Total Synthesis of Nannocystin A

Article abstract of DOI:10.1021/acs.orglett.6b02729

Nannocystin A is a 21-membered cyclodepsipeptide showing remarkable anticancer properties. Described is the total synthesis of nannocystin A, which features an asymmetric vinylogous Mukaiyama aldol reaction for efficient assembly of the penultimate open-c

Full text of DOI:10.1021/acs.orglett.6b02729

Letter
pubs.acs.org/OrgLett
Total Synthesis of Nannocystin A
Zhantao Yang,†,‡ Xiaolong Xu,† Chun-Hua Yang,†,‡ Yunfeng Tian,† Xinyi Chen,† Lihui Lian,†
Wenwei Pan,† Xuncheng Su,§ Weicheng Zhang,*,† and Yue Chen*,†
†State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research,
Nankai University, Tianjin 300353, P. R. China
‡College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, P. R. China
§State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: Nannocystin A is a 21-membered cyclodepsipeptide showing
remarkable anticancer properties. Described is the total synthesis of nannocystin
A, which features an asymmetric vinylogous Mukaiyama aldol reaction for efficient
assembly of the penultimate open-chain precursor and a pivotal intramolecular
Heck cross-coupling for the final macrocyclization.
econdary metabolites from microorganisms constitute a
large reservoir of valuable chemotherapeutic agents such as
MDA-MB231 (IC50 6.5 nM).2 In contrast, the reference drug
docetaxel suffered a considerable drop (nearly 2000-fold) in
activity against MDA-A1 (IC50 570 nM) with respect to MDA-
MB231 (IC50 0.3 nM). These results demonstrated the
potential of 1 as a novel lead compound for the development
of anticancer drugs.
S
antibiotics and anticancer drugs.1 Recently, a class of cyclic
depsipeptides named nannocystins were isolated independently
by two research teams through cultivation of the myxobacterial
strains Nannocyctis sp. ST201196 and Nannocyctis sp. MB1016,
respectively.2,3 Nannocystin A (1) features a 21-membered
polyketide−tripeptide macrocycle bearing a novel α,β-epoxy
amide substructure, along with nine chiral centers and two
Parallel to Bronstrup’s research,2 Hoepfner et al. found that 1
̈
displayed differential inhibitive properties (IC50 values ranging
from 0.5 μM to 5 nM) against 472 cancer cell lines.3 Different
from some known actin-binding cyclodepsipeptides such as
chondramide C,4 jasplakinolide,5 seragamide A,6 and miur-
aenamide,7 the primary target of 1 was identified to be the
eukaryotic translation elongation factor (eEF1α).
continuous E-configured alkenes (Figure 1). Bronstrup et al.
̈
showed that 1 displayed potent antiproliferative activities
toward 14 cancer cell lines at low nanomolar levels, and it
retained excellent inhibitory effect against the drug-resistant cell
line MDA-A1 (IC50 12 nM) compared to the related cell line
To date, only preliminary studies have been carried out on
their mechanism of action and pharmaceutical applications.
Moreover, the issue regarding whether the epoxide moiety in 1
is a critical component of the pharmacophore is still
unknown.2,3 Hence, there is an urgent need to explore the
chemical synthesis of nannocystin A, the leading species from
the natural nannocystin congeners. More important, systematic
structure variations will ensue to gain insight into key structural
elements that account for its high antiproliferative properties
and aid in developing more potent eEF1α-targeting analogues.
As the first step toward this aim, we report herein the total
synthesis of nannocystin A (1) in an efficient route.8
Retrosynthetically, the steric environment of the 6E,8E-diene
from the southern polyketide segment is less congested than
Received: September 10, 2016
Figure 1. Structure of nannocystin A (1).
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02729
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
that of the northern tripeptide segment in 1 (Figure 2).
Accordingly, the C7−C8 bond tethering the two E-alkenes is
Scheme 1. Synthesis of the Polyketide Fragment 3
the allylic alcohol 11 was converted to 12 via Sharpless
asymmetric epoxidation with excellent stereoselectivity (dr
>10:1). Formation of 3 was secured through stepwise
oxidations.
Next, union of N-Boc-3-hydroxy-D-valine (6) and homo-
allylic alcohol 7 was pursued. Unfortunately, condensation of 6
and 7 under standard esterification conditions (EDC/DMAP,
DIC/DMAP)15 failed to give the desired product, presumably
due to steric hindrance. Hence, we turned our attention to the
Mitsunobu reaction,16 which required the use of anti-
homoallylic alcohol 1317 as the coupling partner (Scheme 2).
Scheme 2. Synthesis of 3-Hydroxy-D-valine Homoallylic
Ester (15) TFA Salt
Figure 2. Retrosynthetic analysis of nannocystin A (1).
To our delight, Mitsunobu reaction between 13 and 6
proceeded smoothly to give 14 in 70% yield. The Boc group
of 14 was then removed with TFA to liberate the amine moiety
ready to be coupled to the tyrosine carboxyl group.
With the key building blocks 3 and 15 in hand, the next stage
was the preparation of the Heck precursor 2 via amide coupling
reactions. Incorporation of 3 into the tripeptide derivative
turned out to be a nontrivial task. The major challenge was the
development of a suitable peptide coupling sequence that is
compatible with the potentially reactive epoxy group. By testing
different coupling strategies, we eventually found a satisfactory
approach to 2 as shown in Scheme 3.
Starting from TBS-protected tyrosine derivative 16, which
was prepared from commercially available D-tyrosine in three
steps,18 coupling of 16 and N-methyl-N-Fmoc-L-isoleucine
(17) followed by Fmoc deprotection produced the dipeptide
19. A second amide coupling was accomplished in 52% yield
under standard condensation conditions using HATU and
DIPEA. Treatment of the resulting 20 with lithium hydroxide
led to the hydrolysis of both the methyl ester and the TBS
our preferred site for macrocyclization. In the synthetic
direction, a ring-closing intramolecular E-selective Heck cross-
coupling was envisioned to fulfill the task.9,10 Further
disconnection of the open-chain precursor 2 gave rise to five
building blocks, including the vinyl iodide bearing epoxy acid 3,
N-methyl-L-isoleucine 4, 3,5-dichloro-D-tyrosine 5, N-Boc-3-
hydroxy-D-valine 6, and homoallylic alcohol 7. The synthesis of
3 called for an asymmetric vinylogous Mukaiyama aldol
reaction11 to construct the carbon skeleton and a Sharpless
asymmetric epoxidation12 to install the chiral epoxide group.
The other fragments 47 were easily accessible according to
the literature.13
The forward synthesis commenced with the preparation of 3
(Scheme 1). Following Kobayashi’s protocol,11 8 was subjected
to TiCl4-mediated vinylogous Mukaiyama aldol condensation
with (E)-3-iodo-2-methylacrylaldehyde (21). Efficient control
of stereoselectivity (dr >10:1) was observed in the reaction,
with the predominant isomer 9 isolated in 51% yield after silica
gel flash chromatography.14 After methylation and reduction,
B
DOI: 10.1021/acs.orglett.6b02729
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Completion of the Total Synthesis of 1
REFERENCES
■
(1) (a) Demain, A. L. Appl. Microbiol. Biotechnol. 1999, 52, 455−463.
(b) Verpoorte, R. Drug Discovery Today 1998, 3, 232−238.
(c) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311−335.
(2) Hoffmann, H.; Kogler, H.; Heyse, W.; Matter, H.; Caspers, M.;
Schummer, D.; Klemke-Jahn, C.; Bauer, A.; Penarier, G.; Debussche,
L.; Bronstrup, M. Angew. Chem., Int. Ed. 2015, 54, 10145−10148.
̈
(3) Krastel, P.; Roggo, S.; Schirle, M.; Ross, N. T.; Perruccio, F.;
Aspesi, P., Jr.; Aust, T.; Buntin, K.; Estoppey, D.; Liechty, B.; Mapa, F.;
Memmert, K.; Miller, H.; Pan, X.; Riedl, R.; Thibaut, C.; Thomas, J.;
Wagner, T.; Weber, E.; Xie, X.; Schmitt, E. K.; Hoepfner, D. Angew.
Chem., Int. Ed. 2015, 54, 10149−10154.
(4) (a) Waldmann, H.; Hu, T. S.; Renner, S.; Menninger, S.; Tannert,
R.; Oda, T.; Arndt, H. D. Angew. Chem., Int. Ed. 2008, 47, 6473−6477.
(b) Eggert, U.; Diestel, R.; Sasse, F.; Jansen, R.; Kunze, B.; Kalesse, M.
Angew. Chem., Int. Ed. 2008, 47, 6478−6482.
(5) Tannert, R.; Milroy, L. G.; Ellinger, B.; Hu, T. S.; Arndt, H. D.;
Waldmann, H. J. Am. Chem. Soc. 2010, 132, 3063−3077.
(6) Arndt, H. D.; Rizzo, S.; Nocker, C.; Wakchaure, V. N.; Milroy, L.
G.; Bieker, V.; Calderon, A.; Tran, T. T.; Brand, S.; Dehmelt, L.;
Waldmann, H. Chem. - Eur. J. 2015, 21, 5311−5316.
(7) Karmann, L.; Schultz, K.; Herrmann, J.; Muller, R.; Kazmaier, U.
Angew. Chem., Int. Ed. 2015, 54, 4502−4507.
(8) During the preparation of our manuscript, two alternative total
syntheses of nannocystin A were reported; see: (a) Huang, J.; Wang,
Z. Org. Lett. 2016, 18, 4702−4705. (b) Liao, L.; Zhou, J.; Xu, Z.; Ye, T.
Angew. Chem., Int. Ed. 2016, 55, 13263−13266.
group, which was accompanied by a third amide condensation
with 15 to afford the penultimate open-chain intermediate 2.
Finally, intramolecular Heck macrocyclization proceeded
smoothly to give the product 1 in 58% yield. It was noteworthy
that the labile epoxy group was well tolerated in the Heck
macrocyclization conditions. The spectra (1H NMR, 13C NMR,
HRMS) of our synthetic 1 are in good agreement with the
literature data,3 thus completing the total synthesis of
nannocystin A.
In summary, total synthesis of nannocystin A 1 was achieved
from readily available starting materials in 4.1% overall yield
and 10 steps for the longest linear sequence. On the basis of the
established route, synthesis and biological evaluation of
structural analogues of 1 are currently in progress and will be
reported in due course.
(9) For leading reviews, see: (a) Beletskaya, I. P.; Cheprakov, A. V.
Chem. Rev. 2000, 100, 3009−3066. (b) Dounay, A. B.; Overman, L. E.
Chem. Rev. 2003, 103, 2945−2963.
(10) For recent examples of applying Heck macrocyclization in total
synthesis, see: (a) Li, P.; Li, J.; Arikan, F.; Ahlbrecht, W.; Dieckmann,
M.; Menche, D. J. Am. Chem. Soc. 2009, 131, 11678−11679. (b) Jagel,
̈
J.; Maier, M. E. Synthesis 2009, 2881−2892. (c) Li, P.; Li, J.; Arikan, F.;
Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Org. Chem. 2010, 75,
2429−2444. (d) Dieckmann, M.; Rudolph, S.; Dreisigacker, S.;
Menche, D. J. Org. Chem. 2012, 77, 10782−10788. (e) Symkenberg,
G.; Kalesse, M. Angew. Chem., Int. Ed. 2014, 53, 1795−1798.
(f) Reddy, K. M.; Yamini, V.; Singarapu, K. K.; Ghosh, S. Org. Lett.
2014, 16, 2658−2660. (g) Nguyen, M. H.; Imanishi, M.; Kurogi, T.;
Smith, A. B. J. Am. Chem. Soc. 2016, 138, 3675−3678. (h) Das, S.;
Paul, D.; Goswami, R. K. Org. Lett. 2016, 18, 1908−1911.
(11) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
13604−13605. For a recent review, see: Kalesse, M.; Cordes, M.;
Symkenberg, G.; Lu, H.-H. Nat. Prod. Rep. 2014, 31, 563−594.
(12) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974−
5976.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02729.
(13) See the Supporting Information for their preparation.
(14) The diastereoselectivity was estimated by examining the NMR
spectroscopy of the crude product.
(15) Tsakos, M.; Schaffert, E. S.; Clement, L. L.; Villadsen, N. L.;
Poulsen, T. B. Nat. Prod. Rep. 2015, 32, 605−632.
(16) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K.
Chem. Rev. 2009, 109, 2551−2651.
(17) For some representative synthesis of 13, see: (a) Brown, H. C.;
Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919−5923. (b) Corey, E. J.;
Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495−5496.
(c) Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 6517−
6520.
Detailed experimental procedures, spectroscopic data,
1
and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangweicheng@nankai.edu.cn.
*E-mail: yuechen@nankai.edu.cn.
Notes
(18) See the Supporting Information for details.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was kindly supported by the National Natural
Science Foundation of China (NNSFC) (No. 81573282),
Program for New Century Excellent Talents in University to
Y.C., and Hundred Young Academic Leaders Program of
Nankai University to Y.C.
C
DOI: 10.1021/acs.orglett.6b02729
Org. Lett. XXXX, XXX, XXX−XXX