A R T I C L E S
Nicolaou et al.
the first total synthesis of platencin (1) through an asymmetric
route.8a Herein we present the full account of our work in this
area that led to considerable improvements of the originally
developed route.
Results and Discussion
Figure 1. Molecular structures of platencin [(-)-1] and platensimycin [(-)-
2].
Our total synthesis endeavors toward platencin, first as a
racemate and then in its enantiomerically pure form, proceeded
through a number of phases and evolved into a highly efficient
and streamlined process. Below we describe these studies in
approximately the chronological sequence they occurred.
Initial Retrosynthetic Analysis. Figure 2 shows our retrosyn-
thetic analysis of 1. Only a cursory inspection of the platencin
molecule was needed to identify the first retrosynthetic discon-
nection, that of the amide bond, which revealed fragments 3
and 4 as potential precursors. Aniline derivative 3 was thought
to be the ideal precursor for reasons of convenience and
practicality, given the expected sensitivity of the exocyclic
olefinic bond of the final product and the neutral conditions
under which the TMSE group could be removed. Applying two
consecutive retrosynthetic alkylations on tricyclic fragment 4
led to enone 5 as the required key intermediate for the ketolide
domain of the molecule. The latter was envisioned to arise from
a ketoaldehyde, derived from 6 (R ) H or protecting group)
through an aldol condensation. A radical pathway starting from
xanthate 9a or hydrazone 12, and proceeding through species
8 (R ) H or protecting group) and 7 (R ) H or protecting
group), was then traced on the basis of a homoallylic radical
rearrangement.10 Our initial analysis adopted xanthate 9a as the
potential precursor of the first radical species of the envisioned
cascade and connected it to ketone 10. Disconnection of the
indicated carbon-carbon bonds within [3.2.1] bicyclic system
10 through a retro conjugate addition of an allyl group and a
retro palladium-catalyzed cyclization revealed enol ether 11 as
a potential precursor.10a The latter intermediate was then traced
back to hydroxymethyl enone 15 as a starting material. Our
alternative plan makes use of a hydrazone radical precursor of
type 12, which can be traced through ketone 13 by a similar
retrosynthetic sequence, employing a gold(I)-catalyzed cycliza-
tion11 of an enol ether such as 14 back to acetylenic hydroxym-
ethyl enone 16.
hydrophobic ketolide portion. Platensimycin consists of a
tetracyclic framework that contains a cyclic ether, whereas
platencin features an exclusively carbocyclic framework with
only three rings. Like its sibling, platencin exhibits potent and
broad in Vitro and in ViVo antibiotic activity against Gram-
positive bacteria, including activity against a variety of drug-
resistant bacteria such as MRSA (1 µg/mL vs 0.5 µg/mL for
platensimycin) and vancomycin-resistant Enterococcus faecium
(VREF, <0.06 µg/mL vs 0.01 µg/mL for platensimycin).
Platencin also exhibited comparable in ViVo efficacy in a
continuous infusion mouse model against S. aureus infection
with no indication of toxicity. As might be expected from their
close structural relationship, platencin and platensimycin operate
through similar mechanisms of action. Each was shown to
inhibit lipid biosynthesis in whole-cell labeling studies, but
neither exhibited any activity against nucleic acid, protein
biosynthesis, or cell wall construction. At a molecular level,
platensimycin is a potent and selective inhibitor of FabF, the
elongation condensing enzyme; however, platencin inhibits this
enzyme with much lower potency. Platencin derives its overall
potency from a dual inhibition mechanism involving moderate
inhibition of both FabF and the initiation condensing enzyme
FabH.5 It should be noted that a recent report questioned the
validity of the strategy to combat bacteria based on fatty acid
biosynthesis since bacteria were found to sequester the needed
fatty acids from their hosts.4
The structural novelty and potent activity of these antibiotics
has attracted considerable attention, with a number of total
syntheses of platensimycin7 and platencin8 reported to date.
Several reports have also described the design and synthesis of
related structures,9 some of which are also potent antibiotics.9a,b,d,e
In 2008, we published our preliminary results culminating in
(7) For the total synthesis of platensimycin, see: (a) Nicolaou, K. C.; Li,
A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2006, 45, 7086. For formal
syntheses of platensimycin, see: (b) Nicolaou, K. C.; Edmonds, D. J.;
Li, A.; Tria, G. S. Angew. Chem., Int. Ed. 2007, 46, 3942. (c) Zou,
Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B. Org.
Lett. 2007, 9, 1825. (d) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem.
Commun. 2007, 1922. (e) Li, P.; Payette, J. N.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 9534. (f) Tiefenbacher, K.; Mulzer, J. Angew.
Chem., Int. Ed. 2007, 46, 8074. (g) Lalic, G.; Corey, E. J. Org. Lett.
2007, 9, 4921. (h) Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.; Gibe,
R.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2008, 47, 944. (i) Kim,
C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem.,
Int. Ed. 2008, 47, 4009. For a review on the approaches to
platensimycin and related analogues, see: (j) Tiefenbacher, K.; Mulzer,
J. Angew. Chem., Int. Ed. 2008, 47, 2548.
First-Generation Synthesis of Racemic Tricyclic Enone
(()-5. As part of our preliminary studies toward platencin (1),
we explored the xanthate-based homoallylic rearrangement route
to tricyclic ketone (()-5 using racemic materials (Scheme 1).
(9) (a) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds,
D. J. Angew. Chem., Int. Ed. 2007, 46, 4712. (b) Nicolaou, K. C.;
Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero, A. J. Am. Chem.
Soc. 2007, 129, 14850. (c) Nicolaou, K. C.; Stepan, A. F.; Lister, T.;
Li, A.; Montero, A.; Tria, G. S.; Turner, C. I.; Tang, Y.; Wang, J.;
Denton, R. M.; Edmonds, D. J. J. Am. Chem. Soc. 2008, 130, 13110.
(d) Yeung, Y.-Y.; Corey, E. J. Org. Lett. 2008, 10, 3877. (e) Shen,
H. C.; Ding, F.; Singh, S. B.; Parthasarathy, G.; Soisson, S. M.; Ha,
S. N.; Chen, X.; Kodali, S.; Wang, J.; Dorso, K.; Tata, J. R.;
Hammond, M. L.; MacCoss, M.; Colletti, S. L. Bioorg. Med. Chem.
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(8) For total syntheses of platencin, see: (a) Nicolaou, K. C.; Tria, G. S.;
Edmonds, D. J. Angew. Chem., Int. Ed. 2008, 47, 1780. (b) Hayashida,
J.; Rawal, V. H. Angew. Chem., Int. Ed. 2008, 47, 4373. For formal
syntheses of platencin, see: (c) Tiefenbacher, K.; Mulzer, J. Angew.
Chem., Int. Ed. 2008, 47, 6199. (d) Yun, S. Y.; Zheng, J.-C.; Lee, D.
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Schaapman, M. C.; Van Delft, F. L.; Rutjes, F. P. J. T. Angew. Chem.,
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K. J. Am. Chem. Soc. 2008, 130, 11292. (g) Austin, K. A. B.; Banwell,
M. G.; Willis, A. C. Org. Lett. 2008, 10, 4465. (h) Tiefenbacher, K.;
Mulzer, J. J. Org. Chem. 2009, 74, 2937. (i) Varseev, G. N.; Maier,
M. E. Angew. Chem., Int. Ed. 2009, 48, 3685.
(10) (a) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc.
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