Total synthesis of cyclotheonamide C by use of an α-keto cyanophosphorane methodology for peptide assembly

Article abstract of DOI:10.1002/ejoc.200800591

The total synthesis of cyclotheonamide C (3), a macrocyclic pentapeptide incorporating an α-keto homoarginine (k-Arg) and a vinylogous dehydrotyrosine (V-ΔTyr) unit, has been achieved. For comparison of macrocyclisation feasibility, two linear pentapeptides bearing free ketone functions at the k-Arg units were prepared, by use of tandem oxidation/coupling reactions on α-keto cyanophosphorane precursors as the key processes for pentapeptide elaboration. Successful activation and coupling at the pentapeptide V-ΔTyr C terminus led to the target molecule core, and thus provided a short total synthesis of the target compound. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800591

FULL PAPER
DOI: 10.1002/ejoc.200800591
Total Synthesis of Cyclotheonamide C by Use of an α-Keto Cyanophosphorane
Methodology for Peptide Assembly
Stéphane P. Roche,[a] Sophie Faure,[a] Lahssen El Blidi,[a] and David J. Aitken*[a,b]
Respectfully dedicated to Professor Jean-Claude Gramain
Keywords: Macrocyclic peptide / α-Keto β-amino acids / α-Keto cyanophosphoranes / Total synthesis / Natural product
synthesis
The total synthesis of cyclotheonamide C (3), a macrocyclic
pentapeptide incorporating an α-keto homoarginine (k-Arg)
and a vinylogous dehydrotyrosine (V-∆Tyr) unit, has been
achieved. For comparison of macrocyclisation feasibility, two
linear pentapeptides bearing free ketone functions at the k-
Arg units were prepared, by use of tandem oxidation/coup-
ling reactions on α-keto cyanophosphorane precursors as the
key processes for pentapeptide elaboration. Successful acti-
vation and coupling at the pentapeptide V-∆Tyr C terminus
led to the target molecule core, and thus provided a short
total synthesis of the target compound.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
spiring work that has led to elegant preparations of CtA
and CtB.[4] From a strictly chemical perspective, we were
attracted by the unique combination of the k-Arg and the
fully conjugated V-∆Tyr feature present in CtC (3), and we
were drawn into a total synthesis venture targeting this
member of the Ct family.
Introduction
The cyclotheonamides (Cts, 1–9, Figure 1) are a family
of cyclic pentapeptides isolated from the marine sponges
Theonella swinhoei and Theonella ircinia during the 1990s
and the early 2000s.[1] The constituent Ct amino acids are:
a hydrophobic -amino acid (-Xaa), α-keto homoarginine
(k-Arg), -proline (Pro), -2,3-diaminopropanoic acid
(Dpr) bearing an exocyclic Nα-formyl, acetyl or substituted
-alanyl group, and a vinylogous -tyrosine derivative (V-
Tyr), bearing an extra hydroxy group in the case of CtE5
(9) or being fully conjugated due to an extra double bond
(V-∆Tyr) in the case of CtC (3). These metabolites are po-
tent inhibitors of serine proteases such as thrombin and
trypsin, exhibiting IC50 values in the 2.9–200 n range.[1]
Central to the biological activity is the highly electrophilic
k-Arg moiety, which interacts with the serine side chain of
the enzymes’ active site triads.[2] This potent activity has
inspired some structure–activity studies on synthetic ana- Figure 1. The cyclotheonamide (Ct) family.
logues.[3] Understandably, the challenge of Ct total synthe-
sis has caught the attention of several research groups, in-
At an early stage in our reflections on an appropriate
synthetic approach, the elaboration of the k-Arg unit from
[a] Université Blaise Pascal – Clermont-Ferrand 2, Laboratoire de a readily accessible α-arginine precursor, followed immedi-
Synthèse et Etudes de Systèmes à Intérêt Biologique (CNRS
UMR 6504),
ately by peptide coupling to a -Phe fragment in a one-pot
operation, seemed an attractive approach for a convergent
synthesis of CtC. One means of achieving this objective was
an adaptation of Nemoto’s MAC methodology,[5] and we
have recently reported our results obtained by that route.[6]
An interesting alternative strategy was Wasserman’s sequen-
tial oxidation/coupling sequence starting from an α-keto cy-
anophosphorane derivative 10; ozonolysis of this function
24 avenue des Landais, 63177 Aubière cedex, France
[b] Université Paris-Sud 11, Laboratoire de Synthèse Organique &
Méthodologie, Institut de Chimie Moléculaire et des Matériaux
d’Orsay (CNRS UMR 8182),
15 rue Georges Clemenceau, 91405 Orsay cedex, France
Fax: +33-1-69156278
E-mail: david.aitken@u-psud.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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generates the α-keto acyl cyanide 11, which is trapped in paper we describe the total synthesis of CtC by this ap-
situ by an amine or an alcohol to provide an α-keto amide proach, which further delineates the scope of the tandem
or ester 12 in a one-pot procedure (Figure 2).[7]
reaction for α-keto amide formation, providing a compara-
tive analysis of two different macrocyclisation locations
(Figure 3).
Results and Discussion
Figure 2. Wasserman’s one-pot α-keto cyanophosphorane ap-
proach for the synthesis of α-keto amides and esters.
We began with the construction of two dipeptide frag-
ments containing Pro and the nonproteinogenic Dpr amino
acid (Scheme 1). General approaches to the synthesis of
α,β-diamino acids were reviewed recently.[14] The orthogo-
nally protected derivative 13 was prepared by Izumiya’s pro-
cedure[15] and was coupled with Pro-OBn by use of EDCI/
HOBt. Hydrogenation in the presence of Pd/C simulta-
neously cleaved the benzyl carbamate and the benzyl ester
to afford the zwitterionic dipeptide 14 in 84% yield over
two steps. A variety of reagents and conditions were exam-
ined for the mild N-formylation of this compound, the ob-
jective being to minimise the formation of the undesired
diketopiperazine 16. Optimal conditions required addition
of substrate 14 to preformed acetic-formic mixed anhydride
for a prolonged reaction time with cooling (below 10 °C),
and these furnished Nα-CHO-Nβ-Boc-Dpr-Pro (15) in 82%
yield; side-product 16 was formed in only 10% yield. The
dipeptide Nα-CHO-Dpr-Pro-OAllyl (17), with a free Nβ
amine, was easily obtained from dipeptide 15 in two steps
(94% yield) by successive esterification with allyl alcohol
and cleavage of the tert-butyl carbamate with trifluoroacetic
acid (Scheme 1).
This methodology can be conveniently adapted for poly-
mer-supported synthesis[8] and has been variously exploited
in natural product synthesis,[9] preparation of substrates for
enzymatic transformations,[10] construction of molecular
platforms[11] and the synthesis of peptide derivatives with
protease inhibitory properties.[12] Indeed, Wasserman used
this approach in his synthesis of CtE2 and CtE3.[13] We de-
cided to examine this methodology further, with the objec-
tive of expedient access to different peptide intermediates
for macrocyclisation studies leading to the CtC core. In this
Scheme 1. Preparation of the Dpr-Pro building blocks 15 and 17.
Reagents and conditions: a) Pro-OBn, EDCI, HOBt, CH2Cl2, 0 °C
to room temp., 12 h; b) H2 (3.4 atm), Pd/C, MeOH, 2 h, 84% (2
steps); c) HCO2H/Ac2O, THF, 8–10 °C, 12 h, 82%; d) EDCI,
DMAP, allyl alcohol, CH2Cl2, 0 °C to room temp., 5 h, then
iPr2NEt, THF, 0 °C, 10 min; e) TFA/CH2Cl2 (1:1), 1 h at 0 °C, then
workup with iPr2NEt, THF, 0 °C, 10 min, 94% (2 steps); EDCI =
N-[3-(dimethylamino)propyl]-NЈ-ethylcarbodiimide hydrochloride,
DMAP = 4-(dimethylamino)pyridine, HOBt = 1-hydroxybenzotri-
azole, TFA = trifluoroacetic acid.
The target α-keto cyanophosphoranes were synthesised
from the protected arginine derivative Nα-Boc-Nδ,Nω-Z2-
Arg (18), prepared by Ottenheijm’s procedure[16]
(Scheme 2). One-step preparation of α-keto cyanophos-
Figure 3. Retrosynthetic analysis of CtC, identifying α-keto cyano-
phosphorane and amine intermediates, providing three assembly
combinations leading to two macrocyclisation sites.
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Total Synthesis of Cyclotheonamide C
phorane 19 was achieved in 78% yield by EDCI/DMAP-
mediated condensation with (triphenylphosphoranylidene)-
acetonitrile, under Wasserman’s conditions.[7] However,
elaboration of 19 into a tripeptide α-keto cyanophos-
phorane proved to be more difficult. Indeed, after numer-
ous attempts, TFA-mediated deprotection of Nα followed
by EDCI/DMAP coupling of dipeptide 15 provided the de-
sired tripeptide 20 only in a poor 22% yield (Scheme 2). We
suspected that significant decomposition of the β-amino-α-
keto cyanophosphorane arose during the acidic N-deprotec-
tion procedure, so we decided to change the nature of the
amine protecting group. A straightforward Boc to Fmoc
exchange was achieved, to provide Nα-Fmoc-Nδ,Nω-Z2-Arg
(21) in 68% yield (Scheme 2). This compound was then
transformed into the α-keto cyanophosphorane 22 in 41%
yield. Although this yield was lower than that for 19, the
following steps were much improved: base-mediated depro-
tection of 22, followed by EDCI/DMAP coupling of dipep-
tide 15, proceeded smoothly to afford the target tripeptide
α-keto cyanophosphorane 20 in 75% yield. These observa-
tions suggest that α-keto cyanophosphoranes derived from
α-amino acids are more prone to decomposition under
acidic conditions, and that, as a consequence, base-labile
(or neutral) functions are a more suitable choice of Nα-pro-
tecting group.[17]
Scheme 2. Preparation of the α-keto cyanophosphorane compo-
nents 19 and 20. Reagents and conditions: a) (triphenylphosphor-
anylidene)acetonitrile, EDCI, DMAP, CH2Cl2, 0 °C to room temp.,
12 h, 78%; b) TFA/CH2Cl2 (1:1), 1 h at 0 °C, then workup with
Na2CO3 (10%), followed by EDCI, DMAP, 15, CH2Cl2, 0 °C to
room temp., 12 h, 22% (2 steps); c) TFA/CH2Cl2, 1 h at 0 °C, then
FmocCl, Na2CO3 dioxane/water (3:2), 0 °C to room temp., 12 h,
68% (2 steps); d) EDCI, DMAP, (triphenylphosphoranylidene)ace-
tonitrile, CH2Cl2, 0 °C to room temp., 5 h, 41%; e) CH3CN/
NHEt2, 0 °C to room temp., 1 h, then EDCI, DMAP, 15, CH2Cl2,
0 °C to room temp., 12 h, 75% (2 steps). EDCI = N-[3-(dimeth-
ylamino)propyl]-NЈ-ethylcarbodiimide hydrochloride, DMAP = 4-
(dimethylamino)pyridine, TFA = trifluoroacetic acid, Fmoc = (9-
fluorenyl)methyloxycarbonyl.
We next turned our attention to the preparation of the
nucleophilic partners (amines) for the one-pot synthesis of
α-keto amides. The targets were dipeptide 27 and tetrapep-
tide 31, incorporating the unique vinylogous dehydrotyro-
sine (V-∆Tyr) feature,[18] and were constructed as follows chemoselectively with LiAlH4 to give the primary alcohol
(Scheme 3). The Z-dehydrotyrosine dipeptide 23 was avail- 25 in 79% yield. Taylor’s one-pot oxidation/vinylogation
able from our previous work,[19] and a Boc to Fmoc pro- protocol[20,21] with activated manganese(IV) oxide and tert-
tecting group switch (97% yield) was carried out at the N butoxycarbonylmethylene triphenylphosphorane provided
terminus to produce dipeptide 24, which was reduced the requisite vinylogous dipeptide 26 in 58% yield, with the
Scheme 3. Preparation of the nucleophilic components 27 and 31. Reagents and conditions: a) TFA/CH2Cl2, 1 h at 0 °C, then FmocCl,
Na2CO3 dioxane/water (3:2), 0 °C to room temp., 12 h, 97% (2 steps); b) LiAlH4, THF, 0 °C, 1 h, 79%; c) Ph3P=CHCO2Me, MnO2,
CH2Cl2, 40 °C, 36 h, 58%; d) Et2NH/CH3CN, 1:2, 0 °C to room temp., 1 h, 90%; e) LiAlH4, THF, 0 °C, 1 h, 86%; f) Ph3P=CHCO2tBu,
MnO2, CH2Cl2, 40 °C, 36 h, 74%; g) NaOH (1 ); 100%; h) DPPCl, 17, iPr2NEt, THF, –20 °C to room temp., 12 h, 81%; i) TFA/
CH2Cl2, 1 h at 0 °C, then Na2CO3, 99%. DPPCl = diphenylphosphoryl chloride, TFA = trifluoroacetic acid, Fmoc = (9-fluorenyl)
methyloxycarbonyl.
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E configuration exclusively at the new alkene moiety. This
As we had begun to expect, coupling of the C terminus
convenient operation obviated the need for the isolation of of dipeptide 29 with dipeptide amine 17 turned out to be
the unstable aldehyde intermediate. Final N-terminal depro- something of a challenge. DCC, EDCI and PyBrop all gave
tection was achieved smoothly under basic conditions to unsatisfactory results. After some effort, we were able to
provide the dipeptide amine 27 in 90% yield.
optimise the coupling conditions by using DPPCl, which
The conversion of dipeptide 23 into compound 28 by the furnished the new tetrapeptide 30 in a gratifying 81% yield.
reduction/oxidation/vinylogation sequence was reported by Liberation of the free N-terminal amine was achieved sim-
us previously[19] and was reproduced in 64% yield. Hydroly- ply through treatment of 30 with trifluoroacetic acid, to
sis of the C-terminal ester of dipeptide 28 could not be give 31 in near quantitative yield (Scheme 3).
achieved without at least partial cleavage of the aryl silyl
With all the appropriate components in hand, we began
ether, an observation that highlighted the particular behav- work on the oxidation/coupling sequence using different re-
iour of the fully conjugated system of the V-∆Tyr fragment. actant combinations (Scheme 4). In the first reaction
We decided to optimise the double transformation and ob- (path a), ozonolysis of the arginine α-keto cyanophos-
tained dipeptide 29 in quantitative yield by use of 1  so- phorane 19 was carried out at –78 °C for 15 min to form
dium hydroxide (Scheme 3).
the electrophilic α-keto acyl cyanide intermediate, to which
Scheme 4. Tandem α-keto cyanophosphorane oxidation/coupling combinations and the synthetic end-game. Reagents and conditions:
a) 19, O3, CH2Cl2, –78 °C, 15 min, then 27, –78 °C to room temp., 1 h, 47%; b) HCO2H, room temp., 1 h; c) EDCI, DMAP, 15, 0 °C to
room temp., 12 h, 21% (2 steps); d) TFA/CH2Cl2, 1 h at 0 °C, then TBTU, HOBt, DMF/CH2Cl2 (2:1, 5 m), 0 °C to room temp., 24 h,
51%; e) 20, O3, CH2Cl2, –78 °C, 15 min, then 27 –78 °C to room temp., 18 h, 48%; f) 19 (2.5 equiv.), O3, CH2Cl2, –78 °C, 15 min, then
31, –78 °C to room temp., 18 h, 58%; g) TFA/CH2Cl2, 1 h at 0 °C, then Pd(PPh3)4, AcOH, room temp., 1 h; h) HF·py, anisole, room
temp., 12 h, 46%. EDCI = N-[3-(dimethylamino)propyl]-NЈ-ethylcarbodiimide hydrochloride, DMAP = 4-(dimethylamino)pyridine, HOBt
= 1-hydroxybenzotriazole, TFA = trifluoroacetic acid, TBTU = O-(benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium tetrafluoroborate.
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Total Synthesis of Cyclotheonamide C
dipeptide amine 27 was added to deliver the complex tri-
peptide 32, containing the α-keto homoarginine moiety, in
an encouraging 47% yield. This tripeptide was then elabo-
rated into pentapeptide 33, appropriate for macrocyclis-
ation at the Dpr-V-∆Tyr junction. Selective N-deprotection
in the presence of the C-terminal tert-butyl ester with for-
mic acid was moderately successful, and EDCI/DMAP
coupling of dipeptide 15 afforded 33 in 21% yield over the
two steps. A more direct approach (path b) brought its re-
wards: ozonolysis of the α-keto cyanophosphorane tripep-
tide 20 and subsequent addition of dipeptide amine 27 af-
forded the same linear pentapeptide 33 in a single step and
an improved 48% yield (Scheme 4).
Conclusions
In completing the second total synthesis of CtC 3 to date,
we have underlined the versatility of the α-keto cyanophos-
phorane oxidation/coupling approach for the assembly of
complex polypeptides. The construction of each of the lin-
ear pentapeptides 33 and 34 with naked ketones was
achieved, allowing direct comparison between k-Arg-Pro
and Dpr-V-∆Tyr macrocyclisation sites. The latter approach
provided an expedient and elegant route to the target CtC
core, facilitating the convergent synthesis of CtC from three
accessible starting materials: the Arg-derived cyanophos-
phorane 18 and the dipeptides 15 and 27.
An alternative combination strategy (path c) led to the
linear pentapeptide 34, suited for macrocyclisation at the k-
Arg-Pro junction. Ozonolysis of the arginine α-keto cyano-
phosphorane 19, followed by addition of the tetrapeptide
amine 31, furnished 34 in 58% yield (Scheme 4). The rela-
tive accessibility of the arginine derivative 19 allowed us to
use this component in excess (2.5 equiv.) in the reaction,
which contributed to the improved yield in relation to the
previous reactant combinations (paths a and b) leading to
33 (Scheme 4).
Two linear pentapeptides were thus available for the end-
game of the CtC synthesis. Disappointingly, we were unable
to produce the advanced macrocyclic intermediate 36 from
pentapeptide 34 (Scheme 4). The sequential C,N-deprotec-
tion steps (trifluoroacetic acid followed by palladium-cata-
lysed allyl ester cleavage) appeared to proceed normally, to
generate the zwitterionic intermediate 35, but this resisted
macrocyclisation efforts under various sets of reaction con-
ditions; only degraded materials were obtained. Previously,
other groups working on Ct syntheses had reported success-
ful macrocyclisation at the Pro-k-Arg junction, but in those
cases the k-Arg ketone function was masked as a protected
secondary alcohol.[4a,4c] Clearly, this is a much less simple
operation with the naked ketone function in place.
Experimental Section
General: Solvents were dried and purified by standard procedures.
Commercial reagents were used as obtained without further purifi-
cation. Thin-layer chromatography (TLC) was carried out on alu-
mina 60 F254 (Merck) plates and flash column chromatography
was carried out on 15 cm length columns of silica gel (40–63 µm,
Merck). Melting points were determined with a Reichert micro-
scope apparatus and are uncorrected. IR spectra were recorded on
a Perkin–Elmer 881 spectrometer. Optical rotations were measured
on a Jasco DIP-370 polarimeter, in a 10 cm quartz cell. Chemical
ionization mass spectra (CI-MS) with methane as ionization gas
was recorded on an HP 5989B spectrometer (70 eV). Electrospray
ionization mass spectra (ESI-MS) were recorded on a micro q-tof
Micromass instrument (3000 V), and high-resolution mass spectra
(HR-MS) were recorded on the same instrument with an internal
lock mass (H3PO4) and an external lock mass (Leu-enkephalin).
NMR spectra were recorded on a Bruker AC 400 spectrometer, op-
erating at 400 MHz for 1H and 100 MHz for 13C. Spectra were
taken at room temperature in deuterated solvents (as indicated)
with use of the residual solvent signals as internal standards. Ele-
mental analyses were performed on
shEA 1112 apparatus in the Microanalytical Laboratory,
UMR 7565, Université Henri Poincaré, Nancy.
Nβ-Boc-Dpr-Pro (14): Nα-Z-Nβ-Boc-Dpr (13,[15] 1.82 g, 5.4 mmol,
a Thermofinnigan Fla-
Of the previous Ct syntheses, only Wasserman had at- 1 equiv.) was dissolved in CH2Cl2 (20 mL) under argon and cooled
to 0 °C. A mixture prepared by treating commercially available Pro-
OBn·HCl (1.57 g, 6.5 mmol, 1.2 equiv.) in CH2Cl2 (5 mL) with tri-
ethylamine (904 µL, 6.5 mmol, 1.2 equiv.) was added to this solu-
tion at 0 °C over a period of 10 min. Next, hydroxybenzotriazole
(1.09 g, 8.1 mmol, 1.5 equiv.) was added. The resulting solution was
stirred for 10 min, EDCI (1.55 g, 8.1 mmol, 1.5 equiv.) was then
added, and the reaction mixture was stirred and allowed to warm
to room temp. over 12 h. CH2Cl2 (20 mL) was added, and the mix-
ture was washed successively with citric acid solution (5%; 20 mL)
and saturated NaHCO3 solution (20 mL). The organic layer was
tempted a macrocyclisation involving Dpr as the N ter-
minus; the carboxylate unit was V-Tyr (activated with DCC/
PFP-OH). The conjugated nature of the V-∆Tyr partner im-
plicated in the proposed macrocyclisation of 33 was the
source of some concern; in the event, the simultaneous
acidic deprotection of the C- and N-terminal functions of
33 followed by treatment with several phosphoryl-based
coupling systems (DPPA, DPPCl, FDPP) led to the forma-
tion of the CtC core in yields in the 25–50% range. The best
results, however, were obtained with the uronium coupling dried with MgSO4 and evaporated under reduced pressure to afford
the crude product. Purification by flash chromatography with use
of a gradient of EtOAc/cyclohexane (3:7 to 1:1) afforded the dipep-
tide Nα-Z-Nβ-Boc-Dpr-Pro-OBn as a white solid (2.47 g, 4.7 mmol,
87%). Rf = 0.65 (EtOAc/cyclohexane, 4:6); m.p. 115–116 °C. [α]2D0
reagent TBTU together with a catalytic amount of HOBt,
which provided clean access to the macrocyclic pentapep-
tide 37, which was isolated in a satisfying 51% yield, with
the naked k-Arg ketone intact (Scheme 4).[22] Only one step
remained for completion of the synthesis: complete depro-
tection of the phenol and guanidine moieties was achieved
with HF·pyridine in the presence of anisole, to give CtC (3)
in 46% yield after purification. This sample had NMR and
mass spectroscopic data identical to those of the natural
product.
1
= –42.0 (c = 1.80, CHCl3). H NMR (CDCl3): δ = 1.36 (s, 9 H),
1.75–1.82 (m, 3 H), 1.92–1.97 (m, 1 H), 3.21 (m, 1 H), 3.38 (m, 1
H), 3.66 (m, 2 H), 4.53 (m, 1 H), 4.61 (d, J = 7.0 Hz, 1 H), 5.02
(m, 2 H), 5.05 (s, 1 H), 5.14 (d, J = 12.2 Hz, 2 H), 5.61 (d, J =
8.2 Hz, 1 H), 7.19–7.29 (m, 10 H) ppm. 13C NMR (CDCl3): δ =
24.9 (CH2), 28.4 (3ϫCH3), 28.9 (CH2), 42.7 (CH2), 47.1 (CH2),
52.3 (CH), 59.0 (CH), 67.0, 67.1 (2 CH2), 79.5 (C), 128.0, 128.1,
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128.2, 128.4, 128.5, 128.6 (10ϫCH), 135.4, 136.3 (2 C), 156.0,
allowed to warm to room temp. over a specified period. The solvent
was evaporated under reduced pressure to afford the crude product,
which was purified by flash chromatography.
156.1 (2 C), 169.4 (C), 171.6 (C) ppm. IR (KBr): ν = 770, 1170,
˜
1220, 1450, 1510, 1650, 1720, 2990, 3020, 3440 cm–1. CI-MS: m/z
= 951 [2M + H – Boc]+, 564 [M + K]+, 526 [M + H]+, 426 [M +
H – Boc]+.
Nα-CHO-Dpr-Pro-OAllyl (17): Nα-CHO-Nβ-Boc-Dpr-Pro-OAllyl
was obtained by the General Procedure for peptide coupling with
EDCI/DMAP (reaction time of 12 h), from dipeptide 15 (150 mg,
0.45 mmol, 1 equiv.) and allyl alcohol (104 mg, 122 µL, 1.8 mmol,
4 equiv.). Purification by flash chromatography with EtOAc/MeOH
(97:3) afforded the desired pure product (156 mg, 0.42 mmol, 94%)
as a white solid. Rf = 0.59 (EtOAc/cyclohexane, 9:1); m.p. 112–
115 °C. [α]2D0 = –56.2 (c = 1.01, CHCl3). 1H NMR (CDCl3): δ =
This dipeptide Nα-Z-Nβ-Boc-Dpr-Pro-OBn (1.17 g, 2.23 mmol) was
dissolved in methanol (58 mL), and palladium on carbon (Pd 10%,
95 mg, 0.09 mmol, 0.04 equiv.) was added. The solution was shaken
under H2 (3.4 atm) in a Parr apparatus for 2 h. The solution was
filtered through a Celite pad, washed with methanol (3ϫ20 mL),
and evaporated under reduced pressure with a bath temperature
below 30 °C to afford the crude product 14 (655 mg, 2.17 mmol, 1.35 (s, 9 H, 3ϫCH3), 1.91–2.00 (m, 3 H, CH2, Pro), 2.19–2.21 (m,
97%) as a white solid, which was used without further purification
in the next step. Rf = 0.50 (1-propanol/H2O, 7:3); m.p. 116–118 °C.
[α]2D0 = –5.0 (c = 1.10, NaOH 1 ). 1H NMR (D2O): δ = 1.34 (d, J
1 H, CH2, Pro), 3.23 (dd, J = 7.0, 14.0 Hz, 1 H, CH2N, Dpr), 3.45
(m, 1 H, CH2N, Dpr), 3.72 (t, J = 6.0 Hz, 2 H, CH2N, Pro), 4.46
(dd, J = 3.8, 9.0 Hz, 1 H, CHα, Pro), 4.55 (t, J = 6.0 Hz, 2 H, CH2,
= 8.0 Hz, 9 H), 1.80–1.95 (m, 2 H), 2.07–2.24 (m, 2 H), 3.30–3.49 Allyl), 4.95 (q, J = 6.5 Hz, 1 H, CHα, Dpr), 5.18 (dd, J = 1.3,
(m, 2 H), 3.51–3.63 (m, 2 H), 3.97 (t, J = 8.0 Hz, 0.5 H), 4.22 (dd, 10.5 Hz, 1 H, CH2=CH, Allyl), 5.27 (dd, J = 1.3, 17.2 Hz, 1 H,
J = 6.0, 8.0 Hz, 0.5 H), 4.34 (br. s, 1 H) ppm. 13C NMR (D2O): δ
CH2=CH, Allyl), 5.35 (t, J = 6.3 Hz, 1 H, NH), 5.85 (m, 1 H,
= 22.0 (CH2), 27.5 (3ϫCH3), 29.2 (CH2), 40.0 (CH2), 47.3 (CH2), CH2=CH, Allyl), 7.27 (d, J = 8.4 Hz, 1 H, NH), 8.10 (s, 1 H,
51.7 (CH), 62.1 (CH), 80.5 (C), 155.7 (C), 166.3 (C), 178.7 (C) ppm.
NCHO) ppm. 13C NMR (CDCl3): δ = 24.8 (CH2, Pro), 28.2
(3ϫCH3, Boc), 28.8 (CH2, Pro), 42.1 (CH2N, Dpr), 47.1 (CH2N,
IR (KBr): ν = 1170, 1278, 1369, 1650, 1710, 2977, 3341 (br) cm–1.
˜
CI-MS: m/z = 324 [M + Na]+, 284 [M + H – H2O]+, 228 [M + H – Pro), 49.4 (CHα, Dpr), 59.0 (CHα, Pro), 65.7 (CH2, Allyl), 79.3
tBuO]+, 184 [M + H – H2O – Boc]+.
[OC(CH3)3], 118.7 (CH2=), 131.5 (CH=), 156.0 (NHCOO), 161.4
(NHCHO), 169.0 (NHCO, Dpr), 171.3 (CO2Allyl) ppm.
Nα-CHO-Nβ-Boc-Dpr-Pro (15): Acetic anhydride (1.1 mL,
11.8 mmol, 2.6 equiv.) was added slowly at 0 °C under argon to
formic acid (0.53 mL, 14.1 mmol, 3.1 equiv.). This reaction mixture
was stirred for 10 min at room temp. and was then heated at 55 °C
for a further 1.5 h. The mixture was then cooled to 0 °C and diluted
with dry THF (40 mL), and the dipeptide 14 (1.37 g, 4.55 mmol,
1 equiv.) was added. The reaction mixture was stirred for a further
15 h at a constant temperature of 8–10 °C. The mixture was evapo-
rated under reduced pressure to furnish the crude product (1.37 g),
which was recrystallised from EtOAc/cyclohexane (9:1) to afford
the desired pure product 15 as a white solid (1.23 g, 3.73 mmol,
82%). Rf = 0.62 (1-propanol/H2O, 7:3); m.p. 178–180 °C. 1H NMR
([D6]DMSO): δ = 1.42 (s, 9 H), 1.88–2.02 (m, 3 H), 2.15–2.27 (m,
1 H), 3.09 (m, 1 H), 3.28 (m, 1 H), 3.70 (m, 2 H), 4.32 (m, 1 H),
4.87 (m, 1 H), 6.79 (t, J = 5.6 Hz, 1 H), 8.07 (s, 1 H), 8.31 (d, J =
8.4 Hz, 1 H), 12.55 (br. s, 1 H) ppm. 13C NMR ([D6]DMSO): δ =
24.3 (CH2), 28.1 (3ϫCH3), 28.7 (CH2), 41.6 (CH2), 46.5 (CH2),
48.8 (CH), 58.4 (CH), 78.0 (C), 155.6 (C), 161.0 (CH), 168.1 (C),
The
dipeptide
Nα-CHO-Nβ-Boc-Dpr-Pro-OAllyl
(40 mg,
0.11 mmol) was treated with a solution of CH2Cl2/TFA (1:1, 3 mL)
at 0 °C for 1 h, and the solvents were then evaporated under re-
duced pressure. The residue was dissolved in and concentrated from
CH2Cl2 (3ϫ30 mL) to furnish the trifluoroacetate salt. The free
dipeptide amine 17 was generated by treating a solution of this salt
in THF (500 µL) with diisopropylethylamine (18 µL, 0.10 mmol,
1 equiv.) for 10 min at 0 °C. This solution was used immediately in
the next step. Rf = 0.10 (EtOAc/MeOH, 9:1). ESI-MS: m/z = 292
[M + Na]+, 270 [M + H]+, 252 [M + H – H2O]+.
General Procedure for Coupling with (Triphenylphosphoranylidene)-
acetonitrile: Carboxylic acid (1 mmol) was dissolved under argon
in CH2Cl2 (25 mL), and the mixture was cooled to 0 °C in an ice
bath. 4-(Dimethylamino)pyridine (0.1 mmol, 0.1 equiv.) and EDCI
(1.1 mmol, 1.1 equiv.) were added successively to the reaction mix-
ture, which was stirred for a further 5 min. (Triphenylphosphor-
anylidene)acetonitrile (1.2 mmol, 1.2 equiv.) was then added in one
portion, and the reaction mixture was stirred and allowed to warm
to room temp. over the specified period. Water (40 mL) was added,
and the mixture was extracted with CH2Cl2 (3ϫ30 mL). The com-
bined organic layers were dried with MgSO4 and concentrated un-
der reduced pressure to afford the crude residue, which was purified
by flash chromatography.
173.1 (C) ppm. IR (KBr): ν = 1170, 1253, 1530, 1648, 1707, 2976,
˜
3260 cm–1. ESI-MS: m/z = 681 [2M + Na]+, 367 [M + K]+, 352 [M
+ Na]+, 330 [M + H]+. C14H23N3O6 (329.35): calcd. C 51.06, H
7.04, N 12.76; found C 50.68, H 7.14, N 12.69.
Diketopiperazine Cyclo-[Nβ-Boc-Dpr-Pro] (16): This compound was
obtained by evaporation of the mother liquor from the recrystalli-
sation described above, as a white, amorphous solid (132 mg,
0.47 mmol, 10%). Rf = 0.54 (EtOAc/MeOH, 9:1). 1H NMR
(CDCl3): δ = 1.31 (s, 9 H), 1.88 (m, 1 H), 1.95 (m, 1 H), 2.04 (m,
1 H), 2.10 (m, 1 H), 3.48 (m, 3 H), 3.68 (m, 1 H), 4.02 (m, 2 H),
5.12 (br. s, 1 H), 6.84 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ =
22.8 (CH2), 27.9 (CH2), 28.3 (3ϫCH3), 39.6 (CH2), 45.4 (CH2),
56.8 (CH), 59.2 (CH), 80.3 (C), 157.4 (C), 165.0 (C), 170.0 (C) ppm.
Nα-Boc-Nδ,Nε-Z2-Arg-C(PPh3)CN (19): Product 19 was synthe-
sised by the General Procedure for coupling with (triphenylphos-
phoranylidene)acetonitrile (reaction time of 12 h), from the known
Nα-Boc-Nδ,Nε-Z2-Arg (18,[16] 700 mg, 1.29 mmol), and was ob-
tained after purification by flash chromatography with a gradient
of EtOAc/cyclohexane (3:7 to 4:6) as a white foam (832 mg,
1.01 mmol, 78%). Rf = 0.29 (EtOAc/cyclohexane, 4:6); m.p. 74–
77 °C. 1H NMR (CDCl3): δ = 1.32 (s, 9 H), 1.51–1.69 (m, 3 H),
1.70–1.79 (m, 1 H), 3.86 (m, 1 H), 4.03 (m, 1 H), 5.00 (br. s, 1 H),
5.03 (s, 2 H), 5.16 (s, 2 H), 5.19 (d, J = 8.0 Hz, 1 H), 7.15–7.56 (m,
25 H), 9.31 (br. s, 1 H), 9.52 (br. s, 1 H) ppm. 13C NMR (CDCl3):
δ = 24.9 (CH2), 28.4 (3ϫCH3), 30.4 (CH2), 44.7 (CH2), 47.3 (d, J
= 130 Hz, C), 56.0 (CH), 67.1 (CH2), 68.8 (CH2), 79.0 (C), 120.9
(d, J = 15 Hz, C), 121.3 (d, J = 88 Hz, 3ϫC), 127.6, 128.3, 128.8,
129.3, 133.2, 133.5 (25ϫCH), 134.8, 137.0 (2 C), 155.6, 156.0 (2
General Procedure for Peptide Coupling Reaction with EDCI/
DMAP: Carboxylic acid (1 mmol, 1 equiv.) was dissolved under
argon in CH2Cl2 (5 mL), and the mixture was cooled to 0 °C. Suc-
cessively, the free amine (0.77 mmol, 0.77 equiv.) or alcohol
(4.0 mmol, 4.0 equiv.) and 4-(dimethylamino)pyridine (24 mg,
0.2 mmol, 0.2 equiv.) were added. This solution was stirred over
10 min, EDCI (230 mg, 1.2 mmol for amines; 307 mg, 1.6 mmol
for alcohols) was then added, and the stirred reaction mixture was
5072
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5067–5078

Total Synthesis of Cyclotheonamide C
C), 160.7 (C), 164.0 (C), 194.6 (C) ppm. IR (KBr): ν = 1150, 1273,
under reduced pressure, and the residue was dissolved in and con-
centrated from CH2Cl2 (3ϫ40 mL) to furnish the crude amine
(90 mg, quant.), which was used without further purification.
˜
1507, 1596, 1705, 2364, 2867, 2945, 3425 cm–1. C47H48N5O7P
(825.89): calcd. C 68.35, H 5.86, N 8.48; found C 67.28, H 6.03, N
8.42.
The second step then involved the General Procedure for peptide
coupling with EDCI/DMAP (reaction time of 12 h), with crude
amine (0.095 mmol, 1.0 equiv.) added as the last component and
dipeptide 15 (41 mg, 0.12 mmol, 1.3 equiv.). The crude reaction
product was washed successively with water (5 mL) and a saturated
NaCl solution (5 mL) and was then dried with MgSO4 and evapo-
rated under reduced pressure to furnish the crude product
(125 mg). The desired tripeptide derivative 20 was obtained after
purification by flash chromatography with a gradient of EtOAc/
cyclohexane (10:0 to 9:1) as a white solid (74 mg, 0.071 mmol,
75%). When this procedure was reproduced on a larger scale (1–
3 g) isolated product yields were lower (ca. 50%). Rf = 0.40
(EtOAc/cyclohexane, 1:1); m.p. 83–85 °C. [α]2D0 = –3.1 (c = 1.85,
Nα-Fmoc-Nδ,Nε-Z2-Arg (21): The known Nα-Boc-Nδ,Nε-Z2-Arg
(18,[16] 300 mg, 0.55 mmol, 1 equiv.) was treated at 0 °C with a solu-
tion of CH2Cl2/TFA (1:1, 14 mL) for 1 h, and the solvents were
then evaporated under reduced pressure. The residue was dissolved
in and concentrated from CH2Cl2 (3ϫ30 mL) to furnish the tri-
fluoroacetate salt. This material was dissolved in dioxane (10 mL)
at 0 °C, and a solution of Na2CO3 (10%; 7.0 mL, 6.7 mmol,
12 equiv.) was added. After the system had been stirred for 10 min,
a white precipitate had formed. 9-Fluorenylmethyl chloroformate
(157 mg, 0.61 mmol, 1.1 equiv.) was then added, and the reaction
mixture was stirred and allowed to warm to room temp. over 12 h.
Water (40 mL) was added, and the aqueous phase was extracted
with CH2Cl2 (3ϫ30 mL). The combined organic phases were
washed with a citric acid solution (5%; 30 mL), dried with MgSO4
and evaporated under reduced pressure to afford the crude product,
which was purified by flash chromatography with a gradient of
EtOAc/MeOH (from 10:0 to 9:1) to afford pure material 21 as a
white solid (250 mg, 0.38 mmol, 68%). Rf = 0.50 (EtOAc/MeOH,
95:5); m.p. 36–38 °C (EtOAc/cyclohexane, 1:1). [α]2D0 = +5.4 (c =
1.25, CHCl3). 1H NMR (CDCl3): δ = 1.60–1.80 (m, 3 H), 1.81–
1.90 (m, 1 H), 3.95 (m, 2 H), 4.18 (br. s, 1 H), 4.41 (m, 2 H), 4.43
(br. s, 1 H), 5.10 (s, 2 H), 5.19 (s, 2 H), 6.03 (d, J = 8.5 Hz, 1 H),
7.20–7.41 (m, 18 H), 9.20–9.40 (m, 2 H) ppm. 13C NMR (CDCl3):
δ = 24.9 (CH2), 28.6 (CH2), 44.2 (CH2), 47.2 (CH), 53.7 (CH), 67.0
(CH2), 67.1 (CH2), 68.9 (CH2), 119.9 (2ϫCH), 125.1 (CH), 127.0,
127.6, 127.8, 128.3, 128.7 (15ϫCH), 134.7, 136.6 (2 C), 141.3,
141.4 (2 C), 143.8, 144.0 (2 C), 155.7, 156.3 (2 C), 160.5 (C), 163.7
1
CHCl3). H NMR (CDCl3): δ = 1.21 (s, 9 H, 3ϫCH3), 1.41–1.76
(m, 4 H, CH2, Pro, Arg), 1.79–1.98 (m, 4 H, CH2, Pro, Arg), 2.79
(td, J = 7.0, 13.5 Hz, 1 H, CH2N, Dpr), 3.11 (td, J = 6.7, 13.5 Hz,
1 H, CH2N, Dpr), 3.55 (m, 2 H, CH2N, Pro), 3.93 (t, J = 7.1 Hz,
2 H, CH2N, Arg), 4.30 (dd, J = 3.5, 8.3 Hz, 1 H, CHα, Pro), 4.85
(q, J = 6.7 Hz, 1 H, CHα, Dpr), 4.96 (s, 2 H, CH2, Z), 5.00 (m, 1
H, CHα, Arg), 5.19 (s, 2 H, CH2, Z), 6.02 (br. s, 1 H, βNH, Dpr),
6.60 (d, J = 7.0 Hz, 1 H, αNH, Dpr), 6.79 (br. s, 1 H, NH, Arg),
7.15–7.70 (m, 25 H, CHar), 7.97 (s, 1 H, NHCHO), 9.20 (br. s, 1
H, NH), 9.38 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ = 24.6,
24.8 (2 CH2, Pro, Arg), 28.3 (3ϫCH3), 29.1 (CH2, Pro), 30.2 (CH2,
Arg), 42.8 (CH2N, Dpr), 45.6 (CH2N, Arg), 47.5 (CH2N, Pro), 48.1
(d, J = 127 Hz, C=P), 49.0 (CHα, Dpr), 54.6 (CHα, Arg), 60.8
(CHα, Pro), 67.1 (CH2, Z), 68.9 (CH2, Z), 79.2 [OC(CH3)3], 120.3
(d, J = 15 Hz, CN), 122.5 (d, J = 93 Hz, 3ϫCipso-P), 127.8, 127.9,
128.0, 128.2, 128.3, 128.4, 128.6, 128.8, 129.2, 129.3, 133.4, 133.6
(25ϫCHar), 134.9, 136.8 (2 Cipso, Z), 156.0, 156.5 (2 NHCOO, Z),
160.6 (NHCHO), 160.7 (NHCOO, Boc), 164.1 [NC(=NH)N],
169.4 (NHCO, Dpr), 170.6 (NHCO, Pro), 193.6 (CO) ppm. IR
(C), 174.7 (C) ppm. IR (KBr): ν = 740, 1102, 1258, 1379, 1502,
˜
1611, 1723, 3066, 3393 cm–1. ESI-MS: m/z = 687 [M + Na]+, 665
[M + H]+. C37H36N4O8 (664.71): calcd. C 66.86, H 5.46, N 8.43;
found C 66.68, H 5.48, N 8.58.
(KBr): ν = 1109, 1253, 1381, 1438, 1508, 1638, 1718, 2180 (CN),
˜
Nα-Fmoc-Nδ,Nε-Z2-Arg-C(PPh3)CN (22): Product 22 was synthe-
sised by the General Procedure for coupling with (triphenylphos-
phoranylidene)acetonitrile (reaction time 5 h), from 21 (2.00 g,
3.0 mmol), and obtained after purification by flash chromatog-
raphy with a gradient of EtOAc/cyclohexane (1:1 to 10:0) as a white
solid (1.16 g, 1.22 mmol, 41%). The desired compound 22 was crys-
tallised from EtOAc/cyclohexane, 1:1. Rf = 0.40 (EtOAc/cyclohex-
ane, 1:1); m.p. 105–107 °C. [α]2D0 = +28.8 (c = 1.00, CHCl3). 1H
NMR (CDCl3): δ = 1.75–1.85 (m, 3 H), 2.06 (br. s, 1 H), 3.77 (br.
s, 1 H), 3.94 (m, 2 H), 4.07 (dd, J = 7.9, 17.8 Hz, 1 H), 4.17 (dd, J
= 7.9, 17.8 Hz, 1 H), 4.83 (br. s, 1 H), 4.92 (s, 2 H), 4.98 (d, J =
6.6 Hz, 2 H), 5.61 (d, J = 7.5 Hz, 1 H), 7.00–7.60 (m, 33 H), 9.11
(br. s, 1 H), 9.39 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 24.6
(CH2), 30.7 (CH2), 44.7 (CH2), 47.2 (CH), 47.6 (d, J = 125 Hz, C),
56.3 (CH), 66.8 (CH2), 67.2 (CH2), 68.9 (CH2), 120.0 (4ϫCH),
120.7 (d, J = 15 Hz, C), 122.5 (d, J = 93 Hz, 3ϫC), 124.9 (2ϫCH),
125.4, 127.1, 127.7, 128.2, 128.4, 128.8, 129.2, 133.6 (27ϫCH),
134.8, 137.0 (2 C), 141.3, 144.0, 144.2 (4 C), 155.9, 156.0 (2 C),
3400 cm–1. ESI-MS: m/z = 1037 [M + H]+. HR-MS: m/z calcd. for
[C56H61N8O10P,
H]+
1037.4327;
found
1037.4294
(–3.1 ppm). C56H61N8O10P (1037.11): calcd. C 64.85, H 5.93, N
10.80; found C 64.25, H 6.05, N 10.97. Pure product 20 was ana-
lysed by reversed-phase HPLC on a C18 column with a mobile
phase gradient from CH3CN/H2O (1:9 to 9:1), tR = 21.4 min: LC-
MS: m/z = 1037 [M + H]+. After storage in the deep freezer for one
week, reversed-phase HPLC analysis under the same conditions
indicated the presence of two components with tR1 = 21.4 min and
tR2 = 21.8 min: each showed LC-MS: m/z = 1037 [M + H]+.
N-Fmoc-D-Phe-∆Tyr(OTIPS)-OMe (24): The known dipeptide es-
ter N-Boc--Phe-∆Tyr(OTIPS)-OMe (23,[19] 3.59 g, 6.02 mmol,
1 equiv.) was treated at 0 °C with a solution of CH2Cl2/TFA (1:1;
20 mL) for 1 h, and the solvents were then evaporated under re-
duced pressure. The residue was dissolved in and concentrated from
CH2Cl2 (3ϫ30 mL) to furnish the trifluoroacetate salt. This mate-
rial was dissolved in dioxane (60 mL) at 0 °C, and a solution of
Na2CO3 (10%; 40 mL) was added. After the system had been
stirred for 10 min, a white precipitate had formed. 9-Fluorenyl-
methyl chloroformate (1.71 g, 6.61 mmol, 1.1 equiv.) was then
added, and the reaction mixture was stirred and allowed to warm
to room temp. over 18 h. Water (100 mL) was added, and the
aqueous phase was extracted with CH2Cl2 (5ϫ30 mL). The com-
160.7 (C), 164.0 (C), 193.8 (C) ppm. IR (KBr): ν = 1103, 1252,
˜
1380, 1441, 1510, 1607, 1720, 2177 (CN), 2929, 3394 cm–1. ESI-
MS: m/z = 986 [M + K]+, 970 [M + Na]+, 948 [M + H]+, 840 [M
+ H – BnOH]+. C57H50N5O7P (948.02): calcd. C 72.22, H 5.32, N
7.39; found C 72.35, H 5.47, N 7.57.
Nβ-Boc-Nα-CHO-Dpr-Pro-Nδ,Nε-Z2-Arg-C(PPh3)CN (20): Nα- bined organic phases were washed with a citric acid solution (5%;
Fmoc-Nδ,Nε-Z2-Arg-C(PPh3)CN (22, 90 mg, 0.095 mmol) was
treated at 0 °C with CH3CN/NHEt2 (2:1; 7.5 mL) for 30 min and at
room temp. for a further 30 min. The solvents were then evaporated
30 mL), dried with MgSO4 and evaporated under reduced pressure
to afford the crude product, which was purified by flash
chromatography with EtOAc/cyclohexane (20:80) as eluent. Prod-
Eur. J. Org. Chem. 2008, 5067–5078
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5073

S. P. Roche, S. Faure, L. El Blidi, D. J. Aitken
FULL PAPER
uct 24 was isolated as a white foam (4.18 g, 5.81 mmol, 97%). Rf
= 0.22 (EtOAc/cyclohexane, 2:8); m.p. 70–73 °C. [α]2D0 = +21.2 (c =
1.00, CHCl3). H NMR (CDCl3): δ = 1.11 (d, J = 7.2 Hz, 18 H),
673 [M + H – H2O]+. HR-MS: m/z calcd. for [C42H50N2O5Si +
H]+ 691.3567; found 691.3570 (+1.3 ppm). C42H50N2O5Si (690.95):
calcd. C 73.01, H 7.29, N 4.05; found C 73.01, H 7.34, N 4.11.
1
1.25 (hept, J = 7.2 Hz, 3 H), 3.17 (m, 1 H), 3.31 (m, 1 H), 3.77 (s,
3 H), 4.17 (t, J = 6.0 Hz, 1 H), 4.29 (m, 1 H), 4.49 (m, 1 H), 4.78
(br. s, 1 H), 5.71 (d, J = 6.0 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 2 H),
7.22–7.38 (m, 9 H), 7.41 (t, J = 7.0 Hz, 3 H), 7.51 (dd, J = 7.5,
N-Fmoc-D-Phe-V-∆Tyr(OTIPS)-OtBu (26): The general procedure
for oxidation/vinylogation was followed, with heating at 40 °C, with
the dipeptide alcohol 25 (4.39 g, 6.35 mmol). After purification by
flash chromatography with a gradient of EtOAc/cyclohexane (1:9
to 2:8), the product 26 was obtained as a yellow foam (2.92 g,
3.71 mmol, 58%). Rf = 0.28 (EtOAc/cyclohexane, 2:8); m.p. 86–
13.0 Hz, 2 H), 7.76 (d, J = 7.5 Hz, 2 H), 7.90 (br. s, 1 H) ppm. 13
C
NMR (CDCl3): δ = 12.7 (3ϫCH), 17.9 (6ϫCH3), 37.8 (CH2), 47.0
(CH), 52.5 (CH3), 56.2 (CH), 67.2 (CH2), 120.0, 120.1 (6ϫCH),
121.6 (C), 125.1 (CH), 126.1 (C), 127.0, 127.7, 128.7, 129.5, 131.9
(10ϫCH), 134.2 (CH), 136.5 (C), 141.2, 141.4 (4ϫC), 143.7 (C),
1
89 °C. [α]2D0 = +20.2 (c = 1.20, CHCl3). H NMR ([D6]acetone): δ
= 1.10 (d, J = 6.8 Hz, 18 H, 6ϫCH3), 1.22 (hept, J = 6.8 Hz, 3 H,
3ϫSiCH), 1.51 (s, 9 H, 3ϫCH3), 3.14 (m, 1 H, CH2Ph), 3.39 (m,
1 H, CH2Ph), 4.22 (m, 2 H, CH2, Fmoc), 4.41 (t, J = 8.0 Hz, 1 H,
CH, Fmoc), 4.91 (br. s, 1 H, CHα), 5.93 (d, J = 15.0 Hz, 1 H,
CHα=CH V-∆Tyr), 6.81 (s, 1 H, CHδ=C V-∆Tyr), 6.88 (d, J =
8.0 Hz, 2 H, CHar), 7.19–7.44 (m, 11 H, 9ϫCHar + NH +
CHβ=CH V-∆Tyr), 7.57–7.66 (m, 4 H, CHar), 7.84 (d, J = 8.0 Hz,
2 H, CHar), 8.87 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3): δ =
12.7 (3ϫSiCH), 17.9 (6ϫCH3), 28.1 [OC(CH3)3], 37.7 (CH2Ph),
47.1 (CH), 56.4 (CHα), 67.0 (CH2), 80.3 [OC(CH3)3], 119.2
(CHα=CH, V-∆Tyr), 119.9, 120.1 (6ϫCHar), 125.0 (CHar), 127.2,
127.8 (4ϫCHar), 128.6 (2ϫCipso), 128.9, 129.4 (4ϫCHar), 131.1
157.6 (C), 165.6 (C), 170.5 (C) ppm. IR (KBr): ν = 765, 1230, 1535,
˜
1660, 1700, 2400, 2910 cm–1. ESI-MS: m/z = 741 [M + Na]+. HR-
MS: m/z calcd. for [C43H50N2O6Si + H]+ 719.3516; found 719.3497
(δ = –2.7 ppm). C43H50N2O6Si (718.96): calcd. C 71.84, H 7.01, N
3.90; found C 72.39, H 7.02, N 3.92.
General Procedure for Reduction of Esters to Corresponding
Alcohols: Lithium aluminium hydride (2.3 mmol, 2.3 equiv.) was
suspended at 0 °C under argon in THF (30 mL). A solution of ester
(1 mmol) in THF (6 mL) was added dropwise over 5 min, and the
reaction mixture was then stirred for a specified time and, when
stated, allowed to warm to room temp. After this time, the reaction
was cautiously quenched at 0 °C successively with water (4 mL) and
HCl solution (1 , 4 mL). After the system had been stirred for
10 min, MgSO4 was added in excess and the mixture was stirred for
a further 30 min. After filtration, solids were washed with EtOAc
(3ϫ20 mL), and the combined filtrates were evaporated under re-
duced pressure to furnish the crude product, which was purified by
flash chromatography to afford the desired pure product.
(2ϫCHar), 134.2 (CHδ=C, V-∆Tyr), 136.3 (Cipso), 141.3 (2ϫCipso
,
Fmoc), 142.7 (CHβ=CH, V-∆Tyr), 143.6 (2ϫCipso, Fmoc), 156.3
(CH=Cγ, V-∆Tyr), 156.9 (NHCOO), 166.2 (NHCO), 169.9 (CO2
tBu) ppm. IR (KBr): ν = 740, 913, 1150, 1273, 1507, 1596, 1704,
˜
2867, 2945, 3427 cm–1. HR-MS: m/z calcd. for [C48H58N2O6Si +
Na]+ 809.3962; found 809.3978 (+2.0 ppm). C48H58N2O6Si
(787.07): calcd. C 73.25, H 7.43, N 3.56; found C 73.55, H 7.34, N
3.54.
General Procedure for One-Pot Oxidation/Vinylogation of Alcohol
with Activated MnO2 and Phosphorane: Allylic alcohol (0.35 mmol,
1 equiv.) was dissolved under argon in CH2Cl2 (10 mL). Activated
D-Phe-V-∆Tyr(OTIPS)-OtBu (27): Protected vinylogous dipeptide
26 (50 mg, 0.063 mmol, 1 equiv.) was treated at 0 °C with CH3CN/
NHEt2 (2:1; 4.5 mL) for 30 min and at room temp. for a further
manganese(IV) oxide (305 mg, 3.5 mmol, 10 equiv.) and a stabilised 30 min. The solvents were then evaporated under reduced pressure,
phosphorane (0.52 mmol, 1.5 equiv.) were added in succession. The
reaction mixture was heated at 40–55 °C. After 24 h, a further por-
tion of activated manganese(IV) oxide (305 mg, 3.5 mmol,
and the residue was dissolved in and concentrated from CH2Cl2
(3ϫ40 mL) to furnish the crude dipeptide amine 27, which was
generally used without further purification for the next step. On
10 equiv.) was added, and the mixture was stirred at reflux for a one occasion, the product was purified by flash chromatography
further 12 h. Solids were removed by filtration through Celite and
washed with CH2Cl2 (3ϫ40 mL). The combined organic filtrates
were evaporated under reduced pressure to furnish the crude prod-
uct as a brown oil, which was purified by flash chromatography to
afford the desired vinylogated product.
with use of a gradient of EtOAc/cyclohexane (2:8 to 3:7) to afford
the pure free amine 27 (32 mg, 0.057 mmol, 90%) as a yellow solid.
Rf = 0.50 (EtOAc/cyclohexane, 4:6). [α]2D0 = –1.8 (c = 1.01, CHCl3).
1H NMR (CDCl3): δ = 1.01 (d, J = 7.2 Hz, 18 H, 6ϫCH3), 1.17
(hept, J = 7.2, Hz, 3 H, 3ϫCHSi), 1.43 (s, 9 H, 3ϫCH3), 1.49 (br.
s, 2 H, NH2), 2.85 (dd, J = 8.8, 13.7 Hz, 1 H, CH2Ph), 3.23 (dd, J
= 4.0, 13.7 Hz, 1 H, CH2Ph), 3.71 (dd, J = 4.0, 8.8 Hz, 1 H, CHα),
5.65 (d, J = 15.4 Hz, 1 H, CHα=CH V-∆Tyr), 6.57 (s, 1 H, CHδ=C
V-∆Tyr), 6.71 (s, J = 8.6 Hz, 2 H, CHar), 7.17–7.32 (m, 8 H,
7ϫCHar + CHβ=CH V-∆Tyr), 8.78 (br. s, 1 H, NH) ppm. 13C
N-Fmoc-D-Phe-∆Tyr(OTIPS)-CH2OH (25): Product 25 was syn-
thesised by the General Procedure for reduction, with a reaction
time of 1 h at 0 °C, from the dipeptide ester 24 (498 mg, 0.69 mmol,
1 equiv.). Purification by flash chromatography with a gradient of
EtOAc/cyclohexane (2:8 to 1:1) afforded product 25 as a white
foam (379 mg, 0.55 mmol, 79%). Rf = 0.60 (EtOAc/cyclohexane,
1:1); m.p. 48–51 °C. [α]2D0 = +32.6 (c = 1.40, CHCl3). 1H NMR
(CDCl3): δ = 1.10 (d, J = 7.2 Hz, 18 H), 1.25 (hept, J = 7.2 Hz, 3
H), 1.81 (br. s, 1 H), 3.13 (m, 2 H), 4.19 (t, J = 6.7 Hz, 1 H), 4.31
(br. s, 2 H), 4.48 (dd, J = 7.0, 10.4 Hz, 1 H), 4.49–4.56 (m, 1 H),
5.41 (br. s, 1 H), 5.98 (s, 1 H), 6.77 (d, J = 8.5 Hz, 2 H), 6.84 (m,
2 H), 7.22 (m, 2 H), 7.26–7.38 (m, 6 H), 7.42 (t, J = 7.4 Hz, 2 H),
7.52 (dd, J = 7.5, 11.0 Hz, 2 H), 7.77 (br. s, 3 H) ppm. 13C NMR
(CDCl3): δ = 12.6 (3ϫCH), 17.9 (6ϫCH3), 38.5 (CH2), 47.1 (CH),
57.1 (CH), 64.3 (CH2), 67.2 (CH2), 117.4 (CH), 120.0, 120.4
NMR (CDCl3):
δ = 12.7 (3ϫSiCH), 18.0 (6ϫCH3), 28.3
(3ϫCH3), 40.4 (CH2Ph), 56.6 (CHα), 80.4 [OC(CH3)3], 119.4
(CHα=CH, V-∆Tyr), 120.1 (2ϫCHar), 127.1 (CHar), 127.6 (Cipso),
129.0, 129.6 (4ϫCHar), 129.7 (Cipso), 130.9 (2ϫCHar), 133.2
(CHδ=C, V-∆Tyr), 137.5 (Cipso), 142.8 (CHβ=CH, V-∆Tyr), 156.8
(CH=Cγ, V-∆Tyr), 166.2 (NHCO), 172.8 (CO2tBu) ppm. ESI-MS:
m/z = 565 [M + H]+, 509 [M + H – C4H8]+. (–)ESI-MS: m/z = 563
[M – H]–. HR-MS: m/z calcd. for [C33H48N2O4Si + Na]+ 587.3281;
found 587.3300 (+3.2 ppm).
N-Boc-D-Phe-V-∆Tyr(OTIPS)-OMe (28): Product 28 was synthe-
(6ϫCH), 124.9 (CH), 126.7 (C), 127.4, 128.9, 129.3, 129.5, 130.1 sised in two steps. The first step followed the General Procedure
(10ϫCH), 133.8, 135.8 (2 C), 141.3, 143.6 (4 C), 155.5 (C), 155.8
for reduction with the known dipeptide ester N-Boc--Phe-∆Tyr-
(C), 169.9 (C) ppm. IR (KBr): ν = 740, 913, 1267, 1504, 1604, 1667,
(OTIPS)-OMe (23,[19] 2.00 g, 3.35 mmol, 1 equiv.), with a reaction
˜
2887, 2945, 3300, 3410 (br) cm–1. ESI-MS: m/z = 713 [M + Na]+, time of 2.5 h at room temp. The allylic alcohol dipeptide N-Boc--
5074
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5067–5078

Total Synthesis of Cyclotheonamide C
Phe-∆Tyr(OTIPS)-CH2OH was obtained after purification by flash
chromatography with EtOAc/cyclohexane (2:8) as a white foam
was cooled to –20 °C under argon, and diisopropylethylamine
(119 µL, 0.68 mmol, 1.1 equiv.) was added slowly. The reaction
(1.64 g, 2.88 mmol, 86%). Rf = 0.16 (EtOAc/cyclohexane, 2:8); m.p. mixture was stirred briskly for a further 20 min, and a solution
36–38 °C. [α]2D0 = +20.5 (c = 1.40, CHCl3). H NMR (CDCl3): δ =
1.01 (d, J = 7.5 Hz, 18 H), 1.18 (hept, J = 8.0 Hz, 3 H), 1.29 (s, 9
of diphenylphosphoryl chloride (154 mg, 0.65 mmol, 1.05 equiv.) in
THF (1 mL) and a solution of dipeptide 17 (217 mg, 0.81 mmol,
1
H), 3.02 (d, J = 10.8 Hz, 2 H), 4.21 (t, J = 7.2 Hz, 2 H), 4.31 (br. 1.3 equiv.) in THF (2ϫmL) were then successively added dropwise.
s, 1 H), 4.49 (t, J = 7.2 Hz, 1 H), 4.88 (br. s, 1 H), 5.76 (s, 1 H), The reaction mixture was stirred for a further 1 h at –20 °C and
6.68 (d, J = 8.0 Hz, 2 H), 6.75 (d, J = 8.0 Hz, 2 H), 7.09–7.20 (m, was then allowed to warm to room temp. over 24 h. The solvent
5 H), 7.79 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 12.6 (3ϫCH), was evaporated under reduced pressure, and the residue was taken
17.9 (6ϫCH3), 28.2 (3ϫCH3), 38.3 (CH2), 56.6 (C), 64.2 (CH2),
80.6 (C), 116.8 (CH), 119.2 (2ϫCH), 126.8 (C), 127.2 (CH), 128.9, NaHCO3 solution (5ϫ15 mL) until the aqueous phase was trans-
129.3, 129.4 (6ϫCH), 133.9 (C), 136.1 (C), 155.2 (C), 155.4 (C), parent. The organic phase was dried with MgSO4 and evaporated
up with EtOAc (40 mL). This solution was washed with a saturated
170.3 (C) ppm. IR (CHCl ): ν = 760, 1260, 1500, 1510, 1680, 1720, to furnish the crude product, which was purified by flash
˜
3
2820, 2850, 3420 (br) cm–1.
chromatography with a gradient of CH2Cl2/MeOH (98:2 to 95:5)
to afford the pure desired protected tetrapeptide 30 as a yellow
foam (353 mg, 0.50 mmol, 81%). Rf = 0.50 (CH2Cl2/MeOH, 9:1);
The second step followed the General Procedure for oxidation/
vinylogation, with heating at 50 °C and use of the allylic alcohol
dipeptide N-Boc--Phe-∆Tyr(OTIPS)-CH2OH (200 mg, 0.35
mmol), to afford the desired product 28 after purification by flash
chromatography with EtOAc/cyclohexane (1:9), as a pale yellow
foam (162 mg, 0.26 mmol, 74%). Rf = 0.42 (EtOAc/cyclohexane,
3:7); m.p. 71–73 °C. [α]2D0 = +68.0 (c = 1.60, CHCl3). 1H NMR
(CDCl3): δ = 1.02 (d, J = 7.2 Hz, 18 H, 6ϫCH3), 1.16 (hept, J =
7.2, Hz, 3 H, 3ϫSiCH), 1.34 (s, 9 H, 3ϫCH3), 3.00 (dd, J = 7.1,
13.8 Hz, 1 H, CH2Ph), 3.13 (dd, J = 7.1, 13.8 Hz, 1 H, CH2Ph),
3.64 (s, 3 H, OCH3), 4.51 (q, J = 7.1 Hz, 1 H, CHα), 5.08 (d, J =
8.4 Hz, 1 H, NH), 5.59 (d, J = 15.4 Hz, 1 H, CHα=CH V-∆Tyr),
6.53 (s, 1 H, CHδ=C V-∆Tyr), 6.67 (d, J = 8.6 Hz, 2 H, CHar), 7.13
1
m.p. 110–112 °C. [α]2D0 = –66.4 (c = 2.00, CHCl3). H NMR ([D6]-
acetone): δ = 1.36 (s, 9 H, 3ϫCH3), 1.90–1.96 (m, 3 H, CH2, Pro),
2.25 (m, 1 H, CH2, Pro), 3.00 (t, J = 13.2 Hz, 1 H, CH2, Phe), 3.27
(m, 2 H, CH2, Phe + OH), 3.33 (dd, J = 4.0, 13.8 Hz, 1 H, CH2N,
Dpr), 3.48 (m, 1 H, CH2N, Dpr), 3.77 (m, 1 H, CH2N, Pro), 3.90
(m, 1 H, CH2N, Pro), 4.53 (br. s, 1 H, CHα, Pro), 4.59 (m, 2 H,
CH2, Allyl), 4.72 (m, 1 H, CHα, Phe), 5.00–5.09 (m, 1 H, CHα,
Dpr), 5.20 (m, 1 H, CH2=CH Allyl), 5.32 (m, 1 H, CH2=CH Allyl),
5.91 (m, 1 H, CH2=CH Allyl), 6.02 (d, J = 15.3 Hz, 1 H, CHα=CH
V-∆Tyr), 6.44 (d, J = 8.6 Hz, 1 H, NH), 6.74 (s, 1 H, CHδ=C V-
∆Tyr), 6.83 (d, J = 8.6 Hz, 2 H, CHar), 7.25–7.52 (m, 8 H, 7ϫCHar
+ CHβ=CH V-∆Tyr), 7.98 (d, J = 8.6 Hz, 1 H, NH), 8.17 (s, 1 H,
NCHO), 8.89 (br. s, 1 H, NH), 8.97 (d, J = 8.7 Hz, 1 H, NH) ppm.
13C NMR ([D6]acetone): δ = 25.6 (CH2, Pro), 28.7 (3ϫCH3, Boc),
31.7 (CH2, Pro), 38.5 (CH2, Phe), 42.0 (CH2N, Dpr), 47.8 (CH2N,
Pro), 50.4 (CHα, Dpr), 57.4 (CHα, Phe), 59.8 (CHα, Pro), 66.0
(CH2, Allyl), 79.5 [OC(CH3)3], 116.4 (2ϫCHar), 118.3 (CH2=CH,
Allyl), 120.4 (CHα=CH, V-∆Tyr), 127.3 (CHar), 127.5 (Cipso), 129.2
(2ϫCHar), 130.4 (Cipso), 130.5, 132.6 (4ϫCHar), 133.4 (CH=CH2,
Allyl), 135.1 (CHδ=C, V-∆Tyr), 139.1 (Cipso), 141.2 (CHβ=CH,
V-∆Tyr), 156.8 (CH=Cγ, V-∆Tyr), 158.9 (NHCOO), 162.2
(NHCHO), 167.3 (NHCO, Phe), 169.6 (NHCO, V-∆Tyr), 169.9
(d, J = 8.6 Hz, 2 H, CHar), 7.15–7.26 (m, 6 H, 5ϫCHar
+
CHβ=CH V-∆Tyr), 7.47 (s, 1 H, NH) ppm. 13C NMR (CDCl3): δ
= 12.6 (3ϫSiCH), 17.9 (6ϫCH3), 28.3 (3ϫCH3), 37.5 (CH2Ph),
51.4 (OCH3), 56.0 (CHα), 80.6 [OC(CH3)3], 116.8 (CHα=CH, V-
∆Tyr), 120.1 (2ϫCHar), 127.0 (CHar), 127.1 (Cipso), 128.6 (Cipso),
128.8, 129.4, 131.2 (6ϫCHar), 135.0 (CHδ=C, V-∆Tyr), 136.5
(Cipso), 144.0 (CHβ=CH, V-∆Tyr), 155.9 (CH=Cγ, V-∆Tyr), 157.0
(NHCOO), 167.3 (NHCO), 170.4 (CO Me) ppm. IR (CHCl ): ν =
˜
2
3
760, 1235, 1506, 1532, 1590, 1675, 1700, 2880, 2950, 3300 cm–1.
HR-MS: m/z calcd. for [C35H50N2O6Si + Na]+ 645.3336; found
645.3343 (+1.2 ppm). C35H50N2O6Si (622.87): calcd. C 67.49, H
8.09, N 4.50; found C 67.52, H 8.09, N 4.59.
(NHCO, Dpr), 172.7 (CO Allyl) ppm. IR (KBr): ν = 760, 1235,
˜
2
1506, 1532, 1590, 1675, 1700, 2880, 2950, 3300 cm–1. ESI-MS: m/z
= 726 [M + Na]+, 704 [M + H]+, 604 [M + H – Boc]+. HR-MS:
m/z calcd. for [C37H45N5O9 + Na]+ 726.3115; found 726.3108 (δ =
–1.0 ppm). C37H45N5O9·H2O (721.80): calcd. C 61.57, H 6.56, N
9.70; found C 61.33, H 6.48, N 9.74.
N-Boc-D-Phe-V-∆Tyr-OH (29): The protected vinylogous dipeptide
28 (156 mg, 0.25 mmol, 1 equiv.) was dissolved in EtOH (95%;
6 mL), and the solution was cooled to 0 °C over 10 min. A sodium
hydroxide solution (1 ; 3.8 mL, 3.8 mmol, 15 equiv.) was added
slowly to the reaction mixture, which was stirred for a further 6 h
at 0 °C. The yellow solution was concentrated under reduced pres-
sure to remove the ethanol, taken to pH 1 with a HCl solution (1 ,
3 mL) and extracted with EtOAc (3ϫ20 mL). Combined organic
extracts were evaporated under reduced pressure to afford the car-
boxylic acid 29 as a yellow solid (113 mg, 0.25 mmol, 100%). This
product was used without further purification. Rf = 0.00 (EtOAc/
MeOH, 9:1). 1H NMR ([D6]acetone): δ = 1.24 (s, 9 H), 2.90 (dd, J
= 7.1, 13.0 Hz, 1 H), 3.19 (dd, J = 7.1, 13.0 Hz, 1 H), 4.49 (m, 1
H), 5.75 (d, J = 15 Hz, 1 H), 6.25 (d, J = 8.0 Hz, 1 H), 6.69 (d, J
= 8.0 Hz, 2 H), 6.70 (s, 1 H), 7.10–7.25 (m, 5 H), 7.25 (s, 1 H), 7.37
(d, J = 8.0 Hz, 2 H), 8.45 (br. s, 1 H), 8.57 (br. s, 1 H), 10.0–11.0
(br. s, 1 H) ppm. 13C NMR ([D6]acetone): δ = 28.7 (3ϫCH3), 38.3
(CH2), 57.9 (CH), 79.8 (C), 116.4 (CH), 117.6 (2ϫCH), 127.3 (C),
127.4 (CH), 129.0 (2ϫCH), 129.3 (C), 129.6 (2ϫCH), 132.1
(2ϫCH), 136.4 (CH), 138.5 (C), 146.3 (CH), 156.8 (C), 159.2 (C),
168.8 (C), 172.2 (C) ppm.
D
-Phe-V-∆Tyr-Nα-CHO-Dpr-Pro-OAllyl (31): Protected tetrapep-
tide 30 (353 mg, 0.50 mmol) was treated at 0 °C with a solution of
CH2Cl2/TFA (1:1; 14 mL) for 1 h, and solvents were then evapo-
rated under reduced pressure. The residue was dissolved in and
concentrated from CH2Cl2 (3ϫ30 mL) to furnish the trifluoroacet-
ate salt, which was taken up with water (40 mL) to give a solution
at pH 2.0, and the solution was adjusted to pH 7.0 with a saturated
NaHCO3 solution. The resulting aqueous phase was extracted with
EtOAc (3ϫ20 mL), dried with MgSO4 and evaporated under re-
duced pressure to afford the pure tetrapeptide amine 31 (299 mg,
0.49 mmol, 99%) as a yellow solid, which was used for the next
step without further purification. Rf = 0.00 (CH2Cl2/MeOH, 9:1).
1H NMR ([D6]acetone): δ = 1.64–1.78 (m, 3 H), 2.01 (m, 1 H),
2.80 (m, 1 H), 3.00 (m, 1 H), 3.21 (m, 2 H), 3.39 (m, 2 H), 3.55
(m, 2 H), 3.71–3.85 (m, 1 H), 4.26 (m, 1 H), 4.36 (m, 2 H), 4.77
(m, 1 H), 4.94 (t, J = 8.5 Hz, 1 H), 5.07 (m, 1 H), 5.66 (m, 1 H),
5.77 (m, 1 H), 6.51 (d, J = 8.1 Hz, 2 H), 6.61 (d, J = 8.3 Hz, 1 H),
6.68 (d, J = 7.8 Hz, 1 H), 6.88 (s, 1 H), 6.98 (d, J = 8.2 Hz, 2 H),
7.00–7.22 (m, 7 H), 7.47 (d, J = 8.2 Hz, 1 H), 7.92 (s, 1 H) ppm.
N-Boc-
carboxylic acid 29 (280 mg, 0.62 mmol, 1 equiv.) in THF (3ϫmL)
D
-Phe-V-∆Tyr-Nα-CHO-Dpr-Pro-OAllyl (30): A solution of
Eur. J. Org. Chem. 2008, 5067–5078
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5075

S. P. Roche, S. Faure, L. El Blidi, D. J. Aitken
FULL PAPER
13C NMR ([D6]acetone): δ = 27.2 (CH2), 31.7 (CH2), 37.3 (CH2),
= 1.01 (d, J = 7.2 Hz, 18 H, 6ϫCH3), 1.25 (m, 3 H, 3ϫSiCH),
41.8 (CH2), 48.1 (CH2), 50.2 (CH), 50.3 (CH), 59.8 (CH), 66.2 1.40 (s, 9 H, 3ϫCH3), 1.49 (s, 9 H, 3ϫCH3), 1.60–1.92 (m, 8 H,
(CH2), 116.5 (2ϫCH), 118.5 (CH2), 122.1 (CH), 127.1 (C), 127.3
(CH), 129.2, 130.4 (4ϫCH), 130.6 (C), 132.1 (2ϫCH), 133.2 (CH),
135.2 (CH), 140.0 (C), 141.3 (CH), 159.4 (C), 162.4 (CH), 167.2
(C), 169.5 (C), 172.4 (C), 175.3 (C) ppm.
CH2, Pro + k-Arg), 3.23 (m, 1 H, CH2, Phe), 3.37 (m, 3 H, CH2,
Phe + CH2N Dpr), 3.66 (m, 2 H, CH2N, Pro), 3.90–3.99 (m, 1 H,
CH2N, k-Arg), 4.02–4.11 (m, 1 H, CH2N, k-Arg), 4.48 (m, 1 H,
CHα, Pro), 4.92 (m, 1 H, CHα, Dpr), 5.02 (dd, J = 8.2, 14.0 Hz, 1
H, CHα, Phe), 5.13 (m, 3 H, CHα k-Arg + CH2 Z), 5.31 (m, 2 H,
CH2, Z), 5.80 (d, J = 15.3 Hz, 1 H, CHα=CH V-∆Tyr), 6.39 (br. s,
1 H, NH), 6.81 (s, 1 H, CHδ=C V-∆Tyr), 6.88 (d, J = 8.4 Hz, 2 H,
2ϫCHar), 7.10–7.35 (m, 19 H, 17ϫCHar + CHβ=CH V-∆Tyr +
NH), 7.89 (d, J = 7.2 Hz, 1 H, NH), 8.13 (s, 1 H, NCHO), 8.17
(d, J = 8.4 Hz, 1 H, NH), 9.12 (s, 1 H, NH), 9.32 (br. s, 1 H,
NH), 9.51 (br. s, 1 H, NH) ppm. 13C NMR ([D6]acetone): δ = 14.7
(3ϫSiCH), 18.4 (6ϫCH3), 25.6 (CH2, Pro), 26.0 (CH2, k-Arg),
27.9 (CH2, Pro), 28.6 (3ϫCH3, Boc or CO2tBu), 28.8 (3ϫCH3,
Boc or CO2tBu), 30.7 (CH2, k-Arg), 37.7 (CH2, Phe), 43.4 (CH2N,
Dpr), 45.2 (CH2N, k-Arg), 48.2 (CH2N, Pro), 50.6 (CHα, Dpr),
55.4 (CHα, k-Arg), 55.9 (CHα, Phe), 60.9 (CHα, Pro), 67.4 (CH2,
Z), 69.5 (CH2, Z), 79.4 [OC(CH3)3], 80.5 [OC(CH3)3], 120.1
(CHα=CH, V-∆Tyr), 120.9 (2ϫCHar), 127.5, 128.6, 128.8, 129.1,
129.4, 130.6 (15ϫCHar), 130.8 (2ϫCipso), 132.4 (2ϫCHar), 135.4
General Procedure for Tandem Oxidation/Coupling Reactions: A
solution of α-keto cyanophosphorane (1.1 to 2.1 mmol, 1.1 to
2.1 equiv.) in CH2Cl2 (30–60 mL) was purged at –78 °C with O2 for
5 min and then ozonised (Ozone generator 502, Fischer technol-
ogy) for 20 min until the solution turned deep yellow-green. The
solution containing the α-keto acyl cyanide intermediate was
purged with argon for 15 min until it became light yellow. A solu-
tion of free peptide amine (1.0 mmol, 1.0 equiv.) in CH2Cl2 (3–
6 mL) was then added to the reaction mixture, and the resulting
solution was stirred at –78 °C for a further 1 h and warmed slowly
to room temp. over a specified time. The solvent was evaporated
under reduced pressure to afford the crude residue, which was im-
mediately purified by flash chromatography.
Nα-Boc-Nδ,Nε-Z2-k-Arg-
D-Phe-V-∆Tyr(OTIPS)-OtBu (32): Prod-
(CHδ=C, V-∆Tyr), 136.4 (Cipso, Phe), 138.1 (Cipso, Z), 138.4 (Cipso
,
uct 32 was synthesised by the General Procedure for tandem oxi-
dation/coupling (reaction time 1 h), from α-keto cyanophos-
phorane 19 (56 mg, 0.068 mmol, 1.2 equiv.) and amine 27 (32 mg,
0.057 mmol, 1 equiv.). The crude product (120 mg) was purified im-
mediately by flash chromatography with EtOAc/cyclohexane (1:9)
to provide the desired tripeptide 32 as a yellow foam (30 mg,
0.027 mmol, 47%). Rf = 0.12 (EtOAc/cyclohexane, 2:8); m.p. 102–
104 °C. [α]2D0 = –3.6 (c = 1.50, CHCl3). 1H NMR (CDCl3): δ = 1.01
(d, J = 7.2 Hz, 18 H, 6ϫCH3), 1.18 (m, 3 H, SiCH), 1.35 (s, 9 H,
3ϫCH3), 1.41 (s, 9 H, 3ϫCH3), 1.48–1.58 (m, 3 H, CH2, k-Arg),
1.72–1.78 (m, 1 H, CH2, k-Arg), 2.99–3.18 (m, 2 H, CH2, Phe),
3.87 (m, 2 H, CH2N, k-Arg), 4.02 (br. s, CHα, Phe), 4.69 (m, 1 H,
CHα, k-Arg), 5.03 (m, 2 H, CH2, Z), 5.07 (m, 2 H, CH2, Z), 5.52
(d, J = 15.6 Hz, 1 H, CHα=CH V-∆Tyr), 5.70 (m, 1 H, NH), 6.56
(s, 1 H, CHδ=C V-∆Tyr, V-∆Tyr), 6.71 (d, J = 8.8 Hz, 2 H, CHar),
7.10–7.38 (m, 19 H, 17ϫCHar + CHβ=CH V-∆Tyr + NH), 7.57
(m, 1 H, NH), 9.10–9.30 (m, 2 H, NH) ppm. 13C NMR ([D6]ace-
tone): δ = 12.3 (3ϫSiCH), 18.3 (6ϫCH3), 24.6 (CH2, k-Arg), 25.6
(CH2, k-Arg), 28.2 (3ϫCH3, Boc or CO2tBu), 28.4 (3ϫCH3, Boc
or CO2tBu), 37.7 (CH2, Phe), 44.7 (CH2N, k-Arg), 56.0 (CHα), 58.1
(CHα), 67.3 (CH2, Z), 69.3 (CH2, Z), 80.4 [OC(CH3)3], 80.9 [O-C-
(CH3)3], 120.1 (CHα=CH, V-∆Tyr), 120.9 (2ϫCHar), 127.4, 127.7,
128.4, 128.8, 129.3 (8ϫCHar), 130.4 (Cipso), 129.5, 130.2, 130.4
(5ϫCHar), 130.4 (Cipso, V-∆Tyr), 131.9, 132.4 (4ϫCHar), 135.2
Z), 144.3 (CHβ=CH, V-∆Tyr), 156.6 (NHCOO, Z), 157.2 (CH=Cγ,
V-∆Tyr), 157.5 (NHCOO, Z), 161.5 (NHCOO, Boc), 161.9
(NHCHO), 164.6 [NC(=NH)N], 166.7 (2ϫNHCO, Phe + Dpr),
169.9 (NHCO, k-Arg), 170.0 (NHCO, Pro), 172.6 (CO2tBu), 196.2
(CO, k-Arg) ppm. IR (KBr): ν = 689, 914, 1172, 1268, 1368, 1508,
˜
1600, 1721, 2869, 2947, 3291 cm–1. ESI-MS: m/z = 1367 [M +
K]+, 1351 [M + Na]+, 1329 [M + H]+. HR-MS: m/z calcd. for
[C70H93N9O15Si + H]+ 1328.6639; found 1328.6586 (δ = –4.0 ppm).
C70H93N9O15Si (1328.63): calcd. C 63.28, H 7.06, N 9.49; found C
63.21, H 7.15, N 9.44.
Nα-Boc-Nδ,Nε-Z2-k-Arg- -Phe-V-∆Tyr-Nα-CHO-Dpr-Pro-OAllyl
D
(34): Product 34 was synthesised by the General Procedure for tan-
dem oxidation/coupling (reaction time 18 h) from the α-keto cyano-
phosphorane 19 (191 mg, 0.23 mmol, 2.1 equiv.) and amine 31
(65 mg, 0.107 mmol, 1 equiv.). The crude product (231 mg) was
purified immediately by flash chromatography with a gradient of
CH2Cl2/MeOH (100:0 to 98:2) to provide the pure linear pentapep-
tide 34 as a yellow-orange foam (72 mg, 0.062 mmol, 58%). Rf =
0.20 (CH2Cl2/MeOH, 95:5); m.p. 96–98 °C. [α]2D0 = –12.7 (c = 1.00,
1
CHCl3). H NMR ([D6]acetone): δ = 1.24 (s, 9 H, 3ϫCH3), 1.50–
1.72 (m, 6 H, CH2, Pro + k-Arg), 1.75–1.89 (m, 2 H, CH2, Pro +
k-Arg), 2.70–3.00 (br. s, 2 H, CH2, Phe + OH), 3.08 (m, 1 H, CH2,
Phe), 3.26 (m, 2 H, CH2N, Dpr), 3.65 (m, 2 H, CH2N, Pro), 3.85
(m, 2 H, CH2N, k-Arg), 4.33 (m, 1 H, CHα, Pro), 4.46 (m, 2 H,
CH2, Allyl), 4.81 (m, 1 H, CHα, Phe), 4.90 (m, 1 H, CHα, k-Arg),
4.95–5.02 (m, 3 H, CHα, Dpr + CH2, Z), 5.06 (m, 1 H, CH2=CH,
Allyl), 5.13–5.22 (m, 3 H, CH2=CH, Allyl + CH2, Z), 5.78 (m, 1
H, CH2=CH, Allyl), 5.91 (d, J = 15.2 Hz, 1 H, CHα=CH V-∆Tyr),
6.22 (br. s, 1 H, NH), 6.60 (s, 1 H, CHδ=C V-∆Tyr), 6.67 (d, J =
8.8 Hz, 2 H, 2ϫCHar), 6.72 (br. s, 1 H, NH), 7.10–7.35 (m, 19 H,
17ϫCHar + CHβ=CH V-∆Tyr + NH), 7.98 (br. s, 1 H, NH), 8.03
(CHδ=C, V-∆Tyr), 136.4 (Cipso), 137.9 (2ϫCipso
, Z), 144.3
(CHβ=CH, V-∆Tyr), 156.4 (NHCOO, Z), 157.6 (NHCOO, Z),
158.6 (CH=Cγ, V-∆Tyr), 161.4 (NHCOO, Boc), 163.1 [NC(=NH)
N], 166.6 (NHCO, Phe), 166.9 (NHCO, k-Arg), 170.3 (CO2Me),
197.8 (CO, k-Arg) ppm. IR (KBr): ν = 1098, 1253, 1450, 1378,
˜
1446, 1508, 1608, 1654, 1720, 2976, 3393 cm–1. ESI-MS: m/z = 1140
[M + H + MeOH]+, 1118 [M + H]+. HR-MS: m/z calcd. for
[C61H80N6O12Si + H]+ 1117.5682; found 1117.5703 (+1.9 ppm).
Nβ-Boc-Nα-CHO-Dpr-Pro-Nδ,Nε-Z2-k-Arg-
D-Phe-V-∆Tyr(OTIPS)- (s, 1 H, NCHO), 8.64 (br. s, 1 H, NH), 9.05–9.40 (m, 2 H,
OtBu (33): Product 33 was synthesised by the General Procedure
for tandem oxidation/coupling (reaction time 18 h), from the tri-
peptide α-keto cyanophosphorane 20 (74 mg, 0.071 mmol,
1.1 equiv.) and amine 27 (36 mg, 0.064 mmol, 1 equiv.). The crude
product (110 mg) was purified immediately by flash chromatog-
raphy with a gradient of CH2Cl2/MeOH (100:0 to 98:2) to provide
the desired linear pentapeptide 33 as a yellow-orange foam (41 mg,
0.031 mmol, 48 %). Rf = 0.30 (CH2Cl2/MeOH, 95:5); m.p. 132–
2ϫNH) ppm. 13C NMR ([D6]acetone): δ = 25.5 (2ϫCH2, Pro +
k-Arg), 26.2 (CH2, Pro or k-Arg), 26.3 (CH2, Pro or k-Arg), 28.6
(3ϫCH3, Boc), 38.0 (CH2, Phe), 42.0 (CH2N, Dpr), 45.1 (CH2N,
k-Arg), 47.9 (CH2N, Pro), 50.4 (CHα, Dpr), 56.1 (CHα, Phe), 59.8
(2 ϫ CHα, Pro + k-Arg), 66.0 (CH2, Allyl), 67.3 (CH2, Z), 69.4
(CH2, Z), 79.5 [OC(CH3)3], 116.4 (2ϫCHar), 118.3 (CH2=CH, Al-
lyl), 121.6 (CHα=CH, V-∆Tyr), 127.4 (Cipso), 127.7, 128.5, 128.8,
129.2, 129.8, 130.0 (17ϫCHar), 130.3 (Cipso), 131.8 (CH=CH2, Al-
lyl), 135.3 (CHδ=C, V-∆Tyr), 136.4 (2 ϫ Cipso, Phe + Z), 138.4
1
135 °C. [α]2D0 = –47.8 (c = 1.90, CHCl3). H NMR ([D6]acetone): δ
5076
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5067–5078

Total Synthesis of Cyclotheonamide C
(Cipso, Z), 141.9 (CHβ=CH, V-∆Tyr), 156.6 (2ϫNHCOO, Z), 157.0 (1.5 mL) and anisole (0.22 mL). The reaction mixture was stirred
(CH=Cγ, V-∆Tyr), 158.9 (NHCOO, Boc), 162.4 (NHCHO), 164.5 at room temp. for 12 h, and argon was then bubbled through the
[NC(=NH)N], 167.5 (NHCO, Phe), 167.6 (NHCO, k-Arg), 169.5 mixture for 3 h. Water (10 mL) was added, and the solution was
(NHCO, V-∆Tyr), 170.2 (NHCO, Dpr), 172.3 (CO2Allyl), 197.2
concentrated under reduced pressure. Preparative HPLC purifica-
tion (XTerra prep MS C18, 10 µm, 10ϫ150 mm, CH3CN/H2O +
0.1% TFA, 25:75, flow 1 mLmin–1), followed by lyophilisation and
filtration through a SPE cartridge (Waters OASIS HLB 3cc) with
(CO, k-Arg) ppm. IR (KBr): ν = 1097, 1175, 1447, 1512, 1610,
˜
1652, 1720, 2928, 3390 cm–1. ESI-MS: m/z = 1188 [M + Na]+, 1156
[M + H]+. HR-MS: m/z calcd. for [C60H69N9O15 + H]+ 1156.4991;
found 1156.5043 (+4.5 ppm). C60H69N9O15 (1156.25): calcd. C MeOH as eluent, afforded 3 as yellow foam (8.4 mg, 0.012 mmol,
1
62.33, H 6.01, N 10.90; found C 61.70, H 6.25, N 10.67.
46%). H NMR (CD3OD): δ = 1.45–1.78 (m, 3 H), 1.86–2.10 (m,
3 H), 2.14–2.35 (m, 2 H), 2.84 (m, 1 H, Dpr β), 3.04 (dd, J = 9.1,
13.0 Hz, 1 H, Phe β), 3.08–3.20 (m, 2 H, k-Arg ε), 3.23–3.42 (m, 1
H, Phe β), 3.56 (m, 1 H, Pro δ), 3.78 (m, 1 H, Pro δ), 4.15 (m, 1
H, k-Arg β), 4.29 (m, 1 H, Dpr β), 4.53 (m, 1 H, Pro α), 4.75 (m,
1 H, Dpr α), 5.03 (m, 1 H, Phe α), 6.21 and 6.15 (d, J = 15.8 Hz,
1 H, V-∆Tyr α), 6.75 and 6.82 (d, J = 8.6 Hz, 2 H, V-∆Tyr), 6.91
(s, 1 H, V-∆Tyr δ), 7.13–7.38 (m, 6 H), 7.41 and 7.45 (d, J = 8.7 Hz,
2 H, V-∆Tyr), 8.06 and 8.07 (s, 1 H, CHO) ppm. 13C NMR
(CD3OD): δ = 23.5 (CH2), 25.6 (CH2), 25.7 (CH2), 30.5 (CH2),
40.8 (2ϫCH2), 41.8 (CH2), 49.5 (CH2), 49.8 (CH), 54.4 (CH), 55.5
(CH), 61.6 (CH), 116.2 (2ϫCH), 121.8 (CH), 126.5 (C), 127.4
(CH), 129.1 (2ϫCH), 129.9 (C), 130.6 (2ϫCH), 130.7 (2ϫCH),
136.9 (CH), 137.0 (C), 140.5 (CH), 158.2 (C), 159.4 (C), 162.9
(CH), 168.4 (C), 171.2 (C), 171.6 (C), 171.9 (C), 176.1 (C) ppm.
(13C chemical shifts were determined from HMQC and HMBC
experiments). ESI-MS: m/z = 730 [M + H]+, 748 [M + H +
H2O]+. HR-MS: m/z calcd. for [C36H44N9O8 + H2O]+ 748.3418;
found 748.3435 (+2.2 ppm).
Cyclo[Nα-CHO-Dpr-Pro-Nδ,Nε-Z2-k-Arg-
D
-Phe-V-∆Tyr(OTIPS)]
(37): Protected pentapeptide 33 (160 mg, 0.12 mmol, 1 equiv.) was
treated at 0 °C with a solution of CH2Cl2/TFA (1:1; 6 mL) for 1 h,
and the solvents were then evaporated under reduced pressure. The
residue was dissolved in and concentrated from CH2Cl2
(3ϫ30 mL) to furnish the crude trifluoroacetate salt. This residue
was dissolved in CH2Cl2 (20 mL) and washed with a solution of
NaHCO3 (pH 8; 5 mL) and then with water (5 mL). The organic
phase was dried with MgSO4 and concentrated under reduced pres-
sure to afford the crude N,C-deprotected pentapeptide (142 mg,
0.12 mmol, quant.). This material was engaged in macrocyclisation
reactions without further purification. A sample of crude depro-
tected pentapeptide (40 mg, 0.034 mmol, 1 equiv.) was dissolved in
a mixture of CH2Cl2/DMF (2:1; 6 mL; 0.005 ) at 0 °C under ar-
gon. TBTU (22 mg, 0.068 mmol, 2 equiv.) and HOBt (1 mg,
0.007 mmol, 0.2 equiv.) were added successively, and the solution
was stirred briskly and allowed to warm to room temp. over 24 h.
The solvent was evaporated under reduced pressure to afford a
crude residue (53 mg), which was purified by flash chromatography
with a gradient of CH2Cl2/MeOH (100:0 to 9:1) to provide the pure
macrocycle 37 as a pale yellow foam (20 mg, 0.017 mmol, 51%). Rf
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all significant new compounds;
1H NMR and HR-MS spectra for compound 3.
= 0.27 (CH2Cl2/MeOH, 95:5). [α]2D2 = +44.0 (c = 0.80, CHCl3). H
1
NMR ([D6]acetone): δ = 1.10 (d, J = 7.3 Hz, 18 H, 6ϫCH3), 1.29
(m, 3 H, 3ϫSiCH), 1.55–2.15 (m, 8 H, CH2, Pro + k-Arg), 2.73
(m, 1 H, CH2N, Dpr), 3.11 (dd, J = 9.5, 13.9 Hz, 1 H, CH2, Phe),
3.28 (dd, J = 5.8, 13.9 Hz, 1 H, CH2, Phe), 3.39 (dd, J = 6.5,
16.5 Hz, 1 H, CH2N, Pro), 3.56 (dd, J = 7.0, 16.5 Hz, 1 H, CH2N,
Pro), 4.00 (m, 2 H, CH2N, k-Arg), 4.23 (t, J = 6.9 Hz, 1 H, CH2N,
Dpr), 4.55 (dd, J = 4.9, 8.4 Hz, 1 H, CHα, Pro), 4.78 (dd, J = 6.5,
10.3 Hz, 1 H, CHα, Dpr), 4.84 (dd, J = 5.9, 9.7 Hz, 1 H, CHα,
Phe), 5.12 (m, 3 H, CHα, k-Arg + CH2, Z), 5.32 (m, 3 H, CH2, Z
+ NH), 5.95 (d, J = 15.0 Hz, 1 H, CHα=CH V-∆Tyr), 6.84 (s, 1 H,
CHδ=C V-∆Tyr), 6.86 (d, J = 8.8 Hz, 2 H, 2ϫCHar), 7.14–7.52 (m,
19 H, 17ϫCHar + CHβ=CH V-∆Tyr + NH), 7.86 (br. s, 1 H, NH),
8.04 (br. s, 1 H, NH), 8.10 (s, 1 H, NCHO), 8.68 (s, 1 H, NH), 9.30
(br. s, 1 H, NH), 9.49 (br. s, 1 H, NH) ppm. 13C NMR ([D6]ace-
tone): δ = 13.4 (3ϫSiCH), 18.3 (6ϫCH3), 25.5 (CH2, Pro), 26.0
(CH2, k-Arg), 28.5 (CH2, Pro), 32.6 (CH2, k-Arg), 38.7 (CH2, Phe),
41.6 (CH2N, Dpr), 44.7 (CH2N, k-Arg), 48.6 (CH2N, Pro), 49.1
(CHα, Dpr), 56.1 (CHα, Phe), 59.7 (CHα, k-Arg), 60.0 (CHα, Pro),
67.2 (CH2, Z), 69.6 (CH2, Z), 120.7 (CHα=CH, V-∆Tyr +
2ϫCHar), 127.5, 128.5, 128.8, 129.0, 129.2, 129.6, 130.1
(13ϫCHar), 130.6 (2ϫCipso), 131.6 (CHar), 132.0 (2ϫCHar), 133.4
(CHar), 135.4 (CHδ=C, V-∆Tyr), 136.3 (Cipso, Phe), 138.0 (Cipso, Z),
138.5 (Cipso, Z), 142.0 (CHβ=CH, V-∆Tyr), 156.6 (NHCOO, Z),
157.3 (NHCOO, Z), 160.0 (CH=Cγ, V-∆Tyr), 161.1 (NHCHO),
161.5 [NC(=NH)N], 164.4 (NHCO, Phe), 166.1 (NHCO, Dpr),
169.5 (NHCO, V-∆Tyr), 170.1 (NHCO, Pro), 174.5 (NHCO, k-
Arg), 196.1 (CO, k-Arg) ppm. ESI-MS: m/z = 1186 [M + H +
MeOH]+, 1154 [M + H]+. HR-MS: m/z calcd. for [C61H75N9O12Si
+ H]+ 1154.5383; found 1154.5377 (δ = –0.5 ppm).
Acknowledgments
Financial support form the French Ministère de la Recherche,
(PhD grant to S. P. R.) is gratefully acknowledged. We are very
grateful to B. Légeret for mass spectral analyses.
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Eur. J. Org. Chem. 2008, 5067–5078
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5077

S. P. Roche, S. Faure, L. El Blidi, D. J. Aitken
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Received: June 18, 2008
Published Online: September 9, 2008
5078
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5067–5078