Total synthesis and antibacterial properties of carbaplatensimycin

Article abstract of DOI:10.1021/ja076126e

The chemical synthesis and biological evaluation of carbaplatensimycin, the carbon analogue of the recently reported antibiotic platensimycin has been accomplished. Carbaplatensimycin exhibited similar potency to the natural product as an antibacterial ag

Full text of DOI:10.1021/ja076126e

Published on Web 11/08/2007
Total Synthesis and Antibacterial Properties of Carbaplatensimycin
K. C. Nicolaou,* Yefeng Tang, Jianhua Wang, Antonia F. Stepan, Ang Li, and Ana Montero
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry,
UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093
Received August 14, 2007; E-mail: kcn@scripps.edu
The recent isolation of platensimycin (1, Figure 1)1 has attracted
considerable interest from both biological and chemical circles due
to its unique pharmacological profile. Indeed, platensimycin is the
first antibiotic discovered in over 40 years that exerts its antibacterial
effect through a novel mechanism of action, manifested by its
impressive activity against a variety of drug-resistant bacteria,
including methicilin- and vancomycin-resistant strains.1 As such,
platensimycin represents a unique opportunity for the development
of critically needed antibiotics. The complex molecular architecture
and exquisite antibacterial activity render platensimycin a worthy
target for chemical synthesis, and syntheses of both the racemate
and natural (-)-enantiomer have been reported.2 Additionally, its
Figure 1. Structures of platensimycin (1), adamantaplatensimycin (2), and
first bioactive designed analogue, adamantaplatensimycin (2, Figure
carbaplatensimycin (3) and ORTEP view of 3 with the thermal ellipsoids
1), has been disclosed from these laboratories.3 In this communica-
at 30% probability level.
tion, we report the total synthesis and antibacterial properties of
ingly, this reaction proceeded smoothly and with inversion of
carbaplatensimycin (3, Figure 1), the all-carbon-cage isostere of
the natural product.
Platensimycin eradicates bacteria through the selective inhibition
configuration at the formyl-bearing stereocenter to afford aldehyde
11 as the desired C10 epimer in high yield (92%). Reduction of
this aldehyde to alcohol 12 (NaBH4, 99% yield) was followed by
of the elongation-condensing enzyme â-ketoacyl-(acyl carrier
a Barton-McCombie deoxygenation5 of the corresponding xanthate
protein) synthases I/II (Fab F/B) in the type II bacterial fatty acid
ester (13) to furnish hydrocarbon 14 in 65% overall yield for the
biosynthetic pathway. X-ray crystallographic analysis of the plat-
two steps. Finally, a two-step protocol involving regioselective
ensimycin complex with its target FabF protein indicates a hydrogen
dihydroxylation (cat. OsO4, NMO) of the exocyclic olefin, followed
bonding interaction between the ether oxygen of the molecule and
by oxidative cleavage of the resulting diol with NaIO4, revealed
key carbocyclic enone 15 in 72% overall yield.
The completion of the synthesis of carbaplatensimycin (3)
followed a similar pathway to that previously employed in the
the T270 threonine residue of its target. It was with the aim of
investigating the effect of this ethereal hydrogen bond acceptor on
the platensimycin bioactivity that the synthesis of carbaplatensi-
mycin (3) was undertaken.
syntheses of platensimycin and adamantaplatensimycin (Scheme
2).2a,b,3 Thus, enone 15 was sequentially alkylated with MeI (92%
yield) and allyl iodide (87% yield) [KHMDS, THF/HMPA (5:1),
-78 f -10 °C] to afford advanced intermediate 16. Cross-
metathesis of the latter compound with excess boronate 17 was
achieved using Grubbs’ second generation catalyst to furnish vinyl
boronate 18 in 85% yield (and as a 6:1 mixture of E:Z isomers).6
Boronate cleavage using Me3NO as the oxidant led to clean
formation of aldehyde 19 (85% yield),6a which was subsequently
transformed into carboxylic acid 20 through a Pinnick oxidation
(95%). Finally, coupling of acid 20 with aniline 212a gave protected
intermediate 22 (80% yield), which, after sequential treatment with
aqueous LiOH and aqueous HCl, yielded the targeted compound,
carbaplatensimycin (3), in 82% overall yield. Crystallization of
carbaplatensimycin from acetone/hexanes gave colorless crystals
(mp 217-219 °C) that were used to prove unambiguously its
structure by X-ray crystallographic analysis (see ORTEP drawing,
Figure 1).
For the chemical synthesis of carbaplatensimycin, we made use
of aldehyde 4, an intermediate employed in the asymmetric
synthesis of platensimycin,2b which was readily obtained in
enantiomerically enriched form (ee > 98%) in eight steps (42%
overall yield) from known 3-(2-dioxolanyl)propionic acid. This
intermediate was first converted to carbocycle 15 as shown in
Scheme 1. Thus, addition of TMSCN to intermediate 4 in the
presence of Et3N furnished TMS-protected cyanohydrin 5.
Subsequent removal of the silyl protecting group, followed by
treatment of the resulting free cyanohydrin with ethyl vinyl ether
in the presence of PPTS furnished 1-ethoxyethyl (EE) ether 7 in
80% overall yield for the three steps (and as an inconsequential
1:1:1:1 mixture of epimers at C10 and the acetal carbon of the EE
group). Treatment of 7 with KHMDS at low temperature, followed
by warming to 0 °C, induced intramolecular conjugate addition of
the transient anion so generated onto the bisenone subunit to afford
tricycle 8 in 70% yield and as a single epimer at C10. Wittig
olefination of the latter intermediate gave triene 9 (92% yield), the
newly introduced double bond serving as a temporary protecting
device for the required carbonyl functionality.4
The antibacterial activity of carbaplatensimycin (3) against an
array of bacterial strains, including methicilin-resistant Staphylo-
coccus aureus (MRSA) and vancomycin-resistant Enterococcus
faecium (VREF), was determined and compared to those of
platensimycin (1) and adamantaplatensimycin (2). As shown in
Table 1, the minimum inhibitory activities (MIC) for the new
Reduction of the nitrile moiety present in 9 with Red-Al ensured
the formation of aldehyde 10 (90% yield), from which the EE-
protected alcohol was excised through the action of SmI2. Pleas-
9
14850
J. AM. CHEM. SOC. 2007, 129, 14850-14851
10.1021/ja076126e CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Construction of Carbocyclic Core Intermediate 15a
Scheme 2. Completion of the Synthesis of Carbaplatensimycin
(3)a
a Reagents and conditions: (a) KHMDS (0.5 M in toluene, 2.0 equiv),
MeI (8.0 equiv), THF:HMPA (5:1), -78f-10 °C, 1 h, 92%; (b) KHMDS
(0.5 M in toluene, 4.0 equiv), allyl iodide (8.0 equiv), THF:HMPA (5:1),
-78f-10 °C, 1 h, 87%; (c) Grubbs gen. II (10 mol %), 17 (5.0 equiv),
benzene, 80 °C, 1 h, 85%; (d) Me3NO (6.0 equiv), THF, 65 °C, 2 h, 85%;
(e) NaClO2 (5.0 equiv), NaH2PO4 (7.0 equiv), 2,3-dimethylbutene (10
equiv), t-BuOH:H2O (1:1), 25 °C, 1 h, 95%; (f) 20 (1.0 equiv), 21 (3.0
equiv), HATU (4.0 equiv), Et3N (6.0 equiv), DMF, 25 °C, 20 h, 80%; (g)
2 N aq. LiOH (30 equiv), THF, 45 °C, 6 h; then 2 N aq. HCl (60 equiv),
THF, 45 °C, 24 h, 82% overall yield.
a Reagents and conditions: (a) TMSCN (1.5 equiv), Et3N (0.5 equiv),
CH2Cl2, 25 °C, 1 h; (b) TBAF (1.0 M in THF, 1.5 equiv), THF, 25 °C, 1
h; (c) ethyl vinyl ether (excess), PPTS (0.5 equiv), CH2Cl2, 25 °C, 12 h,
80% over 3 steps; (d) KHMDS (0.5 M in toluene, 1.5 equiv), THF, -78 f
25 °C, 0.5 h, 70%; (e) CH3PPh3Br (2.5 equiv), KHMDS (0.5 M in toluene,
2.0 equiv), THF, -78 f 0 °C, 1 h, 92%; (f) Red-Al (3.5 M in toluene, 5.0
equiv), THF, -20 f 25 °C, 6 h, 90%; (g) SmI2 (0.1 M in THF, 2.5 equiv),
THF:t-BuOH (10:1), -10 f 25 °C, 2 h, 92%; (h) NaBH4 (1.5 equiv), THF:
CH3OH (2:1), 0 f 25 °C, 30 min, 99%; (i) CS2 (3.0 equiv), KHMDS (0.5
M in toluene, 3.0 equiv), THF, -78 f 25 °C, 1 h; then MeI (3.0 equiv),
THF, 25 °C, 1 h, 99%; (j) n-Bu3SnH (1.5 equiv), AIBN (0.75 equiv),
Table 1. Minimum Inhibitory Concentration (MIC) Values (µg
mL-1) of 1, 2, and 3 against a Variety of Bacterial Strainsa
1
2
3
t
benzene, 80 °C, 0.5 h, 65%; (k) OsO4 (2.5 wt % in BuOH, 5 mol %),
NMO (50 wt % in H2O, 2.0 equiv), acetone:H2O (8:1), 0 °C, 4 h, 80%; (l)
NaIO4 (2.0 equiv), THF:H2O (1:1), 25 °C, 1 h, 92%.
MRSA
VREF
Staphylococcus aureus
Staphylococcus epidermidis
Bacillus cereus
0.2-0.4
0.4-0.8
0.2-0.6
<0.2
2.2-4.4
<0.2
1.3-1.8
1.3-1.8
1.1-2.2
0.5-1.1
8.8-11.1
3.3-4.4
1.1-2.2
1.1-2.2
0.4-1.1
0.2-0.5
17.6-22.0
1.1-2.2
analogue (3) against a number of Gram-positive bacteria lie in the
same order of magnitude as those of the natural product (1) and
adamantaplatensimycin (2). For example, the MIC values for 1, 2,
and 3 against MRSA were found to be 0.2-0.4, 1.3-1.8, and 1.1-
2.2 µg mL-1, respectively, while the corresponding values against
VREF for these compounds are 0.4-0.8, 1.3-1.8, and 1.1-2.2
µg mL-1. However, the similar potency of carbaplatensimycin (3)
against these bacteria to that of adamantaplatensimycin (2) indicates
the important contribution of the ether oxygen of the natural product
to its antibacterial activity. All three platensimycins (1-3) were
tested and found inactive (MIC > 88 µg mL-1) against the
following Gram-negative bacterial strains: E. coli, B. cepacia, S.
typhimurium, P. aeruginosa.
The reported synthesis of carbaplatensimycin (3) adds a new,
bioactive platensimycin analogue to this promising class of antibiot-
ics. At the same time, these investigations confirmed the positive
role that the ether oxygen plays in the biological activity of
platensimycin. This information may prove useful in the rational
design of new antibacterial agents based on the platensimycin lead
structure.
Lysteria monocytogenes
a The antibacterial activity was determined by National Committee for
Clinical Laboratory Standards (NCCLS) broth microdilution methods.
Inocula of MRSA (ATCC 33591), VREF (ATCC 51575), S. aureus (ATCC
29213), S. epidermidis (ATCC 35989), B. cereus (ATCC 11778), and L.
monocytogenes (ATCC 10115) were prepared and treated as described in
the Supporting Information.
Supporting Information Available: Complete ref 1, experimental
procedures, and compound characterization (PDF, CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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X-ray crystallographic assistance, respectively. This material is
based upon work supported by the National Science Foundation
under Grant No. 0603217, as well as the Skaggs Institute for
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