Synthesis of the pluramycins 2: Total synthesis and structure assignment of saptomycin B

Article abstract of DOI:10.1002/anie.201308017

A concise, highly convergent total synthesis of saptomycin B, a member of the pluramycin class of antitumor antibiotics, is reported. The target compound was assembled from four building blocks (a tricyclic platform, two sugars, and an alkynal) in 15% yield through 10 synthetic operations. The key steps included the regioselective installation of two amino sugars (l-vancosamine and d-angolosamine) on the tricycle and the efficient construction of the tetracyclic skeleton by an aldol reaction followed by formation of the pyranone. The unknown configuration at C14 was assigned as R.

Full text of DOI:10.1002/anie.201308017

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Angewandte
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DOI: 10.1002/anie.201308017
Natural Products Synthesis
Synthesis of the Pluramycins 2: Total Synthesis and Structure
Assignment of Saptomycin B**
Kei Kitamura, Yoshihiko Maezawa, Yoshio Ando, Takenori Kusumi, Takashi Matsumoto,* and
Keisuke Suzuki*
Dedicated to Professor Dieter Seebach and Dr. Shinichi Kondo
Abstract: A concise, highly convergent total synthesis of
saptomycin B, a member of the pluramycin class of antitumor
antibiotics, is reported. The target compound was assembled
from four building blocks (a tricyclic platform, two sugars, and
an alkynal) in 15% yield through 10 synthetic operations. The
key steps included the regioselective installation of two amino
sugars (l-vancosamine and d-angolosamine) on the tricycle
and the efficient construction of the tetracyclic skeleton by an
aldol reaction followed by formation of the pyranone. The
unknown configuration at C14 was assigned as R.
Although this class of natural products has attracted much
interest from the synthetic community owing to the intriguing
bioactivity and challenging structures, synthetic endeavors
had long been hampered until the recent total synthesis of
a congener, isokidamycin, by Martin and co-workers.[3] In
connection with our long-standing synthetic interest in the
aryl C-glycosides,[4] we are now pleased to report the first total
synthesis of saptomycin B (1) and the assignment of the C14
configuration.
The basis of our synthetic plan was the viability of the bis-
C-glycosylation of anthrone platforms with rigorous regio-
and stereochemical control.[5] Scheme 1 shows our retrosyn-
thetic analysis of 1. Anthrol 2 was envisaged as the immediate
precursor on the assumption of the late-stage introduction of
the C7 carbonyl group. We reasoned that the introduction of
this carbonyl group at a late stage of the synthesis would be
favorable in view of the pronounced photolability of anthra-
Saptomycin B (1) was isolated from Streptomyces sp. HP530
from a soil sample collected in Chiba, Japan, by Sapporo
Breweries researchers.[1a] It shows in vitro and in vivo anti-
tumor activity against human and murine tumor cell lines.
This compound belongs to the pluramycin family of anti-
biotics,[2] which share a common bis-C-glycoside chromo-
phore with a distinctive six-carbon-atom side chain in which
the configuration at C14 was previously unspecified.[1b]
[*] Dr. K. Kitamura, Y. Maezawa, Dr. Y. Ando, Prof. Dr. T. Kusumi,
Prof. Dr. K. Suzuki
Department of Chemistry, Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
E-mail: ksuzuki@chem.titech.ac.jp
Homepage: http://www.chemistry.titech.ac.jp/~org_synth/
Prof. Dr. T. Matsumoto
School of Pharmacy
Tokyo University of Pharmacy and Life Sciences
1432-1, Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
[**] This research was supported by a Grant-in-Aid for Specially
Promoted Research (No. 23000006) from the JSPS. We thank Prof.
Naoki Abe (Tokyo University of Agriculture) for kindly providing
spectroscopic data of saptomycin B.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308017.
Scheme 1. Synthetic plan for saptomycin B (1). Bn=benzyl.
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quinone C-glycosides.[6] For the sake of simplicity, an azide
functional group was selected as the surrogate for both
nitrogen functionalities to enable the simultaneous develop-
ment of the dimethylamino groups.[7] The g-pyrone in 2 would
be accessible from alkynone 3 by 6-endo cyclization.[8]
Alkynone 3 was dissected into the bis-C-glycosyl anthrone 4
and the chiral, nonracemic alkynal 5, which incorporates part
of the A ring and the side chain. We planned to prepare
alkynal 5 in both enantiomeric forms for the assignment of the
C14 configuration. Finally, the bis-C-glycosyl anthrone 4
would be obtained from anthrone 6 by the stepwise installa-
tion of two sugar moieties, N,N-dimethyl-l-vancosamine at
C10 and d-angolosamine at C8. The two differences from the
model study[5] are: 1) Both glycosyl donors, 7 and 8,[9] possess
azido functionalities as equivalents of the dimethylamino
groups, and 2) anthrone 6 has an extra methyl group at C5,
which should not be a problem. The successful realization of
this synthetic plan is presented below.
Scheme 3. Synthesis of the enantiomeric alkynals (R)- and (S)-5:
a) LDA, 12, THF, ꢀ788C!RT, 10 h (95%, d.r.>99:1); b) H2 (balloon),
Lindlar catalyst, quinoline, EtOAc, room temperature, 5 h (93%);
c) LiAlH4, Et2O, 08C, 1 h; d) TPAP (5 mol%), NMO, MS (4 ꢀ), CH2Cl2,
08C!RT, 2 h; e) CBr4, PPh3, Zn, CH2Cl2, room temperature, 3 h (84%
from 14); f) nBuLi, THF, ꢀ78!ꢀ208C; DMF, ꢀ78!08C, 2 h (80%).
LDA=lithium diisopropylamide, TPAP=tetrapropylammonium per-
ruthenate, NMO=4-methylmorpholine N-oxide, MS=molecular
sieves.
The first stage of the successful synthetic route to 1 was
the stepwise, regiocontrolled installation of two amino sugars
on the racemic tricycle 6[10] (Scheme 2). Upon the reaction of
yield (d.r. > 99:1). The newly formed stereogenic center was
verified by X-ray crystallographic analysis.[11] Semihydroge-
nation of 13 gave the Z alkene 14 (93% yield). Next, removal
of the chiral auxiliary in 14 (LiAlH4) and oxidation with
TPAP[13] gave the corresponding aldehyde 15, which was
subjected to a Corey–Fuchs reaction[14] to give dibromide 16
in 84% overall yield in three steps. The treatment of 16 with
nBuLi followed by DMF gave alkynal (R)-5 (99% ee) in 80%
yield.[15] For comparative purposes, the enantiomeric alde-
hyde (S)-5 was prepared from (R)-11 by the same protocol.
The bis-C-glycoside 4 was treated with LDA (ꢀ78!08C)
and combined with the R alkynal 5 at ꢀ788C to afford aldol
Scheme 2. Bis-C-glycosylation of tricycle 6: a) Sc(OTf)3 (30 mol%),
Drierite, ClCH2CH2Cl, ꢀ30!ꢀ108C, 3 h (82%); b) Sc(OTf)3
(50 mol%), Drierite, ClCH2CH2Cl, ꢀ30!288C, 12 h (96%); c) CH3I,
NaH, TBAI, DMF, 08C, 5 h (99%). DMF=N,N-dimethylformamide,
TBAI=tetrabutylammonium iodide.
the l-vancosaminyl acetate 7 with anthrone 6 (2 equiv) in the
presence of Sc(OTf)3 (30 mol%; Drierite, 1,2-dichloroethane,
ꢀ30!ꢀ108C, 3 h), the mono-C-glycoside 9 was obtained in
82% yield as a 1:1 mixture of diastereomers at C5. The
regioselectivity of C-glycoside formation was assigned by an
NOE study, and the b configuration was established on the
basis of 1H NMR spectroscopy (J1,2).[11] The C-glycoside 9 was
combined with the d-angolosaminyl acetate 8 (2 equiv;
Sc(OTf)3, Drierite, ꢀ30!288C, 12 h) to give the bis-C-
glycoside 10 in 96% yield. The anomeric configurations of
the C-glycoside moieties were both b.[11] Methylation of 10
with CH3I and NaH (DMF, catalytic TBAI) protected the C11
phenol group to give anthrone 4.
Alkynal 5 was prepared in both enantiomeric forms by
asymmetric alkylation with the Seebach auxiliary
(Scheme 3).[12] The lithium enolate derived from (S)-11 was
combined with propargyl iodide 12 to give amide 13 in 95%
Scheme 4. Formation of the A ring: a) LDA, ꢀ78!08C, 1 h, then
(R)-5, ꢀ788C, 1 h (89%); b) IBX, DMSO, CH2Cl2, room temperature,
3 h (81%); c) K2CO3, MeOH, room temperature, 6 h (96%). IBX=2-
iodoxybenzoic acid, DMSO=dimethyl sulfoxide.
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methyl protecting group were detached by careful treatment
with BBr3 at ꢀ908C (CH2Cl2, 1 h) to give the final product
(14R)-1. The low temperature was critical at this stage;
substantial decomposition of 1 occurred even at ꢀ788C.
For the purification of 1, besides shielding from light, two
additional precautions were needed. The dimethylamino
group in the angolosamine moiety was highly prone to
oxidation by air to the corresponding N-oxide. Whereas
chromatography on regular silica gel led to considerable loss
of material, aminopropyl-modified silica gel was effective.[19]
Chromatography (preparative TLC on aminopropyl-modi-
fied SiO2; toluene/methanol 9:1) in the dark under argon
cleanly gave (14R)-1 in 62% yield as a reddish-orange
powder.
The 14S congener of 1 was also synthesized from 4 and the
enantiomeric alkynal, (S)-5. The synthesis proceeded
uneventfully to give the final product in similar overall yield
(Scheme 6). Careful purification (see above) gave (14S)-1 as
a reddish-orange powder.
The synthetic samples (14R)-1 and (14S)-1 were clearly
distinguishable by 1H NMR spectroscopy (600 MHz,
CD3OD),[11] thus proving their stereochemical integrity: No
epimerization at C14 occurred during any of the synthetic
transformations for both epimers, which were ready for
comparison with the natural product.
Scheme 5. Completion of the total synthesis of (14R)-1: a) PhI-
(OCOCF3)2, H2O, MeCN, 08C, 1 h; b) DBU, MeCN, 08C, 30 min, then
air, room temperature, 1 h (67% from (14R)-2); c) PMe3, CH2Cl2, room
temperature, 4 h; 37% aqueous HCHO, NaBH3CN, AcOH, MeCN,
08C!RT, 2 h (65%); d) BBr3, CH2Cl2, ꢀ908C, 1 h (62%). DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene.
(14R)-17 in 89% yield (Scheme 4). The oxidation of (14R)-17
with IBX[16] gave 1,3-diketone (14R)-3 in 81% yield without
1
affecting the aromatic system. The H NMR spectrum sug-
gested that (14R)-3 mostly existed in the tautomeric form
shown. The key A-ring annulation occurred cleanly in 96%
yield upon the treatment of (14R)-3 with K2CO3 (MeOH,
room temperature). On this occasion, the 5-exo cyclization
did not compete.[8] The use of methanol as the solvent was
crucial to attain a reasonable reaction rate.
Scheme 5 shows the final stages of the synthesis. In
anticipation of the potential photoinduced degradation, all
manipulations hereafter were performed in brown glassware.
Tetracycle (14R)-2 was carefully oxidized (PhI(OCOCF3)2,
aqueous MeCN, 08C)[17] to the corresponding naphthoqui-
none (14R)-18, which was not isolated, but treated directly
with DBU at 08C. Exposure to air then afforded anthraqui-
none (14R)-19 in 67% overall yield.[18] Quinone (14R)-19 was
reasonably stable at room temperature when stored in the
dark. Next, the two azides in (14R)-19 were simultaneously
converted into N,N-dimethylamino groups via the corre-
sponding iminophosphoranes (PMe3, CH2Cl2, 08C!RT),
which underwent subsequent reductive dimethylation (for-
malin, NaBH3CN, AcOH, 08C!RT) to give diamine (14R)-
20 in 65% yield.[6] Finally, the two benzyl groups and the
Scheme 6. Synthesis of (14S)-1: a) LDA, THF, ꢀ78!08C, 1 h, then
(S)-5, ꢀ788C, 1 h (90%); b) IBX, DMSO, CH2Cl2, room temperature,
3 h (84%); c) K2CO3, MeOH, room temperature, 6 h (89%); d) PhI-
(OCOCF3)2, H2O, MeCN, 08C, 1 h; e) DBU, MeCN, 08C, 30 min, then
air, room temperature, 1 h (59% from 3); f) PMe3, CH2Cl2, room
temperature, 4 h; 37% aqueous HCHO, NaBH3CN, AcOH, MeCN,
08C!RT, 2 h (64%); g) BBr3, CH2Cl2, ꢀ908C, 1 h (73%).
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1 tended to coincide, and even the 13C NMR spectra
(150 MHz) overlapped completely. Upon close inspection of
[4] a) M. Shigeta, T. Hakamata, Y. Watanabe, K. Kitamura, Y.
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[5] See the preceding communication in this issue: K. Kitamura, Y.
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anie.201308016.
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1
the H NMR spectrum, fortunately, a small but clear differ-
ence was noted in the chemical shifts of two hydrogen atoms
near the stereogenic center in question (14-H and one of 16-
CH2); comparison of these signals enabled us to conclude that
the configuration at C14 in the natural product is R.[11]
From a synthetic point of view, the route described is
enabled by the efficient assembly of four building blocks, that
is, tricycle 6, glycosyl donors 7 and 8, and alkynal 5, in 10
synthetic operations to provide saptomycin B (1) in 15%
chemical yield. This convergent route would enable access to
various pluramycin-related natural/non-natural compounds.
Further studies are currently under way.
Received: September 12, 2013
Published online: December 16, 2013
[9] K. Kitamura, M. Shigeta, Y. Maezawa, Y. Watanabe, D.-S. Hsu,
Y. Ando, T. Matsumoto, K. Suzuki, J. Antibiot. 2013, 66, 131.
[10] For the preparation of tricycle 6, see the Supporting Information.
[11] For structure assignment, see the Supporting Information.
[12] a) T. Hintermann, D. Seebach, Helv. Chim. Acta 1998, 81, 2093;
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8707.
Keywords: amino sugars · antibiotics · C-glycosylation ·
pluramycins · total synthesis
.
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