Total synthesis of (±)-platencin

Article abstract of DOI:10.1021/ol2013439

A novel route to (±)-platencin is reported, in which the highly stereoselective alkylative quaternization of a cyclohexenone scaffold via 1,4-diastereoinduction and two radical carbon-carbon bond-forming reactions that involve titanium(III)-mediated cycli

Full text of DOI:10.1021/ol2013439

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3698–3701
Total Synthesis of (()-Platencin
Takehiko Yoshimitsu,* Shoji Nojima, Masashi Hashimoto, and Tetsuaki Tanaka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita,
Osaka 565-0871, Japan
yoshimit@phs.osaka-u.ac.jp
Received May 19, 2011
ABSTRACT
A novel route to (()-platencin is reported, in which the highly stereoselective alkylative quaternization of a cyclohexenone scaffold via 1,4-
diastereoinduction and two radical carbonÀcarbon bond-forming reactions that involve titanium(III)-mediated cyclization and stannyl-radical-
mediated skeletal rearrangement are utilized.
Drug resistance that results from genetic mutations in
bacterial strains, such as methicillin-resistant Staphylococ-
cus aureus (MRSA), is one of the most pressing concerns in
the clinical environment. Massive effort to screen natural
resources that would potentially overcome the drug resis-
tance has led to the discovery of platencin (1)1À3 and plate-
nsimycin (2),1,4 both of which are highly potent antibiotics
with a novel chemical scaffold, from the strains of Strep-
tomyces platensis (Figure 1).
(FabF) andIII(FabH)5 whereas platensimycin (2) selectively
inhibits FabF. As platencin (1) and platensimycin (2)
potently inhibit the growth of antibiotic-resistant bacteria
fatal to humans through their unique mechanisms, both
compounds have caught the attention of the scientific
community with the prospect that they would serve as
new antibiotics. Nevertheless, despite these attractive
properties, their clinical application is still fraught with
many hurdles due to poor in vivo efficacy that stems from
rapid clearance from tissues. Therefore, intensive effort is
being made to solve these problems, including chemical mod-
ification of the natural compounds and wide-range screening
for natural platencin/platensimycin congeners with a view to
discovering potent analogues with improved pharmacoki-
netic properties suitable for clinical trials. In this context,
chemical access to these potent antibiotic leads that would
allow us to design and, create new platencin/platensimycin
analogues is highly demanded.6 In this paper, we disclose a
new route to (()-platencin (1), which features the stereo-
selective preparation of a quaternized cyclohexenone scaf-
fold via 1,4-diastereoinduction followed by two radical
transformations that involve a titanium(III)-mediated
cyclization7 and a homoallylic radical rearrangement.8
In our retrosynthetic analysis, platencin (1) was dis-
sected to platencinic acid (3) that would be accessible from
tricyclic intermediate 4 in a few steps involving radical
skeletal rearrangement (Scheme 1). Intermediate 4 that
possesses vicinal tertiaryÀquaternary stereocenters would
Figure 1. Platencin and platensimycin.
These compounds share a 3-amino-β-resorcylic acid
anilide linkage that attaches similar complex terpenoid
motifs with unique bond connectivity. Although they are
structurally similar, they differ in the mode of action that is
responsible for their antibiotic activities. Platencin (1)
blocks two proteins essential for bacterial fatty acid bio-
synthesis, β-ketoacylÀacyl carrier protein (ACP) synthase II
r
10.1021/ol2013439
Published on Web 06/20/2011
2011 American Chemical Society

Scheme 1. Retrosynthesis of Platencin (1)
Scheme 2. Stereoselective Synthesis of Tricyclic Motif 5 via
Radical Cyclization
be traced back to epoxide 6, with the prospect that epoxide
6 would undergo radical cyclization with a low valent
organotitanium(III)7 species to afford tricyclic ketone 5, a
suitable precursor for compound 4. Epoxide 6 would
reasonably be obtained from enone 7 that is accessible from
alcohol 8, which in turn would be prepared by the alkylative
quaternization of alcohol 9. As will be seen, our approach in
this line features highly stereoselective processes that involve
the transformation of epoxy enone 6 into tricyclic com-
pound 5 through the thermodynamic epimerization of the
radical center as well as the quaternization of compound 9
via the alkoxy-directed 1,4-diastereoinduction. It should be
mentioned that the stereocenter of the hydroxyl group of 9,
despite its disappearance at the later stage of the synthesis,
plays a pivotal role in forming other requisite stereocenters
relevant to those of the target natural product.
To our delight, the prospect was indeed found to be realizable.
Thus, alcohol 9 that was derived by desilylation of compound
12 with TBAF was subjected to alkylation with 2,3-dibromo-
propene using 3 equiv of LDA to furnish compound 8 in a
highly stereoselective manner (ca. 96:4) along with a small
amount of regioisomer.12 The stereochemical outcome
may be rationalized by a chelating model, in which the
conformation of lithium alkoxide intermediate i is fixed to
allow the alkylation to stereoselectively take place from the
less hindered site (Scheme 3). This represents a rare
instance of a highly stereoselective direct quaternization
of an enolate having “fixed geometry”.
The synthesis commenced with the alkylation of known
enone 109 with iodide fragment 11 that was prepared
from 1,3-propanediol10 to provide compound 12 as a 1:1
diastereomeric mixture in 69% yield (Scheme 2). The next task
was the quaternization of compound 12 by alkylation of the
corresponding enolate with 2,3-dibromopropene. Although
the alkylation of compound 12 with 2,3-dibromopropene was
found to provide a mixture of nearly equal amounts of two
diastereomers with respect to the quaternary stereocenter, it
occurred to us that if free alcohol 9 was used as the substrate a
chelation-controlled alkylation could be operative to possibly
allow stereoselective construction of the quaternary carbon.11
Scheme 3. Proposed Rationale for Highly Stereoselective Qua-
ternization of Compound 9
Org. Lett., Vol. 13, No. 14, 2011
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Then, alcohol 8 was again protected as TBS ether 13,
which was subjected to reductive enone carbonyl transpo-
sition with DIBAL followed by acid treatment to furnish
enone 7 in 83% yield. Regioselective epoxidation of enone
7 with mCPBA took place smoothly to give epoxide 14 in
80% yield as a diastereomeric mixture (dr = 2:3).13 Then,
epoxide 14 was transformed into compound 6 in 78% yield
by treatment witht-BuONa in the presence of Pd(PPh3)4 in
heated 1,4-dioxane. With bicyclic compound 6, the key
radical cyclization was examined by using a low-valent
titanium(III) reagent generated in situ under NugentÀ
RajanBabu conditions.7a The cyclization of epoxide 6
that constitutes two diastereomers (ca. 2:3) under the
conditions was found to successfully provide the desired
tricyclic compound 5 as a single stereoisomer in 87% yield,
indicating that both diastereomeric epoxides were trans-
formed into compound 5 irrespective of their original
stereochemistry.14 This result is attributable to the inter-
mediacy of diastereomerically single radical ii that arose by
rapid epimerization of the carbon radical center: the
thermodynamically preferential conformation of ii in
which the bulky TBS group is situated at the equatorial
position allows intermediate ii to undergo stereoselective
cyclization (Scheme 4).
(1) For selected reviews on the chemistry of platencin and platensi-
mycin, see: (a) Palanichamy, K.; Kaliappan, K. P. Chem. Asian J. 2010,
5, 668–703. (b) Lu, X.; You, Q. Curr. Med. Chem. 2010, 17, 1139–1155.
(c) Harsh, P.; O’Doherty, G. A. Chemtracts 2009, 22, 31–40. (d)
Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548–
2555.
Scheme 4. Plausible Mechanism for Highly Stereoselective Ra-
dical Cyclization of Epoxy Enone 6 to Yield Single Tricycle 5
(2) Selected papers on isolation of platencin and its congeners: (a)
Jayasuriya, H.; Herath, K. B.; Zhang, C.; Zink, D. L.; Basilio, A.;
Genilloud, O.; Diez, M. T.; Vicente, F.; Gonzalez, I.; Salazar, O.; Pelaez,
F.; Cummings, R.; Ha, S.; Wang, J.; Singh, S. B. Angew. Chem., Int. Ed.
2007, 46, 4684–4688. (b) Wang, J.; Kodali, S.; Lee, S. H.; Galgoci, A.;
Painter, R.; Dorso, K.; Racine, F.; Motyl, M.; Hernandez, L.; Tinney,
E.; Colletti, S.; Herath, K.; Cummings, R.; Salazar, O.; Gonzalez, I.;
Basilio, A.; Vicente, F.; Genilloud, O.; Pelaez, F.; Jayasuriya, H.;
Young, K.; Cully, D.; Singh, S. B. Proc. Natl. Acad. Sci. U.S.A. 2007,
104, 7612–7616. (c) Singh, S. B.; Ondeyka, J. G.; Herath, K. B.; Zhang,
C.; Jayasuriya, H.; Zink, D. L.; Parthasarathy, G.; Becker, J. W.; Wang,
J.; Soisson, S. M. Bioorg. Med. Chem. Lett. 2009, 19, 4756–4759. (d)
Zhang, C.; Ondeyka, J.; Dietrich, L.; Gailliot, F. P.; Hesse, M.; Lester,
M.; Dorso, K.; Motyl, M.; Ha, S. N.; Wang, J. Bioorg. Med. Chem. 2010,
18, 2602–2610. (e) Yu, Z.; Smanski, M. J.; Peterson, R. M.; Marchillo,
K.; Andes, D.; Rajski, S. R.; Shen, B. Org. Lett. 2010, 12, 1744–1747. (f)
Zhang, C.; Ondeyka, J.; Herath, K.; Jayasuriya, H.; Guan, Z.; Zink,
D. L.; Dietrich, L.; Burgess, B.; Ha, S. N.; Wang, J. J. Nat. Proc. 2011,
74, 329–340. (g) Herath, K.; Attygalle, A. B.; Singh, S. B. Tetrahedron
Lett. 2008, 49, 5755–5758.
(3) Syntheses of platencin: (a) Nicolaou, K. C.; Tria, G. S.; Edmonds,
D. J. Angew. Chem., Int. Ed. 2008, 47, 1780–1783. (b) Hayashida, J.;
Rawal, V. H. Angew. Chem., Int. Ed. 2008, 47, 4373–4376. (c) Tiefen-
bacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 6199–6200. (d)
Yun, S. Y.; Zheng, J.-C.; Lee, D. Angew. Chem., Int. Ed. 2008, 47, 6201–
6203. (e) Waalboer, D. C. J.; Schaapman, M. C.; Van Delft, F. L.;
Rutjes, F. P. J. T. Angew. Chem., Int. Ed. 2008, 47, 6576–6578. (f)
Nicolaou, K. C.; Toh, Q.-Y.; Chen, D. Y.-K. J. Am. Chem. Soc. 2008,
130, 11292–11293; addition/correction: J. Am. Chem. Soc. 2008, 130,
14016. (g) Austin, K. A. B.; Banwell, M. G.; Willis, A. C. Org. Lett. 2008,
10, 4465–4468. (h) Tiefenbacher, K.; Mulzer, J. J. Org. Chem. 2009, 74,
2937–2941. (i) Varseev, G. N.; Maier, M. E. Angew. Chem., Int. Ed. 2009,
48, 3685–3688. (j) Ghosh, A. K.; Xi, K. Angew. Chem., Int. Ed. 2009, 48,
5372–5375. (k) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J.; Kar, M. J.
Am. Chem. Soc. 2009, 131, 15909–15917. (l) Hirai, S.; Nakada, M.
Tetrahedron Lett. 2010, 51, 5076–5079. (m) Hirai, S.; Nakada, M.
Tetrahedron 2011, 67, 518–530. (n) Singh, V.; Sahu, B. C.; Bansal, V.;
Mobin, S. M. Org. Biomol. Chem. 2010, 8, 4472–4481. (o) Li, P.;
Yamamoto, H. Chem. Commun. 2010, 46, 6294–6295.
(6) Selected papers on synthesis of platencin analogues: (a) Barykina,
O. V.; Rossi, K. L.; Rybak, M. J.; Snider, B. B. Org. Lett. 2009, 11, 5334–
5337. (b) Waalboer, D. C. J.; Leenders, S. H. A. M.; Schuelin-Casonato,
T.; van Delft, F. L.; Rutjes, F. P. J. T. Chem.;Eur. J. 2010, 16, 11233–
11236. (c) Tiefenbacher, K.; Gollner, A.; Mulzer, J. Chem.;Eur. J.
2010, 16, 9616–9622. (d) Leung, G. Y. C.; Li, H.; Toh, Q.-Y.; Ng,
A. M.-Y.; Sum, R. J.; Bandow, J. E.; Chen, D. Y.-K. Eur. J. Org. Chem.
2011, 183–196.
(7) (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988,
110, 8561–8562. (b) Green, M. L. H.; Lucas, C. R. J. Chem. Soc.,
Dalton Trans. 1972, 1000–1003. (c) RajanBabu, T. V.; Nugent, W. A.
J. Am. Chem. Soc. 1989, 111, 4525–4527. For pertinent reviews, see:
ꢀ
(d) Barrero, A. F.; Quilez del Moral, J. F.; Sanchez, E. M.; Arteaga,
J. F. Eur. J. Org. Chem. 2006, 1627–1641. (e) Cuerva, J. M.; Justicia, J.;
Oller-Lopez, J. L.; Oltra, J. E. Top. Curr. Chem. 2006, 264, 63–91. For
some recent reports on Ti(III)-mediated cyclization of epoxides with
alkenes, see: (f) Mandal, S. K.; Paira, M.; Roy, S. C. J. Chem. Sci.
ꢀ
2010, 122, 423–426. (g) Fernandez-Mateos, A.; Madrazo, S. E.;
ꢀ
ꢀ
Teijon, P. H.; Gonzalez, R. R. J. Org. Chem. 2009, 74, 3913–3918.
(h) Mandal, S. K.; Paira, M.; Roy, S. C. J. Org. Chem. 2008, 73, 3823–
3827. (i) Chakraborty, T. K.; Samanta, R.; Das, S. J. Org. Chem. 2006, 71,
3321–3324.
(8) (a) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem.
Soc. 1998, 120, 4916–4925. Also see ref 3k. For selected reviews, see: (b)
Nonhebel, D. C. Chem. Soc. Rev. 1993, 347–359. (c) Dowd, P.; Zhang,
W. Chem. Rev. 1993, 93, 2091–2115.
(9) Bhosale, R. S.; Bhosale, S. V.; Bhosale, S. V.; Wang, T.;
Zubaidha, P. K. Tetrahedron Lett. 2004, 45, 7187–7188.
(10) For details, see Supporting Information.
(11) The pioneering work on 1,4-chiral induction of δ-hydroxyl
acyclic esters, in which a tertiary stereocenter R to the ester carbonyl
group is successfully created by δ-hydroxyl directed alkylation or
aldolization, has been reported. (a) Narasaka, K.; Ukaji, Y.; Watanabe,
K. Bull. Chem. Soc., Jpn. 1987, 60, 1457–1464. (b) Narasaka, K.; Ukaji,
Y. Chem. Lett. 1986, 81–84. (c) Narasaka, K.; Ukaji, Y.; Watanabe, K.
Chem. Lett. 1986, 1755–1758.
(12) A small amount (11%) of a regioisomer, which may be produced
via γ-deprotonation followed by R-alkylationÀisomerization reactions,
was obtained together with unreacted starting material 9 (13%). Two
authentic diastereomers 8 and epi-8 were derived from the correspond-
ing products obtained by alkylation of compound 12 with 2,3-dibromo-
propene, followed by desilylation with TBAF. The selective production
of compound 8 was unambiguously confirmed by careful analyses of
TLC and 1H NMR spectra of the two diastereomers. For details, see
Supporting Information.
(4) (a) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.;
Galgoci, A.; Painter, R.; Parthasarathy, G.; Tang, Y. S.; Cummings, R.;
Ha, S.; Dorso, K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.; Herath, K.;
Zhang, C.; Hernandez, L.; Allocco, J.; Basilio, A.; Tormo, J. R.;
Genilloud, O.; Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S. H.; Michael,
B.; Felcetto, T.; Gill, C.; Silver, L. L.; Hermes, J. D.; Bartizal, K.;
Barrett, J.; Schmatz, D.; Becker, J. W.; Cully, D.; Singh, S. B. Nature
2006, 441, 358–361. (b) Singh, S. B.; Jayasuriya, H.; Ondeyka, J. G.;
Herath, K. B.; Zhang, C.; Zink, D. L.; Tsou, N. N.; Ball, R. G.; Basilio,
A.; Genilloud, O.; Diez, M. T.; Vicente, F.; Pelaez, F.; Young, K.; Wang,
J. J. Am. Chem. Soc. 2006, 128, 11916–11920; addition/correction: J.
Am. Chem. Soc. 2006, 128, 15547.
(5) For reviews on fatty acid synthesis, see: (a) Wright, H. T.;
Reynolds, K. A. Curr. Opin. Microbiol. 2007, 10, 447–453. (b) Good-
man, C. D.; McFadden, G. I. Curr. Pharm. Des. 2008, 14, 901–916. (c)
€
Haebich, Dieter; von Nussbaum, F. Chem. Med. Chem. 2006, 1, 951–
954. (d) Johansson, P.; Wiltschi, B.; Kumari, P.; Kessler, B.; Vonrhein,
C.; Vonck, J.; Oesterhelt, D.; Grininger, M. Proc. Natl. Acad. Sci. U.S.
A. 2008, 105, 12803–12808.
(13) No stereochemical assignment of the isomers was made.
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Org. Lett., Vol. 13, No. 14, 2011

group. The Mg-mediated transformation of ester 16 in MeOH
gave methyl ester 17 that was produced via reduction of the
carbonÀcarbon double bond and the ketone carbonyl group
concomitant with transesterification with the solvent.15 Then,
ester 17 was transformed into xanthate 4 in 70% yield, a
material suitable for radical skeletal rearrangement.8
Xanthate 4, when reacted with n-Bu3SnH in the presence of
AIBN, underwent radical rearrangement to furnish desired
compound 18 in 73% yield. With this architecture relevant to
platencin, installation of the double bond at the C6 position
(platencin numbering) was then examined. Desilylation of
compound 18 with LiBF4 afforded lactone 19 via facile
cyclization of the resultant hydroxyl ester.16 Although the
hydrolysis of lactone 19 was found to be problematic because
the resultant hydroxyl carboxylic acid (structure not shown)
readily underwent lactonization during workup processes to
regenerate lactone 19, careful treatment of the crude car-
boxylic acid with IBX allowed us to successfully deliver keto
carboxylic acid 20 without the accompanying undesired
lactonization.17 Compound 20 was then esterified with tri-
methylsilyldiazomethane in MeOH to provide ketone 21 in
96% yield over three steps from 19. Next, ketone 21 was
converted into the corresponding TMS enol ether, which was
successfully oxidized with IBX-NMO in DMSO to provide
enone 22 in 57% yield in two steps.18 Hydrolysis of enone 22
with aq NaOH afforded platencinic acid (3) quantitatively,
which, by subjecting to the known amidation reaction with
3-amino-β-resorcylic acid,3b eventually furnished (()-platen-
cin (1). The spectroscopic and analytical data of synthetic
platencin exactly matched those reported in the literature.
In conclusion, we have established a new route to (()-
platencin that features the stereoselective quaternization of
a cyclohexenone motif through chelation-controlled alky-
lation followed by two successful radical reactions, i.e.,
highly stereoselective radical cyclization as well as skeletal
rearrangement. It should be noted that the present route is
applicable to the asymmetric production of platencin simply
by switching racemic fragment 11 to chiral 11. On the basis of
the present route, the derivatization of new platencin analo-
gues is underway with a view to discovering potent antibiotic
leads through structureÀactivity relationship studies.
Scheme 5. Completion of Total Synthesis of (()-Platencin (1)
Acknowledgment. This work was supported by a
Grant-in-Aid [KAKENHI No. 16790021] and a Grant-
in-Aid for Scientific Research on Innovative Areas [No.
22136006] from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (MEXT).
Next, tricyclic compound 5 was subjected to side-chain
elongation (Scheme 5). Compound 5 was first oxidized
with Dess-Martin periodinane to afford aldehyde 15
quantitatively. Then, aldehyde 15 was alkynylated with
lithium ethoxy acetylide to give alcohol as a diastereo-
meric mixture (dr = 1:2; structure not shown), which, in
turn, was subjected to dehydration with PPTS to provide
R,β-unsaturated ester 16 in 71% yield in two steps.
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H/13C NMR spectra
of products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) In this reaction, 5% of minor β-hydroxy diastereomer was
formed and could be separated from the desired isomer by silica gel
chromatography. For details, see Supporting Information.
It should be mentioned that pretreatment of 15 with
LHMDS to form a ketone lithium enolate was quite impor-
tant to avoid undesired alkynylation at the ketone carbonyl
(16) Metcalf, B. W.; Burkhart, J. P.; Jund, K. Tetrahedron Lett. 1980,
21, 35–36. either TBAF nor HF Py, a common desilylating agent, gave
the desired compound.
3
(17) For details, see Supporting Information.
(18) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.
Angew. Chem., Int. Ed. 2002, 41, 996–1000.
(14) At this stage, a tiny amount of the minor product that was
generated from a minor diastereomer (4%) could be completely sepa-
rated by silica gel column chromatography.
Org. Lett., Vol. 13, No. 14, 2011
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