Preparation, modification, and evaluation of cruentaren a and analogues

Article abstract of DOI:10.1002/chem.200901817

An expeditious total synthesis of the highly cytotoxic F-ATPase inhibitor cruentaren A. (1) is described based on a. ring-closing alkyne metathesis (RCAM) reaction for the formation of the macrocylic ring. Other key transformations comprise a. C-acylation

Full text of DOI:10.1002/chem.200901817

DOI: 10.1002/chem.200901817
Preparation, Modification, and Evaluation of Cruentaren A and Analogues
Martin Bindl,[a] Ludovic Jean,[a] Jennifer Herrmann,[b] Rolf Mꢀller,[b] and
Alois Fꢀrstner*[a]
Abstract: An expeditious total synthe-
sis of the highly cytotoxic F-ATPase in-
hibitor cruentaren A (1) is described
based on a ring-closing alkyne meta-
thesis (RCAM) reaction for the forma-
tion of the macrocylic ring. Other key
transformations comprise a C-acylation
of the benzyl lithium reagent derived
from orsellinic acid ester 9 with Wein-
reb amide 7, a CBS reduction of the re-
sulting ketone 10, and a Soderquist
propargylation of aldehyde 21 with al-
lenylborane (S)-27 to set the C-15
chiral center of the required alcohol
fragment 25. The RCAM precursor 33
was assembled by acylation of 25 with
acid fluoride 32, since more conven-
tional methods for ester bond forma-
tion were unproductive. Moreover, the
choice of the protecting groups, in par-
ticular for the secondary alcohol at C-
9, which is prone to engage in translac-
tonization, turned out to be critical; a
relatively stable TBDPS ether had to
be chosen for this site, which was re-
moved in the final step of the synthesis
with aqueous HF since other fluoride
sources met with failure. The successful
synthetic route was then expanded
beyond the natural product, bringing a
series of analogues into reach that fea-
ture incremental but deep-seated struc-
tural modifications. Three of these fully
synthetic compounds turned out to be
as or even more cytotoxic than cruen-
taren A itself against L-929 mouse fi-
broblast cells, reaching IC50 values as
low as 0.7 ngmLꢀ1.
Keywords: alkynes · macrolides ·
metathesis · natural products · total
synthesis
Introduction
and natural product total synthesis in particular are forced
to justify and redefine their possible future role.
The wisdom of ages encoded in natural products has served
the well being of mankind long before chemistry and medi-
cine became scientific disciplines. Despite this fact, it is now
also well recognized that natural products themselves often
do not make good drugs as they were not evolved by nature
to cure human diseases. Nevertheless, they continue to serve
as invaluable leads in the quest for novel compounds that
can be used as drugs.[1,2] Even though this particular branch
of medicinal chemistry was successful on many occasions, it
is increasingly challenged by alternative paradigms of drug
development.[3] Thus, natural product chemistry in general
The concept of “diverted total synthesis” may provide
such new vistas.[4,5] Rather than merely chasing a target as
defined by nature, this strategy exploits the power of synthe-
sis for the preparation of designed analogues. Such a synthe-
sis-driven molecular editing process allows us to graft incre-
mental but deep-seated changes onto a given lead structure,
with the focus on such compounds that are inaccessible by
conventional derivatization of the natural product itself.
Several examples are documented in the recent literature
and fully synthetic products obtained by diverted total syn-
thesis campaigns have already entered late-stage clinical
trials.[6]
As part of our own endeavors in this arena, we now pro-
vide a full account on a program modeled around cruent-
AHCTUNGTREGaNNUN ren A (1). This complex benzolactone derivative was isolat-
ed together with the ring-contracted congener cruentaren B
(2) from the fermentation broth of the myxobacterium By-
ssovorax cruenta by Hçfle and co-workers.[7,8] While 2 is
largely inactive, 1 inhibits the growth of various yeasts and
filamentous fungi and exhibits impressive levels of in vitro
cytotoxicity. The reported IC50 values reach the low nano-
molar range even for the multidrug-resistant cervix carcino-
[a] Dr. M. Bindl, Dr. L. Jean, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
Fax : (+49)208-306-2994
E-mail: fuerstner@mpi-muelheim.mpg.de
[b] Dipl.-Chem. J. Herrmann, Prof. R. Mꢀller
Saarland University, Department of Pharmaceutical Biotechnology
66041 Saarbrꢀcken (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901817.
12310
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12310 – 12319

FULL PAPER
Results and Discussion
Retrosynthetic analysis and strategic considerations: Despite
the awesome power of ring-closing olefin metathesis,[16] the
stereoselective formation of macrocyclic Z alkenes still rep-
resents a largely unsolved problem. To address this chal-
lenge, our group has introduced ring-closing alkyne meta-
thesis (RCAM) as an alternative strategy,[17,18] since the re-
sulting cycloalkynes can be reduced, in a predictable and
highly stereoselective manner, to either the Z or E olefin.[19]
Even though RCAM has already served many total synthe-
sis projects exceedingly well,[18,20–22] its application to cruen-
taren A is not immediately obvious. The necessary 12-mem-
bered cycloalkyne F to be forged en route to 1 is considera-
bly strained, and the dense array of functional groups in the
cyclization precursor E challenges the catalyst to be used
(Scheme 1).[23] If successful, however, this approach would
ensure high selectivity during the formation of the macrocy-
clic scaffold and allow assembly of the target in a conver-
gent manner from the four relatively simple building blocks
A–D; convergence, however, is an indispensable prerequi-
site for any synthesis blueprint to be upgraded to a diverted
total synthesis exercise at a later stage.
ma cell line KB-V1 (IC50 =0.6 ngmLꢀ1).[8] However, neither
up-regulation of caspase activity nor the other usual signs of
apoptosis were found for histocytic lymphoma U-937 cells,
which are reported to arrest in the G0/1 phase of the cell
cycle after incubation with 1.[8]
Equally striking is the fact that cruentaren A is one of the
most potent inhibitors of eukaryotic F0F1-ATPases (IC50 =
15–30 nm; F-ATPase=F-type adenosine triphosphatase)
known to date but apparently does not affect the F1-ATPase
in E. coli to any appreciable extent.[8] Likewise, Na+/K+-
and V-ATPases remain operative, even though sister com-
pounds such as the salicylate lactones apicularene (3) or sal-
icylihalamide (4) are potent inhibitors of these evolutionary
related proton pumps.[9–11] This functional dissimilarity was
tentatively explained by distinct differences in the 3D struc-
tures of 1 and 3. Whereas NMR spectroscopic and crystallo-
graphic data show that 1 features a stabilizing hydrogen
bond between the phenolic 3-OH group and the adjacent
lactone carbonyl, the bicyclic skeleton of 3 enforces a con-
formation that orients the carbonyl away from the possible
3-OH hydrogen bond donor.[7]
Cruentaren A has been obtained by fermentation in isola-
tion yields of up to 3.2 mgLꢀ1,[8b] thus making total synthesis
obsolete on supply grounds. However, by following the logic
of diverted total synthesis, deliberate digression from a flexi-
ble synthesis blueprint should open unique opportunities for
probing the bioactivity profile of this enticing macrolactone
in more detail. Following up on a preliminary communica-
tion in which we reported the conquest of 1,[12] we now pres-
ent the optimized synthesis and show how deviations from
this route led to a collection of designer analogues with, in
part, increased bioactivity. None of these structural variants
could be made, without undue preparative efforts, if one
were to start from the natural product itself. Our data pre-
sented herein complement the work published by Maier and
co-workers, who pursued similar goals.[13–15]
Scheme 1. Retrosynthetic analysis of 1 based on ring-closing alkyne meta-
thesis (RCAM).
Hçfleꢂs report that 1 undergoes rapid and quantitative
translactonization with formation of 2 under acidic and
basic conditions suggests that particular attention must be
paid to the protecting group for the 9-OH function.[7,8] In
contrast, the O-methylation pattern of the arene ring seems
more manageable because methyl ethers ortho to a benzoic
acid ester are known to be cleaved faster by boron halides
than methyl ethers at the para position.[24] This differential
reactivity should allow us to distinguish between the phenol-
ic sites even at a late stage of the synthesis.
Chem. Eur. J. 2009, 15, 12310 – 12319
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12311

A. Fꢀrstner et al.
Preparation of the building blocks: Our approach to the re-
quired salicylic acid segment 14 is notably short, efficient,
and scalable (Scheme 2). Specifically, alkylation of the N-
propionyloxazolidinone 5[25] with 1-iodo-2-butyne gave prod-
uct 6 in high yield and with excellent diastereoselectivity
(dr=97:3; dr=diastereomeric ratio), which was converted
to the corresponding Weinreb amide 7 by following estab-
lished protocols.[26] Amide 7 was then reacted with the
benzyl lithium reagent formed by deprotonation of ester 9[21]
with LDA at a low temperature to give multigram amounts
of 10 per batch.[27]
the CBS reduction,[28] the configuration of the newly formed
chiral center of the major isomer 12 (deꢁ85%; de=diaste-
reomeric excess) was determined as 9R by Mosher ester
analysis (see the Supporting Information).[31] However, the
two isomers were not separable at this point. Gratifyingly,
diastereomerically pure material could be secured by rou-
tine flash chromatography at the stage of the metathesis
precursor (see below).
Since cruentaren A is predisposed for translactoniza-
tion,[7,8] the choice of the protecting group for the secondary
hydroxyl group at C-9 may be critical. Therefore several de-
rivatives (13a–c) were prepared prior to cleavage of the
ester group. For compound 13a (R=TBDPS), this transfor-
mation was best effected with TASF in DMF,[32,33] which
cleanly distinguished between the two silyl functions.
The synthesis of the polyketide sector (Scheme 3) com-
menced with the alkylation of ent-5 with the readily avail-
able propargyl iodide 15.[34] A sequence comprising LiBH4
reduction of the resulting product 16, which was found to be
diastereomerically pure by NMR spectroscopy, Lindlar hy-
drogenation, and oxidation of the resulting alcohol 17 af-
forded aldehyde 18 as a suitable electrophilic partner for the
subsequent boron aldol reaction, providing compound 19
(deꢂ96%) in high overall yield.[25,35] Conversion into alde-
hyde 21 by conventional means allowed us to set the then
only missing stereocenter by application of the excellent
Scheme 2. 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,
ACHTUNGTRENNUNG
ꢀ208C, 92%; d) 2-trimethylsilylethanol, DIAD, PPh3, THF, 08C!RT,
86%; e) i) LDA, THF, ꢀ788C; ii) TMEDA, 7, ꢀ100!ꢀ788C, 79%; f) 11,
catecholborane, toluene, ꢀ788C, 95% (85% de); g) TBDPSOTf, 2,6-luti-
dine, CH2Cl2, ꢀ788C!RT, 98%; h) MOMCl, (iPr)2NEt, DMAP,
(nBu)4NI, CH2Cl2; i) trichloroacetyl chloride, pyridine, THF, 08C!RT;
j) TASF, DMF, 08C, 85 % (14a); k) TBAF, THF, 84% (14b, over
2 steps), 88% (14c, over 2 steps). DIAD=N,N’-diisopropylcarbodiimide;
DMAP=4-dimethylaminopyridine; LDA=lithium diisopropylamide;
MOM=methoxymethyl;
TMEDA=N,N,N’,N’-tetramethylethylenedi-
ACHTUNGTRENNUNGamine; TBDPS=tert-butyldiphenylsilyl; TASF=tris(dimethylamino)sul-
fonium difluorotrimethylsilicate; TBAF=tetra-n-butylammonium fluo-
ride.
Several methods were tested for the subsequent asymmet-
ric reduction of this ketone, amongst which the CBS proto-
col led to the most satisfactory outcome.[28,29] Optimal results
were obtained with the B-butyl oxazaborolidine (R)-11[30]
and catecholborane as the stoichiometric reducing agent, be-
cause the uncatalyzed reduction of the carbonyl group and
competing hydroboration of the alkyne in 10 are minimized
when working with this particular reagent at low tempera-
tures. In line with the established stereochemical course of
Scheme 3. a) NaN
G
MeOH, 08C!RT, 83%; c) Lindlar catalyst, H2 (1 atm), EtOAc, pyridine,
96%; d) Dess–Martin periodinane, pyridine, CH2Cl2, 08C, 92%; e) ent-5,
Et2BOTf, (iPr)2NEt, CH2Cl2, ꢀ78!08C, 83%; f) TBSOTf, 2,6-lutidine,
CH2Cl2, ꢀ788C!RT, 93%; g) i) LiBH4, THF, MeOH, 08C, 83%;
ii) Dess–Martin periodinane, pyridine, CH2Cl2, 08C, 85%; h) 27, Et2O,
ꢀ788C, 92%; i) TESCl, imidazole, DMF, 508C, 96%; j) nBuLi, THF,
MeI, ꢀ788C!RT; k) HF·pyridine, THF, pyridine, 08C!RT, 95% (over
both steps). TBS=tert-butyldimethylsilyl; TES=triethylsilyl.
12312
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12310 – 12319

Preparation, Modification, and Evaluation of Cruentaren A and Analogues
FULL PAPER
asymmetric propargylation technology developed by Soder-
quist.[36] Specifically, exposure of 21 to allenylborane (S)-27,
which can be readily prepared as a well behaved and stor-
able material from commercial 26 and allenylmagnesium
bromide,[37] afforded homopropargyl alcohol 22 in high
purity. After some optimization, isolated yields of >90%
and diastereoselectivites of >95% were consistently ob-
tained in batches furnishing more than one gram of the de-
sired product. The configuration of the newly formed alco-
hol was assigned by Mosher ester analysis (see the Support-
ing Information)[31] and corresponded to the prediction of
the proposed transition-state model.[36] Temporary protec-
tion of the free OH group as TES ether 23 paved the way to
the nonterminal alkyne 25 as the other required component
for the envisaged alkyne metathesis reaction.[38] The final se-
lective cleavage of the TES group was accomplished with
HF·pyridine in pyridine/THF as the reaction medium. It was
noticed that the use of Teflon flasks rather than the usual
glassware was highly beneficial, as fewer equivalents of HF
and shorter reaction times sufficed to reach complete con-
version. This minimized parasitic side reactions and provid-
ed gram amounts of the required alcohol 25 in good overall
yield.
in refluxing toluene, but the yield of 30 remained low and
the scalability of the reaction was poor.
In view of these difficulties, we were very pleased to ob-
serve that the corresponding acid fluoride,[42,43] formed upon
treatment of acid 29 with 2,4,6-trifluorotriazine (31, cyanuric
fluoride) in the presence of pyridine, reacted smoothly with
the sodium salt of alcohol 25, furnishing ester 30 in a re-
markable 90% yield. This method was then immediately ap-
plied to the proper acid 14. Even though the reaction condi-
tions are very mild, substrates 14b and 14c bearing a MOM
or a trichloroacetyl group at O-9, respectively, again fur-
nished the 6-membered lactone 28 as the only product.
Gratifyingly though, the TBDPS group in 14a provided suit-
able protection against this undesirable path, thus making
ester 33 available in an excellent 91% isolated yield on a
gram scale, uncontaminated with lactone 28 (Scheme 5). It
is also important to note that the corresponding ester de-
rived from the minor diastereomer formed during the CBS
reduction of ketone 10, which had been carried through up
to this point, could be separated at this stage by convention-
al flash chromatography (for its use, see Scheme 9).
Elaboration of the alkyne metathesis precursor: In contrast
to our expectations, the seemingly trivial esterification of 14
and 25 turned out to be a major issue. First, it was noticed
that the reaction of acid 14b featuring a MOM-protected al-
cohol at C-9 invariably afforded the 6-membered lactone 28
as the only product under a variety of experimental condi-
tions, with no trace of the desired ester being detectable
(Scheme 4). Secondly, model studies showed that even the
simplified salicylic acid 29 could not be engaged in produc-
tive esterification with alcohol 25 upon recourse to the stan-
dard methods commonly used for the formation of sterically
hindered ester bonds.[39] The only hit was obtained with 1-
methyl-2-chloropyridinium iodide (Mukaiyamaꢂs reagent)[40]
Scheme 5. a) 31, pyridine, CH2Cl2, ꢀ258C; b) 25, NaHMDS, THF,
ꢀ788C!RT; 91% (over both steps); c) 43 (10 mol%), toluene, CH2Cl2,
808C, 87% or 44 (20 mol%), Ph3SiOH (40 mol%), MS 4 ꢃ, toluene,
808C, 81%; d) Lindlar catalyst, H2 (1 atm), EtOAc, quinoline, 96%;
.
e) MgBr2 Et2O, Et2O, 93%; f) [Zn(N3)
N
08C, 65%; g) PPh3, aq THF, 508C, 91%; h) Bu3P, THF, then 39, HBTU,
HOAt, (iPr)2NEt, DMF, 72%; i) BCl3, CH2Cl2, ꢀ788C, 88%; 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-azabenzotriazole.
Scheme 4. a) Me2C=C
ACHTUNGTRENNUNG
b) see ref. [39]; c) 25, 1-methyl-2-chloropyridinium iodide, toluene, reflux,
40%; d) i) cyanuric fluoride, pyridine, CH2Cl2; ii) 25, NaHMDS, THF,
ꢀ78!08C, 90%. NaHMDS=sodium hexamethyldisilazide
Chem. Eur. J. 2009, 15, 12310 – 12319
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12313

A. Fꢀrstner et al.
Ring-closing alkyne metathesis: With diyne 33 in hand, the
key step of the total synthesis could be tried, by using the
different alkyne metathesis catalysts currently available.
Even though Maier and co-workers had successfully used
42 and 43 as well as all other structurally defined alkyne
metathesis precatalysts known to date.
Diyne 33 constitutes a stringent test for the functional-
group compatibility of this new system. We were pleased to
find that 44/Ph3SiOH furnished the desired strained cycloal-
kyne 34 in almost the same yield (81%) as the established
combination 43/CH2Cl2 (87%). This result highlights the re-
markable application profile of the new catalyst, which is
also capable of rigorously distinguishing between the al-
kynes and the alkene in the substrate. This and other results
make us confident that 44 and 45 constitute a significant
step forward in our quest for alkyne metathesis catalysts
that combine excellent performance and tolerance with
much improved practicality and user-friendliness.[47]
[44]
ꢃ
[(tBuO)3W CC(Me)3] (42)
developed by Schrock for a
similar purpose,[13,14] this particular catalyst failed to afford
any of the desired cycloalkyne 34 but rather cleaved the ter-
minal THP acetal of our cyclization precursor. This outcome
is ascribed to the appreciable Lewis acidity of 42, which had
already previously surfaced on several occasions.[17b] Gratify-
ingly though, the molybdenum catalyst generated in situ by
activation of 43[45] with CH2Cl2 in toluene, as previously de-
scribed by our group,[46] cleanly cyclized diyne 33 to the cor-
responding cycloalkyne 34 in toluene at 808C.
Completion of the total synthesis: After Lindlar reduction
of cycloalkyne 34, the terminal OTHP group in 35 was
transformed into the allylic azide 37 under Mitsunobu con-
ditions with the zinc azide·pyridine adduct as the nucleo-
phile (Scheme 5).[48] No SN2ꢂ process was interfering under
these conditions, whereas the use of sodium azide or diphe-
nylphosphoryl azide resulted in complex mixtures.[49] From
there on, our initial route to cruentaren A featured two sep-
arate operations for the conversion of 37 into amide 40; al-
though reasonably productive, we revisited this sequence,
since amine 38 turned out to be sensitive and difficult to
work with. Gratifyingly, replacement of Ph3P in the Stau-
dinger reduction of 37 by Bu3P[50] furnished an aza–ylid in-
termediate that is sufficiently reactive for direct coupling
with acid 39 activated by HBTU/HOAt.[51] This revised pro-
tocol cuts one step out of the longest linear sequence en
route to the target and improved the overall yield.
As expected, the fully protected cruentaren A 40 thus
formed underwent selective cleavage of the methyl ether ad-
jacent to the salicylateꢂs carbonyl group on treatment with
BCl3 at ꢀ788C, whereas the distal methyl ether remained
intact. This convenient elaboration of the correct substitu-
tion pattern in the aromatic segment was accompanied by
removal of the TBS ether in the amide portion of the mole-
cule.
During the course of this project, parallel work in our
group resulted in the development of an alternative catalyst
for alkyne metathesis that is much easier to handle than the
very air and moisture sensitive complexes 42 and 43. Specifi-
cally, the molybdenum nitride species 44, which can be
made from cheap ingredients in a single high-yielding opera-
tion (Scheme 6), was found to effect a variety of model
We were apprehensive that the final step consisting of the
cleavage of the two remaining silyl groups at O-9 and -17 in
41 might be far from trivial. The tendency of the 9-OH
group to engage in translactonization had interfered with
our initial attempts to form ester 33 (see Scheme 4) and also
transpires from the ease with which 1 ring-contracts to 2
under basic and acidic conditions.[52]
Scheme 6. a) TMSCl, DME, reflux; b) LiHMDS, hexane, 64% (over both
steps); c) Ph3SiOH (3 equiv), toluene, 808C, then pyridine (5 equiv),
81%. DME=1,2-dimethoxyethane.
Whereas the standard fluoride sources met with complete
failure (TBAF with or without HOAc or NH4Cl; TASF/
DMF, DMA, or MeCN; HF/pyridine), the tempered charac-
ter of aqueous HF (pKA ꢁ3.14) in MeCN allowed us to per-
form this critical step with remarkable ease.[53] Under these
conditions, both silyl groups in 41 were cleaved within 2 h
reaction time, affording cruentaren A (1) in a well reprodu-
cible 84% yield; none of the ring-contracted isomer 2 was
detected in the crude mixture by HPLC/MS analysis
(<2%). Suffice it to say that the analytical and spectroscop-
alkyne metathesis reactions with good to excellent yields
after ligand exchange with Ph3SiOH.[47] The resulting com-
plex 48 can be stabilized and isolated in the form of the pyr-
idine adduct 45, which is sufficiently stable to be weighed in
air, yet provides active catalyst solutions.[47] It should be
noted that manipulations in air are totally inconceivable for
12314
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12310 – 12319

Preparation, Modification, and Evaluation of Cruentaren A and Analogues
FULL PAPER
ic properties of synthetic 1 matched those reported for the
natural product in all regards.
Analogues: After completion of the total synthesis, the next
immediate goal was the preparation of all other possible
ACHTUNGTRENNUNGstereoACHTUNGTRENNUNGisomers at the amide terminus. To this end, com-
pounds 49 and ent-49, bearing antipodal Evans auxiliaries,
were subjected to chromium-Reformatsky reactions with bu-
tanal (Scheme 7).[54–56] Although reported to be highly anti-
selective,[54] these transformations furnished in our hands
almost equal amounts of the corresponding syn- and anti-
aldol products. Since these isomers could be separated, how-
ever, workable amounts of the required isomeric acids 52,
54, and 56 were secured.
Scheme 8. a) Bu3P, THF, then 52, HBTU, HOAt, (iPr)2NEt, 77% (58a)
or 54, HBTU, HOAt, (iPr)2NEt, 76% (59a) or 56, HBTU, HOAt,
(iPr)2NEt, 71% (60a); b) BCl3, CH2Cl2, ꢀ788C; c) aq HF (48% w/w),
MeCN, 08C!RT, 69 % (58b), 72% (59b), 72% (60b).
RCAM, were high yielding, bearing testament to the robust-
ness of the chosen methodology.
Another analogue, which is hardly available by starting
from the natural product, is compound 71, featuring an ester
rather than an amide linkage between the macrolactone and
the hydroxy acid sector (Scheme 10). This product was read-
ily attained by esterification of alcohol 36 with acid 39 in
the presence of HOAt and HBTU. The subsequent adjust-
ment of the methylation pattern and removal of the silyl
groups was again uneventful under the previously optimized
conditions.
Prompted by the fact that the hydroxy group at C-9 in 1 is
chemically noninnocent and readily engages in translactoni-
zation with formation of the biologically inactive congener
cruentaren B (2),[7,8] we finally targeted 9-deoxy-cruent-
Scheme 7. a) CrCl2, LiI, butanal, THF, 85% (50+51a, dr 2:3), 87%
(53a+55a, dr=3:2); b) TBSOTf, 2,6-lutidine, CH2Cl2, 788C!RT, 88 %
(51b), 86% (53b), 88% (55b); c) LiOH, H2O2, aq THF, 08C, 98% (52),
90% (54), 91% (56).
With this set of b-hydroxy acids in hand, the fully synthet-
ic cruentaren A analogues 58–60 could be obtained by start-
ing from azide 37 by application of the one-pot Staudinger
reduction/acylation sequence outlined above (Scheme 8).
Final cleavage of the protecting groups was invariably per-
formed with BCl3 and aqueous HF, without any scrambling
or ring contraction interfering.
The fact that the CBS reduction of ketone 10 was not en-
tirely selective allowed us to accumulate sufficient amounts
of ester 61, which is epimeric at C-9 to ester 33 used for the
total synthesis of cruentaren A (see above). Ester 61 was
then processed into 9-epi-cruentaren A (68) by following the
now established route (Scheme 9). All steps, including
AHCTUNGTREGaNNNU ren A (82) in which this particular deactivation pathway
should be cut off. To this end, the benzyl lithium derivative
formed upon deprotonation of 9 with LDA was subjected to
alkylation (rather than acylation) with iodide 73, giving rise
to alkyne 74 in almost quantitative yield (Scheme 11).
Cleavage of the trimethylsilyl ester followed by conversion
of the resulting acid 75 into acid fluoride 76 set the stage for
a high yielding esterification with alcohol 25. Product 77 un-
derwent smooth ring-closing alkyne metathesis on treatment
with catalytic amounts of 43 activated in situ with CH2Cl2,[46]
and the resulting strained cycloalkyne 78 was subjected to
Lindlar semi-hydrogenation. The elaboration of alkene 79
Chem. Eur. J. 2009, 15, 12310 – 12319
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12315

A. Fꢀrstner et al.
Scheme 9. a) 43 (10 mol%), toluene, CH2Cl2, 808C, 85%; b) Lindlar cata-
lyst, H2 (1 atm), EtOAc, quinoline, 93%; c) MgBr2·Et2O, Et2O, 91%;
d) [Zn(N3)2 ACHTUNGTRENNUNG
.(pyridine)2], PPh3, DIAD, toluene, 08C, 65%; e) Bu3P, THF,
then 39, HBTU, HOAt, (iPr)2NEt, DMF, 76%; f) BCl3, CH2Cl2, ꢀ788C;
g) aq HF (48% w/w), MeCN, 08C!RT, 72% (over 2 steps).
Scheme 11. a) PPh3, imidazole, I2, CH2Cl2, 72%; b) i) LDA, THF, ꢀ788C;
ii) TMEDA, 73, ꢀ788C, 98%; c) TBAF, THF, 95%; d) 31, pyridine,
CH2Cl2, 08C; e) 25, NaN
(SiMe3)2, THF, ꢀ788C!RT; 92% (over both
steps); f) 43 (10 mol%), toluene, CH2Cl2, 808C, 86%; g) Lindlar catalyst,
H2 (1 atm), EtOAc, quinoline, 93%; h) i) MgBr2·Et2O, Et2O, 91%;
ii) [Zn(N3)2 ACTHNUTRGNEUNG
.(pyridine)2], PPh3, DIAD, toluene, 08C, 68%; iii) PPh3, aq
THF, 508C, 93%; i) 39, HBTU, HOAt, (iPr)2NEt, DMF, 76%; j) i) BCl3,
CH2Cl2, ꢀ788C; ii) aq HF (48% w/w), MeCN, 08C!RT, 81% (over both
steps).
into the targeted cruentaren analogue 82 was high yielding
and did not require any modification of the reaction condi-
tions worked out before.
Biological evaluation: The cytotoxicity of cruentaren A (1)
and the assortment of fully synthetic analogues was evaluat-
ed with the mouse fibroblast cell line l-929 used by Hçfle
and co-workers in their initial screen (Table 1).[7] For syn-
thetic cruentaren A, an IC50 of 4.9 ngmLꢀ1 was found, which
is slightly higher than the IC50 values reported by Hçfle
(1.2 ngmLꢀ1)[7] and Maier et al. (0.42 ngmLꢀ1)[14a] for natural
and synthetic 1, respectively. Importantly, three of the six
synthetic analogues prepared during this study turned out to
Scheme 10. a) 39, HBTU, HOAt, (iPr)2NEt, CH2Cl2, DMF, 91%; b) BCl3,
CH2Cl2, ꢀ788C; c) aq HF (48% w/w), MeCN, 08C!RT, 80% (over
2 steps).
12316
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12310 – 12319

Preparation, Modification, and Evaluation of Cruentaren A and Analogues
Table 1. Cytotoxicity of cruentaren A and synthetic analogues against
FULL PAPER
proximately 60% of all recorded events were gated to gen-
erally exclude smaller cell debris from the analysis. In un-
treated cultures, however, most of the cells (ca. 50%) were
in the G1 phase, whereas approximately 25% were found in
the G2/M phase. After 24 h treatment with cruentarens, the
number of cells in the G1 phase increased to nearly 70%,
accompanied by a decreased number of L-929 mouse fibro-
blasts in the G2/M phase (~15%). Prior to the cell-cycle
analyses, the cells were checked under a microscope reveal-
ing a slowed proliferation of treated cultures compared to
the control samples (which were treated either with 0.5 or
1.0% MeOH). Furthermore, induction of apoptosis by the
cruentarens was not detected since we did not observe a
sub-G1 population during flow cytometric measurements.
L-929 mouse fibroblast cells.[a]
Compound
IC50 [ngmLꢀ1
]
1
4.9
58
59
60
68
71
82
n.a.[b]
0.7
3.0
0.9
15.9
12.8
[a] Values represent the average of two measurements, incubation time:
5 d, in-screen validation against known cytotoxic compounds. [b] n.a.=
not active <1 mm.
be as or even more effective in our assay than the natural
product itself.
Specifically, our data show that the stereochemical fea-
tures of the b-hydroxy acid amide terminus are closely
linked to the observed activity. Whereas the anti-configured
derivative 58 with an OH group of opposite configuration to
that of the natural product is hardly active, the potency of
product 60 incorporating an enantiomeric syn-aldol unit is
similar to that of 1. The anti-aldol derivative 59 featuring an
OH with the correct (S)-configuration and 9-epi-cruent-
Conclusion
The total synthesis of the complex macrolide curentaren A
(1) reported above bears witness for the power of alkyne
metathesis and the remarkable performance of the catalysts
able to effect this transformation. Specifically, the strained
and polyfunctional cycloalkyne 34 could be forged in excel-
lent yield either by recourse to the established but very sen-
sitive catalyst system 43/CH2Cl2[46]or with the aid of the
much more user friendly reagent combination 44/Ph3SiOH
recently discovered by our group.[47] Cycloalkyne 34 then
served as the key intermediate for the total synthesis of 1
and for the preparation of a tableau of designer analogues,
all of which incorporate deep-seated structural changes that
could not be easily attained by derivatization of the natural
product itself. Since no less than three of these “cruentaren-
like” compounds turned out to rival the potency of the natu-
ral lead, these results illustrate the power of “diverted total
synthesis”,[4] which we had already encountered in previous
exercises modeled around a host of structurally diverse nat-
ural products of biological significance.[58,59]
ACHTUNGTRENNUNGaren A (68) turned out to be even more cytotoxic than the
natural lead, whereas 9-deoxy-cruentaren A (82) is a factor
of two less potent. A similar level of activity is retained
upon formal replacement of the amide linkage by an ester
bond, as realized in 71. Taken together, our results confirm
the impressive cytotoxicity of this family of benzolactone
derivatives and show for the first time that molecular editing
of their framework is promising.[57]
A cell cycle analysis showed that incubation of L-929
mouse fibroblast cells with those cruentarens that have IC50
values <1 mm led to an accumulation of cells in the G1
phase (Figure 1). This cell-cycle arrest was already reported
by Kunze and co-workers for cruentaren A when using
human histiocytic carcinoma U-937 cells for their screen.[8]
In our study, cells were treated with synthetic cruent-
A
Experimental Section
The entire experimental section containing the procedures, compound
characterization data, and description of the bioassays can be found in
the Supporting Information.
Acknowledgements
Generous financial support by the MPG, the Chemical Genomics Center
(CGC) initiative of the MPG, and the Fonds der Chemischen Industrie is
gratefully acknowledged. We thank Dr. E. Moulin and Dipl.-Chem. V.
Hickmann for initial bioassays, and our NMR, MS, and chromatography
departments for excellent support during the entire program.
Figure 1. Summary of cell-cycle analyses showing the relative number of
cells in G1- (red), S- (green) and G2/M (blue) phase. Approximately 60%
viable cells were gated during acquisition. In total, 5000 cells per sample
(measured in duplicate) were analyzed by using a Watson algorithm for
histogram plots with the software FlowJo 7.2.5 (TreeStar Inc.).
[1] For
a discussion, see the following and references therein: K.
Kumar, H. Waldmann, Angew. Chem. 2009, 121, 3272–3290; Angew.
Chem. Int. Ed. 2009, 48, 3224–3242; b) I. Paterson, E. A. Anderson,
Chem. Eur. J. 2009, 15, 12310 – 12319
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12317

A. Fꢀrstner et al.
Science 2005, 310, 451–453; c) J. Mann, Nat. Rev. Cancer 2002, 2,
143–148.
6232–6247; Angew. Chem. Int. Ed. 2006, 45, 6086–6101; i) A. Hov-
eyda, A. R. Zhugralin, Nature 2007, 450, 243–251.
[2] For a detailed analysis of how many drugs introduced to the market
over the last decades derive from natural products, see: a) D. J.
Newman, G. M. Cragg, K. M. Snader, J. Nat. Prod. 2003, 66, 1022–
1037; b) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2007, 70, 461–
477; c) G. M. Cragg, P. G. Grothaus, D. J. Newman, Chem. Rev. 2009,
109, 3012–3043.
[3] See, for example: S. L. Schreiber, Science 2000, 287, 1964–1969.
[4] a) R. M. Wilson, S. J. Danishefsky, J. Org. Chem. 2006, 71, 8329–
8351; b) J. T. Njardarson, C. Gaul, D. Shan, X.-Y. Huang, S. J. Dani-
shefsky, J. Am. Chem. Soc. 2004, 126, 1038–1040.
[17] a) A. Fꢀrstner, G. Seidel, Angew. Chem. 1998, 110, 1758–1760;
Angew. Chem. Int. Ed. 1998, 37, 1734–1736; b) A. Fꢀrstner, O.
Guth, A. Rumbo, G. Seidel, J. Am. Chem. Soc. 1999, 121, 11108–
11113.
[18] Reviews: a) A. Fꢀrstner, P. W. Davies, Chem. Commun. 2005, 2307–
2320; b) W. Zhang, J. S. Moore, Adv. Synth. Catal. 2007, 349, 93–
120; c) A. Mortreux, O. Coutelier, J. Mol. Catal. A 2006, 254, 96–
104.
[19] For the stereocomplementary conversion of cycloalkynes to the cor-
responding E alkenes by trans-hydrosilylation/protodesilylation, see:
a) F. Lacombe, K. Radkowski, G. Seidel, A. Fꢀrstner, Tetrahedron
2004, 60, 7315–7324; b) A. Fꢀrstner, M. Bonnekessel, J. T. Blank, K.
Radkowski, G. Seidel, F. Lacombe, B. Gabor, R. Mynott, Chem.
Eur. J. 2007, 13, 8762–8783.
[20] a) A. Fꢀrstner, O. Larionov, S. Flꢀgge, Angew. Chem. 2007, 119,
5641–5644; Angew. Chem. Int. Ed. 2007, 46, 5545–5548; b) A.
Fꢀrstner, K. Grela, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc.
2000, 122, 11799–11805; c) A. Fꢀrstner, K. Radkowski, J. Grabow-
ski, C. Wirtz, R. Mynott, J. Org. Chem. 2000, 65, 8758–8762; d) A.
Fꢀrstner, C. Mathes, K. Grela, Chem. Commun. 2001, 1057–1059;
e) A. Fꢀrstner, D. De Souza, L. Parra-Rapado, J. T. Jensen, Angew.
Chem. 2003, 115, 5516–5518; Angew. Chem. Int. Ed. 2003, 42, 5358–
5360; f) A. Fꢀrstner, L. Turet, Angew. Chem. 2005, 117, 3528–3532;
Angew. Chem. Int. Ed. 2005, 44, 3462–3466; g) A. Fꢀrstner, S.
Flꢀgge, O. Larionov, Y. Takahashi, T. Kubota, J. Kobayashi, Chem.
Eur. J. 2009, 15, 4011–4029; h) A. Fꢀrstner, D. De Souza, L. Turet,
M. D. B. Fenster, L. Parra-Rapado, C. Wirtz, R. Mynott, C. W. Leh-
mann, Chem. Eur. J. 2007, 13, 115–134; i) A. Fꢀrstner, T. Dierkes,
Org. Lett. 2000, 2, 2463–2465; j) A. Fꢀrstner, A. Rumbo, J. Org.
Chem. 2000, 65, 2608–2611; k) A. Fꢀrstner, F. Stelzer, A. Rumbo,
H. Krause, Chem. Eur. J. 2002, 8, 1856–1871; l) A. Fꢀrstner, K.
Grela, Angew. Chem. 2000, 112, 1292–1294; Angew. Chem. Int. Ed.
2000, 39, 1234–1236.
[5] For the related concept of “function-oriented synthesis”, see: P. A.
Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res.
2008, 41, 40–49.
[6] For representative examples, see: a) H. Choi, D. Demeke, F.-A.
Kang, Y. Kishi, K. Nakajima, P. Nowak, Z.-K. Wan, C. Xie, Pure
Appl. Chem. 2003, 75, 1–17; b) A. Rivkin, T.-C. Chou, S. J. Dani-
shefsky, Angew. Chem. 2005, 117, 2898–2910; Angew. Chem. Int.
Ed. 2005, 44, 2838–2850; c) U. Klar, B. Buchmann, W. Schwede, W.
Skuballa, J. Hoffmann, R. B. Lichtner, Angew. Chem. 2006, 118,
8110–8116; Angew. Chem. Int. Ed. 2006, 45, 7942–7948; d) T.-C.
Chou, X. Zhang, Z.-Y. Zhong, Y. Li, L. Feng, S. Eng, D. R. Myles,
R. Johnson, Jr., N. Wu, Y. I. Yin, R. M. Wilson, S. J. Danishefsky,
Proc. Natl. Acad. Sci. USA 2008, 105, 13157–13162.
[7] a) L. Jundt, H. Steinmetz, P. Luger, M. Weber, B. Kunze, H. Reich-
enbach, G. Hçfle, Eur. J. Org. Chem. 2006, 5036–5044; b) L.-P. Mol-
leyres, G. Hçfle, H. Reichenbach, H. Steinmetz (Syngenta Participa-
tions AG), PCT Int. Appl. WO 2003044005A120030530, 2003.
[8] a) B. Kunze, F. Sasse, H. Wieczorek, M. Huss, FEBS Lett. 2007, 581,
3523–3527; b) B. Kunze, H. Steinmetz, G. Hçfle, M. Huss, H. Wiec-
zorek, H. Reichenbach, J. Antibiot. 2006, 59, 664–668.
[9] Reviews: a) J. A. Beutler, T. C. McKee, Curr. Med. Chem. 2003, 10,
787–796; b) L. Yet, Chem. Rev. 2003, 103, 4283–4306.
[10] a) X.-S. Xie, D. Padron, X. Liao, J. Wang, M. G. Roth, J. K. De
Brabander, J. Biol. Chem. 2004, 279, 19755–19763; b) M. R. Boyd,
C. Farina, P. Belfiore, S. Gagliardi, J. W. Kim, Y. Hayakawa, J. A.
Beutler, T. C. McKee, B. J. Bowman, E. J. Bowman, J. Pharmacol.
Exp. Ther. 2001, 297, 114–120; c) M. Huss, H. Wieczorek, J. Exp.
Biol. 2009, 212, 341–346.
[11] For total syntheses of salicylihalamide and other benzolactone natu-
ral products from our group, see: a) A. Fꢀrstner, T. Dierkes, O. R.
Thiel, G. Blanda, Chem. Eur. J. 2001, 7, 5286–5298; b) A. Fꢀrstner,
O. R. Thiel, N. Kindler, B. Bartkowska, J. Org. Chem. 2000, 65,
7990–7995; c) A. Fꢀrstner, G. Seidel, N. Kindler, Tetrahedron 1999,
55, 8215–8230; d) A. Fꢀrstner, N. Kindler, Tetrahedron Lett. 1996,
37, 7005–7008.
[21] A. Fꢀrstner, A.-S. Castanet, K. Radkowski, C. W. Lehmann, J. Org.
Chem. 2003, 68, 1521–1528.
[22] a) N. Ghalit, A. J. Poot, A. Fꢀrstner, D. T. S. Rijkers, R. M. J. Lis-
kamp, Org. Lett. 2005, 7, 2961–2964; b) B. Aguilera, L. B. Wolf, P.
Nieczypor, F. P. T. J. Rutjes, H. S. Overkleeft, J. C. M. van Hest,
H. E. Schoemaker, B. Wang, J. C. Mol, A. Fꢀrstner, M. Overhand,
G. A. van der Marel, J. H. van Boom, J. Org. Chem. 2001, 66, 3584–
3589; c) M. IJsselstijn, B. Aguilera, G. A. van der Marel, J. H. van
Boom, F. L. van Delft, H. E. Schoemaker, H. S. Overkleeft, F. P. J. T.
Rutjes, M. Overhand, Tetrahedron Lett. 2004, 45, 4379–4382; d) S.
Groothuys, S. A. M. W. van den Broek, B. H. M. Kuijpers, M. Jssel-
stijn, F. L. van Delft, F. P. J. T. Rutjes, Synlett 2008, 111–115; e) P.
Kraft, C. Berthold, Synthesis 2008, 543–550; f) S. Schulz, S. Yildiz-
han, K. Stritzke, C. Estrada, L. E. Gilbert, Org. Biomol. Chem.
2007, 5, 3434–3441.
[12] A. Fꢀrstner, M. Bindl, L. Jean, Angew. Chem. 2007, 119, 9435–
9438; Angew. Chem. Int. Ed. 2007, 46, 9275–9278.
[13] a) V. V. Vintonyak, M. E. Maier, Angew. Chem. 2007, 119, 5301–
5303; Angew. Chem. Int. Ed. 2007, 46, 5209–5211; b) V. V. Vinto-
nyak, M. E. Maier, Org. Lett. 2007, 9, 655–658.
[23] a) R. R. Schrock, C. Czekelius, Adv. Synth. Catal. 2007, 349, 55–77;
b) R. R. Schrock, Chem. Rev. 2002, 102, 145–179.
[14] a) V. V. Vintonyak, M. Calꢄ, F. Lay, B. Kunze, F. Sasse, M. E. Maier,
Chem. Eur. J. 2008, 14, 3709–3720; b) M. E. Maier, J. Ritschel, AR-
KIVOC 2008, xiv, 314–329.
[15] For a synthesis of cruentaren B, see: T. K. Chakraborty, A. K. Chat-
topadhyay, J. Org. Chem. 2008, 73, 3578–3581.
[16] a) R. H. Grubbs, Angew. Chem. 2006, 118, 3845–3850; Angew.
Chem. Int. Ed. 2006, 45, 3760–3765; b) R. R. Schrock, Angew.
Chem. 2006, 118, 3832–3844; Angew. Chem. Int. Ed. 2006, 45, 3748–
3759; c) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18–
29; d) A. Fꢀrstner, Angew. Chem. 2000, 112, 3140–3172; Angew.
Chem. Int. Ed. 2000, 39, 3012–3043; e) S. J. Connon, S. Blechert,
Angew. Chem. 2003, 115, 1944–1968; Angew. Chem. Int. Ed. 2003,
42, 1900–1923; f) A. Deiters, S. F. Martin, Chem. Rev. 2004, 104,
2199–2238; g) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew.
Chem. 2005, 117, 4564–4601; Angew. Chem. Int. Ed. 2005, 44, 4490–
4527; h) A. Gradillas, J. Pꢅrez-Castells, Angew. Chem. 2006, 118,
[24] For pertinent examples, see: a) R. M. Garbaccio, S. J. Stachel, D. K.
Baeschlin, S. J. Danishefsky, J. Am. Chem. Soc. 2001, 123, 10903–
10908; b) J. Zhu, J. A. Porco, Jr., Org. Lett. 2006, 8, 5169–5171.
[25] J. R. Gage, D. A. Evans, Org. Synth. 1990, 68, 83–91.
[26] G. J. Kramp, M. Kim, H.-J. Gais, C. Vermeeren, J. Am. Chem. Soc.
2005, 127, 17910–17920.
[27] For similar acylation processes, see: a) E. Moulin, S. Barluenga, N.
Winssinger, Org. Lett. 2005, 7, 5637–5639; b) M. A. Marsini, K. M.
Gowin, T. R. R. Pettus, Org. Lett. 2006, 8, 3481–3483; c) C. N.
Lewis, P. L. Spargo, J. Staunton, Synthesis 1986, 944–946.
[28] a) E. J. Corey, C. J. Helal, Angew. Chem. 1998, 110, 2092–2118;
Angew. Chem. Int. Ed. 1998, 37, 1986–2012; b) B. T. Cho, Tetrahe-
dron 2006, 62, 7621–7643.
[29] Other methods tried were
a Noyoriꢂs transfer hydrogenation,
Alpine-borane, DIP-Cl, Alpine-hydride, and LiAlH4 modified with
1,1’-binapthol; the obtained de values were invariably below 20%.
12318
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12310 – 12319

Preparation, Modification, and Evaluation of Cruentaren A and Analogues
FULL PAPER
[30] D. J. Mathre, T. K. Jones, L. C. Xavier, T. J. Blacklock, R. A.
Reamer, J. J. Mohan, E. T. T. Jones, K. Hoogsteen, M. W. Baum,
3095–3115; e) K. C. Nicolaou, H. J. Mitchell, K. C. Fylaktakidou,
R. M. Rodrꢈquez, H. Suzuki, Chem. Eur. J. 2000, 6, 3116–3148.
E. J. J. Grabowski, J. Org. Chem. 1991, 56, 751–762.
[31] J. M. Seco, E. QuiÇoꢆ, R. Riguera, Chem. Rev. 2004, 104, 17–118.
[32] a) R. Noyori, I. Nishida, J. Sakata, J. Am. Chem. Soc. 1983, 105,
1598–1608; b) K. A. Scheidt, H. Chen, B. C. Follows, S. R. Chemler,
D. S. Coffey, W. R. Roush, J. Org. Chem. 1998, 63, 6436–6437.
[33] a) C. Aꢇssa, R. Riveiros, J. Ragot, A. Fꢀrstner, J. Am. Chem. Soc.
2003, 125, 15512–15520; b) A. Fꢀrstner, M. D. B. Fenster, B. Fasch-
ing, C. Godbout, K. Radkowski, Angew. Chem. 2006, 118, 5636–
5641; Angew. Chem. Int. Ed. 2006, 45, 5510–5515; c) A. Fꢀrstner, T.
Nagano, J. Am. Chem. Soc. 2007, 129, 1906–1907; d) A. Fꢀrstner,
L. C. Bouchez, J.-A. Funel, V. Liepins, F.-H. Porꢅe, R. Gilmour, F.
Beaufils, D. Laurich, M. Tamiya, Angew. Chem. 2007, 119, 9425–
9430; Angew. Chem. Int. Ed. 2007, 46, 9265–9270; e) A. Fꢀrstner,
L. C. Bouchez, L. Morency, J.-A. Funel, V. Liepins, F.-H. Porꢅe, R.
Gilmour, D. Laurich, F. Beaufils, M. Tamiya, Chem. Eur. J. 2009, 15,
3983–4010.
[44] J. H. Freudenberger, R. R. Schrock, M. R. Churchill, A. L. Rhein-
gold, J. W. Ziller, Organometallics 1984, 3, 1563–1573.
[45] C. C. Cummins, Chem. Commun. 1998, 1777–1786.
[46] a) A. Fꢀrstner, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 1999,
121, 9453–9454; b) A. Fꢀrstner, C. Mathes, C. W. Lehmann, Chem.
Eur. J. 2001, 7, 5299–5317.
[47] M. Bindl, R. Stade, E. K. Heilmann, A. Picot, R. Goddard, A. Fꢀrst-
ner, J. Am. Chem. Soc. 2009, 131, 9468–9470.
[48] M. C. Viaud, P. Rollin, Synthesis 1990, 130–132.
[49] a) H. M. Sampath Kumar, B. V. Subba Reddy, S. Anjaneyulu, J. S.
Yadav, Tetrahedron Lett. 1998, 39, 7385–7388; b) A. S. Thompson,
G. R. Humphrey, A. M. DeMarco, D. J. Mathre, E. J. J. Grabowski,
J. Org. Chem. 1993, 58, 5886–5888.
[50] F. Compostella, S. Ronchi, L. Panza, S. Mariotti, L. Mori, G. De Lib-
ero, F. Ronchetti, Chem. Eur. J. 2006, 12, 5587–5595.
[51] L. A. Carpino, J. Am. Chem. Soc. 1993, 115, 4397–4398.
[52] Maier and co-workers solved this problem by carrying the alkyne in
the macrocycle through the synthesis as a rigidifying structural ele-
ment that prevents translactonization, see ref. [13,14].
[53] For a precedent, see: Y. Ogawa, M. Nunomoto, M. Shibasaki, J.
Org. Chem. 1986, 51, 1625–1627.
[54] a) L. Wessjohann, T. Gabriel, J. Org. Chem. 1997, 62, 3772–3774;
b) T. Gabriel, L. Wessjohann, Tetrahedron Lett. 1997, 38, 4387–
4388.
[34] Prepared in analogy to: J.-P. Roduit, H. Wyler, Helv. Chim. Acta
1985, 68, 403–414.
[35] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127–2129.
[36] a) C. Lai, J. A. Soderquist, Org. Lett. 2005, 7, 799–802; b) C. H.
Burgos, E. Canales, K. Matos, J. A. Soderquist, J. Am. Chem. Soc.
2005, 127, 8044–8049.
[37] H. Hopf, I. Bçhm, J. Kleinschroth, Org. Synth. 1981, 60, 41–48.
[38] Attempts were made to shorten the route to the nonterminal alkyne
by using a methyl substituted analogue of 27 in the propargylation
reaction, see: E. Canales, A. Z. Gonzalez, J. A. Soderquist, Angew.
Chem. 2007, 119, 401–403; Angew. Chem. Int. Ed. 2007, 46, 397–
399. However, the yields remained low and the reagent turned out
to be more difficult to handle.
[55] For reviews on the Reformatsky reaction, see: a) A. Fꢀrstner, Syn-
thesis 1989, 571–590; b) R. Ocampo, W. R. Dolbier, Jr., Tetrahedron
2004, 60, 9325–9374.
[56] For reviews on the use of CrCl2 in organic synthesis, see: a) A.
Fꢀrstner, Chem. Rev. 1999, 99, 991–1045; b) K. Takai, Org. React.
2004, 64, 253–612.
[39] The following methods resulted in essentially no product formation:
oxalyl chloride, then Et3N; EDC/HOBt; DCC/DMAP; Yamaguchi
esterification; N,N’-carbonyldiimidazole; PySSPy/PPh3, then AgBF4;
[57] The only other SAR investigation into the cruentarens reported to
date could not identify any analogue retaining or even surpassing
the activity of the natural lead, see ref. [14a].
DIAD, PPh3; di-2-thienylcarbonate, then Hf
G
[58] a) A. Fꢀrstner, C. Nevado, M. Waser, M. Tremblay, C. Chevrier, F.
´
[40] a) T. Mukaiyama, M. Usui, E. Shimada, K. Saigo, Chem. Lett. 1975,
1045–1048; b) see also: A. Fꢀrstner, C. Mꢀller, Chem. Commun.
2005, 5583–5585.
[41] a) B. Haveaux, A. Dekoker, M. Rens, A. R. Sidani, J. Toye, L.
Ghosez, Org. Synth. 1980, 59, 26–34; b) see also: A. Fꢀrstner, H.
Weintritt, J. Am. Chem. Soc. 1998, 120, 2817–2825.
Teply, C. Aꢇssa, E. Moulin, O. Mꢀller, J. Am. Chem. Soc. 2007, 129,
9150–9161; b) A. Fꢀrstner, D. Kirk, M. D. B. Fenster, C. Aꢇssa, D.
De Souza, C. Nevado, T. Tuttle, W. Thiel, O. Mꢀller, Chem. Eur. J.
2007, 13, 135–149; c) A. Fꢀrstner, E. Kattnig, G. Kelter, H.-H.
Fiebig, Chem. Eur. J. 2009, 15, 4030–4043.
[59] a) A. Fꢀrstner, K. Radkowski, H. Peters, G. Seidel, C. Wirtz, R.
Mynott, C. W. Lehmann, Chem. Eur. J. 2007, 13, 1929–1945; b) P.
Buchgraber, M. M. Domostoj, B. Scheiper, C. Wirtz, R. Mynott, J.
Rust, A. Fꢀrstner, Tetrahedron 2009, 65, 6519–6534; c) A. Fꢀrstner,
F. Feyen, H. Prinz, H. Waldmann, Tetrahedron 2004, 60, 9543–9558.
ˇ
[42] J. Pospꢈsil, C. Mꢀller, A. Fꢀrstner, Chem. Eur. J. 2009, 15, 5956–
5968.
[43] a) G. A. Olah, M. Nojima, I. Kerekes, Synthesis 1973, 487–488;
b) M. J. S. Dewar, I. J. Turchi, J. Org. Chem. 1975, 40, 1521–1523;
c) S. C. Mayer, M. M. Joulliꢅ, Synth. Commun. 1994, 24, 2367–2377;
d) K. C. Nicolaou, R. M. Rodrꢈquez, H. J. Mitchell, H. Suzuki, K. C.
Fylaktakidou, O. Baudoin, F. L. van Delft, Chem. Eur. J. 2000, 6,
Received: July 1, 2009
Published online: October 9, 2009
Chem. Eur. J. 2009, 15, 12310 – 12319
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12319