Total synthesis and structural revision of sekothrixide

Article abstract of DOI:10.1021/ol5006856

The first total synthesis of 14-membered macrolide sekothrixide and the originally proposed structure are reported. Seven contiguous asymmetric centers in the side chain were constructed using ring-openings of several kinds of epoxide. Assembly of the lef

Full text of DOI:10.1021/ol5006856

Letter
pubs.acs.org/OrgLett
Total Synthesis and Structural Revision of Sekothrixide
Naoki Terayama,† Eiko Yasui,† Megumi Mizukami,‡ Masaaki Miyashita,† and Shinji Nagumo*,†
†Department of Applied Chemistry Kogakuin University Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan
‡Hokkaido Pharmaceutical University, School of Pharmacy, Katsuraoka 7-1, Otaru, Hokkaido 047-0264, Japan
S
* Supporting Information
ABSTRACT: The first total synthesis of 14-membered
macrolide sekothrixide and the originally proposed structure
are reported. Seven contiguous asymmetric centers in the side
chain were constructed using ring-openings of several kinds of
epoxide. Assembly of the left segment and right segment was
performed on the basis of the RCM reaction to generate 14-
membered lactones having an E-trisubstituted olefin. These
synthetic results led to a revision of C4, C6, and C8
stereochemistry in the structure of natural sekothrixide.
ultidrug resistance (MDR) is a serious problem in
cancer chemotherapy. Cellular desensitization to a broad
agreement with natural sekothrixide, and eventually, the
absolute configuration of sekothrixide was revised as structure
1. We report herein the first total synthesis of sekothrixide (1)
by means of acyclic stereocontrol based on several types of
epoxy ring opening and revision of the proposed structure of
sekothrixide.
M
range of chemotherapeutic agents is often associated with
overexpression in tumor-cell membranes of P-glycoprotein,
which excretes drugs from the cell interior through a molecular
pump.1 Seto et al. reported that sekothrixide, isolated from
Saccharothrixide sp. CF24, exhibited cytocidal activity against
colchicine-resistant KB cells (KB-C2) with an IC50 of 6.5 μg/
mL in EAGLE’s minimum essential medium.2 Furthermore, it
showed synergistic activity against KB-C2 with an IC50 of 1.0
μg/mL in the presence of colchicines (1.5 μg/mL). Their first
report showed a planar structure, composed of a 14-membered
β-ketolactone possessing an E-10,11-trisubstituted olefin and a
highly oxygenated long side chain (Figure 1). Five years later,
We designed a convergent synthetic route consisting of the
left segment A and right segment B (Scheme 1). These
Scheme 1. Retrosynthetic Analysis of Structure 2
Figure 1. Revised and proposed structures of sekothrixide.
the relative configuration of the seven continuous stereocenters
in the side chain was determined by chemical degradation and
1
careful analyses of H and 13C NMR spectra of the compound
obtained.3 In contrast, stereocenters at the C4, C6, and C8
positions were assigned on the basis of results of computational
chemistry.3 Although the absolute configuration of sekothrixide
was not verified by any other experiment, Seto et al. proposed
the three-dimensional structure of 2 by also considering that
four stereocenters in the 14-membered lactone ring were in
accordance with Celmer’s rule.4 Interesting biological proper-
ties as well as the unique structure of sekothrixide stimulated us
to set about its total synthesis. As described below, the
stereoisomer 2 obtained by our synthetic effort was not in
segments were expected to be joined by esterification and ring-
closing metathesis (RCM) reaction.5,6 Segment B could be
obtained using stereoselective alkylation7 and enzymatic
desymmetrization of meso-2,4-dimethyl-1,5-pentadiol.8 Seg-
ment A could be synthesized from C through selective cleavage
of silylene9 and subsequent homologation. Construction of
Received: March 5, 2014
© XXXX American Chemical Society
A
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Letter
seven contiguous asymmetric centers in C could be synthesized
from G (via D, E, and F) based on ring-openings of several
kinds of epoxide. This plan requires that the ring-opening of D
occurs adjacent to the secondary alcohol.
Scheme 3. Synthesis of Left Segment 18
Initially, we aimed at the total synthesis of the originally
proposed sekothrixide 2. Reduction of epoxy alcohol 310 with
Red-Al11 resulted in epoxide opening to generate a mixture of
1,3-diol and 1,2-diol with a ratio of ca. 2:1. After oxidative
degradation of the undesired 1,2-diol with NaIO4, purified 1,3-
diol was converted to alcohol 4 by protection with a di-tert-
butylsilylene group12 and removal of a p-methoxybenzyl group
(Scheme 2). Oxidation of 4 with IBX followed by Wittig
Scheme 2. Synthesis of Enone 9
overall yield. To our delight, when the secondary alcohol was
protected with a trimethylsilyl group, nucleophilic attack
occurred preferentially adjacent to the TMS silyl ether. Thus,
treatment of 12 with Me2CuLi resulted in a highly
regioselective opening to generate 13 in high yield after
treatment with NaIO4. Diol 13 was converted to 15 via removal
of the MOM group upon treatment with anisole and AlCl3,20
regioselective acetalization, and protection with ethyl vinyl
ether. The next task was regioselective cleavage of silylene.9
Treatment of 15 with MeLi in Et2O did not result in any
reaction. Interestingly, addition of TMEDA promoted prefer-
ential cleavage of the Si−O bond at the terminal side, leading to
primary alcohol 16 in 85% yield. After oxidation of 16 with
TPAP, the aldehyde obtained was converted to terminal alkene
17 through Wittig reaction. Removal of the di-tert-butylme-
thylsilyl group, which was highly stable, was accomplished by
CsF in DMSO at 120 °C to afford the left segment 18.
reaction afforded the conjugated ester 5, which was trans-
formed to trans-epoxy sulfide 6 by sequential DIBAH
reduction, Katsuki−Sharpless (KS) epoxidation,13 and sulfide
formation upon treatment with PhSSPh/nBu3P/pyridine.14 The
key alkylation of epoxy sulfide 6 with Me3Al occurred
successfully with double inversion via episulfonium ion to
afford sulfide 7 as a single stereoisomer in 80% yield.15
Protection of 7 with a MOM group followed by m-CPBA
oxidation produced sulfone 8 in excellent yield, followed by
conversion to 9 in three steps: (1) coupling with 1,2-
epoxybutane under basic conditions, (2) IBX oxidation, and
(3) elimination upon treatment with DBU.
Three asymmetric centers at C17−C19 have been
introduced by a sequential method consisting of Corey−
Bakshi−Shibata (CBS) reduction,16 KS epoxidation of the
secondary allyl alcohol,17 and ring-opening of anti-epoxy
alcohol with an organocopper reagent (Scheme 3). When a
stoichiometric amount of chiral oxazaborolidine was used, CBS
reduction of 9 furnished the desired alcohol 10 as a major
component with an epimeric ratio of 15:1.18 The absolute
configuration at the C19 position was confirmed using a
modified Mosher’s method.19 Secondary allylic alcohol 10 was
subjected to KS epoxidation with L-DIPT at −30 °C, which was
nicely matched with the S configuration at the C19 position,
generating β-epoxide 11 as a single isomer in 83% yield. Next,
our attention was focused on regiochemical control in the ring-
opening of epoxide with a Gilman reagent. At first, substitution
of epoxy alcohol 11 with Me2CuLi proceeded nonselectively to
give a mixture of 1,3-diol 13 and 1,2-diol 14 with a ratio of ca.
1:1, which was treated with NaIO4 and subsequently purified by
column chromatography on silica gel leading to pure 13 in 39%
Scheme 4 shows the synthesis of right segment 24. Optically
active alcohol 19,21 which was prepared by a chemoenzymatic
method,8 initially was converted to 21 through oxidation with
IBX, Horner−Emmons elongation with phosphonate 20,22 and
catalytic hydrogenation. Stereoselective methylation7 of 21
Scheme 4. Synthesis of Right Segment 24
B
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produced trimethyl compound 22 in 83% yield, which was
transformed into 2323 in six steps: (1) reduction with LiBH4,24
(2) silylation, (3) removal of the MPM group, (4) iodination,
(5) coupling with a propenyl Grignard reagent in the presence
of CuI, and (6) desilylation. Furthermore, 23 was converted to
24 by (1) IBX oxidation, (2) a Mukaiyama aldol reaction with
ketene silyl acetal,25 and (3) hydrolysis of the resulting ester.
Also ent-24, the right segment of 1, was synthesized from ent-
2323 in a similar way.
Scheme 5. Synthesis of Sekothrixide 1
With the left segment 18 and right segment 24 prepared,
assembly of the 14-membered lactone was performed on the
basis of macrocyclic RCM. Treatment of both segments with 2-
methyl-6-nitrobenzoic anhydride, Et3N, and DMAP provided
25 in 72% yield.26 Upon treatment with Grubbs’ second
catalyst in refluxing CH2Cl2, RCM of 25 occurred E-selectively
to afford 14-membered lactone, which was subjected to removal
of the silyl group using TBAF. The alcohol 26 obtained was
finally converted to the proposed sekothrixide structure 2 by
the sequence of oxidation with TPAP and removal of the
protective group. The 13C NMR spectrum showed a character-
istic E-allyl methyl carbon peak at approximately δ 18.0.27
However, the 1H and 13C NMR spectra of 2 did not match that
of natural sekothrixide, with the greatest differences involving
peaks from the ketolide portion. The methylene protons for C2
of natural sekothrixide gave signals at δ 3.50 and 3.29, while
peaks from the corresponding protons in 2 were observed at δ
3.49 and 3.40. The C4 proton of 2 gave a peak δ 0.19 upfield of
that for the corresponding proton (δ 2.91) in the natural
product. A characteristic peak for C7−H in the natural product
appeared at δ 0.51 but was not observed in 2. In contrast, peaks
assigned to the side chain were very similar between 2 and
natural sekothrixide, suggesting that errors existed in the 14-
membered lactone. These findings led to an attempt at
convergent assembly of 18 and ent-24 in a manner similar to
that used to produce 2. As a result, we succeeded in the
synthesis of 1, for which the 1H and 13C NMR spectra and the
high-resolution mass spectrum were identical to those for
natural sekothrixide. The optical rotation of synthetic
sekothrixide was [α]D = −46.4 (c = 0.18, MeOH), which had
the same sign as that for natural sekothrixide [[α]D = −45.1 (c
= 1.00, MeOH)]. Consequently, the relative and absolute
configurations of sekothrixide were unequivocally determined
to be that shown as structure 1.
In conclusion, we have accomplished the first total synthesis
of sekothrixide (1) (Scheme 5). The left segment 18, which
possesses seven contiguous asymmetric centers, was con-
structed stereoselectively using stereospecific alkylation of
epoxysulfide 6 with Me3Al, regioselective substitution of an
epoxide linked to silyloxy group 12 with Me2CuLi and
regioselective cleavage of silylene 15. Notably, the key RCM
reaction proceeded stereoselectively to generate 14-membered
lactones having an E-trisubstituted olefin. Total synthesis of 1
revised the C4, C6, and C8 stereochemistry of the originally
proposed structure 2, which was against Celmer’s rule. The
established route would be applicable to the syntheses of other
stereoisomers of the lactone portion. These findings will
contribute to the development of effective chemotherapy
agents against MDR.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures along with experimental and spectro-
scopic data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bt13071@ns.kogakuin.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate financial support from the Ministry of
Education, Culture, Sports, Science and Technology, Japan (a
Grant-in-Aid for Scientific Research (B) (No. 19350027) and
the Advanced Promotion Research Program for Education of
Graduate School).
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