Stereocontrolled formal synthesis of (±)-platensimycin

Article abstract of DOI:10.1021/ol801584r

(Chemical Equation Presented) The caged structure of platensimycin, known as Nicolaou's key intermediate for total synthesis of platensimycin, was synthesized stereoselectively by using the following key steps: (i) diastereoselective Diels-Alder reaction

Full text of DOI:10.1021/ol801584r

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4049-4052
Stereocontrolled Formal Synthesis of
(()-Platensimycin
Jun-ichi Matsuo,* Kosuke Takeuchi, and Hiroyuki Ishibashi
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
jimatsuo@p.kanazawa-u.ac.jp
Received July 12, 2008
ABSTRACT
The caged structure of platensimycin, known as Nicolaou’s key intermediate for total synthesis of platensimycin, was synthesized stereoselectively
by using the following key steps: (i) diastereoselective Diels-Alder reaction between γ-benzoyloxy enone and tert-butyldimethylsiloxydiene,
(ii) formation of a dihydropyran ring by intramolecular catalytic oxypalladation, and (iii) transannular radical cyclization of monothioacetal with
tributyltin hydride and AIBN.
Platensimycin (1), which was isolated from Streptomyces
platensis by Merck’s research group in 2006, has potent,
broad-spectrum Gram-positive antibacterial activity and
exhibits no cross-resistance to antibiotic-resistant bacteria,
including methicillin-resistant Staphylococcus aureus (MRSA),
vancomycin-resistant enterococci (VRE), and linezolid-
resistant and macrolide-resistant pathogens.1 Platensimycin
(1) selectively inhibits FabF, an elongation condensing
enzyme of fatty-acid biosynthesis, which is highly conserved
among key pathogens. In addition to the novelty in the
biological activity of 1, the characteristic caged structure of
1 has attracted the interest of organic chemists, and several
research groups have reported total and formal synthesis
of 1.2,3
in Scheme 1. We expected that the C12-C15 bond of 2
Scheme 1. Retrosynthesis of 2
We planned a stereocontrolled synthesis of 2, a key
intermediate in Nicolaou’s total synthesis of 1,2a as shown
(1) (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, S. B.; Barrett, J.; Schmatz,
D.; Becker, J. W.; Cully, D.; Singh, S. B. Nature 2006, 441, 358. (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.; Vincente,
F.; Pelaez, F.; Young, K.; Wang, J. J. Am. Chem. Soc. 2006, 128, 11916.
would be formed by transannular radical cyclization4 of
R-alkoxy radical5 3 and that a six-membered cyclic ether
ring of 3 would be constructed by palladium-catalyzed
intramolecular alkenyl ether formation from 5 to 4. We
10.1021/ol801584r CCC: $40.75
Published on Web 08/15/2008
2008 American Chemical Society

envisioned that compound 5 would be accessible by dias-
tereoselective Diels-Alder reaction of enone 6 and siloxy-
diene 7.6 The key feature of our plan is that all stereocenters
in 2 are controlled by the stereochemistry presented in 6.
Thus, stereochemistries at C8 and C9 are controlled by the
diastereoselective Diels-Alder reaction, while those at C12
and C15 are determined inevitably by the transannular
cyclization.
readily in the presence of silica gel.10 Other oxidation
methods such as Swern oxidation11 and PDC12 gave inferior
results because of the lability of formed ꢀ,γ-epoxy ketone
under the reaction conditions. Protection of the hydroxy
group of 11 with TBSCl and benzoyl chloride gave 12a and
12b, respectively.
Next, the Diels-Alder reaction of thus-prepared dieno-
philes 12a,b with siloxydienes 13a,b was investigated (Table
1).13 The Diels-Alder reaction between TBS-protected
enone 12a and trimethylsiloxydiene 13a in the presence of
pyridine and 2,6-di-tert-butyl-4-methylphenol (BHT) at 200
°C (in toluene, sealed tube) gave the corresponding
Diels-Alder adducts (14a and 15a) in 32% yield with low
diastereoselectivity (14a:15a ) 4:1) after acidic treatment
(entry 1). The yield and selectivity were improved by
employing benzoyl-protected enone 12b instead of 12a,
presumably due to the lower LUMO level of 12b (entry 2).
After screening various reaction conditions, it was found that
the Diels-Alder reaction between 12b and tert-butyldim-
ethylsiloxydiene 13b at 180 °C without any solvents gave
the desired Diels-Alder adduct 14b and its diastereomer 15b
in 83% combined yield in a ratio of 14b:15b ) 11:1 after
treatment with trifluoroacetic acid (entry 3). This further
improvement of chemical yield and diastereoselectivity might
be explained by better thermal stability of 13b than that of
13a and by effective steric repulsion between the benzoyloxy
group of 12b and TBS group of 13b in the transition state
of the Diels-Alder reaction. The mixture of two diastere-
omers (14b and 15b) was employed in the next step because
of difficulty in separation at this stage.
O-TBS and O-benzoyl-protected enones 12a,b were
prepared from 1,3-cyclohexadiene (8) as shown in Scheme
2. Allylboration of 8 with allyldibromoborane7 gave 9 in
Scheme 2. Preparation of Enone 12a,b
Selective protection of the less-hindered carbonyl group
by Noyori’s procedure14 followed by hydrolysis of the
benzoyl group and separation of diastereomers gave 16 in
80% yield as a single diastereomer. Catalytic oxypalladation
of 16 by using a catalytic amount of palladium(II) chloride
and copper(II) acetate under oxygen atmosphere in dimethy-
lacetamide15 gave 17a and 17b in 73% combined yield (17a:
17b ) 10:1).16 The mixture of isomers was employed in
the following steps.
To form a carbon-carbon bond between C12 and C15
by radical cyclization, we needed to prepare alkene 19 from
ketone 17. Reduction of the keto group of 17 followed by
dehydration of the resulting alcohol via mesylate did not give
19. It was found that vinyl triflate 18, which was prepared
from 17 with KHMDS and N-(5-chloro-2-pyridyl)trifimide,17
71% yield after oxidative workup. The homoallylic double
bond of 9 was selectively oxidized with VO(acac)2 and tert-
butyl hydroperoxide8 to afford epoxide 10 in 89% yield.
Oxidation of the hydroxy group of 10 with Dess-Martin
periodinane9 gave the corresponding ꢀ,γ-epoxy ketone and
successive isomerization to γ-hydroxy enone 11 took place
(2) (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed.
2006, 45, 7086. (b) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S.
Angew. Chem., Int. Ed. 2007, 46, 3942. (c) Li, P.; Payette, J. N.; Yamamoto,
H. J. Am. Chem. Soc. 2007, 129, 9534. (d) Lalic, G.; Corey, E. J. Org.
Lett. 2007, 9, 4921. (e) Nicolaou, K. C.; Pappo, D.; Tsung, K. Y.; Gibe,
R.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2008, 47, 944. (f) Kim, C. H.;
Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem., Int. Ed.
2008, 47, 4009. (g) Zou, Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.;
Snider, B. B. Org. Lett. 2007, 9, 1825. (h) Nicolaou, K. C.; Tang, Y.; Wang,
J. Chem. Commun. 2007, 1922. (i) Tiefenbacher, K.; Mulzer, J. Angew.
Chem., Int. Ed 2007, 46, 8074. (j) Tiefenbacher, K.; Mulzer, J. Angew.
Chem., Int. Ed. 2008, 47, 2548.
(3) Total synthesis of platencin, a platensimycin analogue: (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. (c)
Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 6199. (d)
Yun, S. Y.; Zheng, J.-C.; Lee, D. Angew. Chem., Int. Ed. 2008, 47, 6201.
(4) Transannular cyclization of cyclooct-4-enyl radical: (a) Dowbenko,
R. J. Am. Chem. Soc. 1964, 86, 946. (b) Dowbenko, R. Tetrahedron 1964,
20, 1843. (c) Friedman, L. J. Am. Chem. Soc. 1964, 86, 1885. (d) Gancarz,
R. A.; Kice, J. J. J. Org. Chem. 1981, 46, 4899. (e) Winkler, J. D.; Sridar,
V. J. Am. Chem. Soc. 1986, 108, 1708.
(10) Isomerization of ꢀ,γ-epoxycyclohexanones: Delay, F.; Ohloff, G.
HelV. Chim. Acta 1979, 62, 2168.
(11) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(12) (a) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399. (b)
Herscovici, J.; Egron, M.-J.; Antonakis, K. J. Chem. Soc., Perkin Trans. 1
1982, 1967.
(13) Some examples for the Diels-Alder reaction between 2-alkyl-2-
cyclohexen-1-ones and 13a: (a) Danishefsky, S.; Kitahara, T. J. Org. Chem.
1975, 40, 538. (b) Inokuchi, T.; Okano, M.; Miyamoto, T.; Madon, H. B.;
Takagi, M. Synlett 2000, 1549.
(5) (a) Rawal, V. H.; Singh, S. P.; Dufour, C.; Michoud, C. J. Org.
Chem. 1991, 56, 5245. (b) Mesmaeker, A. D.; Waldner, A.; Hoffmann, P.;
Mindt, T.; Hug, P.; Winkler, T. Synlett 1990, 687.
(14) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
(6) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
(7) Frantz, D. E.; Singleton, D. A. Org. Lett. 1999, 1, 485.
(15) (a) Smith, A. B.; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett.
1998, 39, 8765. (b) Hosokawa, T.; Hirata, M.; Murahashi, S.-I.; Sonoda,
A. Tetrahedron Lett. 1976, 1821.
(8) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136.
(16) Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier, M. Tetrahedron
Lett. 1989, 30, 4925.
(9) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
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Org. Lett., Vol. 10, No. 18, 2008

Table 1. The Diels-Alder Reaction Between 12a,b and 13a,b
entry
1
enone
diene (equiv)
conditions
yield (%)a
32
14:15
12a
13a (4.0)
(1) py (1.0 equiv), BHTb (cat.), toluene, 200 °C, 34 h
(2) 0.01 N aq HCl
14a:15a ) 4:1
2
3
12b
12b
13a (4.0)
13b (2.5)
(1) py (1.0 equiv), BHTb (cat.), toluene, 180 °C, 25 h
(2) 0.01 N aq HCl
60
83
14b:15b ) 8:1
14b:15b ) 11:1
(1) neat, 180 °C
(2) TFA, CH2Cl2
a Combined yield of 14 and 15. b 2,6-Di-tert-butyl-4-methylphenol.
was reduced to 19 in good yield by using a palladium
(18% yield), which was formed by reduction of R-alkoxy
radical intermediate with tributyltin hydride followed by acid
catalyst, formic acid, and tributylamine (Scheme 3).18
Scheme 4. Transannular Radical Cyclization of 20 to 2
Scheme 3
.
Preparation of 19 by Palladium-Catalyzed Alkenyl
Ether Formation
hydrolysis. It was also observed by TLC analysis that
elimination of the phenylthio group of 20 to 19 proceeded
in refluxing toluene. Tributyltin hydride was found to be a
better hydrogen source in this transannular radical cyclization
than tris(trimethylsilyl)silane and triphenyltin hydride. At the
outset, we tried to prepare the phenylselenoacetal for radical
cyclization.22 However, the preparation of the phenylsele-
noacetal by the reaction of 19 with benzeneselenol23 gave
compound 21, which might be formed by reductive cleavage
of a tentatively introduced benzeneselenyl group.24
In summary, we have established a stereocontrolled
synthesis of the platensimycin core 2 with the following key
findings. (1) Diastereoselective Diels-Alder reaction pro-
ceeded efficiently by the combination of enone 12b and
siloxydiene 13b. The steric and electronic factors of the
benzoyl group of 12b and TBS group of 13b significantly
affected the Diels-Alder reaction. (2) Intramolecular alkenyl
ether formation to construct a dihydropyran ring was
performed by oxypalladation with a catalytic amount of
Reduction of vinyl triflate 18 by the use of tributyltin hydride
and palladium(0)19 gave alkene 19 in only 37% yield.
Monothioacetal 20, a precursor for radical cyclization, was
prepared by reaction of alkenyl ether 19 and benzenethiol
at 50 °C without any solvents (Scheme 4).20 Transannular
radical cyclization of monothioacetal 2021 was accomplished
by using tributyltin hydride in the presence of AIBN in
refluxing toluene. Subsequent deprotection of the acetal group
gave 2 in 57% yield in two steps along with compound 22
(17) (a) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1997, 74, 77. (b) Comins, D. L.; Dehghani, A. Tetrahedron Lett.
1992, 33, 6299.
(18) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821.
(19) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 4630.
(22) Reaction of 1-alkoxyalkyl radicals from selenoacetal: (a) Rawal,
V. H.; Singh, S. P.; Dufour, C.; Michoud, C. J. Org. Chem. 1991, 56, 5245.
(b) Mesmaeker, A. D.; Waldner, A.; Hoffmann, P.; Mindt, T.; Hug, P.;
Winkler, T. Synlett 1990, 687. (c) Nishiyama, Y.; Yamamoto, H.; Nakata,
S.; Ishii, Y. Chem. Lett. 1993, 841.
(20) When the addition of benzenethiol to the alkenyl ether moiety was
carried out by employing a catalytic amount of PPTS, deprotection of the
acetal group of 19 also took place.
(21) Reductive radical cyclization of monothioacetal: (a) Yadav, V. K.;
Fallis, A. G. Tetrahedron Lett. 1988, 29, 897. (b) Sato, K.; Sasaki, M. Org.
Lett. 2005, 7, 2441.
(23) Braga, A. L.; Silveira, C. C.; Zeni, G.; Severo Filho, W. A.; Stefani,
H. A. J. Chem. Res. (S) 1996, 206.
(24) Lee, J. S.; Fuchs, P. L. Org. Lett. 2003, 5, 2247.
Org. Lett., Vol. 10, No. 18, 2008
4051

palladium(II) chloride and copper(II) acetate under oxygen
atmosphere. (3) The caged structure was constructed by
transannular radical cyclization of conformationally rigid
monothioacetal 20 by using tributyltin hydride and AIBN
in refluxing toluene with minimization of the elimination of
benzenethiol from 20 to 19 and reduction of 20 to 21. This
convergent synthesis of 2 will be useful for the synthesis of
platensimycin analogues which might improve the pharma-
cokinetic properties25 of 1.
Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801584R
Acknowledgment. This study was financially supported
(25) Singh, S. B.; Herath, K. B.; Wang, J.; Tsou, N.; Ball, R. G.
by the Uehara Memorial Foundation and a Grant-in-Aid for
Tetrahedron Lett. 2007, 48, 5429.
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Org. Lett., Vol. 10, No. 18, 2008