Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D

Article abstract of DOI:10.1002/anie.201812096

The new approach to the anticancer agent rhizoxin D described herein does not cohere with the conventional logic of metathesis, according to which macrocycles are best closed at a disubstituted olefinic site; rather, the trisubstituted C11?C12 alkene flanked by an allylic -OH group served as the pivot point for synthesis. This motif was attained in good yield and excellent selectivity by a sequence of alkyne metathesis, trans-hydrostannation and cross coupling. Because the exact same substructure is prominently featured in numerous other natural products, the underpinning strategy, though unusual, might bear more general relevance.

Full text of DOI:10.1002/anie.201812096

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Accepted Article
Title: Metathesis at an Implausible Site: A Formal Total Synthesis of
Rhizoxin D
Authors: Alois Fürstner, Pol Karier, Felix Ungeheuer, Andreas Ahlers,
Felix Anderl, and Christian Wille
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10.1002/anie.201812096
Angewandte Chemie International Edition
Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D
Pol Karier, Felix Ungeheuer, Andreas Ahlers, Felix Anderl, Christian Wille, and Alois Fürstner
[*] Dr. P. Karier, Dr. F. Ungeheuer, Dr. A. Ahlers, F. Anderl, C. Wille, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Supporting Information and ORCHID identification number(s) for the author(s) of this article can be
found under: http://doi.org/10.1002/anie. 201812096.
1
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10.1002/anie.201812096
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Abstract: The new approach to the anticancer agent rhizoxin D described herein does not cohere with
the conventional logic of metathesis, according to which macrocycles are best closed at a
disubstituted olefinic site; rather, the trisubstituted C11-C12 alkene flanked by an allylic –OH group
served as the pivot point for synthesis. This motif was attained in good yield and excellent selectivity
by a sequence of alkyne metathesis, trans-hydrostannation and cross coupling. Because the exact
same substructure is prominently featured in numerous other natural products, the underpinning
strategy, though unusual, might bear more general relevance.
Rhizoxin (3) was originally isolated as an antifungal agent from cultures of the rice pathogenic
fungus Rhizopus chinensis.[1] It was later recognized, however, that it is not the fungus itself but a
bacterial endosympiont of the genus Burkholderia which is the actual producer of this macrolide and
numerous congeners such as 1 and 2.[2] Endowed with remarkable in vitro cyctotoxicity and in vivo
antitumor activity, this class of compounds spawned massive investigations into its chemistry,
biological properties and medicinal significance.[3] Importantly, 3 had been selected for phase II
clinical trials: activity against non-small-cell lung cancer was recorded with apparently only modest
symptomatic and hematological toxicity;[4] unfortunately, however, the response rate of patients
with advanced melanoma, breast, ovarian, colorectal or renal cancer was rather disappointing and
the studies were therefore discontinued.[5] In mechanistic terms, the rhizoxins act as spindle poisons
targeting the maytansine binding site on eukaryotic tubulin.[6-8] In this context, it is perhaps relevant
to note that maytansine had also proven inadequate as a chemotherapeutic agent but now plays a
preeminent role as warhead of clinically approved antibody-drug-conjugates (ADC’s).[9] It needs to be
seen whether or not rhizoxin qualifies for similar applications.
The unsaturated variant rhizoxin D (1), derived from the same source organism,[2, 10] is the
likely biosynthetic precursor of 3; it can also be transformed by chemical means into WF-1360F (2)
and 3.[3] Since the biological activity of 1 is similar to that of 2 and 3, this polyunsaturated compound
served as focal point for total synthesis in the past (Scheme 1).[3] Though rather diverse in detail, the
different approaches reported in the literature are surprisingly conservative as to the closure of the
macrocyclic ring, in that most of them converged to an intramolecular Horner-Wadsworth-Emmons
2
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(HWE) olefination for the formation of the C2-C3 enoate bond.[11-18] Only a single total synthesis
relied on macrocyclization at the 1,3-diene subunit via a modestly efficient intramolecular Stille cross
coupling.[19]
Scheme 1. Three representative and biosynthetically related rhizoxin derivatives; analysis of prior
total syntheses (site and yield of macrocyclization).
One might expect that the rhizoxins also lend themselves to ring closing olefin metathesis
(RCM), which is arguably one of the most successful entries into macrocyclic rings since the advent of
highly active and functional group tolerant catalysts.[20, 21] This anticipation, however, proved
premature: it was reported by the Altmann group that attempted closure of the 16-membered core
at the disubstituted C9C10 olefin by RCM failed, despite extensive experimentation (Scheme 2).[22]
In striking contrast, ring closing alkyne metathesis (RCAM) worked exceedingly well at this
demanding site, affording the ostensibly more strained cycloalkyne in appreciable 69 % yield.[22]
Unfortunately, however, the congested microenvironment precluded direct trans-reduction of the
acetylenic entity to the E-alkene from occurring. Rather, an indirect solution had to be found,
commencing with formation of the corresponding hexacarbonyl dicobalt complex, which was
3
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subjected to reductive decomplexation, followed by isomerization of the resulting Z-alkene to the
required E-isomer under free radical conditions.[22]
Scheme 2. Different metathesis-based approaches to rhizoxin D (and WF-1360F); E = Si, Ge, Sn.
This surprisingly involved situation encouraged us to pursue an arguably counterintuitive
solution: Rather than targeting the disubstituted C9-C10 double bond as the deceptively obvious site
for metathetic ring closure,[20-23] we contemplated that the trisubstituted C11-C12 alkene might
actually be more appropriate: This stratagem  although very much in dissent with conventional
wisdom[24, 25]  builds upon recent advances in directed trans-addition reactions to internal
alkynes.[26] Most notably, propargylic alcohols lend themselves to highly regio- and stereoselective
trans-hydrometalation, whereby an R3E- residue (E = Si, Ge, Sn) is faithfully delivered to the more
crowded site proximal to the –OH function.[27] This course is rooted in cooperativity between the
protic group and the polarized [Cp*RuCl] unit of the catalyst: the resulting hydrogen bond increases
the affinity of the substrate to the ruthenium center and imposes directionality onto the ensuing
transition state.[26, 28] From the synthetic vantage point, this methodology opens a concise gateway to
trisubstituted alkenes, not least of the type featured in the macrocyclic frame of 1.[29, 30] For its
illustrious pedigree,[11-19, 22] this target was deemed an ideal testing ground that allows the
competitiveness of this approach to be tested. Although not pursued herein, we like to mention that
4
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a strategically placed R3E-substutent at the C12 position of the carbon framework potentially
provides access to various analogues too;[29, 31] differing from the parent natural product at a site that
has not yet been addressed in previous structure/activity relationship (SAR) studies.
Scheme 3. a) 1-bromo-2-butyne, NaH, THF, 93 %; b) nBuLi, THF, 78 °C; c) TBSCl, imidazole, CH2Cl2,
0 °C  RT, 79 % (over two steps); d) OsO4 (0.22 mol%), NMO, CH2Cl2, acetone; e) NaIO4, pyridine, 1,4-
dioxane/water, 69 % (over two steps); f) 13, ZnCl2, CH2Cl2, 90 % (dr = 6:1); g) MeNH(OMe)HCl, AlMe3,
CH2Cl2, 0 °C  RT, 67 % (pure diastereomer); h) TMSCl, imidazole, CH2Cl2, pyridine, 0 °C  RT; i) 14,
tBuLi, CeCl32LiCl, THF, 78 °C; j) camphorsulfonic acid (cat.), CH2Cl2/MeOH, 0 °C (87 % over three
steps); k) 4-nitrobenzaldehyde, SmI2 (40 mol%), THF, 25 °C, 80 %; l) Me3OBF4, proton sponge,
CH2Cl2, 0 °C  RT; m) K2CO3, THF/MeOH, 63 % (over both steps); m) diethyl phosphonoacetic acid,
EDCHCl, DMAP, CH2Cl2, 72 %; Ar = 4-nitrophenyl; DMAP = 4-dimethylaminopyridine; EDC = 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide;
butyldimethyl-silyl; TMS = trimethylsilyl.
NMO =
N-methylmorpholine-N-oxide;
TBS =
tert-
The substrate that allowed this concept to be tested was assembled as shown in Scheme 3.
Of the different routes to aldehyde 7 investigated, the sequence starting off with a [2,3]-Wittig
rearrangement of the allyl propargyl ether 5 was found to be most practical,[32] not least because the
5
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required alcohol precursor 4 is readily available in optically pure form (>99 % ee) on multigram scale
by enzymatic resolution;[33] moreover, the alkyl tail renders 5 non-volatile and hence easy to work
with. Oxidative cleavage of the double bond in the derived enyne 6 furnished aldehyde 7, which was
engaged in a Mukaiyama-type aldol reaction/lactonization sequence with the mixed ketene acetal 13
to give the corresponding -lactone 8 in high yield and good diastereoselectivity in favor for the anti-
aldol isomer;[34, 35] the observed 1,3-asymmetric induction concurs with the generally accepted model
for Lewis acid mediated additions to -silyloxy aldehydes.[36] Since opening of the strained ring of 8
with organometallic reagents proved erratic, the lactone was transformed into the corresponding
Weinreb amide 9 prior to ketone formation;[37, 38] best results were obtained, after transient
protection of the –OH group as a labile TMS-ether, when the organolithium species formed from
14[39] and tBuLi was transmetallated with CeCl32LiCl to temper the basicity of the reagent.[40]
Subsequent Evans-Tishchenko redox esterification with p-nitrobenzaldehyde of the resulting hydroxy
ketone 10 set the 1,3-anti diol motif in an appropriately differentiated format.[41-43] Product 11 thus
formed was subjected to O-methylation before the p-nitrobenzoate was exchanged for a diethyl
phosphonoacetate group to afford compound 12 in readiness for fragment coupling.
The required partner was attained by Sharpless epoxidation of crotyl alcohol (15),[44] followed by
opening of the resulting product 16 with lithiated 1,3-pentadiyne[45] in the presence of Et2AlCl
(Scheme 4).[46] The high selectivity in favor of the desired product 17 ( 10:1) is best appreciated
upon comparison with the rather poor regiochemical outcome ( 4:1) obtained with lithio
trimethylsilylacetylide as the reagent under otherwise identical conditions. Diol 17 was elaborated
into the terminal epoxide 18, which reacted under copper catalysis with the Grignard reagent derived
from 4-bromo-cyclopent-1-ene. The resulting compound 19 was transformed into ketal 20 prior to an
exquisitely selective reduction of the homopropargylic triple bond with Red-Al.[47] Deprotection of
]
the ketal, periodate cleavage of the released diol 21 and selective oxidation[48 of the resulting
hemiacetal furnished the rather unstable aldehyde 22. We acknowledge that this desymmetrization
strategy echoes pioneering work in the rhizoxin arena by Williams and coworkers,Fehler! Textmarke nicht
definiert.[13] which had later also been elegantly adapted by other groups.[14, 17] As expected, the union of
22 with phosphonate 12 by HWE to give the cyclization precursor 23 was straightforward.
6
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Scheme 4. a) Ti(OiPr)4 (4 mol%), D-(+)-diisopropyl tartrate (6 mol%), tBuOOH, MS 4Å, CH2Cl2, 20 °C,
78 % (er = 5:1); b) 1,3-pentadiyne, nBuLi, Et2AlCl, CH2Cl2, 78 °C  0 °C, 95 %; c) TsCl, pyridine,
CH2Cl2, 0 °C  RT, 97 %; d) DBU, CH2Cl2, 0 °C  RT, 83 %; e) (i) 4-bromocyclopentene, Mg*, Et2O; (ii)
18, CuI, Et2O, 40 °C, 78 %; f) OsO4 (4 mol%), NMO, acetone/H2O, 68 %; g) acetone, pyridinium p-
toluenesulfonate (cat.), 83 %; h) Red-Al, THF; i) pTsOH (15 mol%), aq. MeOH, 40 °C, 93 % (over two
steps); j) NaIO4 adsorbed on SiO2, CH2Cl2; k) PIDA, TEMPO (14 mol%), Yb(OTf)3, CH2Cl2, 57 % (over two
steps); l) 12, LiCl, DBU, MeCN, then 22, 0 °C, 86 %; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; PIDA =
phenyliodine(III) diacetate; Red-Al = sodium bis(2-methoxyethoxy)aluminum hydride; TEMPO =
2,2,6,6-tetramethylpiperidin-1-oxyl radical; Ts = p-toluenesulfonyl.
With diyne 23 in hand, the project entered the critical assembly stage (Scheme 5).
Gratifyingly, RCAM of this highly functionalized substrate proceeded well,[49] furnishing the desired
product 24 in 67-70 % yield despite the considerable strain inherent to this polyunsaturated 16-
membered ring. It is of note, however, that recourse to [Mo(N(tBu)Ar)3] (30)/CH2Cl2 as the catalyst
system was necessary,[50] whereas the more convenient molybdenum alkylidyne complexes endowed
with silanolate ligands gave mixtures of 24 and an acyclic dimer formed by homo-metathesis of 23.
7
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Scheme 5. a) 30 (10 mol%), toluene, CH2Cl2, 80 °C, 67-70 %; b) TBAF, THF, 50 °C  10 °C, 90 %; c)
TBAF, THF, 15 °C; d) 31 (15 mol%), MS 5 Å, toluene, 50 % (over two steps); e) [Cp*RuCl]4 (1.25
mol%), Bu3SnH, 1,2-dichloroethane; f) MeI, CuTC, [Ph2PO2][NBu4], DMSO, 70 % (over two steps); g)
[(cod)Pd(Me)(Cl)], THF, 56 % (over two steps); h) TBDPSCl, imidazole, CH2Cl2, 60 °C; i) TBSCl,
imidazole, DMAP, CH2Cl2, 71 % (over two steps); Ar = 4-methoxyphenyl; cod = 1,5-cyclooctadiene;
Cp* = pentamethylcyclopentadienyl; CuTC = copper thiophene-2-carboxylate; TBAF = tetra-n-
butylammonium fluoride; TBDPS = tert-butyldiphenylsilyl.
This outcome is in line with earlier observations, which suggest that silanolate-based
catalysts such as 31 (and variants thereof)[51, 52]are rather bulky and find limitations when it comes to
metathesize sterically hindered triple bonds; propargylic alcohols protected with large O-
substituents, as present in 23, seem to fall into this category.[53]
To check this aspect, we deliberately cleaved both TBS-ether groups in 23 and subjected the
resulting diol 25 to RCAM with complex 31 as the catalyst. In line with our expectations, this slimmer
substrate did indeed afford the macrocyclic product 26, although the overall yield was lower (50 %
over two steps). This quantitative aspect notwithstanding, it is remarkable that a Schrock-type
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alkylidyne such as 31, which is inherently nucleophilic and basic at the carbynyl carbon,[54] proves
compatible with free primary and secondary –OH groups. Studies are underway in this laboratory to
further evolve this striking yet arguably enabling chemical virtue.
With a robust entry into 26 in place, we were in the position to investigate the decisive
downstream functionalization of this cycloalkyne. The key trans-hydrostannation reaction proved
[26, 27, 55]
exquisitely selective when catalyzed by [Cp*RuCl]4
the resulting crude stannane 27 was
directly subjected to C-methylation, which could be accomplished in two different ways by following
protocols previously developed in our group: specifically, compound 27 was treated with MeI in the
presence of CuTC as promotor and [Ph2PO2][NBu4] as an essentially neutral tin scavenger;[28]
alternatively, it suffices to expose 27 to stoichiometric [(cod)Pd(Cl)(Me)]; this latter method
mandates handling of a single reagent and is therefore recommended when working with small
amounts of (precious) compounds.[56] Anyway, either procedure proved adequate, furnishing the
required trisubstituted alkene 28 as a single regio- and stereoisomer in good yield. To complete the
formal total synthesis of rhizoxin D (1), 28 was converted into the literature-known compound 29,
which intercepts the route described by the Pattenden group.[19] In parenthesis we note, that this
detour might actually not be needed as diol 28 itself could probably be elaborated into 1 by selective
oxidation followed by olefination of the resulting aldehyde with compound 32 (or an equivalent
thereof). Because our investigation was mainly directed to provide proof-of-concept for a non-
conventional metathesis strategy, we refrained from exploring this shortcut, as the rhizoxins had
failed to find clinical approval.
9
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Scheme 6. Propargyl alcohols as gateway to common structural motifs
In conceptual terms, the results outlined above show that alkyne metathesis in concert with
contemporary hydrometalation chemistry opens a reliable, selective and  by virtue of the rich
chemistry of the C-ER3 bond – inherently flexible entry into various types of (trisubstituted) alkenes
and related motifs; some readily accessible patterns are depicted in Scheme 6. In addition to C
pursued herein, the list includes substructures such as D,[57] E,[58] or G[59] as encountered in
innumerous natural products, especially those of polyketide origin. The underlying strategy is hence
likely of more general relevance since it might be translated to the synthesis of a very large number
of (bioactive) target compounds. At the meta-level, one might even argue that motifs of type C-G
deserve consideration as privileged assembly sites, although we certainly appreciate that this notion
needs further scrutiny. In any case, the concept manifest in the present study is definitely distinct
from the common reasoning that disubstituted rather than trisubstituted alkenes are necessarily the
best sites for metathetic ring closure, especially when it comes to the formation of challenging
macrocyclic rings.[20-25] Work is in progress that intends to test this non-traditional yet potentially
enabling conclusion in other challenging settings.
Acknowledgements
Generous financial support by the MPG is gratefully acknowledged. We thank the analytical
departments of our Institute for excellent cooperation.
For the Table of Contents
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Counterintuitive: The 1,3-diene region within the macrocyclic core of rhizoxin D is known to be
crowded. Interestingly, ring closing alkyne metathesis (RCAM) proved better apt to meet this
challenge than olefin metathesis (RCM); of particular note is the fact that the trisubstituted rather
than the disubstituted alkene constitutes the more adequate assembly site. Either finding seems to
violate common knowledge.
Keywords: Alkynes  1,3-Dienes  trans-Hydrostannation  Macrocycles  Metathesis  Natural Products
11
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15
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