Gram-scale synthesis of iejimalide B

Article abstract of DOI:10.1002/chem.201100178

IejimalideB (2) is the most promising member of a small family of marine polyene macrolides endowed with remarkably selective activity against human cancer cell lines. As this product, however, is hardly available from the natural sources, a detailed evaluation requires the development of an efficient and practical synthetic approach. This challenge has now been met by adapting the first total synthesis of 2 previously reported by our group to the needs of high material throughput. Redesigning the access routes to the five required building blocks in combination with a careful optimization of the fragment coupling processes provided gram amounts of this valuable compound in a sequence of no more than 16 linear steps with an overall yield of about 7 %. Key elements of the successful strategy include: i) three hydrostannylation processes of elaborate terminal alkynes with "lower order" stannyl cuprates, ii) a Brown allylation, a Noyori transfer hydrogenation, and a Marshall propargylation to set the chiral centers at C9, C17, C22 and C23, and iii) a modified Takai-Utimoto olefination for the preparation of the very labile skipped 1,4-diene flanking the ester group. The assembly process benefited from a particularly mild protocol for the Stille cross-coupling previously developed in this laboratory, which clearly outperformed the alternative Suzuki reaction in terms of yield and scalability. The 24-membered macrocyclic frame was forged by a remarkably selective ring-closing metathesis reaction (RCM), in which two out of the ten double bonds present in the cyclization precursor were selectively activated with the aid of a second-generation Grubbs catalyst. Copyright

Full text of DOI:10.1002/chem.201100178

DOI: 10.1002/chem.201100178
Gram-Scale Synthesis of Iejimalide B
Julien Gagnepain, Emilie Moulin, and Alois Fꢀrstner*[a]
Abstract: Iejimalide B (2) is the most
provided gram amounts of this valua-
ble compound in a sequence of no
more than 16 linear steps with an over-
all yield of about 7%. Key elements of
the successful strategy include: i) three
hydrostannylation processes of elabo-
rate terminal alkynes with “lower
order” stannyl cuprates, ii) a Brown al-
lylation, a Noyori transfer hydrogena-
tion, and a Marshall propargylation to
set the chiral centers at C9, C17, C22
and C23, and iii) a modified Takai–Uti-
moto olefination for the preparation of
promising member of a small family of
marine polyene macrolides endowed
with remarkably selective activity
against human cancer cell lines. As this
product, however, is hardly available
from the natural sources, a detailed
evaluation requires the development of
an efficient and practical synthetic ap-
proach. This challenge has now been
met by adapting the first total synthesis
of 2 previously reported by our group
to the needs of high material through-
put. Redesigning the access routes to
the five required building blocks in
combination with a careful optimiza-
tion of the fragment coupling processes
the very labile skipped 1,4-diene flank-
ing the ester group. The assembly pro-
cess benefited from a particularly mild
protocol for the Stille cross-coupling
previously developed in this laboratory,
which clearly outperformed the alter-
native Suzuki reaction in terms of yield
and scalability. The 24-membered mac-
rocyclic frame was forged by a remark-
ably selective ring-closing metathesis
reaction (RCM), in which two out of
the ten double bonds present in the
cyclization precursor were selectively
activated with the aid of a second-gen-
eration Grubbs catalyst.
Keywords: asymmetric catalysis
cross-coupling metathesis
natural products · total synthesis
·
·
·
Introduction
tivity profile of the iejimalides and the recorded anticancer
agents in the NCI database.[5] Remarkably, Kobayashi et al.
also claimed in vivo efficacy of 3 and 4 against P388 leuke-
mia in mice at doses of 200 mgkgꢀ1 dꢀ1.[2b]
In 1988, Kobayashi and co-workers reported the isolation of
the polyene macrolides of the iejimalide family (1–4) from
the marine tunicate Eudistoma cf. rigida collected off Ie
island in the Okinawa archipelago.[1] The proposed constitu-
tion of these extremely scarce secondary metabolites (0.003–
0.006% of the tunicates wet weight) was corrected and their
stereostructure established only 15 years later after a re-ex-
traction from a Cystodytes sp.[2] Although more recent data
suggest that these compounds might actually be produced
by symbiotic cyanobacteria rather than the tunicates them-
selves,[3] the very limited supply of 1–4 from the natural
sources severely hampered a detailed biological evaluation.
As the original publication had only shown cytotoxicity
against two murine leukemia cell lines,[1] the promising ac-
tivity of the iejimalides against a multitude of human cancer
cell lines in vitro transpired only after the re-isolation cam-
paign had enabled a more detailed screening.[2b,4] These
studies also indicated a lack of homology between the selec-
The mechanism of action responsible for the promising
cytotoxicity of the iejimalides remains to be fully investigat-
ed. Yet, the available information suggests that V-ATPases
are one of the relevant biological targets,[6,7] which might
also explain the reported anti-osteoporotic activity of 1–4.[8]
Depending on the particular cell type, these macrolides
cause cell cycle arrest, induce apoptosis, and modulate the
steady state level of several gene products associated with
cell cycle progression and cell death.[9,10] Furthermore, it has
been shown that their cytotoxicity is not caused by tubulin
binding, whereas the actin cytoskeleton of fibroblast cells is
strongly perturbed upon incubation with micromolar con-
centrations of iejimalide B and analogues.[10]
[a] Dr. J. Gagnepain, Dr. E. Moulin, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
Fax : (+49)208-306-2994
E-mail: fuerstner@kofo.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100178.
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FULL PAPER
The first total synthesis of all naturally occurring iejima-
lides reported by our group provided sufficient amounts of
these valuable compounds for an independent biological
evaluation.[10–12] The promising results obtained in the first
round encouraged us to perform a more detailed screening;
this extended program did not only rely on various cell-
based assays, but also included colony-based assays using ex-
perimental tumors as well as in vivo testing in mice against
selected human cancer xenografts.[13] As such a campaign,
however, mandates a secured material supply, a truly practi-
cal and scalable synthesis of iejimalide B (2) as the most
promising member of the series had to be devised. Given
the potency of 2, we arbitrarily targeted one gram of this
particular compound; the chemistry that enabled us to reach
this goal is outlined below. At the same time, our endeavor
at the chemistry/biology interface was also intended to lay a
solid basis for a synthesis-driven exploration of the structur-
al space surrounding the natural products themselves.[14]
This second part of our agenda, together with details con-
cerning the biological activities of the iejimalides and a
panel of non-natural analogues, is disclosed in the accompa-
nying paper.[13]
the aid of a Grubbs-type catalyst, we were pleased to find
that this risky maneuver opened access to 2 and conge-
ners.[10,11b] It is also obvious that the overall strategy is well
suited for the synthesis of analogues by introducing the de-
sired structural “point-mutations” into one or more of the
parent fragments A–E. In view of these inherent advantages,
the basic synthesis blueprint was kept unchanged during the
up-scaling campaign.
Yet, we had learned during our early work that several in-
termediates en route to 2 are unusually sensitive toward
acid, base and gentle warming; moreover, facile double-
bond isomerizations in the presence of even weak nucleo-
philes had plagued the preparation of fragments C and E.
Although these difficulties could ultimately be mas-
tered,[10,11] it was clear that each building block and all frag-
ment coupling processes needed scrupulous reinvestigation
for larger-scale material throughput.
The N-formylserine segment: The tail of the iejimalides ter-
minates in an N-formylserine moiety, which imparts signifi-
cant polarity onto the compounds despite of their apolar
cores. Sulfatation of the primary hydroxyl group, as dis-
played by iejimalide C (3) and D (4), increases the polar
character even further.[1,2]
Results and Discussion
Although the preparation of the required building block
A follows established procedures of peptide chemistry, care-
ful compliance with the optimized reaction conditions is
mandatory because of the proclivity of N-formylserine de-
rivatives toward racemization, formyl cleavage and oxazo-
line formation (Scheme 2). In fact, even gentle warming of
the reaction mixture upon O-TBS protection of the hydroxyl
group of commercial benzyl serinate 5 may cause partial or
complete racemization within short periods of time. No such
problems, however, were encountered when the silylation
was performed at ambient temperature (ee ꢁ99%, 6.7 g
scale).[17] In this context it is of note that the rotatory power
of 6 is strongly concentration dependent; therefore it is ad-
visable to check the optical purity of the material by HPLC.
Whereas a literature procedure employs trifluoroethoxy
formate in the formylation step,[18] we found the use of
cheap formic acid in combination with EDC and catalytic
amounts of DMAP much more practical. The resulting
Synthesis plan and strategic considerations: Our initial anal-
ysis had dissected the iejimalide structure into five building
blocks A–E of similar size and complexity, which allow the
molecular frame to be assembled in a highly convergent
manner (Scheme 1).[10,11] The flexibility of this plan paid divi-
dends when the originally intended macrolactonization for
the formation of the 24-membered core essentially met with
failure.[11a,15] Without undue preparative efforts, the assem-
bly process could be re-programmed toward macrocycliza-
tion by ring-closing metathesis (RCM)[16] at the C11 C12
bond. Even though this tactics required selective activation
of two out of ten olefins in the metathesis precursor with
ꢀ
Scheme 2. a) TBSCl, DBU, MeCN, 08C!RT, quant.; b) EDC·HCl,
DMAP, HCOOH, 08C ! RT, 94 %, >98% ee; c) H2 (1 atm), Pd/C cat.,
EtOAc, MeOH, 98%; DMAP=4-dimethylaminopyridine, EDC=N-(3-
dimethylaminopropyl)-N’-ethylcarbonyldiimide, TBS=tert-butyldimethyl-
silyl.
Scheme 1. Disconnection of 2 into five building blocks of similar size and
complexity.
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A. Fꢀrstner et al.
product 7 was obtained in 94% yield on a 6.8 g scale with
an uncompromised ee of 98–99%. The final hydrogenolysis
of the benzyl ester over palladium on charcoal was best per-
formed in a mixed solvent system comprising EtOAc and
MeOH to avoid precipitation of the resulting acid 8, which
may occlude the catalyst and hence cause the reaction to
cease.[19]
The tail region: Since the preparation of the Eastern seg-
ment B defines the longest linear sequence of the total syn-
thesis and therefore determines the overall yield, particular
care was paid to the optimization of all individual steps. The
original route, though quite efficient, was not considered
satisfactory in practical terms (Scheme 3). Although the ini-
tial Heck coupling of 9 with 10 gave yields of up to 84%,[10]
the reproducibility of the reaction on larger scale was poor.
Moreover, the need for two N-Boc substituents, which had
to be removed in a stepwise fashion later in the sequence, is
deemed inappropriate with regard to step count and atom
economy.[20,21]
Scheme 4. a) Br2, CH2Cl2, 08C, then DBU, 08C ! RT, 92%; b) Pd-
ACHTUNGRENN(UG OAc)2 (2.5 mol%), PAHCUTNTGRNE(NUGN o-tolyl)3 (5 mol%), Et3N, 1008C, 68%; c) MeNH2,
EtOH; d) 4-O2NC6H4-O-C(O)-OCH2CH2SiMe3, Et3N, CH2Cl2, 85%
(over both steps); e) Dibal-H, CH2Cl2, ꢀ788C, 86%; f) MnO2, CH2Cl2;
g) Pd
G
70% (over both steps); h) TBAF, THF, 08C, 87%; i) (Bu3Sn)2, BuLi,
THF, CuCN, ꢀ788C ! RT, then 20, ꢀ788C, 95%; j) I2, Et2O, 0 8C ! RT,
90%; k) (i) Et4NF, MeCN, 408C; (ii) 8, HOBt, EDC·HCl, N-methylmor-
pholine, CH2Cl2, 90% (over two steps). HOBt=1-hydroxy-1H-benzotri-
azole, TBAF=tetra-n-butylammonium fluoride; Teoc=2-(trimethylsilyl)-
ethoxycarbonyl.
Scheme 3. Original route to a key intermediate representing synthon B:
a) Pd
ACHTUNGTRENNUNG(OAc)2 (3 mol%), PACHUTNTGERN(NUNG o-tolyl)3 (6 mol%), Et3N, 1008C, up to 84%,
cf. ref. [10].
After the removal of the C-silyl group with TBAF in THF
at low temperature to avoid premature cleavage of the N-
Teoc substituent, various options for the further elaboration
of the resulting product 20 were explored. Although the
original route involving temporary protection of the hydrox-
yl group as a pivalate ester followed by hydrozirconation/io-
dination of the terminal alkyne scaled well,[10] stannylcupra-
tion of 20 followed by iodine for tin exchange (21 ! 12)
constitutes a superior alternative. It circumvents problems
caused by variable qualities of commercial [Cp2Zr(H)Cl]
and is less expensive; moreover, the protection/deprotection
of the alcohol group is avoided, thus reducing the step
count. Careful optimization of the reaction conditions
showed that the use of the “lower-order” stannyl cuprate
generated from Bu3SnCu and LiCN in THF at ambient tem-
perature gave optimal results.[28] Under these conditions, ex-
cellent yields and selectivities were secured (95%, >3 g
scale, E/Z >30:1), whereas the same reaction, when per-
formed at ꢀ788C, resulted in a 1:1 mixture of double bond
isomers. Cleavage of the Teoc-group in 12 followed by intro-
duction of the N-formylserine moiety with the aid of EDC
and HOBt readily provided gram amounts of the “Eastern”
segment 22 (1.15 g, single largest batch) in readiness for
fragment coupling.
A very convenient alternative was found with phthalimide
14, which is readily available by standard N-alkylation
(91%, >90 g scale) (Scheme 4). A palladium-catalyzed
Heck reaction[22] with bromide 9, for which an expedient
two-step/one-pot preparation was devised (92% overall,
100 g scale), gave diene 15 in well reproducible yields of
68% on a 50 gram scale. As the product can be collected by
crystallization from the crude mixture, a further up-scaling
of this transformation should be straightforward. Cleavage
of the phthalimide with methylamine[23] followed by intro-
duction of an N-Teoc group,[24] which had previously turned
out advantageous in the downstream Marshall propargyla-
tion,[25] provided multigram amounts of 16 (11.1 g, single
largest batch) after the first flash chromatography necessary
during this route. Adjustment of the oxidation state gave al-
dehyde 17 without difficulties, which was subjected to a pal-
ladium-catalyzed, zinc-induced reaction with propargyl me-
sylate 18 carrying a bulky TIPS group at the alkyne termi-
nus. This large substituent renders the Marshall propargyla-
tion highly diastereoselective,[26] furnishing the anti-config-
ured compound 19 in pure form in 70% yield on a >10
gram scale.[27]
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Gram-Scale Synthesis of Iejimalide B
FULL PAPER
Elaboration of the Southern sector: Commercial 4-penteno-
ic acid chloride (23) was selected as point of departure for
the preparation of the required coupling partner, as it react-
ed cleanly with bis-trimethylsilylacetylene in the presence of
AlCl3 (Scheme 5); the resulting ketone 24 could be conven-
iently purified by Kugelrohr distillation (83%, >16 g).[29]
The subsequent transfer hydrogenation under Noyoriꢂs con-
ditions also worked admirably well, furnishing propargyl al-
cohol 26 in 98% yield (>8 g scale) and 98.8% ee, provided
that the isopropanol serving as the reductant and the solvent
was carefully degassed.[30] As previously mentioned, howev-
er, the seemingly routine O-methylation of the secondary
hydroxyl group in 26 required careful optimization.[10] Best
results were obtained using nBuLi in THF as the base and
DMSO as an aprotic dipolar cosolvent.[29] Under these con-
ditions, good reproducibility and a high yield of 27 were se-
cured when working on a multigram scale.
Next, we were committed to improve the selective cleav-
age of the double bond in 27 in the presence of the alkyne,
which had relied on the use of OsO4 (10 mol%) in combina-
tion with NaIO4 and 2,6-lutidine in the original total synthe-
sis.[10] After some experimentation it was found that ozono-
lysis in MeOH is a much better solution, provided that the
reaction was monitored by the use of Sudan red 7B as an in-
dicator.[31,32] This dye decolorizes once the alkene has been
completely consumed; therefore the reaction can be stopped
in time to avoid any over-oxidation of the alkyne unit. This
reliable protocol allowed for significant material through-
put.
Two different variants for the elaboration of the aldehyde
group in 28 into the required terminal 1,3-diene moiety
were investigated. However, the shorter route via Weinreb
amide 29[34] turned out to be troublesome because of partial
isomerization of the (Z)-configured trisubstituted alkene
during the reduction with either Dibal-H or LiAlH4. This
step was much cleaner with the corresponding ester 30,
which was prepared as a single isomer by a modified Still–
Gennari olefination[35] employing only substoichiometric
amounts of [18]crown-6 as additive.[36] The use of either tol-
uene or THF gave similar results, but the isolation of the
somewhat volatile product was easier with the latter solvent
(85%, >7 g scale). Reduction of 30 with Dibal-H followed
by oxidation of the resulting allylic alcohol 31 furnished al-
dehyde 32. Although the use of excess MnO2 is effective for
this purpose, problems with partial isomerization of the a,b-
unsaturated system were occasionally observed. This unde-
sirable process could be largely avoided by recourse to cata-
lytic TEMPO in combination with NCS as the final oxidant
in a biphasic CH2Cl2/buffer medium (Z/E >20:1 in all cases
investigated).[37,38] 32 was immediately subjected to a Wittig
olefination with preformed Ph3P=CH2 followed by desilyla-
tion of the resulting product with K2CO3 in MeOH. From
the practical viewpoint it is important to note that the four
operations, by which enoate 30 was converted into diene 33,
did not mandate rigorous purification of the intermediates
and therefore gave a satisfactory 71% overall yield after a
single flash chromatography.
A chemoselective hydrometalation of the alkyne in the
presence of the 1,3-diene transforms compound 33 into the
required building block in readiness for fragment coupling
with alkenyl iodide 22. Although hydroboration with pinacol
borane, entrained by the addition of catalytic amounts of 9-
H-9-BBN,[39] gave acceptable yields in reactions using
ꢂ500 mg of substrate,[10] the transformation was erratic
upon further scale-up. Gratifyingly, however, stannylcupra-
tion of 33 with the lower order cyanocuprate formed from
Bu3SnCu and LiCN,[28] which had already worked exquisitely
well during the advancement of Marshall-adduct 20 to al-
kenyl iodide 22, was found clearly superior in terms of yield
and scalability. Moreover, the subsequent fragment coupling
of the resulting stannane 35 with alkenyl iodide 22, when
performed according to the Stille protocol previously devel-
ꢃ
Scheme 5. a) Me3SiC CSiMe3, AlCl3, 08C
!
208C, 83%; b) 25
(0.6 mol%), iPrOH, 98%, 98.8% ee; c) BuLi, THF, ꢀ788C, then DMSO,
MeI, ꢀ258C ! RT, 99 %; d) O3, Sudan red 7B cat., then PPh3, 92%; e)
(F3CCH2O)2P(O)CH(Me)CONACHTNUGRTNEUNG
(OMe)(Me),[33] [18]crown-6, KHMDS,
THF, ꢀ788C, 72% (E/Z 1:11); f) Dibal-H, CH2Cl2, ꢀ788C, 63% (E/Z
ꢄ3:1); g) (F3CCH2O)2P(O)CH(Me)COOMe, KHMDS, [18]crown-6
(0.8 equiv), THF, ꢀ788C, 85%; h) Dibal-H, CH2Cl2, ꢀ788C; i) TEMPO
(20 mol%), Bu4NCl (20 mol%), NCS, CH2Cl2, aq. phosphate buffer
(pH 8.6); j) Ph3P=CH2, THF, ꢀ788C; k) K2CO3, MeOH, 71% (over steps
h)–k)); l) (Bu3Sn)2, BuLi, CuCN, ꢀ788C ! RT, then 33, ꢀ788C, 81%;
m) pinacolborane, 9-H-9-BBN (10 mol%), THF, 458C, 56%; TEMPO=
2,2,6,6-tetramethyl-1-piperinyloxy; NCS=N-chlorosuccinimide.
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A. Fꢀrstner et al.
oped by our group for challenging cases,[40–42] secured gram
amounts of the fully functional Southern sector 36 in well
reproducible 87% yield (1.3 g, single largest batch)
(Scheme 6). This result clearly exceeds the outcome of the
competing Suzuki reaction[43] between boronate 34 and
iodide 22, which delivered the same product in only 66%
yield, even though the conditions had previously been care-
fully optimized.[10] We tentatively ascribe the superior per-
formance of the Stille coupling to the fact that the used
rived from Bu3SnCu and LiCN (see above).[28] Respectable
amounts of compound 38 became available in excellent
yield and purity by this modification (86%, >8.3 g scale),
which was subjected to allylic oxidation with MnO2. To this
end, it was beneficial to use a large excess of the oxidant, as
shorter reaction times generally furnished purer product.[45]
The resulting aldehyde 39 then underwent a productive
Brown allylation under salt-free conditions[46] to give alcohol
40 in essentially quantitative yield and excellent optical
purity (95% ee, HPLC), which was methylated on exposure
to Meerwein salt in the presence of proton sponge as the
optimal base. Overall, this four-step sequence secured gener-
ous amounts of compound 41 as a surrogate of building
block D (71% overall, >6 g single largest batch).
A significant improvement in the preparation of the
second northern subunit E hinged upon the proper choice of
a single protecting group. Our original approach (Scheme 8)
had started with the PMB-protected Roche ester derivative
42, which did not provide access to the required intermedi-
ate 46 by reduction/Wittig olefination because of serious
racemization of the chiral center under the chosen condi-
tions (<55% ee of 46).[10] Therefore we had to run a
Horner–Emmons olefination of the derived aldehyde 43
with phosphonate 44 at low temperature, which delivered
the enoate 45 in acceptable optical purity (ꢁ92% ee), albeit
as the unwanted Z isomer. This outcome could be corrected
by treatment of 45 with PhSSPh and AIBN, but the long re-
action time (96 h) and necessary high loading of the radical
initiator were far from optimal.[10]
cocktail of catalytic [PdACHTNUGTRNEGNU(PPh3)4], copper thiophenecarboxy-
late (CuTC), and Ph2PO2NBu4 in DMF ensures particularly
mild and essentially neutral conditions, and is therefore well
suited for delicate bond-forming reactions as is the case with
the heat- and base-sensitive polyene 36.[40,41] The fluoride-
free and essentially neutral conditions ensure compatibility
of this method with the primary -OTBS ether and preclude
epimerization of the racemization-prone N-formyl serine
residue.
Scheme 6. a) [Pd
ACHTUNGTRENNUNG(PPh3)4] (4 mol%), [Ph2PO2]ACHUTNGTREN[NGUN NBu4], CuTC, DMF, 87%;
CuTC=copper thiophene-2-carboxylate.
Evolution of a practical synthesis of the acid perimeter: Al-
though the large-scale synthesis of segment D followed our
previous route, the procedures were partly modified to
enable high material throughput (Scheme 7). Most notably,
the first step of the sequence became more reliable upon re-
placement of the “higher-order” stannyl cuprate generated
from [Bu3Sn(Bu)Cu]Li and LiCN, which had been recom-
mended in the literature and was therefore used in our orig-
inal approach,[44] by the “lower-order” stannyl cuprate de-
Scheme 8. Original approach toward segment E: a) Dibal-H, CH2Cl2,
ꢀ788C; b) 44, LiHMDS, THF, ꢀ788C ! ꢀ408C; c) PhSSPh, AIBN,
THF, reflux, 77% (over three steps, E/Z = 20:1), cf. ref. [10].
Following a lead from the work of Ley and co-workers,[47]
who did not report any problems with racemization when
working with the analogous Roche ester derivative 48 carry-
ing a bulky TBDPS-ether, the sequence of Dibal-H reduc-
tion followed by conventional Wittig olefination with freshly
Scheme 7. a) (Bu3Sn)2, BuLi, THF, CuCN, ꢀ788C
!
RT, then 37,
ꢀ788C, 86%; b) MnO2, CH2Cl2, 88%; c) (ꢀ)-Ipc2BCH2CH=CH2, Et2O,
ꢀ1008C, 99%, 95% ee; d) [Me3O]+ [BF4]ꢀ, proton sponge, CH2Cl2, 08C
! RT, 95%. Ipc=isopinocampheyl.
prepared
Ph3P=C(Me)COOEt
was
reinvestigated
(Scheme 9). We were pleased to note that this simple
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Gram-Scale Synthesis of Iejimalide B
FULL PAPER
moto olefination. Despite the excellent track record of this
transformation,[51] partial isomerization of the double bond
could not be suppressed when the reaction was performed
under the standard conditions. However, this problem was
circumvented by a modification which we believe might be
beneficial in other challenging cases too. Whereas Takai–
Utimoto olefinations are usually carried out under “Barbier-
type” conditions by mixing the aldehyde, CHI3 and the ap-
propriate amount of CrCl2 in an ethereal solvent,[54] we
found it possible and advantageous to form the intermediate
chromium carbenoid reagent prior to the addition of the
carbonyl partner.[55] To this end, CHI3 and CrCl2 were
stirred in THF/1,4-dioxane (1:6) at ambient temperature
before a solution of isomerically pure aldehyde 51 in diox-
ane was introduced. Under these conditions, the olefination
proceeded very fast and cleanly, delivering the desired al-
kenyl iodide 53 with excellent E selectivity (E/Z >20:1);
only traces of isomeric compounds were detected in the
crude mixture, and 53 was isolated in pure form in an appre-
ciable 59% yield over two steps (Scheme 9). In practical
terms, the preparation of the chromium carbenoid derived
from CHI3 and the TEMPO oxidation of alcohol 51 were
best performed in parallel; since the oxidation (15 min) as
well as the olefination step (30 min) both proceed rapidly,
significant amounts of material can be quickly brought
through, even though the largest batch of 53 produced in
this way was restricted to one gram of product. As expected,
the reaction of this iodide with stannane 41, using again the
three-component cocktail (Pd0, CuTC, Ph2PO2NBu4) previ-
ously described by our group,[40,41] proceeded smoothly, as
did the final saponification of the ethyl ester in 55 under
standard conditions. Overall, the modifications outlined
above secured an excellent supply of the acid perimeter 56
as required for the gram scale total synthesis of iejimalide B.
Scheme 9. a) TBDPSCl, imidazole, DMAP cat., CH2Cl2, 90%, cf. ref.
[48]; b) (i) Dibal-H, hexane, ꢀ788C; (ii) Ph3P=C(Me)COOEt, CH2Cl2,
82%; c) TBAF, THF, 08C ! RT, 86%; d) TEMPO (1 mol%), KBr,
NaOCl, CH2Cl2, aq. phosphate buffer (pH 7.4); e) CrCl2ACHTUNGTRENNNUG
(THF)1.8, THF/
(PPh3)4]
[NBu4], CuTC, DMF, 84%; g) aq. LiOH, MeOH,
THF, 80%. TBDPS=tert-butyldiphenylsilyl.
1,4-dioxane, CHI3, then 51, 59% (over both steps); f) 41, [Pd
(4 mol%), [Ph2PO2]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
change furnished product 50 with >99% ee after cleavage
of the silyl group.
With multigram amounts of optically pure alcohol 50 in
hand, we were in the position to study the crucial oxidation
to aldehyde 51 in greater depth, which was arguably one of
the most delicate operations in the original synthesis.[10] As
expected, 51 is exceptionally sensitive since the double bond
can migrate from conjugation to the ester into conjugation
to the aldehyde (in 52). This bias was previously experi-
enced when 51 was prepared with Dess–Martin periodi-
nane[49] with or without addition of various amounts of bases
to neutralize possible traces of acid in the medium. As the
crude aldehyde was immediately subjected to a subsequent
Takai–Utimoto olefination,[50,51] the required alkenyl iodide
53 was invariably obtained as a mixture with the undesired
diene 54, which could not be separated by flash chromatog-
raphy at this stage.[52] Only after the subsequent Stille reac-
tion with alkenyl stannane 41 and saponification of the ester
groups in the resulting products were we able to obtain acid
56 in acceptable purity, which represents the northern sector
of iejimalide B.[10]
Completion of the total synthesis: Our previous experi-
ences[11a] together with complementary results from the liter-
ature[15] taught us that the seemingly routine esterification of
the acid fragment 56 with the allylic alcohol 36 is far from
trivial. The labile nature of both reaction partners, the steric
hindrance of the alcohol group, and the peculiarities of a
skipped a,b,d,e-unsaturated acid component collectively ac-
count for the difficulties previously encountered. Not sur-
prisingly therefore, this step required serious study during
the up-scaling campaign.
After extensive screening and careful optimization, it was
found that ester 57 was formed in well reproducible 82%
yield with EDC·HCl as the activating agent, provided that
the following conditions were scrupulously met
(Scheme 10): acid 56, the activating agent and catalytic
amounts of 4-pyrrolidinylpyridine were stirred in CH2Cl2
until TLC showed complete conversion of 56 to a less polar
product representing the activated adduct.[56,57] Only then, a
solution of alcohol 36 in the minimum amount of CH2Cl2
was introduced[57] before most of the solvent was removed
by a stream of argon and stirring of the essentially neat, vis-
cous mixture was continued overnight. This protocol was
After considerable experimentation it was found that the
use of catalytic TEMPO in combination with NaOCl in buf-
fered medium (pH 7.4)[53] allowed aldehyde 51 to be pre-
pared in isomerically pure form. The reaction was repeated
several times and found well reproducible on different
scales. This aldehyde, however, must be processed without
delay to the corresponding alkenyl iodide 53 by a Takai–Uti-
Chem. Eur. J. 2011, 17, 6964 – 6972
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6969

A. Fꢀrstner et al.
The final cleavage of the TBS group on the serine residue
in 59 was essentially quantitative with TBAF in THF at 08C.
Utilizing this route, we were able to prepare slightly more
than one gram of iejimalide B (2). Suffice it to say that the
analytical and spectral data of this material matched those
of the samples previously prepared in this laboratory[10] as
well as those reported in the literature for the natural prod-
uct in all regards.[1,2]
Conclusion
The gram-scale total synthesis of the marine natural product
iejimalide B was accomplished in no more than 16 steps in
the longest linear sequence (7% overall yield, 41 steps
total). This closes the supply problem which had precluded
a serious (pre)clinical evaluation of this promising anticanc-
er agent for more than two decades. Moreover, this endeav-
or laid the ground for an extensive synthesis-driven mapping
of the pharmacophore of this macrolide, which led to a rep-
resentative collection of fully synthetic analogues of the nat-
ural lead.[13] Importantly, several of these “iejimalide-like”
compounds are similarly potent but significantly more selec-
tive toward a panel of human tumor cell lines. Details of
this work in the realm of “diverted total synthesis”[64,65] are
outlined in the accompanying paper.[13]
Scheme 10. a) EDC·HCl, 4-pyrrolidinylpyridine (12 mol%), CH2Cl2, 08C,
then 36, 82%; b) 58 (10 mol%), toluene, 508C, 72%; c) TBAF, THF,
08C, 99%.
found reliable, providing good amounts of the metathesis
precursor 57 (1.17 g, single largest batch).
Experimental Section
The entire Experimental Section, including compound characterization
data, can be found in the Supporting Information.
In contrast to performing the ring-closing metathesis of
polyene 57 in CH2Cl2 at ambient temperature as described
in our first total synthesis,[10,11b] it was found beneficial to
run the reaction in toluene[58] at 508C under a constant
stream of argon; a concentration of 10ꢀ3 m was found opti-
mal. This set-up allowed the catalyst loading to be reduced
from 20 mol% (in two portions) to 10 mol% (lower
amounts of 58[59,60] gave similar results, but incomplete con-
version was noticed in a few runs). After quenching of the
catalyst with ethyl vinyl ether and evaporation of the sol-
vent, the crude metathesis product was purified by flash
chromatography on silica; the addition of 1 mol% of Et3N
to the hexane/EtOAc eluent rendered the isolation much
easier and gave analytically pure macrocycle 59 in yields
that consistently exceeded 70% as a single isomer (only
traces of the corresponding Z isomer were detected in the
crude product). Even though the largest batches used no
more than 300 mg of the metathesis precursor 57, we have
no reason to believe that the reaction would not work simi-
larly well with larger amounts of material. Even though the
power of RCM nowadays needs no further demonstration
and has become common knowledge,[16] we do consider the
closure of the 24-membered polyene 59 by selective activa-
tion of two out of ten double bonds as a triumph of the
ruthenium carbene complexes developed by Grubbs[61] and
as a highlight of our own work in the area of metathesis-
based macrocyclization reactions.[62,63]
Acknowledgements
Generous financial support by the MPG, the Chemical Genomics Center
(CGC Initiative of the MPG), the Fonds der Chemischen Industrie, the
Alexander von Humboldt Foundation and the Association pour la Re-
cherche sur le Cancer (fellowships to E.M.) is gratefully acknowledged.
We sincerely thank the NMR, MS and chromatography departments of
our Institute for their excellent support during the entire iejimalide proj-
ect.
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Gram-Scale Synthesis of Iejimalide B
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Received: January 18, 2011
Published online: May 9, 2011
6972
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