compatibility of specific protecting groups, cognizant of the
possibility of ꢀ-elimination in the ꢀ-chloro-D-leu residue. The
TBS ether 22 was coupled to 1-aminobutyl bis-N-Boc-
guanidine 23 (bis-Boc agmatine), and the Cbz group was
cleaved to give 24 (Scheme 3). Coupling with the O-MOM
ꢀ-chloro-D-leu subunit 21 in the presence of DEPBT as a
preferred reagent7,11 proceeded uneventfully in spite of the
modest yield. Sequential deprotection of the TBS and
O-MOM groups with HF in aqueous MeCN, then the N-Boc
groups with TFA, afforded the intended aglycon 25. The 1H
and 13C spectral characteristics matched those published for
aeruginosin 205B (2)1 except for the absence of resonances
due to the sulfated D-xylopyranosyl moiety.8 Thus, the
reported values for the Pla and Cleu subunits were quasi-
identical to those in the synthetic sample of 205B aglycon
(25). The same was also true for the Choi subunit with
allowance made for C-6, which carries a glycosidic moiety
in the natural product. Compound 25 inhibited the enzyme
thrombin at IC50 ) 0.31 µM.
and Nemoto proposal,3 we planned the synthesis with the
intention of securing the 3-sulfate in the D-xylopyranosyl
subunit of aeruginosin 205B (7a). Model studies indicated
that the 2-thiopyridyl carbonate (TOPCAT) was a suitable
method for anomeric activation.12 The requisite glycosyl
donor 26 was prepared in a straightforward manner.8
Treatment of a mixture of 12 and 26 in ether-DCM with
AgOTf in the presence of tetramethylurea as an acid
scavenger12 led to the desired R-anomer 27 (43%), easily
separable from the ꢀ-anomer 28 (53%) by column chroma-
tography in 96% yield (Scheme 4). Many attempts to enrich
the mixture in the R-anomer 27 were not successful.
Nevertheless, we were pleased that glycoside synthesis of
the axially oriented C-6 hydroxyl group in 12 had proceeded
in such high yield and reasonable selectivity. Hydrolysis of
the ester groups and amide coupling with the Agma amine
led to 30. Cleavage of the N-Boc group was followed by
coupling with the Cleu-O-Bn-D-Pla acid subunit 21 to give
31 (Scheme 4).
Scheme 4. Synthesis of Presumed Aeruginosin 205B (7a)
Scheme 3
.
Synthesis of Presumed Aeruginosin 205B (7a)
Aglycone (25)
In order to definitively confirm our findings, we proceeded
with the total synthesis of the presumed aeruginosin 205B
(7a). This presented some logistic issues related to the choice
of orthogonally compatible protecting groups as well as the
order of subunit assembly due to the sensitivity of the
O-sulfate group to protic acid and aqueous basic conditions.
Additionally, R-glycosylation of the axially disposed C-6
hydroxyl group of the Choi subunit presented an additional
challenge. While regioselective O-sulfation of suitably
protected intermediates was not considered as a problem per
se, the need for excess reagents and the final global
deprotection to yield the intended target without loss of the
chlorine atom through possible ꢀ-elimination or reduction,
loomed as potential obstacles. Extensive model studies with
preferentially O-protected methyl R-D-xylopyranosides, fol-
lowed by O-sulfation and deprotection, led us to opt for a
global deprotection of the assembled penultimate precursor
under conditions of hydrogenolysis. Based on the Toyooka
At this point, all that remained was the sulfation of the
D-xylopyranosyl unit, followed by global deprotection.
Extensive model studies led us to use a large excess of
SO3-pyridine complex at 50 °C for 2 days. Nevertheless,
(12) For example, see: (a) Lou, B.; Huynh, H. K.; Hanessian, S. In
PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Dekker: New
York, 1997; Chapter 19, p 431. (b) Hanessian, S.; Mascitti, V.; Rogel, O.
J. Org. Chem. 2002, 67, 3346.
(11) For example, see: (a) Li, H.-T.; Jiang, X.-H.; Ye, Y.-H.; Fan, C.-
X.; Romoff, T.; Goodman, M. Org. Lett. 1999, 1, 91. (b) Fan, C.-X.; Hao,
X.-L.; Ye, Y.-H. Synth. Commun. 1996, 26, 1455
.
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