Synthetic approaches to the southern part of cyclotheonamide C

Article abstract of DOI:10.1016/j.tetlet.2003.09.196

A synthetic equivalent of the southern segment of cyclotheonamide C, a cyclopentapeptide isolated from the sponge Theonella, has been synthesized via complementary Wadsworth-Emmons or palladium-catalysed methodologies followed by tandem oxidation/vinyloga

Full text of DOI:10.1016/j.tetlet.2003.09.196

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8827–8830
Synthetic approaches to the southern part of cyclotheonamide C
David J. Aitken,* Sophie Faure and Ste´phane Roche
Laboratoire SEESIB-CNRS (UMR 6504), De´partement de Chimie, Universite´ Blaise Pascal—Clermont-Ferrand II,
24, Avenue des Landais, 63177 Aubie`re cedex, France
Received 29 July 2003; revised 19 September 2003; accepted 23 September 2003
Abstract—A synthetic equivalent of the southern segment of cyclotheonamide C, a cyclopentapeptide isolated from the sponge
Theonella, has been synthesized via complementary Wadsworth–Emmons or palladium-catalysed methodologies followed by
tandem oxidation/vinylogation in 41% overall yield (five steps) from readily available starting materials.
© 2003 Elsevier Ltd. All rights reserved.
Over the last decade, a family of nine macrocyclic
pentapeptides named cyclotheonamides (CtA–CtEn)
has been isolated from Theonella and Ircinia sponges by
the groups of Fusetani1 and Murakami2 (Fig. 1). These
macrocyclic compounds contain unusual amino acid
residues and act as powerful inhibitors of thrombin and
other serine proteases (trypsin, plasmin, etc.).1–4 Three
residues (northern part) interact directly with the
enzyme active site while the other two (southern part)
play a structural role. The novel structure and potential
therapeutic value of these compounds has stimulated
considerable interest; however, only four cyclotheon-
amides have been prepared by total synthesis (CtA,3,5
CtB,6 CtE2,7 CtE37). Within the group, cyclotheon-
amide C (CtC) has the unique feature of a vinylogous
a,b-dehydrotyrosine moiety v-DTyr.1b The present work
describes the efficient synthesis of ‘South-C’ 1, a key
synthetic equivalent of the southern fragment
C(12)ꢀN(19) of CtC.
In particular, we have examined and compared two
complementary routes leading to the a,b-didehydro-
tyrosine derivative 2: via Wadsworth–Emmons reaction
of a phosphorylglycine or via palladium-catalysed coup-
ling of a dehydroalanine derivative (Scheme 1).
Previous work on dehydroamino acids8 suggested that
dipeptide 2 might be obtained by Wadsworth–Emmons
reaction of the phosphonoglycine derivative 6 with the
corresponding protected p-hydroxybenzaldehyde 7.
Compound 6 was obtained in 95% yield by coupling of
N-Boc-
D
-Phe
5
and dimethoxyphosphorylglycine
methyl ester 4, the latter readily prepared by deprotec-
tion of its commercially available benzyl carbamate
precursor 3 immediately before use (Scheme 2). The
aldehyde partner 7 bearing a silyl ether protecting
group was prepared simply from p-hydroxybenzalde-
hyde.9 Wadsworth–Emmons reaction of 6 with 7 in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
at low temperature (−20°C) provided the dipeptide 2 in
74% yield in a Z/E ratio of 90/10. Use of other bases
(NaH, tBuOK) gave lower yields (536%) and complete
loss of Z/E selectivity (Table 1). The isomers of 2 were
easily separated by flash chromatography on silica gel
and the Z double bond configuration of the major
1
isomer was assigned according to H NMR analysis.
Previous studies on dehydroamino acids have shown
that the vinyl proton signal of the E isomer appears
l=0.2–0.7 ppm downfield from that of the Z isomer
(Scheme 2).10 This first convergent strategy provided
pure (Z)-2 in three steps from phosphorylglycine
derivative 3 with a 62% overall yield.
Figure 1. Members of the cyclotheonamide (Ct) family.
* Corresponding author. Tel.: +33-4-73-40-74-81; fax: +33-4-73-40-
77-17; e-mail: aitken@chimie.univ-bpclermont.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.196

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D. J. Aitken et al. / Tetrahedron Letters 44 (2003) 8827–8830
Scheme 1. Retrosynthetic analysis of 1, a synthetic equivalent of the southern part of CtC.
efforts to oxidize this alcohol to aldehyde 15 met with
The second strategy proceeds via the dehydroalanine
(DAla) building block 10 and introduces the DTyr
moiety by palladium-catalysed coupling (Scheme 1).
The intermediate 10 was prepared in two steps and in
difficulty, due to product instability and considerable
loss of material on attempted isolation and purification.
We therefore carried out the subsequent vinylogation
reaction on 14 after minimal work-up of the oxidation
reaction. Several mild oxidants—Dess–Martin periodi-
nane (DMP), manganese dioxide, O2–TEMPO–
CuCl19—were investigated prior to the Wadsworth–
Emmons reaction with the anion of methyl diethylphos-
phonoacetate (Table 3). Only moderate yields (42–55%)
of 1 were obtained. We therefore adapted the system
for a ‘one-pot’ transformation, which required use of
(carbomethoxymethylene)triphenylphosphorane as the
nucleophile. A DMP-based protocol20 was inefficient,
68% yield (Scheme 3). Coupling of N-Boc- -Phe 5 and
D
DL-Ser-OMe 8 provided the dipeptide 9 which was
readily dehydrated using cuprous chloride and 1-(3-
dimethylaminopropyl)-3-ethyl carbodiimide hydrochlo-
ride (EDCI).11 We first investigated the Heck coupling
reaction.12 Silyl ether protection of p-iodophenol gave
compound 12 which was reacted with 10 in the presence
of different catalytic systems (Scheme 3, Table 2). The
coupling reaction provided the expected Z isomer
exclusively, but in only 30–35% yield at best, due in
part to incomplete conversion of the substrate. The
most useful result was obtained with Herrmann’s cata-
lyst (palladium acetate and tris-o-tolylphosphine as lig-
and).13 The absence of a phosphine ligand gave similar
conversion but led annoyingly to cleavage of the silyl
ether protecting group. The inefficiency of the Heck
coupling is probably due to cumulative unfavorable
electronic and steric effects, arising from the electron-
rich iodoaryl component and the a,a-disubstituted
alkene partner.
21
but use of MnO2 provided target compound 1 in 75%
yield with exclusively the E configuration for the new
double bond (Table 3).22
We therefore turned our attention towards the Suzuki
coupling reaction.14 In this case, the stereoelectronic
effects prevalent in the alkene and aryl reacting part-
ners should now promote the reaction.15 The appropri-
ate components—bromoalkene 11 and boronic acid
derivative 13—were synthesized from the dipeptide 10
and p-iodophenol 12, respectively (Scheme 3).16,17 Grat-
ifyingly, Suzuki coupling provided the required com-
pound 2 as a single Z isomer in 76% yield. The
combination of two additives, ethanol and water, accel-
erates the reaction.18 In the absence of water, the
reaction time was longer and partial transesterification
occurred. In the absence of both water and ethanol, the
reaction was much less efficient (Table 2).
The last sequence of this synthesis of ‘South-C’ 1 is the
vinylogation of compound 2 by conversion into the
aldehyde 15 followed by a Wittig-type reaction (Scheme
4). Chemoselective reduction of intermediate 2 with
LiAlH4 gave primary alcohol 14 in high yield. Initial
Scheme 2. Reagents and conditions: (a) H2 (3 atm), 10% Pd/C,
MeOH, quant.; (b) EDCI, HOBt, CH2Cl2, rt, 95%; (c) TIPS-
Cl, imidazole, CH2Cl2, 95%; (d) see Table 1.

D. J. Aitken et al. / Tetrahedron Letters 44 (2003) 8827–8830
Table 1. Wadsworth–Emmons reaction of 6 with 7
8829
Entry
Conditions (d)
Yield of 2 (%)
Z/E ratio
Yield of (Z)-2 (%)
1
2
3
tBuOK, CH2Cl2, −78°C
NaH, THF, −20°C
DBU, CH2Cl2, −20°C
0
36
74
–
0
18
67
50/50
90/10
Scheme 3. Reagents and conditions: (a) Isobutyl chloroformate, Et3N, DL-Ser-OMe, CH2Cl2, 87%; (b) EDCI, CuCl, CH2Cl2, 80%;
(c) NBS, CH2Cl2 then Et3N, 86%; (d) see Table 2; (e) see Table 2; (f) TIPSCl, imidazole, CH2Cl2, 94%; (g) tBuLi, B(OiPr)3, THF,
−78°C then HCl (2 M), 58%.
Table 2. Palladium-catalysed Heck and Suzuki coupling reaction conditions
Entry
Alkene
Arene
Catalytic system
Solvent
Temperature
Time (h)
Yield of 2 (%)
1
2
3
4
5
6
10
10
10
11
11
11
12
12
12
13
13
13
3% Pd(OAc)2, Bu4NBr, NaHCO3
10% Pd(OAc)2, 20% PPh3, Et3N
5% Pd(OAc)2, 10% P(o-tolyl)3, Et3N
3% Pd(PPh3)4, K2CO3
3% Pd(PPh3)4, K2CO3, 20% EtOH
3% Pd(PPh3)4, K2CO3, 20% EtOH, 10% H2O Toluene
DMF
100°C
Reflux
Reflux
Reflux
Reflux
Reflux
24
48
96
48
16
1
34a
22
30
CH3CN
CH3CN
Toluene
Toluene
16
57b
76
a Yield of the corresponding phenol, due to silyl ether cleavage.
b Partial transesterification occurred to provide the ethyl ester derivative with an additional 17% yield.
Scheme 4. Reagents and conditions: (a) LiAlH4, THF, 0°C, 86%; (b) oxidation: see Table 3; (c) Wadsworth–Emmons: see Table
3; (d) ‘one-pot’ oxidation–vinylogation: see Table 3.
Table 3. Obtention of 1 by oxidation–vinylogation of compound 14
Entry
Strategy
2 steps
2 steps
2 steps
Conditions
Yield of 1 (%)
1
2
3
(b) DMP (1.5 equiv.), py, CH2Cl2, 1 h; (c) (EtO)2POCH2CO2Me/NaH (3 equiv.), THF, −0°C to
rt, 1 h
(b) MnO2 (15 equiv.), CH2Cl2, D, 36 h; (c) (EtO)2POCH2CO2Me/NaH (3 equiv.), THF, −0°C to
rt, 1 h
(b) TEMPO (0.1 equiv.), CuCl (0.1 equiv.), O2, 12 h; (c) (EtO)2POCH2CO2Me/NaH (3 equiv.),
THF, −0°C to rt, 1 h
42
49
55
4
5
‘One-pot’
‘One-pot’
(d) DMP (1.2 equiv.), PhCO2H (2 equiv.), Ph3PꢁCHCO2Me (1.5 equiv.), CH2Cl2/DMSO, rt, 1 h
(d) MnO2 (20 equiv.), Ph3PꢁCHCO2Me (1.5 equiv.), CH2Cl2, D, 24 h
20
75

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D. J. Aitken et al. / Tetrahedron Letters 44 (2003) 8827–8830
van der Baan, J. L.; Ottenheijm, C. J. J. Org. Chem.
In
conclusion,
two
complementary
synthetic
approaches have led successfully to key compound 1, a
synthetic equivalent of the southern fragment
C(12)ꢀN(19) of cyclotheonamide C, bearing three
mutually orthogonal protecting groups. The second
route has the advantage of providing intermediate 2 via
a fully stereoselective Suzuki coupling reaction. How-
ever, the phosphonoglycine-based strategy leading to 2
is more expedient (even allowing for chromatographic
separation of stereoisomers). Beginning with this
sequence, the target compound 1 was prepared in five
steps from readily available materials with 41% overall
yield.
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7. (a) Wasserman, H. H.; Zhang, R. Tetrahedron Lett. 2002,
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Acknowledgements
We are grateful to the MENRT for a PhD grant (to
S.R.) and to the CNRS for financial support.
8
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22. Compound 1: white powder, mp 71–73°C, [h]2D5=+68 (c
1.6, CHCl3), 1H NMR (400 MHz, CDCl3) l 1.02 (d,
J=7.2 Hz, 18H), 1.16 (hept, J=7.2 Hz, 3H), 1.34 (s, 9H),
3.00 (dd, J=13.8, 7.1 Hz, 1H), 3.13 (dd, J=13.8, 7.1 Hz,
1H), 3.64 (s, 3H), 4.51 (m, 1H), 5.08 (d, J=8.4 Hz, 1H),
5.59 (d, J=15.4 Hz, 1H), 6.53 (s, 1H), 6.67 (d, J=8.6 Hz,
2H), 7.13 (d, J=8.6 Hz, 2H), 7.15–7.26 (m, 6H), 7.47 (s,
1H). 13C NMR (100 MHz, CDCl3) l 12.6 (3CH), 17.9
(6CH3), 28.2 (3CH3), 37.5 (CH2), 51.4 (CH3), 56.0 (CH),
80.6 (C), 116.8 (CH), 120.1 (2CH), 127.0 (CH), 127.1 (C),
128.6 (C), 128.8 (2CH), 129.4 (2CH), 131.2 (2CH), 135.0
(CH), 136.5 (C), 144.0 (CH), 155.9 (C), 157.0 (C), 167.3
(C), 170.4 (C). Elemental analysis calcd for
C35H50N2O6Si: C, 67.49; H, 8.09; N, 4.50. Found: C,
67.52; H, 8.09; N, 4.59.