Syntheses of aza-analogues of macrosphelides via RCM strategy and their biological evaluation

Article abstract of DOI:10.1016/j.tet.2011.08.014

Syntheses of 16-membered macrolactams, which were aza-analogues of macrosphelides, could be established effectively by a ring-closing metathesis (RCM) strategy. Novel 19 analogues and six aza-macrosphelide-epothilone hybrids were furnished according to si

Full text of DOI:10.1016/j.tet.2011.08.014

Tetrahedron 67 (2011) 7681e7685
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Syntheses of aza-analogues of macrosphelides via RCM strategy and their
biological evaluation
Kenji Sugimoto a, Yuta Kobayashi a, Ayana Hori a, Takashi Kondo a, Naoki Toyooka b, Hideo Nemoto c,
,
Yuji Matsuya a
*
a Graduate School of Medicines and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
b Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
c Lead Chemical Co. Ltd., 77-3 Himata, Toyama 930-0912, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2011
Received in revised form 4 August 2011
Accepted 5 August 2011
Available online 12 August 2011
Syntheses of 16-membered macrolactams, which were aza-analogues of macrosphelides, could be es-
tablished effectively by a ring-closing metathesis (RCM) strategy. Novel 19 analogues and six aza-mac-
rosphelideeepothilone hybrids were furnished according to simple operations. Biological assay of these
artificial aza-macrosphelides revealed that some of them showed stronger apoptosis-inducing activity
against human lymphoma cells than the parent compound.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Macrosphelide
Aza-analogue
RCM strategy
Apoptosis-inducing activity
1. Introduction
derivatization of macrosphelides and the impressive work on the
structural arrangement of ester (epothilone) to amide (ixabe-
In the field of drug discovery, syntheses of ‘non-natural’ natural
products1 have received much attention because natural products
possess highly promising frameworks for biological activities. Their
importance was proved as diversity-oriented synthesis proposed
by Schreiber and Burke.2 and also known for natural products-
based libraries practiced by Waldmann et al.3 Similarly, natural
product hybrids were recognized as another promising approach
for novel lead compounds, and numerous artificial hybrids were
introduced in the review summarized by Tietze et al.1a Further-
more, as a fact, more than a half of recent drugs on market have
been developed via some modifications of naturally occurring re-
sources.4 Considering such significant potential of ‘non-natural’
natural product, our research was progressed to afford several ar-
tificial biologically active molecules derived from natural sources,
such as OSW-1 derivatives,5 denosomin,6 and macrosphelide ana-
logues.7 During our research program aiming at development of
potential anti-tumor agents under RCM-based divergent synthesis
of macrosphelides, we could fortunately find a notable macro-
sphelideeepothilone hybrid having higher potency than the parent
natural macrosphelide.7g Encouraged by our successful RCM-based
plone),8 which has been believed as one of the hopeful solutions to
metabolic instability in vivo, we next designed aza-analogues
(azaMSs) of bioactive macrosphelides A, B, and oxidized 3 by re-
placement of the one ester oxygen in the macrolactone scaffold by
nitrogen as shown in Fig. 1. We will describe herein an effective
synthesis of artificial aza-macrosphelides, 4-azaMSs, 10-azaMSs,
and 16-azaMSs, and their hybrids with epothilones utilizing our
RCM strategy practically and also report a biological evaluation of
those derivatives as an apoptosis inducer on human lymphoma
cells.
2. Result and discussion
Our synthesis commenced with common enantiopure second-
ary alcohol 4 as a C7eO10 fragment, which was prepared from
commercially available methyl L-lactate according to our preceding
total syntheses of macrosphelides (Scheme 1).7l Alcohol 4 was
condensed with 5, which was readily prepared by the asymmetric
dihydroxylation9 of ethyl sorbate, under Yamaguchi condition to
afford ester 6. Selective desilylation of the TBS group followed by
condensation with N-protected
b
-amino acid 810 afforded the
N4eO16eO10eC7 segment 9. The N-terminus of 9 was trans-
formed into acryloyl amide via deprotectionecondensation steps
then removal of the TBDPS group with TBAFeAcOH furnished the
* Corresponding author. Tel.: þ81 76 434 7530; fax: þ81 76 434 5047; e-mail
address: matsuya@pha.u-toyama.ac.jp (Y. Matsuya).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.014

7682
K. Sugimoto et al. / Tetrahedron 67 (2011) 7681e7685
Fig. 1. Macrosphelides and their aza-analogues.
Scheme 1. Reagents and conditions: (a) 5, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene; then 4, DMAP, 84%; (b) AcOH, THF, H2O, 70%; (c) EDCI, DMAP, CH2Cl2, quant.; (d) (1) TFA,
CH2Cl2; (2) acryloyl chloride, DIPEA, CH2Cl2, 77% (two steps); (e) TBAF, AcOH, THF, 66%; (f) Grubbs’ cat. second, CH2Cl2, 78%; (g) (1) TFA, CH2Cl2, 65% (4-azaMSe1a); (2) DMP, CH2Cl2,
50% (4-azaMSe2a), and 47% (4-azaMSe3a).
RCM precursor 11a. RCM was conducted with Grubbs’ catalyst
second generation to give the corresponding macrolactam 12a in
satisfactory yield. Cleavage of the MEM group by TFA afforded the
desired azamacrosphelide 4-azaMSe1a. DesseMartin oxidation
gave the partially oxidized hydroxyketone 4-azaMSe2a and the
fully oxidized diketone 4-azaMSe3a in 50% and 47% yield,
respectively.
a silylationesaponification sequence from commercially available
methyl (R)-hydroxybutyrate, was lead to the requisite
C13eO16eO4 fragment 15 via Yamaguchi esterification with 4
followed by selective desilylation. In parallel with that, the known
allyl alcohol 1611 was subjected to cross metathesis with ethyl ac-
rylate and subsequent hydrolysis provided the C5eN10 fragment
18. After condensation of alcohol 15 with amino acid 18, resultant
19 was transformed into the RCM precursor 21a through a removal
of the Boc group, introduction of the acryloyl group, and selective
desilylation. RCM of 21a uneventfully established the desired
10-Aza-macrosphelides were also prepared from
4
as
a C13eO16 fragment by the alteration of the ring-closure position
(Scheme 2). Carboxylic acid 13, which was obtained by
Scheme 2. Reagents and conditions: (a) 13, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene; then 4, DMAP, 95%; (b) AcOH, THF, H2O, 84%; (c) ethyl acrylate, Grubbs’ cat. second,
CH2Cl2, 92%; (d) (1) MEMCl, DIPEA, TBAI, CHCl3, 99%; (2) NaOH, MeOH, THF, H2O, quant.; (e) 18, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene; then 15, DMAP, 91%; (f) (1) TFA,
CH2Cl2; (2) acryloyl chloride, DIPEA, CH2Cl2, 74% (two steps); (g) TBAF, AcOH, DMF, 67%; (h) Grubbs’ cat. second, CH2Cl2, 76%; (i) (1) DMP, CH2Cl2; (2) TFA, CH2Cl2, 80% (two steps,
10-azaMSe2a); (j) (1) TFA, CH2Cl2, 71% (10-azaMSe1a); (2) DMP, CH2Cl2, 88% (10-azaMSe3a).

K. Sugimoto et al. / Tetrahedron 67 (2011) 7681e7685
7683
Table 1
macrolactam 22a. Deacetalization afforded the diol 10-azaMSe1a
Chemical yields for the transformations described in Scheme 4
and DesseMartin oxidation gave the diketone 10-azaMSe3a. On
the other hand, the hydroxyketone 10-azaMSe2a was provided in
80% via an oxidationedeprotection sequence.
Compound
R
Yield (%)
a (three steps)
b
c
dd(1) dd(2)
Starting from the common fragment 4 as a C7eO10 unit, we
could prepare 16-azaMSs in a similar fashion (Scheme 3). The
C7eO10eN16 chain was assembled by dehydrative condensation
b
c
Ph
PhCH2
66
72
61
62
79 50
61 94
73
71
between alcohol 4 and a,b-unsaturated carboxylic acid 18. Further
d
e
64
68
54a 83
56
skeletal elongation was accomplished upon treatment with TFA
and condensation with 13. Deprotection and acryloylation of the
O4-terminus followed by removal of the TBDPS group set up the
RCM precursor 27. Exposure of 27 to Grubbs’ catalyst second gen-
eration gave the desired macrolactam in good yield. Finally, the
combination of DesseMartin oxidation and acidic deacetalization
provided 16-azaMSe1a, 16-azaMSe2a, and 16-azaMSe3a.
55
36
74 31a,b 83
32c
53
f
72
31 59
Next, we examined syntheses of N-substituted 10-aza ana-
logues, including aza-macrosphelideeepothilone hybrids contain-
ing a thiazole side chain, utilizing the RCM protocol (Scheme 4 and
chemical yields in each step are summarized in Table 1). Removal of
the Boc group on 19, subsequent reductive amination with 2-
picoline-borane and acryloylation of the N-terminus afforded sec-
a
The reactions were performed in refluxing benzene using modified Hovey-
daeGrubbs’ cat. second as an RCM catalyst. The other RCM reactions were in CH2Cl2
using Grubbs’ cat. second. See, Supplementary data.
b
The reaction was repeated two times using recovered substrate.
PDC was used as an oxidant.
c
Scheme 3. Reagents and conditions: (a) 18, 2,4,6-trichlorobenzoyl chloride, Et3N, toluene; then 4, DMAP, 94%; (b) (1) TFA, CH2Cl2; (2) 13, EDCI, DMAP, CH2Cl2, 91% (two steps); (c)
AcOH, THF, H2O, 92%; (d) acryloyl chloride, DIPEA, CH2Cl2, 77%; (e) TBAF, AcOH, DMF, 59%; (f) Grubbs’ cat. second, CH2Cl2, 82%; (g) (1) DMP, CH2Cl2; (2) TFA, CH2Cl2, 21% (two steps,
16-azaMSe2a); (h) (1) TFA, CH2Cl2, 71% (16-azaMSe1a); (2) DMP, CH2Cl2, 48% (16-azaMSe3a).
Scheme 4. Reagents and conditions: (a) (1) TFA, CH2Cl2; (2) RCHO, 2-picoline$BH3, AcOH, MeOH; (3) acryloyl chloride, DIPEA, CH2Cl2; (b) TBAF, AcOH, DMF; (c) RCM (see, Table 1);
(d) (1) TFA, CH2Cl2 (10-azaMSe1bef); (2) DMP or PDC, CH2Cl2 (10-azaMSe3bef).
ondary acrylamides 20bef. Desilylation of the TBDPS ethers fol-
lowed by treatment with Grubbs’ catalyst second generation
successfully gave N-substituted macrolactam 22bef in good yields.
Compounds 10-azaMSe1bef were furnished by acidic cleavage of
the MEM group and they were finally oxidized to 10-azaMSe3bef
with DesseMartin periodinane or PDC.
As depicted in Scheme 5, N-benzyl derivatives of 4-azaMSs were
prepared from the formerly synthesized N4eO16eO10eC7 frag-
ment 9. After deprotection on nitrogen, reductive amination with
benzaldehyde, followed by condensation led to acryl amide 10b.
Desilylated 11b was allowed to react with Grubbs’ catalyst to afford
macrolactam 12b and the further deacetalizationeoxidation pro-
tocol established 4-azaMSe1b and 4-azaMSe3b, respectively.
Including a reductive amination step, the C13eN16 fragment 16
was uneventfully transformed into N-benzyl 16-azaMSs according
to Scheme 6. Allyl alcohol 16 was protected by a TBDPS group to
give silyl ether 29. Then removal of the Boc group, reductive ami-
nation with benzaldehyde, followed by condensation with car-
boxylic acid 13 furnished the O4eN16eC13 fragment 30. After
desilylation, installation of the corresponding C5eO10 fragment
was achieved by esterification with
a,b-unsaturated carboxylic acid
5. Selective removal of the TBS group and acryloylation set up the

7684
K. Sugimoto et al. / Tetrahedron 67 (2011) 7681e7685
Scheme 5. Reagents and conditions: (a) (1) TFA, CH2Cl2; (2) PhCHO, 2-picoline$BH3, AcOH, MeOH; (3) acryloyl chloride, DIPEA, CH2Cl2, 59% (two steps); (b) TBAF, AcOH, THF, quant.;
(c) Grubbs’ cat. second, CH2Cl2, 63%; (d) (1) TFA, CH2Cl2, 58% (4-azaMSe1b); (2) DMP, CH2Cl2, 53% (4-azaMSe3b).
Scheme 6. Reagents and conditions: (a) TBDPSCl, imidazole, DMAP, DMF, 76%; (b) (1) TFA, CH2Cl2; (2) PhCHO, 2-picoline$BH3, AcOH, MeOH; (3) 13, EDCI, DMAP, CH2Cl2, 87% (three
steps); (c) AcOH, THF, H2O, 76%; (d) 5, EDCI, DMAP, CH2Cl2, 37% (81% br s, m); (e) AcOH, THF, H2O, 93%; (f) acryloyl chloride, DIPEA, CH2Cl2, 90%; (g) TBAF, AcOH, THF, 73%; (h)
Grubbs’ cat. second, CH2Cl2, quant.; (i) (1) TFA, CH2Cl2, 49% (90% br s, m) (16-azaMSe1b); (2) DMP, CH2Cl2, 63% (16-azaMSe3b).
triene 34. After desilylation of 34, metathesis in the presence of
Grubbs’ catalyst produced the desired 16-membered lactam 36.
Finally, cleavage of the MEM ether afforded 16-azaMSe1b and
DesseMartin oxidation provided 16-azaMSe3b.
Having prepared kinds of aza-analogues of macrosphelides, we
performed examinations of apoptosis-inducing activities on human
apoptotic and secondary necrotic cells, revealed that the NeH an-
alogues have no activities on cancer cell possibly due to their low
lipophilicity (data not shown in Table 2). On the other hand, the N-
substituted aza-derivatives were suggested to be a potent candi-
date for anti-tumor agent. Compared with the diol series (azaMS-
1), the diketo-derivatives (azaMS-3) were proved to cause apo-
ptosis more efficiently with low level of undesired necrosis. Among
them, the epothiloneeazaMS hybrid 10-azaMSe3f exhibits a larger
influence on lymphoma cells and the N-benzyl derivative 16-
azaMSe3b showed comparable potency with 3, which was pre-
viously reported by us as the most potent apoptosis inducer among
the natural-type macrosphelides. Finally we could fortunately find
that the N-phenethyl derivative 10-azaMSe3c serves as a specific
apoptosis inducer with largest 43.0% early apoptosis and slight
3.53% secondary necrosis.
lymphoma cell line (U937) after exposure of 10 mM of each azaMS
(Table 2).7 The assay, which was evaluated by percentage of early
Table 2
Evaluation of apoptosis-inducing activity of synthesized azaMS compounds
3. Conclusion
In conclusion, we could exhibit a potential of our RCM strategy
for the construction of the fundamental macrolactam framework of
aza-macrosphelides by delivering a large number of its analogues
in the highly convergent, operationally simple manner. Addition-
ally, this work let us reconfirm that the design of aza-analogue of
natural products could be one of the promising derivatizations for
practical drug discovery. Further syntheses and biological evalua-
tions of azaMSs are now proceeding in our laboratory.
Compound
(X]Y] -OH)
Early apoptosisa
(secondary
necrosis)
Compound
(X]Y]O)
Early apoptosisa
(secondary
necrosis)
a
10-azaMSe1b
10-azaMSe1c
10-azaMSe1d
10-azaMSe1e
10-azaMSe1f
4-azaMSe1b
16-azaMSe1b
1.29 (0.26)
0.52 (0.32)
2.05 (2.23)
1.62 (1.58)
2.34 (1.87)
0.99 (1.08)
0.63 (0.42)
10-azaMSe3b
10-azaMSe3c
10-azaMSe3d
10-azaMSe3e
10-azaMSe3f
4-azaMSe3b
16-azaMSe3b
2.72 (0.58)
43.0 (3.53)
7.26 (2.63)
6.12 (2.99)
16.5 (1.33)
2.51 (0.99)
22.5 (1.97)
4. Experimental
4.1. General
Control
0.78 (0.84)
Compound (3)
27.3 (19.6)
The results showing higher potency than the others are expressed as bold value.
a
Represented as fraction of cells (%). Human lymphoma cells (U937) were treated
with 10 mM concentrations of each azaMS compound for 12e14 h. Percentage of
early apoptotic and secondary necrotic cells were measured by means of flow
Materials were obtained from commercial suppliers and used
cytometry. Results are presented as an average of three experiments.
without further purification unless otherwise noted. Anhydrous THF

K. Sugimoto et al. / Tetrahedron 67 (2011) 7681e7685
7685
Giorgi, G.; Sgaragli, G.; Alderighi, D.; Ghiron, C.; Corelli, F.; Radi, M.; Botta, M.
ChemMedChem 2008, 3, 745e748.
was purchased from Kanto Chemical Co., Inc. Anhydrous Et2O,
CH2Cl2, dioxane, DMF, DMSO, toluene, and MeCN were purchased
from Wako Pure Chemical Industries. Anhydrous MeOH, EtOH,
iPrOH, and NEt3 were dried and distilled according to the standard
protocols. Otherwise noted, all reactions were performed using
oven-dried glassware, sealed with a rubber septum under a slight
positive pressure of argon. Flash column chromatography was car-
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Acknowledgements
This work was supported by the JST with grant ‘A Research for
Promoting Technological Seed’ (for Y.M.).
Supplementary data
Experimental procedures and characterization data for all new
compounds are available in Supplementary data. Supplementary
data related to this article can be found online. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tet.2011.08.014.
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