Synthesis and antibacterial properties of (-)-nor-platencin

Article abstract of DOI:10.1021/ol902194q

An asymmetric Diels-Alder reaction between acrolein and 1-benzyloxymethyl-1,3-cyclohexadiene affords a bicyclic aldehyde that was elaborated in 11 steps to nor-platencin. nor-Platencin is 4-16 times less active than platencin against several resistant str

Full text of DOI:10.1021/ol902194q

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5334-5337
Synthesis and Antibacterial Properties
of (-)-nor-Platencin
Olga V. Barykina,† Kerri L. Rossi,‡ Michael J. Rybak,‡ and Barry B. Snider*,†
Department of Chemistry, MS 015, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
and Anti-InfectiVe Research Laboratory, Eugene Applebaum College of Pharmacy & Health
Sciences, Wayne State UniVersity, 259 Mack AVenue, Detroit, Michigan 48201
snider@brandeis.edu
Received September 22, 2009
ABSTRACT
An asymmetric Diels-Alder reaction between acrolein and 1-benzyloxymethyl-1,3-cyclohexadiene affords a bicyclic aldehyde that was elaborated
in 11 steps to nor-platencin. nor-Platencin is 4-16 times less active than platencin against several resistant strains of Staphylococcus aureus,
macrolide-resistant Enterococcus faecalis, and vancomycin-resistant Enterococcus faecium.
Scientists at Merck recently isolated the novel antibiotics
platensimycin (1)1,2 and platencin (2)3 (see Figure 1). These
compounds are the first potent inhibitors of bacterial fatty
acid biosynthesis (Fab), which is needed for the survival of
bacterial pathogens. This pathway is highly conserved among
bacteria and is distinct from the mammalian pathway.
† Brandeis University.
‡ Wayne State University.
(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, 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.
Figure 1. Structures of platensimycin (1), platencin (2), and nor-
platencin (3).
2006, 128, 11916–11920
(2) For a review, see: Manallack, D. T.; Crosby, I. T.; Khakham, Y.;
Capuano, B. Curr. Med. Chem. 2008, 15, 705–710
.
Platensimycin blocks the fatty acid condensing enzyme
ꢀ-ketoacyl-[acyl carrier protein] synthase II (FabF) selec-
tively, whereas platencin inhibits both enzymes FabF and
ꢀ-ketoacyl-[acyl carrier protein] synthase III (FabH) with IC50
values of 1.95 and 3.91 µg/mL in Staphylococcus aureus.
These antibiotics do not exhibit cross-resistance to key
antibiotic resistant strains, including methicillin-resistant S.
aureus, vancomycin-intermediate S. aureus and vancomycin-
.
(3) (a) Wang, J.; Kodali, S.; Lee, S. H.; Galgoci, A.; Painter, R.; Dorso,
K.; Racine, F.; Motyl, M.; Hernandez, L.; Tinney, E.; Colletti, S. L.; Herath,
K.; Cummings, R.; Salazar, O.; Gonzalez, I.; Basilio, A.; Vicente, F.;
Genilloud, O.; Pelaez, F.; Jayasuriya, H.; Young, K.; Cully, D. F.; Singh,
S. B. Proc. Nat. Acad. Sci. U.S.A. 2007, 104, 7612–7616. (b) 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.
10.1021/ol902194q CCC: $40.75
Published on Web 10/21/2009
 2009 American Chemical Society

resistant Enterococcus faecium. Platencin shows potent in
vivo efficacy without any observed toxicity.
of keto aldehyde 5, R ) H or Me, which can be prepared
by homologation of Diels-Alder adduct 6, which will be
synthesized from the readily available 1,3-cyclohexadien-
emethanol (7a, R ) H)8 and acrolein (8a, R ) H) or methyl
vinyl ketone (8b, R ) Me). Use of methyl vinyl ketone
would introduce the methyl group early in the synthesis. Use
of acrolein would require methylation of 4a, as in the
platencin syntheses.7
As expected from the novel structures and potent antibacterial
activity, both platensimycin (1)4,5 and platencin (2)6 have been
the object of intense synthetic interest. Numerous analogues
of platensimycin have also been prepared, establishing that
the aromatic moiety is crucial for activity, but that there is
some room for structural modification of the tricyclic
diterpenoid moiety.7 No close analogues of platencin have
been prepared. We speculated that the exo-methylene group
of platencin is not needed for biological activity but is present
simply because it is a structural feature of the terpenoid
precursor. The exo-methylene group is acid-sensitive and
may also decrease the metabolic stability of platencin.
Finally, the exo-methylene group complicates the synthesis
by introducing both reactive functionality and an additional
chiral center at the carbon marked by an asterisk. Our goal
therefore was to develop a short synthesis of nor-platencin
(3), which lacks the exo-methylene group of platencin (2).
Our retrosynthesis is outlined in Scheme 1. We planned
to prepare nor-platencin (3) from enone 4, R ) H or Me,
The Diels-Alder reaction of 7a, R1 ) H, with methyl
vinyl ketone (8b) proceeded poorly either thermally or with
Lewis acid catalysis but gave a reasonable yield of racemic
Diels-Alder adduct 6a and stereo- and regioisomers by
reaction “on water”.9 Unfortunately, the Diels-Alder adducts
were difficult to work with because they exist as a mixture
of open and hemiketal tautomers. We were able to prepare
6b, R1 ) TBS and R2 ) Me, but all attempts to homologate
this by a Wittig reaction resulted in enolization of the hin-
dered methyl ketone. For these reasons we turned to acrolein
(8a) as the dienophile and readily available 1,3-cyclohexa-
dienylmethyl benzyl ether (7b)10 as the diene. The protecting
group will prevent formation of hemiacetals and will be
removed without an additional step during hydrogenation of
the double bond. Enolization should not occur during
homologation of 6c because the carbonyl group is an
aldehyde rather than a methyl ketone.
Scheme 1. Retrosynthesis of nor-Platencin (3)
In the reaction of 7b with acrolein (8a) as the dienophile,
we were able to take advantage of MacMillan’s asymmetric
Diels-Alder reaction using 10% of imidazolidinone 911 as
the catalyst in 19:1 CH3CN/H2O for 5 days (see Scheme 2).
Scheme 2. Diels-Alder Reaction of 7b and 8a
using methods developed for the synthesis of platencin (2).
Enone 4 will be prepared by an intramolecular aldol reaction
(4) For a review of early syntheses of platensimycin, see: Tiefenbacher,
K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548–2555
.
(5) For more recent syntheses of platensimycin, see: (a) Nicolaou, K. C.;
Pappo, D.; Tsang, K. Y.; Gibe, R.; Chen, D. Y.-K. Angew. Chem., Int. Ed.
2008, 47, 944–946. (b) Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.;
Lee, E. Angew. Chem., Int. Ed. 2008, 47, 4009–4011. (c) Matsuo, J.;
Takeuchi, K.; Ishibashi, H. Org. Lett. 2008, 10, 4049–4052. (d) Ghosh,
A. K.; Xi, K. J. Org. Chem. 2009, 74, 1163–1170. (e) Yun, S. Y.; Zheng,
This afforded a 9:1 mixture of the desired endo adduct 6c
and exo adduct 10, from which 6c (32%) and 10 (4%) were
(7) For syntheses of platensimycin analogues, see: (a) 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, 13110–13119. (b) Yeung, Y.-Y.; Corey, E. J. Org. Lett. 2008,
10, 3877–3878. (c) Wang, J.; Lee, V.; Sintim, H. O. Chem.-Eur. J. 2009,
15, 2747–2750. (d) Shen, H. C.; Ding, F.-X.; 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. Lett. 2009, 19, 1623–1627. (e) Jang, K. P.; Kim, C. H.; Na, S. W.;
Kim, H.; Kang, H.; Lee, E. Bioorg. Med. Chem. Lett. 2009, 19, 4601–
4602.
J.-C.; Lee, D. J. Am. Chem. Soc. 2009, 131, 8413–8415
.
(6) For syntheses and formal syntheses of platencin, see: (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) Tiefenbacher, 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) Nicolaou, K. C.; Toh, Q.-Y.; Chen, D. Y.-K.
J. Am. Chem. Soc. 2008, 130, 11292–11293. (f) Waalboer, D. C. J.;
Schaapman, M. C.; van Delft, F. L.; Rutjes, F. P. J. T. Angew. Chem., Int.
Ed. 2008, 47, 6576–6578. (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.
(8) (a) Botica, I.; Mirrington, R. N. Aus. J. Chem. 1971, 24, 1467–1480.
See also: (b) Hickson, C. L.; McNab, H. J. Chem. Soc., Perkin Trans. 1
1988, 339–342. (c) Hunig, S.; Kahanek, H. Chem. Ber. 1957, 90, 238–
245.
Org. Lett., Vol. 11, No. 22, 2009
5335

isolated in pure form along with an additional 10% of impure
6c. Other conditions, including MeOH/H2O and CH3NO2/
H2O, were less successful. Chiral HPLC established that the
ee of the major product 6c is 87%. Our yield does not
compare favorably with that reported by MacMillan for the
reaction of 1,3-cyclohexadiene with 8a catalyzed by 5% of
9, which gave a 14:1 mixture of endo and exo isomers in
82% yield with 94% ee for the endo isomer.11a However, in
his synthesis of hapalaindole Q, Kerr carefully optimized
the Diels-Alder reaction of 1,3-dimethyl-1,3-cyclohexadiene
with 3-(3-(N-tosyl)indolyl)acrolein catalyzed by 40% of 9
to obtain a maximum yield of 35% with 85:15 endo/exo
selectivity and 93% ee for the endo isomer.11c As Kerr also
noted in his synthesis,11c the rapid and enantioselective
assembly of the key intermediate 6c makes this route
attractive despite the modest yield.
Scheme 3. Synthesis of Tricyclic Enone 4a
The lower ee in our case could result from an uncatalyzed
background reaction. Reaction of 7b and 8a for 5 days
without catalyst 9 afforded Diels-Alder adducts in 10%
yield. The background reaction will be much less significant
in the presence of catalyst 9 because the diene is consumed
in the more rapid catalyzed reaction. The ee can probably
be improved somewhat by increasing the catalyst loading.
Equilibration of both 6c and 10 with aqueous NaOH in EtOH
afforded the identical 3:1 mixture of 6c and 10. The catalyst
controls the stereochemistry adjacent to the aldehyde center
so that epimerization of exo adduct 10 will give ent-6c,
providing another possible explanation for the lower ee.
However, the isolation of a 9:1 mixture of endo isomer 6c
and exo isomer 10 suggests that epimerization is not a major
issue.
tion of 13 afforded a mixture of 1,5-diols 16 in 77% yield.
Swern oxidation appears to be the method of choice for the
oxidation of 1,5-diols to keto aldehydes,14 because other
procedures give the δ-lactone as a byproduct.15 Swern
oxidation of 16 using i-Pr2EtN,16 rather than Et3N, gave the
unstable keto aldehyde 5a, which was treated with NaOH
in EtOH to give the desired cyclohexenone 4a17 in 70%
overall yield from 16.
Homologation of 6c by a Horner-Wittig reaction12 now
proceeded smoothly to give 11 as a 3:2 mixture of
stereoisomers in 67% yield (see Scheme 3). Hydrolysis
of 11 in a two-phase system13 with aqueous HCl in CH2Cl2
and THF provided the homologated aldehyde 12 in 90%
yield. Addition of MeMgBr to 12 afforded secondary
alcohol 13 in 99% yield as a mixture of stereoisomers.
Buffered PCC oxidation of 13 gave ketone 14 in >90%
yield. To our surprise, hydrogenation of 14 afforded
mainly tetrahydropyran 15. Hydrogenation and hydro-
genolysis provided the desired saturated hydroxy ketone,
which cyclized to form the hemiketal. Further reduction,
probably by dehydration to the enol ether and hydrogena-
tion, afforded 15.
Alkylation of 4a with LHMDS and MeI in 10:1 THF/
HMPA afforded 87% of 4b containing a few percent of the
stereoisomer (see Scheme 4).6b Elaboration of 4b to car-
Scheme 4. Completion of the nor-Platencin (3) Synthesis
We therefore decided to carry out the hydrogenation and
hydrogenolysis before formation of the ketone. Hydrogena-
(9) Chanda, A.; Fokin, V. V. Chem. ReV. 2009, 109, 725–748.
(10) Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem.
1988, 53, 4877–4883.
(11) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243–4244. (b) Northrup, A. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 2458–2460. (c) Kinsman, A. C.;
Kerr, M. A. J. Am. Chem. Soc. 2003, 125, 14120–14125. (d) Wilson, R. M.;
Jen, W. S.; Macmillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616–
11617. (e) MacMillan, D. W. C.; Lelais, G. Aldrichimica Acta 2006, 39,
79–87. (f) Gordillo, R.; Houk, K. N. J. Am. Chem. Soc. 2006, 128, 3543–
3553.
(12) Earnshaw, C.; Wallis, C. J.; Warren, S. J. Chem. Soc., Perkin Trans.
1 1979, 12, 3099–3106.
boxylic acid 18 was carried out using procedures developed
by Corey for the preparation of a platensimycin analogue
(13) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata,
J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239–3242.
5336
Org. Lett., Vol. 11, No. 22, 2009

and by Mulzer for the synthesis of platencin.6h,7b Treatment
of 4b with t-BuOK and methyl acrylate in ether/t-BuOH for
30 min at 0 °C provided a 5:1 mixture of ester 17 and the
diastereomer from which the desired isomer 17 was isolated
in 39% yield by preparative HPLC. Hydrolysis of 17 afforded
acid 18 in 71% yield. Amide formation was accomplished
by reaction of acid 18 with protected aniline 195d,6a,18 using
HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylu-
ronium hexafluorophosphate) in DMF for 38 h to give
trimethylsilylethyl ester 20 (58%), which was hydrolyzed
with TASF in DMF to provide (-)-nor-platencin (3) in 56%
yield.
The antibiotic acitivity of nor-platencin (3) was determined
against several resistant strains of S. aureus, macrolide-
resistant E. faecalis, and vancomycin-resistant Enterococcus
faecium. The minimum inhibitory concentration (MIC) data
shown in Table 1 indicate that nor-platencin (3) is 4-16
times less potent than platencin (2) as an antibiotic. As with
platencin (2), the best activity is shown against vancomycin-
resistant E. faecium. The reduced potency of 3 indicates that
the exo-methylene group of platencin (2) contributes mod-
estly to the antibiotic activity.
Table 1. Antibiotic Activity of Platencin (2) and nor-Platencin
(3)
platencin nor-platencin
(2) MIC,
µg/mLa
(3) MIC,
µg/mLb
organism and genotype
S. aureus (MSSA)
0.5
1
4
4
S. aureus (MRSA)
S. aureus (MRSA) plus serum
S. aureus (MRSA macrolide-R and
Linezolid-R)
S. aureus (VISA)
S. aureus (VRSA)
8
>32
1
0.5
1
ND
ND
2
<0.06
>64
4
8
16
4
S. aureus (hVISA)
S. aureus (MRSA daptomycin-R)
E. faecalis (macrolide-R)
E. faecium (vancomycin-R)
E. coli
4
16
0.25
>32
a Data from ref 3a. b MIC determined according to Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;
ApproVed Standard, 8th ed.; Document M07-A8; Clinical and Laboratory
Standards Institute: Wayne, Pennsylvania, 2008. ND ) not determined.
R ) resistant.
In conclusion, an asymmetric Diels-Alder reaction be-
tween acrolein (8a) and 1-benzyloxymethyl-1,3-cyclohexa-
diene (7b) affords bicyclic aldehyde 6c that was elaborated
in 11 steps to nor-platencin (3). nor-Platencin (3) is 4-16
times less potent than platencin (2) against several bacterial
strains, indicating that the exo-methylene group of platencin
(2) contributes modestly to the antibiotic activity.
(14) (a) Cheˆnevert, R.; Courchesne, G.; Caron, D. Tetrahedron: Asym-
metry 2003, 14, 2567–2571. (b) Maddess, M. L.; Tackett, M. N.; Watanabe,
H.; Brennan, P. E.; Spilling, C. D.; Scott, J. S.; Osborn, D. P.; Ley, S. V.
Angew. Chem., Int. Ed. 2007, 46, 591–597. (c) Mukaiyama, T.; Pudhom,
K.; Yamane, K.; Arai, H. Bull. Chem. Soc. Jpn. 2003, 76, 413–425. (d)
Karche, N. P.; Pierry, C.; Poulain, F.; Oulyadi, E. L.; Pannecoucke, X.;
Quirion, J. C. Synlett 2007, 123–126.
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM-50151) for support of this work.
(15) See, for instance Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.;
Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57–59.
(16) Rose, N. G. W.; Blaskovich, M. A.; Evindar, G.; Wilkinson, S.;
Luo, Y.; Fishlock, D.; Reid, C.; Lajoie, G. A. Org. Synth. 2002, 79, 216–
227. Much lower yields of 5a were obtained using Et3N.
Supporting Information Available: Complete experi-
1
mental procedures and copies of H and 13C NMR spectral
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) The synthesis of 4a by an asymmetric intramolecular Robinson
annulation was recently reported. Li, P.; Yamamoto, H. Chem. Commun.
2009, 541, 2–5414.
(18) Heretsch, P.; Giannis, A. Synthesis 2007, 2614–2616.
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