Concise total synthesis of cruentaren A

DOI: 10.1002/anie.200703839

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Angewandte Chemie - International Edition p. 9275 - 9278 (2007)

Update date:2022-08-04

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Authors:

Fuerstner, Alois

Bindl, Martin

Jean, Ludovic

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Article abstract of DOI:10.1002/anie.200703839

Converging on the target: The highly cytotoxic F-ATPase inhibitor cruentaren A constitutes an interesting lead in the quest for innovative chemotherapeutic agents for the treatment of various diseases, including cancer. Its synthesis was achieved in an overall yield of 3% by an expeditious convergent route involving a ring-closing aikyne metathesis reaction (RCAM) for the formation of the macrocyclic ring (see picture). (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200703839

Angewandte

Chemie

DOI: 10.1002/anie.200703839

Natural Product Synthesis

Concise Total Synthesis of Cruentaren A**

Alois Fürstner,* Martin Bindl, and Ludovic Jean

Bioassay-guided fractionation of the fermentation broth of

the myxobacterium Byssovorax cruenta led to the discovery

of the benzolactone cruentaren A (1) and its ring-contracted

for the solid-state structures.^[1–3]Equally striking is the fact

that 1 constitutes one of the most potent inhibitors of F₁-

ATPase of mammals and yeast known to date,but does not

affect F₁-ATPase in E. coli to any noticeable extent.^[2]

Given the role of ATPases in the pathophysiology of

various human diseases,including cancer,selective inhibitors

of such transport proteins constitute promising leads in the

quest for novel chemotherapeutic agents.^[3,5,6]It is therefore

of considerable interest to evaluate the potential of cruentar-

en A in more detail. Although 1 can be obtained in up to

3.2 mgL^ꢀ1by fermentation,^[1,2]total synthesis provides addi-

tional opportunities. Deliberate digression from the ulti-

mately successful path,as accommodated in an adequate

synthesis blueprint,will provide analogues with structural

changes that are otherwise inaccessible. Therefore,we were

prompted to extend our program on the targeted pursuit,

structural editing,and biological evaluation of cytotoxic

natural products to cruentaren A.^[7]Prompted by the recent

disclosure of the first total synthesis of 1 by Vintonyak and

Maier,^[8]we now report our conquest of this enticing target.

combination of ring-closing alkyne metathesis

(RCAM) and Lindlar reduction was deemed ideally suited

for the construction of the Z alkene embedded in the 12-

membered lactone moiety of 1. RCAM was introduced by our

research group in 1998,^[9]and has since then served many total

syntheses projects exceedingly well.^[10–12]In parallel to the

current application,the total synthesis of 1 by Vintonyak and

Maier^[8]also took advantage of this methodology,which

allows the target to be dissected into building blocks of similar

size and complexity. Our approach to the required salicylic

acid segment 14 is notably short and efficient (Scheme 1).

Thus,deprotonation of ester 9 derived from the readily

available acid 8^[13]with LDA followed by acylation of the

resulting benzyllithium derivative with Weinreb amide 7^[14]

gave ketone 10 on a multigram scale. Subsequent Corey–

Bakshi–Shibata (CBS) reduction^[15]afforded alcohol 12 with

appreciable diastereomeric purity (de ꢁ 85%),which was

converted into the TBDPS ether 13. This ether turned out to

be sufficiently stable to allow for a selective cleavage of the

trimethylsilylethyl ester with TASF in DMF.

The synthesis of the polyketide sector (Scheme 2) com-

menced with the alkylation of ent-5^[16]with propargyl iodide

15. A sequence comprising a reduction of the resulting

product 16 with LiBH₄,Lindlar hydrogenation,and oxidation

of the alcohol group afforded aldehyde 18 as a suitable

electrophilic partner for the subsequent Evans-aldol reac-

tion,^[16,17]which gave compound 19 (ꢂ 96% de) in high overall

yield. Conversion into aldehyde 21 by conventional means

allowed us to set the then only missing stereocenter by

application of the excellent asymmetric propargylation tech-

nology recently disclosed by Soderquist and co-workers.^[18]

Specifically,exposure of 21 to the enantiopure allenylborane

congener cruentaren B (2).^[1]While 2 is largely inactive, 1

exhibits pronounced antifungal activity and remarkable

cytotoxicity against a panel of human cancer cell lines,with

IC₅₀values in the (sub)nanomolar range,^[1,2]including the

multidrug-resistant KB-V1 cell line,for which an IC ₅₀value of

0.6 mgmL^ꢀ1has been reported.

Cruentaren A is highly reminiscent of other macrocyclic

salicylate lactones such as salicylihalamide (3) and apicular-

en A (4),^[3,4]even though it features an allylamide rather than

an enamide linkage in its side chain. Yet,preliminary data

indicate that this structural resemblance may not translate

into functional analogy,since 1 selectively inhibits eukaryotic

F-ATPases (IC₅₀value: 15–30 nm),while being largely inef-

fective against Na⁺/K⁺- or V-ATPases;^[1,2]3 and 4,in contrast,

are exceedingly potent inhibitors of these proton pumps.^[3,5]

This dissimilar biological profile might be caused by the

distinctly different shapes of these compounds,as ascertained

[*] Prof. A. Fürstner, Dipl.-Chem. M. Bindl, Dr. L. Jean

Max-Planck-Institut für Kohlenforschung

45470 Mülheim an der Ruhr (Germany)

Fax: (+49)208-306-2994

E-mail: fuerstner@mpi-muelheim.mpg.de

[**] Generous financialsupport from the MPG and the Fonds der

Chemischen Industrie is gratefully acknowledged. We thank Dr. R.

Mynott and his team for expert NMR spectroscopic support.

Angew. Chem. Int. Ed. 2007, 46, 9275 –9278

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

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Communications

Scheme 1. a) NaN(SiMe₃)₂, 1-iodo-2-butyne, THF, ꢀ788C, 89%;

b) EtOH, Ti(OEt)₄, reflux, 85%; c) (MeO)(Me)NH·HCl, iPrMgCl, THF,

ꢀ208C, 92%; d) 2-trimethylsilylethanol, DIAD, PPh₃, THF, 08C!RT,

86%; e) 1. LDA, THF, ꢀ788C; 2. TMEDA, 7, ꢀ1008C!ꢀ788C, 79%;

f) 11, catecholborane, toluene, ꢀ788C, 95% (85% de); g) TBDPSOTf,

2,6-lutidine, CH₂Cl₂, ꢀ788C!RT, 98%; h) TASF, DMF, 08C, 85%.

DIAD=diisopropylazodicarboxylate; LDA=lithium diisopropylamide;

TMEDA=N,N,N’,N’-tetramethylethylenediamine; TBDPS=tert-butyldi-

phenylsilyl; Tf=trifluoromethanesulfonyl, TASF=tris(dimethylamino)-

sulfonium difluorotrimethylsilicate.

Scheme 2. a) NaN(SiMe₃)₂, 15, THF, ꢀ788C, 85%; b) LiBH₄, THF,

MeOH, 08C, 80%; c) Lindlar catalyst, H₂(1 atm), EtOAc, pyridine;

d) Dess–Martin periodinane, pyridine, CH₂Cl₂, 08C, 82% (over two

steps); e) ent-5, Et₂BOTf, (iPr)₂NEt, CH₂Cl₂, ꢀ788C!08C, 85%;

f) TBSOTf, 2,6-lutidine, CH₂Cl₂, ꢀ788C!RT, 85%; g) 1. LiBH₄, THF,

MeOH, 08C, 90%; 2. Dess–Martin periodinane, pyridine, CH₂Cl₂, 08C,

87%; h) 27, Et₂O, ꢀ788C, 75%; i) TESCl, imidazole, DMF, 508C, 80%;

j) nBuLi, THF, MeI, ꢀ788C!RT; k) HF·pyridine, THF, pyridine, 82%

(over both steps). TBS=tert-butyldimethylsilyl; TES=triethylsilyl.

(S)-27,which can be readily prepared as a storable material

from commercial 26 and allenylmagnesium bromide,afforded

propargyl alcohol 22 in 75% yield and greater than 95% de.

The configuration of the newly formed secondary alcohol was

ascertained by analysis of the corresponding Mosher esters

and is in full accord with the proposed transition-state

model.^[18]Temporary protection of the free hydoxy group in

22 paved the way to the nonterminal alkyne 25 as the other

required component for the envisaged alkyne metathesis

reaction.^[19]

Scheme 3. a) Me₂C C(NMe₂)(Cl), 4-dimethylaminopyridine, Et₃N,

08C!RT, quant.

In contrast to the straightforward preparation of the

major building blocks,the seemingly trivial esterification of

14 and 25 posed considerable problems. All attempts to join

them by using carbodiimide-based reagents,the standard

activating agents commonly employed in peptide synthesis,by

means of activated esters and thioesters,or by the Yamaguchi

method^[20]either led to complete failure or resulted in the

decomposition of the valuable materials. Application of 1-

methyl-2-chloropyridinium iodide (Mukaiyamaꢀs reagent),^[21]

which had previously served as the only successful means for a

related esterification,^[22]led to only modest yields (< 40%).

Likewise,the use of carbonyldiimidazole (CDI),employed by

Vintonyak and Maier in their approach to 1,^[8]was unsat-

isfactory in terms of yield and reaction time,and did not scale

well.

view of these difficulties,we were pleased to find that the

corresponding acid fluoride 32 performed exquisitely well,^[24]

thereby resulting in a remarkably clean and highly reprodu-

cible formation of 33 (Scheme 4); no trace of d-lactone 28 or

any other by-product was detected in the crude mixture. The

acid fluoride 32 was best prepared by treatment of 14 with

2,4,6-trifluoro-1,3,5-triazene (29) and pyridine.^[24a]It is also

worth mentioning that the ester derived from the minor

diastereomer of acid 14,produced in the CBS reduction step,

could be conveniently removed at this stage by flash

chromatography.

With a reliable esterification method at hand,the

formation of the macrocyclic ring by RCAM was investi-

gated.^[9–12]Although the Schrock alkylidyne 30^[25]had proven

effective in many advanced cases in the past,^[9,11]only

cleavage of the terminal THP acetal was observed when 33

was exposed to this catalyst. Gratifyingly though,the use of

Attempts to form the corresponding acid chloride invar-

iably led to the formation of the six-membered lactone 28,but

did not afford any of the desired ester 33 (Scheme 3).^[23]In

9276 www.angewandte.org

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Angew. Chem. Int. Ed. 2007, 46, 9275 –9278

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Angewandte

Chemie

two silyl groups at O-9 and O-17 in 41 remained to be

accomplished to complete the total synthesis.

We were apprehensive that this ultimate synthetic man-

oeuver might be far from trivial. The tendency of the 9-OH

group to engage in translactonization had already been

experienced during our initial attempts to form ester 33 (see

Scheme 3),and can be seen even more clearly from the ease

with which 1 ring-contracts to 2 under basic as well as acidic

conditions.^[1]While our work was in progress,Vintonyak and

Maier reported that they could remedy this problem only by

carrying the alkyne through to the very end of the synthesis,

where it served as a rigidifying structural element to inhibit

such ring contraction.^[8]Since we had deliberately chosen to

reduce the alkyne early on for synthetic convenience and to

protect the endangered 9-OH group as a particularly stable

TBDPS ether,it was essential to consider the options for the

ultimate deprotection very prudently.

Unsurprisingly,the use of standard fluoride sources met

with failure (TBAF with or without HOAc or NH₄Cl; TASF/

DMF, N,N-dimethylacetamide (DMA) or MeCN; HF/pyri-

dine); the tempered character of aqueous HF (pK_Aꢁ 3.14) in

MeCN,^[29]however,allowed us to perform this critical step

with ease. Under these conditions,the TBS ether at O-17 and

the TBDPS ether at O-9 were cleaved within two hours to

afford cruentaren A (1) in a highly reproducible 84% yield;

none of the ring-contracted isomer 2 could be detected in the

crude mixture by HPLC/MS analysis (< 2%). Suffice it to say

that the analytical and spectroscopic properties of synthetic 1

matched those reported for the natural product in all

regards.^[1,8]We have hence completed a convergent total

synthesis of this interesting F-ATPase inhibitor,which

favorably compares with the previous approach in terms of

all usual empirical indices (ca. 3% overall,21 steps in the

longest linear sequence). On this sound basis,we are now

attempting to develop an even shorter “second generation”

approach,and intend to explore the synthetic modularity

inherent in the underlying blueprint.

Scheme 4. a) 29, pyridine, CH₂Cl₂, ꢀ258C; b) 25, NaN(SiMe₃)₂, THF,

ꢀ788C!RT; 91% (over both steps); c) 31 (10 mol%), toluene,

CH₂Cl₂, 808C, 87%; d) Lindlar catalyst, H₂(1 atm), EtOAc, quinoline,

96%; e) MgBr₂·Et₂O, Et₂O, 93%; f) [Zn(N₃)₂·(pyridine)₂], PPh₃, DIAD,

toluene, 08C, 65%; g) PPh₃, aq THF, 508C, 91%; h) 39, HBTU, HOAt,

(iPr)₂NEt, DMF, 64%; i) BCl₃, CH₂Cl₂, ꢀ788C, 83%; j) aq HF (48%

w/w), MeCN, 08C!RT, 84%. HBTU=O-(benzotriazol-1-yl)-N,N,N’N’-

tetramethyluronium hexafluorophosphate; HOAt=1-hydroxy-7-azaben-

zotriazole.

Received: August 21,2007

Published online: October 31,2007

Keywords: alkynes · macrolides · metathesis · natural products ·

protecting groups

the molybdenum complex 31,activated in situ by CH Cl₂as

previously described by our research group,^[26,27]resulted in

the clean cyclization of this polyfunctionalized substrate,thus

delivering cycloalkyne 34 in excellent yield (Scheme 4).

Lindlar reduction followed by elaboration of the terminal

OTHP group into amine 38 proceeded in respectable overall

yield,provided that the labile azide 37 was subjected to the

Staudinger reduction without undue delay.

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Amine 38 was coupled with acid 39^[16,17]to furnish product

40,which represents fully protected cruentaren A. In accord

with previous findings,treatment of this compound with BCl ₃

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

www.angewandte.org

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[28] a) R. M. Garbaccio,S. J. Stachel,D. K. Baeschlin,S. J. Dani-

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