Total Synthesis of Skyllamycins A–C

Article abstract of DOI:10.1002/chem.201704277

The skyllamycins are a family of highly functionalized non-ribosomal cyclic depsipeptide natural products which contain the extremely rare α-OH-glycine functionality. Herein the first total synthesis of skyllamycins A–C is reported, together with the biofilm inhibitory activity of the natural products. Linear peptide precursors for each natural product were prepared through an efficient solid-phase route incorporating a number of synthetic modified amino acids. A novel macrocyclization step between a C-terminal amide and an N-terminal glyoxylamide moiety served as a key transformation to install the unique α-OH-glycine unit and generate the natural products in the final step of the synthesis.

Full text of DOI:10.1002/chem.201704277

A Journal of
Accepted Article
Title: Total Synthesis of Skyllamycins A-C
Authors: Richard James Payne, Andrew Giltrap, Jake Haeckl, Kenji
Kurita, and Roger Linington
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201704277
Link to VoR: http://dx.doi.org/10.1002/chem.201704277
Supported by

10.1002/chem.201704277
Chemistry - A European Journal
COMMUNICATION
Total Synthesis of Skyllamycins A-C
Andrew M. Giltrap,[a] F. P. Jake Haeckl,[b] Kenji L. Kurita,[b] Roger G. Linington[b] and Richard J.
Payne[a]*
Dedicated to Professor Chris Abell on the occasion of his 60th Birthday
O
O
R2
Abstract: The skyllamycins are a family of highly functionalized non-
ribosomal cyclic depsipeptide natural products which contain the
extremely rare α-OH-glycine functionality. Herein we report the first
total synthesis of skyllamycins A-C, together with the biofilm
inhibitory activity of the natural products. Linear peptide precursors
for each natural product were prepared through an efficient solid-
phase route incorporating a number of synthetic modified amino
acids. A novel macrocyclization step between a C-terminal amide
H
N
H
N
R2
R1
R1
N
COOH
O
H
Skyllamycin A
O
Me
O
O
N
H
1
( )
OH
HN
O
O
O
O
O
OH
O
N
HN
Skyllamycin B
H
H
H
2
( )
N
O
O
N
H
O
OH
NH
N
H
HO
Skyllamycin C
3
( )
and
a
N-terminal glyoxylamide moiety served as
a
key
N
O
transformation to install the unique α-OH-glycine unit and generate
the natural products in the final step of the synthesis.
H
Figure 1. Structure of skyllamycins A-C (1-3).
Skyllamycins A (1), B (2), and C (3) are a family of non-
ribosomal cyclic depsipeptide natural products isolated from
Steptomyces sp.[1] (Figure 1). They contain a number of unusual
structural features: three -OH amino acids (-OH-Phe, -OH-O-
Me-Tyr, -OH-Leu) (blue), an N-terminal cinnamoyl residue
The skyllamycins also possess interesting biological activity.
They were initially discovered in the search for novel agents that
inhibit the platelet-derived growth factor (PDGF) signaling
pathway. We recently re-isolated them in our search for
inhibitors of Pseudomonas aeruginosa biolfilms.[1c] Traditional
antibiotics target bacteria in the platonic state, however the
formation of biofilms allow bacteria to evade their action.[5] As
such, agents which inhibit biofilm formation or clear pre-attached
biofilms, a major contributor to the persistence of nosocomial
infections, represent a potentially useful therapeutic strategy. To
our knowledge, the skyllamycins are the first known class of
cyclic peptide biofilm disruptors. Given their highly unusual
structural features, together with their important anti-biofilm
activity, we sought to develop a concise total synthesis of
skyllamycins A-C (1-3) which is described herein which, to date,
have not succumbed to total synthesis.
(red),
extremely rare -OH-Gly residue (purple). The biosynthetic
origin of these modifications has been recently investigated.[1b]
single P450 monoxygenase (P450sky was found to be
a -Me-aspartic acid (-Me-Asp) (green) and the
A
)
responsible for catalyzing the β-hydroxylation of Phe, Leu and
O-Me-Tyr, producing the (3S)-diastereomer in each case,[2]
however the exact timing at which the -OH-Gly residue is
installed remains unknown. Indeed, -OH-Gly residues are
extremely rare and to date this unusual moiety has only been
found in one other natural product, the structurally simpler linear
peptide anti-tumour agent spergualin.[3]
The stereochemistry of the amino acids present in 1-3 was not
assigned during the initial isolation; however further work by
Süssmuth and co-workers[4] confirmed the absolute
configuration of the amino acids via a combination of chiral
HPLC/GC and Marfey’s analysis. Due to the instability of the
-OH-Gly residue, the configuration could not be confirmed
experimentally. Instead, by estimating the distances between
protons using NOESY measurements, followed by molecular
dynamics simulations, the authors proposed that the -OH-Gly
residue was (S)-configured. These calculations also predicted
the presence of a strong intramolecular hydrogen bond network
when the -OH-Gly residue was in the (S)-configuration.
Retrosynthetically, we envisioned a novel macrocyclization
step to generate the -OH-Gly residue that would necessitate
preparation of modified linear peptides 4-6 containing a C-
terminal amide and a N-terminal glyoxylamide functionality
(Scheme 1A). We reasoned that, due to the inherent instability
of the -OH-Gly in linear peptides,[6] formation in the final step
would reduce the likelihood of decomposition during synthesis.
Indeed, the stability of this residue in the natural products is
proposed to be due to a hydrogen-bonding network in the
mature structure.[1b] Furthermore, the presence of this
intramolecular hydrogen-bonding network during the cyclization
reaction could potentially induce -OH-Gly formation with the
desired (S)-stereochemistry. Glyoxylamides 4-6 in turn could be
accessed from resin-bound 7-9 by resin cleavage followed by
oxidative cleavage of the N-terminal serine residue.[7] We
envisioned that resin-bound peptides 7-9 could be prepared via
Fmoc-solid-phase peptide synthesis (SPPS) from Sieber amide
resin which possesses a linker that can be cleaved under mild
acidic conditions (1% TFA in CH2Cl2).[8]
[a]
[b]
Andrew Giltrap and Prof. Richard J. Payne
School of Chemistry
The University of Sydney
Sydney, NSW 2006, AUSTRALIA
E-mail: richard.payne@sydney.edu.au
F. P. Jake Haeckl, Dr Kenji L. Kurita and Prof. Roger L. Linington
Department of Chemistry
Before the assembly of skyllamycins A-C could begin,
synthesis of the unusual amino acids present in the natural
products was required (Scheme 1B). The suitably protected -
OH-Leu 10, -OH-Phe 11, -OH-O-Me-Tyr 12 were synthesized
utilizing a unified strategy, namely organometallic addition to
Garner’s aldehyde[9] followed by deprotection, oxidation and
protecting group manipulations[10] (see Supporting Information
for synthetic details). The -OH groups were protected as an
oxazolidine, based on the pseudo-proline moiety commonly
Simon Fraser University
Burnaby, British Columbia BC V5A 1S6, Canada
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201704277
Chemistry - A European Journal
COMMUNICATION
used for serine and threonine residues in SPPS[11] to improve
the quality of the linear peptide synthesized through the
induction of turns in the peptide backbone. Protected -Me-Asp
13 was synthesized by adapting a procedure from Goodman et
al.[12] Finally, cinnamic acids 14 and 15 were synthesized via
Sonogashira cross-coupling followed by Lindlar reduction.[13]
coupled, the latter under microwave conditions, to yield the
resin-bound pentapeptide 18.
1) 10 vol% piperidine in DMF, 2 x 3 min
NHFmoc
2) Fmoc-D-Trp-OH, PyAOP, NMM, DMF, 16 h
3) Ac2O:Pyridine (1:9, v/v), 10 min
4) 10 vol% piperidine in DMF, 2 x 3 mn
H
O
Fmoc
N
O
N
N
O
O
H
12
5) , HATU, HOAt, iPr2EtN, DMF, 16 h
NH
16
NHFmoc
O
N
COOH
O
N
H
COOH
O
1) 10 vol% piperidine
in DMF, 2 x 3 min
2) Fmoc-Pro-OH, HATU,
HOAt, iPr2EtN, DMF
MW, 50 oC, 1 h
H
O
OH
O
O
OH
O
O
O
O
N
H
O
O
O
N
H
O
HN
HN
FmocHN
O
O
O
O
1) 10 vol% piperidine in DMF,
O
OH
N
O
N
OH
HN
HN
O
2 x 3 min
O
O
N
H
H2N
O
O
N
O
O
11
2) , HATU, HOAt, iPr2EtN,
N
H
O
N
H
O
N
FmocN
DMF, 16 h
OH
NH
NH
cyclization
N
H
HO
N
H
HO
O
O
H
H
3) 10 vol% piperidine in DMF
2 x 3 min
O
O
O
O
N
N
N
N
N
N
H
N
N
O
O
O
O
4) Fmoc-Gly-OH, HATU, HOAt,
iPr2EtN, DMF, MW, 50 oC, 1 h
H
H
H
R2
Me
H
R2
Me
H
4
1
Skyllamycin A
Skyllamycin B
NH
NH
5
6
2
O
O
Skyllamycin C 3
H
H
17
18
1) resin cleavage
2) oxidative cleavage
NHFmoc
Scheme 2. Synthesis of resin-bound intermediate 18.
O
O
H
R2
H
Sieber amide resin
N
N
N
COOPhiPr
B
H
O
O
O
O
O
O
O
N
H
HO
HO
N
O
Resin-bound 18 served as the key intermediate for the
synthesis of the three natural products (1-3). In the case of
skyllamycin A (1), Fmoc--Me-Asp(PhiPr)-OH (13) was coupled
to resin-bound 18 for 16 h, employing HATU coupling conditions
(Scheme 3). The synthesis of skyllamycins B (2) and C (3) was
continued by the coupling of Fmoc-Asp(PhiPr)-OH. Iterative
O
O
O
O
FmocN
FmocN
O
N
O
O
N
NH2
H
O
10
11
N
H
O
O
O
N
N
HO
O
SPPS
N
O
HO
H
PhiPrOOC
O
FmocN
FmocHN COOH
NH
R2
Fmoc-SPPS
utilizing
benzotriazol-1-yl-oxytripyrrolidino-
O
12
13
phosphonium hexafluorophosphate (PyBOP) to couple Fmoc-
Ala-OH and side chain unprotected Fmoc-Thr-OH, followed by
HATU-mediated coupling of cinnamic acid 14 or 15 afforded
resin-bound peptides 19-21.
7
8
9
Me
H
OH
OH
H
O
O
14
15
Next, the key on-resin esterification step was carried out
utilizing oxazolidine-protected Fmoc--OH-Leu-OH 10, N,N’-
Scheme 1. A) Retrosynthetic analysis of skyllamycins A-C (1-3). B) Synthetic
building blocks 10-15 required for the total synthesis of 1-3.
diisopropylcarbodiimide
(DIC)
and
catalytic
N,N-
dimethylaminopyridine (DMAP) affording resin-bound 22-24.
Importantly, we could not detect any epimerization of the -OH-
Leu moiety under the DMAP-catalyzed esterification conditions.
Our initial synthetic efforts toward linear peptide precursors 7-9
employed strongly acidic conditions for side-chain deprotection
which caused decomposition of the -OH-O-Me-Tyr residue via
deoxygenation and dehydration pathways (an observation also
made in the synthesis of Callipeltin B by Lipton and co-
workers).[14] This prevented the use of the standard protecting
groups used in Fmoc-SPPS. As such, the more exotic phenyl
isopropyl group (PhiPr) was used for the protection of the side
chain carboxylate of Asp/β-Me-Asp that can be cleaved under
With the key ester bond now in place, Fmoc-D-Leu-OH was
effectively coupled to resin-bound peptides 23 and 24 as
described previously, using HATU, HOAt and iPr2NEt at 50 °C
for 1 hour under microwave heating. Unfortunately, when these
conditions were applied to resin-bound intermediate 22
containing the -Me-Asp residue, a significant amount of by-
product with a mass 18 Da less than the product was observed.
This was likely owing to aspartimide formation[16] promoted by a
conformational change in the peptide backbone induced by the
-Me group. Gratifyingly, this side-reaction could be suppressed
by excluding an additional base from the coupling reaction,
instead utilizing DIC and HOAt at 50 °C with microwave heating.
These optimized conditions were subsequently employed,
followed by elongation with side chain unprotected Fmoc-Ser-
OH to afford resin-bound peptides 7-9.
mildly acidic conditions,[15] while the side chain indole of the
Trp residue was carried through the SPPS unprotected.
D-
To begin the synthesis, Fmoc-
D-Trp-OH was loaded onto
Sieber amide resin using
(7-azabenzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP)
and N-methylmorpholine (NMM) (Scheme 2). Next, oxazolidine-
protected Fmoc--OH-O-Me-Tyr-OH (12) was coupled for 16 h
using
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-
b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-hydroxy-7-
azabenzotriazole (HOAt) and iPr2NEt to yield resin-bound
dipeptide 16. Due to the hindered nature of the oxazolidine-
protected N-terminus, Fmoc-Pro-OH was coupled under
optimized conditions, namely HATU, HOAt and iPr2NEt with
microwave irradiation at 50 °C for 1 hour to afford 17. Protected
Fmoc--OH-Phe-OH (11) and Fmoc-Gly-OH were subsequently
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10.1002/chem.201704277
Chemistry - A European Journal
COMMUNICATION
O
O
R2
COOPhiPr
O
O
R2
COOH
H
N
H
N
H
N
H
N
N
H
H
N
N
N
O
O
N
H
O
O
O
N
O
O
OH
O
O
O
O
N
O
O
N
O
H
H
HN
N
N
O
O
O
O
O
O
O
O
O
SPPS
OH
H
O
H
HN
O
O
O
N
O
N
N
N
N
N
NH2
H
NH2
O
O
N
H
N
H
N
N
O
O
O
O
O
O
H
H2N
N
H
N
NH
HO
TFA:iPr3SiH:CH2Cl2
HO
N
N
O
(1:5:94), 30 min
H
NH
H
NH
HO
O
O
O
18
NH
NH
R2
O
19
20
21
Me
H
R2
Me
H
R2
7
25
26
27
Me 11%
H
8
9
H
H
12%
12%
H
10
, DIC, CH2Cl2,
30 min, then DMF,
DMAP, 16 h
NaIO4, Na2HPO4 buffer,
10 min, then (CH2OH)2
O
R2
O
O
R2
COOPhiPr
H
H
H
N
H
N
O
R2
O
R2
H
H
N
H
N
H
N
N
N
N
N
N
COOPhiPr
N
H
COOH
N
H
COOH
O
H
H
O
O
O
O
O
N
O
O
OH
O
O
O
OH
O
O
O
O
N
O
O
N
O
O
N
H
O
N
H
H
H
N
O
N
HN
HN
O
O
O
O
O
O
O
O
O
O
O
N
O
NFmoc
O
N
OH
O
OH
HN
HN
N
O
O
N
H
O
MeCN, 60 oC, 25 h
NH2
H
O
H2N
O
O
1) 10 vol% piperidine
in DMF 2 x 3 min
N
O
O
O
N
H
H
N
H
O
O
N
H
O
O
O
O
N
N
N
N
HO
NH
OH
NH
N
H
HO
N
H
HO
2) Fmoc-D-Leu-OH, DIC,
HOAt, DMF, MW, 50 oC, 1 h
3) 10 vol% piperidine
in DMF 2 x 3 min
N
N
O
O
H
H
N
N
H
O
O
NH
NH
H
R2
R2
O
O
4) Fmoc-Ser-OH, PyBOP,
NMM, DMF, 1 h
1
2
3
Me
H
Skyllamycin A
Skyllamycin B
Skyllamycin C
4
Me
H
32%
19%
33%
62%
63%
68%
R2
R2
5
6
7
Me
H
22
23
24
Me
H
5) 10 vol% piperidine
in DMF 2 x 3 min
H
H
8
9
H
H
Scheme 4. Total Synthesis of skyllamycins A-C (1-3).
Scheme 3. Synthesis of resin-bound intermediates 7-9.
Interestingly, the next conditions trialed, namely incubation of
glyoxylamide 5 in MeCN at 60 °C at a final concentration of 1
mM for 25 h, resulted in the consumption of starting material,
and the formation of a new peak, again with the mass of the
desired natural product 2 but with a different retention time to
those generated under the acidic conditions above. This new
product was isolated by HPLC in 42% yield. Gratifyingly, whilst
the isolated material was a 1:1 mixture of two compounds,
significant overlap was observed between one set of signals in
With the fully assembled linear resin-bound intermediates 7-9
in hand, the next step involved cleavage from resin. To this end,
resin-bound 7-9 were treated with 1% TFA in CH2Cl2 with 5%
iPr3SiH as a cation scavenger, affording the desired linear
peptides 25-27 in 11-12% yield after HPLC purification.
Importantly, these mildly acidic conditions effected removal of
the PhiPr group and cleavage of the pseudo-proline
isopropylidene moieties.
1
the H-NMR and the spectrum of the isolated natural product.
The synthetic mixture was next compared to an authentic
Having generated linear peptides 25-27, the key oxidative
cleavage step was next attempted on the N-terminal Ser residue
to generate the requisite glyoxylamide moiety. To this end, a
solution of NaIO4 (2 eq.) was added to 25-27 in a 1:1 v/v mixture
of Na2HPO4 buffer (pH = 9) and MeCN for 10 min before being
quenched with ethylene glycol, acidified and immediately
purified by HPLC. Pleasingly, this yielded target glyoxylamides
4-6 in 62-68% yield after HPLC purification. The identity of the
glyoxylamide was confirmed by the presence of the
corresponding hydrate [M+H3O]+ ion in the MS[7a] (see
Supporting Information).
sample of skyllamycin
B (2) via UPLC-MS co-injection
experiments, which further supported the presence of the natural
product. Finally, this mixture was separated by an optimized
HPLC protocol to afford pure synthetic skyllamycin B (2) in 19%
yield from the cyclization reaction that possessed almost
identical NMR spectra to the isolated natural product (see
Supporting Information).
With the cyclization methodology validated on skyllamycin B
(2), glyoxylamides 4 and 6 were subjected to the same
conditions, namely incubation in MeCN at 60 °C for 25 h at a
concentration of 1 mM. Analysis of the crude reactions revealed
the consumption of starting material and formation of new peaks
with the desired mass of the natural products. After HPLC
purification, synthetic skyllamycins A (1) and C (3) were isolated
in 32% and 33% yield, respectively from the cyclization reaction.
The retention time of synthetic 1 and 3 was shown to be
identical to the isolated natural products via UPLC-MS co-
injection studies (see Supporting Information). In addition,
comprehensive NMR comparisons between synthetic and
isolated skyllamycins A (1), B (2) and C (3) showed very strong
overlap suggesting that the synthetic materials were identical to
the authentic isolated natural products (see Supporting
Information). Furthermore, highly analogous ORD spectra
With the glyoxylamides 4-6 in hand, the critical cyclization with
concomitant formation of the -OH-Gly residue was attempted
on skyllamycin B precursor 5. Initially glyoxylamide 5 was
reacted in a solution of 1% TFA in MeCN for 20 h and the
reaction was monitored by HPLC-MS. Gratifyingly, two new
peaks were observed during HPLC analysis, both with the
desired mass of skyllamycin B (2). Unfortunately, when the
HPLC purified products were analyzed by 1H-NMR spectroscopy
neither compound was a good match for the authentic natural
product. While the identity of the products of the cyclization was
not determined, we hypothesize that these products are cyclic
hemiacetals formed via the attack of one of the side chain
hydroxyls onto the glyoxylamide.
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10.1002/chem.201704277
Chemistry - A European Journal
COMMUNICATION
between the synthetic and isolated skyllamycins A-C suggested
that they were the same enantiomer (see Supporting
Information). Finally, the synthetic natural products were
analyzed in a P. aeruginosa biofilm inhibition assay alongside
the authentic natural products. Pleasingly, the synthetic and
isolated products 1-3 showed comparable biofilm inhibition
activity, further confirming the identity of the synthetic natural
products (see Supporting Information).
H. Yildiz, R. G. Linington, Antimicrob. Agents Chemother. 2014,
58, 1092-1099.
[2]
[3]
a) S. Uhlmann, R. D. Süssmuth, M. J. Cryle, ACS Chem. Biol.
2013, 8, 2586-2596; b) K. Haslinger, C. Brieke, S. Uhlmann, L.
Sieverling, R. D. Süssmuth, M. J. Cryle, Angew. Chem. Int. Ed.
2014, 53, 8518-8522.
a) T. Takeuchi, H. Iinuma, S. Kunimoto, T. Masuda, M. Ishizuka,
M. Takeuchi, M. Hamada, H. Naganawa, S. Kondo, H. Umezawa,
J. Antibiot. 1981, 34, 1619-1621; b) H. Umezawa, S. Kondo, H.
Iinuma, S. Kunimoto, Y. Ikeda, H. Iwasawa, D. Ikeda, T. Takeuchi,
J. Antibiot. 1981, 34, 1622-1624.
In conclusion, we have successfully completed the first total
synthesis of skyllamycins A-C (1-3). A key final macrocyclization
step with concomitant formation of the unusual -OH-Gly moiety
was used to construct the natural products, which were identical
in all respects to isolated skyllamycins A-C. This work lays the
foundation for further studies into the biosynthesis of these
natural products, the generation of synthetic skyllamycin
analogues, as well as the interrogation of the mechanism of their
biofilm inhibitory activity. Studies toward this end will be reported
in due course.
[4]
[5]
[6]
[7]
V. Schubert, F. Di Meo, P. L. Saaidi, S. Bartoschek, H. P. Fiedler,
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L. Lebreton, J. Annat, P. Derrepas, P. Dutartre, P. Renaut, J. Med.
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24, 735-765.
[8]
P. Sieber, Tetrahedron Lett. 1987, 28, 2107-2110.
P. Garner, J. M. Park, J. Org. Chem. 1987, 52, 2361-2364.
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Tetrahedron 1996, 52, 11673-11694; b) N. Okamoto, O. Hara, K.
Makino, Y. Hamada, J. Org. Chem. 2002, 67, 9210-9215; c) A.
Nishida, H. Sorimachi, M. Iwaida, M. Matsumizu, T. Kawate, M.
Nakagawa, Synlett 1998, 389-390.
Acknowledgements
[9]
[10]
We thank Dr. Ian Luck and Dr. Nick Proschogo (University of
Sydney) for NMR spectroscopy and mass spectrometry
technical support, respectively, and Walter Bray (UC, Santa
Cruz) for support with the biofilm screening. We thank the
Australian Postgraduate Award and John A. Lamberton
Scholarship for PhD funding (A.M.G), ARC Future Fellowship to
R.J.P (FT130100150), and NSERC Discovery support to R.G.L.
(RGPIN-2016-03962).
[11]
[12]
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[14]
T. Wöhr, F. Wahl, A. Nefzi, B. Rohwedder, T. Sato, X. Sun, M.
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Keywords: solid-phase synthesis • natural products • biofilms •
peptides • cyclic peptides
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This article is protected by copyright. All rights reserved.

10.1002/chem.201704277
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The total synthesis of the complex
cyclic peptide natural products
skyllamycin A, B and C is described.
The successful syntheses hinged on
an unprecedented macrocyclization
reaction in the last step that furnished
the natural products through the
generation of the unusual -OH-Gly
moiety.
Andrew M. Giltrap, F. P. Jake Haeckl,
Kenji L. Kurita, Roger G. Linington and
Richard J. Payne*
Page No. – Page No.
Total Synthesis of Skyllamycins A-C
This article is protected by copyright. All rights reserved.