Total synthesis of the tubulin inhibitor WF-1360f based on macrocycle formation through ring-closing alkyne metathesis

Article abstract of DOI:10.1002/anie.201300576

Key steps in this total synthesis of the antimitotic natural product WF-1360F (3) include the formation of the macrocycle through ring-closing alkyne metathesis and the subsequent conversion of the ensuing alkyne moiety into an E-configured double bond. As illustrated by the synthesis of 4, the macrocyclic vinyl iodide 2 can also serve as a common precursor for the synthesis of side-chain-modified rhizoxin analogues (see scheme; TIPS=triisopropylsilyl). Copyright

Full text of DOI:10.1002/anie.201300576

Angewandte
Chemie
DOI: 10.1002/anie.201300576
Total Synthesis
Total Synthesis of the Tubulin Inhibitor WF-1360F Based on
Macrocycle Formation through Ring-Closing Alkyne Metathesis **
Christian M. Neuhaus, Marc Liniger, Martin Stieger, and Karl-Heinz Altmann*
Rhizoxin (1) is a 16-membered macrolide that was first
isolated in 1984 from the plant pathogenic fungus Rhizopus
chinensis by Okuda and co-workers and shown to be the
causative phytotoxin of the rice seedling blight.[1,2] In 2005,
Hertweck and co-workers demonstrated that rhizoxin (1) is
not a fungal metabolite but is produced by a bacterial
endosymbiont of the genus Burkholderia.[3] Rhizoxin (1) is
a potent inhibitor of eukaryotic tubulin polymerization[4] and
it exhibits pronounced in vitro and in vivo antitumor
activity;[5] the compound has been advanced to Phase II
clinical trials but has not shown any relevant clinical
efficacy.[6] In addition to 1, a number of rhizoxin congeners
have been isolated from fermentation broths of Rhizopus
chinensis[4,5a,7] and Burkholderia rhizoxina.[8] These include
the desepoxy variants WF-1360F (2) and rhizoxin D (3);[4] the
growth inhibitory activity of WF-1360F (2) has been reported
to be similar to that of 1[5a] or even significantly higher.[8]
The total synthesis of rhizoxins has been explored in
significant detail, with the majority of the work being directed
at rhizoxin D (3) as the final target structure.[9] Only a single
synthesis of rhizoxin (1) has been completed so far[10] and no
synthesis of 2 has been reported. We have been interested in
developing a new synthesis of 2 and 3 as part of a program
directed at the biological evaluation of side-chain-modified
rhizoxins. In this context we have explored the possibility of
macrocycle formation by ring-closing metathesis (RCM),[11]
a strategy that had not been employed in any previous
rhizoxin synthesis; the immediate cyclization product was to
be vinyl iodide 5, which would serve as the common precursor
for 2 and 3 and different side-chain-modified analogues
(Scheme 1). However, in spite of extensive efforts, 5 could not
be obtained from either diene 4 or a diverse number of
alternative RCM substrates (Scheme 1).[12]
Scheme 1. PG=protecting group.
A
modification of the synthetic strategy was thus
required, leading us to consider ring-closing alkyne meta-
thesis (RCAM)[13] as an alternative approach to macrocycle
formation, as this would allow us to capitalize on the
chemistry developed in the course of the synthesis of 4 to
the largest extent possible. Based on Fꢀrstnerꢁs excellent
work on catalyst development,[14] RCAM has evolved into
a valuable tool for the total synthesis of macrocycles.[15] In this
report we now describe the first total synthesis of the natural
product WF-1360F (2) based on macrocyclization by RCAM
followed by a highly selective radical reduction/isomerization
sequence to install the macrocyclic (E,E)-diene unit.
[*] M. Sc. C. M. Neuhaus,[+] M. Sc. M. Liniger,[+] Prof. Dr. K.-H. Altmann
Swiss Federal Institute of Technology (ETH) Zꢀrich
Department of Chemistry and Applied Biosciences
Institute of Pharmaceutical Sciences, HCI H405
Wolfgang-Pauli-Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: karl-heinz.altmann@pharma.ethz.ch
Homepage: http://www.pharma.ethz.ch/institute_groups/
institute_groups/pharmaceutical_biology/
Retrosynthetically, the initial disconnections of WF-1360F
(2) and rhizoxin D (3) led to diyne 6 (Scheme 2), which was to
be elaborated into the natural products by RCAM/triple-
bond reduction, followed by Stille coupling, to complete the
side chain, deprotection of the C13 hydroxy group, and
directed epoxidation (for 2). Diyne 6 would be obtained by
Horner–Wadsworth–Emmons (HWE) reaction between
phosphonate 7 and aldehyde 8. The former would be accessed
from methyl ketone 9 and unsaturated aldehyde 10 by means
of a Paterson aldol reaction,[16] followed by stereoselective
Dr. M. Stieger
Basilea Pharmaceutica International Ltd.
Basel (Switzerland)
[+] These authors contributed equally to this work.
[**] This work was supported by the Swiss National Science Foundation
(SNF) (Project 200021_126511). We are very grateful to Prof. Dr.
Alois Fꢀrstner, MPI fꢀr Kohlenforschung, Mꢀlheim (Germany), for
the generous donation of samples of his catalysts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300576.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Scheme 3. a) MnO2, CH2Cl2, RT; b) 14, CH2Cl2, reflux, 45% (based on
14); c) LiAlH4, Et2O, 08C; d) MnO2, CH2Cl2, RT, 82% (2 steps);
e) NaH, MeI, THF/DMF 3:1, 08C, 99%; f) MeMgCl, THF, ꢀ208C!
08C, 93%; g) (+)-DIPCl, NEt3, CH2Cl2, ꢀ788C!ꢀ258C; h) (NMe4)BH-
(OAc)3, AcOH, MeCN, ꢀ408C!ꢀ208C, 66% (2 steps); i) TIPSOTf,
2,6-lutidine, CH2Cl2, ꢀ788C, 97%; j) CME-carbodiimide-TsO, DMAP,
(EtO)2P(O)CH2COOH, CH2Cl2, 08C!RT, 82%. CME=N-cyclohexyl-N’-
(2-morpholinoethyl), DIPCl=chlorodiisopinocampheylborane,
DMAP=4-dimethylaminopyridine, OTf=trifluoromethanesulfonate,
TsO =p-toluenesulfonate.
Scheme 2. Target structure and retrosynthesis. TBS=tert-butyldi-
methylsilyl, TIPS=triisopropylsilyl.
the corresponding stannane 12 was achieved by an ultra-
sound-promoted Barbier-type reaction[22] of 21, Mg turnings,
and tributyltin chloride (quantitative, 80% purity by 1H NMR
analysis). Stannane 12 proved to be extremely prone to
protodestannylation even on exposure to buffered silica gel,
which precluded chromatographic purification. Fortunately,
the purity of the material obtained after simple extractive
workup was sufficient for the next step. Thus, transmetalation
of 12 with Coreyꢁs bromoborane complex (prepared from
BBr3 and bistosylated (R,R)-DPEN (22))[23] under conditions
elaborated by Williams et al.[24] and subsequent reaction with
aldehyde 11 at ꢀ788C furnished secondary alcohol 23 in very
good yield and with high diastereoselectivity (74% over
2 steps, d.r. 10:1, 94% recovery of 22). In contrast, conditions
relying solely on Felkin–Anh control (BF3·Et2O) led to poor
diastereoselectivity (d.r. 1.9:1).[25] Esterification of 23 with
acryloyl chloride and subsequent RCM with the Hoveyda–
Grubbs II catalyst[11] (10 mol%) gave dihydropyrone 24;
hydrogenation of the latter with Pearlmanꢁs catalyst
(5 mol%) then furnished d-lactone 25 as a single isomer in
74% overall yield for the three-step sequence from 23.[26] The
elaboration of 25 into alkyne 8 was only possible after
conversion into the corresponding (protected) lactol 26, while
all attempts to install the triple bond by Corey–Fuchs
chemistry in the presence of the lactone moiety led to
complete decomposition of starting material. Tris(silyl ether)
26 was obtained from 25 by DIBALH reduction followed by
treatment with TBDPSCl in 90% yield (2 steps) as a single
isomer (all substituents on the tetrahydropyran ring in
equatorial positions).[27] Selective cleavage of the primary
TBS ether with NaIO4 in aqueous THF[28] followed by Swern
oxidation, Corey–Fuchs alkynylation, and in situ trapping of
1,3-reduction of the resulting b-hydroxy ketone; aldehyde 8
was to be derived from aldehyde 11 and stannane 12 as early
intermediates.
The synthesis of building block 7 commenced with the
MnO2-mediated oxidation of 2-butyn-1-ol (13) followed by
Wittig olefination of the resulting aldehyde with phosphoni-
um ylide 14[17] to provide ester 15 in moderate yield (45%)
(Scheme 3). Reduction of 15 with LiAlH4 and oxidation of the
resulting allylic alcohol with MnO2 afforded the requisite
aldehyde 10. Reaction of 10 with the boron enolate derived
from ketone 9[18] (obtained from alcohol 16[18] by methylation
with MeI/NaH at 08C followed by reaction with MeMgCl in
92% overall yield) under optimized conditions afforded b-
hydroxy ketone 17 in roughly 70% yield; this material still
contained some impurities, mainly isopinocampheol, which
could only be separated after the following step. Reduction of
17 with (NMe4)BH(OAc)3[19] gave the desired 1,3-anti diol 18
as the only isolable isomer in 66% yield (from 9). Treatment
of 18 with TIPSOTf at ꢀ788C provided the C13 TIPS-ether
(rhizoxin numbering) in 97% yield as a single regioisomer.
Carbodiimide-mediated esterification of this intermediate
with diethylphosphonoacetic acid finally furnished building
block 7 in good yield (82%).
The synthesis of building block 8 departed from butane-
1,4-diol, which was monobenzylated;[20] monobenzyl ether 19
was oxidized and the resulting aldehyde was a-methylenated
in situ (CH2NMe2Cl, DBU) in excellent yield (86%), employ-
ing a modification of a procedure originally developed by
Ogasawara and co-workers (Scheme 4).[21] Reduction with
LiAlH4 to give alcohol 20, followed by Appel reaction then
furnished the allylic chloride 21. Conversion of the latter into
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Scheme 4. a) (COCl)2, DMSO, NEt3, CH2Cl2, ꢀ788C!08C, then
CH2NMe2Cl, DBU, RT, 86%; b) LiAlH4, THF, 08C, 96%; c) CCl4, PPh3,
MeCN, RT, 95%; d) Mg, Bu3SnCl, THF, ultrasound, 08C!RT, quant.,
80% purity; e) BBr3, ligand 22, CH2Cl2, RT, then 12, RT, 18 h, then 11,
ꢀ788C, 74% (2 steps, d.r. 10:1); f) acryloyl chloride, DIEA, CH2Cl2,
ꢀ408C, 85%; g) Hoveyda–Grubbs II catalyst, DCE, reflux, 89%; h) H2
(9 bar), Pd(OH)2-C, EtOAc, RT, 98%; i) DIBALH, CH2Cl2, ꢀ788C;
j) TBDPSCl, imidazole, CH2Cl2, RT, 90% (2 steps); k) NaIO4, THF/
water (4:1), RT, 87%; l) (COCl)2, DMSO, NEt3, CH2Cl2, ꢀ788C!RT,
96%; m) CBr4, PPh3, CH2Cl2, ꢀ788C, 99%; n) nBuLi, MeI, THF, ꢀ788C
to RT, 94%; o) TBAF, AcOH, THF, 08C!RT, quant. (28/29, 2:1);
p) TEMPO, BAIB, Yb(OTf)3 (cat.), CH2Cl2, 08C!RT, 62%. BAIB=bis-
(acetoxy)iodobenzene, Bn=benzyl, DBU=1,8-diazabicyclo[5.4.0]-
undec-7-ene, DCE=1,2-dichloroethane, DIBALH=diisobutylaluminum
hydride, DIEA=N,N-diisopropyl ethyl amine, TBAF=tetrabutylammo-
nium fluoride, TBDPS=tert-butyldiphenylsilyl, TEMPO=2,2,6,6-tetra-
methylpiperidin-1-oxyl.
Scheme 5. a) LiCl, DBU, THF/MeCN 3:1, 08C!RT, 81% (88% brsm);
b) catalyst 30a or 30b, MnCl2, toluene, 5 ꢁ molecular sieves, 1258C,
30a: 69%, 30b: 63% (67% brsm); c) 1. [Co2(CO)8], CH2Cl2, RT; 2. 1-
ethylpiperidine hypophosphite, benzene, reflux, 74% over 3 cycles, Z
only; d) AIBN, PhSH, benzene, reflux, 88%, E/Z=20:1; e) [PdCl2-
(MeCN)2], DMF, RT, 68%; f) HF·py, py, THF, 08C!RT, 54%;
g) tBuOOH, [VO(acac)2], benzene, 08C!RT, 65%, 29% after prepara-
tive RP-HPLC. acac=acetylacetonato, AIBN=azobisisobutyronitrile,
brsm=based on recovered starting material, py=pyridine.
related to the larger scale of the reaction with 30b (900 mmol
of 6 vs. 45 mmol for 30a). For the ring-closure to proceed
efficiently, a temperature of at least 1208C was mandatory
(with reaction times between 3 h and 27 h), which in turn
highlights the exceptional thermal stability of catalysts 30a
and 30b.
the intermediate lithium acetylide with MeI then afforded
alkyne 27 in excellent overall yield (78% over 4 steps).
Simultaneous cleavage of both silyl ethers with TBAF/AcOH
produced an inseparable mixture of lactols 28 and 29 (each
as a pair of diastereoisomers; 2:1 ratio in favor of the de-
sired regioisomer 28), which was treated with bis-
(acetoxy)iodobenzene (2.2 equiv) in the presence of catalytic
amounts of TEMPO (19 mol%) and Yb(OTf)3 (4 mol%)[29]
to produce the desired building block 8 as a single isomer in
62% yield (based on bis(TBDPS ether) 27).[30]
Building blocks 7 and 8 were connected in a high-yielding
HWE reaction (DBU/LiCl)[31] to afford diyne 6 as the
substrate for ring-closure by RCAM (Scheme 5). Gratify-
ingly, treatment of 6 with 10 mol% of the Fꢀrstner catalyst
30a[14,15] (Scheme 5) gave the desired macrocycle 31 in an
impressive 69% yield. A somewhat lower yield of 31 was
obtained with catalyst 30b (63%), although this may not be
statistically significant; alternatively, the difference may be
The subsequent reduction of the alkyne moiety in 31
proved to be more challenging than expected. While all
attempts at transition-metal-catalyzed hydrogenation, hydro-
stannylation, hydroboration, and hydrozirconation of the
triple bond met with failure, hydrosilylation was possible with
(EtO)3SiH and Trostꢁs [CpRu(MeCN)3]PF6 catalyst (Cp =
cyclopentadienyl) but not with the [Cp*Ru(MeCN)3]PF6
complex (Cp* = pentamethylcyclopentadienyl).[32] However,
yields after protodesilylation with AgF[33] were low (30–40%
over 2 steps), selectivities were unsatisfactory (E:Z = 1:4.7 to
1:2.6), and the reaction lacked reproducibility. Ultimately, the
most efficient way of processing alkyne 31 was its conversion
into Z olefin 32 by in situ reductive decomplexation of the
corresponding acetylenehexacarbonyl dicobalt complex with
ethylpiperidine hypophosphite (EPHP).[34,35] Using this
approach, 32 was ultimately obtained in 74% yield as
a single isomer after three reaction cycles, which were
required to achieve complete consumption of the starting
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
alkyne 31; full consumption of 31 was mandatory, as 31 and 32
were inseparable. The subsequent Z to E isomerization
proceeded smoothly with AIBN/PhSH in benzene at reflux
and delivered E olefin 33 in 88% yield (E/Z = 20:1).[36] The
overall yield of 33 from 19 (longest linear sequence) was
6.8% (20 steps).
The conversion of 33 into rhizoxin D (3) by means of Stille
coupling with stannane 34 and subsequent removal of the
TIPS protecting group with HF·pyridine has been described
previously.[18,37] Following the corresponding literature pro-
cedures, 3 could be obtained in 37% overall yield, which is
somewhat lower than the yields that have been reported for
this two-step sequence (50%[18] and 76%[37]). No attempts
were made to optimize the transformation of 33 into 3, but we
note that both the protected Stille coupling product as well as
value has been reported against the P388 mouse leukemia cell
line.[5a] Deletion of one alkene unit in the side chain with
concomitant replacement of the oxazole heterocycle by
a pyridine moiety resulted in only a moderate increase in
IC50 values (6- to 10-fold) for 37, which indicates that
analogues with truncated (and potentially more stable) side
chains can retain relevant biological activity.[40] Desoxy
analogues 3 and 36 both proved to be significantly less
active than their corresponding epoxide-containing congeners
(more than 10-fold less active). This is somewhat surprising, as
the activity of rhizoxin D (3) has been implied to be
comparable to that of rhizoxin (1);[9] however, to the best of
our knowledge, no original data on the effects of 3 on
mammalian cells are available in the literature.[41]
In summary, we have accomplished the total synthesis of
the antimitotic natural product WF-1360F (2), based on
macrocyclic ring-closure by RCAM and the efficient con-
version of the ensuing alkyne moiety into the required E-
configured double bond. The successful implementation of
this strategy is highly remarkable, as all attempts to achieve
the corresponding ring-closure by RCM had failed in our
hands. Our approach provides efficient access to vinyl iodide
33, which can serve as a common precursor for the synthesis
of side-chain-modified rhizoxin analogues for structure–
activity studies and lead optimization.
3
were prone to decomposition and thus difficult to
purify.[27,38] In a final step directed epoxidation of the 11,12
double bond in 3 with tBuOOH/[VO(acac)2][39] provided the
natural product WF-1360F (2) in 65% yield and approx-
imately 73% purity. Purification by preparative RP-HPLC
gave analytically pure 2. The NMR data for 3 and 2 were in
perfect agreement with literature data on natural rhizoxin D[7]
and WF-1360F,[8] respectively. Stannane 35 was employed to
elaborate vinyl iodide 33 into the side-chain-modified rhi-
zoxin analogues 36 and 37; the overall yield of 36 was
significantly higher than that of 3 (65% vs. 37%; Scheme 6).
Received: January 22, 2013
Published online: && &&, &&&&
Keywords: drug discovery · metathesis · natural products ·
.
rhizoxin · total synthesis
[1] S. Iwasaki, H. Kobayashi, J. Furukawa, M. Namikoshi, S. Okuda,
Z. Sato, I. Matsuda, T. Noda, J. Antibiot. 1984, 37, 354 – 362.
[2] Elucidation of the absolute configuration of 1: S. Iwasaki, M.
Namikoshi, H. Kobayashi, J. Furukawa, S. Okuda, A. Itai, A.
Kasuya, Y. Iitaka, Z. Sato, J. Antibiot. 1986, 39, 424 – 429.
[3] L. P. Partida-Martinez, C. Hertweck, Nature 2005, 437, 884 – 888.
[4] M. Takahashi, S. Iwasaki, H. Kobayashi, S. Okuda, T. Murai, Y.
Sato, T. Haraguchi-Hiraoka, H. Nagano, J. Antibiot. 1987, 40,
66 – 72.
[5] a) S. Kiyoto, Y. Kawai, T. Kawakita, E. Kino, M. Okuhara, I.
Uchida, H. Tanaka, M. Hashimoto, H. Terano, M. Kohsaka, H.
Aoki, H. Imanaka, J. Antibiot. 1986, 39, 762 – 772; b) T. Tsuruo,
T. Ohhara, H. Iida, S. Tsukagoshi, Z. Sato, I. Matsuda, S.
Iwasaki, S. Okuda, F. Shimizu, K. Sasagawa, M. Fukami, K.
Fukuda, M. Arakawa, Cancer Res. 1986, 46, 381 – 385.
[6] a) H. L. McLeod, L. S. Murray, J. Wanders, A. Setanoians, M. A.
Graham, N. Pavlidis, B. Heinrich, W. W. Ten Bokkel Huinink,
D. J. Wagener, S. Aamdal, J. Verweij, Br. J. Cancer 1996, 74,
1944 – 1948; b) A. R. Hanauske, G. Catimel, S. Aamdal, W.
Ten Bokkel Huinink, R. Paridaens, N. Pavlidis, S. B. Kaye, A. Te
Velde, J. Wanders, J. Verweij, Br. J. Cancer 1996, 73, 397 – 399.
[7] S. Iwasaki, M. Namikoshi, H. Kobayashi, J. Furukawa, S. Okuda,
Chem. Pharm. Bull. 1986, 34, 1387 – 1390.
Scheme 6. a) [PdCl2(MeCN)2], DMF, RT, 97%; b) HF·py, py, THF,
08C!RT, 67%; c) 1. tBuOOH, [VO(acac)2], benzene, 08C!RT;
2. preparative RP-HPLC, 34%.
The antiproliferative activity of 2, 3, 36, and 37 was
assessed against the human pancreatic and colon cancer cell
lines MiaPaCa and HCT116, respectively (Table 1). For WF-
1360F (2), IC50 values were in the single-digit nanomolar
range, which is in general agreement with the data reported
for natural 2 on K-562 and L929 cells;[8] a sub-nanomolar IC50
Table 1: Antiproliferative acitivity of WF-1360F (2), rhizoxin D (3), and
analogues 37 and 36 (IC50 values [nm]).[a]
Compd.
MiaPaCa
HCT116
2
3
37
36
5.1ꢁ0.74
4.5ꢁ0.38
75ꢁ6.9
45ꢁ1.8
49ꢁ6.6
29ꢁ6.1
[8] K. Scherlach, L. P. Partida-Martinez, H.-M. Dahse, C. Hertweck,
J. Am. Chem. Soc. 2006, 128, 11529 – 11536.
[9] For a review see: J. Hong, J. D. White, Tetrahedron 2004, 60,
5653 – 5681.
[10] M. Nakada, S. Kobayashi, S. Iwasaki, M. Ohno, Tetrahedron Lett.
1993, 34, 1039 – 1042.
1432ꢁ246
297ꢁ2.4
[a] Cells were exposed to the tested compound for 72 h. Data are average
values ꢁstandard error of the mean. For details see the Supporting
Information.
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[11] For a general review on the metathesis reaction see: A. H.
Hoveyda, A. R. Zhugralin, Nature 2007, 450, 243 – 251.
[12] These efforts will be reported elsewhere.
[26] The cis substitution pattern in 25 was confirmed by the large
trans-diaxial coupling constants (> 10 Hz).
[27] J. A. Lafontaine, D. P. Provencal, C. Gardelli, J. W. Leahy, J. Org.
Chem. 2003, 68, 4215 – 4234.
[13] For a general review see: A. Fꢀrstner, P. W. Davies, Chem.
Commun. 2005, 2307 – 2320.
[28] J. Li, D. Menche, Synthesis 2009, 1904 – 1908.
[29] This system is similar to the iodosylbenzene/TEMPO/Yb(OTf)3
system: J.-M. Vatꢂle, Synlett 2006, 2055 – 2058.
[14] See, for example: a) J. Heppekausen, R. Stade, A. Kondoh, G.
Seidel, R. Goddard, A. Fꢀrstner, Chem. Eur. J. 2012, 18, 10281 –
10299; b) J. Heppekausen, R. Stade, R. Goddard, A. Fꢀrstner, J.
Am. Chem. Soc. 2010, 132, 11045 – 11057.
[15] See, for example: a) J. Willwacher, N. Kausch-Busies, A.
Fꢀrstner, Angew. Chem. 2012, 124, 12207 – 12212; Angew.
Chem. Int. Ed. 2012, 51, 12041 – 12046; b) W. Chaładaj, M.
Corbet, A. Fꢀrstner, Angew. Chem. 2012, 124, 7035 – 7039;
Angew. Chem. Int. Ed. 2012, 51, 6929 – 6933; c) V. Hickmann, A.
Kondoh, B. Gabor, M. Alcazaro, A. Fꢀrstner, J. Am. Chem. Soc.
2011, 133, 13471 – 13480; d) K. Lehr, R. Mariz, L. Leseurre, B.
Gabor, A. Fꢀrstner, Angew. Chem. 2011, 123, 11575 – 11579;
Angew. Chem. Int. Ed. 2011, 50, 11373 – 11377; e) K. Micoine, A.
Fꢀrstner, J. Am. Chem. Soc. 2010, 132, 14064 – 14066.
[16] I. Paterson, J. M. Goodman, M. A. Lister, R. C. Schumann, C. K.
McClure, M. D. Norcross, Tetrahedron 1990, 46, 4663 – 4684.
[17] M. Handa, K. A. Scheidt, M. Bossart, N. Zheng, W. R. Roush, J.
Org. Chem. 2008, 73, 1031 – 1035.
[18] J. D. White, P. R. Blakemore, N. J. Green, E. B. Hauser, M. A.
Holoboski, L. E. Keown, C. S. Nylund Kolz, B. W. Phillips, J.
Org. Chem. 2002, 67, 7750 – 7760.
[19] D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc.
1988, 110, 3560 – 3578.
[20] M. T. Crimmins, A. C. DeBaillie, J. Am. Chem. Soc. 2006, 128,
4936 – 4937.
[21] S. Takano, K. Inomata, K. Samizu, S. Tomita, M. Yanase, M.
Suzuki, Y. Iwabuchi, T. Sugihara, K. Ogasawara, Chem. Lett.
1989, 1283 – 1284.
[30] Selective oxidation of 29 led to lactone 38, which was isolated in
13% yield.
[31] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masamune, W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25,
2183 – 2186.
[32] B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2005, 127, 17644 –
17655.
[33] F. Lacombe, K. Radkowski, G. Seidel, A. Fꢀrstner, Tetrahedron
2004, 60, 7315 – 7324.
[34] So far EPHP has been employed only in the radical deoxyge-
nation of alcohols and vicinal diols: O. Jang, D. H. Cho,
Tetrahedron Lett. 2002, 43, 5921 – 5924.
[35] The use of NaH2PO2·H2O in 2-methoxyethanol (S. Takai, P.
Ploypradith, A. Hamajima, K. Kira, M. Isobe, Synlett 2002, 588 –
592) led to opening of the d-lactone ring by transesterification.
No reduction was observed in DMSO or CH3CN/H2O.
[36] A new method for the conversion of alkynes into E olefins has
recently been reported by the Fꢀrstner group. Unfortunately,
1,3-enyne units could not be hydrogenated by this method: K.
Radkowski, B. Sundararaju, A. Fꢀrstner, Angew. Chem. 2013,
125, 373 – 378; Angew. Chem. Int. Ed. 2013, 52, 355 – 360.
[37] A. S. Kende, B. E. Blass, J. R. Henry, Tetrahedron Lett. 1995, 36,
4741 – 4744.
[38] The stability of rhizoxin (1) has been investigated: V. J. Stella, K.
Umprayn, W. N. Waugh, Int. J. Pharm. 1988, 43, 191 – 199.
[39] K. B. Sharpless, R. C. Michaelson, J. Am. Chem. Soc. 1973, 95,
6136 – 6137.
[40] See also: Y. Kato, Y. Ogawa, T. Imada, S. Iwasaki, N. Shimazaki,
T. Kobayashi, T. Komai, J. Antibiot. 1991, 44, 66 – 75.
[41] The activity of 17-desmethoxy-17-hydroxyrhizoxin D has been
reported to be similar to that of 17-desmethoxy-17-hydroxy-WF-
1360F.[5a]
[22] Y. Naruta, Y. Nishigaichi, K. Maruyama, Chem. Lett. 1986,
1857 – 1860.
[23] E. J. Corey, C.-M. Yu, S. S. Kim, J. Am. Chem. Soc. 1989, 111,
5495 – 5496.
[24] D. R. Williams, K. G. Meyer, K. Shamim, S. Patnaik, Can. J.
Chem. 2004, 82, 120 – 130.
[25] The absolute configuration of alcohol 23 was secured by Mosher
ester analysis: T. R. Hoye, C. S. Jeffrey, F. Shao, Nat. Protoc.
2007, 2, 2451 – 2458.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Total Synthesis
C. M. Neuhaus, M. Liniger, M. Stieger,
K.-H. Altmann*
&&&& — &&&&
Total Synthesis of the Tubulin Inhibitor
WF-1360F Based on Macrocycle
Formation through Ring-Closing Alkyne
Metathesis
Key steps in this total synthesis of the
antimitotic natural product WF-1360F (3)
include the formation of the macrocycle
through ring-closing alkyne metathesis
and the subsequent conversion of the
ensuing alkyne moiety into an E-config-
ured double bond. As illustrated by the
synthesis of 4, the macrocyclic vinyl
iodide 2 can also serve as a common
precursor for the synthesis of side-chain-
modified rhizoxin analogues (see
scheme; TIPS=triisopropylsilyl).
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!