Chemistry - A European Journal
10.1002/chem.201704379
COMMUNICATION
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de-acetylation gave ancorinoside A (1) in 48% yield as a
chemically and enantiomerically pure solid after recrystallisation
from methanol (scheme 9). The NMR signals were assigned on
grounds of HSQC and HMBC spectra, and by comparison with
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those of the natural isolate. Our synthetic product showed an
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optical rotation of [$]
D
= +7.0 (c = 0.09, MeOH), in contrast to
2
5
[
$]
D
= "5.5 (c = 0.09, MeOH) reported for the natural isolate.
1
This deviation might be due to impurities visible in the H and
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1
3
C NMR spectra of the latter. The CD spectrum of our synthetic
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sample is in line with that reported for the natural isolate,
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including a positive Cotton effect (%& = +0.46 MeOH, ' = 285
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nm).
Hence, we assume that the absolute configuration
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proposed by Ohta et al. for the natural product is correct.
Scheme 7. Synthesis of disaccharide 30. Reagents and conditions: a) Pd/C,
, EtOAc, rt, 3.5 h; 99%; b) TEMPO, BAIB, CH Cl /H O, rt, 2 h; 97%; c)
CO , BnBr, DMF, 0 °C!rt, 3 h; 93%. TEMPO = 2,2,6,6-tetramethyl-1-
piperidinyloxyl, BAIB = bisacetoxyiodobenzene.
%
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2
2
2
%
K
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!./."
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#$
The subsequent removal of the silyl group in acetic acid
afforded the primary alcohol 31 with almost quantitative yield.
We abstained from using TBAF in order to avoid a possible
migration of acetyl protection groups and the generation of by-
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products. The oxidation with DMP provided aldehyde 8 which
was E-olefinated with Ley’s !-ketophosphonate 9 in 45% yield
%&'
%
%
%
[
2c,4,6]
(
scheme 8).
During this HWE reaction a time-dependent
%-
(%%-
decomposition of product 6 was observed which set in prior to a
complete consumption of 8 and which was due to a base-
induced cleavage of the 1!4 glycosidic bond of the diglycoside.
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Scheme 9. Synthesis of ancorinoside A (1). Reagents and conditions: a) NEt
AgO CCF , THF, 0 °C, 3 h; 63%; b) Pd/C, H , EtOAc, rt, 8 h; 84%; c) NaOMe,
MeOH, rt, 1 h; 48%.
3
,
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In summary, we accomplished the first total synthesis of
ancorinoside A (1) in an overall yield of 1.6% over 18 steps in
the longest linear reaction sequence. The fact that a precursor
as delicate as the dicarboxylic acid 5, featuring glycosidic bonds
and potentially unprotected hydroxy groups on the sugar moiety,
can be cyclised under basic Dieckmann conditions is worth
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mentioning. We are confident that
a similar approach is
Scheme 8. Synthesis of the !-ketothioester 6. Reagents and conditions: a)
AcOH/THF/H O, 3/1/1, rt, 2.5 h; 92%; b) DMP, CH Cl , rt, 2 h; 79%; c) i) 9,
NaH, THF, 0 °C, 1 h; ii) 8, THF, rt, 16 h; 45%.
2
2
2
applicable also to the synthesis of the remaining ancorinosides
B-D (2-4).
Keywords: tetramic acid • total synthesis • glycoconjugates •
ancorinosides • natural products
We followed Ley’s protocol for the silver-mediated coupling
of amino ester 7 and thioester 6 to afford !-ketoamide 32 in 63%
[
2c,4]
yield when carried out under exclusion of light.
Since 32 was
[
1]
a) S. Ohta, E. Ohta, S. Ikegami, J. Org. Chem. 1997, 62, 6452-6453; b)
E. Ohta, S. Ohta, S. Ikegami, Tetrahedron, 2001, 57, 4699-4703; c) M.
Fujita, Y. Nakao, S. Matsunaga, M. Seiki, Y. Itoh, R.W.M. van Soest, N.
Fusetani, Tetrahedron, 2001, 57, 1229-1234.
obtained as a mixture of various rotamers and tautomers, a full
assignment of its NMR signals was not possible. A first attempt
to cyclise it to the corresponding tetramic acid under basic
Dieckmann conditions failed due to simultaneous deacetylations
and transesterifications leading to a mixture of unidentified
products. However, by first debenzylating diester 32
hydrogenolytically we obtained the saturated diacid 5 in 84%
yield as an approximately 9:1 mixture of the keto and enol forms.
A final base-induced Dieckmann cyclisation with concomitant
[2]
a) A. D. Wright, C. Osterhage, G. M. König, Org. Biomol. Chem. 2003,
1, 507-510; b) H. V. K. Wangun, H.-M. Dahse, C. Hertweck, J. Nat.
Prod. 2007, 70, 1800-1803; c) S. Loscher, R. Schobert, Chem. Eur. J.
2
013, 19, 10619-10624.
[
3]
a) M. Petroliagi, O. Igglessi-Markopoulou, J. Markopoulos, Heterocycl.
Commun. 2000, 6, 157-164; b) M. Zaghouani, B. Nay, Nat. Prod. Rep.
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