Scheme 1. Synthesis of Mycosamine Donors
Figure 1. Structure of amphotericin B and synthetic analogs.
intriguing aspects of this model the role of C20-OH has
not been experimentally explicitly tested with derivatives
thatdonot extensivelyalter the mycosamine orits relation-
ship to the macrocycle. We therefore designed analogues
that would directly probe the putative H-bonding interac-
tion between mycosamine and ergosterol and further map
out subtleties of the mycosamine subunit on the activity of
the polyene macrolide antibiotic AmB. In approaching the
problem, we decided to take a course of action that
minimized the perturbations of the mycosamine itself.
Thus it was our intention to maintain the overall polar
and structural characteristics of the parent sugar.
observed that the relative configuration at C20 is not a
determinant for activity, and yet the corresponding C20-
methyl ether analog is 50-fold less effective (Figure 1).
Interestingly, the preparation of AmB that incorporates
the ent-C20-epi-mycosamine displays 100-fold decreased
activity in yeast. These results implicate a key role for
mycosamine in AmB wherein the aminosugar is not merely
a polar headgroup and, importantly, whose role is more
significant than merely forming a hydrogen bond to sterols
residing nearby.
The early literature of AmB describes simple derivatives
at the C-16-CO2H and mycosamine-NH2 that provide
some indication of their importance.1 For example, AmB
methyl ester (AmE, 2) is equipotent to AmB in yeast
(AmB = 0.30 μM and AmE = 0.25 μM), but mycosamine
N-acetamides are inactive, leading to the suggestion that a
basic amine at C30 is necessary.9 Caffrey has determined
that the aglycone of AmB is inactive, thus underscoring the
relevance of the aminosugar itself.7 Moreover, we have
shown that amphotericin B incorporating N,N-bis(amino-
propylene) derived mycosamines display enhanced fun-
gicidal activity and possess an improved therapeutic
window.10
Aninteraction involvingmycosamine C20 and ergosterol
hydroxyl groups was suggested some time ago to be critical
in enabling the sterol to stabilize the putative barrel-stave
pore in fungal membranes.11 More recently, studies have
been conducted with conformationally rigidified analogs
in which short hydrophobic tethers linked the mycosamine
amine with the C-16 carboxylic acid.12 It is well worth
noting that the calculated conformation for the three
structures prepared and analyzed did not correlate to the
most stable conformation relating mycosamine and
the macrocycle, discussed in detail below. Despite the
We have described an improved glycosidation method
for the AmB aglycone in the context of a synthesis of C-35
deoxyAmB.13,14 The approach relies on the use of the C20-
mycosamine epimer as a donor because of exquisite
anomeric control that ensues in the coupling reaction.
Thus, the route enables rapid access to C20-derivatives
and provides a point of entry for studies at this locus.
Consequently, our investigation was designed to develop a
general approach to the mycosamine platform (Scheme 1).
The synthesis commences with the conversion of 2-ace-
tylfuran 3 to allylic alcohol 4 in five steps following the
route developed by O’Doherty.15 This resulting alcohol
was engaged in a directed epoxidation reaction and subse-
quently protected to afford epoxide 5. The synthesis of the
mycosamine donor analog was completed by epoxide
opening with azide, acylation of the resultant alcohol,
and generation of the corresponding trichloroacetimidate
(8), whose configuration was established by comparison to
previously synthesized donors.4 The synthesis route is
shorter than any previously described14a and, more im-
portantly, allows for facile manipulation of different
groups of the sugar.
A semisynthetic route that commences with the natural
product was relied upon to access a suitably protected
aglycone (Scheme 2).7b AmB was subjected to amine
(9) Cheron, M.; Cybulska, B.; Mazerski, J.; Grzybowska, J.;
Czerwinski, A.; Borowski, E. Biochem. Pharmacol. 1988, 37, 827.
(10) Paquet, V.; Carreira, E. M. Org. Lett. 2006, 8, 1807.
(11) (a) Baginsky, M.; Resat, H.; Borowski, E. Biochim. Biophys.
Acta 2002, 1567, 63. (b) Baran, M.; Mazerski, J. Biophys. Chem. 2002, 95,
125. (c) Langlet, J.; Berges, J.; Caillet, J.; Demaret, J. P. Biochim.
Biophys. Acta 1994, 1191, 79.
(13) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K.
J. Am. Chem. Soc. 1988, 110, 4696.
(14) (a) Manthorpe, J. M.; Szpilman, A. M.; Carreira, E. M. Synthe-
sis 2005, 3380. (b) Szpilman, A. M.; Carreira, E. M. Org. Lett. 2009, 11,
1305.
(12) Matsumori, N.; Sawada, Y.; Murata, M. J. Am. Chem. Soc.
2005, 127, 10667.
(15) Guo, H.; O’Doherty, G. A. Angew. Chem., Int. Ed. 2007, 46,
5206.
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