Studies toward the Synthesis of an Oxazole-Based Analog of (-)-Zampanolide

Letter

Studies toward the Synthesis of an Oxazole-Based Analog of

Christian P. Bold, Cindy Klaus, Bernhard Pfei ﬀ er, Jasmine Schu

−)-Zampanolide

rmann, Rafael Lombardi,

Daniel Lucena-Agell, J. Fernando D í az, and Karl-Heinz Altmann*

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ABSTRACT: Studies are described toward the synthesis of an

oxazole-based analog of (−)-zampanolide (2). Construction of

(

−)-dactylolide analog 22 was achieved via alcohol 5 and acid 4

through esteriﬁcation and Horner−Wadsworth−Emmons (HWE)-

based macrocyclization; however, attempts to attach (Z,E)-

sorbamide to 22 proved unsuccessful. The C(8)−C(9) double

bond of the macrocycle was prone to migration into conjugation with the oxazole ring, which may generally limit the usefulness of

zampanolide analogs with aromatic moieties as tetrahydropyran replacements.

2−18

(

−)-Zampanolide (1) (Figure 1) is a marine macrolide with

analogs for SAR studies.

While these studies have shown

potent in vitro antitumor activity that was ﬁrst isolated in 1996

that mono(macro)cyclic analogs lacking the C bridge between

C(11) and C(15) can retain sub-μM antiproliferative activity,

they are still substantially less potent than the natural

,13−15

product.

At the same time, recent work from our own

group has demonstrated that the removal of the C(13)

methylene group (see also ref 16) or the complete

replacement of the tetrahydropyran ring by a suitably

substituted morpholine moiety is well tolerated, with the

corresponding analogs still exhibiting nanomolar IC₅₀values

for the inhibition of cancer cell growth in vitro.

Figure 1. Structure of (−)-zampanolide (1) and oxazole-based

zampanolide analog 2.

When inspecting the tubulin-bound structure of (−)-zam-

from the marine sponge Fasciospongia rimosa by Tanaka and

Higa. In 2009, 1 was reisolated from Cacospongia mycofijensis

panolide (1), it is immediately obvious that C(10), C(11),

O(11′), C(15), and C(16) are all in the same plane (as for all

,6-syn-disubstituted tetrahydropyran-based systems with the 2

by Northcote and co-workers, who also established that the

compound was a microtubule-stabilizing agent (MSA). The

and 6 substituents in an equatorial orientation). This situation

is recapitulated in meta-substituted 5- or 6-membered aromatic

rings, except that bond angles are slightly diﬀerent from those

in THP-based systems, which leads to not exactly super-

imposable positions of the atoms attached to the ring. We were

nevertheless intrigued by the question if aromatic heterocycles

could serve as THP bioisosteres in zampanolide and perhaps

inhibition of cancer cell proliferation by (−)-zampanolide (1)

is thus based on the same mechanism of action as for the

anticancer drugs paclitaxel, taxotere, cabazitaxel, and ixabepi-

lone. However, 1 is the only MSA that interacts with tubulin

by covalent bond formation, which entails 1,4-addition of

His229 in the β-tubulin subunit to the enone moiety in the

macrocycle.

also in other bioactive natural products incorporating a 2,6-syn-

The structure of (−)-zampanolide (1) is composed of a

macrobicyclic core comprising a 20-membered macrolactone

ring and an embedded 2,6-syn-disubstituted tetrahydropyran

19,20

disubstituted THP motif as part of a bicyclic scaﬀold.

In a

proof-of-concept study we thus embarked on the synthesis of

oxazole-based zampanolide analog 2 (Figure 1), where the

oxygen in the aromatic ring mimics the natural THP oxygen.

(

THP) moiety, as well as a (Z,E)-sorbamide-derived side chain

that is connected to C(19) of the macrolactone ring via a

hemiaminal group.

Received: February 1, 2021

Published: February 26, 2021

Several total syntheses of (−)-zampanolide (1) have been

−9

reported

since the pioneering work of Smith and co-

10,11

workers on (+)-zampanolide,

absolute conﬁguration of natural zampanolide as 11S, 15S, 19S,

0S. Part of the chemistry developed in the context of these

total syntheses has also served as a basis for the preparation of

which had established the

2021 American Chemical Society

238

Org. Lett. 2021, 23, 2238−2242

Organic Letters

protein are obvious (Figure 2 ).

Letter

Preliminary modeling studies have indicated that the

replacement of the THP ring in 1 by the oxazole ring in 2

can be accommodated in the structure of the tubulin−

zampanolide (1) complex without major distortions in the

conformation of the macrolactone ring; in addition, no

unfavorable steric interactions of the oxazole ring with the

Scheme 2. Synthesis of Vinyl Iodide 7

oxazoline formed in the initial reaction between 9 and 8 with a

strong base, oxazole 11 could be obtained in 48% overall

yield from 9. Formylation of 11 (n-BuLi, DMF) followed by

a Corey−Fuchs reaction furnished alkyne 13 in 40% yield

over 3 steps; the latter was then converted into vinyl iodide 7

25,26

by stannylcupration/iodination with Bu Sn(Bu)CuCNLi

and N-iodosuccinimide (82%).

In accordance with our original synthetic plan, initial

attempts toward the elaboration of vinyl iodide 7 into alcohol

The overall strategy for the synthesis of 2 was conceived in

analogy to our approach toward the synthesis of 1 and

,17,18

diﬀerent zampanolide analogs (Scheme 1).

Thus, macro-

involved iodine−lithium exchange on 7, followed by reaction

of the ensuing vinyllithium species with PMB-protected R-

glycidol (6) in the presence of BF ·Et O. Unfortunately, none

Scheme 1. Retrosynthesis of Oxazole-Zampanolide Analog 2

of the desired alcohol 5 was obtained when using either n-BuLi

or t-BuLi to eﬀect iodine/lithium exchange. With n-BuLi, only

the product of protodehalogenation could be isolated (29%

yield), while t-BuLi gave the product of protodehalogenation

together with the elimination product 13. This stands in

marked contrast to the successful opening of the epoxide ring

in 6 with a variety of vinyllithiums generated from vinyl iodides

related to 7 in the synthesis of 1 or of zampanolide

12,17,18

analogs.

Ghosh et al., as part of their total synthesis of 1, have

described the construction of the C(16)−C(17) double bond

by cross-metathesis. Thus, 5 was attempted to be accessed

from oleﬁns 14 (obtained from 12 by Wittig reaction (Scheme

); see the Supporting Information (SI)) and 15 or 16 ,

cyclization was to rely on an intramolecular Horner−

Wadsworth−Emmons (HWE) reaction, while the elaboration

of the (Z,E)-sorbamide-derived side chain was to be based on

an aza-aldol reaction, for which we have recently also

Scheme 3. Unsuccessful Attempt towards 5 by Cross-

Metathesis

developed a stereoselective variant.

The precursor for the HWE macrocyclization would be

obtained by the esteriﬁcation of acid 4 and alcohol 5. The

latter was envisioned to be accessible from vinyl iodide 7 via

iodine/lithium exchange and subsequent epoxide opening in

PMB-protected R-glycidol (6). Oxazole 7 was planned to be

assembled from aldehyde 9 and p-toluenesulfonylmethyl

respectively, by Grubbs II mediated cross-metathesis in

CH Cl or toluene. Unfortunately, again none of the desired

product 5 or 17, respectively, could be obtained; instead both

starting oleﬁns were reisolated.

Hoarau and co-workers have reported the palladium-

catalyzed C(2)-selective coupling of an unfunctionalized

isocyanide (TosMIC, 8) in a van Leusen oxazole synthesis,

followed by formylation and elaboration of the ensuing

aldehyde into vinyl iodide 7 by Corey−Fuchs alkynylation

and stannylcupration/iodination.

As depicted in Scheme 2, the synthesis of vinyl iodide 7

departed from 1,3-propanediol (10), which was converted into

aldehyde 9 by mono-TBDPS protection and subsequent Swern

oxidation in 85% yield. Employing a modiﬁed, two-step van

Leusen procedure that involves treatment of the 4-methoxy-

oxazole with a vinyl iodide (Pd(OAc) , CyJohnPhos,

Cs CO , 1,4-dioxane, 110 °C). Applying Hoarau’s conditions

28,29

to 11 and vinyl iodide 18

(see Scheme 4 for the structure

of 18) or the corresponding TBS-ether, however, solely led to

decomposition of the latter and reisolation of oxazole 11.

239

Org. Lett. 2021, 23, 2238−2242

Organic Letters

The Supporting Information is available free of charge at

Letter

Scheme 4. Building Block Assembly and Macrocyclization

activity of alcohol 21 was assessed against A549 human lung

carcinoma cells. The IC of 21 was 12.4 μM, compared to 127

nM for the corresponding analog incorporating the natural 4-

methylene THP moiety. While this seems to indicate that the

oxazole moiety is not a suitable bioisostere for the THP ring in

zampanolide-derived structures, the results have to be

interpreted with some care. It is well conceivable that

isomerization of the C(8)−C(9) double bond occurs under

the conditions of the cellular experiments, thus destroying the

enone system that is critical for the covalent interaction of 1

with tubulin.

In summary, we have established an eﬃcient route for the

synthesis of an oxazole-derived analog of the non-natural

enantiomer of the (−)-dactylolide alcohol 21, but the desired

conversion into the corresponding analog of (−)-zampanolide

(

1) could not be accomplished. We have found the modiﬁed

zampanolide macrocycle to be highly susceptible to the

migration of the C(8)−C(9) double bond, which makes it

doubtful if the replacement of the THP ring in 1 by any

aromatic moiety would yield useful analogs. Analogs of other

THP-containing natural products will have to be investigated

to assess the potential of such an approach for the optimization

of natural product leads in drug discovery.

Gratifyingly, the coupling of 11 and 18 could be achieved by

Negishi cross-coupling, which furnished the desired homo-

ASSOCIATED CONTENT

sı Supporting Information

■

allylic alcohol 5 in 80% yield (Scheme 4).

Subsequent Yamaguchi esteriﬁcation of 5 with acid 4

followed by global desilylation aﬀorded diol 19 in 55% yield

https://pubs.acs.org/doi/10.1021/acs.orglett.1c00378.

over 2 steps. Oxidation of 19 with DMP gave a keto aldehyde

Experimental procedures, full analytical data for all new

that underwent smooth Ba(OH) -mediated HWE oleﬁnation,

compounds, including H and C NMR spectra, and

details of the modeling studies leading to the minimized

structures shown in Figure 2 (PDF )

to furnish the macrolactone 20 as a crude product. While H

NMR analysis indicated a yield of approximately 84%, all

attempts to purify the material were unsuccessful. Upon

standard silica gel chromatography, partial migration of the

C(8)−C(9) double bond into conjugation with the oxazole

ring occurred. Addition of triethylamine to the eluent only

aggravated the problem and resulted in complete conversion of

AUTHOR INFORMATION

■

Corresponding Author

Karl-Heinz Altmann − ETH Zu

Chemistry and Applied Biosciences, Institute of

Pharmaceutical Sciences, 8093 Zurich, Switzerland;

0 into this undesired regioisomer. Therefore, the crude

rich, Department of

macrolactone was directly submitted to oxidative PMB-

cleavage with DDQ. After extensive screening of diﬀerent

puriﬁcation methods, the free alcohol 21 could be puriﬁed by

orcid.org/0000-0002-0747-9734; Email: karl-

heinz.altmann@pharma.ethz.ch

ﬂash column chromatography with acidic silica gel (SiO ·

HCl) and was ﬁnally obtained in 36% yield over 3 steps from

9. DMP oxidation of alcohol 21 gave the crude aldehyde

2, which is an analog of the non-natural enantiomer of the

marine macrolide (+)-dactylolide. Given the susceptibility of

the macrocycle to double bond migration upon exposure to

silica gel and an anticipated lability of the C(19) stereocenter

Authors

Christian P. Bold − ETH Zu

and Applied Biosciences, Institute of Pharmaceutical Sciences,

8093 Zurich, Switzerland

Cindy Klaus − ETH Zurich, Department of Chemistry and

Applied Biosciences, Institute of Pharmaceutical Sciences,

8093 Zurich, Switzerland; orcid.org/0000-0001-5977-

1158

Bernhard Pfeiﬀer − ETH Zu

and Applied Biosciences, Institute of Pharmaceutical Sciences,

8093 Zurich, Switzerland

Jasmine Schurmann − ETH Zu

and Applied Biosciences, Institute of Pharmaceutical Sciences,

8093 Zurich, Switzerland

Rafael Lombardi − ETH Zu

and Applied Biosciences, Institute of Pharmaceutical Sciences,

8093 Zurich, Switzerland

rich, Department of Chemistry

under acidic conditions (SiO ·HCl), crude 22 was directly

used in the following aza-aldol reaction. However, none of the

desired hemiaminal 2 could be isolated upon mixing 22 with a

solution of (Z,E)-sorbamide (3) that had been pretreated with

DIBAL-H for 50 min, conditions that had been successfully

rich, Department of Chemistry

employed in the total synthesis of 1. While the mass of 2

could be detected in the HRMS spectrum of the crude material

rich, Department of Chemistry

obtained after extractive workup, the H NMR spectrum was

completely uninformative. The only interpretable signals were

those of 3 (of which a 10-fold excess was used) and a signal at

.2 ppm, corresponding to unreacted aldehyde 22 (ca. 27%).

In order to gain some preliminary understanding of the

biological consequences of the replacement of the 2,6-syn-

disubstituted tetrahydropyran moiety in the zampanolide

macrocycle by a planar aromatic ring, the antiproliferative

rich, Department of Chemistry

Daniel Lucena-Agell − Centro de Investigaciones Biológicas

Margarita Salas, Consejo Superior de Investigaciones

Cientíﬁcas, 28040 Madrid, Spain

240

Org. Lett. 2021, 23, 2238−2242

Organic Letters

Wang, G.; White, J. D.; Chen, Q.-H. Synthesis and Antiproliferative

Letter

J. Fernando Díaz − Centro de Investigaciones Biológicas

Margarita Salas, Consejo Superior de Investigaciones

Cientí ﬁ cas, 28040 Madrid, Spain; orcid.org/0000-0003-

and antiproliferative activity of desTHPdactylolides. Bioorg. Med.

Chem. 2018, 26, 3514−3520.

(

14) Chen, G.; Patanapongpibul, M.; Jiang, Z.; Zhang, Q.; Zheng, S.;

Evaluation of New Zampanolide Mimics. Org. Biomol. Chem. 2019,

743-3319

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c00378

7, 3830−3844.

(15) Chen, G.; Jiang, Z.; Zhang, Q.; Wang, G.; Chen, Q.-H. New

Zampanolide Mimics: Design, Synthesis, and Antiproliferative

Evaluation. Molecules 2020, 25, 362.

Notes

(

16) Henry, J. L.; Wilson, M. R.; Mulligan, M. P.; Quinn, T. R.;

The authors declare no competing ﬁnancial interest.

Sackett, D. L.; Taylor, R. E. Synthesis, Conformational Preferences,

and Biological Activity of Conformational Analogues of the

Microtubule-Stabilizing Agents, (−)-Zampanolide and (−)-Dactylo-

lide. MedChemComm 2019, 10, 800−805.

ACKNOWLEDGMENTS

We gratefully acknowledge ﬁnancial support by the Swiss

National Science Foundation (Projects 200021_149253 and

■

(17) Brutsch, T. M.; Berardozzi, S.; Rothe, M. L.; Horcajo, M. R.;

00020_175744 (K.H.A.)). Funding was also obtained from

Díaz, J. F.; Altmann, K.-H. A Method for the Stereoselective

Construction of the Hemiaminal Center in Zampanolides. Org. Lett.

2020, 22, 8345−8348.

Ministerio de Ciencia e Innovaci_n PID2019-104545RB-I00

and Fondo de Investigaciones Sanitarias COV20/01007

(

18) Bold, C. P.; Gut, M.; Schurmann, J.; Lucena-Agell, D.; Gertsch,

(

J.F.D.) and H2020-MSCA-ITN-2019 860070 TUBINTRAIN

J.F.D.). We are indebted to Dr. Bernhard Pfeiﬀer and Philipp

J.; Díaz, J. F.; Altmann, K.-H. Synthesis of Morpholine-Based Analogs

of (−)-Zampanolide and Their Biological Activity. Chem. Eur. J. 2020,

DOI: 10.1002/chem.202003996 .

Waser (ETHZ) for NMR support, to Kurt Hauenstein

ETHZ) for technical advice, and to Oswald Greter, Louis

(

19) We are aware of only one other example, where a meta-

Bertschi, Michael Meier, and Daniel Wirz (ETHZ) for HRMS

spectra acquisition.

substituted aromatic moiety has been explored as a THP surrogate in

natural product, namely a phenyl analog of peloruside A (pelofen):

Van der Eycken, J.; Smans, G.; Cornelus, J.; Van den Bossche, D.;

Jacobs, N. Preparation of peloruside analogs as antiproliferative

agents. PCT Int. Appl. (2015), WO 2015079009 A1 20150604.

(20) The replacement of 2,5-syn-disubstituted tetrahydrofuran rings

has been investigated more frequently. See, e.g.: (a) Neves, A. R.;

Trefzger, O. S.; Barbosa, N. V.; Honorato, A. M.; Carvalho, D. B.;

Moslaves, I. S.; Kadri, M. C. T.; Yoshida, N. C.; Kato, M. J.; Arruda,

C. C. P.; Baroni, A. C. M. Effect of isoxazole derivatives of

tetrahydrofuran neolignans on intracellular amastigotes of Leishmania

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