asymmetric synthesis of (ꢀ)-NAC (Scheme
4)21 based on the initial construction of the biaryl pharmaco-
phore 16 using an Ullmann coupling22,23 followed by elabora-
tion of the B-ring. A noteworthy feature of this approach is the
concluding ruthenium-catalysed asymmetric hydrogenation of
enamide 18 to install the C7 acetamide function in quantitative
yield (er 96:4).24
8
9
H2O2, MeSO3H
PhMe, 50 °C
HONO 33%
MeO
MeO
MeO
MeO
MeO
90% from 9
MeO
We now report an asymmetric synthesis of (ꢀ)-NAC that
resembles the AstraZeneca route strategically but differs sub-
stantially in tactics. We also describe the synthesis of a colchi-
noleRGD peptide conjugate designed for selective delivery of
the drug to tumour vasculature.
NHAc
OH
NHAc
OH
(–)-N-acetylcolchinol (2)
O
10
Scheme 2.

4702
G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
Br
2. Results and discussion
MeO
O
MeO
O
OMe
O
2.1. Synthesis of (ꢀ)-N-acetylcolchinol
MeO
MeO
15
OBn
MeO
1. BuLi, THF, –78 °C
2. CuBr•P(OEt)3 (1.5 equiv)
3. add 15 (1.1 equiv)
r.t. 18 h; 45 °C, 48 h
4. aq HOAc
O
Our synthesis, summarised in its entirety in Scheme 5, can be
divided into three phases. Phase 1, construction of the biaryl
pharmacophore, began with the bromoarene 19, prepared in
91% yield by the bromination of commercial 3,4,5-trimethoxy-
benzaldehyde.25 Protection of the aldehyde as its 1,3-dioxolane
derivative 20 enabled halogenemetal exchange and borylation
O
Br
N
Cy
BnO
16
14
77%
1. 10% HCl, MeOH, 65 °C
2. K2CO3, 90 °C
91%
1
to afford boronic acid 21 in ca. 97% yield. H and 13C NMR
MeO
MeO
spectra recorded on the crude boronic acid revealed minor impu-
rities but attempts to remove them by recrystallisation gave poor
recoveries and no improvement; therefore, the crude boronic
acid was used in the next step. The key SuzukieMiyaura cou-
pling26 between boronic acid 21 and the bromoacetophenone
derivative 2227 was achieved using freshly prepared Pd(PPh3)4
(4 mol %) and sodium carbonate as the base in refluxing aque-
ous ethanol to give the biaryl 23 in 52% yield on a 112 mmol
scale (Scheme 5).28 Other bases known to be beneficial in the
case of hindered or highly oxygenated substrates such as cae-
sium fluoride29 and barium hydroxide30 gave complex mixtures
in our case. Attempts to use heterogeneous Pd/C as the catalyst
under phosphine-free conditions were similarly fruitless.31
MeO
1. Pd(OH)2, H2
MeO
2. NH2OH•HCl
pyr-EtOH
MeO
MeO
3. Fe (powder)
Ac2O, AcOH
NHAc
O
46%
HO
BnO
17
18
100%
er = 96:4
Ru(methallyl)2, (S)-i-PrFerroTANE
2 (120 psi), MeOH, 65 °C
H
(S)-N-acetylcolchinol (2)
Scheme 4.
MeO
OBn
O
MeO
B
MeO
MeO
MeO
O
MeO
MeO
ethane-1,2-diol
TsOH•H2O
Br
MeO
MeO
MeO
MeO
22 (1.0 equiv)
1. t-BuLi, Et2O–THF, –78 °C
MeO
PhMe, Δ (–H2O)
91% (183 mmol scale)
2. B(OMe)3 then aq HCl
ca 97% (157 mmol scale)
Pd(PPh3)4 (4 mol%)
O
2 M NaCO3, EtOH, Δ, 1 h
O
O
Br
O
Br
20
O
HO
OH 52% (112 mmol scale)
19
21
BnO
(mp 38–40 °C)
23
(mp 82–83 °C)
CO2H
O
K2CO3 (3.5 equiv)
B
EtOH–H2O (1:1), Δ, 30 min
68% (36.9 mmol scale)
O
CO2H
(+)-TarB-NO2
O2N
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
1. MsCl, NEt3
CH2Cl2, –40 °C
(+)-TarB–NO2 (2.0 equiv)
PtO2 (cat), H2
MeO
MeO
MeO
MeO
2. TMGN3 (4.0 equiv)
–40 °C to r.t.
LiBH4, THF, r.t.
EtOH–CH2Cl2 (3:1)
90% (30 mmol scale)
90% (27 mmol scale)
OH
O
O
N3
95% (19.7 mmol scale)
er > 99:1
BnO
25
BnO
24
BnO
17
(mp 182–183 °C)
BnO
26
(mp 162–164 °C)
(mp 154–156 °C)
LiAlH4
THF, r.t., 12 h
96% (17.8 mmol scale)
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H2, Pd/C, i-PrOH
Ac2O, pyridine
MeO
MeO
99% (27.5 mmol scale)
CH2Cl2, r.t., 1 h
99% (15 mmol scale)
NH
NH
NH2
H
O
H
O
BnO
HO
BnO
27
(mp 122–124 °C)
28
2
(mp 196–197 °C)
(mp 150–151 °C)
Scheme 5.

G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
4703
The second phase of the synthesis, construction of the
seven-membered B-ring, was easily accomplished by an intra-
molecular aldol reaction. Treatment of the keto aldehyde 23
with potassium carbonate in refluxing ethanol consistently
generated the dibenzosuberone derivative 17 in 68% yield.
The reaction was complete within 30 min and prolonged heat-
ing failed to attain the 91% yield reported by the AstraZeneca
group21 for the identical transformation. Hydrogenation of the
double bond in 17 without detriment to the benzyl ether group
was achieved by using Adams’ catalyst (PtO2) instead of Pd/C.
The goal of the third phase of the synthesis was the intro-
duction of the stereogenic centre at C7 by asymmetric reduc-
tion of the ketone 24. The Noyori ruthenium-catalysed
asymmetric hydrogenation32 which had served us well in
our first synthesis of NAC19,33 gave racemic alcohol 25. A
CoreyeBakshieShibata reduction34 using 5 mol % of the
(S)-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2-c][1,3,2]ox-
azaborole catalyst gave the desired (R)-alcohol 25 with high er
(>99:1) but the yield, on a 2.5 mmol scale, was only 65%.35,36
The best of the three methods examined involved reduction of
ketone 24 with a chiral acyloxyborohydride generated in situ
from lithium borohydride and 2 equiv of the cheap homochiral
bifunctional Lewis acid (þ)-TarBeNO2.37 Alcohol (R)-25 was
obtained in 90% yield with an er >99:1. With only 1 equiv of
(þ)-TarBeNO2, the yield was comparable but the er decreased
slightly to 96:4.38,39
To complete the synthesis of NAC the hydroxyl function in
(R)-25 was converted to the azide 26 in a one-pot procedure.
Mesylation of 25 gave an unstable benzylic mesylate interme-
diate which was treated with tetramethylguanidinium azide
(4 equiv) in situ at ꢀ40 ꢁC. On gradual warming to rt, nucle-
ophilic substitution occurred to give the desired azide in 95%
yield. Chiral HPLC indicated an er >99:1 in accord with clean
inversion by an SN2 mechanism. Three methods were used to
reduce the azide 26 to the amine 27 the best being lithium
aluminium hydride in THF. Hydrogenolysis was complicated
by competing hydrogenolysis of the benzyl ether even with
palladium hydroxide as catalyst whereas zinc and ammonium
chloride only gave a 78% yield and required 40 equiv of zinc.
Acetylation of the amine 27 followed by hydrogenolysis of
the benzyl ether 28 using the standard conditions gave (ꢀ)-
N-acetylcolchinol in excellent yield.
in the presence of PdCl2eP(tBu)3 as described by Baldwin and
co-workers.44 Therefore, the Suzuki coupling remains the most
practical method for the synthesis of the biaryl 23.
MeO
MeO
1. t-BuLi (2 equiv)
MeO
MeO
MeO
MeO
Et2O, –78 °C
2. Bu3SnCl (2 equiv)
–78 °C to r.t.
83% (10 mmol scale)
O
O
O
Br
O
Bu3Sn
20
29
MeO
MeO
MeO
OBn
O
O
Br
O
22 (1.2 equiv)
Pd(PPh3)4 (20 mol%)
O
PPh3 (47 mol%), CuI (40 mol%)
DMF, Δ , 106 h
OBn
30 (mp 103–106 °C)
52% (7 mmol scale)
Scheme 6.
2.2. Synthesis of a colchinoleRGD peptide conjugate
NAC, as the pro-drug ZD6126 (3), was developed by Astra-
Zeneca as a vascular disrupting agent for the treatment of ad-
vanced solid tumours. NAC binds to tubulin in immature
proliferating endothelial cells lining the tumour blood vessels
leading to blood vessel congestion with consequent tumour ne-
crosis from hypoxia and nutrient deprivation.45 ZD6126 showed
sufficient promise to warrant phase II clinical trials. Unfortu-
nately, vascular disrupting agents can cause acute coronary and
other thrombophlebitic syndromes, alterations in blood pressure,
hot flashes, neuropathy and tumour pain.46 After adverse coro-
nary effects were observed with ZD6126, further development
ceased. We now describe a synthesis of the NACeRGD peptide
conjugate (34, Scheme 7) designed for selective delivery of the
drug to tumour vasculature. The design of conjugate 34 was
based on four principles. Firstly, previous studies had established
that the acetamido group in colchicinoids is not necessary for tu-
bulin binding and therefore its modification should not impinge
on biological activity.47 Secondly, Kessler’s c[RGDfK] peptide
ligand48 binds selectively and with high affinity to aVb3 integrin,
a transmembrane adhesion receptor involved in angiogenesis
and metastasis, which is overexpressed in tumour vasculature.49
Thirdly, the terminal amino group in the lysine residue is not im-
plicated in integrin-binding and therefore it is an ideal linkage
function.50 Fourthly, synthetic conjugates of doxorubicin and cy-
clic RGD peptides induce tumour regression in mice at 1/10th
the dose of doxorubicin alone in accord with selective delivery
of the drug to tumour vasculature and its endocytosis.51
The prime blemish in the forgoing route was the modest yield
of the Suzuki coupling. We therefore examined a small selection
of alternative Pd(0)-catalysed coupling methods in an effort at
improvement. The Negishi coupling40 gave virtually no biaryl
in our hands but the Stille coupling41 was more fruitful. The
stannane 29 was prepared as shown in Scheme 6 and coupled
with the o-bromoacetophenone 22 in 52% yield using the rather
´
harsh conditions developed by Saa and Martorell for the synthe-
sis of highly hindered biaryls.42 However, the long reaction
times (106 h) in refluxing DMF in the presence of 20 mol % of
Pd(0) were impractical and efforts to ameliorate the conditions
by using an array of ligands [e.g., P(2-furyl)3 and P(tBu)3] and
catalysts [PdCl2(PhCN)2, PdCl2(MeCN)2, Pd2(dba)3] were to
no avail. Similarly fruitless were the addition of caesium fluo-
ride43 or the tandem use of copper(I) iodide and caesium fluoride
TheKesslerc[RGDfK]peptidewassynthesisedonsolidphase
bya modification ofan earlier procedure48,52 as showninScheme
7. A commercial Wang resin pre-loaded with N-a-FmoceL-
AspeOAll was first deprotected and elongated by a conventional
Fmoc deprotectioneamino acid condensation protocol. The
resulting pentapeptide 32 was then cyclised on-resin to give 33
after allyl deprotection and removal of the last Fmoc group.

4704
G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
O
H
O
H
N
NHDde
N
NHDde
CO2All
O
O
i, ii, i, iii
i, iv, i, v
FmocHN
HN
HN
vi
O
O
CO2All
Pbf
NH
Pbf
NH
NH
O
NH
O
NHFmoc
H
N
H
N
O
O
O
HN
NH
NH
O
N
H
N
H
O
31
O
O
H
H
H H
32
33
vii, viii, ix, x
OMe
OMe
OMe
H
N
MeO
MeO
O
MeO
MeO
H
N
O
O
N
O
H
2 M HCl
HN
HN
MeO
MeO
O
O
MeOH, Δ, 45 H
NH
H
N
99%
HO
NH2
NH
NHAc
NH2•HCl
H
H
HO
N
H
O
HO
HO
35
O
2
34
H
H
Scheme 7. Reagents and conditions: (i) piperidineeDMF (1:4), rt, 10 min (ꢃ2); (ii) N-a-FmoceGlyeOH (2 equiv), HCTU (2 equiv), DIPEA (4 equiv), DMF, rt,
2 h (ꢃ2); (iii) N-a-FmoceArg(Pbf)eOH (2 equiv), HCTU (2 equiv), DIPEA (4 equiv), DMF, rt, 2 h (ꢃ2); (iv) N-a-Lys(Dde)eOH, HCTU (2 equiv), DIPEA
(4 equiv), DMF, rt, 2 h (ꢃ2); (v) N-a-FmocePheeOH (2 equiv), HCTU (2 equiv), DIPEA (4 equiv), DMF, rt, 2 h (ꢃ2); (vi) Pd(PPh3)4 (0.3 equiv), CHCl3e
AcOHeN-methylmorpholine (37:2:1), rt, 4 h; then piperidineeDMF (1:4), rt, 10 min; then HCTU (3 equiv), DIPEA (10 equiv), DMF, rt, 24 h; (vii) H2Ne
NH2$H2O, DMF, rt, 5 min (ꢃ2); (viii) adipic anhydride (10 equiv), DIPEA (12 equiv), rt, 20 h; (ix) colchinol$HCl (3 equiv), HCTU (3 equiv), HOBt (3 equiv),
DIPEA (6 equiv), DMF, rt, 60 h; (x) TFAe(i-Pr)3SiHeH2O (95:2.5:2.5), rt, 1 h. HCTU¼2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexa-
fluorophosphate, HOBt¼1-hydroxybenzotriazole, Dde¼2(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl, Pbf¼2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-
sulfonyl.
The colchinol was appended to the Kessler peptide 33 via
an adipoyl linker. Attachment of the linker began with cleav-
age of the Dde protector from the lysine in 33 with hydrazine
hydrate followed by N-acylation with adipic anhydride.
Finally coupling of colchinol (35) to the peptide 33 followed
by Pbf deprotection and cleavage from the resin gave the
target conjugate in 16% overall yield from 31.
benzophenone; dichloromethane and toluene were distilled
from calcium hydride; diisopropylethylamine, pyridine and
triethylamine were distilled from potassium hydroxide; meth-
anol was distilled from magnesium methoxide. All reactions
were magnetically stirred and were monitored by thin layer
chromatography (TLC) using SiO2 on pre-coated aluminium
foil sheets, layer thickness 0.25 mm. Compounds were visual-
ised by UV (254 and 366 nm) and 20% phosphomolybdic acid
in ethanol w/v. Column chromatography was performed on
silica gel 60 (35e70 mm). Optical rotations were recorded
on an Optical Activity AA-1000 polarimeter (units in
10ꢀ1 deg cm2 gꢀ1). Melting points were measured on a Griffin
electrothermal apparatus and are uncorrected. IR spectra were
recorded on a Perkin Elmer Spectrum One FT-IR spectrometer
as thin films supported on sodium chloride plates or on a
Diffuse Reflectance sampling cell. Absorptions are reported
as values in cmꢀ1 followed by the relative intensity: s¼strong,
m¼medium, w¼weak. 1H and 13C NMR spectra were re-
3. Conclusions
An 11-step asymmetric synthesis of (aR,7S)-(ꢀ)-N-acetyl-
colchinol from commercially available 3,4,5-trimethoxybenzal-
dehyde was accomplished in 23% overall yield. All of the
intermediates except azide 26 were either solid or crystalline.
The synthesis is longer than our previous syntheses19 (8e9
steps) but the simplicity of the present route is better suited to
larger scale. The yield of the key SuzukieMiyaura coupling
step was disappointing (52%) and is substantially lower than re-
cent syntheses of allocolchicinoids by Fagnou53 and DeShong54
featuring Pd-catalysed biaryl construction. Our route is capable
of further abbreviation. For example, after this work was com-
plete, we accomplished the conversion of azide 26 to NAC in
one pot by hydrogenation in the presence of acetic anhydride.
corded on Bruker DPX300 or DRX500 Fourier Transform
¨
spectrometers using an internal deuterium lock. All spectra
were obtained in 5 mm diameter tubes, and the chemical shift
in parts per million is quoted relative to the residual signals of
chloroform (dH 7.26, dC 77.4) or methanol (dH 3.34, dC 49.9)
as the internal standard unless otherwise specified. Multiplic-
ities in the 1H NMR spectra are described as: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, quin¼quintet, m¼multiplet,
br¼broad and app¼apparent. Coupling constants (J) are
reported in hertz. The numbers of protons attached to carbon
in the 13C NMR spectra were revealed by the DEPT spectral
editing technique. Signal assignments were based on COSY,
HMQC and HMBC correlations. Mass spectrometry was
4. Experimental
4.1. General
Where appropriate, solvents and reagents were dried by
distillation from the usual drying agents prior to use: diethyl
ether and tetrahydrofuran were distilled from sodium/

G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
4705
carried out on a VG autospec mass spectrometer, operating at
70 eV, using electron impact ionisation (EI). Electrospray ion-
isation (ES) was performed on either a Micromass LCT TOF
spectrometer or a Waters-Micromass ZMD spectrometer. High
resolution mass spectrometry (HRMS) was obtained by peak
matching using perfluorokerosene or reserpine as a standard.
Ion mass/charge (m/z) ratios are reported as values in atomic
mass units followed, in parenthesis, by the peak intensity
relative to the base peak (100%). Mass spectra were recorded
151.0 mmol, 97%) as a pale yellow amorphous solid which
was used in the next step without further purification. nmax (di-
amond compression system): 3436 s, 2943 s, 1682 s, 1599 s,
1
1455 s, 1317 s, 762 s cmꢀ1. H NMR (500 MHz, CDCl3):
d 9.73 (1H, s, CHO), 7.10 (1H, s, C5H), 4.14 (2H, s, 2OH),
3.94 (6H, s, OCH3), 3.89 (3H, s, OCH3). 13C NMR (75 MHz,
CDCl3): d 194.0 (CHO), 156.5 (C6), 154.2 (C4 and C3),
148.2 (C2), 134.8 (C1H), 110.0 (C5H), 61.38 and 60.95
(C3OCH3 and C4OCH3), 56.69 (C2OCH3). HRMS (ESþ):
found: 263.0703. C10H13BNaO6 requires: 263.0697.
1
on samples judged to be ꢄ95% pure by H and 13C NMR
spectroscopy unless otherwise stated. High performance liquid
chromatography (HPLC) was carried out on a Dionex Auto-
sampler Model ASI-100 with the columns and eluents
specified.
4.4. 20-Acetyl-40-benzyloxy-4,5,6-trimethoxybiphenyl-2-
carbaldehyde (23)
Aq Na2CO3 (2 M, 112 mL, 224 mmol) was added to a de-
gassed solution of 1-(50-benzyloxy-20-bromophenyl)-ethanone
(22)27 (34.2 g, 112 mmol), and Pd(PPh3)4 (5.2 g, 4.5 mmol) in
DME (1.2 L). The reaction mixture was stirred for 5 min
before addition of a solution of 21 (26.9 g, 112 mmol) in
EtOH (224 mL) and then the mixture was heated to reflux
for 1 h under nitrogen. After cooling to rt, water (400 mL)
was added and aqueous layer was extracted with EtOAc
(3ꢃ1.5 L) and then with CH2Cl2 (800 mL). The combined
organic extracts were washed with brine (2.0 L), dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The
dark brown residue was then purified by column chromatogra-
phy on silica (1:1, Et2Oehexane) to give the title compound
(24.1 g, 58.1 mmol, 52%) as a yellow solid. A sample recrys-
tallised from MeOH gave mp 82e83 ꢁC. nmax (diamond com-
pression system): 3363 m, 2940 s, 1692 s, 1587 s, 1452 s, 1139
4.2. 2-(20-Bromo-30,40,50-trimethoxyphenyl)-[1,3]-dioxolane
(20)
To a solution of 2-bromo-3,4,5-trimethoxybenzaldehyde
(19)23,25 (50.0 g, 183.2 mmol) in toluene (500 mL) were added
PTSA$H2O (2.8 g, 14.65 mmol) and ethylene glycol (113 g,
1.8 mol). The mixture was stirred under reflux for 48 h with
continuous removal of water using a DeaneStark apparatus.
After cooling to rt, the reaction mixture was transferred to
a separating funnel and washed with aqueous sodium bicar-
bonate (2ꢃ500 mL) and with brine solution (500 mL). The
organic phase was dried over anhydrous MgSO4 and concen-
trated in vacuo to afford a yellow oily residue which was
purified by column chromatography on silica gel (4:1, hex-
aneeEt2O) to give the title compound as a colourless oil
(42.3 g, 132.6 mmol, 91%) which slowly solidified on stand-
ing: mp 38e40 ꢁC. nmax (diamond compression system):
1
s cmꢀ1. H NMR (500 MHz, CDCl3): d 9.63 (1H, s, CHO),
7.50e7.46 (2H, m, ArH), 7.44e7.42 (3H, m, ArH), 7.37
(1H, m app d, J 7.3, C30H), 7.34 (1H, s, C3H), 7.14 (2H, br
s, C50H, C60H), 5.15 (2H, s, CH2Ph), 3.96 (3H, s, OCH3),
3.94 (3H, s, OCH3), 3.54 (3H, s, OCH3), 2.31 (3H, s,
O]CeCH3). 13C NMR (75 MHz, CDCl3): d 200.4 (CO),
190.9 (CHO), 158.7 (C40), 153.4 (C4), 150.8 (C6), 147.6
(C5), 141.4 (C20), 136.5 (CH2CPh), 134.4 (C50H), 133.5
(C10), 129.8 (C2), 129.0 (2CPhHmeta), 128.5 (CPhHpara),
127.9 (2CPhHortho), 124.4 (C10), 117.0 (C60H), 115.6 (C30H),
105.7 (C3H), 70.6 (CH2Ph), 61.3 (OCH3), 60.9 (OCH3),
56.3 (OCH3), 29.0 (COCH3). HRMS (ESþ): found:
443.1477. C25H24NaO6 requires: 443.1465. Found: C 71.25,
H 5.8. C25H24O6 requires: C 71.41, H 5.75%.
3096 m, 2939 s, 1570 s, 1330 s, 1172 s cmꢀ1 1H NMR
.
(500 MHz, CDCl3): d 7.00 (1H, s, ArH), 6.04 (1H, s, C2H),
4.18e4.13 (2H, m, OCH2), 4.10e4.05 (2H, m, OCH2), 3.89
(3H, s, C50OCH3), 3.88 (6H, br s, C40OCH3, C30OCH3). 13C
NMR (75 MHz, CDCl3): d 153.3 (C30), 151.3 (C50), 144.3
(C10), 132.2 (C40), 110.0 (C60), 106.7 (C20H), 102.8 (C2H),
65.8 (2OCH2), 61.45 and 61.42 (C40OCH3, C40OCH3), 56.5
(C30OCH3). HRMS (ESþ): found: 319.0175. C12H16O759Br re-
quires: 319.0181. Found: C 45.2, H 4.75, Br 24.8. C12H15BrO5
requires: C 45.16, H 4.74, Br 25.04%.
4.3. 6-Formyl-2,3,4-trimethoxyphenyl boronic acid (21)
tert-Butyllithium (203 mL of a 1.7 M solution in pentane,
345 mmol) was added to a solution of bromoarene 20 (50 g,
157 mmol) in dry Et2O (1 L) at ꢀ78 ꢁC. The resulting white
slurry was stirred at the same temperature for 10 min before
the addition of freshly distilled trimethylborate (52 mL,
48.85 g, 470 mmol) at ꢀ78 ꢁC. The mixture was allowed to
warm to rt overnight before addition of 4 M HCl (600 mL).
The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3ꢃ500 mL). The combined organic extracts were
washed with brine solution (1 L), dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The residue was
triturated with hexane to afford the title compound (36.25 g,
4.5. 3-Benzyloxy-9,10,11-trimethoxy-dibenzo[a,c]-
cyclohepten-5-one (17)
K2CO3 (17.8 g, 129.1 mmol) was added to a solution of keto
aldehyde 23 (15.5 g, 36.9 mmol) in 1:1 EtOHeH2O (900 mL)
and refluxed under nitrogen for 30 min. The reaction mixture
was cooled to rt and brine solution (900 mL) was added to it.
The aqueous phase was then extracted with CH2Cl2 (3ꢃ1 L),
dried over anhydrous Na2SO4 and concentrated in vacuo to
give a yellow solid which was recrystallised from EtOAcehex-
ane to afford the title compound (10.1 g, 25.0 mmol, 68%) as
a pale yellow crystalline solid: mp 182e183 ꢁC. nmax (diamond

4706
G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
compression system): 1649 s, 1598 s cmꢀ1
.
1H NMR
extracted with CH2Cl2 (3ꢃ300 mL). The combined organic ex-
tracts were washed with 10% aq NaOH (2ꢃ400 mL), dried over
anhydrous Na2SO4, filtered and concentrated in vacuo to afford
a white solid. HPLC analysis of the crude solid (Chiralpak AS,
5% 2-propanol in hexanes, 0.5 mL minꢀ1, l 220 nm) showed
the product to have an ee of 98.43%; tR: 64.78 min for the major
enantiomer; 57.86 min for the minor enantiomer. Recrystallisa-
tion from EtOAcehexane afforded the title compound (11.0 g,
27.0 mmol, 90%) as colourless needles: mp 154e156 ꢁC. Rf:
0.2 (1:1, hexaneeEt2O). [a]D þ116.5 (c 0.84, CHCl3) (99.3%
ee). nmax (diamond compression system): 3530 s, 3047 s,
2938 s, 1899 m, 1595 s, 1463 s, 922 m, 831 s cmꢀ1. 1H NMR
(500 MHz, CDCl3): d 7.49 (2H, d, J 7.7, ArH), 7.42e7.38
(3H, m, ArH, C1H), 7.35e7.32 (2H, m, ArH, C4H), 6.97 (1H,
dd, J 3.0, 8.6, C2H), 6.58 (1H, s, C8H), 5.14 (2H, s, CH2Ph),
4.63e4.59 (1H, m, C5H), 3.90 (6H, br s, C9OCH3 and
C10OCH3), 3.62 (3H, s, C11OCH3), 2.59e2.53 (1H, m,
C6HAHB), 2.45e2.41 (1H, m, C7HAHB), 2.37e2.32 (1H, m,
C7HAHB), 1.94e1.88 (1H, m, C6HAHB), 1.84 (1H, d, J 4.3,
OH). 13C NMR (75 MHz, CDCl3): d 158.6 (C3), 152.6 (C9),
151.1 (C11), 143.7 (C4a), 141.3 (CH2CPh), 137.5 (C7a),
135.9 (C10), 131.3 (C1H), 128.9 (2CPhHmeta), 128.3 (CPhHpara),
128.0 (2CPhHortho), 125.8 (C11b), 124.7 (C11a), 113.1 (C2H),
109.2 (C4H), 107.8 (C8H), 75.7 (C5H), 70.3 (CH2Ph), 61.4
(C10OCH3), 61.2 (C11OCH3), 56.4 (C9OCH3), 41.7 (C6H2),
30.9 (C7H2). HRMS (ESþ): found: 429.1669. C25H26O5Na
requires: 429.1672. Found: C 73.6, H 6.35. C25H26O5 requires:
C 73.87, H 6.45%.
Alternative procedure. A 25 mL flame-dried two-neck
round-bottom flask, equipped with a rubber septum and mag-
netic stirrer, was flushed with nitrogen and charged with
(S)-1-methyl-3,3-diphenyl-tetrahydropyrrolo[1,2-c][1,3,2]oxa-
zaborole (122 mL of 1 M solution in toluene, 0.12 mmol) un-
der nitrogen. A 2 M solution of BH3$Me2S (BMS) in dry
THF (62.0 mL, 0.123 mmol) was added whereupon separate
solutions of ketone 24 (1.0 g, 2.5 mmol) in 2.2 mL of THF
and a 2 M solution of BH3$SMe2 (2.2 mL) were added simul-
taneously via a syringe pump over 0.5 h. After addition was
complete the reaction mixture was stirred for an additional
15 min before the slow addition of MeOH (9 mL), followed
by 10% aq HCl (8 mL). The reaction mixture was extracted
with CH2Cl2 (3ꢃ10 mL). The combined organic extracts
were washed with brine (20 mL), dried over anhydrous
Na2SO4, filtered and concentrated in vacuo to give a white
solid. HPLC analysis of the crude solid as above showed the
product to have an ee of 99.3%. Recrystallisation from
EtOAcehexane gave colourless needles (0.65 g, 1.6 mmol,
65%).
(500 MHz, CDCl3): d 8.00 (1H, d, J 8.9, C1H), 7.48e7.46
(2H, m, ArH), 7.42e7.39 (3H, m, ArH, C4H), 7.36e7.33
(1H, m, ArH), 7.19 (1H, d, J 12, C7H), 7.17 (1H, dd, J1 8.9,
J2 2.1, C2H), 6.78 (1H, s, C8H), 6.53 (1H, d, J 12, C6H),
5.17 (2H, s, CH2Ph), 3.99 (3H, s, OCH3), 3.95 (3H, s,
OCH3), 3.43 (3H, s, OCH3). 13C NMR (75 MHz, CDCl3):
d 193.2 (C5), 158.6 (C3), 153.1 (C9), 152.5 (C11), 144.3
(C10), 143.1 (C4a), 140.0 (C7H), 136.7 (CH2CPh), 134.4
(C1H), 132.1 (C6H), 130.1 (C11b), 128.9 (2CPhHmeta), 128.4
(CPhHpara), 128.0 (2CPhHortho), 126.0 (C7a), 125.7 (C11a),
118.4 (C2H), 111.2 (C4H), 109.3 (C8H), 70.4 (CH2Ph), 61.7
(C10OCH3), 61.3 (C11OCH3), 56.3 (C9OCH3). HRMS
(ESþ): found: 425.1356. C25H22NaO5 requires: 425.1359.
Found: C 74.8, H 5.75. C25H22O5 requires: C 74.61, H 5.51%.
4.6. 3-Benzyloxy-9,10,11-trimethoxy-6,7-dihydro-
dibenzo[a,c]cyclohepten-5-one (24)
To a solution of enone 17 (12.0 g, 29.85 mmol) in 3:1
EtOHeCH2Cl2 (800 mL) was added PtO2 (0.27 g, 1.2 mmol).
The reaction mixture was degassed five times with hydrogen
and stirred under 1 atm of H2 for 1 h. The reaction mixture
was filtered through Celite and washed thoroughly with
CH2Cl2 (500 mL) and concentrated in vacuo. The residual
white solid was recrystallised from EtOAcehexane to afford
colourless needles of the title compound (10.85 g, 26.9 mmol,
90%): mp 162e164 ꢁC. nmax (diamond compression system):
3345 m, 2939 s, 1686 s, 1594 s, 1001 s, 863 s cmꢀ1. 1H NMR
(500 MHz, CDCl3): d 7.52 (1H, d, J 8.5, C1H), 7.47 (2H, d,
J 7.3, ArH), 7.42e7.39 (2H, m, ArH), 7.36e7.33 (1H, t,
J 7.3, ArH), 7.17 (1H, dd, J 3.0, 8.5, C2H), 7.15 (1H, d, J 3.0,
C4H), 6.60 (1H, s, C8H), 5.12 (2H, s, CH2Ph), 3.90 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 3.50 (3H, s, OCH3), 3.08 (1H, t,
J 13.7, C7HAHB), 2.99e2.83 (2H, m, C6HAHB), 2.64 (1H, d,
J 13.7, C7HAHB). 13C NMR (75 MHz, CDCl3): d 206.9 (C5),
158.1 (C3), 153.0 (C9), 152.4 (C11), 141.8 (C4a), 140.7
(CH2CPh), 136.8 (C7a), 136.0 (C10), 133.1 (C1H), 128.9
(2CPhHmeta), 128.4 (CPhHpara), 127.9 (2CPhHortho), 127.1
(C11b), 124.0 (C11a), 118.6 (C2H), 112.7 (C4H), 107.3
(C8H), 70.4 (CH2Ph), 61.4 (C10OCH3), 61.1 (C11OCH3),
56.3 (C9OCH3), 48.1 (C6H2), 30.4 (C7H2). HRMS (ESþ):
found: 405.1691. C25H25O5 requires: 405.1697. Found: C
74.05, H 6.05. C25H24O5 requires: C 74.24, H 5.98%.
4.7. (5R)-(þ)-3-Benzyloxy-9,10,11-trimethoxy-6,7-dihydro-
5H-dibenzo[a,c]cyclohepten-5-ol (25)
Ketone 24 (11.0 g, 27.2 mmol) was dried in a Kugelrohr
apparatus by heating at 85 ꢁC (0.1 mmHg) for 1 h and then
4.8. (7S)-(ꢀ)-7-Azido-9-benzyloxy-1,2,3-trimethoxy-6,7-
dihydro-5H-dibenzo[a,c]cycloheptene (26)
37
dissolved in a 0.4 M solution of (þ)-TarBeNO2 (138 mL,
54.5 mmol) in THF under N2. This solution was stirred for
45 min and then a 2 M LiBH4 solution in THF (33.0 mL,
68.1 mmol) was added over 90 min via syringe pump. After
addition was complete, the reaction mixture was stirred for
another 30 min and then it was poured into water (200 mL).
Aq HCl (10%, 200 mL) was added and the reaction mixture
A solution of alcohol 25 (8.0 g, 19.7 mmol) in dry CH2Cl2
(80 mL) was cooled to ꢀ40 ꢁC. Triethylamine (4.1 mL,
29.5 mL) was added followed by the addition of methanesul-
fonyl chloride (1.8 mL, 23.6 mmol) at ꢀ40 ꢁC. After stirring
at ꢀ40 ꢁC for 30 min, a solution of tetramethylguanidinium

G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
4707
azide (15.6 g, 98.5 mmol) in dry CH2Cl2 (40 mL) was added
and the temperature was raised slowly to rt [Hazard].z After stir-
ring at rt for 24 h, water (100 mL) was added and mixture was
transferred to a separating funnel. The organic phase was sepa-
rated and the aqueous phase was extracted with CH2Cl2
(2ꢃ100 mL). The combined organic extracts were washed
with brine (100 mL), dried (Na2SO4) and the solvent removed
in vacuo. The residue was then purified by column chromatog-
raphy (SiO2, 9:1, hexaneeEtOAc) to give the title compound
(8.05 g, 18.7 mmol, 95%) as a colourless oil. [a]D ꢀ133.6 (c
1, CHCl3). HPLC using a Chiralpak AD column (5% i-PrOH
in hexanes, 0.5 mL minꢀ1, l 200 nm) indicated an ee 98.7%:
tR 7.4 min for the minor enantiomer; 9.5 min for major enantio-
mer. nmax (diamond compression system): 3366 m, 3063 s, 2940
A sample recrystallised from MeOH gave mp 122e124 ꢁC.
[a]D ꢀ88.4 (c 1, CHCl3). nmax (diamond compression system):
3369 m, 2928 s, 1738 s, 1594 s, 1455 s, 831 s cmꢀ1. 1H NMR
(500 MHz, CDCl3): d 7.48 (2H, m, ArH), 7.42e7.37 (3H, m,
2ArH and C1H), 7.35e7.32 (1H, m, ArH), 7.29 (1H, d, J 3.0,
C4H), 6.94 (1H, dd, J 3.0, 8.6, C2H), 6.57 (1H, s, C8H), 5.14
(2H, s, CH2Ph), 3.90 (6H, s, 2OCH3), 3.82 (1H, dd, J 11.6,
6.4, C5H), 3.62 (3H, s, OCH3), 2.45e2.38 (2H, m, C7H2),
2.34e2.27 (1H, m, C6HAHB), 1.75e1.69 (1H, m, C6HAHB),
1.44 (2H, br s, NH2). 13C NMR (75 MHz, CDCl3): d 161.2
(C3), 158.6, 158.4 (C9, C11), 152.7 (C10), 151.2 (C4a),
143.3 (C7a), 141.3 (CH2CPh), 137.5 (C11b), 136.1 (C11a),
131.4 (C1H), 129.0 (2CPhHmeta), 128.9 (CPhHpara), 128.0
(2CPhHortho), 112.3 (C2H), 110.0 (C4H), 107.7 (C8H), 70.3
(CH2Ph), 61.4 (C10OCH3), 61.2 (C11OCH3), 56.4
(C9OCH3), 51.3 (C5H), 41.9 (C6H2), 30.7 (C7H2). HRMS
(ESþ): found: 406.2015. C25H28NO4 requires: 406.2013.
Found: C 73.6, H 6.75, N 3.35. C25H27NO4 requires: C 74.05,
H 6.71, N 3.45%.
1
s, 2104 s, 1595 s, 1461 s, 833 s cmꢀ1. H NMR (500 MHz,
CDCl3): d 7.49 (2H, d, J 7.7, ArH), 7.43e7.40 (3H, m, 2ArH
and C11H), 7.36e7.34 (1H, m, ArH), 7.22 (1H, d, J 3.0,
C8H), 6.99 (1H, dd, J 3.0, 8.4, C10H), 6.59 (1H, s, C4H),
5.14 (2H, s, CH2Ph), 4.43 (1H, dd, J 7.1, 11.3, C7H), 3.91
(6H, s, 2OCH3), 3.65 (3H, s, OCH3), 2.58e2.44 (2H, m,
C5HAHB, C6HAHB), 2.33 (1H, td, J 12.8, 7.6, C5HAHB), 2.01
(1H, td, J 7.4, 12.8, C6HAHB). 13C NMR (75 MHz, CDCl3):
d 158.6 (C9), 153.0 (C3), 151.3 (C1), 141.6 (CH2CPh), 139.1
(C7a), 137.3 (C4a), 135.1 (C2), 131.7 (C11H), 129.0
(2CPhHmeta), 128.4 (CPhHpara), 128.0 (2CPhHortho), 126.7
(C11a), 124.6 (C11b), 113.6 (C10H), 110.5 (C8H), 107.9
(C4H), 70.5 (CH2Ph), 61.5 (C2OCH3), 61.4 (C7H), 61.2
(C1OCH3), 56.4 (C3OCH3), 39.3 (C6H2), 30.8 (C5H2).
HRMS (ESþ): found: 454.1736. C25H25N3O4Na requires:
454.1737.
Attempts to displace the mesylate with sodium azide in DMF
were thwarted by competing elimination. A Mitsunobu reaction
involving the alcohol 25 (0.15 mmol scale), Zn(N3)2$2pyr57
(1.1 equiv), triphenylphosphine (2.0 equiv) and diisopropyl
azodicarboxylate (2.0 equiv) gave a 67% yield of the azide 26
along with recovered starting material. The yield based on
recovered starting material was 97%.
4.10. (5S)-(ꢀ)-N-(3-Benzyloxy-9,10,11-trimethoxy-6,7-
dihydro-5H-dibenzo[a,c]cyclohepten-5-yl) acetamide (28)
To a solution of amine 27 (6.1 g, 15.0 mmol) in CH2Cl2
(50 mL) was added pyridine (4.8 mL, 60.0 mmol) followed
by acetic anhydride (4.9 mL, 52.5 mmol). The resulting reac-
tion mixture was stirred at rt for 1 h and then quenched with wa-
ter (100 mL) and extracted with CH2Cl2 (3ꢃ100 mL). The
combined organic extracts were washed with 10% aq HCl
(100 mL) and with brine (100 mL), dried (Na2SO4), and con-
centrated in vacuo to afford the crude amide 28 (6.6 g,
14.8 mmol, 99%) as a white fluffy solid. Chiral HPLC of the
crude product on a Chiralcel OD-RH column eluting with
15e25% MeCN in H2O (1.0 mL minꢀ1) revealed an er¼98:2;
tR (major)¼29.8 min; tR (minor)¼27.6 min. A sample recrys-
tallised from MeOHeH2O gave mp 196e197 ꢁC. [a]D27 ꢀ86.9
(c 1, CHCl3). nmax (diamond compression system): 3259 s,
2932 s, 1635 s, 1610 s, 1375 m, 1153 m, 1100 m, 696
1
s cmꢀ1. H NMR (500 MHz, CD3OD): d 8.48 (1H, d, J 8.1,
4.9. (5S)-(ꢀ)-3-Benzyloxy-9,10,11-trimethoxy-6,7-dihydro-
5H-dibenzo[a,c]cyclohepten-5-ylamine (27)
NH), 7.46 (2H, d, J 7.7, ArH), 7.39e7.30 (4H, m, 3ArH,
C1H), 6.95 (1H, m, C2H), 6.94 (1H, d, J 2.6, C4H), 6.72 (1H,
s, C8H), 5.13 (2H, AB system, JAB¼JBA¼12, CH2Ph), 4.68e
4.63 (1H, m, C5H), 3.88 (3H, s, C9OCH3), 3.86 (3H, s,
C10OCH3), 3.49 (3H, s, C11OCH3), 2.51 (1H, dd, J 12.2,
5.3, C7HAHB), 2.32e2.20 (2H, m, C7HAHB, C6HAHB), 1.97
(3H, s, NHAc), 1.96e1.89 (1H, m, C6HAHB). 13C NMR
(75 MHz, CD3OD): d 172.4 (C]O), 159.7 (C3), 153.9 (C9),
152.1 (C11), 142.5, 142.4 (C10, C4a), 138.8 (CH2CPh), 136.6
(C7a), 132.2 (C1H), 129.5 (2CPhHmeta), 128.9 (CPhHpara),
128.6 (2CPhHortho), 128.3 (C11b), 126.2 (C11a), 113.4 (C2H),
110.9 (C4H), 109.2 (C8H), 71.1 (CH2Ph), 61.6 (C10OCH3),
61.4 (C11OCH3), 56.6 (C9OCH3), 50.4 (C5H), 40.0 (C6H2),
31.5 (C7H), 22.7 (O]CeCH3). HRMS (ESþ): found:
470.1939. C27H29NNaO5 requires: 470.1938. Found: C 72.2,
H 6.5, N 3.05. C27H29NO5 requires: C 72.46, H 6.53, N
3.13%. 1H NMR spectra recorded in CDCl3 were complicated
by rotamers.
To a stirred solution of azide 26 (7.7 g, 17.8 mmol) in THF
(150 mL) under nitrogen was added dropwise a solution of
LiAlH4 in THF (1 M, 27 mL, 26.8 mmol) with ice bath cooling.
After stirring overnight at rt, water (20 mL) was added drop-
wise to destroy excess hydride followed by 10% aq NaOH
(200 mL). The mixture was filtered and the organic layer was
separated and the aqueous layer then extracted with CH2Cl2
(3ꢃ200 mL). The combined organic extracts were washed
with brine (300 mL), dried (Na2SO4) and concentrated under
reduced pressure. The yellow oily residue was then purified
by column chromatography (SiO2, 5% Et3NeEtOAc) to give
the title compound (6.9 g, 17.1 mmol, 96%) as a white solid.
z
HAZARD: the use of tetramethylguanidinium azide in dichloromethane is
risky owing to the potential formation of explosive diazidomethane.55 Aceto-
nitrile has been recommended as a safer alternative.56

4708
G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
4.11. (5S)-(ꢀ)-N-(3-Hydroxy-9,10,11-trimethoxy-6,7-
dihydro-5H-dibenzocylohepten-5-yl)-acetamide [(aR,7S)-
(ꢀ)-N-acetylcolchinol] (2)
103.8 (C5H), 65.0, 64.9 (C40H2, C50H2), 60.4 (C4OCH3),
60.1 (C2OCH3), 55.6 (C3OCH3), 29.0, 28.9, 28.8
(3CH2CH2Sn), 27.1 (3CH2CH3), 13.66, 13.63 (3CH3), 11.6
(3CH2Sn). LRMS (ESþ): m/z 529 [Mþ, 15%], 531 (25), 471
(65), 473 [MþꢀC4H7, 90%], 475 (100). HRMS (ESþ): found:
473.1504. C20H35O1518Sn requires: 473.1501.
A 500 mL round-bottom flask was charged with acetamide
28 (12.3 g, 27.5 mmol), 10% Pd/C (4.4 g, 4.1 mmol) and
2-propanol (300 mL). The reaction mixture was carefully de-
gassed five times with hydrogen and stirred under 1 atm of
H2 for 2 h. The reaction mixture was then filtered through Celite
and the residue thoroughly washed with methanol. The com-
bined filtrate and washes were concentrated under reduced
pressure affording a white fluffy solid. Chiral HPLC of the
crude product on a Chiralcel OD-RH column eluting with
15e25% MeCN in H2O (1.0 mL minꢀ1) revealed an er¼97:3;
tR (major)¼24.4 min; tR (minor)¼22.0 min. The white solid
was recrystallised from EtOHeH2O to give the title compound
(9.8 g, 27.4 mmol, 99%) as white crystals: mp 152e154 ꢁC; lit.
Mp 150 ꢁC (EtOH).14 [a]D27 ꢀ34.0 (c 1, CHCl3). nmax (diamond
compression system): 3326 s, 2931 s, 2860 m, 1537 s, 1455 s,
4.13. 1-(40-Benzyloxy-600-[1000,3000]-dioxolan-2000-yl-200,300,400-
trimethoxybiphenyl-20-yl)-ethanone (30)
A 100 mL flame-dried round-bottomed flask, equipped with
a water condenser and a nitrogen inlet, was charged with 1-(50-
benzyloxy-20-bromophenyl)-ethanone 22 (2.13 g, 7.0 mmol),
triphenylphosphine (0.865 g, 3.3 mmol), CuI (0.53 g,
2.8 mmol), Pd(PPh3)4 (1.61 g, 1.4 mmol), 2,6-di-tert-butyl-4-
methylphenol (one small crystal), DMF (35 mL) and stannane
29 (4.44 g, 8.4 mmol). The reaction mixture was stirred for
5 min at rt and then refluxed for 106 h, before addition of
water (50 mL) at rt. The layers were separated and the aqueous
layer extracted with hexaneseEt2O (1:1) mixture (4ꢃ50 mL).
The combined organic extracts were washed with brine
(2ꢃ50 mL), dried over anhydrous Na2SO4, filtered and con-
centrated in vacuo. The residue was then purified by column
chromatography on silica gel (1:1, hexaneseEt2O/Et2O) to
give the title compound (1.69 g, 3.63 mmol, 52%) as a white
amorphous solid which was recrystallised from CH2Cl2ehex-
anes affording the title compound (1.46 g, 3.14 mmol) as col-
ourless prisms: mp 103e106 ꢁC (CHCl3). Rf 0.09 (1:1,
hexaneseEt2O). nmax (CHCl3): 2940 m, 2891 m, 1690 s,
1600 s, 1563 m, 1483 s, 1463 s, 1402 s, 1335 m, 1281 m,
1233 m, 1197 m, 1150 m, 1094 s, 1040 m, 1003 m, 909 s,
1
1226 s, 1050 m, 826 m cmꢀ1. The H and 13C NMR spectro-
scopic data recorded at 500 and 125 MHz, respectively, were
identical to those reported previously.19
The er of (ꢀ)-2 is easily enhanced by crystallisation because
(ꢂ)-2 is much less soluble in MeOH and crystallises readily as
colourless prisms. Thus, a sample of 2 (94% ee) was dissolved
in hot MeOH. On cooling to rt, the crystals of (ꢂ)-2 were col-
lected by filtration leaving (ꢀ)-2 (>99% ee) in solution. On ad-
dition of H2O to the filtrate, the (ꢀ)-2 then crystallised as a fine
white powder. An X-ray crystal structure of (ꢂ)-2 recrystallised
from MeOH showed one tightly bound MeOH molecule for
each molecule of (ꢂ)-2 in the crystal lattice. An X-ray structure
of (ꢀ)-NAC$H2O has been determined.58
1
732 s cmꢀ1. H NMR (500 MHz, CDCl3): d 7.49e7.48 (2H,
m, ArH), 7.44e7.41 (3H, m, ArH), 7.38 (1H, m, C30H),
7.21 (1H, d, J 8.1, C60H), 7.14 (1H, dd, J 2.6, 8.1, C50H),
7.01 (1H, s, C500H), 5.37 (1H, s, C2000H), 5.14 (2H, s, CH2Ar),
4.07e4.01 (2H, m, C4000H, C5000H), 3.94 (3H, s, C400OCH3),
3.89 (3H, s, C300OCH3), 3.87e3.79 (2H, m, C4000H, C5000H),
3.59 (3H, s, C200OCH3), 2.14 (3H, s, O]CeCH3). 13C NMR
(75 MHz, CDCl3): d 201.2 (C1), 158.3 (C40), 153.5 (C400),
151.2 (C200), 143.0 (C300), 141.6 (CH2C), 136.8 (C20), 133.6
(C60H), 130.8 (C600), 128.9 (2CPhHmeta), 128.4 (2CPhHortho),
128.2 (C10), 127.9 (CPhHpara), 126.9 (C100), 117.6 (C50H),
114.4 (C30H), 105.3 (C500H), 101.5 (C2000H), 70.4 (CH2Ph),
65.5, 65.4 (C4000H2, C5000H2), 61.1 (C300OCH3), 60.9
(C200OCH3), 56.1 (C400OCH3), 29.4 (O]CeCH3). LRMS
(ESþ): m/z 487 [MþþNa, 100%], 488 (5), 465 [MþþH, 90%],
466 (5). HRMS (ESþ): found: 465.1923. C27H29O7 requires:
465.1913.
4.12. Tributyl-(6-[10,30]-dioxolan-20-yl-2,3,4-
trimethoxyphenyl)-stannane (29)
tert-Butylithium (13 mL of a 1.52 M solution in pentane,
20.0 mmol) was added to a solution of bromoarene 20
(3.19 g, 10.0 mmol) in dry Et2O (50 mL) at ꢀ78 ꢁC. The re-
sulting black mixture was stirred at ꢀ78 ꢁC for 55 min before
the dropwise addition of tributyltin chloride (5.4 mL, 6.51 g,
20.0 mmol) at ꢀ78 ꢁC. The mixture was allowed to warm to
rt overnight and the solvent removed in vacuo. The residue
was purified by column chromatography on silica gel (3:1,
hexaneseEt O) and distilled under reduced pressure (Kugel-
¨
rohr) to afford the title compound (4.39 g, 8.3 mmol, 83%)
2
as a colourless oil: bp 175 ꢁC (bath), 0.15 mmHg (Kugelrohr).
¨
Rf 0.27 (3:1, hexaneseEt2O). nmax (CHCl3): 2956 s, 2930 s,
2872 m, 2852 m, 1583 m, 1464 m, 1377 s, 1310 s, 1197 m,
A solution of biaryl 30 (107 mg, 0.23 mmol) in CH2Cl2
(10 mL) was treated with 6 M HCl (6 mL). The biphasic mix-
ture was stirred for 20 min at rt and the layers were separated.
The organic layer was washed with brine (10 mL), dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The
residue was then purified by column chromatography on silica
gel (3:2, hexaneseAcOEt) to give the keto aldehyde 23
1
1163 m, 1101 s, 1044 m, 733 s cmꢀ1. H NMR (500 MHz,
CDCl3): d 7.03 (1H, s, C5H), 5.57 (1H, s, C20H), 4.14 (2H,
m, C40H, C50H), 4.02 (2H, m, C40H, C50H), 3.88 (3H, s,
C3OCH3), 3.86 (3H, s, C4OCH3), 3.82 (3H, s, C2OCH3),
1.63e1.41 (6H, m, 3CH2CH2Sn), 1.38e1.26 (6H, m,
3CH2CH3), 1.05 (6H, m, 3CH2Sn), 0.88 (9H, t, J 7.17,
3CH3). 13C NMR (75 MHz, CDCl3): d 157.3 (C2), 153.9
(C4), 140.9 (C6), 139.0 (C3), 126.3 (C1), 104.7 (C20H),
1
(95 mg, 0.22 mmol, 98%) displaying H and 13C NMR spec-
troscopic data identical to those described above.

G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
4709
4.14. Solid phase synthesis of colchinoleRGD peptide
conjugate 34
17e18 min) and the eluent removed by freeze drying to give
the target conjugate 34 (38 mg, 0.04 mmol, 16% based on
the estimated peptide resin loading of 0.23 mmol/g) as a white
4.14.1. Solid phase synthesis of FmoceD-Phe-Lys(Dde)-
Arg(Pbf)-Gly-AspeOAll (32)
solid. 1H NMR (500 MHz, DMSO-d6):
d
8.39e8.35
(1H, m, N13H), 8.27e8.19 (2H, m, N4H, N44H), 8.07e7.96
(2H, m, N1H, N7H), 7.76(1H, t, J5.5, N37H), 7.62e7.58(1H, m,
N10H), 7.53 (1H, t, J 5.7, N29H), 7.22e7.09 (6H, m, C21H,
C25H, C22H, C23H, C24H, C55H), 7.02 (1H, s, N31H),
6.75e6.73 (1H, m, C58H), 6.72 (1H, s, C49H), 6.67 (1H, dd,
J 8.3, 2.2, C56H), 4.62 (1H, dt, J 8.4, 5.9, C2H), 4.50e4.41
(2H, m, C5H, C8H), 4.16e4.11 (1H, m, C11H), 4.05e3.88
(1H, m, C14HAHB), 3.83e3.80 (1H, m, C45H), 3.77e3.73
(6H, m, C60H3, C61H3), 3.45 (3H, s, C62H3), 3.25e3.21 (1H,
dd, J 15.0, 4.1, C14HAHB), 3.08e3.02 (4H, m, C28H2,
C36H2), 2.95e2.90 (1H, m, C19HAHB), 2.80 (1H, dd, J 13.2,
5.6, C19HAHB), 2.74e2.68 (1H, m, C16HAHB), 2.53e2.43
(4H, m, C46H2, C47H2), 2.37e2.34 (1H, m, C16HAHB),
2.20e2.02 (5H, m, C33HAHB, C39H2, C42H2), 1.90e1.85
(1H, m, C33HAHB), 1.73e1.67 (1H, m, C26HAHB), 1.52e
1.10 (9H, m, C26HAHB, C27H2, C35H2, C40H2, C41H2),
1.03e0.99 (2H, m, C34H2). 13C NMR (125 MHz, DMSO-d6):
d 172.05 (C12), 171.92 (C9), 171.60 (C38), 171.10 (C43),
170.94 (C15), 170.57 (C17), 169.90 (C6), 169.48 (C3), 156.61
(C57), 156.41 (C30), 151.79 (C50), 150.26 (C52), 141.70
(C59), 140.50 (C51), 137.19 (C20), 134.67 (C48), 130.36
(C55H), 129.03 (C22H, C24H), 128.06 (C21H, C25H),
126.24 (C23H), 124.68 (C54), 124.38 (C53), 112.84 (C56H),
110.12 (C58H), 107.94 (C49H), 60.46 (C61H3, C62H3), 60.37
(C60H3), 55.77 (C45H), 54.50 (C8H), 54.31 (C5H), 51.81
(C11H), 48.84 (C2H), 43.19 (C14H2), 40.23 (C46H2), 39.59
(C28H2), 39.51 (C36H2), 38.36 (C19H2), 38.17 (C16H2),
35.17 (C39H2), 35.10 (C42H2), 30.82 (C33H2), 30.10
(C47H2), 28.80 (C35H2), 28.50 (C26H2), 28.41 (C27H2),
25.16 (C40H2), 24.96 (C41H2), 22.79 (C34H2). LRMS (ESþ):
m/z 1029 [MþþH, 100%], 1030 (60), 731 (30). HRMS (ESþ):
found: 1029.5044. C51H69N10O13 requires: 1029.5046.
Commercial N-a-FmoceL-Asp(Wang LL)eOAll resin (No-
vobiochem, 0.65 g,loading0.35 mmol/g, 0.23 mmol)wasdepro-
tected with piperidineeDMF (1:4). Standard Fmoc protocols
were then used to append in sequence N-a-FmoceGlyeOH, N-
a-FmoceL-Arg(Pbf)eOH, N-a-FmoceL-Lys(Dde)eOH and
N-a-FmoceD-PheeOH. HCTU was used as coupling agent.
4.14.2. Synthesis of the resin-bound c[RGDfK] 33
A solution of Pd(PPh3)4 in CHCl3eAcOHeN-methylmor-
pholine (37:2:1, 8 mL) was added to peptide resin 32 and the
resulting mixture agitated for 4 h at rt. The resin was filtered
and washed consecutively with DIPEAeDMF (5:95,
3ꢃ10 mL), diethyldithiocarbamic acid sodium salteDMF
(0.5:99.5, 3ꢃ10 mL), DMF (3ꢃ10 mL) and finally CH2Cl2
(2ꢃ10 mL). After removal of the remaining Fmoc group with
piperidineeDMF (1:4) as described above, the cyclisation
was achieved by adding HCTU (3 equiv) in DMF (5 mL). After
24 h, the resin was washed with DMF (3ꢃ10 mL) and CH2Cl2
(3ꢃ10 mL) to give the resin-bound c[RGDfK] peptide 33.
60
50 OMe
49
H
37
47
61
35
39
41
42
51 OMe
52
22 21
N
38
48
53
34
9
46
40
O
36
19
23
H
7
45
59
58
20
44
O
33
N
54
43
OMe
O
6
N
25 HN4
5
62
24
55
8
O
H
O
3
2
56
57
10
11
12
NH
16
17
H
29
32
30 NH2
27
H6O3
N
H1O8
HN1
O
28
26
15
13
N
H
14
O
NH
O
31
34
H
H
4.14.3. c[RGDfK(adipoyl-colchinol)] 34
Removal of the Dde protecting group was accomplished by
twofold treatment of 33 with hydrazine monohydrate in DMF
(2:98, 5 mL) for 5 min before washing with DMF (10ꢃ1 mL).
The resin was then suspended in DMF (5 mL) and adipic anhy-
dride (290 mg, 2.3 mmol, 10.0 equiv) and DIPEA (0.5 mL,
2.8 mmol, 12.0 equiv) were added. After agitation for 20 h,
the resin was washed with DMF. The resin was suspended in
a solution of HCTU (285 mg, 0.7 mmol, 3.0 equiv), HOBt
(106 mg, 0.7 mmol, 3.0 equiv) and DIPEA (0.24 mL,
1.4 mmol, 6.0 equiv) in DMF (3 mL). Colchinol hydrochloride
(35, 245 mg, 0.7 mmol, 3.0 equiv) in DMF (3 mL) was added
and the mixture was agitated for 60 h before exhaustive washing
with DMF followed by CH2Cl2. Treatment of the resin with
TFAe(i-Pr)3SiHeH2O (95:2.5:2.5, 6 mL) for 1 h was followed
by washing with TFA (2ꢃ1 mL). The combined filtrate and
washings were concentrated in vacuo and Et2O (10 mL) was
added to the residue. The resultant white precipitate was centri-
fuged and washed with more Et2O (3ꢃ). The crude peptide
was then purified by preparative reverse phase HPLC (Thermo
Hypersil Keystone Hyperprep C18 column, 50e95%
MeCNþ0.1% TFA in waterþ0.1% TFA, 5 mL minꢀ1, tR
4.15. Colchinol hydrochloride (35)
(ꢀ)-N-Acetylcolchinol (0.1 g, 0.3 mmol) was dissolved in
2 mL of a (1:1) mixture of 2 M aq HCl and MeOH. The solution
was refluxed for 24 h before removal of the solvent in vacuo.
The residue was washed several times with Et2O and dried in
vacuo affording the target molecule (0.09 mg, 0.25 mmol,
85%) as a fluffy white powder that was used without further pu-
1
rification in the next step: mp 192e194 ꢁC (Et2O). H NMR
(500 MHz, CD3OD): d 7.36 (1H, d, J 8.3, C10H), 6.90 (1H, d,
J 8.3, C20H), 6.89 (1H, s, C40H), 6.80 (1H, s, C80H), 4.05e
3.95 (1H, m, C50H), 3.91 (3H, s, C90OCH3), 3.87 (3H, s,
C100OCH3), 3.58 (3H, s, C110OCH3), 2.70e2.55 (2H, m,
C70H), 2.40e2.25 (1H, m, C60HAHB), 2.15e2.05 (1H, m,
13
C60HAHB). C NMR (125 MHz, CD3OD): d 158.8 (C30),
154.6 (C90), 152.5 (C110), 143.0 (C100), 137.0 (C4a0), 136.1
(C7a0), 133.5 (C11b0), 127.3 (C10H), 125.8 (C11a0), 115.8
(C20H), 110.5 (C40H), 109.1 (C80H), 61.9 (C100OCH3), 61.8
(C110OCH3), 57.0 (C90OCH3), 52.6 (C50H), 39.3 (C60H2),
30.9 (C70H2). nmax (neat): 2900 s, 1611 s, 1454 s, 1405 m,

4710
G. Besong et al. / Tetrahedron 64 (2008) 4700e4710
1332 m, 1229 s, 1146 m, 1089 s, 1057 m, 1005 m, 820 m cmꢀ1
.
26. Suzuki, A. Handbook of Organopalladium Chemistry for Organic Synthe-
sis; Negishi, E.-i., de Meijere, A., Eds.; Wiley-Interscience: 2002; Vol. 1,
pp 249e262; Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633e9695.
LRMS (ESþ): m/z 299 [MþꢀNH3Cl, 100%], 316 [MþꢀCl,
96%], 317 (25), 285 (50). HRMS (ESþ): found: 316.1555.
C18H22NO4 (MþH) requires: 316.1549.
27. Bolton, R. E.; Moody, C. J.; Pass, M.; Rees, C. W.; Tojo, G. J. Chem. Soc.,
Perkin Trans. 1 1988, 2491e2499.
28. (a) For preceding uses of the Suzuki coupling in the synthesis of colchi-
cinoids see: Banwell, M. G.; Cameron, J. M.; Collis, M. P.; Crisp,
G. T.; Gable, R. W.; Hamel, E.; Lambert, J. N.; Mackay, M. F.; Reum,
M. E.; Scoble, J. A. Aust. J. Chem. 1991, 44, 705e728; (b) Banwell,
M. G.; Cameron, J. M.; Corbett, M.; Dupuche, J. R.; Hamel, E.; Lambert,
J. N.; Lin, C. M.; Mackay, M. F. Aust. J. Chem. 1992, 45, 1967e1982; (c)
Joncour, A.; Decor, A.; Thoret, S.; Chiaroni, A.; Baudoin, O. Angew.
Chem., Int. Ed. 2006, 45, 4149e4152.
Acknowledgements
We thank AstraZeneca (Alderley Edge) for financial
support and James Titchmarsh for chiral HPLC analyses.
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