Synthesis and Molecular Editing of Callyspongiolide, Part 1: The Alkyne Metathesis/trans-Reduction Strategy

Article abstract of DOI:10.1002/chem.201804987

A path-scouting investigation into the highly cytotoxic marine macrolide callyspongiolide is reported that capitalizes on the selective formation of the C10?C11 alkene site. While the closure of the macrocycle by ring closing alkyne metathesis (RCAM) with

Full text of DOI:10.1002/chem.201804987

A Journal of
Accepted Article
Title: Synthesis and Molecular Editing of Callyspongiolide, Part 1 The
Alkyne Metathesis / trans-Reduction Strategy
Authors: Alois Fürstner, Guillaume Mata, and Bernhard Wölfl
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Synthesis and Molecular Editing of Callyspongiolide, Part 1:
The Alkyne Metathesis / trans-Reduction Strategy
Guillaume Mata, Bernhard Wölfl, and Alois Fürstner*
Abstract: A path-scouting investigation into the highly cytotoxic marine macrolide callyspongiolide is reported
that capitalizes on the selective formation of the C10-C11 alkene site. While the closure of the macrocycle by
ring closing alkyne metathesis (RCAM) with the aid of a molybdenum alkylidyne complex was high yielding, the
envisaged semi-reduction of the cycloalkyne to the corresponding E-alkene proved challenging. The reasons are
likely steric in origin, in that the methyl branches on either side of the alkyne seem to prevent effective
coordination of the substrate to the ruthenium catalyst, which must carry a bulky Cp* ligand to ensure high
trans-selectivity. This notion is supported by the preparation of a callyspongiolide analogue, in which the two
methyl groups in question are excised; its formation by RCAM followed by trans-hydrostannation/proto-
destannation was straightforward. In parallel work the formation of the fully functional building block 54
showed that the presence of an unprotected OH group allows even hindered substrates to be processed: the
protic group adjacent to the triple bond engages with a chloride ligand on the ruthenium catalyst in hydrogen
bonding and hence assists in substrate binding. Moreover, the preparation of an alkynylogous callyspongiolide
analogue is described.
Introduction
Bioassay-guided fractionation of the methanol extract of a sponge of the Callyspongia genus collected off the
Indonesian coast line led to the isolation of callyspongiolide (4.6 mg, 0.00092% wet weight).[1] This captivating
macrolide endowed with a highly unusual dienyne side chain exhibits remarkable cytotoxicity against human
Jurkat J16 T and Ramos B lymphocytes with IC50 values of 70 nM and 60 nM respectively. Moreover, increased
levels of hypodiploid nuclei were observed at low EC50 levels of 80 nM.[1] Most notably, however, cell death
seems to be triggered by a caspase-independent pathway: compounds that have a non-apoptotic mode of
action are particularly interesting leads since apoptotic signaling is suppressed in many tumor cells and one of
the causes for drug resistance.[2]
*
Dr. G. Mata, B. Wölfl, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Supporting Information for this article can be found on the WWW under ###################
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Callyspongiolide immediately attracted attention from the synthetic community for this potentially relevant
biological profile as well for its scarcity. These studies culminated in several partial and total syntheses,[3,4,5,6]
which corrected the absolute configuration originally assigned to the macrolide core by the isolation team and
firmly established the previously unknown configuration of the C21 chiral center in the side chain. Based on this
work, callyspongiolide is correctly described by structure 1.
Scheme 1. Two conceivable approaches to callyspongiolide based on RCAM followed by semi-reduction; R = generic
protecting group or substituent; X = halide; the bent drawing of the alkyne units throughout this paper is for convenience
only and has no physical meaning
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Our program devoted to this potential lead compound intended to expedite biological profiling by providing
meaningful amounts of the natural product itself as well as of pertinent analogues. At the same time, the chosen
route should capitalize on methodology concurrently developed in this laboratory. Both objectives might be
reached when forging the macrocyclic frame by ring closing alkyne metathesis (RCAM)[7,8,9] followed by semi-
reduction of the resulting product (Scheme 1). A priori, this tactics can be applied at the E-configured C10-C11
alkene or at the Z-configured enoate site. In assessing these alternatives, one has to consider two possible
pitfalls: in the former case, the critical conversion of a cyclic alkyne C into the required E-alkene in A in the
presence of other reducible sites is a non-trivial task.[10] On the other hand, RCAM of ynoates had been
essentially impossible with the classical catalysts;[11] only after the advent of molybdenum alkylidynes endowed
with silanolate ligands has a small number of examples been reported in the literature, none of which is
anywhere close in complexity to the projected formation of a building block of type E from ynoate F[12] Therefore
it was not obvious at the outset of our investigations, which of the two conceivable routes shown in Scheme 1
might be ultimately more appropriate in the present context. Outlined below is a first part of our program that
scouts the alkyne metathesis/trans-reduction strategy. As this study had been initiated before the absolute
stereochemistry of callyspongiolide was corrected, the enantiomer ent-1 originally proposed by the isolation
team[1] dictated the stereochemical format of our investigation.
Results and Discussion
Model Study on trans-Reduction. Whereas a dissolving metal reduction for the conversion of an alkyne into the
corresponding E-alkene is obviously precluded for a polyfunctional compound of type C, the trans-addition
chemistry[13] currently developed in our laboratory might allow this transformation to be accomplished (Scheme
2). In conceptual terms, the direct ruthenium catalyzed trans-hydrogenation is most desirable: this reaction is
usually distinguished by excellent E/Z-ratios but struggles at the current stage of development with competing
isomerization, particularly if the resulting alkene product is branched at the -position.[14] Such a substitution
pattern incentivizes the migration of the incipient disubstituted double bond by the formation of a more stable
trisubstituted olefinic product.[15,16] Since callyspongiolide has methyl branches on either side of the E-alkene, it
seemed necessary to consider possible alternatives.
The mechanistically related trans-hydrostannation does not have the problem of double bond isomerization; it is
therefore more robust and has proven remarkably tolerant toward a host of reducible functional groups.[17]
Since protodestannation of the resulting alkenylstannanes is facile, this reaction opens a practical gateway to E-
alkenes. While trans-hydrostannation has already served the total synthesis of natural products well,[18] the
compliance of sterically demanding substrates has not yet been studied in the necessary detail. Since the use of
bulky [Cp*Ru]-based catalysts is mandatory for high trans-selectivity,[17,19] this issue might become critical en
route to callyspongiolide in view of the encumbrance of the C10C11 E-alkene site in question.
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Scheme 2. Two chemoselective ways for the conversion of alkynes into E-alkenes that promise to be compatible with other
reducible sites; Cp* = pentamethyl-cyclopentadienyl
Table 1. Model studies on trans-hydrostannation relevant for the projected total synthesis of callyspongiolide.a
Entry Catalyst b
Substrate
Product c
Ratio (Regioisomers) Yieldd
1
[Cp*Ru(MeCN)3]PF6
4:1
95%e
2
3
[Cp*Ru(MeCN)3]PF6
[Cp*RuCl]4
n.d.
< 10%e
80%
20:1
4
5
[Cp*Ru(MeCN)3]PF6
[Cp*RuCl]4
6:1
7:1
90%
52% (81%)f
a Unless stated otherwise, all reactions were performed by adding Bu3SnH (1.1 equiv.) over the course of 5 min to a solution
b
of the substrate and the catalyst in CH2Cl2 (0.1 M) at ambient temperature under Ar; [Cp*Ru(MeCN)3]PF6 (10 mol%) or
c
d
[Cp*RuCl]4 (2.5 mol%), unless stated otherwise; only the major regioisomer present in the mixture is shown; yield of
analytically pure product; e [Cp*Ru(MeCN)3]PF6 (5 mol%); f NMR yield in brackets
The model reactions shown in Table 1, however, augured well for the projected case. Specifically, trans-
[20]
hydrostannation of the substrate shown in entry 1 with the cationic complex [Cp*Ru(MeCN)3]PF6
as
precatalyst furnished the expected mixture of regioisomeric stannanes with excellent trans-selectivity; they
converge to the same alkene product upon protodestannation. This example was meant to test whether methyl
branches on either side of the triple bond would interfere. Somewhat unexpectedly though, this precatalyst
[21]
failed with the protic substrate shown in entry 2, whereas the neutral complex [Cp*RuCl]4
worked very well,
most likely because hydrogen bonding between the –OH group and the catalytically active [Cp*RuCl] fragment
assists substrate binding (entry 3).[19, 22] A cycloalkyne with a transannular enoate served as simplified
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callyspongiolide core model (entries 5/6); gratifyingly, this substrate worked with either catalyst, although the
efficiency of the cationic and the neutral precursor complexes proved markedly different.
Preparation of a First Analogue. Confronted with this notable catalyst dependence, it seemed prudent to first
pursue the synthesis of a callspongiolide analogue lacking the methyl branches at C9 and C12. This modification
follows the logic of “diverted total synthesis” in that the targeted compound 19 cannot be made without undue
effort by modification of the natural product itself;[23,24] provided the excision of the two chiral centers does not
compromise the biological activity,[25] such structural editing potentially pays off in a massive synthetic dividend.
Scheme 3. Preparation of the building blocks: a) a) O3, CH2Cl2, ─78 °C, 5h then Me2S, 0 °C; b) i) 12TFA (20 mol%), Cu(TFA)2
(50 mol%), LiCl, Na2S2O8, MeCN, H2O, 10 °C, ii) NaBH4, 0 °C; iii) KOH, 23 °C, 72% (over four steps, d.r. > 20:1,); c)
propynylmagnesium bromide, 1,4-dioxane, 81 %; d) TBSOTf, 2,6-lutidine, CH2Cl2, 98 %; e) CH3I, nBuLi, THF, 78 °C to RT,
quant.; f) TBAF, HOAc, DMF, 92 %; g) O2 (1 atm), [Cu(MeCN)4]BF4 (5 mol%), 2,2’-bipyridine (5 mol%), TEMPO (5 mol%), NMI
(10 mol%), MeCN; h) TESCl, DMAP, Et3N, CH2Cl2, 98 %; i) propynyllithium, BF3·OEt2, THF, -78 °C, 60 %; j) bis(2,2,2-
trifluoroethyl)phosphonoacetic acid, HOBt, EDC, CH2Cl2, 76 %. DMAP = 4-dimethylaminopyridine; EDC = 1-ethyl-3-(3’-
dimethylaminopopyl)-carbodiimide hydrochloride; HOBt = 1-hydroxybenzotriazole; NMI = 1-methylimidazole; TBAF = tetra-
n-butylammonium fluoride, TBDPS = tert-butyldiphenylsilyl; TEMPO = 2,2,6,6-tetramethylpiperidin-1-oxyl; TES = triethylsilyl;
TFA = trifluoroacetic acid; Tf = trifluoromethanesulfonyl
(R)-(+)--Citronellol served as point of departure (Scheme 3). O-Silylation followed by ozonolysis of 2 furnished
aldehyde 3,[26] which was subjected to organocatalytic -chlorination followed by reductive work-up to give the
terminal epoxide 4 in good yield and high diastereomeric purity (d.r. = 97:3) on a multigram scale.[27,28] The
subsequent opening of the epoxide with propargylmagnesium bromide[29] required careful optimization: It was
found that the use of 1,4-dioxane as the solvent allowed side reactions to be largely suppressed[30] and the
desired product 5 to be isolated in well reproducible 81% yield on a multigram scale. The elaboration of 5 into
the required aldehyde 7 was uneventful; reference, however, is made to the final oxidation step which worked
nicely with O2 as terminal oxidant following a convenient procedure reported by Stahl and coworkers.[31]
The necessary reaction partner 11 was obtained from commercial glycidol by TES protection, regioselective
epoxide opening with propynyllithium in the presence of BF3Et2O and esterification of the resulting alcohol 10
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with bis(2,2,2-trifluoroethyl)phosphonoacetic acid (Scheme 3).[32] A Still-Gennari olefination[33] of 7 with 11 gave
enoate 13 in acceptable yield after chromatographic separation of the minor E-isomer (Scheme 4). Ring closing
alkyne metathesis with the help of the molybdenum alkylidyne complex 20 [34,35] proceeded quantitatively within
10 min at 80°C, furnishing cycloalkyne 14 in 93% yield. Equally gratifying was the fact that the critical trans-
hydrostannation of this compound catalyzed by [Cp*Ru(MeCN)3]PF6 was high yielding.[17,19,22] The expected
mixture of regioisomeric alkenylstannanes 15, each of which was formed with impeccable trans-selectivity (Z:E >
20:1), was subjected to protodestannation to give the desired (E)-alkene 16 as a single product. Swern oxidation
of the primary TES-ether provided a very sensitive aldehyde, which was immediately elaborated into alkenyl
iodide 17 by Takai olefination[36] and deprotection in readiness for Sonogashira coupling with the side chain
fragment 25. As expected, this step was uneventful despite the presence of the carbamate unit in 18, which had
been introduced by reaction of 17 with chlorosulfonyl isocyanate.[37,38] Product 19 thus formed represents a first
analogue of callyspongiolide.
Scheme 4. Preparation of the analogue lacking the methyl branches: a) 11, 18-crown-6, KHMDS, THF, -78 °C, Z:E = 4:1, 57%;
b) 20 (15 mol%), toluene, MS 5 Å, 80 °C, 93%; c) [Cp*Ru(MeCN)4]PF6 (10 mol%), Bu3SnH, CH2Cl2, α:β = 1:1, Z:E = 20:1, 95%;
d) [(Ph2PO2)Cu], DMF, 71%; e) (COCl)2, DMSO, NEt3, CH2Cl2, ─70 °C to ─30 °C; f) CHI3, CrCl2, THF, 0 °C, E:Z = 12:1; g) CSA,
MeOH, 53% over 3 steps; h) chlorosulfonyl isocyanate, CH2Cl2, 0 °C, then H2O, THF, 23 °C, 1h, 95%; i) 25, Pd(PPh3)4 (10 mol%),
CuI, DiPEA, THF, 74%; CSA
= 10-camphorsulfonic acid; DiPEA = diisopropylethylamine; KHMDS = potassium
hexamethyldisilazide; MS = molecular sieves
The required side chain sector was best prepared by a Mukaiyama aldol reaction.[39] Specifically, aldehyde 21
was reacted with keteneacetal 22 in the presence of a chiral Lewis acid catalyst formed in situ from N-Tos-L-
valine and BH3THF (Scheme 5).[40] The optical purity of 23 reached the limits of detection (ee > 99%) after
recrystallization of the crude material (ee = 89%); the enantiomer was prepared analogously (see the Supporting
Information). The constitution and absolute configuration of this product were confirmed by single crystal X-ray
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diffraction (Figure 1). Suffice it to say that the Ye group published a closely related approach while our work was
in progress, although they chose to protect the phenolic site in the starting aldehyde, which adds an extra step
and prevents easy recrystallization of the crude product.[3] Likewise, their elaboration into alkyne 25 slightly
differed from our route. We found it most convenient to subject 23 to a concomitant protection of the alcohol
and the phenol; subsequent adjustment of the oxidation state followed by a Horner-Wadsworth-Emmons
olefination and global deprotection with HF/pyridine gave the required enyne 25 in good overall yield.
Scheme 5. Preparation of the side chain: a) N-Tos-L-Valine, BH3·THF, THF, 0 °C, then aldehyde 21, ─78 °C, 72%, 89% ee, >99%
ee after recrystallization; b) TBSOTf, 2,6-lutidine, CH2Cl2, 97%; c) i) DIBAL-H, toluene, ─78 °C, 96%; ii) Dess-Martin
periodinane, CH2Cl2, 76%; d) i) diethyl ((3-trimethylsilyl)prop-2-yn-1-yl)phosphonate, nBuLi, THF, ─78 °C, 96%, E:Z = 20:1; ii)
HF·pyridine, 98%; DIBAL-H = diisobutylaluminum hydride
Figure 1. Structure of compound 23 in the solid state.
A First Approach towards Callyspongiolide. Encouraged by this success, we embarked into a synthesis of the
proper natural product (Scheme 6). The preparation of the southern fragment used epoxide 4 for the alkylation
of the propionate enolate derived from amide 26.[41] It sufficed to treat the resulting product 27 with acid to
induce cyclization with formation of lactone 28, which was MOM-protected prior to conversion to the internal
alkyne 30 according to a procedure previously developed in our laboratory.[42,43] To this end, the lactone
carbonyl group of 28 was transformed into dichloro-olefin 29,[44] which was then treated with MeLi under iron
catalysis[45] to give the desired alkyne 30 on a multigram scale. Note that the methyl cap in 30 derives from the
organometallic reagent, which likely traps a lithium carbenoid intermediate formed in the first place by
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lithium/halogen exchange. Standard protecting group manipulations followed by oxidation of the primary
alcohol 31 gave aldehyde 32 in readiness for fragment coupling.
Scheme 6. Reagents and conditions: a) LDA, LiCl, THF, then 4, d.r. = 20:1, 70%; b) H2SO4, H2O, 1,4-dioxane, 100 °C, 90%; c)
MOMCl, DIPEA, CH2Cl2, 98%; d) CCl4, PPh3, THF, 80 °C, 68%-72%; e) MeLi, Fe(acac)3 (12 mol%), Et2O, 1,2-diaminobenzene (25
mol%), 0 °C to RT, 73%; f) (i) HCl, MeOH, 60 °C; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 89%; g) CSA (15 mol%), CH2Cl2, MeOH, 0 °C,
60% (+31% of fully deprotected material); h) Dess-Martin periodinane, NaHCO3, 79%; CSA = (─)-camphor-10-sulfonic acid;
MOMCl = (chloromethyl)methylether
The preparation of the required northern fragment started from propargyl alcohol, which was hydrosilylated to
give product 33 on scale (Scheme 7). The derived aldehyde 34 was reacted with allenylboronate 35 in the
presence of (R)-TRIP (5 mol%) to afford the anti-configured homopropargyl alcohol 36 in high yield and
selectivity.[46] After formation of phosphonoacetate ester 40 (Scheme 8), a Still-Gennari olefination with
aldehyde 32 furnished Z-41 in 67% yield along with the corresponding E-isomer (Z:E = 6:1), which were separable
by standard flash chromatography. The subsequent macrocyclization by RCAM proceeded once again smoothly
with the help of the molybdenum alkylidyne 20, which attests to the excellent selectivity of the catalyst for
alkynes in the presence of other -systems.
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Scheme 7. Reagents and conditions: a) PhMe2SiH, Karstedt catalyst, Na, THF, 70 °C, 76%; b) PCC, CH2Cl2, 90%; c) 35, (R)-TRIP
(5 mol%), toluene, 0 °C, 81%, d.r. = 20:1; d) 37, [Ir(cod)Cl]2 (2.5 mol%), (R)-DM-Segphos (5 mol%), THF, HCO2H, Na2SO4, 70 °C,
65%, d.r. = 8:1, 82% ee, 55% (pure diastereoisomer); e) (i) TBAF, THF, 18h; (ii) NaOH, toluene, 110 °C, 1h, 74% (over both
steps); cod = cyclooctadiene; TBAF = tetra-n-butylammonium fluoride; TIPS = tri(isopropyl)silyl.
While the presence of the two flanking methyl branches did not affected alkyne metathesis to any noticeable
extent, it was unfortunate to learn that these groups were detrimental for the envisaged trans-hydrometalation
of cycloalkyne 42. Despite considerable experimentation, neither trans-hydrostannation nor trans-
hydrosilylation[47] proved viable. Changing the catalyst ([Cp*Ru(MeCN)3]PF6, [Cp*RuCl]4), reagent (Bu3SnH,
BnMe2SiH, (EtO)3SiH), solvent (CH2Cl2 or neat)[48] and reaction temperature did not lead to any meaningful
conversion.[49] Moreover, it should be noted that attempted trans-hydrostannation under free radical conditions
could not solve the problem either:[50] rather, isomerization of the Z-configured enoate in 42 with formation of
44 was the only outcome, while no addition to the triple bond took place under the chosen conditions.
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Scheme 8. Reagents and conditions: a) bis(2,2,2-trifluoroethyl)phosphonoacetic acid, EDCI·HCl, HOBt·H2O, CH2Cl2, 70%; b)
[18]-crown-6, KHMDS, THF, ─78 °C, then 32, E:Z = 6:1, 67% of Z isomer (+5% of E isomer); c) 20 (15 mol%), toluene, MS 5 Å,
70 °C, 80%; d) see Text; e) Ph3SnH, AIBN, toluene, 80 °C, Z:E = 4:1, 60%; f) AgF, MeOH, THF, H2O, 92%; g) (i) K2OsO4·2H2O,
NaIO4, 2,6-lutidine, 1,4-dioxane/water (3:1); (ii) CrCl2·THF, CHI3, THF, 25% (unoptimized, over two steps); h) CSA, MeOH,
68%; i) chlorosulfonyl isocyanate, CH2Cl2, 0 °C, then H2O, THF, 71%, (E:Z > 20:1); i) alkyne 25, Pd(PPh3)4 (15 mol%), CuI, DIPEA,
THF, 68%; AIBN = azobisisobutyronitrile; CSA = 10-camphorsulfonic acid, DIPEA = Diisopropylethylamine; EDCI = 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide, HOBt = hydroxybenzotriazole, KHMDS = potassium hexamethyldisilazide
A Second Analogue: Alkynylogous Callyspongiolide. For the failure of the trans-reduction, product 42 was
elaborated into the callyspongiolide analogue 46 comprising a triple bond in lieu of the E-alkene site (Scheme 8).
To this end, 42 was elaborated to the corresponding alkenyl iodide 45. As expected, carbamate formation and
attachment of the side chain were uneventful despite the various protic sites; the desired product 46 was
obtained in an unoptimized 68% yield.
Intelligence Gathering. It was clear at this point that the RCAM/trans-reduction strategy would not open a truly
competitive route to callyspongiolide. However, the difference between the model compounds shown in Table 1
as well as cycloalkyne 14  all of which had succumbed to trans-hydrometalation in respectable yields  and
substrate 42 is non-intuitive. As metal catalyzed trans-addition chemistry is still in its childhood, we were
motivated to investigate a few more aspects for the sake of a better understanding of the field at large.
In a first foray, we tested whether the –SiMe3Ph substituent in 42 might be the culprit (Scheme 9). [Cp*Ru]-
fragments are able to coordinate to (electron rich) aromatic rings in an 6-fashion.[51] Yet, the desilylated
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substrate 47 was just as resilient as the parent compound from which it derived, no matter whether
[Cp*Ru(MeCN)3]PF6 or [Cp*RuCl]4 was used as precatalyst for attempted trans-hydrostannation. Detrimental
catalyst poisoning by irreversible formation of arene sandwich complexes can therefore be safely excluded as
the road block.
Scheme 9. Reagents and conditions: a) AgF, MeOH, THF, H2O, 92%; b) [Cp*Ru(MeCN)3]PF6 (10 mol%) or [Cp*RuCl]4 (2.5
mol%), Bu3SnH, CH2Cl2.
Scheme 10. Reagents and conditions: a) CDI, CH2Cl2, 80%; b) 31, NaH, THF, 79%; c) 20 (15 mol%), toluene, MS 4 Å and 5 Å,
70 °C, 74%; d) (i) K2CO3, MeOH, 90%; (ii) TESCl, Et3N, CH2Cl2, 90%; e) [Cp*RuCl]4 (100 mol%), Bu3SnH, CH2Cl2, ─50 °C, α:β = 9:1,
Z:E = 20:1, then P(CH2OH)3, 71%; f) [(Ph2PO2)Cu], DMF, 70%; CDI = carbonyl-diimidazole; TES = trimethylsilyl; MS = molecular
sieves
Next, we investigated whether assisted substrate binding might allow the problem to be remedied. Previous
work from this laboratory had shown that unprotected OH groups adjacent to a triple bond favor substrate
binding because they engage in hydrogen bonding with the [RuCl] unit of the catalyst; this effect is particularly
pronounced at low temperature.[19,22] In an attempt to study whether such assisted binding might override the
adverse steric effects operative in 42, we targeted alcohol 52 as an adequate substrate. For its preparation, we
saw an opportunity to test the limits of alkyne metathesis by subjecting diyne 50 to the reaction. This compound
was readily accessed from the terminal alkyne derivative 39 via the stable carbamate 49; compound 39 was
readily available from aldehyde 34 via Krische proparylation (Scheme 7).[52,53] Whereas metathesis reactions
engaging two terminal acetylene derivatives[54] remain erratic in our hands, compound 50 comprising one
terminal and one internal alkyne reacted readily on treatment with our molybdenum alkylidyne complex 20 in
the presence of molecular sieves to trap the released propyne. This example corroborates our previous
conclusion that RCAM reactions of this type of substrate are robust and reliable, certainly when performed with
molybdenum alkylidyne catalysts bearing silanolate ligands.[55,56]
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Cleavage of the carbonate tether in 51 followed by silylation of the primary –OH group gave access to
homopropargyl alcohol 52, which allowed the influence of the protic site onto trans-hydrostannation to be
tested. In fact, treatment with Bu3SnH in the presence of the chloride-containing precatalyst [Cp*RuCl]4 under
standard conditions furnished the desired product 53 as a single regio- and diastereomer, but the reaction
ceased prior to reaching full conversion. Upon lowering the temperature to 50°C[22] and increasing the loading
of the ruthenium complex to one equivalent, however, could stannane 53 be isolated in 71% yield. The derived
E-alkene 54 is a fully functional building block for the synthesis of callyspongiolide if one relocates
macrocyclization to the enoate site. This example confirms the positive influence of an unprotected –OH group
on trans-hydrostannation but also shows that the effect does not necessarily suffice to guarantee efficient
catalyst turnover. Future catalyst development must hence try to address the issue that a purely steric mismatch
between a given substrate and the necessary bulky [Cp*Ru] complexes designates an important limitation of
contemporary trans-addition chemistry which is highly selective and functional group tolerant otherwise.
Conclusion
While closure of the macrocyclic frame of the potently cytotoxic marine macrolide callyspongiolide by ring
closing alkyne metathesis (RCAM) at the C10-C11 site worked nicely and attests to the maturity of this
transformation, the envisaged conversion of the resulting cycloalkyne to the desired E-alkene by ruthenium-
catalyzed trans-hydrometalation proved difficult. All gathered evidence suggests that the problem is steric in
origin. In line with this notion, the callyspongiolide analogue 19 lacking the methyl branches on either side of the
E-alkene could be readily made by this methodology. As trans-addition chemistry is currently dependent on the
use of ruthenium complexes endowed with a bulky Cp* ligand, future catalyst development must try to find
slimmer alternatives to overcome this inherent limitation. In view of this lesson, we refocused our effort to
closure of the macrocyclic ring at the enoate functionality of callyspongiolide as outlined in the accompanying
paper.[57]
Experimental Section
All experimental details can be found in the Supporting Information. The material includes compound
characterization data, additional crystallographic information and copies of spectra of new compounds.
Acknowledgements
Generous financial support by the Swiss National Science Foundation (fellowship to G. M.) and the MPG is
gratefully acknowledged. We thank the analytical departments of our Institute for expert support of this study,
in particular Dr. R. Goddard and J. Rust for solving the X-ray structure of compound 23.
12
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For the Table of Contents
Non-Innocent: trans-Addition reactions to alkynes have recently gained momentum by the
introduction of [Cp*RuCl]-based catalysts (Cp* = pentamethylcylcopentadienyl). As the bulky Cp*
ligand is mandatory for high selectivity, steric hindrance in the substrates can be critical. This is
illustrated by the fact that the seemingly innocent methyl branches on the rigid backbone of
callyspongiolide play a key role in determining a viable path to this cytotoxic macrolide.
Keywords: alkyne metathesis  macrolides  natural products  total synthesis  trans-reduction
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