A nine-step total synthesis of (-)-platencin

Article abstract of DOI:10.1021/jo9001855

Within 1 year, platencin, a recently discovered antibiotic, has become a highly competitive synthetic target, due to its promising bioactivity and its unusual complex molecular architecture. Herein, a particularly concise total synthesis of platencin star

Full text of DOI:10.1021/jo9001855

A Nine-Step Total Synthesis of (-)-Platencin
Konrad Tiefenbacher* and Johann Mulzer*
Institute of Organic Chemistry, UniVersity of Vienna, W a¨ hringerstrasse 38, 1090 Vienna, Austria
johann.mulzer@uniVie.ac.at; konrad.tiefenbacher@uniVie.ac.at
ReceiVed January 28, 2009
Within 1 year, platencin, a recently discovered antibiotic, has become a highly competitive synthetic
target, due to its promising bioactivity and its unusual complex molecular architecture. Herein, a particularly
concise total synthesis of platencin starting from inexpensive perillaldehyde is described. The key features
of this approach are (1) a highly diastereoselective Diels-Alder reaction with Rawal’s dienesforming
the first all-carbon quaternary center, (2) a ring-closing metathesis to generate the strained tricylic skeleton,
(
3) a hydration/dehydration strategy to efficiently shift the endocyclic alkene to the exoposition, and (4)
a 1,4-addition of a hindered ketone enolate to methyl acrylate to create the second all-carbon quaternary
center. In view of the brevity (nine linear steps) and the overall yield of 10%, our synthesis compares
favorably with all the previous ones.
Introduction
The rise of multiresistant bacteria is a serious and urgent
threat, especially in hospitals, where antibiotics are permanently
used and bacteria strains easily evolve that withstand multiple
antibiotic classes. Infections by gram-positive pathogens such
as methicillin-resistant Staphylococcus aureus (MRSA), van-
comycin-resistant enterococci (VRE), and penicillin-resistant
FIGURE 1. Structures of platensimycin (1) and platencin (2).
mycin-resistant enterococci, and Streptococcus pneumoniae.
3
1
Streptococcus pneumonia (PRSP) are especially worrying.
Just recently, platensimycin B
natural derivatives of platensimycin, have been discovered.
1
3
-B , less biologically active
From these observations, the urgency to develop new antibiotics
is obvious. Since novel antibiotics usually address well-known
targets just at different binding sites or through new binding
4
Owing to the unique mode of action, no cross-resistances to
existing drugs have been observed so far. In addition, the toxicity
profile seems to be good. However, the in vivo efficacy is low,
due to the limited metabolic stability, so that suitable synthetic
derivatives will have to be prepared and investigated to find
2
3
modes, the discovery of platensimycin (1) and platencin (2,
Figure 1) is a breakthrough in antibiotics research.
This is due to the fact that compounds 1 and 2 address an
apparently ideal biological target. They are the first potent
inhibitors of bacterial fatty acid biosynthesis (Fab), which is
essential to the survival of the pathogens, distinct from the
mammalian pathway and generally highly conserved among
bacteria. While platensimycin is blocking the fatty acid con-
densing enzyme FabF selectively, platencin is inhibiting the
enzymes FabF and FabH. These compounds thus display a
broad-spectrum antibiotic activity against many drug-resistant
pathogens such as methycillin-, macrolide-, and linezolid-
resistant S. aureus, vancomycin intermediate S. aureus, vanco-
1
more promising drug candidates.
(2) (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. (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; J. Am. Chem. Soc. (Addition/Correction) 2006,
1
28, 15547. (c) Singh, S. B.; Herath, K. B.; Wung, J.; Tsou, N.; Ball, R. G.
Tetrahedron Lett. 2007, 48, 5429. (d) Singh, S. B.; Wang, J.; Basilio, A.;
Genilloud, O.; Hernandez, P.; Tormo, J. R. WO 2005009391, 2005 (CAN 142:
196607).
(
1) (a) H a¨ bich, D.; von Nussbaum, F. ChemMedChem 2006, 1, 951. (b)
Holzgrabe, U.; Dingermann, T.; Z u¨ ndorf, I. Pharm. Unserer Zeit 2006, 35, 388.
1
0.1021/jo9001855 CCC: $40.75  2009 American Chemical Society
J. Org. Chem. 2009, 74, 2937–2941 2937
Published on Web 03/04/2009

Tiefenbacher and Mulzer
6
a
SCHEME 1. First-Generation Synthesis of the Core
Fragment 6 of Platencin (2)
SCHEME 2. Nicolaou’s Endgame and Potential
Alternatives
Not surprisingly, the unusual structure and the promising
biological activity have attracted great interest from the scientific
5
community, leading to one total and eight formal syntheses of
6
1
during the last 2 years and two total and five formal syntheses
of 2sall published in 2008. Our goal was to develop a short
total synthesis of platencin based on our previous five-step
6
c
formal synthesis (Scheme 1).
Perillaldehyde (3) was chosen as the starting material because
it is inexpensive and can be converted to the advanced core
system 4 in three steps. The disadvantage of this first-generation
approach is the shift of the endo-cycloalkene (in 4) to the
thermodynamically less favored exo position (in 6). As this
operation furnished a 3:1 mixture of 6 and 4 and required 2.5
equiv of chromium reagent, we decided to replace it with a more
suitable methodology. Another issue is the endgame, that is,
the conversion of intermediate 6 into platencin (2). In Nicolaou’s
vinyl boronate 9. A two-step oxidation furnished carboxylic acid
1
0. We envisioned a more convergent route from 7 to 10 either
by alkylation with the appropriately functionalized allyl halides
1 or 12 or by a conjugate enolate 1,4-addition to an acrylic
1
ester. We are now pleased to note that due to the improvements
reported in this full account our new synthesis produces
substantial amounts of pure 2 in only nine linear steps with
satisfactory stereo- and regiocontrol.
6
a
benchmark approach (Scheme 2), 6 was first methylated to 7
and then converted to 8 via allylation and cross metathesis with
(
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.; 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. (b) Jayasuriya, H.; Herath, K. B.; Zhang, C.;
Zink, D. L.; Basilio, A.; Genilloud, O.; Teresa Diez, M.; Vicente, F.; Gonzalez,
I.; Salazar, O.; Pelaez, F.; Cummings, R.; Ha, S.; Wang, J.; Singh, S. B. Angew.
Chem., Int. Ed. 2007, 46, 4684.
Results and Discussion
Synthesis of the Core Fragment 6: The first step in the
synthesis is the Diels-Alder reaction between perillaldehyde
(3) and a suitable diene. The traditional Danishefsky diene (13a)
fails to react with poor dienophiles such as cyclohex-1-
enecarbaldehydes under regular conditions. Therefore, we
(
4) Zhang, C.; Ondeyka, J.; Zink, D. L.; Burgess, B.; Wang, J.; Singh, S. S.
Chem. Commun. 2008, 5034.
5) Review on the synthesis of platensimycin: (a) Tiefenbacher, K.; Mulzer,
(
7
J. Angew. Chem., Int. Ed. 2008, 47, 2548. Total synthesis of platensimycin: (b)
Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2006, 45, 7086.
Formal synthesis of platensimycin: (c) Nicolaou, K. C.; Edmonds, D. J.; Li, A.;
Tria, G. S. Angew. Chem., Int. Ed. 2007, 46, 3942. (d) Zou, Y.; Chen, C.-H.;
Taylor, C. D.; Foxman, B. M.; Snider, B. B. Org. Lett. 2007, 9, 1825. (e)
Nicolaou, K. C.; Tang, Y.; Wang, J. Chem. Commun. 2007, 1922. (f) Li, P.;
Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534. (g)
Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2007, 46, 8074. (h) Lalic,
G.; Corey, E. J. Org. Lett. 2007, 9, 4921. (i) Nicolaou, K. C.; Pappo, D.; Tsang,
K. Y.; Gibe, R.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2008, 47, 944. (j) Kim,
C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem., Int. Ed.
decided to use the much more reactive Rawal diene (13b),
which after exposure to 3 in refluxing toluene for 4.5 h, followed
by acidic treatment, furnished the desired cycloadduct 14 in 68%
yield and excellent diastereoselectivity (20:1, Scheme 3). Later,
the Rutjes group did add 13a to 3; however, as expected, high
pressure conditions (15 kbar), which traditionally limit the scale
6e
up of a reaction, had to be used.
The selective methylenation of the neopentylic aldehyde
function of 14 in the presence of the unsaturated ketone was
unproblematic if just a slight excess of the Wittig reagent was
used at 0 °C. Under these conditions, triene 15 was obtained in
2
008, 47, 4009. Derivatives of platensimycin: (k) Nicolaou, K. C.; Lister, T.;
Denton, R. M.; Montero, A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2007, 46,
712. (l) Nicolaou, K. C.; Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero,
4
A. J. Am. Chem. Soc. 2007, 129, 14850. (m) Kaliappan, K. P.; Ravikumar, V.
Org. Lett. 2007, 9, 2417. Synthetic studies toward the tetracyclic core system: (n)
Ghosh, A. K.; Xi, K. Org. Lett. 2007, 9, 4013. Short synthesis of the aromatic
part: (o) Heretsch, P.; Giannis, A. Synthesis 2007, 17, 2614.
8
0% yield. Ring-closing metathesis (RCM) of 15 with Grubbs’
8
2 2
second-generation catalyst (7 mol %) in refluxing CH Cl led
to 4 in 90% isolated yield. Since the reaction was slow, the
catalyst was added in three portions over 36 h. As expected,
(
6) (a) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem., Int. Ed.
2
4
6
6
008, 47, 1780. (b) Hayashida, J.; Rawal, V. H. Angew. Chem., Int. Ed. 2008,
7, 4373. (c) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47,
199. (d) Yun, S. Y.; Zheng, J.-C.; Lee, D. Angew. Chem., Int. Ed. 2008, 47,
201. (e) Waalboer, D. C. J.; Schaapman, M. C.; Van Delft, F. L.; Rutjes,
(7) Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999, 64, 3039.
(8) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl,
M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 2546.
F. P. J. T. Angew. Chem., Int. Ed. 2008, 47, 6576. (f) Nicolaou, K. C.; Toh,
Q.-Y.; Chen, D. Y.-K. J. Am. Chem. Soc. 2008, 130, 11292; J. Am. Chem. Soc.
(
Addition/Correction) 2008, 130, 14016. (g) Austin, K. A. B.; Banwell, M. G.;
Willis, A. C. Org. Lett. 2008, 10, 4465.
2
938 J. Org. Chem. Vol. 74, No. 8, 2009

A Nine-Step Total Synthesis of (-)-Platencin
SCHEME 3. Synthesis of Tricycle 4
SCHEME 5. Completion of the Total Synthesis of
Platencin (2)
SCHEME 4. Conversion of the Endocyclic to the Exocyclic
Alkene via Bromination or Hydration
clean and reproducible formation of 5 was achieved. On second
sight, this is not so surprising, as Ru(II) species are known to
act as Lewis acid catalysts in several transformations, such as
(
hetero)-Diels-Alder reactions, Mukaiyama aldol reactions, oxa-
11
ene reactions, and Claisen rearrangements. With allylic
bromide 5 finally in hand, chromium(II) reduction furnished a
separable 3:1 mixture of 6 and 4. Several other reduction
conditions were explored, but to no avail. For instance, Zn,
AcOH, MeOH, 22 °C resulted in an unfavorable 1:0.7 ratio of
6
e
6
and 4; for Pd(dba)
ratio was 1:0.8, whereas NaBH
furnished complex product mixtures.
3
, PBu
3
, Et
3
N, HCOOH, THF, reflux, the
4
/CeCl , MeOH or LAH, Et
3
2
O
Grubbs’ first-generation catalyst under the same conditions did
not furnish any product.
Finally, to avoid the use of stochiometric amounts of
chromium and to increase the 6/4 ratio, a concise hydration/
dehydration strategy was devised. Thus, our RCM product 4
was hydrated to 16 (formed as an inconsequential 1.5:1
diastereomeric mixture) via the trifluoroacetate and subsequent
saponification. The following dehydration was performed with
a selection of dehydrating reagents, which varied considerably
with respect to their regioselectivity. Thus, whereas Burgess
For the isomerization of 4 to 6 (Scheme 4), we first tried to
9
improve our initial Mori-type bromination/chromium(II) reduc-
tion sequence. As the allylic bromination under literature
conditions (NBS, MeOH, CH Cl , 0 °C) saddled us with
2 2
considerable amounts of undesired bromoethers, we explored
a series of other bromination and chlorination protocols (for
10a
instance, NBS, (BzO)
NBA, acetone, water, rt;
NaOCl, H PO , hexane, 0 °C), which all yielded complex
2 4 3
, CCl , reflux; NCS, Yb(OTf) , TMSCl;
1
2
13
1
0b
10c
reagent (THF, CH
mixtures of 6 and 4, Martin’s sulfurane led to satisfactory results
7:1 at 20 °C and 10:1 at 0 °C). Although this selectivity was
somewhat lower than that which the Nicolaou group had
2 2 2
Cl ) or SOCl , pyridine gave ca. 1:1
2 2
NBS, CH Cl , silica gel, rt;
1
0d
3
4
(
product mixtures. Without an alcohol additive, no reaction was
observed. Finally, after a lot of experimentation, we found that
the bromoether formation we observed under our standard
6
f
reported, this method proved highly practical for procuring
the desired exo-olefin.
2 2
conditions (NBS, MeOH, CH Cl , 0 °C) could be suppressed
Completion of the Total Synthesis: After having established
an exceptionally direct and selective access to the core fragment
by replacing methanol with the much bulkier tBuOH. Neverthe-
less, the yield was unsatisfying and variable, until we discovered
that the reaction proceeded smoothly when impure, dark samples
of 4 (obtained from cursorily performed column chromatography
of the RCM mixture) were used. Assuming that the dark
impurity is some ruthenium species which catalyzes the allylic
bromination, we skipped the chromatography and added NBS
and tBuOH directly to the crude RCM reaction mixture. Indeed,
6
, we decided to keep the endgame as short and convergent as
6
a,b
possible. Thus, after methylation of 6 to 7 (Scheme 5),
we
1
4
tried the alkylation of 7 with known allylic bromide 11 or the
easily accessible iodide 12 under various conditions, but only
starting material could be isolated in all cases. With 6-methoxy-
1
-tetralone (17) as a simple test substrate, alkylation to 18 with
(
11) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101,
2067.
(12) Reviews on the chemistry of the Burgess reagent: (a) Taibe, P.;
(
9) (a) Omoto, M.; Kato, N.; Sogon, T.; Mori, A. Tetrahedron Lett. 2001,
2, 939. (b) Abad, A.; Agull o` , C.; Cunat, A. C.; Marzal, I. A.; Gris, A.; Navarro,
I.; Ramirez de Arellano, C. Tetrahedron 2007, 63, 1664.
10) (a) Yamanaka, M.; Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron
4
Mobashery, S. In Encyclopedia of Reagents for Organic Synthesis; PaquetteL. A.,
Ed.; John Wiley & Sons: Chichester, UK, 1995; Vol. 5, pp 3345-3347. (b)
Burckhardt, S. Synlett 2000, 559.
(13) Margaros, I.; Vassilikogiannakis, G. J. Org. Chem. 2007, 72, 4826.
(14) Pergament, I.; Reich, R.; Srebnik, M. Bioorg. Med. Chem. Lett. 2002,
12, 1215.
(
Lett. 2002, 43, 2403. (b) Hiranuma, S.; Shimizu, T.; Yoshioka, H. Chem. Pharm.
Bull. 1991, 39, 2167. (c) Since it was observed that silica gel (TLC) accelerates
the reaction in the presence of an alcohol additive. (d) Nussbaumer, C.; Frater,
G.; Kraft, P. HelV. Chim. Acta 1999, 82, 1016.
J. Org. Chem. Vol. 74, No. 8, 2009 2939

Tiefenbacher and Mulzer
iodide 12 could be achieved in 90% yield, while bromide 11
failed. Although not successful for 7, this result at least indicated
that, in principle, iodide 12 could be a useful alkylation agent
to form tertiary carbon centers, with the advantage of further
functionalization by oxidation or coupling at the vinyl boronate
position. Fortunately, our second approach, conversion of 7 into
the enolate followed by 1,4-addition to methyl acrylate, worked
and gave us an easily separable 4:1 mixture of 19 and its
diastereomer. Interestingly, the diastereomeric ratio was not
affected by lowering the temperatureseven at -78 °C, the same
ratio was observed. The synthesis was completed by ester
suspension was quickly added to a solution of aldeyde 6 (1.71 g,
7.83 mmol) in THF (100 mL) at 0 °C. After stirring for 20 min at
this temperature, water (500 mL) was added and the aqueous layer
was extracted three times with diethyl ether. The combined organic
phases were dried over magnesium sulfate, filtered, silica gel (6 g)
was added, and the solvent was carefully removed under vacuum.
Purification of the adsorbed material by column chromatography
(
60 g silica gel) using hexane/ethyl acetate ) 10:1 as an eluent
yielded triene 15 (1.36 g, 80%) as a colorless oil: R ) 0.46 (hexane/
f
2
0
1
EtOAc 3:1); [R]
D
2 2
) +88.2 (c ) 1.10, CH Cl ); H NMR (400
MHz, CDCl ) δ ) 6.58 (d, J ) 10.1 Hz, 1H), 5.96-5.86 (m, 2H),
3
5.26 (d, J ) 10.8 Hz, 1H), 5.17 (d, J ) 17.6 Hz, 1H), 4.76 (s, 1H),
6b
hydrolysis and direct coupling of the carboxylic acid with the
4.72 (s, 1H), 2.69-2.57 (m, 1H), 2.41-2.28 (m, 2H), 2.20-2.09
5o,15
6a,b
(
1
1
(
3
1
m, 1H), 1.84-1.72 (m, 2H), 1.72 (s, 3H), 1.69-1.60 (m, 2H),
unprotected aniline 20.
In contrast to previous endgames,
1
3
.57-1.44 (m, 2H); C NMR (100 MHz, CDCl
57.2 (CH), 148.8 (C), 143.3 (CH), 127.0 (CH), 115.8 (CH
), 42.3 (C), 40.0 (CH ), 38.3 (CH), 38.1 (CH), 32.0 (CH
0.6 (CH ), 25.9 (CH ), 21.1 (CH ); IR (film) ν˜ ) 2930, 1674,
450, 884 cm ; HRMS(EI) calcd for C15
3
) δ ) 200.2 (C),
), 109.4
),
this protocol is atom economical and does not need cross
metathesis and dummy atoms such as boron or silicon, which
have to be removed oxidatively.
2
CH
2
2
2
2
2
3
1
13
The spectral data ( H, C NMR) of 2 perfectly matched those
-1
+
H
20O [M ] 216.1516,
6
a,b
in the literature.
Moreover, the OH and NH signals were
found 216.1504.
1
unambiguously assigned in the H NMR spectrum by D
exchange (see Supporting Information).
2
O
1,6
(1R,6S,8S)-9-Methyltricyclo[6.2.2.0 ]dodeca-2,9-dien-4-one (4):
A solution of triene 15 (609 mg, 2.82 mmol) and Grubbs’ second-
generation catalyst (72 mg, 0.085 mmol) in degassed (pump, freeze,
2 2
and thaw technique) CH Cl (56 mL) was refluxed overnight. Two
Conclusion
times additional catalyst (48 mg, 0.057 mmol) was added, and the
mixture was refluxed for 8-12 h. After the reaction was finished,
air was blown into the reaction vessel and stirring was continued
for 30 min. Silica gel (4 g) was added, and the solvent was carefully
removed under vacuum. Purification of the adsorbed material by
column chromatography (50 g silica gel) using hexane/ethyl acetate
In summary, a nine-step, protecting-group-free total synthesis
of natural (-)-platencin (2) has been accomplished. We obtained
3
6 mg of 2 with ee >92% (limited only by the optical purity of
the perillaldehyde) in nine linear steps and 10% overall yield.
As a consequence, we have an efficient route at our disposal,
which should also allow the fast and concise synthesis of
derivatives, required for the development of antibiotics with
more suitable pharmacological characteristics.
)
7:1 as an eluent yielded tricycle 4 (478 mg, 90%) as colorless
20
oil: R
f
) 0.43 (hexane/EtOAc 3:1); [R]
D
) -71.3 (c ) 0.98,
1
CH Cl ); H NMR (400 MHz, CDCl ) δ ) 6.97 (d, J ) 10.0 Hz,
1H), 5.93 (dd, J ) 10.0, 0.9 Hz, 1H), 5.80 (s, 1H), 2.57-2.48 (m,
2
2
3
1
3
1
H), 2.42-2.27 (m, 2H), 2.00-1.89 (m, 1H), 1.82 (d, J ) 1.7 Hz,
H), 1.80-1.69 (m, 2H), 1.62-1.53 (m, 1H), 1.41-1.23 (m, 2H),
Experimental Section
13
.02 (ddd, J ) 12.6, 6.3, 1.7 Hz, 1H); C NMR (100 MHz, CDCl
3
)
δ ) 200.4 (C), 157.1 (CH), 142.7 (C), 128.6 (CH, 2C), 41.7 (CH
2
),
),
(2S,4aR,8aS)-2-Isopropenyl-7-oxo-1,3,4,7,8,8a-hexahydro-2H-
39.2 (C), 38.5 (CH), 35.9 (CH), 32.1 (CH
2 2 2
), 27.0 (CH ), 25.6 (CH
naphthalene-4a-carbaldehyde (14): To a refluxing solution of (-)-
perillaldehyde (4.37 g, 29.1 mmol) in anhydrous toluene (82 mL)
was added Rawal diene (4.41 g, 19.4 mmol) in three portions every
-1
20.2 (CH ); IR (film) ν˜ ) 2938, 2861, 1682, 1250, 1202, 766 cm ;
3
+
HRMS(EI) calcd for C13
1R,6S,8S)-9-Hydroxy-9-methyltricyclo[6.2.2.0 ]dodec-2-en-4-
one (16): Trifluoroacetic acid (1.9 mL) was added to a solution of
(320 mg, 1.70 mmol) in CH Cl (5.6 mL) at 0 °C. After 15 min,
H16O [M ] 188.1201, found 188.1205.
1,6
(
3
0 min. After the last addition, the reaction mixture was refluxed
for another 3 h, cooled to rt, and the solvent removed under vacuum.
The oily residue was dissolved in THF (108 mL); 1.2 M aqueous
HCl (44 mL) was added, and the mixture was stirred at rt for 16 h.
After addition of brine (385 mL), the aqueous layer was extracted
three times with diethyl ether. The combined organic phases were
dried over magnesium sulfate, filtered, and the solvent was removed
under vacuum. Purification by column chromatography (130 g silica
gel) using hexane/ethyl acetate ) 3:1 as an eluent yielded aldehyde
4
2
2
the cooling bath was removed and stirring continued for 2 h. The
reaction mixture was diluted with diethyl ether (20 mL), and
aqueous KOH (10%, 20 mL) was slowly added at 0 °C. The cooling
bath was removed, and rigorous stirring continued for 14 h. The
2 2
aqueous layer was extracted three times with CH Cl . The combined
organic phases were dried over magnesium sulfate, filtered, and
the solvent was removed under vacuum. Purification by column
chromatography (18 g silica gel) using hexane/ethyl acetate ) 1:1
1
4 (2.86 g, 68%) as a slightly yellow oil: R ) 0.32 (hexane/EtOAc
f
2
0
1
3
:1); [R]
D
) +170.3 (c ) 1.07, CH
2 2
Cl ); H NMR (400 MHz,
as an eluent yielded alcohol 16 (302 mg, 86%) as a colorless oil:
CDCl
3
) δ ) 9.59 (s, 1H), 6.60 (d, J ) 10.1 Hz, 1H), 6.08 (d, J )
1
R
f
) 0.24/0.29 (hexane/EtOAc 1:1); H NMR (400 MHz, CDCl
3
)
1
2
2
0.1 Hz, 1H), 4.75 (s, 1H), 4.69 (s, 1H), 2.85-2.76 (m, 1H),
δ ) 6.52 (d, J ) 10.1 Hz, 0.4H), 6.47 (d, J ) 10.1 Hz, 0.6H), 5.85
.71-2.60 (m, 1H), 2.43-2.35 (m, 1H), 2.26-2.18 (m, 1H),
.16-2.06 (m, 1H), 1.79-1.56 (m, 4H), 1.69 (s, 3H), 1.31-1.17
(
dd, J ) 10.1, 1.0 Hz, 0.6H), 5.84 (dd, J ) 10.1, 1.0 Hz, 0.4H),
m, 1H); 13C NMR (100 MHz, CDCl
2.49-1.98 (m, 4.4H), 1.74-1.40 (m, 7H), 1.36 (s, 1.8H), 1.34 (s,
(
3
) δ ) 201.6 (CH), 198.5 (C),
), 52.7 (C), 39.2
), 32.6 (CH), 28.1 (CH ), 27.1 (CH ),
); IR (film) ν˜ ) 2931, 1726, 1676, 1452, 1251, 890 cm ;
1
0
.2 H), 1.33-1.27 (m, 0.6H), 1.15-1.09 (m, 0.4H), 1.00-0.92 (m,
1
48.2 (C), 147.9 (CH), 129.9 (CH), 109.7 (CH
2
13
.6H); C NMR (100 MHz, CDCl ) δ ) 200.3 (C), 200.0 (C),
3
(
2
CH
0.9 (CH
3
2
), 38.0 (CH), 32.8 (CH
2
2
2
-
1
157.2 (CH), 156.7 (CH), 127.7 (CH), 127.7 (CH), 71.6 (C), 70.9
(C), 49.3 (CH ), 49.2 (CH ), 41.5 (CH ), 41.5 (CH ), 37.6 (CH),
7.0 (CH), 35.5 (C), 35.3 (C), 34.3 (CH), 34.2 (CH), 31.2 (CH ),
0.8 (CH ), 30.0 (CH ), 29.9 (CH ), 23.8 (CH ), 23.7 (CH ), 23.6
), 21.2 (CH ); IR (film) ν˜ ) 3449, 2926, 1676, 1258, 1121,
+
2
2
2
2
HRMS(EI) calcd for C14
4aR,7S,8aS)-7-Isopropenyl-4a-vinyl-4a,5,6,7,8,8a-hexahydro-
H-naphthalen-2-one (15): To a suspension of tBuOK (2.11 g, 18.8
mmol) in THF (42 mL) was added PPh MeBr (8.39 g, 23.5 mmol)
and stirred for 25 min at rt. At this time, 30 mL of this yellow
18 2
H O [M ] 218.1307, found 218.1300.
3
3
2
(
3
2
3
2
2
1
(
7
CH
2
2
3
-
1
+
18 2
79, 611 cm ; HRMS(EI) calcd for C13H O [M ] 206.1307,
found 206.1297.
(1R,6S,8S)-9-Methylenetricyclo[6.2.2.0 ]dodec-2-en-4-one (6):
To a solution of alcohol 16 (279 mg, 1.35 mmol) in CH Cl (8
mL) was added a solution of Martin’s sulfurane (1.0 g, 1.49 mmol)
1,6
1
6
(
(
15) Coupling of 20 with the acyl chloride led to decomposition.
16) Lee, K.; Lee, J. H.; Boovanahalli, S. K.; Jin, Y.; Lee, M.; Jin, X.; Kim,
2
2
J. H.; Hong, Y.-S.; Lee, J. J. J. Med. Chem. 2007, 50, 1675.
2
940 J. Org. Chem. Vol. 74, No. 8, 2009

A Nine-Step Total Synthesis of (-)-Platencin
in CH
2
Cl
2
(2.5 mL) at 0 °C. After 1.5 h, additional Martin’s
Cl (2.5 mL) was added and
mg, 0.14 mmol) in THF (1.7 mL) was added 1 M aqueous NaOH
(1.7 mL), and the mixture was stirred for 23 h at rt. After the
addition of water (16 mL) and brine (8 mL), the mixture was
washed with diethyl ether twice. The aqueous phase was acidified
with 1.2 M HCl (formation of a white precipitate) and extracted
three times with diethyl ether. The combined organic phases were
dried over magnesium sulfate, filtered, and the solvent was removed
f
sulfurane (300 mg, 0.45 mmol) in CH
2
2
stirring continued for 1 h at 0 °C. The reaction mixture was
concentrated under vacuum, and the residue was purified by column
chromatography (30 g silica gel) using hexane/diethyl ether ) 4:1
as an eluent to yield 6 (229 mg, 90%) as a colorless oil: R
f
) 0.38
2
0
35
(
+
(
1
2
1
hexane/EtOAc 3:1); [R]
D
1
) +27.5 (c ) 0.83, CHCl
3
); [R]
D
)
22.2 (c ) 0.68, CHCl
3
); H NMR (400 MHz, CDCl
3
) δ ) 6.55
under vacuum to give acid 10 (38 mg, 97%): R ) 0.32 (hexane/
2
0
35
d, J ) 10.1 Hz, 1H), 5.86 (d, J ) 10.1 Hz, 1H), 4.84-4.80 (m,
EtOAc 3:1); [R] ) +22.6 (c ) 0.50, CHCl ); [R] ) +20.6
D
3
D
1
H), 4.69-4.66 (m, 1H), 2.49-2.38 (m, 2H), 2.36-2.26 (m, 2H),
(c ) 0.50, CHCl ); H NMR (600 MHz, CDCl ) δ ) 6.47 (d, J )
3
3
.20-2.06 (m, 2H), 2.03-1.94 (m, 1H), 1.82-1.63 (m, 3H),
10.1 Hz, 1H), 5.85 (d, J ) 10.1 Hz, 1H), 4.86-4.84 (m, 1H),
4.70-4.68 (m, 1H), 2.45-2.41 (m, 1H), 2.34-2.29 (m, 1H),
2.29-2.22 (m, 2H), 2.15-2.10 (m, 1H), 2.10-2.05 (m, 1H),
1
3
.54-1.45 (m, 1H), 1.23-1.15 (m, 1H); C NMR (100 MHz,
CDCl
CH ), 41.6 (CH
4.9 (CH ), 26.4 (CH
683, 1429, 1392, 1273, 877 cm ; HRMS(EI) calcd for C13
3
) δ ) 200.0 (C), 156.6 (CH), 148.9 (C), 127.7 (CH), 106.9
), 40.9 (CH ), 36.0 (CH), 35.6 (C), 35.5 (CH),
), 24.5 (CH ); IR (film) ν˜ ) 2939, 2866,
(
3
1
2
2
2
2
.01-1.94 (m, 2H), 1.76-1.66 (m, 3H), 1.63-1.56 (m, 1H),
13
2
2
2
1
.56-1.46 (m, 2H), 1.17 (s, 3H); C NMR (150 MHz, CDCl
204.2 (C), 178.7 (C), 154.4 (CH), 148.7 (C), 126.2 (CH), 107.4
CH ), 47.1 (C), 44.5 (CH ), 39.5 (CH), 36.1 (C), 35.8 (CH), 29.4
CH ), 29.1 (CH ), 28.0 (CH ), 26.6 (CH ), 25.8 (CH ), 21.1 (CH );
) δ
3
-
1
16
H O
)
(
(
+
[
M ] 188.1201, found 188.1206.
2
2
1,6
(
1S,5S,6S,8S)-5-Methyl-9-methylenetricyclo[6.2.2.0 ]dodec-2-en-
2
2
2
2
2
3
6
b
4
-one (7): Preparation was according to Rawal et al:
R ) 0.41
f
IR (film) ν˜ ) 2925, 1707, 1675, 1653, 1457, 1294, 1125, 887, 826
2
0
35
(
hexane/EtOAc 5:1); [R]
D
1
) -19.5 (c ) 0.75, CHCl
3
); [R]
) δ ) 6.49
D
)
-1
[M - H]- 273.1496, found
cm . HRMS(EI) calcd for C17
2
H
21
O
3
-
18.0 (c ) 0.75, CHCl
3
); H NMR (400 MHz, CDCl
3
73.1493.
(
d, J ) 10.0 Hz, 1H), 5.87 (d, J ) 10.0 Hz, 1H), 4.83-4.81 (m,
6b
Platencin (2): According to Rawal et al, to a solution of acid
1
H), 4.68-4.66 (m, 1H), 2.39 (dt, J ) 16.4, 2.7 Hz, 1H), 2.36-2.32
1
0 (40 mg, 0.146 mmol) in MeCN (1.4 mL) were added DMAP
(
(
m, 1H), 2.27 (hex, J ) 6.6 Hz, 1H), 2.16-2.10 (m, 1H), 2.04-1.95
(
36 mg, 0.292 mmol), Et
3
N (61 µL, 0.438 mmol), and DCC (190
Cl ). The mixture was stirred for 7.5 h.
m, 1H), 1.83-1.67 (m, 4H), 1.53-1.46 (m, 1H), 1.29 (ddd, J )
2.6, 8.3, 1.3 Hz, 1H), 1.11 (d, J ) 6.7 Hz, 3H); C NMR (100
µL, 0.190 mmol, 1 M in CH
2
2
1
3
1
To the resulting mixture was added a solution of 3-amino-2,4-
dihydroxybenzoic acid 20 (49 mg,0.292 mmol) in DMF (0.40 mL)
and stirred for additional 40 h. The mixture was directly charged
on a silica gel column (10 g) and purified using EtOAc/hexane/
MHz, CDCl
3
) δ ) 202.0 (C), 155.4 (CH), 148.9 (C), 127.2 (CH),
), 43.7 (CH), 42.6 (CH), 41.2 (CH ), 36.0 (C), 35.6 (CH),
), 26.4 (CH ), 24.9 (CH ), 11.3 (CH ); IR (film) ν˜ )
937, 2867, 1676, 1452, 1392, 1375, 1206, 1166 cm ; HRMS(EI)
1
3
2
06.7 (CH
2
2
4.3 (CH
2
2
2
3
-1
AcOH/MeOH/H
mg, 58%) as a white solid: R
O ) 80:20:0.5:1.0:0.5); [R]
2
O ) 80:20:0.5:1.0:0.5 as an eluent to yield 2 (36
+
calcd for C14
-[(1S,5S,6R,8S)-5-Methyl-9-methylene-4-oxotricyclo[6.2.2.0 ]-
dodec-2-en-5-yl]propionic acid methyl ester (19): To a solution of
(95 mg, 0.47 mmol) in diethyl ether (1.4 mL) and tBuOH (1.4
H18O [M ] 202.1358, found 202.1352.
f
) 0.20 (EtOAc/hexane/AcOH/MeOH/
1,6
3
20
H
2
D
) -15.0 (c ) 0.24, MeOH);
35
23
[
R]
D
) -15.4 (c ) 0.24, MeOH); [R]
D
) -17.4 (c ) 0.24,
) δ ) 11.7 (s, 1H), 11.2 (s,
H), 8.24 (s, 1H), 7.62 (d, J ) 9.1 Hz, 1H), 6.58 (d, J ) 10.1 Hz,
H), 6.51 (d, J ) 9.1 Hz, 1H), 5.93 (d, J ) 10.1 Hz, 1H), 5.30 (s,
H), 4.88-4.86 (m, 1H), 4.70-4.68 (m, 1H), 2.50-2.32 (m, 4H),
.19-2.13 (m, 1H), 2.13-2.08 (m, 1H), 2.04-1.98 (m, 2H),
.86-1.73 (m, 4H), 1.61-1.52 (m, 2H), 1.23 (s, 3H); C NMR
150 MHz, CDCl ) δ ) 205.9 (C), 174.1 (C), 172.5 (C),156.0 (CH),
3
7
1
MeOH); H NMR (600 MHz, CDCl
3
mL) was added tBuOK (105 mg, 0.94 mmol) at 0 °C. After stirring
at this temperature for 5 min, methyl acrylate (0.34 mL, 3.76 mmol)
was added. After 30 min, the reaction was quenched by the addition
1
1
1
2
1
(
1
(
4
of saturated aqueous NH Cl, and the aqueous layer was extracted
three times with diethyl ether. The combined organic phases were
dried over magnesium sulfate, filtered, and the solvent was removed
under vacuum. Purification by column chromatography (10 g silica
gel) using hexane/ethyl acetate ) 7:1 as an eluent yielded a crude
diastereomeric mixture of esters (123 mg, dr 4:1) as colorless oil.
Purification by HPLC yielded ester 19 (71 mg, 52%) as an
13
55.4 (C), 154.4 (C), 148.3 (C), 128.2 (CH), 126.0 (CH), 114.4
), 103.3 (C), 47.7 (C), 44.4 (CH ),
9.4 (CH), 36.3 (C), 35.8 (CH), 32.3 (CH ), 31.0 (CH ), 28.0 (CH ),
6.5 (CH ), 25.7 (CH ), 21.2 (CH ); IR (film) ν˜ ) 2930, 1652,
538, 1456, 1373, 1282 cm ; HRMS(EI) calcd for C24 [M
C), 111.3 (CH), 107.7 (CH
2
2
3
2
1
2
2
2
2
0
2
2
3
analytically pure material: R
+22.7 (c ) 0.60, CHCl
f
) 0.23 (hexane/EtOAc 5:1); [R]
D
-1
H26NO
6
1
)
3
); H NMR (400 MHz, CDCl ) δ )
3
-
-
H] 424.1760, found 424.1766.
6
.46 (d, J ) 10.1 Hz, 1H), 5.83 (d, J ) 10.1 Hz, 1H), 4.85-4.83
(
2
1
m, 1H), 4.69-4.67 (m, 1H), 3.64 (s, 3H), 2.44-2.40 (m, 1H),
Acknowledgment. We thank Lothar Brecker, Susanne Fels-
inger, and Hanspeter K a¨ hlig for NMR spectroscopic assistance,
and Peter Unteregger for mass spectroscopy.
.35-2.28 (m, 1H), 2.24-2.03 (m, 4H), 2.01-1.93 (m, 2H),
13
.76-1.65 (m, 3H), 1.63-1.43 (m, 3H), 1.16 (s, 3H); C NMR
) δ ) 204.0 (C), 174.0 (C), 154.3 (CH), 148.8
(
(
100 MHz, CDCl
C), 126.2 (CH), 107.3 (CH
3
2
), 51.6 (CH
), 29.3 (CH
); IR (film) ν˜ ) 2935, 2867,
3
), 47.2 (C), 44.5 (CH
2
),
3
2
1
9.5 (CH), 36.1 (C), 35.9 (CH), 29.8 (CH
6.6 (CH
739, 1675, 1436, 1306, 1195, 1173, 827 cm ; HRMS(EI) calcd
2
2
), 28.0 (CH
2
),
Supporting Information Available: Experimental details for
compounds 6 (via bromide 5), 12, and 18 and NMR spectra of
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
2
), 25.8 (CH
2
), 21.1 (CH
3
-
1
+
for C18
H
24
O
3
[M ] 288.1725, found 288.1729.
-[(1S,5S,6R,8S)-5-Methyl-9-methylene-4-oxotricyclo[6.2.2.0 ]-
dodec-2-en-5-yl]propionic acid (10): To a solution of ester 19 (41
1,6
3
JO9001855
J. Org. Chem. Vol. 74, No. 8, 2009 2941