Total synthesis, configuration, and biological evaluation of anguinomycin C

DOI: 10.1002/anie.200703134

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Angewandte Chemie - International Edition p. 8707 - 8710 (2007)

Update date:2022-09-26

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Authors:

Bonazzi, Simone

Guettinger, Stephan

Zemp, Ivo

Kutay, Ulrike

Gademann, Karl

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Article abstract of DOI:10.1002/anie.200703134

(Chemical Equation Presented) Against nuclear export! Immunofluorescence assays indicate that anguinomycin C is a potent inhibitor of protein export from the nucleus. Key features in the total synthesis of this antitumor natural product include a Cr-catal

Full text of DOI:10.1002/anie.200703134

Angewandte

Chemie

DOI: 10.1002/anie.200703134

Antitumor Agents

Total Synthesis, Configuration, and Biological Evaluation of

Anguinomycin C**

Simone Bonazzi, Stephan Güttinger, Ivo Zemp, Ulrike Kutay,* and Karl Gademann*

Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday

Natural products provide interesting lead structures for

cancer research and thus enable promising chemical

approaches.^[1]The compound class of the leptomycins is

characterized by an extremely potent antitumor activity on

cancer cell lines, which has drawn the attention of many

synthetic chemists.^[2]Prototypic examples such as leptomy-

cin B and callystatin were, however, found to be too toxic to

normal cells, leading to their failure in the clinical evalua-

tion.^[3]In contrast to these results, two related compounds,

anguinomycin C and D, were reported to display selectivity

for pRB tumor suppressor inactivated, immortalized cells.^[4]

These anguinomycins thus cause apoptosis in such tumor cell

lines in picomolar concentrations, and, remarkably, induce

only growth arrest in normal cells. This astonishing selectivity

for tumor cells must reside in the (minimal) structural

differences between anguinomycin C and leptomycin B;

however, the exact reason is unknown. In addition, the

relative and absolute configuration of the six stereogenic

centers of anguinomycin could not be assigned. In this

communication, we report the total synthesis of anguinomy-

cin C, the determination of the absolute configuration of the

six stereogenic centers, and first experiments on its biological

mode of action.

The total synthesis of anguinomycin C began with the

preparation of the dihydropyran fragment 3 (Scheme 1). We

chose a catalytic, asymmetric hetero-Diels–Alder reaction as

a direct approach to this heterocycle. Treatment of commer-

cially available methoxybutadiene (1) with the protected

propargylic aldehyde 2^[5]in the presence of the Cr^IIIcatalyst 4

(developed by Jacobsen and co-workers)^[6]resulted in product

[*] MSc S. Bonazzi, Prof. Dr. K. Gademann

Chemical Synthesis Laboratory (SB-ISIC-LSYNC)

Swiss Federal Institute of Technology (EPFL)

1015 Lausanne (Switzerland)

Fax: (+41)21-693-9700

E-mail: karl.gademann@epfl.ch

Homepage: http://isic.epfl.ch/lsync

Dr. S. Güttinger, Dipl.-Natw. I. Zemp, Prof. Dr. U. Kutay

Institut für Biochemie

Swiss Federal Institute of Technology (ETH Zürich)

8093 Zürich (Switzerland)

E-mail: ulrike.kutay@bc.biol.ethz.ch

Scheme 1. a) Cr catalyst 4 (2.3 mol%), 4- molecular sieves, 86%,

96% ee; b) para-toluenesulfonic acid, iPrOH, 86%; c) TBAF, THF,

95%; d) 1. [Cp₂ZrHCl], THF, 2. ZnCl₂, THF, 3. [Pd(PPh₃)₄] (5 mol%),

DIBAH (10 mol%), 6, 81%, d.r. >97:3; e) [Pd(PPh₃)₄], (CH₃)₂Zn, THF,

68%, d.r.>97:3; f) TBAF, THF, 99%; g) PPh₃, imidazole, I₂, toluene/

ether, 75%. TBAF: tetrabutylammonium fluoride, TES: triethylsilyl,

THF: tetrahydrofuran, DIBAH: diisobutylaluminum hydride, TIPS:

triisopropylsilyl.

[**] We thank the Swiss National Science Foundation for support

(Projects 200021-115918/1 (K.G.) and 3100A0-101712 (U.K.)), as

well as the Latsis Foundation. This work is part of the planned PhD

thesis of S.B. at ETH Zürich. We thank Dr. B. Schweizer and Dr. R.

Scopelliti for X-ray structural analyses.

Supporting information for this article is available on the WWW

under http://www.angewandte.org or from the author.

Angew. Chem. Int. Ed. 2007, 46, 8707 –8710

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

8707

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Communications

3 in high yield (86%) and enantioselectivity (96% ee). The

oped by Seebach and Hintermann.^[10]This chiral oxazolidi-

none impressively demonstrated its usefulness in the synthesis

of discodermolide by chemists at Novartis.^[11]The benefits,

including higher selectivity and crystallinity of the intermedi-

ates (with the drawback of increased molecular weight), were

also of great use in the reactions described in this commu-

nication. An enantioselective alkylation of the Li enolate of

10^[10]with tigloyl bromide^[12]gave 11 in high yield (92%) and

excellent selectivity (d.r. > 97:3, Scheme 2). Cleavage (and

recycling) of the chiral auxiliary by LiAlH₄followed by a

Swern oxidation gave aldehyde 12^[13]in 98% yield over two

steps. This chiral aldehyde was then transformed in a boron-

mediated aldol reaction using ent-10 to give the syn-aldol 13.

The selectivity of this reaction (87:13 for the desired isomer,

separable by flash chromatography) is less than perfect but

comparable to reactions of similar substrates in the litera-

ture.^[2c]Transformation of compound 13 to the Weinreb amide

was easily accomplished using Al(CH₃)₃, as were subsequent

TBS protection and reduction by DIBAH to the aldehyde

(85% over three steps). Another boron-mediated aldol

reaction gave hydroxy amide 14 featuring an all-syn config-

uration with excellent stereoselectivity (d.r. > 97:3). The

direct reduction of the auxiliary-bound imide 14 to the

aldehyde 15 was possible by LAH in toluene; this surprising

reaction exemplifies the strengths of the DIOZ auxiliary.

Wittig reaction gave the a,b-unsaturated ester, which was

transformed through reduction and subsequent oxidation to

the a,b-unsaturated aldehyde 16. X-ray crystallographic

analysis of 16 (m.p. 75–778C) allowed for the unambiguous

determination of the configuration of the newly formed

stereogenic centers. The transformation to the vinyl iodide 17

following Takai^[14]was possible in excellent yield and stereo-

selectivity.

observed diastereoselectivity of only ca. 5:1 was a conse-

quence of epimerization under the reaction conditions. This

low selectivity was not a problem, as the acetal 3 (as a mixture

of diastereoisomers) was transformed in the presence of acid

in iPrOH^[2o]to the thermodynamically more stable, configura-

tionally homogenous product 5^[2k](after deprotection). This

alkyne was hydrozirconated by using Schwartzꢀs reagent and

then transmetalated in situ to give the vinyl zinc species.

Subsequent Negishi cross-coupling with the readily available

dibromide 6^[7]gave the trisubstituted vinyl bromide 7 in 81%

yield. Interestingly, the addition of small amounts of DIBAH

consistently resulted in higher yields. However, compound 7

displayed the wrong configuration of the trisubstituted olefin;

as a result a stereoinversion was required in this synthesis.

Negishi and co-workers recently reported that similarly

substituted haloalkenes undergo cross-coupling under inver-

sion (and not under retention).^[8]Therefore, vinyl bromide 7

was allowed to react under Pd catalysis with dimethylzinc, and

we observed in the NMR spectrum a clean inversion at the

double bond to the cis compound 8 (68% yield, d.r. > 97:3).

This is even more remarkable, as the reversal of reagents, that

is, first reaction of dibromide 6 with dimethylzinc followed by

the dihydropyran derivative starting from 5, led to low yields

and a mixture of isomers. The mechanism of this stereo-

inversion in the Negishi cross-coupling reaction remains

unknown; in the literature s-bound Pd–allenyl species were

postulated as intermediates.^[8]In the context of our research,

the clean inversion of 7 to 8 was of great use. Removal of the

terminal protecting group and transformation of the hydroxy

group to the iodide 9 was carried out under standard

conditions.

We chose an Evans aldol strategy for the synthesis of the

second fragment,^[9]but opted for the DIOZ auxiliary (4-

isopropyl-5,5-diphenyloxazolidin-2-one), which was devel-

Having both fragments at hand, we chose to merge them

using

procedure developed by Marshall et al.^[2g,s]

Scheme 2. a) LDA, THF then tigloyl bromide, 92%, d.r.>97:3; b) LAH, ether, quant. c) Swern oxidation, 99%; d) Bu₂BOTf, Et₃N, CH₂Cl₂, then 12,

77%, d.r. 87:13; e) CH₃ONHCH₃·HCl, Al(CH₃)₃, CH₂Cl₂, 86%; f) TBSOTf, 2,6-lutidine, 99%; g) DIBAH, quant.; h) ent-10, Bu₂BOTf, Et₃N, CH₂Cl₂,

then aldehyde, 61%, d.r. >97:3; i) LiAlH₄, toluene, 83%; j) (carbethoxyethylidene)triphenylphosphorane, toluene, 99%, k) DIBAH, THF, 93%;

l) MnO₂, CH₂Cl₂86%; m) CrCl₂, CHI₃, THF, quant., d.r. >97:3.

8708 www.angewandte.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8707 –8710

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Angewandte

Chemie

(Scheme 3). Primary alkyl iodide 9 was reacted with 9-

methoxy-BBN and tBuLi and then treated with iodide 17

using [Pd(dppf)Cl₂] as the catalyst (5 mol%) in a DMF/water

mixture in the presence of base. The reaction proceeded

smoothly in spite of the complexity of the substrates,^[15]and

family, whose members mediate the majority of protein

transport between the nucleus and the cytoplasm (for a

review see Ref. ^[19]). CRM1 is the main export factor for

proteins out of the cell nucleus. The protein substrates of

CRM1 contain a short signal sequence, nuclear export signal

(NES), which mediates the specific interaction with CRM1.

The export activity of CRM1 can be selectively inhibited by

leptomycin, which covalently binds to a cysteine in the

substrate-binding domain of CRM1, thereby blocking the

interaction between CRM1 and the NES of the cargo.^[20]

In order to test if anguinomycin C also inhibits the CRM1-

dependent export of proteins from the cell nucleus, we

analyzed how treatment of cells with this compound affects

the intracellular localization of the human protein Rio2. Rio2

is a cytoplasmic protein kinase, which is exported from the

nucleus in a CRM1-dependent manner.^[21]Inhibition of the

CRM1 export pathway leads to accumulation of Rio2 in the

cell nucleus.

We incubated HeLa cells with different concentrations of

either leptomycin B or anguinomycin C for 90 min and then

fixed the cells with paraformaldehyde. The localization of

Rio2 was then determined by indirect immunofluorescence

using specific antibodies directed to human Rio2. Both

anguinomycin C and leptomycin B caused a strong accumu-

lation of Rio2 in the nucleus, whereas in untreated control

cells, Rio2 was localized in the cytoplasm as expected

(Figure 1). This demonstrates that anguinomycin C, like

Scheme 3. a) 9-Methoxy-BBN, tBuLi, ether, THF then b) 17, [Pd-

(dppf)Cl₂] (5 mol%), AsPh₃(15 mol%), Cs₂CO₃, DMF/H₂O, 80%;

c) pyridinium para-toluenesulfonic acid, acetone/H₂O, 95%;

d) 1. DMP, CH₂Cl₂, 2. MnO₂, CH₂Cl₂, 47%; e) HF·pyridine, pyridine,

THF, 86%. BBN: Borabicyclononane, dppf: Ph₂PC₅H₄FeC₅H₄PPh₂,

DMP: Dess–Martin periodinane.

the product 19 featuring the complete carbon skeleton of

anguinomycin C was isolated in 80% yield. The synthesis was

then completed first by acid-catalyzed cleavage of the acetal

(PPTS, acetone/water, 95%) and then by a two-step oxidation

sequence (DMP, then MnO , 47% over two steps). The last

protecting group was removed using HF in buffered pyridine,

and synthetic anguinomycin C (20) was obtained after

purification by semipreparative HPLC (86% yield). The

spectroscopic data of synthetic anguinomycin C (IR, MS, H

and ¹³C NMR, HSQC spectrum) are identical to the published

values of the natural product,^[16]and the optical rotation

([a]_D= À101 (c = 6.4 10^À5, CH₃OH)) matches its literature

value ([a]_D= À128 (c = 0.5, CH₃OH)). These spectroscopic

data establish the absolute configuration of anguinomycin C

(20) as shown in Scheme 3 as (5R,10R,16R,18S,19R,20S).

Even though anguinomycin C is structurally closely

related to leptomycin B, these compounds show differences

in their biological activity. Whereas anguinomycin C is toxic

to immortalized, pRB-inactivated cells in picomolar concen-

tration, it causes only growth arrest of normal cells.^[4]LMB, in

contrast, does not show such a selectivity and is toxic to both

immortalized and normal cells.

Leptomycin B is a specific inhibitor of the protein

Figure 1. Anguinomycin C inhibits CRM1-dependent nuclear export of

Rio2 in HeLa cells. CRM1: Chromosome maintenance region 1.

CRM1.^[17,18]CRM1 belongs to the karyopherin protein

Angew. Chem. Int. Ed. 2007, 46, 8707 –8710

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Communications

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leptomycin B, is a potent inhibitor of CRM1-dependent

protein export from the nucleus. The effect of anguinomy-

cin C treatment was only slightly weaker than for leptomy-

cin B; a complete nuclear accumulation of Rio2 was reached

at 10 nm anguinomycin C and at 5 nm leptomycin B. Together,

these data show that anguinomycin C is an efficient inhibitor

of the CRM1-dependent protein export pathway.

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We report in this communication the first total synthesis

of the antitumor polyketide anguinomycin C (20). Remark-

able transformations in this synthesis include: 1) A Cr-

catalyzed, enantioselective hetero-Diels–Alder reaction for

a quick access to the dihydropyran fragment, 2) a Negishi

reaction under stereoinversion for the synthesis of the

trisubstituted double bond, and 3) utilization of the chiral

DIOZ auxiliary which enabled, for example, the direct

reduction of imide 14 to the aldehyde 15. This convergent

route allowed for the definite establishment of the absolute

configuration of anguinomycin C (20). In addition, we

demonstrated that anguinomycin C inhibits the CRM1-medi-

ated export of proteins from the cell nucleus. The consequen-

ces of this experimental evidence for the reported selectivity

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under investigation in our laboratories.

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Received: July 13, 2007

Published online: October 4, 2007

Keywords: antitumor agents · leptomycins · nuclear export ·

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Total synthesis, configuration, and biological evaluation of anguinomycin C

DOI: 10.1002/anie.200703134

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Article abstract of DOI:10.1002/anie.200703134

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