An expeditious asymmetric formal synthesis of the antibiotic platensimycin

Article abstract of DOI:10.1016/j.tet.2010.04.098

A short enantioselective and protecting group free access to the novel antibiotic platensimycin is reported. The crucial stereogenic information is provided by iridium catalyzed asymmetric hydrogenation.

Full text of DOI:10.1016/j.tet.2010.04.098

Tetrahedron 66 (2010) 6508e6513
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An expeditious asymmetric formal synthesis of the antibiotic platensimycin
Konrad Tiefenbacher , Lars Tr o€ ndlin , Johann Mulzer ,*, Andreas Pfaltz
a
b
a
b,
*
a
University of Vienna, Institute of Organic Chemistry, W a€ hringerstrasse 38, 1090 Wien, Austria
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 March 2010
Received in revised form 9 April 2010
Accepted 22 April 2010
A short enantioselective and protecting group free access to the novel antibiotic platensimycin is reported.
The crucial stereogenic information is provided by iridium catalyzed asymmetric hydrogenation.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 29 April 2010
Keywords:
Asymmetric synthesis
Catalytic hydrogenation
Natural products
Antibiotics
Polycyclic compounds
1. Introduction
OH
OH
O
O
Me
O
Me
H
O
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 like methicillin-
resistant Staphylococcus aureus (MRSA), vancomycin-resistant en-
HO2C
N
H
HO2C
N
H
OH
OH
O
Me
platensimycin (1)
platencin (2)
terococci (VRE), and penicillin-resistant Streptococcus pneumonia
Figure 1. Structures of platensimycin (1) and platencin (2).
1
(
PRSP) are especially worrying. From these observations the ur-
gency to develop new antibiotics is obvious. Since novel antibiotics
usually address well-known targets just at different binding sites or
S. pneumoniae.3 Meanwhile platensimycin B
eB , platensimide A,
1 3
homoplatensimide A as well as platensic acid and its methyl ester,
much less biologically active or even inactive natural derivatives of
2
through new binding modes, the discovery of platensimycin (1)
3
4
and platencin (2, Fig. 1), is a breakthrough in antibiotics research.
platensimycin, have been discovered.
This is due to the fact that compounds 1 and 2 address an ap-
parently 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 platensi-
mycin is blocking the fatty acid condensing enzyme FabF selec-
tively, platencin is inhibiting the enzymes FabF and FabH. These
compounds thus display a broad-spectrum of antibiotic activity
against many drug-resistant pathogens like methycillin-, macro-
lide- and linezolid-resistant S. aureus, vancomycin intermediate-
resistant S. aureus, vancomycin-resistant enterococci, and
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 more promising
1
drug candidates.
Not surprisingly the unusual structure and the promising bi-
ological activity have attracted great interest from the scientific
5
community, leading to three total and eleven formal syntheses of 1
during the last three years.
Some time ago we completed a facile synthesis of racemic 1.5h
We now report our efforts to develop an enantioselective route
(Scheme 1) and to overcome the diastereoselectivity issues during
the conversion of dienone 7 to ketone 9. Specifically the enantio-
selective hydrogenation of unsaturated acid/ester 4a/b and the
diastereoselective hydrogenation of dienone 7 were investigated.
*
Corresponding authors. Fax: þ43 1 4277 52189 (J.M.); fax: þ41 61 267 1103
A.P.); e-mail addresses: johann.mulzer@univie.ac.at (J. Mulzer), andreas.pfaltz@
unibas.ch (A. Pfaltz).
(
0
040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.098

K. Tiefenbacher et al. / Tetrahedron 66 (2010) 6508e6513
6509
OMe
OMe
O
OMe
O
O
O
COOR
COOR
6
3
R = H (4a)
R = H (5a)
R = Me (4b)
R = Me (5b)
O
O
H
O
+
H
O
O
O
O
Me
0
Me
Me
Me
1
7
8
9
Scheme 1. Overview of the formal synthesis of platensimycin.5h
The aim of our synthesis was enone 10, which has been converted
Table 1
Hydrogenation of ester 4b
5
a
into 1 by the Nicolaou group.
. Results and discussion
Carboxylic acid 4a is easily available from inexpensive 6-
Entry
Catalysta
Conversionb [%]
eec [%]
Configuration
2
1
2
.
.
Ir-cat-1
Ir-cat-2
Ir-cat-3
Ir-cat-4
>99
>99
>99
>99
99.1
99.2
86
R
S
R
S
3.
4.
6
93
methoxy-1-tetralone (3) in three steps (Scheme 2; NaBH
duction, one pot eliminationevinylogous Vilsmeier reaction,
oxidation with Ag O) in multigram quantities and excellent overall
yield (83%). Initial attempts to reduce acid 4a in an enantioselective
4
-re-
a
b
c
ꢀ
The counterion is BAr
Conversion was determined by GC (see Experimental section).
Determined by HPLC (see Experimental section).
F
(tetrakis[3,5-bis(trifluoromethyl)phenyl]borate).
2
7
2 n
fashion with Noyori catalyst RuCl (BINAP)(DMF) under a variety
They were also successfully applied for the asymmetric hydroge-
nation of -unsaturated carboxylic esters, a substrate class that has
usually given unsatisfactory results with Ru and Rh catalysts. The
of conditions failed. We therefore explored an iridium-catalyzed
asymmetric hydrogenation of methyl ester 4b (Table 1).
a,b
OMe
OMe
ester 4b was hydrogenated under standard conditions using a range
of iridium complexes under 50 bar of H in CH Cl and a catalyst
2 2 2
OMe
O
loading of 1 mol %. A brief catalyst screening showed that the two
enantiomeric catalysts Ir-cat-1 and Ir-cat-2 gave excellent enantio-
meric excess and full conversion (Table 1, entries 1 and 2). The
a
c
9
phosphinooxazoline complex Ir-cat-3 (entry 3) and the pyr-
10
idineephosphinite Ir-complex Ir-cat-4 (entry 4) also showed full
COOR
COOMe
conversion but lower enantiomeric excess. The optimal catalyst, Ir-
11
3
R = H (4a)
5b
cat-1, which afforded the desired (R)-enantiomer of the saturated
ester 5b in essentially perfect enantiomeric purity and 99% yield,
was then chosen for the actual synthesis. In a preparative reaction on
a multigram-scale the catalyst loading could be reduced to 0.2 mol %
without affecting the enantioselectivity and yield.
b
R = Me (4b)
Scheme 2. Synthesis of the optically active ester 5b. Reagents and conditions: (a)
ꢁ
(
i) NaBH
4
, MeOH; (ii) POCl
3
, DMF, 0e100 C; (iii) AgNO
3
, NaOH, EtOH, water (83%, three
, DCM, 20 h.
steps) (Ref. 6: 54%); (b) DBU, MeI, MeCN (94%) (c) 0.2 mol % Ir-cat-1, 50 bar H
2
Optically active ester 5b was hydrolyzed to the carboxylic acid
5a with K CO in ethanol/water at reflux. To rule out partial race-
mization, a sample was re-esterified with diazomethane and the
Iridium complexes with chiral N,P ligands are efficient catalysts
for the asymmetric hydrogenation of unfunctionalized olefins.
2
3
8

6510
K. Tiefenbacher et al. / Tetrahedron 66 (2010) 6508e6513
2
0
optical rotation of the ester ([
compared to that of the parent material 5b ([
CHCl )). With optically active acid in hand, the synthesis was con-
tinued by the formation of the acid chloride and reaction with TMS-
diazomethane in THF/Et O. The initially formed mixture (w1:1) of
a
]
D
þ52.6 (c 0.90, CHCl
3
)) was
þ52.7 (c 1.16,
chosen, which generated bromide 14 diastereoselectively. Without
purification, 14 was cyclized to tetrahydrofuran 7 under basic con-
2
0
a]
D
14
3
ditions. The allylic bromination of tricycle 6 on the other hand gave
a 1:1-mixture of diastereomeric allylic bromides, which gives us
a hint that the OH-group exerts a directing effect. Attempts to form
tetrahydrofuran 7 directly from compound 13 by CeH-activation via
2
diazoketone 11 and TMS-diazoketone 12 was cleanly converted to
pure 11 during a regular TLC-run. Therefore these conditions were
mimicked (silica gel in hexane/ethylacetate¼12:1) to convert the
mixture to pure 11 on a multigram-scale. Diazoketone 11 was
dissolved in TFA12 and stirred for 1 h at ꢀ15 C to furnish the
optically active tricyclic dienyl-dione 6 in 59% yield over three steps
15
radical 1,5-H-transfer of the alkoxyl radical (PhI(OAc)
, ultrasound) failed, because the tertiary alcohol underwent frag-
mentation to ketone 15 (Scheme 4).
2
, CyH, PhH,
I
2
ꢁ
A selective mono-hydrogenation of 7 to 10 could not be achieved.
The twofold 1,4-reduction of 7 to 9 was also problematic. Several
reaction conditions (Birch conditions, sodium borohydride in
methanol and triethylsilane/trifluoroacetic acid) failed. Under op-
(Scheme 3).
Regio- and stereoselective addition of the required methyl group
to the more hindered ketone in the presence of the double-enone
2
timized hydrogenation conditions (H , Pd/C, KOH, EtOH) a 1:1.9 di-
moiety proved difficult. Various conditions involving MeLi, MeMgCl,
astereomeric mixture of 9 and 8 was obtained (Scheme 5). A higher
selectivity was achieved with Crabtree’s catalyst, which furnished
13
16
MeMgBr, Me
2
Mg, AlMe
3
in different solvents (THF, Et
2
O, toluene)
aseparable 1.3:1 diastereomeric mixture of 9and 8but suffered from
5
i
low conversion. Although Corey later developed a solution to the
problem by using Rh-(COD) BF e(R,R)-DIOP as the catalyst, we
2
4
again explored chiral iridium complexes for this diastereoselective
hydrogenation. Among various catalysts tested, the iridium complex
11
Ir-cat-1 (Table 1) also proved to be the best catalyst for this step,
affording the diastereomeric ketones 9 and 8 in 84% yield with an
improved ratio of ca. 40:1 (via NMR spectroscopy).
5
i,j
The analytical data of 9 matched those reported in literature.
5
h,i,j
The conversion into intermediate 10
of the total synthesis have been reported.
In conclusion we have developed a short enantioselective and
as well as the completion
5
aec
17
protecting group free access to 9, which is thus obtained from the
1
Scheme 3. Synthesis of the optically active tricycle 6. Reagents and conditions: (a) K
2 3
CO ,
easily available intermediate 6 in four steps. All analytical data ( H
EtOH, water, reflux (98%) (b) SOCl
2
, DMF, toluene, rt, 3 h; (c) TMSCHN
2
, THF; then hexane/
13
and C and IR spectra and optical rotations) of our compounds 7
EtOAc (10:1), SiO
2
, rt, 12 h; (d) TFA, ꢀ15 ꢁC, 1 h (three steps, 59%). DMF¼N,N-dime-
5
c,i
and 9 fully matched those reported in the literature.
thylformamide, TMS¼trimethylsilyl, THF¼tetrahydrofuran, TFA¼trifluoroacetic acid.
Scheme 4. Synthesis of the optically active tetracycle 7. Reagents and conditions: (a) MeMgI, THF, Et
2
O, ꢀ78 ꢁC (41%, 66% brsm); (b) NBS, (BzO)
2 4
, CCl , reflux (67%); (c) NaOMe, THF,
ꢁ
0
C, (89%).
and temperatures and additives(CeCl
Finally methylmagnesium iodide under optimized conditions
3
, LiCl) led toproduct mixtures.
3. Experimental
3.1. General
ꢁ
(
3 equiv, THF, ꢀ78 C) selectively delivered the desired tertiary al-
cohol 13, along with recovered starting material. On a multigram-
scale, the resubmission of the crude product mixture to the reaction
conditions proved necessary due to a lower conversion (ca. 62%). For
the activation of the allylic position a free radical bromination was
All reactions were carried out in oven-dried glassware under an
argon atmosphere, unless otherwise stated. Anhydrous toluene was
distilled from sodium/benzophenone under argon. Anhydrous
CH
CaH
THF (tetrahydrofuran) was purchased from Acros (99.85%, water
50 ppm). The hydrogenation reactions were carried out in CH Cl
2
Cl
2
and DMF (N,N-dimethylformamide) were distilled from
2
under argon or reduced pressure, respectively. Anhydrous
<
2
2
from FLUKA (puriss.; absolute; over molecular sieve). All other
solvents were HPLC grade. Reactions were magnetically stirred and
monitored by thin layer chromatography (TLC) with silica gel 60-
F254 plates. Flash column chromatography was performed with
silica gel (0.04e0.063 mm, 240e400 mesh) under pressure. Yields
refer to chromatographically and spectroscopically pure com-
pounds, unless otherwise stated. NMR spectra were recorded on
either a 400 or 600 MHz spectrometer. Unless otherwise stated, all
Scheme 5. Synthesis of key intermediate (9). Reagents and conditions: (a) cat. [Ir(COD)
Py(PCy
5%), KOH, EtOH, H
CH Cl
65 h, (84%), 9:8¼ca. 40:1. brsm¼based on recovered starting material,
COD¼cyclooctadiene, Py¼pyridine, Cy¼cyclohexane.
3
)]PF , H
6 2
(1 bar), CH
2
Cl
2
, over night, (78% brsm), 9:8¼1.3:1; alternatively: Pd/C
(
2
(1 bar), 3 h (90%), 9:8¼1:2; or Ir-cat-1 (2 mol %), H
2
(50 bar),
3
NMR spectra were measured in CDCl solutions and referenced to
2
2
,
1
13
the residual CHCl
3
signal ( H,
d
¼7.26 ppm; C, ¼77.00 ppm). All
d

K. Tiefenbacher et al. / Tetrahedron 66 (2010) 6508e6513
6511
1H and C shifts are given in parts per million (s¼singlet;
d¼doublet; t¼triplet; q¼quadruplet; m¼multiplet; b¼broad sig-
nal). Assignments of proton resonances were confirmed, when
possible, by correlated spectroscopy. High resolution mass spectra
13
¼175.9 (C); 157.8 (C), 136.8 (C), 129.9 (CH), 127.0
3
(100 MHz, CDCl ) d
(C), 113.4 (CH), 112.2 (CH), 55.2 (CH ), 51.7 (CH ), 40.2 (CH), 30.9
3 3
ꢀ1
(CH
2
), 28.8 (CH
2
), 25.8 (CH
1235. HRMS (EI) calcd for C13
2
). IR [cm ]: 2950, 1734, 1503, 1268,
: 220.1099, found: 220.1107.
16 3
H O
2
0
(
HRMS) were performed with a resolution of 10,000.
[a
]
D
þ52.7 (c 1.16, CHCl
3
).
3.1.1. 6-Methoxy-3,4-dihydro-naphthalene-2-carboxylic acid (4a).
3.1.4. (R)-6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic
Compound 4a was prepared via a modification of the known pro-
acid (5a). A mixture of carboxylic ester 5 (6.0 g, 27.2 mmol), etha-
nol (650 mL), water (130 mL), and K CO (13.9 g, 101 mmol) was
2 3
refluxed for 3.5 h. Ethanol was removed under vacuum (down to
100 mbar), water (640 mL) was added and the solution was acidi-
fied to pHw2 via the addition of 3 M HCl. After extraction with
6a
cedure:
to a solution of 6-methoxy-1,2,3,4-tetrahydronaph-
thalen-1-ol6b (15.3 g, 85.8 mmol) in DMF (61 mL) was added POCl
3
ꢁ
(
18.4 mL, 197 mmol) dropwise over 15 min at 0 C. Afterward the
ꢁ
reaction mixture was heated in an oil bath (100 C) for 3.3 h. Sat-
urated aqueous NaOAc-solution (60 mL) was added to the solid
CH
2
Cl
2
(4ꢂ), the combined organic phases were dried over mag-
ꢁ
residue at 0 C. After stirring for 5 min, the solution was neutralized
nesium sulfate, filtered, and the solvent was removed under vac-
with 2 M NaOH and extracted with Et
ganic phases were washed with saturated NaHCO
magnesium sulfate, filtered, and the solvent was carefully removed
under vacuum to leave 15.9 g of aldehyde 16 (98%). The crude al-
dehyde was directly converted to acid 4a via the known protocol.
Analytical data (Mp, IR, NMR) matched those reported.
2
O (3ꢂ). The combined or-
uum to give acid 5a (5.53 g, 98%) as colorless needles.
1
3
, dried over
H NMR (400 MHz, CDCl
3
)
d
¼7.02 (d, J¼8.3 Hz, 1H), 6.71 (dd,
J¼8.3, 2.8 Hz, 1H), 6.63 (d, J¼2.8 Hz, 1H), 3.78 (s, 3H), 3.05e2.82 (m,
13
4H), 2.82e2.73 (m, 1H), 2.27e2.19 (m, 1H), 1.95e1.82 (m, 1H).
NMR (100 MHz, CDCl
¼179.9 (C), 157.8 (C), 136.7 (C), 129.9 (CH),
126.7 (C), 113.4 (CH), 112.3 (CH), 55.3 (CH ), 39.8 (CH), 30.6 (CH ),
). IR [cm ]: 2934, 2838, 1688, 1264, 1241.
C
1
a
3
) d
3
2
ꢀ1
28.7 (CH
2 2
), 25.6 (CH
3
.1.2. 6-Methoxy-3,4-dihydro-naphthalene-2-carboxylic acid methyl
HRMS (EI) calcd for
C
12
H
14
O
3
:
206.0943, found: 206.0939.
2
0
ꢁ
ester (4b). To a solution of 6-methoxy-3,4-dihydro-naphthalene-2-
carboxylic acid (4a) (12.0 g, 58.8 mmol) in MeCN (170 mL) was
added DBU (10.7 g, 70.5 mmol) at 0 C within 5 min. 30 min after
the slow addition of MeI (4.0 mL, 64.6 mmol), the cooling bath was
removed and stirring continued for 15 h. Additional DBU (1.8 g,
[a
]
D
þ56.0 (c 0.50, CHCl
3
). Mp: 126e128 C.
ꢁ
3.1.5. (1S,9R)-Tricyclo[7.2.1.01,6]dodeca-2,5-diene-4,10-dione (6). To
a suspension of acid (5a) (2.00 g, 9.70 mmol) in dry toluene (90 mL)
was added SOCl (1.41 mL,19.4 mmol) and dry DMF (eight drops) at rt
2
1
1.8 mmol) and MeI (0.7 mL,11.2 mmol) was added and after 4 h, all
volatiles were removed under vacuum. Water (360 mL) was added
Cl . The combined
(vigorous gas formation!). After stirring for 3.5 h, all volatiles were
removed under vacuum. To a solution of this grayish solid residue in
THF (40 mL) was added TMS-diazomethane (2 M in Et O, 14.6 mL,
2
to the brown residue and extraction 3ꢂ with CH
2
2
organic phases were dried over magnesium sulfate, filtered, silica
gel was added and the solvent was carefully removed under vac-
uum. Purification of the adsorbed material by column chromatog-
raphy (120 g silica gel) using hexane/ethylacetate¼5:1 as an eluent
29.1 mmol) at rt. After stirring for 30 min, all volatiles were removed
under vacuum and the residue dissolved in hexane/EtOAc 12:1
(120 mL). Silica gel (25 g) was added and the suspension stirred for
16 h. The suspension was filtered under vacuum and washed thor-
oughly with EtOAc. After the solvents were removed under vacuum,
a yellow oil (2.58 g) was obtained. To this crude diazoketone was
yielded ester 4b (12.0 g, 94%) as a colorless oil.
1
R
f
¼0.37 (silica gel, hexane/EtOAc 5:1). H NMR (400 MHz, CDCl
3
)
ꢁ
d
¼7.48 (s,1H), 7.12e7.08 (m,1H), 6.72e6.68 (m, 2H), 3.78 (s, 6H), 2.81
added TFA (80 mL) at ꢀ15 C (vigorous gas formation!) and stirred for
13
(
t, J¼8.2 Hz, 2H), 2.60e2.54 (m, 2H). C NMR (100 MHz, CDCl
¼167.8 (C),160.5 (C),138.8 (C),136.2 (CH),129.7 (CH),126.2 (C),125.5
C),113.6 (CH),111.4 (CH), 55.1 (CH ), 51.4 (CH ), 28.0 (CH ), 21.9 (CH ).
3
)
1.5 h at this temperature. After the addition of EtOAc (600 mL), the
d
organicphasewaswashedwith2 M NaOH (4ꢂ160 mL)and brine. The
(
3
3
2
2
2 2
combined aqueous phases were extracted three times with CH Cl .
ꢀ1
IR [cm ]: 2948, 1701, 1604, 1566, 1434, 1276, 1249, 1208. HRMS (EI)
calcd for C13
The organic phases were combined and the solvents removed under
vacuum. Purification by column chromatography (40 g silica gel) us-
ing hexane/ethylacetate¼1:2 as an eluent yielded ketone 6 (1.08 g,
59% over three steps) as a yellow solid.
ꢁ
H
14
O
3
: 218.0943, found: 218.0945. Mp: 48e50 C.
3
.1.3. (R)-6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic
acid methyl ester (5b). 6-Methoxy-3,4-dihydro-naphthalene-2-
carboxylic acid methyl ester (4b) (6.0 g, 27.5 mmol) and iridium
complex Ir-cat-1 (100.5 mg, 0.055 mmol) were placed in a high
pressure steel autoclave (120 mL) with a mechanical stirrer and
R
CDCl
f
¼0.32 (silica gel, hexane/EtOAc 1:2). 1H NMR (400 MHz,
3
)
d
¼6.78 (d, J¼9.9 Hz, 1H), 6.31 (dd, J¼9.9, 1.8 Hz, 1H),
6.11e6.08 (m, 1H), 2.74e2.68 (m, 1H), 2.57 (dd, J¼15.9, 6.5 Hz, 1H),
2.51e2.39 (m, 2H), 2.32 (ddd, J¼12.0, 5.1, 2.3 Hz, 1H), 2.24 (dd,
13
dissolved in CH
pressure hydrogen line and purged three times prior to pressuriz-
ing the reaction vessel with H . The reaction mixture was stirred for
0 h at 50 bar H and room temperature (rt). After 20 h the residual
2
Cl
2
(60 mL). The autoclave was attached to a high
J¼18.4, 3.6 Hz, 1H), 2.11e2.02 (m, 1H), 1.76e1.65 (m, 2H). C NMR
(100 MHz, CDCl
3
)
d
¼216.1 (C), 186.3 (C), 162.6 (C), 151.7 (CH), 130.0
), 46.5 (C), 46.3 (CH), 42.2 (CH ), 29.2
2 2
), 28.6 (CH ). IR [cm ]: 2954, 1745, 1661, 1623, 1405, 1270,
2
(CH), 124.3 (CH), 48.9 (CH
2
2
ꢀ
1
2
2
(CH
1042, 888. HRMS (EI) calcd for C12
hydrogen gas was released and the solvent was removed. The crude
residue was diluted with n-hexane/EtOAc 20:1 and filtered through
silica gel (h¼8 cm, d¼5 cm). After concentration the product 5b was
obtained as a slightly yellowish oil (6.02 g, 99% yield, 99% ee).
H
12
O
2
: 188.0837, found:
2
0
ꢁ
188.0835. [
a]
D
þ77.8 (c 0.83, CHCl
3
). Mp: 125e127 C.
3.1.6. (1S,9R,10S)-10-Hydroxy-10-methyltricyclo[7.2.1.01,6]dodeca-
2,5-dien-4-one (13). To a solution of ketone 6 (1.98 g, 10.5 mmol) in
THF (145 mL) was added dropwise methylmagnesium iodide (3 M in
ꢁ
The conversion was determined by GC: Restek Rtx-1701, 100 C,
ꢁ
ꢁ
2
min, 7 C/min, 250 C, 10 min, 60 kPa, tR1¼24.0 min (product),
ꢁ
tR2¼26.1 min (starting material).
Et
2
O, 10.5 mL, 31.5 mmol) at ꢀ78 C. After stirring at this tempera-
The enantiomeric excess was determined by HPLC: Daicel
ture for 3 h, the reaction was quenched by the addition of satd aq
NH Cl (50 mL) and water (50 mL). The aqueous phase was extracted
three times with CH Cl . The combined organic phases were dried
i
ꢁ
Chiralcel OD-H, n-heptane/ PrOH 99:1, 20 C, 0.5 mL/min, 220 nm,
R1¼17.0 min ((R)-enantiomer), tR2¼23.3 min ((S)-enantiomer).
4
t
2
2
1
R
f
¼0.44 (silica gel, hexane/EtOAc 3:1). H NMR (400 MHz,
¼7.01 (d, J¼8.5 Hz, 1H), 6.70 (dd, J¼8.5, 2.6 Hz, 1H), 6.62 (d,
J¼2.6 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.02e2.80 (m, 4H),
over magnesium sulfate, filtered, and the solvent was removed un-
der vacuum.
The reaction was repeated with the crude material due to low
conversion.
CDCl
3
)
d
13
2
.77e2.67 (m, 1H), 2.24e2.15 (m, 1H), 1.91e1.79 (m, 1H). C NMR

6512
K. Tiefenbacher et al. / Tetrahedron 66 (2010) 6508e6513
ꢁ
2
at 50 bar H and 40 C. After 65 h the autoclave was cooled to room
Purification by column chromatography (100 g silica gel) using
hexane/ethylacetate¼1:1/1:2 as an eluent yielded alcohol 13
890 mg, 41%, 66% brsm) and recovered ketone 6 (750 mg).
temperature and the residual hydrogen gas was released. The solvent
was removed and the crude residue diluted with hexane/EtOAc 1:1
and filtered through silica gel (h¼5 cm, d¼0.5 cm). After removal of
the solvent the product mixture 8 and 9 was isolated as a brownish oil
(28.7 mg, 84%). The product was analyzed for conversion by GC
(
1
R
f
¼0.20 (silica gel, hexane/EtOAc 1:1). H NMR (400 MHz,
3
CDCl ) d
¼6.65 (d, J¼9.8 Hz, 1H), 6.21 (dd, J¼9.8, 1.8 Hz, 1H), 6.01 (br
t, J¼2.0 Hz, 1H), 3.00e2.89 (m, 1H), 2.42 (dd, J¼15.5, 6.4 Hz, 1H),
ꢁ
ꢁ
ꢁ
2
1
.26e2.10 (m, 3H), 1.98 (d, J¼14.4 Hz, 1H), 1.87 (dd, J¼14.3, 2.4 Hz,
analysis (Restek Rtx-1701, 100 C, 2 min, 7 C/min, 250 C, 10 min;
13
H), 1.61e1.54 (m, 1H), 1.53 (s, 3H), 1.49 (dd, J¼11.1, 2.5 Hz, 1H).
¼187.1 (C), 167.8 (C), 154.2 (CH),129.0 (CH),
22.1 (CH), 80.0 (C), 51.2 (CH ), 49.2 (C), 46.7 (CH), 44.6 (CH ), 33.0
CH ), 30.1 (CH ), 27.9 (CH ). IR [cm ]: 3401, .2938, 1654, 1616,
123, 884. HRMS (EI) calcd for C13
C
60 kPaHe,tR1¼22.28 mincis-dec(8),tR2¼22.63 mintrans-dec(9)). No
NMR (100 MHz, CDCl
3
)
d
starting material (7) (t
R
¼25.20 min) was detected in the chromato-
1
(
1
2
2
gram. The dr could not be determined accurately, because of over-
lapping minor peaks between t
ꢀ
1
3
2
2
R
¼22.2e22.8 min. According to
1
16
H O
2
: 204.1150, found: 204.1152.
analysis by H NMR only traces of compound 8 could be detected (dr
40:1 according to integral of signals at 4.08 ppm and 2.75 ppm,
respectively).
2
0
ꢁ
[
a]
D
þ20.7 (c 0.70, CHCl
3
). Mp: 117e119 C.
3
.1.7. (1S,7R,9S,10S)-7-Bromo-10-hydroxy-10-methyltricyclo
1,6
[
7.2.1.0 ]dodeca-2,5-dien-4-one (14). A mixture of alcohol 13
890 mg, 4.36 mmol), N-bromosuccinimide (1.24 g, 6.97 mmol),
and benzoyl peroxide (42 mg, 0.17 mmol) in CCl (53 mL) was
heated at reflux for 2 h. The reaction mixture was diluted with
CH Cl (100 mL) and washed once with water. The organic phase
3.1.9.1. Analytical data of 9. R
f
¼0.54 (silica gel, hexane/EtOAc
1
(
1:1).
H
NMR (600 MHz, CDCl
3
) d
¼4.08 (t, J¼3.6 Hz, 1H),
4
2.37e2.29 (m, 3H), 2.27e2.23 (m, 2H), 2.11e2.07 (m, 1H),
2.06e2.02 (m, 1H), 1.91e1.85 (m, 2H), 1.82 (td, J¼13.3, 5.8 Hz, 1H),
1.70 (dd, J¼11.3, 3.4 Hz, 1H), 1.65e1.60 (m, 1H), 1.53 (d, J¼11.3 Hz,
2
2
13
was dried over magnesium sulfate, filtered, and the solvent was
removed under vacuum. Purification by column chromatography
3
1H), 1.45e1.42 (m, 1H), 1.41 (s, 3H). C NMR (150 MHz, CDCl )
d
¼210.6 (C), 86.1 (C), 79.3 (CH), 52.8 (CH
44.4 (C), 41.6 (CH ), 40.0 (CH ), 39.2 (CH
). IR [cm ]: 2951, 1705, 1040. HRMS (EI) calcd for
2
), 45.2 (CH), 45.0 (CH),
(
50 g silica gel) using hexane/ethylacetate¼1:1 as an eluent yielded
2
2
2
), 37.1 (CH ), 35.1 (CH ),
2
2
ꢀ
1
bromide 14 (0.82 g, 67%) as a slightly yellow solid.
23.1 (CH
C
(Ref.5i ꢀ10.8 (c 0.84, CHCl
3
2
0
Traces of succinimide are hard to separate by chromatography at
13
H
18
O
2
: 206.1307, found: 206.1303. [
a
]
D
ꢀ12.1 (c 0.95, CHCl
3
);
this stage but can easily be removed after the next step.
3
)).
1
R
f
¼0.27 (silica gel, hexane/EtOAc 1:1). H NMR (400 MHz, CDCl
3
)
d
¼6.64e6.59 (m, 2H), 6.25 (dd, J¼9.8, 1.8 Hz, 1H), 5.42 (ddd, J¼11.6,
3.1.9.2. Analytical data of 8. R
f
¼0.57 (silica gel, hexane/EtOAc
1
7
.2, 2.1 Hz,1H), 2.92e2.84 (m,1H), 2.23e2.12 (m, 2H), 2.05e1.96 (m,
1:1). H NMR (600 MHz, CDCl
J¼14.1 Hz, 1H), 2.34e2.27 (m, 4H), 2.22 (ddd, J¼14.7, 4.4, 1.6 Hz,1H),
2.03e1.99 (m,1H),1.83e1.68 (m, 4H),1.63e1.60 (m,1H),1.42 (s, 3H),
3
)
d
¼3.97 (d, J¼4.5 Hz, 1H), 2.75 (t,
2
3
H),1.88 (dd, J¼14.6, 2.7 Hz,1H),1.61 (dd, J¼11.9, 2.7 Hz,1H),1.54 (s,
13
H). C NMR (100 MHz, CDCl
3
)
d
¼187.2 (C), 162.9 (C), 153.8 (CH),
13
129.0 (CH), 125.5 (CH), 79.5 (C), 52.0 (CH
2
), 50.2 (C), 48.6 (CH), 48.2
1.40 (dd, J¼11.5, 3.7 Hz, 1H), 1.23 (d, J¼11.5 Hz, 1H). C NMR
(150 MHz, CDCl ), 45.4
), 39.4
ꢀ1
(
CH), 44.5 (CH
2
), 41.2 (CH
2
), 32.6 (CH
3
). IR [cm ]: 3423, 2959,1658,
3
)
d
¼212.0 (C), 87.3 (C), 79.8 (CH), 47.6 (CH
), 44.9 (C), 44.7 (CH), 44.4 (CH), 42.7 (CH ), 41.5 (CH
18 2
), 35.0 (CH ), 23.3 (CH ). HRMS (EI) calcd for C13H O :
2
þ
1617, 1158, 1117, 888. HRMS (EI) calcd for C13
H
15
O
2
BrþNa þMeCN:
(CH
(CH
2
2
2
2
0
3
46.0419, found: 346.0415. [
a
]
D
ꢀ39.5 (c 0.76, CHCl
3
). Mp:
2
2
3
ꢁ
122e124 C.
206.1307, found: 206.1304.
3
2
2
.1.8. (1S,7S,9S,12S)-9-Methyl-8-oxatetracyclo[5.3.3.01,609,11]trideca-
,5-dien-4-one (7). To solution of bromide 14 (820 mg,
Supplementary data
a
.90 mmol) in THF (50 mL) was added NaH (209 mg, 8.69 mmol)
ꢁ
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.098.
and methanol (1 mL) at 0 C. After stirring at this temperature for
3
0 min, the reaction was quenched by the addition of water (50 mL)
Cl . The combined organic phases were
and extracted 3ꢂ with CH
2
2
References and notes
dried over magnesium sulfate, filtered, and the solvent was re-
moved under vacuum. Purification by column chromatography
1
. (a) H a€ bich, D.; von Nussbaum, F. ChemMedChem 2006, 1, 951; (b) Holzgrabe, U.;
(
40 g silica gel) using hexane/ethylacetate¼3:2 as an eluent yielded
Dingermann, T.; Zündorf, I. Pharm. Unserer Zeit 2006, 35, 388.
tetrahydrofuran 7 (524 mg, 89%) as a colorless solid.
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.; Jaya-
suriya, 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.;
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suriya, 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. 2006, 128, 15547 (Addition/
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P.; Tormo, J.R. WO 2005009391, 2005 (CAN 142:196607).
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.; Jaya-
suriya, 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.; Gen-
illoud, 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.
¼0.40 (silica gel, hexane/EtOAc 1:1). 1H NMR (400 MHz,
R
f
CDCl
3
)
d
¼6.66 (d, J¼10.0 Hz, 1H), 6.32 (dd, J¼10.0, 1.7 Hz, 1H), 6.12
(
2
d, J¼1.7 Hz, 1H), 4.71 (d, J¼4.3 Hz, 1H), 2.59 (t, J¼6.2 Hz, 1H),
.28e2.14 (m, 2H,), 2.01e1.92 (m, 2H), 1.78 (d, J¼11.4 Hz, 1H),
13
1
(
5
[
.56e1.50 (m, 1H), 1.50 (s, 3H). C NMR (100 MHz, CDCl
C), 160.4 (C), 150.9 (CH), 130.1 (CH), 121.9 (CH), 87.1 (C), 80.0 (CH),
4.9 (CH ), 49.9 (C), 48.7 (CH ), 44.4 (CH), 42.6 (CH ), 22.2 (CH ). IR
cm ]: 2966, 1661, 1628, 1149, 943, 888. HRMS (EI) calcd for
3
)
d¼187.1
2
2
2
3
ꢀ1
2
0
C
H
13 14
O
2
: 202.0994, found: 202.0991. [
a
]
D
þ36.6 (c 0.70, CHCl
3
);
ꢁ
(
Ref. 5i þ33.7 (c 1.25, CHCl
3
)). Mp: 99e101 C.
3
.1.9. (1S,6S,7S,9S,12S)-9-Methyl-8-oxatetracyclo[5.3.3.01,609,11]tri-
(9). (1S,7S,9S,12S)-9-Methyl-8-oxatetracyclo
5.3.3.0 09,11]trideca-2,5-dien-4-one (7) (33.6 mg, 0.166 mmol) and
deca-4-one
[
1,6
4
. (a) Zhang, C.; Ondeyka, J.; Zink, D. L.; Burgess, B.; Wang, J.; Singh, S. S. Chem.
Commun. 2008, 5034; (b) Herath, K. B.; Zhang, C.; Jayasuriya, H.; Ondeyka, J. G.;
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Singh, S. B. Tetrahedron Lett. 2008, 49, 3648.
iridium complex Ir-cat-1 (6.07 mg, 3.32 mol) were placed in a dry
glass vial with a magnetic stirring bar and dissolved in CH Cl
0.8 mL). The vial was placed in an autoclave, which was attached to
a high pressure hydrogen line and purged three times prior to pres-
surizing the reaction vessel with H . The reaction was stirred for 65 h
m
2
2
(
5. Total synthesis of platensimycin: (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J.
Angew. Chem., Int. Ed. 2006, 45, 7086; (b) Ghosh, A. K.; Xi, K. J. Org. Chem. 2009,
2

K. Tiefenbacher et al. / Tetrahedron 66 (2010) 6508e6513
6513
7
4, 1163; (c) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.; Ellery, S. P. J. Am.
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3
942; (e) Zou, Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B. Org. Lett.
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