Preparation of the central tryptophan moiety of the celogentin/moroidin family of anti-mitotic cyclic peptides

Article abstract of DOI:10.1071/CH06324

The central functionalized tryptophan core of the celogentin/moroidin family of cyclic peptides has been prepared. The strategy incorporates a novel preparation of 4-iodobenzaldehyde and employs a Larock annulation as the key step. CSIRO 2006.

Full text of DOI:10.1071/CH06324

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 819–826
Preparation of the Central Tryptophan Moiety of the Celogentin/
Moroidin Family of Anti-Mitotic Cyclic Peptides
Alexander K. L. Yuen,A Katrina A. Jolliffe,A and Craig A. HuttonB,C
A School of Chemistry, University of Sydney, Sydney NSW 2006, Australia.
B School of Chemistry and Bio21 Molecular Science and Biotechnology Institute,
University of Melbourne, Melbourne VIC 3010, Australia.
C Corresponding author. Email: chutton@unimelb.edu.au
The central functionalized tryptophan core of the celogentin/moroidin family of cyclic peptides has been prepared.
The strategy incorporates a novel preparation of 4-iodobenzaldehyde and employs a Larock annulation as the
key step.
Manuscript received: 1 September 2006.
Final version: 2 October 2006.
Introduction
and severe distress, and as such the bush is regarded as a
menace to humans and stock, particularly horses.[2]
Moroidin was first isolated in 1986 by Williams and
co-workers,[1] who were interested in discovering the
causative agent of biological activity in the extract of the
leaves of the Australian rainforest bush Laportea moroides.
Contact with the stinging hairs present on the leaves of
L. moroides causes vasodilation, piloerection, local sweat-
ing, and intense long-lasting pain, which results in anxiety
Moroidin (1, Fig. 1) is an octapeptide composed of two
fused macrocycles. The ‘left-hand’ macrocycle contains a
leucine–tryptophan cross-link while the ‘right-hand’ macro-
cycle contains a histidine–tryptophan cross-link. Extensive
spectroscopic and chemical analysis and molecular mod-
elling performed by Williams and co-workers[1,3] suggested
R2
H
H
N
N
NH2
NH2
O
O
O
O
H
N
O
NH
H
N
O
NH
N
H
N
H
N
H
N
H
HN
O
HN
O
O
CO2R1
N
NH
NH
NH
NH
N
N
NH
CO2R1
N
O
O
O
O
N
H
N
H
H
N
H
N
O
O
1 Moroidin; R1 ϭ H, R2 ϭ H
2 Celogentin E; R1 ϭ Asp, R2 ϭ H
3 Celogentin F; R1 ϭ Arg, R2 ϭ H
4 Celogentin G; R1 ϭ H, R2 ϭ Me
5 Celogentin H; R1 ϭ Asp, R2 ϭ Me
6 Celogentin J; R1 ϭ Arg, R2 ϭ Me
7 Celogentin A; R1 ϭ H
8 Celogentin B; R1 ϭ His
9 Celogentin D; R1 ϭ His-Lys
O
O
O
CO2H
H
H
NH
N
N
N
N
H
N
HN
H
O
O
N
NH2
O
O
H
NH
NH
NH
NH
N
NH
N
O
O
N
H
N
H
O
O
H
N
H
N
CO2H
O
O
11 Stephanotic acid
10 Celogentin C
Fig. 1. Structures of moroidin, celogentins A–J, and stephanotic acid.
© CSIRO 2006 10.1071/CH06324
0004-9425/06/110819

820
A. K. L. Yuen, K. A. Jolliffe, and C. A. Hutton
Moroidin/celogentins
that moroidin was composed entirely of l-amino acids, that
the β-carbon of the leucine residue was appended to the tryp-
tophan C6 and was of (R)-configuration, and that the N-1 of
the histidine imidazole group was bonded to C2 of the cen-
tral tryptohan residue. The structural assignment of moroidin
was unambiguously confirmed by Kobayashi et al. in 2004
by X-ray crystallographic analysis.[4]
In recent years the Kobayashi group has reported the
isolation and characterization of many more members of
this family of natural products, derived from the seeds of
Celosia argentea, along with moroidin itself (Fig. 1).[4–6]
These bicyclic peptides have very closely related structures.
The same ‘left-hand’ macrocycle is present in all members
of the family with the exception that celogentins G, H, and
J (4–6) have an isoleucine residue in place of the valine
residue. All other variation between the family members
occurs in the size and composition of the ‘right-hand’macro-
cycle. All family members (except celogentin K) contain
both tryptophan C2–histidine N-1 and tryptophanC6–leucine
Cβ crosslinks. Stephanotic acid (11) has also recently been
isolated and is closely related to the ‘left-hand’ ring of the
celogentin/moroidin family.[7]
The celogentins (2–10) and moroidin (1) have been shown
to possess potent anti-tubulin activity.[8] The anti-mitotic
activity of the most potent member of the family, celogentin C
(IC50 0.8 × 10−6 M), is more potent than the vinca alkaloid,
vinblastine (IC50 3.0 × 10−6 M), which is the same as that
of moroidin (IC50 3.0 × 10−6 M). The combination of the
remarkable biological activity yet very low natural abundance
(2 × 10−5–3 × 10−3 wt.-%) of these compounds has led to
significant interest in the development of methods toward
their total synthesis.[9–14]
CO2H
H2N
Oxidative coupling
N
CO2H
NH2
CO2H
α-Amination
N
N
H
H2N
Conjugate
addition
CO2H
RHN
Ph
N
ϩ
histidine
O
O
N
N
H
Larock annulation
12
O
iPr
EtO
N
N
Ph
O
I
ϩ
O
N
OEt
NH2
14
O
13
SiEt3
Scheme 1. Retrosynthesis of moroidin/celogentins.
at both stereocentres. Accordingly, our approach to the
celogentin/moroidin bicyclic peptides required the prepara-
tion of oxazolidinone-appended C6-substituted L-tryptophan
derivative 12, which in turn is to be assembled by the Larock
annulation of iodoaniline 13 with propargylglycine derivative
14 according to the method of Cook and co-workers.[16]
Moody and co-workers[9,10] have reported a method
for the generation of the Trp–His cross-link in the ‘right-
hand’ macrocycle of the celogentin/moroidin family. The
key steps include a nucleophilic aromatic substitution of
2-chloro-3-formylindole[9] and catalytic asymmetric hydro-
genation of the subsequently prepared dehydrotryptophan
derivative.[10,11] More recently, Moody and co-workers[12]
prepared the ‘left hand’ ring in the form of stephanotic acid
(11) using a combination of their previous asymmetric hydro-
genation methodology and a non-stereoselective preparation
of the Leu–Trp linkage.
Castle and Srikanth have reported progress towards celo-
gentin C (10), which employs a Larock annulation to generate
the indole moiety of the central tryptophan residue.[13] Cas-
tle and co-workers have also developed a novel route to the
Trp–His linkage using an oxidative coupling, and has
employed this methodology in the preparation of the ‘right-
hand’ macrocycle of celogentin C.[14]
Our retrosynthetic analysis of the celogentin/moroidin
family suggested that Castle’s oxidative coupling was the
most efficient route to the Trp–His cross-link, and that
a conjugate addition approach ought to furnish the Leu–
Trp structure (Scheme 1). Hruby and co-workers[15] have
reported the preparation of β,β-disubstituted α-amino acids
using a conjugate addition–azidation strategy, which employs
Evans’ oxazolidinone auxiliary to control the configuration
Results and Discussion
Cook and co-workers have generated d-tryptophan deriva-
tives through Larock annulation of d-propargylglycine
derivative ent-14.[16] Accordingly, we chose to employ
the corresponding (R)-Schollkopf auxiliary-derived
l-propargylglycine derivative 14 as one of the key interme-
diates for our synthesis. Our approach, therefore, required
3-amino-4-iodocinnamic acid 13 as the Larock annulation
coupling partner to generate the central tryptophan core of
the moroidin/celogentin family.
Initially, weattemptedtoprepare3-amino-4-iodocinnamic
acid from commercially available nitrocinnamates 15 and
16. However, conversion of 4-chloro-3-nitrocinnamate 15 to
the corresponding 4-iodo compound, using the halogen dis-
placement method reported by Burnett and Conner[17] for
substitution of 2,4-dinitrochlorobenzene, was not effective.
Esterification of 3-nitrocinnamic acid 16 and chemoselective
reduction[18] of the nitro-group was then pursued to afford
methyl 3-aminocinnamate 17 in good yield (Scheme 2).
However, iodination of 17 under various conditions led to

Central Tryptophan Moiety of the Celogentin/Moroidin Family
821
i) SOCl2, MeOH
ii) Fe, AcOH
O
HO
CHO
HO2C
NO2
NH2
MeO2C
O
H2, PtO2
87%, 2 steps
HO
16
17
TsOH
O2N
O2N
I2 or ICl
24
25
R1
R2
O
O
O
20%
TFA/CH2Cl2
i) N2O4
ii) NaI
Cl
O
NH2
MeO2C
I
H2N
R3
NO2
HO2C
27 73%
15
18 R1 ϭ I, R2 ϭ R3 ϭ H
19 R1 ϭ R3 ϭ I, R2 ϭ H
20 R1 ϭ R2 ϭ R3 ϭ I
26 94%, 2 steps
CHO
CHO
Fuming HNO3
Scheme 2.
I
I
23 92%
NO2
28 72%
CH3
CHO
CHO
i) H2SO4,
NaNO2
Na2S, S
NaOH
Scheme 4.
ii) KI, H2O
O2N
H2N
I
PPh3
MeO2C
79%
29
21
22 27%
23 46%
I
I
Scheme 3.
O
NO2
MeO2C
MeO2C
NO2
OHC
a complicated mixture of products from which the 6ꢀ-iodo-
(18), 2ꢀ,6ꢀ-diiodo- (19), and 2ꢀ,4ꢀ,6ꢀ-triiodo- (20) compounds
were isolated in varying amounts.
28
30
P(OEt)2 31
BuLi 82%
Fe, AcOH
I
Preparation of the required functionalized cinnamate by
olefination of the corresponding benzaldehyde was therefore
investigated. This approach required 4-iodobenzaldehyde
(23) as the starting material, which is commercially avail-
able but prohibitively expensive. In order to gain access to
multi-gram amounts of 4-iodobenzaldehyde 23, a concise
preparation from inexpensive starting materials was required.
A route from 4-nitrotoluene 21 via 4-aminobenzaldehyde
22[19] was initially investigated (Scheme 3), but the best
isolated yield of 4-iodobenzaldehyde 23 from this two-step
procedure was 12%, the main problem being the inherent
propensity for self-polymerization of 22 into intractable tars.
An alternative route to 23 was then developed starting
from4-nitrobenzaldehyde(24).Toavoidself-polymerization,
the aldehyde functionality was protected as a cyclic acetal.
Hydrogenation of the aromatic nitro-group of acetal 25
was achieved in quantitative yield in the presence of plat-
inum(iv) oxide catalyst, to give the desired aniline 26 in
excellent yield (Scheme 4).[20] Conversion of aniline 26 to
the iodide 27 by a diazo-displacement required non-acidic
conditions in order that the acetal functionality remained
intact. A suitable method was found using liquid N2O4
at low temperature under anhydrous conditions,[21] which
yielded the desired iodoacetal 27 in high yield. This mate-
rial was then deprotected under anhydrous acidic conditions
to afford 4-iodobenzaldehyde 23. This high-yielding, four-
step procedure was found to be an effective means for the
preparation of multi-gram amounts of 4-iodobenzaldehyde
23 from inexpensive starting materials.
MeO2C
NH2
32
Scheme 5.
in quantitative conversion to the desired methyl cinnamate as
a 5:1 mixture of (E)- and (Z)-isomers, from which the desired
(E)-isomer 30 was obtained in 76% yield after recrystalliza-
tion. Alternatively, Horner–Wadsworth–Emmons reaction of
28 using methyl diethylphosphonoacetate 31 was completely
selective for the (E)-isomer, providing 30 in 82% yield
(Scheme 5). Though the Horner–Wadsworth–Emmons reac-
tion provided a slightly higher yield of 30, it was not as
operationally simple as the Wittig reaction on a large scale.
Selective reduction of the nitro group of 30 using iron in
acetic acid/ethanol gave the aniline 32 in high yield.
With the required 3-amino-4-iodocinnamic acid 32 in
hand, Larock annulation with propargylglycine derivative 14
was then investigated. Use of Cook’s conditions[16] (Table 1,
entry 1) gave the tryptophan derivative 33 in 42% yield
(Scheme 6). Increasing the amount of palladium acetate from
5 to 10 mol-% improved the yield slightly (entry 2). Varia-
tion of the palladium catalyst led to the marginally improved
yield of 53% with palladium bis(diphenylphoshinoferrocene)
catalyst (entry 4).
Hydrolysis of the methyl ester of tryptophan deriva-
tive 33 was effective, providing acid 34 in 92% yield
(Scheme 6). However, subsequent coupling of acid 34 to
the Evans oxazolidinone auxiliary 38 under various con-
ditions was unsuccessful, possibly because of the presence
Regioselective nitration of 23 was achieved using the pro-
cedure described by Miller et al.[22] to give 28.Wittig reaction
of aldehyde 28 with commercially available ylide 29 resulted

822
A. K. L. Yuen, K. A. Jolliffe, and C. A. Hutton
of the unprotected indole. Preparation of the correspond-
ing Boc-protected indole 36 was, therefore, undertaken, and
for optimum convergency it was decided to generate 36 by
Larock annulation of the Boc-protected aniline 35.
mixture and performing the reaction at −78◦C resulted
in production of the desired carbamate 35 in good yield
(Scheme 7).
Application of Cook and co-workers’[16] conditions for the
Larockannulationof 35ledtotheformationofBoc-protected
tryptophan derivative 36 in only 27% yield, accompanied by
tryptophan derivative 33 lacking the Boc-group, in 21% yield
(Table 2, entry 1). Conducting the reaction at a lower tem-
perature in order to suppress thermolysis of the Boc group
was only partially effective, with less deprotected compound
33 formed but no improvement in the yield of Boc-indole
derivative 36. Gathergood and Scammells[24] have reported
the preparation of 4-hydroxytryptamines, under modified
Larock annulation conditions, using a Boc-protected iodoani-
line. Their procedure employs 20 mol-% palladium acetate
and 40 mol-% triphenylphosphine ligand. However, applica-
tion of Gathergood and Scammells’ procedure yielded only
8% of Boc-indole 36 with significant amounts of indole 33
formed and starting material 35 recovered. After significant
experimentation, a hybrid procedure that employed 20 mol-%
palladium acetate and 40 mol-% triphenylphosphine (as per
Scammells and Gathergood’s procedure) in the presence
of sodium carbonate and lithium chloride (as per Cook’s
procedure) was developed that yielded 52% of the desired
tryptophan derivative 36, with only trace amounts of 33
observed (entry 4).
Kelly and McNeil[23] reported that simple anilines can
be mono-Boc-protected using two equivalents of sodium
hexamethyldisilazide (NaHMDS) to form the anilide anion,
followed by addition of di-tert-butyl dicarbonate. The second
equivalent of base is required to deprotonate the resul-
tant carbamate, thereby preventing further reaction with
the anilide anion, which would otherwise lead to forma-
tion of a symmetrical urea. However, treatment of 32 with
two equivalents of NaHMDS at room temperature led to
polymerization of the starting material, presumably as a
result of intermolecular addition of the anilide anion to the
methyl ester. Modification of the literature procedure through
inclusionofthedi-tert-butyldicarbonateintheinitialreaction
N
OEt
Catalyst,
EtO
Na2CO3,
LiCl
N
I
14
MeO2C
NH2
SiEt3
N
H
RO2C
32
33 R ϭ Me
34 R ϭ H
LiOH
92%
In order to append the oxazolidinone auxiliary, removal of
the methyl ester was required. However, hydrolysis of 36 was
noteffectiveascompetitivehydrolysisofthecarbamategroup
occurred to yield a mixture of N-protected and unprotected
indoles.
Scheme 6.
Table 1. Larock annulations of iodoaniline 32
With the attachment of the oxazolidinone auxiliary to
Larock adducts 33 and 36 proving problematic, direct prepa-
ration of tryptophan fragment 12 through Larock annulation
of oxazolidinone-appended cinnamate 13 was investigated.
Ester hydrolysis of methyl cinnamate 35 and subsequent cou-
pling to the oxazolidinone 38 were achieved under standard
conditions, to yield functionalized cinnamate 39 in 69% yield
Entry
Catalyst
Catalyst conc.
[mol-%]
Time
[h]
Yield
[%]
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2(PPh3)2
Pd(dppf)Cl2
5
10
20
5
48
48
48
36
42
50
38
53
N
OEt
EtO
N
I
I
NHBoc
Boc2O
NaHMDS
Pd(OAc)2, 14
base, additive
NH2
SiEt3
MeO2C
MeO2C
87%
N
R
MeO2C
32
35
36 R ϭ Boc
33 R ϭ H
Scheme 7.
Table 2. Larock annulations of N-Boc iodoaniline 35
Entry
Pd(OAc)2
[mol-%]
PPh3
[mol-%]
Base
(3 equiv)
Additive
Temp.
[◦C]
Time
[h]
Yield 36
[%]
Yield 33
[%]
1
2
3
4
5
5
20
20
–
–
40
40
Na2CO3
Na2CO3
NEt3
LiCl
LiCl
Bu4NCl
LiCl
100
80
80
48
78
48
48
27
23
8
21
12
47
Na2CO3
80
52
<5

Central Tryptophan Moiety of the Celogentin/Moroidin Family
823
over two steps (Scheme 8). Removal of the Boc protecting
group was then effected upon treatment with 10% sulfuric
acid in 1,4-dioxan to give the aniline 13.
With the oxazolidinone-appended iodoaniline 13 in hand,
we returned to Cook’s optimized conditions for the Larock
annulation with propargylglycine 14, which proceeded in rea-
sonableyieldtoprovidethedesiredfunctionalizedtryptophan
derivative 40 (Scheme 9).
In conclusion, a novel, inexpensive preparation of
4-iodobenzaldehyde 23 has been developed that enabled an
efficient preparation of ortho-iodoaniline 13, which was cou-
pled with propargylglycine 14 using Cook’s modification of
theLarockannulationtoprovide2,6-disubstitutedtryptophan
derivative 40. Elaboration of 40 to provide the Leu–Trp frag-
ment of the celogentin/moroidin family of cyclic peptides is
currently underway.
was dissolved in absolute ethanol (200 mL) and acetic acid (20 mL).
Iron powder (4.82 g, 86.4 mmol) was added and the suspension was
heated at reflux under nitrogen overnight. The mixture was allowed to
cool to room temperature, and was then concentrated under vacuum
and the residue partitioned between ethyl acetate (150 mL) and sat-
urated NaHCO3(aq.) (150 mL). The aqueous phase was extracted with
ethyl acetate (2 × 50 mL) and the combined organic phases were washed
with saturated NaHCO3(aq.) (50 mL), dried over sodium sulfate, and
concentrated under vacuum to give a brown solid. Purification by chro-
matography on silica afforded the title compound 17 (3.80 g, 87%) as a
white solid; mp 81–84◦C. νmax (CH2Cl2)/cm−1 3487, 3398, 3153, 2986,
2951, 2901, 2253, 1817, 1794, 1705, 1636, 1620, 1605. δH (400 MHz,
CDCl3) 7.60 (1H, d, J 16.0, HCCH), 7.16 (1H, m, ArH), 6.92 (1H, d, J
7.7,ArH), 6.82 (1H, m,ArH), 6.70 (1H, dd, J 1.5, 7.7,ArH), 6.37 (1H, d,
J 16.0, HCCH), 3.79 (3H, s, OCH3), 3.63 (2H, br s, NH2). δC (100 MHz,
CDCl3) 167.5, 146.8, 145.2, 135.4, 129.8, 118.7, 117.6, 117.1, 114.1,
51.6. m/z (ESI, positive ion) 178 ([M + Na]+, 100%). HRMS (ESI,
positive ion) C10H11NO2Na requires m/z 200.0682, found [M + Na]+
200.0686.
5,5-Dimethyl-2-(4-nitrophenyl)-[1,3]dioxan 25
Experimental
A
solution of 4-nitrobenzaldehyde 24 (92.0 g, 0.61 mol), 2,2-
Methyl (E)-3ꢀ-Aminocinnamate 17
dimethylpropane-1,3-diol (69.0 g, 0.67 mol), and toluenesulfonic acid
(10.5 g, 0.06 mol) in toluene (1.0 L) was refluxed under Dean–Stark
conditions until no more water was observed to form. The reaction was
allowed to cool, and washed with saturated NaHCO3(aq.) (3 × 400 mL),
water (200 mL), and brine (100 mL). The organic phase was stirred over
sodium sulfate and activated charcoal overnight, filtered, and concen-
trated. The crude solid was recrystallized from methanol/water to afford
the title compound 25 as off-white crystals (136.5 g, 94%), mp 87–88◦C
(lit.[25] 83–85◦C). δH (200 MHz, CDCl3) 8.22 (2H, d, J 8.7, 3ꢀH/5ꢀH),
7.68 (2H, d, J 8.7, 2ꢀH/6ꢀH), 5.46 (1H, s, CH), 3.80 (2H, d, J 11.1,
2 × OCHHꢀ), 3.67 (2H, d, J 11.1, 2 × OCHHꢀ), 1.27 (3H, s, CH3), 0.82
(3H, s, CH3); 1H NMR data is in accordance with literature values.[20]
To a suspension of (E)-3ꢀ-nitrocinnamic acid 16 (4.8 g, 25.0 mmol)
in methanol (50 mL) at 0◦C was added thionyl chloride (2.0 mL,
27.5 mmol). The reaction was stirred under nitrogen at room temper-
ature for 4 h, and then concentrated under vacuum. The crude material
LiOH
MeOH/H2O
I
I
98%
NHBoc
NHBoc
MeO2C
HO2C
35
37
Ph
Et3N, (CH3)3COCl,
THF, Ϫ78–0°C
70%
NH
38
2-(4-Aminophenyl)-5,5-dimethyl-[1,3]dioxan 26
O
O
5,5-Dimethyl-2-(4ꢀ-nitrophenyl)-[1,3]dioxan 25 (40.5 g, 170.7 mmol)
was dissolved in ethyl acetate (480 mL), and platinum(iv) oxide
(774 mg, 3.41 mmol) was added. The resulting suspension was stirred
under an atmosphere of hydrogen for 4.5 h. The catalyst was removed
by filtration and the filtrate was concentrated under vacuum to afford
the title compound 26 as a white solid (35.4 g, 100%), mp 105–106◦C
(lit.[25] 102–104◦C). δH (200 MHz, CDCl3) 7.28 (2H, d, J 8.4, 2ꢀH/6ꢀH),
6.65 (2H, d, J 8.4, 3ꢀH/5ꢀH), 5.29 (1H, s, CH), 3.74 (2H, d, J 11.0,
2 × OCHHꢀ), 3.61 (2H, d, J 11.0, 2 × OCHHꢀ), 1.29 (3H, s, CH3), 0.78
(3H, s, CH3); 1H NMR data in is accordance with literature values.[20]
n-BuLi, Ϫ78°C
Ph
I
O
N
NHR
O
O
10% H2SO4
1,4-dioxane
89%
39 R ϭ Boc
13 R ϭ H
Scheme 8.
2-(4-Iodophenyl)-5,5-dimethyl-[1,3]dioxan 27
Ph
I
A solution of 2-(4-aminophenyl)-5,5-dimethyl-[1,3]dioxan 26 (20.7 g,
100 mmol) in acetonitrile (500 mL) was cooled to −20◦C, and then ice-
cooled nitrogen dioxide/dinitrogen tetroxide (7.00 mL, 220 mmol) was
added by a cannula. The resulting brown slurry was stirred under nitro-
gen at −20◦C for 1.25 h and then sodium iodide (22.5 g, 150 mmol)
was added. Upon completion of gas evolution, the reaction was allowed
to warm to room temperature, and ethyl acetate (500 mL) and water
(500 mL) were then added. The aqueous phase was extracted with
ethyl acetate (250 mL) and the combined organic phases were washed
with saturated Na2S2O3(aq.) (5 × 100 mL) and hydrochloric acid (1 M,
100 mL). The organic phase was dried over sodium sulfate, filtered,
and concentrated under vacuum. The crude product was passed through
a short column of silica and the crude product recrystallized from
methanol/water to afford the title compound 27 as lustrous white flakes
(23.2 g, 73%), mp 75–76◦C. Found C 45.5, H 4.8. C12H15O2I requires
C 45.3, H 4.8%. νmax (CH2Cl2)/cm−1 2952, 2853 (C–H), 2367. δH
(300 MHz, CDCl3) 7.70 (2H, d, J 8.5, ArH), 7.24 (2H, d, J 8.5, ArH),
5.33 (1H, s, CH), 3.75 (2H, d, J 10.8, 2 × OCHHꢀ), 3.62 (2H, d, J 10.8,
2 × OCHHꢀ), 1.27 (3H, s, CH3), 0.79 (3H, s, CH3). δC (75 MHz, CDCl3)
O
N
NH2
O
O
13
Pd(OAc)2
Na2CO3
LiCl
14
40%
N
OEt
EtO
N
Ph
SiEt3
O
N
N
H
O
O
40
Scheme 9.
138.2, 137.3, 128.1, 101.0, 94.7, 30.2, 23.0, 21.8. m/z (EI) 318 (M+•
,

824
A. K. L. Yuen, K. A. Jolliffe, and C. A. Hutton
40%), 317 (100), 232 (33), 231 (100), 232 (38). HRMS (EI) C12H15IO2
requires m/z 318.0117, found 318.0112.
(250 mL) and glacial acetic acid (21.5 mL). The mixture was heated
at reflux under nitrogen for 4.5 h, during which time the reaction mix-
ture darkened. The mixture was allowed to cool to room temperature
and concentrated under vacuum. The dark brown residue was diluted
with ethyl acetate (250 mL), and saturated NaHCO3(aq.) was used to
adjust the pH to approx. 8. The organic phase was separated, the aque-
ous phase was extracted with ethyl acetate (100 mL), and the combined
extracts were dried over sodium sulfate and concentrated under vacuum.
Purification by chromatography on silica afforded the title compound
32 as a pale yellow crystalline solid (6.91 g, 85%), mp 121–123◦C.
νmax (CH2Cl2)/cm−1 3942, 3757, 3692, 3474, 3379, 3049, 2986, 2953,
2831, 2685, 2521, 2409, 2305, 2154, 2125, 2054, 1705, 1636, 1612,
1558. δH (200 MHz, CDCl3) 7.63 (1H, d, J 8.2, 5ꢀH), 7.53 (1H, d, J
16.0, ArCHCH), 6.84 (1H, d, J 1.9, 2ꢀH), 6.63 (1H, dd, J 2.0, 8.2, 6ꢀH),
6.34 (1H, d, J 16.0,ArCHCH), 4.18 (2H, br s, NH2), 3.79 (3H, s, OCH3).
δC (50 MHz, CDCl3) 167.8, 147.8, 144.7, 140.0, 136.2, 119.7, 118.8,
114.2, 86.7, 52.3. HRMS (EI) C10H10INO2 requires m/z 302.9756,
found 302.9761.
4-Iodobenzaldehyde 23
Trifluoroacetic acid (50 mL) was added to
a
solution of
2-(4ꢀ-iodophenyl)-5,5-dimethyl-[1,3]dioxane 27 (23.2 g, 73.0 mmol) in
dichloromethane (250 mL). The reaction mixture was stirred at room
temperature for 23 h, during which time the reaction mixture turned
green. Water (250 mL) was added and NaHCO3 was added slowly
until the pH of the aqueous phase was approx. 8.0. The aqueous phase
was extracted with dichloromethane (40 mL) and the combined organic
phases were dried over sodium sulfate, concentrated under vacuum,
and recrystallized from hexanes (200 mL) to afford the title compound
23 as white crystals (15.5 g, 92%), mp 76–81◦C (lit.[22] 79–80◦C). δH
(200 MHz, CDCl3) 9.96 (1H, s, CHO), 7.92 (2H, d, J 8.4, C-2H/C-5H),
7.59 (2H, d, J 8.4, C-3H/C-4H).
4-Iodo-3-nitrobenzaldehyde 28
Fuming nitric acid (9.40 mL, 223 mmol) was cooled to 0◦C and then
added to 4-iodobenzaldehyde 23 (8.62 g, 37.1 mmol). The resulting
brown solution was stirred at 0◦C for 3.5 h. Ice-water was then added
and the canary yellow precipitate was filtered off, washed with water,
and dried under vacuum over phosphorous pentoxide. The crude prod-
uct was recrystallized from a minimal amount of chloroform/hexanes
to afford the title compound 28 as yellow crystals (7.44 g, 72%), mp
147–148◦C (lit.[22] 141◦C). δH (200 MHz, CDCl3) 10.03 (1H, s, CHO),
8.31 (1H, d, J 2.0, C-2H), 8.27 (1H, d, J 8.1, C-5H), 7.75 (1H, dd, J 2.0,
8.1, C-6H).
Methyl (E)-3ꢀ-tert-Butoxycarbonylamino-4ꢀ-iodocinnamate 35
Methyl (E)-3ꢀ-amino-4ꢀ-iodocinnamate 32 (2.67 g, 8.80 mmol) and
di-tert-butyl dicarbonate (1.92 g, 8.80 mmol) were dissolved in tetra-
hydrofuran (45 mL), cooled to −78◦C, and sodium hexamethyldisi-
lazide (17.6 mL, 1.0 M inTHF) was added dropwise at a rate that kept the
internaltemperaturebelow−60◦C. Uponcompletionoftheaddition, the
reaction mixture remained blood-red. The reaction mixture was stirred
for 3 h, quenched with methanol, and the mixture was allowed to warm
to room temperature. The solvent was removed and the residue parti-
tioned between saturated NH4Cl (aq.) (150 mL) and dichloromethane
(150 mL), the organic phase was separated, and the aqueous layer was
extracted with dichloromethane (50 mL).The combined organic extracts
were dried over sodium sulfate and concentrated under vacuum to give
a pale yellow oil. Purification by chromatography on silica afforded the
title compound 35 as a white solid (3.09 g, 87%), mp 125–127◦C. νmax
(CH2Cl2)/cm−1 3393, 3153, 2984, 2900, 2358, 2253, 1817, 1718, 1639,
1568. δH (200 MHz, CDCl3) 8.29 (1H, d, J 2.1, 2ꢀH), 7.75 (1H, d, J 8.2,
5ꢀH), 7.62 (1H, d, J 15.9, ArCHCH), 6.91 (1H, dd, J 2.1, 8.2, 6ꢀH), 6.86
(1H, br s, NH), 6.49 (1H, d, J 15.9, ArCHCH), 3.80 (3H, s, OCH3),
1.55 (9H, s, C(CH3)3). δC (50 MHz, CDCl3) 167.1, 152.4, 143.8, 139.5,
139.2, 135.7, 123.8, 119.1, 118.8, 90.2, 81.4, 51.7, 28.3. m/z (EI) 403
(M+•, 7%), 347 (39), 303 (100), 220 (78). HRMS (EI) C15H18INO4
requires m/z 403.0281, found 403.0280.
Methyl (E)-3ꢀ-Nitro-4ꢀ-iodocinnamate 30
Method 1
4-Iodo-3-nitrobenzaldehyde 28 (9.41 g, 34.0 mmol) and methyl
(triphenylphosphoranyl)acetate 29 (13.7 g, 41.0 mmol) were dissolved
in dichloromethane (200 mL) and stirred overnight under nitrogen at
room temperature.The resulting yellow solution was concentrated under
vacuum, and the residue purified by chromatography on silica to give
the product as a yellow solid (11.1, 98%, 5:1 E:Z). Recrystallization
from dichloromethane/hexanes afforded the (E)-isomer 30 as a yellow
crystalline solid (8.99 g, 79%), mp 156–157◦C. Found C 36.1, H 2.3, N
4.1. C10H8INO4 requires C 36.1, H 2.4, N 4.2%. νmax (CH2Cl2)/cm−1
3942, 3757, 3691, 3051, 2987, 2927, 2852, 2685, 2521, 2409, 2305,
2154, 2125, 2054, 1720, 1647, 1597, 1553, 1533, 1421. δH (200 MHz,
CDCl3) 8.06 (1H, d, J 8.3, 5ꢀH), 7.97 (1H, d, J 2.1, 2ꢀH), 7.61 (1H, d,
J 16.0, ArCHCH), 7.38 (1H, dd, J 2.1, 8.3, 6ꢀH), 6.53 (1H, d, J 16.0,
ArCHCH), 3.82 (3H, s, OCH3). δC (50 MHz, CDCl3) 166.3, 153.5,
(E)-3ꢀ-tert-Butoxycarbonylamino-4ꢀ-iodocinnamic Acid 37
To
a
suspension of methyl (E)-3ꢀ-tert-butoxycarbonylamino-4ꢀ-
142.5, 140.9, 135.9, 131.8, 124.2, 121.4, 87.6, 52.1. m/z (EI) 333 (M+•
,
iodocinnamate 35 (3.09 g, 7.66 mmol) in methanol (60 mL) was added
a solution of lithium hydroxide (552 mg, 23.0 mmol) in water (20 mL).
The white slurry was stirred at room temperature under nitrogen for
36 h, concentrated under vacuum, and the residue partitioned between
hydrochloric acid (50 mL, 1 M) and 3/1 chloroform/isopropyl alcohol
(250 mL). The organic extract was dried over sodium sulfate, and con-
centrated under vacuum to afford the title compound 37 as a white
solid (2.95 g, 98%) that was used directly in the following reaction. δH
(200 MHz, D2O + NaOD) 7.88 (1H, d, J 8.2, 5ꢀH), 7.55 (1H, br s, 2ꢀH),
7.27 (1H, d, J 16.0, ArCHCH), 7.13 (1H, br d, J 8.2, 6ꢀH), 6.50 (1H, d,
J 16.0, ArCHCH), 1.51 (9H, s, C(CH3)3). δC (50 MHz, D2O + NaOD)
175.7, 156.4, 140.1, 139.5, 136.4, 126.7, 125.9, 125.0, 96.4, 90.2, 82.5,
28.1. m/z (ESI, negative ion) 388 ([M − H]−, 100%).
100%), 302 (67). HRMS (EI) C10H8INO4 requires m/z 332.9498, found
332.9506.
Method 2
To a solution of methyl diethylphosphonoacetate 31 (6.83 g,
33.0 mmol), in tetrahydrofuran (125 mL), was added n-butyllithium
(21 mL, 1.6 M), dropwise at −78◦C. The reaction mixture was stirred
under nitrogen at −78◦C for 1 h and then a cooled solution of 4-iodo-3-
nitrobenzaldehyde 28 (6.87 g, 25.0 mmol) in tetrahydrofuran (125 mL)
was added using a cannula. The reaction mixture was allowed to warm
to 0◦C and was stirred for a further 2 h. Saturated NH4Cl(aq.) (100 mL)
was then added. The resulting precipitate was removed by filtration,
the filtrate was extracted with ethyl acetate (30 mL), dried over sodium
sulfate, and concentrated under vacuum to give a yellow solid. Purifi-
cation by chromatography on silica afforded a mixture of starting
material 28 and product 30. Recystallization from a minimal amount
of dichloromethane/hexanes afforded the title compound 30 (6.75 g,
82%).
(S)-3-[3ꢀ-tert-Butoxycarbonylamino-4ꢀ-iodo-(E)-cinnamoyl]-
4-phenyloxazolidin-2-one 39
A solution of n-butyllithium in hexanes (655 µL, 1.53 M) was added
to a solution of (S)-4-phenyl-2-oxazolidinone 38 (164 mg, 1.00 mmol)
in tetrahydrofuran (5 mL) at −78◦C and the mixture was stirred at
−78◦C for 15 min. In a separate flask a suspension of (E)-3ꢀ-tert-
butoxycarbonylamino-4ꢀ-iodocinnamic acid 37 (389 mg, 1.00 mmol) in
tetrahydrofuran (5 mL) was cooled to −78◦C, and then triethylamine
Methyl (E)-3ꢀ-Amino-4ꢀ-iodocinnamate 32
Methyl (E)-3ꢀ-nitro-4ꢀ-iodocinnamate 30 (8.9 g, 26.9 mmol) and iron
powder (10.5 g, 188 mmol) were suspended in absolute ethanol

Central Tryptophan Moiety of the Celogentin/Moroidin Family
825
(140 µL, 1.0 mmol) and trimethylacetyl chloride (125 µL, 1.00 mmol)
were added. The resulting slurry was stirred at −78◦C for 15 min and
then at 0◦C for 1 h. The mixture was re-cooled to −78◦C and then was
transferred into the oxazolidinone anion solution through a cannula.
The resulting mixture was stirred at −78◦C for 1 h and then allowed to
warmtoroomtemperatureandstirredfor3 h.Thereactionwasquenched
with saturated NH4Cl (aq.) (30 mL), and then was extracted with ethyl
acetate (2 × 30 mL). The combined extracts were dried over sodium
sulfate and concentrated under vacuum to give a yellow solid. Purifica-
tion by chromatography on silica afforded the title compound 39 as a
pale yellow oil (368 mg, 70%). νmax (CH2Cl2)/cm−1 3393, 3390, 3096,
2978, 2930, 2363, 2253, 1817, 1778, 1724, 1684, 1620. δH (400 MHz,
CDCl3) 8.10 (1H, d, J 1.9, 2ꢀH), 7.81 (1H, d, J 15.8, ArCHCH), 7.61
(1H, d, J 8.2, 5ꢀH), 7.56 (1H, d, J 15.8, ArCHCH), 7.27–7.18 (5H, m,
Ph), 6.89 (1H, dd, J 1.9, 8.2, 6ꢀH), 6.73 (1H, br s, NH), 5.41 (1H, dd,
J 3.9, 8.8, OCHCHꢀ), 4.59 (1H, t, J 8.8, OCHCHꢀ), 4.15 (1H, dd, J
3.9, 8.8, PhCH), 1.43 (9H, s, C(CH3)3). δC (100 MHz, CDCl3) 164.1,
153.5, 152.1, 145.1, 139.2, 139.0, 138.8, 135.4, 128.9, 128.4, 125.7,
123.5, 120.0, 118.0, 91.0, 81.2, 69.9, 57.6, 28.1. m/z (ESI, positive ion)
557 ([M + Na]+, 100%). HRMS (ESI, positive ion) C23H23IN2O5Na
requires m/z 557.0549, found 557.0533.
3-[(2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-dihydropyrazin-
2-ylmethyl]-6-(2-methoxycarbonylethenyl)-2-triethylsilylindole 33
Dry N,N-dimethylformamide (5 mL) was added to a flask that
contained lithium chloride (85 mg, 2.0 mmol), aminoiodocinnamate
methyl ester 32 (303 mg, 1.0 mmol), 1,1ꢀ-bis(diphenylphosphino)-
ferrocenylpalladium chloride dichloromethane complex (41.0 mg,
50 µmol), sodium carbonate (318 mg, 3.0 mmol), and propargylglycine
derivative 14 (484 mg, 1.3 mmol). The mixture was degassed (three
freeze–thaw cycles) and heated at 100◦C under nitrogen for 36 h. The
reaction mixture was allowed to cool to room temperature, the solvent
was removed under a stream of nitrogen, and the residue purified by
chromatography on silica to afford the title compound 33 as a yellow
[25]
oil (284 mg, 53%), [α]D
+5.6◦ (c 0.97, CHCl3). νmax (NaCl)/cm−1
3385, 2955, 2935, 2908, 2873, 2251, 1701, 1628, 1605, 1558. δH
(400 MHz, CDCl3) 8.16 (1H, s, NH), 7.82 (1H, d, J 15.9, ArCHCH),
7.74 (1H, d, J 8.4, 4ꢀH), 7.48 (1H, d, J 1.1, 7ꢀH), 7.27 (1H, dd, J 1.4, 8.4,
5ꢀH), 6.45 (1H, d, J 15.9, ArCHCH), 4.25–3.96 (5H, m), 3.91 (1H, t,
J 3.4), 3.73 (3H, s, OCH3), 3.50 (1H, dd, J 3.5, 14.2, CHCHꢀ), 2.84
(1H, dd, J 9.7, 14.2, CHCHꢀ), 2.27 (1H, m, CHCH3), 1.28 (3H, t,
J 7.1, OCH2CH3), 1.20 (3H, t, J 7.1, OCH2CH3), 1.04–0.96 (18H, m,
Si(CH2CH3)3 and CHCH3), 0.68 (3H, d, J 6.8, CHCHꢀ3). δC (100 MHz,
CDCl3) 168.1, 163.5, 162.9, 146.8, 138.4, 135.1, 131.6, 128.3, 124.2,
121.0, 118.0, 114.9, 111.7, 60.7, 60.6, 60.5, 58.6, 51.5, 31.9, 31.6, 19.1,
16.6, 14.4, 14.2, 7.4, 3.5. m/z (EI) 539 (M+•, 86%), 510 (69), 508 (100);
HRMS (ESI, positive ion) C30H46N3O4Si requires m/z 540.3254, found
540.3243.
(S)-3-[3ꢀ-Amino-4ꢀ-iodo-(E)-cinnamoyl]-
4-phenyloxazolidin-2-one 13
N-Boc-protected aniline 39 (838 mg, 1.57 mmol) was dissolved in a
solution of sulfuric acid in 1,4-dioxane (10 mL, 10% v/v) and stirred
under ambient atmosphere at room temperature for 30 min. The reac-
tion was quenched with saturated NaHCO3(aq.) solution (30 mL) and
extracted with ethyl acetate (2 × 20 mL).The combined organic extracts
were dried (sodium sulfate), filtered, and concentrated under vacuum to
afford the crude product as a pale yellow solid. Purification by chro-
matography on silica afforded the title compound 13 as an off-white
3-[(2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-dihydropyrazin-
2-ylmethyl]-6-(2-carboxyethenyl)-2-triethylsilylindole 34
To a solution of methyl ester 33 (284 mg, 0.53 mmol) in methanol
(12 mL) and tetrahydrofuran (6 mL) was added lithium hydroxide
(38.0 mg, 1.58 mmol) in distilled water (6 mL). The resulting solution
was stirred under nitrogen for 5 days at room temperature. The reac-
tion mixture was concentrated under vacuum, partitioned between ethyl
acetate (30 mL) and hydrochloric acid (1 M, 30 mL), and the aque-
ous layer extracted with ethyl acetate (10 mL). The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated under
solid (608 mg, 89%), mp 185–187◦C. Found C 49.9, H 3.5, N 6.4.
[25]
C18H15IN2O3 requires C 49.8, H 3.5, N 6.5%. [α]D
−10.6◦ (c 1.0,
CHCl3). νmax(NaCl)/cm−1 3462, 3366, 3101, 3065, 3032, 2978, 2916,
2363, 1771, 1678, 1616, 1558. δH (300 MHz, CDCl3) 7.88 (1H, d, J 15.7,
ArCHCH), 7.63 (1H, d, J 8.1, 3ꢀH), 7.61 (1H, d, J 15.7,ArCHCH), 7.42–
7.31 (5H, m, Ph), 6.92 (1H, d, J 2.0, 6ꢀH), 6.67 (1H, dd, J 2.0, 8.1, 4ꢀH),
5.54 (1H, dd, J 3.9, 8.8, OCHHꢀ), 4.73 (1H, t, J 8.8, OCHHꢀ), 4.31 (1H,
dd, J 3.9, 8.8, PhCH), 4.17 (2H, s, NH2). δC (75 MHz, CDCl3) 164.6,
147.2, 145.9, 139.4, 139.0, 135.6, 129.2, 128.7, 126.0, 120.0, 117.2,
113.6, 86.9, 70.0, 57.8. m/z 457 (ESI, positive ion) ([M + Na]+, 71%).
HRMS (ESI, positive ion) C18H15IN2O3Na requires 457.0020, found
457.0036.
vacuum to afford the title compound 34 (276 mg, 100%) as a yellow oil,
[25]
[α]D
+4.8◦ (c 1.0, CHCl3). νmax (NaCl)/cm−1 3358, 2957, 2934,
2909, 2874, 1689, 1628, 1605, 1562. δH (400 MHz, CDCl3) 8.10 (1H, s,
NH), 7.85 (1H, d, J 15.8,ArCHCH), 7.77 (1H, d, J 8.8, 4ꢀH), 7.50 (1H, d,
J 1.0, 7ꢀH), 7.29 (1H, dd, J 1.0, 8.8, 5ꢀH), 6.40 (1H, d, J 15.8, ArCHCH),
4.23–3.95 (5H, m), 3.93 (1H, t, J 3.4), 3.52 (1H, dd, J 3.6, 14.2, CHHꢀ),
2.85 (1H, dd, J 9.8, 14.2, CHHꢀ), 2.29 (1H, m, CHCH3), 1.29 (3H, t,
J 7.1, OCH2CH3), 1.22 (3H, t, J 7.1, OCH2CH3), 1.05–0.95 (18H, m,
Si(CH2CH3)3 and CHCH3), 0.70 (3H, d, J 6.8, CHCH3ꢀ ). δC (100 MHz,
CDCl3) 172.2, 163.7, 163.2, 148.4, 138.42, 135.5, 131.8, 128.1, 124.0,
121.0, 118.4, 114.6, 111.9, 60.9, 60.7, 60.6, 58.4, 31.9, 31.7, 19.1, 16.7,
14.4, 14.3, 7.4, 3.6. m/z (ESI, positive ion) 526 ([M + H]+, 100%).
HRMS (ESI, positive ion) C29H43N3O4Si requires m/z 526.3096, found
526.3090.
1-tert-Butoxycarbonyl-3-[(2S,5R)-3,6-diethoxy-5-isopropyl-
2,5-dihydropyrazin-2-ylmethyl]-6-(2-methoxycarbonylethenyl)-
2-triethylsilanylindole 36
Dry N,N-dimethylformamide (5 mL) was added to a flask contain-
ing lithium chloride (90 mg, 2.1 mmol), triphenylphosphine (105 mg,
0.4 mmol), Boc-protected aminoiodocinnamate 35 (403 mg, 1.0 mmol),
palladium(ii) acetate (44.0 mg, 0.2 mmol), sodium carbonate (318 mg,
3.00 mmol), and propargylglycine derivative 14 (484 mg, 1.3 mmol).
The mixture was degassed (three freeze–thaw cycles) and then heated at
80◦C under nitrogen for 48 h. The reaction mixture was allowed to cool
to room temperature, the solvent was removed under a stream of nitro-
gen, and the residue was purified by chromatography on silica to afford
the title compound 36 as a yellow oil (330 mg, 52%). δH (300 MHz,
CDCl3) 8.03 (1H, d, J 1.2, 7ꢀH), 7.80 (1H, d, J 15.9, ArCHCH), 7.61
(1H, d, J 8.2, 4ꢀH), 7.36 (1H, dd, J 1.2, 8.2, 5ꢀH), 6.44 (1H, d, J 15.9,
ArCHCH), 4.23–3.84 (6H, m, 2 × OCH2CH3 and 2 × α-H), 3.82 (3H,
s, OCH3), 3.54 (1H, dd, J 3.8, 14.1, CHCHꢀ), 2.83 (1H, dd, J 10.0, 14.1,
CHCHꢀ), 2.26 (1H, m, CHCH3), 1.73 (9H, s, C(CH3)3), 1.28 (3H, t,
J 7.1, OCH2CH3), 1.15 (3H, t, J 7.1, OCH2CH3), 1.03–0.94 (18H, m,
Si(CH2CH3)3 and CHCH3), 0.67 (3H, d, J 6.8, CHCHꢀ ). δC (100 MHz,
C6D6) 167.8, 163.4, 163.0, 151.2, 146.5, 137.7, 1373.6, 134.7, 131.8,
130.4, 121.1, 120.8, 116.0, 115.5, 83.4, 60.8, 60.7, 60.5, 58.5, 51.6,
31.8, 30.9, 28.3, 19.1, 14.3, 14.2, 8.1, 5.6.
3-[(2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-dihydropyrazin-
2-ylmethyl]-6-{3-oxo-3-[2-oxo-(4S)-phenyloxazolidin-1-yl]prop-
1-enyl}-2-triethylsilylindole 40
Dry N,N-dimethylformamide (4 mL) was added to a flask that contained
lithium chloride (50 mg, 1.18 mmol), palladium(ii) acetate (13 mg,
59 µmol), sodium carbonate (375 mg, 3.54 mmol), and propargyl-
glycine derivative 14 (559 mg, 1.53 mmol).A solution of the iodoaniline
derivative 13 (630 mg, 1.18 mmol) in N,N-dimethylformamide (2 mL)
was added and the mixture was degassed (three freeze–thaw cycles) and
then heated at 100◦C under nitrogen for 48 h. The reaction was allowed
to cool to room temperature, the solvent was removed under vacuum,
and the residue was purified by chromatography on silica to afford the
[25]
title compound 40 (318 mg, 40%) as a yellow oil, [α]D
−33.8◦ (c
1.2, CHCl3). νmax (NaCl)/cm−1 3392, 2957, 2872, 1784, 1772, 1734,
1684, 1628, 1648, 1595, 1558. δH (400 MHz, CDCl3) 8.10 (1H, br s,
NH), 7.93 (2H, s, ArH), 7.73 (1H, d, J 8.4, 4ꢀH), 7.56 (1H, d, J 1.0, 2ꢀH),

826
A. K. L. Yuen, K. A. Jolliffe, and C. A. Hutton
7.41–7.33 (6H, m), 5.58 (1H, d, J 3.8, 8.7, OCHHꢀ), 4.74 (1H, t, J 8.7,
OCHHꢀ), 4.32 (1H, dd, J 3.8, 8.7, PhCH), 4.22–4.06 (5H, m), 3.90 (1H,
t, J 3.4), 3.49 (1H, dd, J 3.5, 14.2, CHHꢀ), 2.83 (1H, dd, J 9.7, 14.2,
[10] J. R. Harrison, C. J. Moody, Tetrahedron Lett. 2003, 44, 5189.
doi:10.1016/S0040-4039(03)01258-9
[11] D. J. Bentley, C. J. Moody, Org. Biomol. Chem. 2004, 2, 3545.
doi:10.1039/B414996C
i
CHHꢀ), 2.26 (1H, m, PrH), 1.28 (3H, t, J 7.2, OCH2CH3), 1.20 (3H,
t, J 7.1, OCH2CH3), 1.03–0.93 (18H, m, Si(CH2CH3)3 and CHCH3),
0.67 (3H, d, J 6.8, CHCHꢀ ). δC (100 MHz, CDCl3) 165.1, 163.5, 162.9,
153.9, 148.9, 139.3, 1383.4, 135.7, 132.0, 129.1, 128.5, 128.4, 125.9,
124.2, 120.9, 118.9, 113.7, 112.2, 69.9, 60.7, 60.6, 60.5, 58.6, 57.9,
31.8, 31.6, 19.1, 16.6, 14.4, 14.3, 7.4, 3.5. m/z (ESI, positive ion) 693
([M + Na]+, 59%), 671 ([M + H]+, 100%). HRMS (ESI, positive ion)
C38H50N4O5SiNa requires m/z 693.3445, found 693.3435.
[12] D. J. Bentley, A. M. Z. Slawin, C. J. Moody, Org. Lett. 2006, 8,
1975. doi:10.1021/OL060153C
[13] S. L. Castle, G. S. C. Srikanth, Org. Lett. 2003, 5, 3611.
doi:10.1021/OL035236X
[14] L. He, L. Yang, S. L. Castle, Org. Lett. 2006, 8, 1165. doi:
10.1021/OL060016F
[15] (a) S. Liao, M. D. Shenderovich, J. Lin, V. J. Hruby, Tetrahedron
1997, 53, 16645. doi:10.1016/S0040-4020(97)10127-2
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Acknowledgment
This work was supported by theAustralian Research Council
(DP0208190).
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