C O M M U N I C A T I O N S
Scheme 2. Reconstruction of Moenomycin Aa
Table 1. Biological Activity and Transglycosylase Inhibition for
Moenomycin A 1 and Derivative 15a
IC50
(
µg/mL)
MIC (µg/mL)
S. aureus
E. faecalis
PBP2
PBP2a
S. aureusb
E. faecalisc
1
15
0.035
0.057
0.042
0.022
0.016
>250
0.063
>250
a For experimental procedures see Supporting Information. b Baterial
strain 29213. c Bacterial strain 29212.
Whether the entire C25 chain is necessary for activity remains to
be established.
The degradation/reconstruction route described here, combined
with approaches to derivatives of the moenomycin pentasaccharide
and the ability to evaluate compounds against purified transglyco-
sylases, may enable the preparation of active moenomycin ana-
logues with shorter lipid chains.
Acknowledgment. This research was supported by the National
Institutes of Health (Grant GM66174) and C.L. was supported by
a Bristol-Myers Squibb Graduate Fellowship in Synthetic Organic
Chemistry. The authors thank Merck & Co., Inc. for the generous
gift of flavomycin.
a Conditions: (a) LDA, PhSeCl, THF, -78 to -5 °C, 77%; (b) LDA,
geranyl bromide, -78 to -5 °C; (c) DIBAL, toluene, 0 °C, 54%, two steps;
(d) (CF3CO)2O, TEA, then NaOMe, MeOH, 63%; (e) TBAF, THF, room
temperature, 99%; (f) ref 10; (g) PBr3, Et2O, 0°C, 80%; (h) 7, NaH, THF/
DMF (7:1), 0°C to room temperature, 66%; (i) TBAF, THF, 0°C, 97%; (j)
Dess-Martin periodinane, NaHCO3, CH2Cl2, room temperature; (k) Na-
ClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O; (l) TMSCHN2, CH2Cl2/
MeOH (1:1),-60 °C, 57%, three steps; (m) DDQ, CH2Cl2/pH 7 buffer (10:
1), 61% (recovered starting material 34%); (n) 2-chloro-1,3,2-benzodioxa-
phosphorin-4-one, 85%; (o) Py, MS 4 Å, room temperature, 1-adamantanecar-
bonyl chloride, then NMM/CCl4/Py/CH3CN/H2O (1:2.5:6:1:1), 2 h, 62%;
(p) 0.1 N LiOH, THF/H2O (1:1), room temperature, then AcOH, 47%.
Supporting Information Available: Experimental procedures and
spectral data for all compounds. Overexpression and purification
conditions for E. faecalis PBP2a are also described. This material is
References
Scheme 3. Synthesis of Moenomycin A Analog (15)a
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