Total synthesis of nannocystin Ax

Article abstract of DOI:10.1039/c7cc00469a

A concise total synthesis of nannocystin Ax, a natural depsipeptide recently isolated from myxobacteria, has been accomplished. By following a convergent strategy, the target molecule was assembled from three fragments. Each fragment can be synthesized expeditiously from readily achievable compounds. The key elements in this total synthesis feature Kobayashi's remote asymmetric induction with vinylketene silyl N,O-acetal, Roush's asymmetric crotylboration of aldehyde, Mitsunobu's esterification and macrocyclization via Stille cross-coupling.

Full text of DOI:10.1039/c7cc00469a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Total Synthesis of Nannocystin Ax
Yan-Hui Zhang,§,† Rong Liu§,† and Bo Liu*,†,‡
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Total synthesis of nannocystin Ax, a natural depsipeptide isolated reported isolation and characterization of a family of depsipeptides
from myxobacteria recently, has been accomplished concisely. By named nannocystins (Fig. 1) with potent activity against cancer cell
following
a convergent strategy, the target molecule was lines at nanomolar concentrations. Structurally, 21-membered
assembled from three fragments. Each fragment can be macrocycles of these natural products consist of a polyketide motif
synthesized expeditiously from readily achievable compounds. and a tripeptide motif, involving derivative of an unnatural D-
The key elements in this total synthesis features Kobayashi’s tyrosine, with 7-9 stereogenic centers. Furthermore, genetic and
remote asymmetric induction with vinylketene silyl N, O-acetal, proteomic studies indicated that the primary target of nannocystins
Roush’s asymmetric crotylboration of aldehyde, Mitsunobu’s is the eukaryotic translation elongation factor 1α (EF-1α), and the
esterification and macrocyclization via Stille cross-coupling.
epoxide moiety is not an essential feature of the pharmacophore.
EF-1α is the identified binding protein of didemnin B,4 a cyclic
Natural products have been playing crucial role in R & D of depsipeptide with failure in phase II clinical trial, so nannocystins
new drugs as a pivotal source with diversified structures and would serve as alternative candidates of new anticancer
intriguing bioactivities.1 Chemical synthesis of natural products therapeutics. Due to long-lasting enthusiasm toward depsipeptides
and their analogs offers opportunities for study on structure- from synthetic community,5 nannocystins have become hot targets
activity relationships (SAR) of novel compounds and their with the intriguing bioactivities as soon as their isolation. Actually,
mechanism of action in biological systems, promoting the possibility total syntheses of nannocystins A and A0 have been achieved by
of identifying pharmaceutically new chemical entities (NCE). In 2015, the Wang group,6a and total synthesis of nannocystin A has also
the Brönstrup group2 and the Hoepfner group3 independently
been accomplished by the Ye group6b and the Chen group.6c
Recently, we completed total synthesis of Nannocystin Ax and
herein present our related synthetic efforts.
To fulfil an expeditious total synthesis, we preferred a
convergent synthetic strategy (Scheme 1). As intramolecular
cross-coupling plays conspicuous role in construction of
macrocycles,7 we planned to employ Stille coupling on
compound
cross coupling precursor
and the acid through amidation. Compound
constructed via Mitsunobu esterification from the amino acid
and the alcohol . Formation of could be accessed from the
dipeptide and compound . These two fragments could be
achievable from several known compounds, i.e. 12
2
to realize macrocyclization of nannocystin Ax. The
can be assembled from the amine
could be
2
3
4
3
5
6
4
7
8
Fig. 1 Representative Structures of Nannocystin A, Ax, A3 and Ay
9
-
.
Our total synthesis was initiated by preparation of the dipeptide
7 from the known compound 9, which is accessible from D-tyrosine
(Scheme 2).8 Protecting the phenol in 9 with chloromethyl methyl
ether in the presence of diisopropylethylamine afforded 13 in 79%
yield. Amidation between 13 and the known compound 109
afforded compound 14 in 85% yield, Boc group of which was
selectively deprotected in the presence of MOM ether with
trimethylsilyl triflate and 2, 6-lutidine, to deliver the dipeptide
†Key Laboratory of Green Chemistry &Technology of Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, China
‡State key Laboratory of Natural Medicines, China Pharmaceutical University,
Nanjing 210009, China†
§Y.H.Z and R.L. contributed equally.
* E-mail: chembliu@scu.edu.cn.
Detailed experimental procedures, spectroscopic data, 1H and 13C NMR spectra and
X-ray crystallographic data of nannocystin Ax. See DOI: 10.1039/x0xx00000x
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Scheme 3 Synthesis of Acid 8
vinylketene silyl N, O-acetal and acetals by Hosokawa et al.13b
However, asymmetric aldol reaction between an acetate-type
vinylketene silyl N, O-acetal and acetal has never been tested.
To our delight, aldol reaction of 11 with acetate-type
vinylketene silyl N, O-acetal 12 13c
mediated by BF3·Et2O,
,
afforded the aldol adduct 15 with 14:1 dr in 88% yield. The
freshly generated allylic chiral center in 15 was introduced
through remote asymmetric induction of the Evans auxiliary in
12 13b
Hydrolysis of this chiral auxiliary was undertaken with
.
lithium hydroxide and hydrogen peroxide to furnish the acid
in 87% yield with 89% ee.
8
Based on a recent green methodology developed by the Ma
group,14 Iron-catalyzed oxidation of a known compound 16
produced the oxidized N-Boc-L-valine
Scheme 4).15 Then compound
5, a known aminoacid
6
was prepared with 85% ee
according to Roush’s enantioselective synthesis of E-δ-stannyl-
anti-homoallylic alcohol via aldehyde crotylboration.16 Since
chirality at benzylic carbon in
desired one in target molecule, its absolute configuration was
inversed by reacting with in Mitsunobu’s condition to give
6 was inconsistent with the
5
6
compound 17 with proper stereochemistry in 70% yield with
10:1 dr. Removal of Boc protection with protonic acids
resulted in destannylation of 17
. So 2, 6-lutidine and
triethylsilyl trifluoromethanesulfonate was employed to
achieve deprotection of tert-butyl carbamate,10 while silyl
protection of the tertiary alcohol was achieved at the same
Scheme 1 Retrosynthetic Analysis
time to afford compound
With compounds
3
with 14:1 dr after purification.
and in hand, we embarked on
3,
7
8
7
in 79% yield.10
assembling these fragments to finalize total synthesis of
nannocystin Ax (Scheme 5). However, amidation between the
Then we started to synthesize the acid
8 from the known
compound 11 (Scheme 3).11 The vinylogous Mukaiyama aldol
reaction has been developed and widely applied in natural
product synthesis.12 By incorporating an Evans auxiliary into
vinylketene silyl N, O-acetal, Kobayashi et al developed an
asymmetric aldol reaction of aldehyde.13a This methodology
was further extended to aldol reaction between E, E-
dipeptide
7 and the acid 8 proved sluggish, probably due to
steric repulsion between these two counterparts in transition
state. Various condensing reagents, such as N-(3-
Scheme 4 Synthesis of the Amine
3
Scheme 2 Synthesis of the Dipeptide
7
2 | J. Name., 2012, 00, 1-3
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nannocystin Ax, so further experiments were executed to rule out
this probability undoubtedly. First, 1H NMR spectra of our synthetic
sample in (CD3)2CO and CDCl3 indicated existence of two
conformers in about 10:1 ratio. Second, variable temperature (VT)
NMR experiments showed that the proton signals of both
conformer merged together gradually from 25 to 70 ℃.26 Third, a
single crystal of nannocystin Ax was fortunately obtained out of
methanol and its X-ray crystallography unequivocally evidenced its
structure and purity; after dissolving this single crystal in DMSO-d6,
a spectrum consisting of a 5:1 mixture of conformers was obtained
again. Accordingly, we completed total synthesis of nannocystin Ax
and proved its existence as conformers in solution beyond question.
In summary, total synthesis of nannocystin Ax was
completed from readily available starting materials.
Establishment of this convergent synthetic strategy sets solid
foundation for preparation of structural analogues of
nannocystin Ax and study on structure-activity relationship.
We acknowledge financial support from the NSFC
(21290180 and 21672153). Financial support from the Open
Fund of State Key Laboratory of Natural Medicines in China
Pharmaceutical University is also acknowledged (SKLNMKF
201601).
Notes and references
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Scheme 5 Total Synthesis of nannocystin Ax
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5
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