Concise Total Synthesis of Enigmazole A

Article abstract of DOI:10.1002/anie.201510026

An efficient entry into the phosphorylated marine macrolide enigmazole A is described. Enigmazole A interferes with c-Kit signaling by an as yet unknown mode of action and is therefore a potential lead in the quest for novel anticancer agents. Key to succ

Full text of DOI:10.1002/anie.201510026

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International Edition: DOI: 10.1002/anie.201510026
German Edition: DOI: 10.1002/ange.201510026
Natural Products
Concise Total Synthesis of Enigmazole A
Andreas Ahlers, Teresa de Haro, Barbara Gabor, and Alois Fürstner*
Abstract: An efficient entry into the phosphorylated marine
macrolide enigmazole A is described. Enigmazole A interferes
with c-Kit signaling by an as yet unknown mode of action and
is therefore a potential lead in the quest for novel anticancer
agents. Key to success is a gold-catalyzed cascade comprising
a [3,3]-sigmatropic rearrangement of a propargyl acetate along
the periphery of a macrocyclic scaffold, followed by a trans-
annular hydroalkoxylation of the resulting transient allenyl
acetate. This transformation mandated the use of a chiral gold
catalyst to ensure a matching double-asymmetric setting. Other
noteworthy steps are the preparation of the oxazole building
the enigmazole core holds considerable promise: It might
help identify the minimum pharmacophore and the structural
determinants responsible for the desired selectivity, while
affinity- or fluorescence-tagged derivatives could enable the
identification of the actual biological target. To this end, it is
necessary to establish a concise entry into this class of
exceedingly rare macrolides, an entry which is sufficiently
robust to allow a meaningful material throughput, yet flexible
enough to accommodate late-stage digressions towards
hybrid analogues.
An elegant total synthesis of enigmazole A (1) as the
parent compound of this series has already been reported, by
Molinski and co-workers, back-to-back with the isolation
paper.[5,6] Their approach hinged upon a selective macro-
lactonization of an almost fully decorated seco-acid which had
to be conformationally biased for cyclization by a supplemen-
tary unsaturation in the frame. We saw the opportunity to
develop a fundamentally different route which envisaged the
concomitant formation of the signature tetrahydropyran ring
and the C5–C7 oxygenation pattern in the final stages of the
synthesis, only after the macrocycle had been closed
(Scheme 1). This task might be accomplished by a gold-
catalyzed reaction cascade[7,8] commencing with a [3,3]-sig-
matropic rearrangement of a propargylic acetate of type C.[9]
The resulting allenyl acetate B is expected to engage with the
same catalyst, and an ensuing transannular hydroalkoxylation
should lead to the formation of the compound A, featuring
a cis-disubstituted tetrahydropyran ring and a properly placed
enol acetate as a handle for the installation of the phosphate
at C5.[10,11] Obviously, the proper phasing of the two events is
critical since any premature intervention of the C11–OH
group across the macrocyclic ring would be detrimental.
However, a simple feasibility study encouraged us to pursue
this route.[12] If successful, the projected sequence provides
opportunities for late-stage modification of the region carry-
ing the distinctive phosphate ester, once the project enters
into the phase of diverted total synthesis. From the purely
chemical vantage point, it would help illustrate the prowess of
p-acid catalysis, which remains surprisingly underrepresented
in total synthesis compared with the overall activity in this
topical field of research.[13,14]
À
block by a palladium-catalyzed C H activation, as well as the
smooth ring-closing alkyne metathesis of a diyne substrate
bearing a propargylic leaving group, which has only little
precedent.
E
nigmazole A (1) and two unnamed congeners (2 and 3)
were isolated from a sponge of the genus Cinachyrella
enigmata collected off the Papua New Guinean coast line
(Scheme 1).[1] These compounds are not only the first
phosphorylated macrolides of marine origin but were
reported to elicit an exceptionally rare phenotypic response
in that they interfere with c-Kit signaling. The c-Kit receptor
is an evolutionary highly conserved transmembrane glyco-
protein with tyrosine kinase activity, which regulates, inter
alia, the proliferation, differentiation, growth, and survival of
hematopoietic cells.[2} The encoding proto-oncogene serves as
an important tumor marker, as mutations resulting in
aberrant c-Kit signaling have been implicated in the develop-
ment, migration, and recurrence of various cancers, most
notably acute myelogenous leukemia and gastrointestinal
stromal tumors.[2] The clinical relevance of this causal nexus is
underlined by the success of kinase inhibitors such as Imatinib
(Gleevec), an approved drug for the treatment of exactly
these tumors, which hits c-Kit as one of its molecular targets.[3]
Interestingly, the available data suggest that the enigma-
zoles do not act as kinase inhibitors but rather interfere with
a different, as yet unknown step of the c-Kit signaling
cascades.[1] Equally noteworthy is the fact that 1–3 were
reported not to distinguish between cells with wild-type or
mutant c-Kit, whereas several minor side fractions of the
crude sponge extract showed high selectivity for malignant
cells expressing mutant c-Kit. The recorded spectral data
suggest that the active components are siblings of 1–3.[1]
Therefore a diverted total synthesis exercise[4] centered on
An oxazole of type H had already been used by the group
of Molinski,[5] but our route to this building block represents
a convenient short cut (Scheme 2). Specifically, a copper-
mediated anti-carbometalation[15] of the commercial prop-
argyl alcohol 4 terminated by an iodine quench and subse-
quent O-methylation furnished compound 5, which partici-
pated in direct coupling with the commercial oxazole-4-
[*] M. Sc. A. Ahlers, Dr. T. de Haro, B. Gabor, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
carboxylate 6 by palladium-catalyzed C H activation.[16] This
À
reaction obviates the need to prefunctionalize the heterocycle
and furnished gram amounts of 7 in a well reproducible yield
of 74%. The aldehyde 8, formed by Dibal-H reduction of 7,
E-mail: fuerstner@kofo.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510026.
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Scheme 1. Structures of 1–3 and retrosynthetic analysis of enigmazole A; R=generic protecting group.
participated exceedingly well in an asymmetric Keck allyla-
tion to give the alcohol 9 with high optical purity.[17] Other
procedures were less productive. Attachment of a Boc-group
then allowed the chiral information to be relayed to a terminal
epoxide. To this end, the double bond in 10 was activated with
IBr and the resulting product 11 was treated with K2CO3 in
MeOH to cleave the cyclic carbamate and close the oxirane
ring.[18,19] A copper-catalyzed opening of the epoxide in 12
with the functionalized Grignard reagent 13,[20] in concert
with routine protecting group management, led to 15 which
was endowed with the necessary orthogonal silyl ethers.
When the reaction of 15 with the functionalized allyltin
reagent 20 was promoted with Coreyꢀs chiral bromoborane
21,[21] the corresponding homoallyl alcohol 22 was obtained
with high diastereoselectivity (d.r. > 10:1) and yield
(Scheme 3). This outcome is rewarding in view of the delicate
character of 20, which bears an elimination-prone propargyl
acetate motif. At the same time, it is instrumental for the
projected transannular cycloetherification cascade in which
the newly set stereocenter at C11 has to play a key role. In
contrast to the ease of formation of 22, the seemingly routine
protection as the corresponding PMB ether failed to afford
workable yields under a variety of reaction conditions.
Gratifyingly, though, a Troc group was better behaved and
equally orthogonal to the silyl ethers as evident from the
selective TBS-cleavage with formation of the compound
23.[22]
the desired cycloalkyne 32 in 79% yield on a 1.2 gram scale
(single largest batch) at ambient temperature. In assessing
this result, one has to consider that propargylic ester
derivatives are inherently challenging substrates for RCAM
and the number of successful applications is limited:[25] All
alkyne metathesis catalysts are Schrock alkylidynes compris-
ing an early-transition-metal center in its highest possible
oxidation state.[26] Unless sufficiently tempered by an appro-
priate ancillary ligand set, their intrinsic Lewis acidity
endangers substituents at the propargylic position as illus-
trated by the generic structure I (see insert in Scheme 4).
Even if the propargyl alcohol remains intact, the presence of
the leaving group opens yet another possible decomposition
pathway in that the emerging alkylidyne of type J, which is
nucleophilic at the carbon atom, might extrude the adjacent
nucleofuge. The molybdenum ate-complex 38, however, has
the right balance: it exhibits high metathesis activity but
leaves even sensitive functionality untouched.[27] The price to
pay in this particular application was the fairly high loading of
38 (31 mol%) necessary for a full, fast, and clean conversion
of the diyne 31, which is endowed with many different donor
sites.
An ultrasound-accelerated Troc cleavage with zinc dust
furnished the alcohol 33 as an adequate substrate for the
critical p-acid-catalyzed reaction cascade. Yet, this compound
did not react when exposed to an assortment of catalysts of
the type LAuX (L = Ph3P, XPhos, NHC; X = SbF6, NTf2,
OTs) in either CH2Cl2 or related solvents. This reluctance
came as a surprise since Ph3PAuNTf2 had proven remarkably
effective in our earlier, though admittedly rudimentary,
model study.[12] We conceived that the most likely explan-
ation[28] for this striking difference is the fact that the possible
p-complexes[29] formed upon initial coordination of the
catalyst to the alkyne in 33 are diastereomeric. If only one
With good amounts of 23 in hand, the assembly and
elaboration of the macrocyclic frame of enigmazole A was
tackled. To this end, 23 was esterified with the acid 30, which
was prepared in a few straightforward steps, as shown in
Scheme 4, using Myers auxiliary to control the enolate
alkylation step.[23] The resulting ester 31 was subjected to
a ring-closing alkyne metathesis (RCAM),[24] which furnished
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Scheme 3. a) LDA, Bu3SnH, THF/pentane, 08C, then 16, pentane,
À788C, 49%; b) 18, Ti(OiPr)4 (10 mol%), (S)-Binol (10 mol%), 4 Š
M.S., CH2Cl2, À208C, 84%, (ꢀ95% ee); c) Ac2O, Et3N, DMAP
(10 mol%), CH2Cl2, 93%; d) NaI, acetone, 708C, 88%; e) Bu3SnSnBu3,
[Pd2(dba)3] (2”1.7 mol%), THF, 558C, 73%; f) 15, 21, CH2Cl2, À788C,
95% (d.r.>10:1); g) TrocCl, DMAP (10 mol%), pyridine, CH2Cl2,
08C!RT, quant.; h) camphorsulfonic acid (20 mol%), CH2Cl2/MeOH
(3:1), 08C!RT, 61% (98% based on recovered starting material).
dba=dibenzylideneacetone, LDA=lithium diisopropylamide,
Troc=trichloroethyloxycarbonyl, Ts=4-toluenesulfonyl.
Scheme 2. a) 1. MeMgBr, CuI, toluene, À788C!RT; 2. I2, THF,
À408C!RT, 74%; b) MeI, NaH, imidazole (10 mol%), THF, À408C!
RT, 64%; c) Pd(OAc)2 (5 mol%), 2-(dicyclohexylphosphino)-biphenyl
(10 mol%), Cs2CO3, 1,4-dioxane, 1108C, 74%; d) Dibal-H, CH2Cl2,
À908C, 80%; e) allyltributyltin, Ti(OiPr)4 (10 mol%), (S)-Binol
(10 mol%), 4 Š M.S., CH2Cl2, À208C, 98% (d.r.>95:5); f) (Boc)2O,
DMAP, MeCN, 92%; g) IBr, toluene, À908C, 54–73%;[19] h) K2CO3,
MeOH, 79% (d.r.>95:5); i) TBSCl, imidazole, DMAP (10 mol%),
THF, 98%; j) 13, CuI (20 mol%), THF, À788C!À408C, 92%;
k) TBDPSOTf, 2,6-lutidine, CH2Cl2, 08C, 88%; l) TMSOTf, 2,4,6-trime-
thylpyridine, CH2Cl2, 97%; Boc=tert-butyloxycarbonyl, Dibal-H=diiso-
propylaluminum hydride, DMAP=4-dimethylaminopyridine,
the desired ketone 35 in readiness for the completion of the
total synthesis.[34]
While this result ultimately paved the way to the target, it
remained to be seen whether the success was in fact rooted in
the match between substrate and catalyst (Scheme 5). One
may take the outcome of the reaction of 33 with the
enantiomeric gold precatalyst (S)-39 as a first indication:
Although the desired product 34 was obtained, the reaction
was erratic, thus giving yields in the range of 50–70%.
Appreciable amounts (20–30%) of a by-product were formed
in all runs; we confidently ascribe to it the structure 40 based
on a detailed NMR investigation (see the Supporting
Information), even though the stereochemistry of the bridg-
ing cyclopropane ring could not be unambiguously eluci-
dated. Evidently, it is the exo-methylene group at C9 rather
M.S.=molecular sieves, TBS=tert-butyldimethylsilyl, TBDPS=tert-
butyldiphenylsilyl, TMS=trimethylsilyl, Tf =trifluoromethanesulfonyl.
of them is disposed for a [3,3]-sigmatropic rearrangement on
conformational grounds, but does not readily form for steric
and/or electronic reasons, no conversion will ensue.[30]
Based on this rationale, we started to screen chiral gold
complexes with the hope of finding a matching substrate/
catalyst pair.[31,32] In fact, the cationic species derived from the
À
than the C11 OH which acts as a competing nucleophile, thus
attacking the activated triple bond prior to allene formation.
This sequence triggers a prototype cycloisomerization which
has ample precedent in p-acid catalysis.[7,8,35]
[33]
dinuclear Biphep complex (R)-39 and 2 AgSbF6 was not
only able to overcome the inertia of the substrate but
provided the desired enol acetate 34 in a well reproducible
yield of no less than 91%. This excellent outcome met our
expectation that the gold catalyzed [3,3]-sigmatropic rear-
An even stronger case is made by the completely different
reactivity observed with 7-epi-33 (Scheme 5), which was
deliberately prepared to test our mechanistic hypothesis by
reacting 15 with the stannane ent-20 and thereafter following
the route outlined above. While 7-epi-33 was simply decom-
posed on treatment with (S)-39, the use of (R)-39 furnished
the benzene derivative 41 as the major product (together with
ca. 10–20% of 34). Its formation can be rationalized by
assuming an attack of the exo-methylene group after the
transient allenyl acetate B (or 5-epi-B) has formed, thus
giving rise to an intermediate of type O which aromatizes by
loss of HOAc.[36]
À
rangement should be faster than the attack of the C11 OH
group onto the resulting allenyl acetate of type B across the
macrocyclic perimeter (Scheme 5). Moreover, the ether bond
formation occurred exclusively at the site distal to the AcO
substituent such that a six-membered rather than eight-
membered ring is closed. The cis stereochemistry at the ring
junctions, as rigorously confirmed by NMR spectroscopy, is
indicative of the pseudo-chairlike transition state K for the
transannular event. Methanolysis of the acetate in 34 released
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Scheme 4. a) NaI, acetone, reflux; b) TBSCl, imidazole, CH2Cl2, 08C, 85% (over both steps); c) LDA, LiCl, THF, À788C!RT, 98% (d.r.=96:4);
d) LDA, then BH3·NH3, THF, 08C!RT, 89%; e) TPAP (5 mol%), NMO, 4 Š M.S., CH2Cl2, 88%; f) CBr4, PPh3, Zn, CH2Cl2, 74%; g) nBuLi, then
MeI, À788C!RT, 97%; h) TBAF, THF, 96%; i) TPAP (10 mol%), NMO·H2O, MeCN, 92%; j) 2,4,6-trichlorobenzoyl chloride, Et3N, then 23,
DMAP, toluene, 08C, quant.; k) 38 (31 mol%), 4 Š M.S., 5 Š M.S., toluene, 79%; l) Zn, HOAc, ultrasonication, 93%; m) (R)-39 (17 mol%),
AgSbF6 (34 mol%), CH2Cl2, 91%; n) K2CO3, MeOH, 95%; o) NaBH4, MeOH, À408C, 61% (+33% of 5-epi-36); p) (i) (FmO)2PNiPr2, tetrazole,
MeCN; (ii) aq. H2O2, 08C, quant.; q) TBAF, HOAc, THF, 408C, 82%. FmO =9-fluorenylmethyloxy, NMO=N-methylmorpholino-N-oxide,
TBAF=tetra-n-butylammonium fluoride, TPAP=tetra-n-propylammonium perruthenate.
Collectively, these greatly different outcomes demon-
strate the critical role of proper stereochemical pairing
between substrate and catalyst. This finding must be seen in
the context of previous literature reports which showed that
gold-catalyzed [3,3]-sigmatropic rearrangements of propar-
gylic esters are reversible and the resulting allenyl derivates
subject to rapid racemization.[37,38] If this were true for 33 and
7-epi-33, the configuration of the acetate-carrying C7 center
should not matter. It remains to be seen whether the
conflicting observations described herein are rooted in the
peculiarities of the chosen catalyst or in the constraints of the
particular substrate. At the meta level, however, this example
bears witness to the notion that target-oriented synthesis
often dissects scope and limitations of a given transformation
more rigorously than collections of model compounds and
hence remains an eminent driver for method development.
With the late-stage transannular cascade successfully
reduced to practice, the conquest of enigmazole A (1) was
only a few steps away (Scheme 4). Reduction of the ketone 35
with excess NaBH4 gave the desired alcohol 36 in good yield,
together with the readily separable 5-epi-36 as a first candi-
date for library synthesis. The attachment of the FmO-
protected phosphate was straightforward,[39] whereas the
global deprotection of 37 required optimization. In the end,
it was accomplished in a single operation using excess TBAF/
HOAc buffer at a slightly elevated temperature to cleave the
FmO substituents as well as the remaining silyl ether. The
spectral data of synthetic enigmazole A (1), which was
isolated as the free acid as well as in salt form, matched
those reported in the literature (for details see the Supporting
Information).[1,5]
Overall, the total synthesis of enigmazole A (1) described
above is robust, concise and convergent, and provides a plat-
form for structural modifications. First forays are currently
being pursued. Although the step count is similar to that of
the only previous synthesis of this promising target (23 versus
24 steps for the longest linear route),[5] the new entry is
considerably more productive (up to 3.3% versus 0.41%) and
conceptually different. It illustrates the power of transannular
functionalization,[11,40] a concept that gains momentum to the
extent that macrocycle formation becomes increasingly more
facile, not least with the help of ever more mature (alkyne)
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Scheme 5. a) (R)-39 (17 mol%), AgSbF6 (34 mol%), CH2Cl2, from 33: 91% (34), from 7-epi-33: [ca. 50% (41) +10–20% (34)]; b) (S)-39
(10 mol%), AgSbF6 (20 mol%), CH2Cl2, from 33: [50–70% (34) + 20–30% (40)], from 7-epi-33: decomposition. L* =chiral ligand.
metathesis catalysts. Furthermore, this project was initially
conceived to showcase our growing confidence in p-acid
catalysis, which still has a long way to go in terms of
applications to elaborate and highly precious substrates.[13]
Though ultimately successful, the still rather empirical flavor
of this topical field became apparent. This conclusion, drawn
from a total synthesis project, invigorates our parallel efforts
to contribute to a deeper mechanistic understanding of noble-
metal catalysis in general.[41]
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Acknowledgements
Generous financial support by the MPG and the Swiss
National Science Foundation (fellowship to T.d.H.) is grate-
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our Institute for excellent support.
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Keywords: alkynes · gold · metathesis · natural products ·
transannular reactions
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Received: October 27, 2015
Published online: December 10, 2015
Angew. Chem. Int. Ed. 2016, 55, 1406 –1411
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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