Formal total synthesis of lactimidomycin

Article abstract of DOI:10.1021/ol401214f

A concise synthesis of an intermediate of lactimidomycin, a glutarimide-containing macrocyclic polyketide produced by an actinomycete, has been accomplished in 35% overall yield from a known vinylketene silyl N,O-acetal by a 10-step sequence that involves two types of asymmetric aldol reactions to install all the stereocenters, the Stille coupling to set up the whole carbon famework, and the Yamaguchi lactonization to construct the 12-membered macrolactone ring.

Full text of DOI:10.1021/ol401214f

ORGANIC
LETTERS
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Vol. XX, No. XX
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Formal Total Synthesis of Lactimidomycin
Tomohiro Nagasawa and Shigefumi Kuwahara*
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science,
Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
skuwahar@biochem.tohoku.ac.jp
Received April 30, 2013
ABSTRACT
A concise synthesis of an intermediate of lactimidomycin, a glutarimide-containing macrocyclic polyketide produced by an actinomycete, has
been accomplished in 35% overall yield from a known vinylketene silyl N,O-acetal by a 10-step sequence that involves two types of asymmetric
aldol reactions to install all the stereocenters, the Stille coupling to set up the whole carbon famework, and the Yamaguchi lactonization to
construct the 12-membered macrolactone ring.
Lactimidomycin (1) is a 12-membered macrolide bear-
ing a glutarimide-containing side chain that was isolated
from Streptomyces amphibiosporus ATCC 53964 by
Sugawara and co-workers as a polyketide antibiotic ex-
hibiting remarkably potent antifungal and antitumor ac-
tivity as well as an inhibitory effect on DNA and protein
biosynthesis (Figure 1).1 Optimization of the fermentation
conditions for lactimidomycin production was later im-
plemented by Shen and co-workers, which led not only
to improved yields of 1 but also to determination of
its absolute stereochemistry and isolation of some new
congeners.2 Their reinvestigation of the biological activity
of 1, structurally related macrolide natural products
including isomigrastatin (2)3 and migrastatin (3),4 and
their semisynthetic derivatives concluded that 1 was
an extremely potent cancer cell migration inhibitor with
IC50 values of 0.60 nM against MDA-MB-231 human
mammary adenocarcinoma cells and 5.03 nM against
4T1 mouse mammary adenocarcinoma cells in a standar-
dized scratch wound healing (SWH) assay, and the poten-
cies of 1 were much superior to those of 2 and 3.5 It was
also reported that 1 and 2 exhibited potent cytotoxicity
against the 4T1 and MDA-MB-231 cell lines at nanomolar
levels.5 Recent biological studieselucidatedthat1inhibited
the elongation step of translation in protein synthesis by
binding to the 60S ribosome and had an in vivo growth-
inhibitory effect on MDA-MB-231 cells subcutaneously
inoculated in mice.6 The reported mode of action of 1,
which is likely to have no direct functional link to cell
migratory ability, prompted a comprehensive biological
re-evaluation of 1, 2, and their synthetic congeners by
7
€
Furstner and co-workers. On the basis of their full doseÀ
response assay, they most recently reached a contradictory
conclusion that lactimidomycin (1) and isomigrastatin (2)
had no appreciable effect on cancer cell migration at
subtoxic doses.
In contrast to continuously disclosed biological and
pharmacological studies on 1À3 including the above-
mentioned controversial issue as well as their action me-
chanism and structureÀactivity relationship studies,8,9 the
(1) Sugawara, K.; Nishiyama, Y.; Toda, S.; Komiyama, N.; Hatori,
M.; Moriyama, T.; Sawada, Y.; Kamei, H.; Konishi, M.; Oki, T. J.
Antibiot. 1992, 45, 1433–1441.
(2) Ju, J.; Seo, J.-W.; Her, Y.; Lim, S.-K.; Shen, B. Org. Lett. 2007, 9,
5183–5186.
(5) 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, 1370–1371.
(6) 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,
209–217.
(3) Woo, E. J.; Starks, C. M.; Carney, J. R.; Arslanian, R.; Cadapan,
L.; Zavala, S.; Licari, P. J. Antibiot. 2002, 55, 141–146.
(4) (a) Nakae, K.; Yoshimoto, Y.; Sawa, T.; Homma, Y.; Hamada,
M.; Takeuchi, T.; Imoto, M. J. Antibiot. 2000, 53, 1130–1136. (b)
Nakamura, H.; Takahashi, Y.; Naganawa, H.; Nakae, K.; Imoto, M.;
Shiro, M.; Matsumura, K.; Watanabe, H.; Kitahara, T. J. Antibiot.
2002, 55, 442–444.
(7) Micoine, K.; Persich, P.; Llaveria, J.; Lam, M.-H.; Maderna, A.;
€
Loganzo, F.; Furstner, A. Chem. Eur. J. 2013, 19, 7370–7383.
r
10.1021/ol401214f
XXXX American Chemical Society

last of which led successfully to the creation of some
structurally simplified migrastin analogues as promising
anticancer agents by Danishefsky and co-workers,10 the
total synthesis of1À3 per se has scarcely been documented;
for 2 and 3 each, two research groups have succeeded in
total synthesis,11,12 and only one group for 1.13 Further-
more, synthetic efforts toward analogues and partial
structures of this family of natural products have been
focused mainly on the 14-membered macrolide 3,9a,10aÀ10-
c,12c,14
while only two reports have so far appeared with
regard to synthetic analogues of the 12-membered macro-
lactones 1 and 2.15 In this context and from its medicinally
important biological activities, lactimidomycin (1) and its
analogues would deserve more attention and synthetic
endeavors. Hoping to further promote the chemistry and
biology of 1 as a potential lead for antitumor drugs, we
describe herein a concise enantioselective synthesis of
truncated macrolide 4, which has previously been trans-
7,13a
€
formed into 1 in four steps by Micoine and Furstner.
Scheme 1 outlines our retrosynthetic analysis of 4. The
target molecule 4 would be derived by macrolactonization
of seco acid 5 coupled with oxidative elimination of the
seleno functionality at the C2 position. We then dissected 5
at its C7ÀC8 single bond into two segments 6 and 7, with
their connection by the Stille coupling reaction in mind.
The vinyl iodide 6 would be prepared from 8 via stereo-
selective installation of a three-carbon unit based on
Figure 1. Lactimidomycin (1), related natural products (2, 3),
and target molecule 4 in the present synthesis.
asymmetric aldol methodology followed by Z-selective
olefination, while the vinylstannane 7 would readily be
obtainable from commercially available acetylenic alcohol
9. The vinylogous aldol 8 bearing two stereogenic centers
at its γ- and δ-positions should be accessible by applying
Kobayashi’s remote asymmetric induction to vinylketene
silyl N,O-acetal 10 and acetaldehyde.16,17
Our three-steppreparation of the vinylstannanesegment
7 from 9 is shown in Scheme 2. Known E-stannyl alcohol
11, obtained by palladium-catalyzed syn-hydrostannation
of 9 according to Chong’s protocol,18 was converted into
iodide 12. Alkylation of ethyl 2-(phenylseleno)acetate with
12 afforded 7 as a racemic mixture.19
(8) For isomigrastatin, see for examples: (a) Ju, J.; Lim, S.-K.; Jiang,
H.; Seo, J.-W.; Shen, B. J. Am. Chem. Soc. 2005, 127, 11930–11931.
(b) Ju, J.; Lim, S.-K.; Jiang, H.; Seo, J.-W.; Her, Y.; Shen, B. Org. Lett.
2006, 8, 5865–5868. (c) Feng, Z.; Wang, L.; Rajski, S. R.; Xu, Z.; Coeffet-
LeGal, M. F.; Shen, B. Bioorg. Med. Chem. 2009, 17, 2147–2153. (d) Ma,
M.; Kwong, T.; Lim, S.-K.; Ju, J.; Lohman, J. R.; Shen, B. J. Am. Chem.
Soc. 2013, 135, 2489–2492 and references cited therein.
(9) For migrastatin, see, for example: (a) Njardarson, J. T.; Gaul, C.;
Shan, D.; Huang, X.-Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126,
1038–1040. (b) Ju, J.; Lim, S.-K.; Jiang, H.; Shen, B. J. Am. Chem. Soc.
2005, 127, 1622–1623. (c) Shan, D.; Chen, L.; Njardarson, J. T.; Gaul,
C.; Ma, X.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U.S.A. 2005, 102,
3772–3776. (d) 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–
5954. (e) Chen, L.; Yang, S.; Jakoncic, J.; Zhang, J. J.; Huang, X.-Y.
Nature 2010, 464, 1062–1066and references cited therein.
(10) (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, 11326–11337. (b) Oskarsson, T.; Nagorny,
P.; Krauss, I. J.; Perez, L.; Mandal, M.; Yang, G.; Ouerfelli, O.; Xiao,
The vinyl iodide segment 6 to be coupled with 7 was
obtained in six steps as shown in Scheme 3. The Kobayashi
vinylogous aldol reaction of the known ketene silyl
N,O-acetal 10 with acetaldehyde proceeded with excellent
ꢀ
D.; Moore, M. A. S.; Massague, J.; Danishefsky, S. J. J. Am. Chem. Soc.
2010, 132, 3224–3228. (c) Lecomte, N.; Njardarson, J. T.; Nagorny, P.;
Yang, G.; Downey, R.; Ouerfelli, O.; Moore, M. A. S.; Danishefsky, S. J.
Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 15074–15078.
(11) For 2, see ref 7 and the following: Krauss, I. J.; Mandal, M.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 5576–5579.
(12) For 3, see ref 10a and the following: (a) Gaul, C.; Njardarson,
J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042–6043. (b)
Reymond, S.; Cossy, J. Eur. J. Org. Chem. 2006, 4800–4804. (c)
Reymond, S.; Cossy, J. Tetrahedron 2007, 63, 5918–5929. (d) Reymond,
(16) Shirokawa, S.-i.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 13604–13605.
(17) For the Kobayashi vinylogous aldol reaction, see also: (a)
Nicolaou, K. C.; Guduru, R.; Sun, Y.-P.; Banerji, B.; Chen, D. Y.-K.
Angew. Chem., Int. Ed. 2007, 46, 5896–5900. (b) Nicolaou, K. C.; Sun,
Y.-P.; Guduru, R.; Banerji, B.; Chen, D. Y.-K. J. Am. Chem. Soc. 2008,
130, 3633–3644. (c) Shinoyama, M.; Shirokawa, S.-i.; Nakazaki, A.;
Kobayashi, S. Org. Lett. 2009, 11, 1277–1280. (d) Wang, L.; Gong, J.;
Deng, L.; Xiang, Z.; Chen, Z.; Wang, Y.; Chen, J.; Yang, Z. Org. Lett.
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Chen, J.; Yang, Z. Org. Lett. 2011, 13, 74–77. (f) Symkenberg, G.;
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(13) See ref 7 and the following: (a) Micoine, K.; Furstner, A. J. Am.
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Scheme 1. Retrosynthetic Analysis of 4
Scheme 2. Preparation of Vinylstannane Segment 7
Scheme 3. Preparation of Vinyl Iodide Segment 6
diastereoselectivity to give 13 (dr >20:1).16,17 After pro-
tection of its hydroxy group as the corresponding TES
ether, the resulting oxazolidinone 14 was reduced with
DIBAL to directly give aldehyde 8. Conversion of 8 into
aldol 17 was best accomplished by exposing 8 to ketene
silyl S,O- acetal 15 in the presence of catalytic amounts of
Sn(OTf)2 and chiral amine 16 in propionitrile according to
the literature,20 furnishing thiol ester 17 in 86% yield along
with a small amount (ca. 10%) of an alcoholic product
generated by deprotection of the TMS group. Reduction
of 17 by Fukuyama’s method gave aldehyde 18 almost
quantitatively,21 which was then subjected to a Z-selctive
Witting olefination to afford 6 (Z/E > 20:1).22
With the two segments 6 and 7 in hand, we proceeded
to the final stage of our synthesis of 4 (Scheme 4). The
coupling of 6 and 7 was conducted according to Corey’s
modification of the Stille coupling reaction to give 19 in
89% yield.23 The product 19 was considered to be gener-
ated as a 1:1 diastereomeric mixture at the C2 stereocenter,
although the diastereomers were indistinguishable both in
1H and 13C NMR spectra. Gratifyingly, saponification of
the ester 19 brought about concomitant selective removal
of the TMS protecting group, giving directly the seco
acid 5 in an excellent yield of 93%. Exposure of 5 to the
Yamaguchi lactonization conditions proceeded smoothly
to afford selenolactone intermediate 20.24,25 Interestingly,
1H NMR analysis of crude 20 indicated that the seleno-
lactone was obtained as a ca. 5:1 mixture of inseparable
diastereomers withrespect tothe C2 position, which would
probably be ascribable to the intervention of equilibrium
(20) Kobayashi, S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. Tetrahedron
1993, 49, 1761–1772.
(21) (a) Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T.
Synlett. 2004, 477–480. (b) Fukuyama, T.; Tokuyama, H. Aldrichimica
Acta 2004, 37, 87–96.
(22) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173–2174.
(23) (a) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 7600–7605. (b) Ohtani, T.; Tsukamoto, S.; Kanda, H.; Misawa, K.;
Urakawa, Y.; Fijimaki, T.; Imoto, M.; Takahashi, Y.; Takahashi, D.;
Toshima, K. Org. Lett. 2010, 12, 5068–5071.
(24) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
Org. Lett., Vol. XX, No. XX, XXXX
C

and deprotection of the TES group,26 furnishing the target
molecule 4 with high E/Z selectivity (>20:1) in 92% yield
from the seco acid 5.27 The 1H and 13C NMR spectra of 4
were identical to those of an authentic sample, and the
specific rotation of 4 [[R]24D À234 (c 1.12, CHCl3)] showed
Scheme 4. Completion of the Synthesis of 4
good agreement with a reported value [[R]22 À232.7
D
(c 1, CHCl3)].13a
In conclusion, the enantioselective synthesis of the lacti-
midomycin precursor 4 was accomplished from the known
ketene silyl N,O-acetal 10 by the concise 10-step sequence
(35% overall yield) that features the highly diastereo-
selective construction of the vinylogous aldol 13, Sn(II)-
catalyzed asymmetric aldol reaction to form the thiol
ester 17, the Stille coupling to assemble the whole carbon
framework, and the Yamaguchi lactonization to install
the 12-membered ring. In addition, the saponification
and oxidative elimination steps (19 f 5 and 20 f 4) were
accompanied by deprotection of the TMS and TES
groups, respectively, as concomitant reactions, which en-
abled the shortening of our synthetic pathway. Our efforts
directed toward the total synthesis of lactimidomycin 1,
beginning with a glutarimide-containing aldehyde (instead
of acetaldehyde in the present formal synthesis), are now in
progress and will be reported in due course.
between the major and the minor diastereomers in the
macrolactonization process. Finally, treatment of the epi-
meric mixture 20 with NaIO4 in aqueous THF induced
both the oxidative elimination of the seleno functionality
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan (Nos. 225127 and 22380064).
(25) It is worth mentioning that the Yamaguchi lactonization of a
seco acid which is identical to 5 except for the presence of a double bond
at the C2ÀC3 position (instead of the PhSe group) as well as a TBSO
group at the C15 position (instead of the TESO group) gave the
corresponding 12-membered lactone (2,6,8,12-tetraene) in a poor yield
of 22%. For the difficulty to prepare analogous unsaturated 12-mem-
bered macrolides, see refs 7 and 13a,13b.
(26) For deprotection of silyl ethers with NaIO4, see: Wang, M.; Li,
C.; Yin, D.; Liang, X.-T. Tetrahedron Lett. 2002, 43, 8727–8729.
(27) We are considering that both epimers of 20 were converted
selectively into the E-configured macrolactone 4 on the basis of ob-
servations by Danishefsky and co-workers in their total synthesis of
isomigrastatin. For details, see ref 11.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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