Catalysis-Based Total Syntheses of Pateamine A and DMDA-Pat A

Article abstract of DOI:10.1021/jacs.8b05094

The marine natural product pateamine A (1) and its somewhat simplified designer analogue DMDA-Pat A (2) (DMDA = desmethyl-desamino) are potently cytotoxic compounds; most notably, 2 had previously been found to exhibit a promising differential in vivo activity in xenograft melanoma models, even though the ubiquitous eukaryotic initiation factor 4A (eIF4A) constitutes its primary biological target. In addition, 1 had also been identified as a possible lead in the quest for medication against cachexia, an often lethal muscle wasting syndrome affecting many immunocompromised or cancer patients. The short supply of these macrodiolides, however, rendered a more detailed biological assessment difficult. Therefore, a new synthetic approach to 1 and 2 has been devised, which centers on an unorthodox strategy for the formation of the highly isomerization-prone but essential Z,E-configured dienoate substructure embedded into the macrocyclic core. This motif was encoded in the form of a 2-pyrone ring and unveiled only immediately before macrocyclization by an unconventional iron-catalyzed ring opening/cross-coupling reaction, in which the enol ester entity of the pyrone gains the role of a leaving group. Since the required precursor was readily available by gold catalysis, this strategy rendered the overall sequence short, robust, and scalable. A surprisingly easy protecting group management together with a much improved end game for the formation of the trienyl side chain via a modern Stille coupling protocol also helped to make the chosen route practical. Change of a single building block allowed the synthesis to be redirected from the natural lead compound 1 toward its almost equipotent analogue 2. Isolation and reactivity profiling of pyrone tricarbonyliron complexes provide mechanistic information as well as insights into the likely origins of the observed chemoselectivity.

Full text of DOI:10.1021/jacs.8b05094

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Article
Catalysis-Based Total Syntheses of Pateamine A and DMDA-Pat A
Chun-Xiang Zhuo, and Alois Fürstner
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05094 • Publication Date (Web): 28 Jul 2018
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Journal of the American Chemical Society
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Catalysis-Based Total Syntheses of Pateamine A and DMDA-Pat A
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Chun-Xiang Zhuo and Alois Fürstner*
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Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany.
ABSTRACT: The marine natural product pateamine A (1) and its somewhat simplified designer analogue DMDA-Pat A (2)
are potently cytotoxic compounds; most notably, 2 had previously been found to exhibit a promising differential in vivo
activity in xenograft melanoma models, even though the ubiquitous eukaryotic initiation factor 4A (eIF4A) constitutes its
primary biological target. In addition, 1 had also been identified as a possible lead in the quest for medication against
cachexia, an often lethal muscle wasting syndrome affecting many immunocompromised or cancer patients. The short
supply of these macrodiolides, however, rendered a more detailed biological assessment difficult. Therefore a new syn-
thetic approach to 1 and 2 has been devised, which centers on an unorthodox strategy for the formation of the highly
isomerization-prone but essential Z,E-configured dienoate substructure embedded into the macrocyclic core. This motif
was encoded in the form of a 2-pyrone ring and unveiled only immediately before macrocyclization by an unconventional
iron catalyzed ring opening/cross coupling reaction, in which the enolester entity of the pyrone gains the role of a leaving
group. Since the required precursor was readily available by gold catalysis, this strategy rendered the overall sequence
short, robust and scalable. A surprisingly easy protecting group management together with a much improved end game
for the formation of the trienyl side chain via a modern Stille coupling protocol also helped to make the chosen route
practical. Change of a single building block allowed the synthesis to be redirected from the natural lead compound 1 to-
ward its almost equipotent analogue 2. Isolation and reactivity profiling of pyrone tricarbonyliron complexes provide
mechanistic information as well as insights into the likely origins of the observed chemoselectivity.
INTRODUCTION
Scheme 1. Iron Catalyzed Pyrone Ring Opening/Cross
Coupling
The many virtues of iron catalysis are increasingly recog-
-4
nized during the last two decades.1 In addition to being
cheap and abundant, benign and largely non-toxic, this
earth-abundant transition metal in the midst of the d-
block elements provides ample opportunity for chemical
discovery. Cross coupling chemistry is deemed repre-
sentative, in that iron catalysts cannot only replace the
still dominant palladium (or nickel) catalysts in many
cases;5-7 rather, they allow substrates to be encompassed
which are largely beyond the classical canon. From the
many recent examples that could be cited in this context,
we refer specifically to 2-pyrones (A). These compounds
undergo formal ring-opening/cross coupling when treat-
ed with a Grignard reagent in the presence of catalytic
amounts of Fe(acac)3 (Scheme 1).8 Since the reaction at
the enol ester subunit proceeds under exceedingly mild
conditions, it outperforms the uncatalyzed attack of
RMgX onto the lactone carbonyl, which readily occurs
otherwise.9 The leaving group, which is integral part of
the heterocyclic ring, is retained in the resulting dienyl
carboxylate product D, and the stereochemistry of the
cyclic substrate is faithfully preserved (unless it gets
scrambled by secondary processes). Therefore the iron
catalyzed ring opening/cross coupling allows pyrones to
be used as robust surrogates for non-thermodynamic 1,3-
diene motifs, which can be difficult to make otherwise.10
The mechanism of this transformation, which has hardly
any precedent in the literature,11,12 awaits experimental
scrutiny. The reaction might commence with π-complex
formation (B)13 with the (loaded) iron catalyst followed by
a formal 1,6-addition reaction (Scheme 1).14 The resulting
enolate C presumably undergoes an electrocyclic ring
opening, although the reasons for the high torquoselec-
tivity as necessary for the exclusive formation of dienoate
D are not intuitive. Alternatively, a C-metalated interme-
diate such as C’ has to be considered, in which a direct
interaction between the metal fragment and the bond to
be broken might be operative.8
Many methods allow the required pyrone substrates to be
made.15 In this context, our group has developed a gold
catalyzed 6-endo-dig cyclization of readily available yno-
ate derivatives, which proved efficient and highly func-
tional group tolerant.16,17 This method has already stood
the test of total synthesis of targets as exigent as neury-
menolide A and the C-glycosidic polyene epipyrone A.18,19
At a next stage of development, this gold catalyzed heter-
ocycle synthesis might be interfaced with the iron cata-
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lyzed ring opening/cross coupling reaction: the pyrone
of chiral auxiliaries.21,22,29 Though elegant and inspiring in
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ring would thus gain the role of a fairly stable and hence
practical relay unit that can be unfolded under mild con-
ditions. Advantage could be taken from this strategy in a
total synthesis of pateamine A (1).20 This remarkable
compound derived from a New Zealand sponge of the
Mycale genus had been regarded as an immunosuppres-
sive agent21,22 until it was recognized as a potent and selec-
tive inhibitor of the eukaryotic initiation factor 4A
(eIF4A).23-26 This ubiquitous enzyme shows RNA helicase
as well as ATPase activity; it is vitally important for con-
trolling the translation step of protein biosynthesis by
recruiting mRNA to the ribosome.27
design, the attained overall yields of 1 on the order of
≤0.09% and ≤0.19%, respectively, are too low to be of
practical relevance. We felt encouraged to search for a
more efficient and potentially scalable gateway to this
compelling target and its sister compound 2; in contrast
to the prior art, one can rightfully expect that such a new
route be entirely predicated on asymmetric catalysis for
the formation of all chiral centers. Formation of the sensi-
tive dienoate motif common to both targets by a se-
quence of gold-catalyzed pyrone cyclization followed by
iron catalyzed pyrone opening/cross coupling was meant
to play a similarly strategic role: since the configurational
integrity of the dienoate is innately linked to the biologi-
cal activity,35 the present case represents a stringent and,
at the same time, relevant test. Outlined below is a full
account on how this plan has been reduced to practice.36
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RESULTS AND DISCUSSON
Many detailed biochemical and biological investigations
have followed up on this important discovery;28 suffice it
to say that 1 and its rationally designed analogue DMDA-
Pat A (2)22,29 both show impressive in vitro cytotoxicity
against numerous human cancer cell lines, with IC50 val-
ues mostly in the single-digit nanomolar range.30 Since 2
is also active against a paclitaxel-resistant uterine sar-
coma, these compounds seem to be poor substrates for P-
glycoprotein mediated drug efflux.29 The fact that 1 and 2
are similarly potent is also noteworthy: this observation
suggests that the “western” C1-C5 region basically enter-
tains scaffolding duties but is not critically involved in
protein binding as clear-sightedly proposed by Romo and
coworkers.22,29,31 In any case, 2 proved efficacious in vivo
against melanoma xenograft models (LOX, MDA-MB-
435), leading to significant regression in tumor size and
weight.30 Since no significant effect on colon cancer and
pancreatic mouse tumor models was noticed, the com-
pound seems to exhibit desirable tumor selectivity. This
encouraging prospect certainly deserves further investiga-
tion; whether it is related to the fact that several melano-
ma types overexpress eIF4A remains to be established.24b
Finally, yet another biological attribute deserves mention-
ing: low doses of 1 were shown to block the onset of ca-
chexia in an ardenocarcinoma mouse model.32 This multi-
factorial muscle-wasting syndrome affects many immun-
ocompromised or cancer patients and can actually be
lethal; no effective treatment for cachexia is currently
available.
Strategic Considerations. For the sake of maximum
flexibility and convergence, pateamine A (1) was discon-
nected as shown in Scheme 2. This plan ensures that the
synthesis can also be redirected toward DMDA-Pat A (2)
by changing a single building block. As mentioned above,
the isomerization-prone Z,E-dienoate is encoded in the
form of a 2-pyrone to be unveiled only immediately prior
to macrocyclization. This tactic of “internal protection”
should render the sequence robust and scalable; on the
longer run, the ability to introduce substituents other
than a methyl group at C22 via the iron catalyzed process
might pay further dividends in a diverted total synthesis
program.37,38
Scheme 2. Retrosynthetic Analysis of 1 and 2 Cen-
tered on the Strategic Use of a Pyrone Building Block
This brief sketch illustrates that pateamine A (1) and
DMDA-Pat A (2) are relevant and promising lead com-
pounds, the evaluation of which had been held up by
short supply; even aquaculture of the producing sponge
had been considered in the past to meet the demand.33
1
had also been subject to two total syntheses: while the
approach described by the Pattenden group,34 in its es-
sence, resorted to the “chiral pool”, the total synthesis
reported by the Romo group was largely based on the use
To this end, however, the iron catalyzed ring open-
ing/cross coupling step must proceed in the presence of
the different heteroatoms donor sites in a substrate of
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Journal of the American Chemical Society
throughput, not least because an inefficient transfor-
type F. While this critical aspect was certainly not clear at
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the outset of the project, previous experiences with more
conventional iron catalyzed C-C-coupling reactions had
shown that various heterocyclic scaffolds are well tolerat-
ed.5-7,39,40 Therefore we were confident that the thiazole
ring would not interfere with this key step. Less obvious
though was the compatibility with the (protected) amine
at C3: (i) this group is inherently elimination-prone;41 (ii)
if it does persist, it could serve together with the ester
carbonyl as a chelating ligand able to sequester the iron
catalyst; (iii) whenever a proton is left on nitrogen (X =
NHR), it will react with the Grignard reagent; such salt
formation could impact on rate and selectivity.
mation is particularly grave late in a multistep sequence.
However, we were optimistic that the improved Stille
protocol previously developed by our group might reme-
dy the problem,43 as this procedure had excelled in a
number of exigent cases in this and other laboratories.44,45
Catalytic Asymmetric Synthesis of the Thiazole
Fragment. In contrast to the reported total syntheses of
1, which had both formed the substituted thiazole ring by
a modified Hantsch condensation reaction,21,34 we chose
dibromothiazole 3 as the starting material (Scheme 4).
Two different routes were explored for its conversion into
alkene 7: actually, simple treatment with allylmagnesium
bromide at low temperature sufficed to form this product,
presumably via a formal ene-type reaction within the
coordination sphere of a magnesium adduct of type 4;
elimination of MgBr2 renders the transformation irre-
versible.46,47 Even better results were obtained upon expo-
sure of 3 to Zn/LiCl;48 regioselective insertion gave the
corresponding organozinc species 6, which was trapped
with allyl bromide in the presence of catalytic CuCN to
give product 7 in 89% yield on a multigram scale.
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Scheme 3. Prior Art:21,34 Elaboration of the Side Chain
Scheme 4.a
These issues are all the more relevant since the previous
total syntheses of 1 had shown that the choice of appro-
priate amine protecting groups is very limited. Romo and
coworkers had been unable to cleave an -NHBoc group off
this site without destroying their advanced material
(Scheme 3).21 As a consequence, they had to resort to a
protecting group exchange prior to elaboration of the
triene side chain; a 1,1-dimethyl-2,2,2-trichloroethoxy-
carbonyl (TCBoc) group ultimately proved viable;21 the
Pattenden group followed this choice.34 In the projected
case, however, the presence of a polyhalogenated site in
the molecule is almost certainly problematic, since alkyl
halides in general are substrates amenable to iron cata-
lyzed C-C-coupling reactions.1-7 Although the TCBoc
group could not be discounted at the outset of our project
given the literature precedent in the pateamine field,21,34
we certainly had to be prepared to find an alternative
solution.
a
Reagents and conditions: (a) Allylmagnesium bromide, Et2O,
−30°C, 50-68%; (b) Zn, LiCl, THF; (c) allyl bromide, CuCN (5
mol%), THF, 0°C, 89%; (d) (i) B2(pin)2, Pt(dba)3 (2.4 mol%), 8
(2.8 mol%), THF, 60°C; (ii) aq. H2O2, NaOH, 91% (91% ee); (e)
TBDPSCl, DMAP, Et3N, CH2Cl2, 0°C → RT, quant.; (f) 4-
MeOC6H4CH(OMe)2, CSA (20 mol%), CH2Cl2, MS 5Å, reflux,
quant.; (g) Dibal-H, CH2Cl2, −78°C, 86%; (h) TBDPSCl, DMAP (12
mol%), imidazole, CH2Cl2, quant.
7 was then subjected to asymmetric diboration of the
terminal alkene catalyzed by a complex formed in situ
from Pt(dba)3 and the TADDOL-derived phosphonite
ligand 8; the primary product 9 was oxidized with H2O2
under standard conditions.49 This two-step/one-pot pro-
cedure proved reliable, scalable and convenient, deliver-
ing diol 10 in 91% yield with 91% ee on a >1.5 g scale (sin-
gle largest batch); the optical purity could be raised to
97% by recrystallization. This result is remarkable as it
shows the compatibility of the catalyst with the donor
The elaboration of the triene sidechain with its tertiary
amine terminus represented yet another aspect to be
carefully considered. Either of the reported total synthe-
ses relied on Stille cross coupling:42 even though carried
out at different sites (c12 versus C14), the yields were in-
variably low (27% and 36%);21,22,34 attempted coupling
with a substrate bearing an already unprotected –NH2 at
C3 had even failed completely (Scheme 3).21 In strategic
terms, these issues are serious handicaps for material
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sites of this heterocyclic substrate; moreover, it compares transfer hydrogenation catalyzed by NiBr2(dme)/(R,R)-
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8
favorably to attempted asymmetric dihydroxylation of 7,
which furnished 10 with <65% ee even though several
chiral ligands were tested (see the Supporting Infor-
mation).50
Me-DUPHOS, even though this method also gave re-
spectable results (97%, dr = 6.5/1).54 Because the nickel
catalyzed reduction also proceeded much more slowly,
the choice between these two alternatives was ultimately
easy.
Scheme 5.a
Scheme 6.a
15
Ar Ar
18
H2N
b)
9
a)
Ar = 3,5-Me2C6H3-
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S
S
OPMB
OPMB
OTBDPS
N
N
OTBDPS
X*
22
H
N
N
Ar
Ar
19
c)
Ph
OBoc
23
S
OPMB
S
N
OTBDPS
OPMB
OTBDPS
a
X*
Reagents and conditions: (a) 16, Pd(OAc)2 (3 mol%), 1,1’-bis(di-
N
H
tert-butylphosphinoferrocene (3.6 mol%), K3PO4, toluene/H2O,
90°C, 88%; (b) PhSiH3, Cu(OAc)2⋅H2O (5 mol%), 17 (5 mol%),
tBuOH, toluene, 0°C, 93% (dr > 25/1); (c) Dibal-H, CH2Cl2,
−78°C, 97%
N
20
24 R,R = 9-fluorendiyl
25 R,R = H, Boc
Ar
R2N
d,e)
Ar
f,g)
Ph
S
S
OPMB
OPMB
Diol 10 was elaborated into two different building blocks
as deemed suitable for the projected total syntheses of 1
and 2. Specifically, mono-silylation of the primary alcohol
was uneventful to give compound 11. Since the compati-
bility of the free –OH group in 11 with the downstream
chemistry could not be taken for granted, we also pre-
pared the differentially protected fragment 12. To this
end, advantage was taken from the ability of the thiazole
N-atom to coordinate onto a Lewis-acidic organometallic
reagent, which had already surfaced in the allylation of
dibromothiazole 3 with allylmagnesium bromide de-
scribed above. In the present context, this affinity was
used to control the regioselective opening of the p-
methoxybenzylidene acetal to give the terminal PMB-
ether via an adduct of type L; the opposite regiochemical
outcome were expected for a non-directed acetal-opening
with Dibal-H.51 Subsequent silylation furnished product 12
in readiness for the attachment of the side chain branch-
ing off C-6 (pateamine numbering).
N
OTBDPS
N
OTBDPS
H2N
BocHN
HOOC
21
26
Ar
Ar
N
H
R
OAr
Ar
Ar
O
O
B
N
P
Ph
O
O
O
B
O
Ph
O
B
OAr
M Ar = 2,4,6-trimethylphenyl
27 Ar = 2-MeOC6H4-
DBU
[Ir*] cat
H
H
22
N
23
N
R
R
N
Ph
Ph
R
N
O
24
a
Reagents and conditions: (a) (i) 18, (R)-VANOL (10 mol%),
We considered various options that might lend them-
selves to a catalytic asymmetric formation of the chiral
centers at C3 and C5 carrying the labile amine group and
the methyl branch, respectively (see the Supporting In-
formation). In the end, the route shown in Scheme 5
proved most adequate: bromide 12 was first subjected to
Suzuki coupling with alkenylboronate 16, which in turn is
readily prepared by a copper catalyzed regio- and stere-
oselective borylation of ethyl but-2-ynoate.52 The resulting
trisubstituted enoate 13 was amenable to a highly produc-
tive and selective asymmetric 1,4-reduction with PhSiH3
as the hydride source in the presence of Cu(OAc)2⋅H2O as
precatalyst and (S,R)-Josiphos 17 as the ligand.53 With a dr
>25/1 and 93% yield of 14 on a 1.15 g scale (single largest
batch), this procedure outperformed an asymmetric
BH3⋅SMe2 (30 mol%), benzoic acid (10 mol%), 2,4,6-
trimethylphenol (20 mol%), m-xylene, 60°C; (ii) aq. HCl, THF,
0°C → RT, 88% (dr ≈ 4:1); (b) 9H-fluoren-9-amine, MS 4Å,
CH2Cl2; (c) (i) [Ir(cod)Cl]2 (3 mol%), 27 (6 mol%), nPrNH2, THF,
50°C; (ii) 23, DBU, THF, 0°C → 50°C; (d) H2NOH⋅HCl, CH2Cl2;
(e) (Boc)2O, Et3N, CH2Cl2, 88% (over four steps, dr > 25/1); (f)
OsO4 (5 mol%), NaIO4, 2,6-lutidine, 1,4-dioxane/H2O, 89%; (g)
NaClO2, NaH2PO4, 2-methyl-2-butene, THF/tBuOH/H2O, 0°C
Although an asymmetric Mannich-type reaction seemed
to be the obvious way to attach the yet missing β-
aminoester group, an indirect solution ultimately proved
advantageous (Scheme 6). Good results were obtained by
a catalytic aza-Cope rearrangement, in which aldehyde 15
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mol%), MeMgBr, −30°C).8 We tentatively explain the
derived from 14 was reacted with allylamine 18 in the
1
2
3
4
5
6
7
8
presence of a catalyst formed in situ from (R)-VANOL,
BH3⋅SMe2 and 2,4,6-trimethylphenol via a supposed array
of type M to give amine 21 (88%, dr ≈ 4:1).55,56 Yet, an
“Umpolung”-type asymmetric allylation/aza-Cope se-
quence eventually turned out to provide a superior solu-
tion:57 to this end, aldehyde 15 was first converted into
imine 22. By virtue of the C-H acidity of the fluorenyl
unit, the derived anion N can be engaged as the nucleo-
philic partner into an iridium catalyzed allylation with
allylcarbonate 23 that is rendered asymmetric by the
phosphoramidite ligand 27. The resulting intermediate O
spontaneously undergoes an aza-Cope rearrangement
under the chosen conditions (THF, 50°C) to furnish 24 in
the first place; imine hydrolysis followed by N-protection
of the resulting amine, as deemed appropriate, gave
25a,b. This sequence is distinguished by an outstanding
diastereoselectivity of >25/1 and an excellent 88% yield
over four steps. Although the single largest batch was
only 250 mg of product, we have no reason to believe that
the transformation would not work equally well on larger
scale.
difference between the model study and the pateamine
case by the proximity of the -NHBoc group. This ar-
rangement can entail chelatation of the incoming organ-
omagnesium (or iron) reagent, which in turn favors the
attack of the nucleophile onto the ester carbonyl.
Scheme 7.a
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This success, however, was the result of careful optimiza-
tion. Most notably, well reproducible results and good
reaction rates mandated the use of a pre-activated iridium
catalyst,58 while the literature procedure had relied on its
in situ preparation.57 Equally important was the removal
of all salts by subjecting 24 to flash chromatography over
alumina prior to cleavage of the imine; in our hands, this
seemingly simple step was best performed with hydroxyl-
amine as the reagent. Product 25 thus formed was elabo-
rated by consecutive cleavage of the double bond under
modified Lemieux-Johnson conditions59 followed by oxi-
dation of the resulting aldehyde to acid 26,60 which con-
stitutes the C1-C11 segment of pateamine A (1).
a
Reagents and conditions: (a) HC≡CLi⋅eda, DMSO, 0°C → RT;
(b) 29, Pd(PPh3)4 (5 mol%), CuI (5 mol%), Et3N, 30°C, 93%; (c)
[(XPhos)AuNTf2] (1 mol%), MeNO2/HOAc (4:1), 89%; (d) 26
(crude), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, DMAP,
CH2Cl2, 72% (over two steps, including acid formation); (e)
MeMgBr, Fe(acac)3 (30 mol%), Et2O/cyclopentyl methyl ether
(CPME), −60°C, 73% (97% brsm, dr ≥ 17/1); (f) TBAF, THF, 87%;
(g) 35, NaHCO3, CH2Cl2, 82%
Gratifyingly though, lowering the temperature to −60°C
increased the differential between this undesirable pro-
cess and the iron catalyzed pyrone ring opening. If seen in
context, it is remarkable that the cross coupling still pro-
ceeds under these cryogenic conditions, at which the
reaction mixture was a rather thick suspension. Yet, the
conversion gets slower and isomerization of the resulting
Z,E-configured product therefore has a higher chance.
This stereochemical ablation is ascribed to a (likely hal-
ide-based) Michael/retro-Michael manifold in the back-
ground.8 Therefore, it was best to stop the reaction prior
to complete conversion and to recover the remaining
starting material. This procedural adjustment allowed us
to obtain the targeted dienoic acid 33 in 73% yield (97%
brsm) with an isomer ratio of ≥17/1 under the conditions
specified in Scheme 7.63 This example showcases the ex-
cellent chemoselectivity as well as compatibility of the
iron catalyzed C-C-bond formation with various electro-
philic positions and different donor sites, which augurs
well for future applications.1-7
The Pyrone Segment and Formation of the Macrocy-
cle. Hydrolytic kinetic resolution (HKR) provides conven-
ient access to large quantities of (S)-propylene oxide,61
which was opened with the ethylene diamine complex of
lithium acetylide in DMSO to give product 28 in good
yield (Scheme 7). A subsequent Sonogashira reaction with
iodoacrylate 2962 furnished enyne 30 as the substrate for
the gold catalyzed cyclization. As expected, this transfor-
mation proceeded smoothly with [(Xphos)AuNTf2] as the
catalyst in MeNO2/HOAc;16,17 it is pointed out that the
choice of the tert-butyl ester is critical as it ensures for-
mation of a 2-pyrone rather than a 4-pyrone ring.
Esterification of pyrone 31 with acid 26 set the stage for
the envisaged iron catalyzed ring opening/cross cou-
pling.8 Initial experiments with the NH(TCBoc) protected
analogue of 32 quickly demonstrated that this N-
substituent was not viable. In contrast, the Boc-protected
compound 32 furnished the desired product 33, but the
yield was unacceptably low. Careful analysis of the crude
material showed that attack of the Grignard reagent onto
the β-amidoester ester group was a major side reaction.
This result came as a surprise since earlier work had
demonstrated that even unhindered methyl esters pass
uncompromised under standard conditions (Fe(acac)3 (5
Because of its sensitivity, compound 33 was elaborated
without delay. Cleavage of the silyl ether furnished seco-
acid 34 which underwent macrolactonization under
modified Mukaiyama conditions64,65 to give the desired
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19-membered ring 36 in 82% yield. The use of 35 escorted Attempted cleavage of the Boc group with trifluoroacetic
1
2
3
4
5
6
7
8
by a non-nucleophilic counterion was critical for success,
whereas more conventional methods for macrocyclization
entailed massive double bond isomerization.66
acid in CH2Cl2 at 0°C or with TMSOTf/2,6-lutidine in
CH2Cl2 at −78°C indeed met with decomposition of this
valuable compound. We were pleased to learn, however,
that the use of HCl in EtOAc/dioxane as solvent afforded
the desired ammonium salt 38, which was directly en-
gaged in a Stille coupling with the amine-bearing stan-
nane 4034 according to the modified procedure previously
developed in this laboratory43 to give pateamine A (1)
upon passing the crude product through a commercial
amine-functionalized chromatography cartridge. While
this result showed that the improved conditions allow for
the use of an amine-bearing substrate in cross coupling,
the yield of ≤ 40% (NMR) over the two steps was deemed
unsatisfactory; moreover, product isolation was rather
tedious in this case.
Elaboraton of the Trienyl Sidechain and Completion
of the Total Synthesis. The need for an -NHBoc (rather
than –NH(TCBoc)) protected substrate in the iron cata-
lyzed pyrone ring opening/cross coupling raised the issue
of how and when to unveil the primary amino group in
the final target without destroying the sensitive polyun-
saturated material. A late stage protecting group inter-
change in accordance with the literature precedent was
the safe but second-best choice.21 Rather, we decided to
scout more direct solutions despite the ostensibly hope-
less forecast: neither had an attempted -NHBoc cleavage
as the ultimate step of the synthesis worked in the past,
nor had it previously been possible to cross couple the
side chain to a macrocyclic partner carrying an unpro-
tected amine at C3 (compare Scheme 3).21 Either of these
scenarios, however, would streamline the end game and
hence economize valuable material.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Importantly, the reversed order of events ultimately
proved not only viable but significantly more productive.
The 84% yield obtained in the Stille reaction of 37 and 40
compares favorably with the 36% and 27% reported in the
literature for almost identical reaction partners.21,34 Most
notably, the final deprotection of the −NHBoc group in 39
− which had failed completely in the past21 − was found to
proceed in well-reproducible 78-81% yield with nothing
but HCl in dioxane/EtOAc; the use of this solvent combi-
nation is mandatory for reasons that are not entirely clear
at this point. This shortened and much improved end
game represents a considerable improvement in practical
terms; the attained overall yield of 5.3%, is more than an
order of magnitude higher than the yields reported in the
prior art (≤0.09% and ≤0.19%).21,34 The prominent role of
(asymmetric) catalysis in the current total synthesis of 1
constitutes an additional asset. The analytical and spec-
tral properties of our samples matched those of pateam-
ine A (1) reported in the literature.70
Scheme 8.a
DMDA-Pat A (2). Based on the insight that the C1-C5
segment of pateamine A (1) is probably structure-
determining but likely not involved in binding of the
compound to its protein target, Romo and coworkers
designed DMDA-Pat A (2) and found this simplified ana-
logue almost equipotent in biological terms.22,29 In pre-
parative regard, the formal excision of the two chiral cen-
ters renders the synthesis much easier, especially since
any maneuvering with the sensitive amino group at C5 is
avoided.
a
Reagents and conditions: (a) DDQ, CH2Cl2/buffer (pH 7), 0°C
→ RT, 96%; (b) SO3⋅pyridine, DMSO, iPr2NEt, CH2Cl2, −20°C; (c)
Ph3PC(Me)CHO, toluene, 80°C, 81% (over both steps); (d) CHI3,
CrCl2, THF, 0°C, 90% (E:Σ other isomers = 94/6); (e) HCl (4 M in
1,4-dioxane), aq. EtOAc, 0°C; (f) 40, Pd(PPh3)4 (30 mol%), CuTC,
[Ph2PO2][NBu4], DMF, ≤40% (NMR, over both steps); (g) 40,
Pd(PPh3)4 (10 mol%), CuTC, [Ph2PO2][NBu4], DMF, 84%; (h)
HCl (4 M in 1,4-dioxane), aq. EtOAc, −20°C → −10°C, 78-81%
This aspect is evident from the comparison of the reaction
metrics of our total synthesis of 1 outlined above with that
of our approach to 2, which has already previously been
communicated (Scheme 9).36 In short, it sufficed to esteri-
fy commercial 4-pentenoic acid with the pyrone fragment
31; hydroboration of the resulting product 41 with 9-H-9-
BBN followed by an alkyl-Suzuki coupling71 with the only
partly protected thiazole building block 11 furnished an
adequate substrate 42 for the envisaged iron-catalyzed
ring opening/cross coupling reaction. As it turned out
that this key transformation proceeded well as long as an
extra equivalent of MeMgBr was used to deprotonate the
free –OH group (see the Supporting Information), the
appropriate seco-acid 43 for macrolactonization was di-
In order to revisit these risky but attractive possibilities,
compound 36 was elaborated without touching the
−NHBoc substituent (Scheme 8). Specifically, oxidative
cleavage of the PMB-ether,67 formation of the correspond-
ing aldehyde and Wittig reaction with the stabilized ylide
proceeded uneventfully, as did the subsequent Takai
olefination,68,69 which gave alkenyl iodide 37 with high
selectivity in favor of the desired E-isomer.
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(Scheme 1):8 initial π-complex formation with the (load-
rectly formed with excellent stereoselectivity (> 18:1). This
reaction could be carried out at −30°C without noticeable
attack of the Grignard reagent onto the ester or the py-
rone carbonyl groups. When compared with the analo-
gous reaction en route to pateamine A (1) itself, which
had to be performed at −60°C (vide supra), it seems likely
that the protected amine at C3 in substrate 32 is culpable
for the enhanced sensitivity of the adjacent ester in the
latter case, presumably by functioning as a chelating sub-
stituent to the incoming organometallic reagent. Anyway,
compound 43 was engaged in the modified Mukaiyama
lactonization reaction to furnish the desired macrodiolide
44 in 64% yield over both steps.36
ed) iron catalyst might entail a formal 1,6-addition14 fol-
lowed by electrocyclic opening of the resulting enolate C
to give the observed dienoate D after work up (Scheme 1);
this latter step, however, mandates rigorous torquoselec-
tivity in order to explain the strict retention of configura-
tion at the former enol ester bond. Alternatively, one
might invoke an intermediate such as C’ that allows for
direct stereochemical communication between the break-
ing bond and the metal center.8 Yet it is idle to speculate
about the late stages as long as even the first steps along
the reaction pathway remain speculative.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The unambiguous clarification of these aspects is a non-
trivial task: short lifetimes of the active iron species,
thermal instability, paramagnetism and uncertainties as
to the spin states represent major analytical challenges on
top of the problems that the elucidation of a catalytic
mechanism poses anyway.1,72 Moreover, the speciation
generated on treatment of a bare iron salt with a Grignard
reagent is complex and case-dependent; even for reac-
tions with methyl donors, an assortment of mononuclear
and/or cluster iron−ate complexes needs to be consid-
ered.73,74 For these and other reasons it is beyond the
scope of the current investigation to draw a conclusive
answer as to the mechanism of pyrone ring opening/cross
coupling. Yet, it was possible to obtain experimental evi-
dence for π-complexation as the triggering event.
Scheme 9.a
Scheme 10. Control Experiments
a
Reagents and conditions: (a) 4-pentenoic acid, 2,4,6-
Cl3C6H2COCl, Et3N, then 31, DMAP, toluene, 0°C → RT, 97%; (b)
(i) 9-H-9-BBN, THF, 0°C → RT; (ii) 11, Pd(OAc)2 (5 mol%),
RuPhos (10 mol%), K3PO4, THF, 50°C, 82%; (c) MeMgBr,
Fe(acac)3 (30 mol%), Et2O/CPME, −30°C; (d) 35, NaHCO3,
CH2Cl2, 64% (brsm, over two steps); (e) TBAF, HOAc, THF,
quant.; (f) SO3⋅pyridine, DMSO, iPr2NEt, CH2Cl2, −20°C; (g)
Ph3PC(Me)CHO, toluene, 80°C, 86% (over two steps); (h) CHI3,
CrCl2, THF, 0°C, 91% (E:Σ other isomers = 94:6); (i) Pd(PPh3)4 (10
mol%), CuTC, [Ph2PO2][NBu4], DMF, 83%
The completion of the synthesis of DMDA-pateamine (2)
then followed the sequence that had led to the parent
natural product 1. Once again, the high efficiency of the
modified Stille coupling is noteworthy. With an overall
yield of >18% for the 12 steps of the longest linear se-
quence (19 steps in total), this approach is shorter and
notably more productive than the literature precedent
(<3.8%, 16 steps longest linear sequence, 36 steps in to-
tal).22,29 It is also significantly shorter and higher yielding
than our own route to the natural lead compound 1,
which demonstrates that the formal excision of the two
chiral centers in the scaffolding domain pays valuable
dividends in preparative terms.
To this end, we resorted to the preparation and study of
fairly stable tricarbonyliron complexes.13 The strong lig-
and field of CO renders such Fe(0) complexes diamagnet-
ic. To confirm their relevance, pyrone 46 was reacted with
MeMgBr in the presence of Fe2(CO)9 as catalyst (Scheme
10). While it is unsurprising that the tightly bound CO
ligands slow down the conversion, the outcome (60 min,
52%, Z/E = 7:1) is qualitatively comparable to the result
obtained under the optimized reaction conditions using
Fe(acac)3 (20 min, 96%, Z/E > 20:1).8 The isolated complex
48 can also be used as catalyst, whereas treatment with
stoichiometric MeMgBr caused decomposition. These
results need to be assessed in the light of previous re-
ports, according to which pyrone tricarbonyliron com-
plexes are attacked by various nucleophiles, including
alkyllithium reagents, at the lactone carbonyl rather than
at the enol ether site.75 Moreover, one has to keep in mind
π-Complexation Studies. As mentioned in the Introduc-
tion, the mechanism of the iron catalyzed pyrone ring
opening/cross coupling is currently unknown. It seems
reasonable – yet is unproven − that the diene subunit of
the pyrone nucleus A serves as key recognition element
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that the tricarbonyliron complex of 1,3-cyclohexadiene
ether) of this polyfunctionalized substrate. This profile is
does not to react with Grignard reagents.76
all the more striking if one considers the prominent role
that the thiazole N-atom had played in steering the allyla-
tion reaction and the later cleavage of the lateral acetal
ring (see Scheme 4). Hence, we conclude that the re-
markable chemoselectivity of the pyrone ring open-
ing/cross coupling, which had enabled the total syntheses
reported above, most likely originates from a pronounced
affinity of the iron catalyst for the heterocyclic π-system,
which outperforms the formation of conventional Lewis
acid/base adducts.
1
2
3
4
5
6
7
8
Scheme 11.a
S
OTBDPS
N
OH
b)
a)
42
43
(CO)3Fe
O
9
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
49a,b
(CO)3Fe
(CO)3Fe
c)
Ph
Ph
Ph
+
O
O
O
O
O
O
O
O
O
O
O
O
51b
50
51a
a
Reagents and Conditions: a) Fe2(CO)9, Bu2O/THF (5:1),
65°C, 13% (≥ 85% brsm); b) 49 (15 mol%), MeMgBr,
Et2O/toluene, −30°C, 55% (brsm); c) Fe2(CO)9, Bu2O/THF
(5:1), 65°C, 22%
Figure 2. Structure of complex 51a in the solid state
Attempted crystallization of 49 met with failure. There-
fore we prepared complexes 51a,b, which show the same
characteristic NMR features (see the Supporting Infor-
mation). The structure of one of the two diastereomers in
the solid state (Figure 2) confirms the η4-bonding interac-
tion and provides additional insights into the mode of
activation.77 Thus, electron back-donation from the metal
into the π*-orbitals entails partial rehybridization, which
imposes a twist-boat conformation onto the formerly flat
heterocyclic ring. As a result, the carboxylate leaving
group is forced out of co-planarity with the diene unit.
The concomitant loss of enol ester character is not only
manifest in the complexation shifts but also in massive
changes in the bond lengths: the C4-C5 double bond is
elongated to no less than 1.429(4) Å (the analogous bond
in a reference pyrone is 1.337(3) Å),78 whereas the C3-C4
bond (1.400(5) Å) is contracted and seems to anticipate
the bonding situation of a 1,6-adduct formed as a likely
next intermediate en route to ring opening.
7.0
6.5
6.0
5.5
5.0
(ppm)
4.5
4.0
3.5
3.0
1
Figure 1. Relevant part of the H NMR spectrum of 42
(top) and the derived adduct 49b (bottom), showing the
massive complexation shifts of the pyrone H-atoms, while
the shift of the thiazole H-atom does not change much.
Reaction of pyrone 42 as the key intermediate en route to
DMDA-Pat A (2) with Fe2(CO)9 was clean but met with
low conversion;77 the resulting two diastereomeric ad-
ducts 49a,b could be separated by HPLC (Scheme 11).
Complex 49b was shown to serve as catalyst for the ring
opening of 42 with MeMgBr to give product 43, although
the conversion was low because of poor solubility in
Et2O/toluene at −30°C. The spectral properties of 49 are
informative too: the pyrone ring is undoubtedly the site of
interaction as evident from complexation shifts (ꢀδ) of up
to −3.2 ppm (H1), −64.9 ppm (C1) and −58.3 ppm (C4)
(Figure 1; the entire data set is contained in the Support-
ing Information). In contrast, the shift of the thiazolyl
H4-atom (ꢀδ = −0.02 ppm) and the resonances assigned
to the oxygenated positions remain almost unchanged.
The iron fragment obviously selects for the π-bonds but
does not engage in adduct formation with the nitrogen,
sulfur and oxygen donor sites (carbonyl, alcohol, silyl
By no means do these model studies give a complete
mechanistic picture. The [Fe(CO)3] complexes discussed
above cannot be more but a dummy of the active inter-
mediates
of
the
catalytic
process
using
Fe(acac)3/MeMgBr; yet, they provide strong evidence for
ring opening/cross coupling being triggered by initial π-
complexation of the pyrone substrate. This molecular
recognition event also forms the basis for the remarkable
chemoselectivity of this transformation. As such, the data
outlined above are deemed a valid starting point for fur-
ther experimental and in silico studies into this unortho-
dox yet enabling transformation.
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1
Journal of the American Chemical Society
ACKNOWLEDGMENT
CONCLUSIONS
Generous financial support by the Alexander-von-Humboldt
2
Foundation (fellowship to C.-X. Z.) and the MPG is gratefully
acknowledged. We thank Dr. C.-L. Sun for exploratory stud-
ies, Dr. L. Huang for preparation of the iron carbonyl com-
plexes, Prof. C. W. Lehmann and Mr. J. Rust for solving the
X-ray structure, Prof. D. Niu, Sichuan University, for valuable
discussions, and the Analytical Departments of our Institute
for excellent support.
3
4
5
6
7
8
9
It may seem counterintuitive to encode the highly isom-
erization-prone Z,E-configured dienoate entity of the
marine macrodiolide pateamine A (1) in the form of a
robust heterocyclic ring. Yet recent advances in iron cata-
lyzed chemistry allowed us to pursue this unorthodox
strategy by which the arguably most sensitive unit of the
targe was unraveled at a late stage. The conditions are
unusually mild for a formal cross coupling event, such
that other electrophilic sites are not compromised even
though reactive organomagnesium species have to be
used as the nucleophlic partners; moreover, the compati-
bility of the iron catalyst with donor sites is noteworthy.
This excellent profile allowed the non-thermodynamic
dienoate substructure of 1 to be revealed with high selec-
tivity, which is known to be critically important for bio-
logical activity. As this transformation also installs the
methyl branch at C22, we parenthetically note that this
strategy provides an additional opportunity for late-stage
modification at a site which is difficult to address other-
wise, although this particular aspect has to await future
studies.
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11
12
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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ties and good material throughput were secured without
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ASSOCIATED CONTENT
Supporting Information. Experimental section including
characterization data and NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Chem. Eur. J. 2016, 22, 237-247.
AUTHOR INFORMATION
Corresponding Author
*fuerstner@kofo.mpg.de
ORCID
Alois Fürstner: 0000-0003-0098-3417
(17) Fürstner, A. Angew. Chem. Int. Ed. 2018, 57, 4215-4233.
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T.; Pototschnig, G.; Fürstner, A. Chem. Eur. J. 2015, 21, 4529-4533.
Notes
The authors declare no competing financial interests.
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ͦͤ
͸
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