Self-Assembly of Disorazole C1 through a One-Pot Alkyne Metathesis Homodimerization Strategy

Article abstract of DOI:10.1002/anie.201501922

Abstract Alkyne metathesis is increasingly explored as a reliable method to close macrocyclic rings, but there are no prior examples of an alkyne-metathesis-based homodimerization approach to natural products. In this approach to the cytotoxic C₂-symmetric marine-derived bis(lactone) disorazole C₁, a highly convergent, modular strategy is employed featuring cyclization through an ambitious one-pot alkyne cross-metathesis/ring-closing metathesis self-assembly process.

Full text of DOI:10.1002/anie.201501922

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201501922
German Edition: DOI: 10.1002/ange.201501922
Alkyne Metathesis
Hot Paper
Self-Assembly of Disorazole C1 through a One-Pot Alkyne Metathesis
Homodimerization Strategy**
Kevin J. Ralston, H. Clinton Ramstadius, Richard C. Brewster, Helen S. Niblock, and
Alison N. Hulme*
Abstract: Alkyne metathesis is increasingly explored as
a reliable method to close macrocyclic rings, but there are no
prior examples of an alkyne-metathesis-based homo-
dimerization approach to natural products. In this approach
to the cytotoxic C2-symmetric marine-derived bis(lactone)
disorazole C1,
a highly convergent, modular strategy is
employed featuring cyclization through an ambitious one-pot
alkyne cross-metathesis/ring-closing metathesis self-assembly
process.
T
he use of ring-closing alkyne metathesis (RCAM) in the
synthesis of natural products[1] has gained prevalence with the
development of reliable, bench-stable catalysts, which have
improved substrate scope over their predecessors.[2] These
catalysts open up options for the application of RCAM-based
strategies to the cyclization of terminal methyl-substituted
alkynes,[1] terminal alkynes,[3] and even combinations of the
two substitution patterns[4] in the synthesis of natural
products. Partial hydrogenation of the resultant macrocyclic
alkyne can now be effected under a range of conditions and
allows access to either E- or Z-alkene geometry.[1a,5] Yet
despite these advances, and in sharp contrast to their alkene
counterparts,[6] the development of alkyne cross-metathesis
(ACM) reactions remains comparatively underdeveloped.[7]
Combining ACM and RCAM reactions to allow self-assembly
processes is limited to a handful of examples, including the
formation of aryleneethynylene macrocycles and a tetrameric
cage structure with 4D2h symmetry.[7a,8] There are no prior
examples of such a self-assembly approach to the synthesis of
complex natural products.
Figure 1. Structure of disorazole C1 and overview of synthetic
approaches to disorazole C1. a) Previous approaches to dimerization
using 1. lactonization, or 2. cross-coupling reactions. b) This work,
self-assembly using alkyne metathesis.
In order to investigate the application of a combined
ACM and RCAM strategy to the synthesis of natural
products, our chosen target was the cytotoxic, C2-symmetric
bis(lactone) disorazole C1 (1; Figure 1),[9] which was first
isolated in 1994 from the fermentation broth of the myxo-
bacterium Sorangium cellulosum.[10] As a family, the disor-
azoles have been shown to possess cytotoxicity in the nm to pm
range and anti-tubulin activity,[11] and current pharmaceutical
interest focuses on their potential for the treatment of drug-
resistant solid tumors.[12,13] However, much remains to be
discovered about the mode of action of these natural
products, including how and where they bind to tubulin,[14]
as this has been demonstrated to be orthogonal to the binding
sites of vincristine and taxol.[14] Until recently, only one total
synthesis of this challenging target was reported.[15,16]
[*] Dr. K. J. Ralston, Dr. H. C. Ramstadius, R. C. Brewster,
Dr. H. S. Niblock, Dr. A. N. Hulme
EaStCHEM School of Chemistry, University of Edinburgh
David Brewster Road, Edinburgh, EH9 3FJ (UK)
E-mail: Alison.Hulme@ed.ac.uk
[**] We thank Prof. A. Fꢀrstner for advice and the generous gift of
a sample of molydenum alkylidyne catalyst 30. We thank Juraj Bella
for assistance with NMR experiments and Dr. Paul Lusby for helpful
discussions. We thank the EC (Marie Curie Fellowship to HCR;
PIEF-GA-2011-301678), the CRUK (studentships to K.J.R. and
H.S.N.; Grant Ref. C21383A6950), the BBSRC, and the EPSRC for
funding.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501922.
ꢁ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Pioneering synthetic work was undertaken by Meyers and
co-workers before the relative and absolute stereochemistry
of disorazole C1 had been fully established.[17] Although the
total synthesis of disorazole C1 was not achieved, this work
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did identify several pivotal issues to be addressed in any
future synthesis; most notably that strategies based on the
homodimerization of a fully formed seco-acid precursor
(strategy 1 in Figure 1a) were not likely to be successful
because of the competing formation of the monomeric 15-
membered lactone, and that the correct choice of protecting
group(s) would be crucial to the successful completion of the
synthesis.[17b] These results are mirrored by the recent work
from Hoveyda and co-workers on a seco-acid precursor,
which has the correct absolute stereochemistry as well as the
E,Z,Z-alkene geometry.[16] Hoffmann et al. also explored
a direct dimerization approach, but in this instance with the
Our approach to the construction of the 30-membered
bis(lactone) differs markedly from the previously reported
approaches in that it relies on self-assembly of the bis-
(lactone) (strategy in Figure 1b). To this end, we targeted the
interception of the Wipf tetradehydro intermediate 2 through
metathesis of the bis(alkyne) precursor 3 (Scheme 1). This
direct metathesis approach is unprecedented in the synthesis
of complex polyketide-derived natural products, but has some
foundation in the formation of cyclophanes.[20] However, it
does provide an additional challenge over other approaches
in that both head-to-tail and head-to-head coupling products
could be formed from the nonsymmetrical bis(alkyne)
precursor.
[18]
À
C9 C10 Z-alkene masked as an alkyne.
Although an
in silico analysis predicted the preferential formation of the
desired bis(lactone) over the monomer,[19] neither was formed
under a range of conditions. A stepwise coupling to generate
the bis(lactone) was achieved by both the Meyers and
Following on from prior work in our group,[21] we planned
the formation of bis(alkyne) 3 through the coupling of
aldehyde 4 and b-hydroxy ketone 5 using a heteroaryl
Evans–Tishchenko (ET) reaction to set the stereochemistry
at C16 (Scheme 1).[22,23] Our initial route to C1–C9 oxazole
aldehyde 4 relied upon a lateral lithiation of protected 4-
hydroxymethyl-2-methyl-oxazole 6[24] and coupling to enyne
aldehyde 7[25] to generate 8 (Scheme 2). Methylation of the
À
À
Hoffmann groups (using C11 C12 and C9 C10 alkyne-
masked precursors, respectively) through sequential esterifi-
cation, unmasking of the second acid and alcohol compo-
nents, and subsequent lactonization.[17a,18]
Avoiding direct dimerization enabled the first successful
total synthesis of disorazole C1 by Wipf and co-workers in
2004.[15] In their approach, the sequential coupling of compo-
À
nents to a C9 C10 alkyne-masked seco-acid through esterifi-
À
cation, Sonogashira coupling at C8’ C9’, and subsequent
lactonization gave the tetradehydro precursor 2, which was
converted to the natural product in two further steps through
PMB deprotection and Lindlar hydrogenation (Scheme 1).[15]
Remarkably, the very recent synthesis of disorazole C1 by
Hoveyda et al. shows that by switching the coupling positions
Scheme 2. Synthesis of the racemic C1–C9 fragment. Reagents and
conditions (PG=MOM): a) 1. nBuLi, THF, À788C, 1 h; 2. HNEt2,
À788C, 45 min; 3. 7, À788C, 45 min, 40%; b) 1. NaH, THF, 08C;
2. MeI, 08C to RT, 18 h, 29%; c) HCl, MeOH, RT, 18 h, 74%; d) DMP,
NaHCO3, CH2Cl2, 08C, 2 h, 43%. PG=protecting group.
À
À
to C10 C11/C10’ C11’ and relying on cross-coupling reac-
tions rather than esterification and lactonization reactions,
dimerization is possible even on an alkene, rather than an
alkyne-masked, precursor (strategy 2 in Figure 1a).[16]
resulting free hydroxy group at C6 gave 9, and deprotection of
the hydroxy group at C1, followed by oxidation generated
racemic aldehyde (Æ)-4 (Scheme 2). This approach was
successful when the protecting group allowed coordination
(e.g. PG = MOM), but not for silyl protecting groups, thus
suggesting an initial lithiation of the 5-position of the oxazole,
with subsequent equilibration to the 2-(lithiomethyl)oxazole
species facilitated by diethylamine.[26] Although a few options
were explored for converting this route to an asymmetric
one,[27] several steps were low-yielding, and we thus pursued
an alternative route to a single enantiomer of the desired
oxazole aldehyde 4, which had the additional advantage that
it would allow a rapid variation of the heterocycle in future
studies.
Commercially available mannitol derivative 10
(Scheme 3) was converted into alkyne 11 by periodate
cleavage, Seyferth–Gilbert homologation with the Ohira–
Bestmann reagent,[28] and acetal hydrolysis. Vinyl iodide 12
was accessed by a highly (E)-selective palladium-catalyzed
hydrostannylation (13, E/Z = 30:1) and subsequent iodonol-
ysis.[29] Negishi coupling and selective monotosylation in the
presence of catalytic dibutyltin oxide[30] furnished secondary
alcohol 14, which then smoothly underwent methylation to
Scheme 1. Retrosynthetic analysis of disorazole C1 (1).
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Scheme 4. Synthesis of the C10–C19 b-hydroxy ketone fragment 3.
Reagents and conditions: a) 1. N-Ts-d-Valine, BH3·THF, CH2Cl2,
À788C, 5 h, 2. HCl, THF:H2O (1:1), 85%, 89% ee; b) TBSOTf, 2,6-
lutidine, CH2Cl2, À788C, 2.5 h, 94%; c) DDQ, CH2Cl2:H2O (18:1), RT,
1.5 h, quant.; d) Swern, 95%; e) ICH2PPh3+IÀ, NaHMDS, HMPA, THF,
À788C, 2 h, 75%; f) 1. BrMgCꢀCCH3, ZnCl2, THF, 08C, 30 min, 2. 20,
[PdCl2(PPh3)2], 08C to RT, 16 h, 92%; g) HF (40% aq.), MeCN, 08C to
RT, 1 h, 99%; h) 1. HNMe(OMe)·HCl, nBuLi, À788C to RT, 30 min,
2. 22, THF:hexane (1:1), À788C to RT, 1.5 h, 82%; i) TBSOTf, 2,6-
lutidine, CH2Cl2, À788C to RT, 2 h, 96%; j) 1. allyl-MgBr, Et2O À20 to
À788C, 2 h, 2. DBU, Et3N, 508C, 18 h, 81%; k) HF (40% aq.), MeCN,
08C to RT, 45 min, 85%.
Scheme 3. Synthesis of the C1–C9 oxazole fragment. Reagents and
conditions: a) NaIO4, NaHCO3 (satd. aq.), MgSO4, CH2Cl2, 08C to RT,
2 h 20 min, 88%; b) dimethyl-1-diazo-2-oxopropylphosphonate, K2CO3
(s), MeOH, 08C to RT, 17 h; c) HCl (conc.), MeOH, Et2O, THF, 6 h
15 min, 66% over 2 steps; d) [PdCl2(PPh3)2], Bu3SnH, Et2O, À308C,
ꢀ
30 min, 60%; e) I2, Et2O, 08C, 5 min, 92%; f) 1. ZnCl2, BrMgC CCH3,
THF, 08C, 15 min; 2. 12, [PdCl2(PPh3)2], 08C to RT, 25 h; g) Bu2SnO,
TsCl, NEt3, CH2Cl2, 08C to RT, 11 h, 60% over 2 steps; h) Me3OBF4,
1,8-bis(dimethylamino)naphthalene; i) KCN, Bu4NI, NaHCO3, DMSO,
608C to 708C, 4 h, 63% over 2 steps; j) H2O2, LiOH·H2O, EtOH, RT,
34 h, 75%; k) HBTU, EtN(iPr)2, SerOMe·HCl, CH3CN, 08C to RT, 10 h,
82%; l) 1. XtalFluor-E, K2CO3, CH2Cl2, À788C to 08C, 50 min;
2. BrCCl3, DBU, À208C to RT, 4 h 45 min, 76%; m) LiOH (aq.), THF,
RT, 8 h, 96%.
The preparation of b-hydroxyketone 5 on a gram scale
allowed the examination of the scope of the ET reaction with
model aryl and heteroaryl aldehydes. Electron-deficient
aldehydes (in particular pyridines and nitrobenzaldehydes)
were shown to undergo a SmIII-catalyzed ET reaction, giving
1,3-anti diol monoester products in good to excellent yields
(> 95:5 d.r.). Unfortunately, indoles, pyrroles, and pyra-
zoles,[23] even those containing electron-withdrawing substitu-
ents at the heteroatom, gave poor yields or failed to react.
Thus, the critical anti stereorelationship at C14–C16 was set
give key tosylate 15. Attempts to couple this tosylate directly
with the 2-position of a 4-substituted oxazole using either
[27]
À
C H activation or lithiation strategies were unsuccessful.
Instead, a step-wise construction of the oxazole was achieved
through conversion of 15 into the corresponding acid 16 by
cyanide displacement and hydrolysis. Subsequent coupling to
serine methyl ester, cyclization, and oxidation provided the
fully functionalized oxazole 17, which model studies suggest
might be readily converted to the desired oxazole aldehyde 4
through DIBAL-H reduction.
A number of routes were pursued to the second key
fragment, the C10–C19 b-hydroxy ketone 5,[31] but its
preparation on a gram scale was eventually achieved as
shown in Scheme 4. Thus, known aldehyde 18 was subjected
to an enantioselective organoborane-mediated Mukaiyama
aldol reaction[32] with the silyl ketene acetal of methyl 2-
methylpropionate to afford b-hydroxyketone 19 in 85% yield
and 89% ee.[19] Silyl protection of the secondary alcohol 20,
deprotection (DDQ) of the PMB-ether, Swern oxidation of
the primary alcohol and a Stork–Zhao–Wittig reaction[33] gave
the key vinyl iodide 21 (Z/E > 99:1). A Negishi coupling was
used to install the enyne portion of the target fragment 5 in
high yield. Subsequent conversion of the ester 22 to the
Weinreb amide 24 was best performed on the free alcohol 23,
which was reprotected (25) for the following allyl Grignard
addition and DBU-mediated isomerization to the enone.
Deprotection (with HF) gave the required b-hydroxyketone 5
and completed the fragment in 11 steps and 28% overall yield
from 18.
Scheme 5. Coupling of the C1–C9 and C10’–C19’ fragments to give
bis(alkyne) intermediate 3. Reagents and conditions: a) 3-NO2PhCHO,
SmI2, THF, À208C, 4 h, 94%; b) PMB-TCA, Sc(OTf)3, PhCH3, 08C to
RT, 1 h, 79%; c) LiOH, MeOH:H2O (10:1), reflux, 18 h, 91%;
d) 1. 2,4,6-trichlorobenzoyl chloride, Et3N, 28, PhCH3, RT, 30 min,
added portionwise to 27 (0.05m in toluene), DMAP, 408C, 30 min
each addition, 2. 408C, 18 h 71%; e) DDQ, CH2Cl2:phosphate buffer
(1:1), RT, 30 min, 77%.
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À
À
Scheme 6. ACM/RCAM self-assembly reaction products. Pathway A: desired head-to-tail bis(alkyne) coupling proceeding via a C9 C10 [or C9’
À
À
C10’] coupled linear dimer intermediate. Pathway B: undesired head-to-head coupling proceeding via a C10 C10’ (shown) or C9 C9’ coupled
linear dimer intermediate. Reagents and conditions: a) 1. 4 ꢂ/5 ꢂ MS (1:1), PhCH3, RT, 20 min; 2. 30 (20 mol%), RT, 16 h; b) DDQ,
CH2Cl2:phosphate buffer (1:1), RT, 30 min, 61%.
using an ET coupling with 3-nitrobenzaldehyde to give 26
(Scheme 5); a PMB protecting group was installed, and the
hydroxy group at C14 was unmasked through subsequent
ester hydrolysis to give 27. Yamaguchi coupling, through the
portionwise addition of the activated acid derived from the
C1–C9 fragment 28 (Scheme 3) to fragment 27 gave the
PMB-protected bis(alkyne) 3 spanning the C1–C9/C10’–C19’
portion of disorazole C1. This bis(alkyne) could be readily
deprotected under the controlled conditions used in the total
synthesis reported by Wipf[15] to give the bis(alkyne) alcohol
29.
With bis(alkynes) 3 and 29 in hand, we could now
explore the ambitious ACM/RCAM self-assembly process
(Scheme 6). We were encouraged by the computational
studies of Hoffmann et al., which suggested that dimer
formation was favored for a C9–C10 based bis(alkyne),[19]
and by our own preliminary modelling studies, which
indicated a thermodynamic preference for the desired head-
to-tail coupling mode for the parent disorazole C1 structure.
For the metathesis reaction, we chose the recently published
molybdenum alkylidyne catalyst 30 from the Fꢀrstner
group.[2a] The reaction was initiated in a glovebox and we
found that the overall yields and conversion were consider-
ably improved if the substrate was stirred with a mixture of
4 ꢁ and 5 ꢁ activated molecular sieves prior to the addition
of the catalyst.[4] The outcome seemed to depend on the initial
amount of catalyst added and could not be improved by the
later addition of further portions of catalyst. The reaction was
best followed by reverse-phase LC-MS (l = 254 nm), which
allowed distinct peaks corresponding to each of the linear (31,
32, 33) and cyclic (2, 34) dimers to be identified. Under
optimum conditions (Scheme 6), cyclic dimers 2 and 34 could
be isolated in an overall yield of 62%; the ratio of the desired
head-to-tail-coupled product 2 to its head-to-head-coupled
regioisomer 34 was approximately 5:1. The formation of the
unwanted cyclic monomer was not discernible by LC-MS,
thus supporting computational predictions.[34] Data for tetra-
dehydrido disorazole C1 (2) was found to be identical in all
regards to that reported by the Wipf group in 2004, and this
intermediate could be converted in two steps via the known
alcohol 35 to the target natural product, disorazole C1 (1),
using the previously reported procedures.[15,35] When we
attempted the self-assembly reaction with the deprotected
bis(alkyne) 29, a complex mixture of products was produced.
While LC-MS indicated a possible correlation with the
predicted linear (36, 37, 38) and cyclic (35, 39) dimers,
isolation of the major peak with the desired m/z[36] gave
material which had distinctly different NMR data to that
which we had already determined for compound 35, thus
indicating a more complex process (perhaps with accompa-
nying double bond isomerism) for the deprotected material.
In conclusion, we have demonstrated the first example of
an alkyne metathesis self-assembly process, using cross-
metathesis and ring-closing metathesis reactions, to give the
C2-symmetric bis(lactone) disorazole C1. The synthetic results
give an intriguing glimpse into the possibility of using such an
approach in the synthesis of complex natural product
architectures and open up new routes to the synthesis of
analogues of this fascinating natural product.
Keywords: alkyne metathesis · cytotoxicity · natural products ·
self-assembly · total synthesis
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corresponding to this desired mass.
Received: February 28, 2015
Revised: March 31, 2015
Published online: April 29, 2015
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