Concise total synthesis of the potent translation and cell migration inhibitor lactimidomycin

Article abstract of DOI:10.1021/ja107141p

An efficient total synthesis of the antiproliferative macrolide and cell migration inhibitor lactimidomycin (3) is reported, which relies on the performance of ring closing alkyne metathesis (RCAM). The strained 12-membered 1,3-enyne 21 as the key intermediate was forged with the aid of [(Ph ₃SiO)₃Mo≡CPh]?OEt₂ (27) as the most effective member of a new generation of powerful alkyne metathesis catalysts. 21 was elaborated to the target by a ruthenium catalyzed trans-hydrosilylation/ proto-desilylation sequence and a highly diastereoselective Mukaiyama aldol reaction controlled by oxazaborolidinone 29 as strategic operations.

Full text of DOI:10.1021/ja107141p

Published on Web 09/10/2010
Concise Total Synthesis of the Potent Translation and Cell Migration Inhibitor
Lactimidomycin
Kevin Micoine and Alois Fu¨rstner*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
Received August 9, 2010; E-mail: fuerstner@kofo.mpg.de
Scheme 1. Glutarimide Macrolides and Retrosynthetic Analysis of
Lactimidomycin (3)
Abstract: An efficient total synthesis of the antiproliferative
macrolide and cell migration inhibitor lactimidomycin (3) is
reported, which relies on the performance of ring closing alkyne
metathesis (RCAM). The strained 12-membered 1,3-enyne
21 as the key intermediate was forged with the aid of
[(Ph3SiO)3MotCPh]·OEt2 (27) as the most effective member of
a new generation of powerful alkyne metathesis catalysts. 21 was
elaborated to the target by a ruthenium catalyzed trans-hydrosi-
lylation/proto-desilylation sequence and a highly diastereoselec-
tive Mukaiyama aldol reaction controlled by oxazaborolidinone
29 as strategic operations.
The family of macrolides derived from the parent compounds
migrastatin (1) and isomigrastatin (2) includes some of the most
promising cell migration inhibitors known to date.1,2 Among them,
the migrastatin core analogues 4-7 are particularly noteworthy as
they were found to inhibit spreading of mammary tumors in mice
without being noticeably cytotoxic.1 These compounds were shown
to selectively target the actin-bundling protein fascin, the overex-
pression of which in malignant tumors is often correlated with a
poor prognosis.3 If clinically viable as inhibitors of metastasis, these
or functionally related small molecules might become an important
second line of defense against cancer, complementing conventional
chemotherapy.
The possible reward of this endeavor brought lactimidomycin
(3) back on stage, a closely related macrolide isolated from
Streptomyces amphibisporus as early as 1992.4,5 Unlike isomigr-
astatin (2), compound 3 is not prone to ring expansion by allylic
rearrangement. A detailed reinvestigation of its biological properties
revealed the potent cell migration inhibitor capacity of 3, which
rivals the best migrastatin analogues.6 Lactimidomycin is also
cytotoxic and exhibits appreciable antiproliferative properties in ViVo
against various tumors including the highly invasive MDA MB 231
human breast adenocarcinoma.4,7 Because nontumorigenic breast
tissue was found to be much less sensitive to 3, the compound holds
an encouraging selectivity profile. In contrast to the fascin inhibitors
4-7, compound 3 interferes primarily with protein synthesis,
blocking the translation-elongation phase by binding to the 60S
ribosome.7 Hence, lactimidomycin and migrastatin differ funda-
mentally in their mode of action at the molecular level, despite an
obvious structural relationship.
but are expected to become even more daunting in the case of 3,
which contains three rather than two alkenes within the macrocycle.
Yet, we opted for a counterintuitive approach, in which the strain
of the precursor is temporarily increased rather than decreased
(Scheme 1). The enthalpic penalty for the formal replacement of
one of the olefins by an alkyne, however, might be counterbalanced
by building upon Danishefsky’s pivotal finding that a late-stage
installation of the enoate double bond was instrumental for the
synthesis of 2.10 The projected incorporation of an alkyne into the
cyclic frame trusts in the power of ring closing alkyne metathesis
(RCAM)11,12 and provides a stringent test for the latest generation
of catalysts developed in our laboratory.13-15 If successful, we
might be rewarded with unambiguous olefin stereochemistry to be
set by semireduction of the interim triple bond.16 Of the two
conceivable scenarios (Scheme 1), Z-enyne B seemed more
promising than its E-enyne counterpart C,17 but this analysis needed
experimental verification. We were hence prepared to pursue both
possible routes.
The required precursors were available in high yield from
aldehyde 13 as a common intermediate, which in turn was derived
from commercial 8 by standard operations, including a Frater-
Seebach alkylation18 and an Evans boron-aldol reaction19 to set
the chiral centers with exquisite selectivity (Scheme 2).20 Extension
of the carbon chain on reaction of 13 with the Ohira-Bestmann
reagent 1721 followed by methylation gave alkyne 14 in good yield.
Alternatively, 13 was subjected to a Julia olefination with sulfone
18,22 which furnished the required Z-enyne 15 in isomerically pure
form.
As part of our agenda concerning the chemistry and biology of
small molecule anticancer agents,8 we developed a concise approach
to lactimidomycin as a first step of a more comprehensive
investigation into the chemical space surrounding this lead com-
pound. The major hurdle derives from the strain inherent to the
12-membered lactone, which incorporates no less than seven sp2-
hybridized C-atoms.9 Problems caused by ring strain had already
surfaced in the only synthesis of isomigrastatin (2) known to date10
Next, 14 and 15 were converted to the corresponding esters 19
and 20, respectively, in preparation for ring closure via RCAM
(Scheme 3). For this purpose, we chose the newly designed complex
9
14064 J. AM. CHEM. SOC. 2010, 132, 14064–14066
10.1021/ja107141p  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2a
be closed with the aid of this complex but furnished a mixture of
(cyclic) dimers and oligomers. In stark contrast, the isomeric
substrate 20 reacted cleanly under high dilution conditions to give
the desired 12-membered enyne 21 as the only product, which was
isolated in 95% (240 mg scale) and 84% (1.2 g scale) yield. The
ring strain of the product is thought to account for the fact that the
cyclization had to be performed at 80 °C, albeit catalyst 27 per se
is fully operative at ambient temperature.13 Since the cyclic enynes
of type B and C are isomeric to each other, the different outcomes
of the reactions of substrates 19 and 20 allow the upper limit of
strain energy to be assessed which can be built-up by alkyne
metathesis; this aspect is currently under investigation in our
laboratory.17 Of equal relevance is the exquisite chemoselectivity
in the cyclization event, as catalyst 27 rigorously distinguished
between the alkene- and alkyne π-bonds of compound 20.
a Reagents and conditions: (a) LDA (2 equiv), THF/HMPA, MeI, -78
°C f 0 °C, 94%; (b) TESCl, pyridine, CH2Cl2, 91%; (c) Dibal-H, CH2Cl2,
-78 °C; (d) Ph3PdC(Me)COOEt, THF, reflux, 92% (over two steps); (e)
Dibal-H, CH2Cl2, -78 °C f 0 °C, 98%; (f) PCC, CH2Cl2, 79%; (g) 16,
Bu2BOTf, Et3N, CH2Cl2, -78 °C f RT, 90%; (h) MeNH(OMe) ·HCl,
Me3Al, THF, -10 °C, 81%; (i) LiAlH4, THF, -78 °C f 0 °C; (j) 17,
K2CO3, MeOH, 0 °C f RT, 61% (over two steps); (k) BuLi, MeI, THF,
73%; (l) 18, KHMDS, THF, -55 °C, 59% (over two steps).
A trans-hydrosilylation/protodesilylation sequence was deemed
ideal for the conversion of 21 to the required E,Z-configured 1,3-
diene 23.23,24 Our previous observation,25 however, that enynes
are reluctant substrates in such transformations got confirmed when
21 was exposed to (EtO)3SiH and [Cp*Ru(MeCN)3]PF6 as the
catalyst. A mixture of regioisomeric alkenylsiloxanes was formed
in low yield, and the workup of the mixture was plagued by
competing siloxane polymerization. Gratifyingly, the use of
BnMe2SiH nicely solved these problems.26 The hydrosilylation was
clean and regioselective, and the subsequent desilylation was
effortless even with commercial TBAF, although this reagent had
previously been found unsuitable for the cleavage of related
alkenylsilanes carrying ordinary trialkylsilyl groups.23-25,27,28
Scheme 3a
The enoate moiety was then installed by quenching of the lithium
enolate derived from 23 with PhSeBr and subsequent oxidative
elimination, following Danishefsky’s lead from the isomigrastatin
series.10,17b Since 23 could be carried through without a protecting
group for the secondary alcohol in the side chain, which had been
liberated concomitantly with the C-Si bond cleavage, a standard
oxidation sufficed to give ketone 25 in readiness for an aldol
reaction with the known aldehyde 28.29 The kinetic lithium enolate
of 25 furnished the desired product as a mixture of isomers (50%,
dr )55:45); attempts to improve on this outcome by using the
corresponding Ipc2B-enolate met with failure.30 Therefore we turned
our attention to a Mukaiyama-aldol process.31 After some experi-
mentation it was found that the tryptophane-derived oxazaboroli-
dinone 29 was the promoter of choice,32 furnishing 26 as the only
isomer, the R-configuration of which was confirmed by Mosher
ester analysis.33 In addition to providing excellent facial bias, the
Lewis acidity of the boron center in 29 is properly adjusted such
that it induces the reaction with ease but does not destroy the acid-
labile product. The final deprotection step had to be carried out
with HF ·pyridine in buffered medium to account for the fact that
lactimidomycin is quite sensitive to more basic fluoride sources.
The spectral data of our synthetic samples were in excellent
agreement with those reported for the natural product.33
a Reagents and conditions: (a) dec-6E-en-8-ynoic acid, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC), DMAP, CH2Cl2, 90%; (b) 27
(5 mol %), toluene; (c) 6-octynoic acid, EDC, DMAP, CH2Cl2, 0 °C f
RT, 96%; (d) 27 (5 mol %), toluene, MS 5 Å, 80 °C, 95%; (e) BnMe2SiH,
[Cp*Ru(MeCN)3]PF6 (10 mol %), CH2Cl2, 0 °C f RT; (f) TBAF, THF, 0
°C f RT, 64% (over both steps); (g) (i) LDA, THF, -78 °C f 0 °C; (ii)
PhSeBr, -78 °C f 0 °C; (h) (i) mCPBA, CH2Cl2, -78 °C; (ii) iPrNEt2,
-78 °C f RT, 64% (over g-h); (i) Dess-Martin periodinane, CH2Cl2, 87%;
(j) (i) LiHMDS, TMSCl, Et3N, THF, -78 °C; (ii) 28, EtCN, then 29, -78
°C; (k) HF ·pyridine, THF/pyridine, 0 °C, 60% (over three steps).
The total synthesis of the translation and cell migration inhibitor
lactimidomycin (3) outlined above illustrates the power of
[(Ph3SiO)3MotCPh]·OEt2 as a representative of the latest genera-
tion of alkyne metathesis catalysts.13 The relevance of this
methodology even for the formation of fairly strained compounds
becomes obvious upon comparison of the RCAM-based approach
to 3 with this RCM-based route to the closely related macrolide
isomigrastatin 2.16 It is believed that the underlying blueprint
provides a firm basis for a synthesis-driven evaluation of this
promising lead compound, since the successful route is short,
productive, and convergent and seems scalable as well as amenable
27 as the arguably most active and selective alkyne metathesis
catalyst known to date.13 The Ph3SiO ligands temper the Lewis
acidity of its Mo(+6) center while imparting outstanding reactivity
on the operative alkylidyne unit. Nevertheless, diyne 19 could not
9
J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010 14065

C O M M U N I C A T I O N S
(11) (a) Fu¨rstner, A.; Seidel, G. Angew. Chem., Int. Ed. 1998, 37, 1734. (b)
Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999,
121, 11108.
to structural diversification. Studies along these lines will be
reported in due course.
(12) (a) Fu¨rstner, A.; Davies, P. W. Chem. Commun. 2005, 2307. (b) Zhang,
W.; Moore, J. S. AdV. Synth. Catal. 2007, 349, 93.
Acknowledgment. Generous financial support by the MPG and
the Fonds der Chemischen Industrie is gratefully acknowledged.
We thank our analytical department for excellent support, Prof. W.
Thiel and Mr. T. Benighaus, Mu¨lheim, for preliminary computa-
tional analyses, and Prof. B. Shen, University of Wisconsin, for
sharing unpublished information on the chiroptical properties of 3
with us.
(13) Heppekausen, J.; Stade, R.; Goddard, R.; Fu¨rstner, A. J. Am. Chem. Soc.
2010, 132, 11045.
(14) (a) Hickmann, V.; Alcarazo, M.; Fu¨rstner, A. J. Am. Chem. Soc. 2010,
132, 11042. (b) Bindl, M.; Stade, R.; Heilmann, E. K.; Picot, A.; Goddard,
R.; Fu¨rstner, A. J. Am. Chem. Soc. 2009, 131, 9468.
(15) For a review on the established alkyne metathesis catalysts, see: Schrock,
R. R.; Czekelius, C. AdV. Synth. Catal. 2007, 349, 55.
(16) In this context it is noteworthy that the RCM en route to isomigrastatin (2)
delivered only 21% of the desired E-olefin together with 36% of the
unwanted Z-isomer. The reaction required a loading of 20 mol% of Grubbs-
II catalyst and heating of the mixture to 110°C in toluene; cf. ref 10.
(17) (a) Intermediate B (R ) SiEt3) was computed to be 8.26 kcal/mol (B3LYP/
TZVP) or 8.19 kcal/mol (B3LYP/TZVPP) less strained than isomer C.
Likewise, the calculations suggest that the alkyne in B should be
significantly less bent than that in C. (b) The strain energy of the analogous
compounds with the enoate in place is prohibitively high, and all attempts
to effect ring closure by RCAM with such substrates were indeed
unsuccessful.
(18) (a) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269. (b)
Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1985, 63, 109.
(19) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
(20) For an analogous building block prepared by the same sequence, differing
only in the chosen protecting group, see: Dunetz, J. R.; Julian, L. D.;
Newcom, J. S.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 16407.
(21) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Mu¨ller, S.; Liepold, B.;
Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(22) Prepared according to: (a) Bonini, C.; Chiummiento, L.; Videtta, V. Synlett
2005, 3067. (b) Bonini, C.; Chiummiento, L.; Videtta, V. Synlett 2006,
2079; for details, see the Supporting Information.
(23) (a) Trost, B. M.; Ball, Z. T.; Jo¨ge, T. J. Am. Chem. Soc. 2002, 124, 7922.
(b) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726. (c) Trost,
B. M.; Ball, Z. T. Synthesis 2005, 853.
(24) For the first application of this methodology to the formation of macrocyclic
E-alkenes, see: Fu¨rstner, A.; Radkowski, K. Chem. Commun. 2002, 2182.
(25) (a) Lacombe, F.; Radkowski, K.; Seidel, G.; Fu¨rstner, A. Tetrahedron 2004,
60, 7315. (b) Fu¨rstner, A.; Bonnekessel, M.; Blank, J. T.; Radkowski, K.; Seidel,
G.; Lacombe, F.; Gabor, B.; Mynott, R. Chem.sEur. J. 2007, 13, 8762.
(26) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895.
(27) See also: Fu¨rstner, A.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 1906.
(28) The reaction is believed to occur via a Si-X intermediate formed upon
selective cleavage of the benzyl substituent; cf. ref 26 and the
following: Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005,
127, 8004.
Supporting Information Available: Experimental section and NMR
spectra of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Gaul, C.; Njardarson, J. T.; Shan, D.; Dorn, D. C.; Wu, K.-D.; Tong,
W. P.; Huang, X.-Y.; Moore, M. A. S.; Danishefsky, S. J. J. Am. Chem.
Soc. 2004, 126, 11326. (b) Shan, D.; Chen, L.; Njardarson, J. T.; Gaul, C.;
Ma, X.; Danishefsky, S. J.; Huang, X.-Y. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 3772. (c) Oskarsson, T.; Nagorny, P.; Krauss, I. J.; Perez, L.;
Mandal, M.; Yang, G.; Ouerfelli, O.; Xiao, D.; Moore, M. A. S.; Massague´,
J.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 3224.
(2) (a) Ju, J.; Lim, S.-K.; Jiang, H.; Seo, J.-W.; Shen, B. J. Am. Chem. Soc.
2005, 127, 11930. (b) Ju, J.; Lim, S.-K.; Jiang, H.; Seo, J.-W.; Her, Y.;
Shen, B. Org. Lett. 2006, 8, 5865. (c) Ju, J.; Rajski, S. R.; Lim, S.-K.;
Seo, J.-W.; Peters, N. R.; Hoffmann, F. M.; Shen, B. Bioorg. Med. Chem.
Lett. 2008, 18, 5951.
(3) Chen, L.; Yang, S.; Jakoncic, J.; Zhang, J. J.; Huang, X.-Y. Nature 2010,
464, 1062.
(4) Sugawara, K.; Nishiyama, Y.; Toda, S.; Komiyama, N.; Hatori, M.;
Moriyama, T.; Sawada, Y.; Kamei, H.; Konishi, M.; Oki, T. J. Antibiot.
1992, 45, 1433.
(5) Ju, J.; Seo, J.-W.; Her, Y.; Lim, S.-K.; Shen, B. Org. Lett. 2007, 9, 5183.
(6) Ju, J.; Rajski, S. R.; Lim, S.-K.; Seo, J.-W.; Peters, N. R.; Hoffmann, F. M.;
Shen, B. J. Am. Chem. Soc. 2009, 131, 1370.
(7) Schneider-Poetsch, T.; Ju, J.; Eyler, D. E.; Dang, Y.; Bhat, S.; Merrick,
W. C.; Green, R.; Shen, B.; Liu, J. O. Nat. Chem. Biol. 2010, 6, 209.
(8) For representative examples, see: (a) Fu¨rstner, A.; Nevado, C.; Waser, M.;
Tremblay, M.; Chevrier, C.; Teply´, F.; A¨ıssa, C.; Moulin, E.; Mu¨ller, O.
J. Am. Chem. Soc. 2007, 129, 9150. (b) Fu¨rstner, A.; Kattnig, E.; Kelter,
G.; Fiebig, H.-H. Chem.sEur. J. 2009, 15, 4030. (c) Bindl, M.; Jean, L.;
Herrmann, J.; Mu¨ller, R.; Fu¨rstner, A. Chem.sEur. J. 2009, 15, 12310.
(d) Nagano, T.; Pospisil, J.; Chollet, G.; Schulthoff, S.; Hickmann, V.;
Moulin, E.; Herrmann, J.; Mu¨ller, R.; Fu¨rstner, A. Chem.sEur. J. 2009,
15, 9697, and references cited therein.
(29) Egawa, Y.; Suzuki, M.; Okuda, T. Chem. Pharm. Bull. 1963, 11, 589.
(30) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(31) Mukaiyama, T. Org. React. 1982, 28, 203.
(32) (a) Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125.
(b) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33,
6907.
(9) For the difficulties arising from the synthesis of an 11-membered ring with
seven sp2-hybridized C-atoms, see: Posp´ısˇil, J.; Mu¨ller, C.; Fu¨rstner, A.
Chem.sEur. J. 2009, 15, 5956.
(10) Krauss, I. J.; Mandal, M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007,
46, 5576.
(33) For details, see the Supporting Information.
JA107141P
9
14066 J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010