An enantioselective approach to (-)-platencin via catalytic asymmetric intramolecular cyclopropanation

Article abstract of DOI:10.1016/j.tetlet.2010.07.088

This Letter describes an enantioselective approach to (-)-platencin. A uniquely functionalized chiral intermediate, which was prepared via the highly enantioselective catalytic asymmetric intramolecular cyclopropanation (CAIMCP) that we have developed, was successfully transformed to Nicolaou's intermediate in his total synthesis of (-)-platencin.

Full text of DOI:10.1016/j.tetlet.2010.07.088

Tetrahedron Letters 51 (2010) 5076–5079
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An enantioselective approach to (ꢀ)-platencin via catalytic asymmetric
intramolecular cyclopropanation
*
Sho Hirai, Masahisa Nakada
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes an enantioselective approach to (ꢀ)-platencin. A uniquely functionalized chiral
intermediate, which was prepared via the highly enantioselective catalytic asymmetric intramolecular
cyclopropanation (CAIMCP) that we have developed, was successfully transformed to Nicolaou’s interme-
diate in his total synthesis of (ꢀ)-platencin.
Received 24 June 2010
Revised 14 July 2010
Accepted 16 July 2010
Available online 6 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The research group at Merck isolated (ꢀ)-platensimycin (1)1
( Fig. 1) and (ꢀ)-platencin (2)2 from Streptomyces platensis MA
7327 and 7339, respectively. These compounds have a 3-amino-
2,4-dihydroxybenzoic acid moiety as the common structure but
differ in their lipophilic and polycyclic moieties.
(ꢀ)-Platensimycin (1) has a tetracyclic framework including a
cyclic ether while (ꢀ)-platencin (2) has a tricyclic framework
which consists of only carbons. (ꢀ)-Platensimycin (1) is a potent
and selective inhibitor of FabF, the condensing enzyme that cata-
lyzes elongation in bacterial fatty acid synthesis.1 (ꢀ)-Platencin
(2) is a moderate inhibitor of both FabF and FabH, the enzyme cat-
alyzing the initial condensation in bacterial fatty acid synthesis.2
Because of their new modes of action, 1 and 2 show potent,
broad-spectrum Gram-positive antibacterial activity, and also ex-
hibit no cross-resistance to antibiotic-resistant bacteria, including
MRSA and VRE.1,2
OH
OH
O
O
O
O
HO2C
N
H
HO2C
N
H
HO
HO
O
(–)-platensimycin (1)
(–)-platencin (2)
Figure 1. Structures of (ꢀ)-platensimycin (1) and (ꢀ)-platencin (2).
research groups, including Snider’s intermediate 33b for 1 and
Nicolaou’s intermediate 44a for 2. Therefore, we set 4 as the target
of our formal total synthesis of (ꢀ)-platencin (2).
We have reported the CAIMCPs with CuOTf and bisoxazoline li-
gand 6.7 Tricyclo[4.4.0.0]decene derivatives
7 thus prepared
(Scheme 2) can serve as the key synthetic intermediates because
they possess useful functional groups such as a cyclopropane, an
alkene, and a ketone. Hence, 7 and related derivatives prepared
by the CAIMCP have been successfully utilized for the enantiose-
lective total synthesis of natural products.8 Moreover, compounds
7 also incorporate the cis-dehydrodecalin skeleton with a quater-
The unique structural features and new modes of action of these
new antibiotics have attracted much attention from the synthetic
and medicinal chemistry communities, and a number of total syn-
theses3–5 as well as SAR studies6 have been reported.
We were interested in the synthesis of compounds 1 and 2, and
their new derivatives because of their biological activity. Moreover,
the structural similarities between 1 and 2 led us to develop enan-
tioselective and divergent approaches to this new class of antibiot-
ics. We herein report the enantioselective formal total synthesis of
(ꢀ)-platencin (2) via the chiral key intermediate which was pre-
pared via a highly enantioselective catalytic asymmetric intramo-
lecular cyclopropanation (CAIMCP) that we have developed.
In the course of the retrosynthetic analysis of 1 and 2, we iden-
tified a common carbon framework, a cis-dehydrodecalin skeleton
possessing a bridgehead stereogenic quaternary carbon, which was
hidden within their structures (Scheme 1). The cis-dehydrodecalin
skeleton was also found in intermediates reported earlier by other
1
2
O
R1
Snider's
intermediate (3)
H
O
dehydrodecalin
skeleton
Nicolaou' s
intermediate (4)
* Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
Scheme 1. cis-Dehydrodecalin skeleton hidden in 1 and 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.088

S. Hirai, M. Nakada / Tetrahedron Letters 51 (2010) 5076–5079
5077
of aldehyde 10. Finally, aldehyde 10 would be prepared from com-
pound 11, which was thought to be prepared by the appropriate
transformations from compound 7a (R = (CH2)2OTBDPS).
R
R
CuOTf
(10 mol %)
H
H
6a or 6b
(15 mol %)
96-97% ee
O
O
ArO2S
N2
On the basis of the retrosynthetic analysis of 4 (Scheme 3), we
SO2Ar
first prepared
a-diazo-b-keto sulfone 5a (R = (CH2)2OTBDPS) to
5a (Ar = Ph)
7a (Ar = Ph)
examine the CAIMCP approach for obtaining compound 7a
(R = (CH2)2OTBDPS) (Scheme 4). Birch reduction of benzoic acid,
methyl ester formation, and subsequent alkylation of the enolate
with tert-butyl bromoacetate afforded compound 12. Reduction
of ester 12 with LiAlH4 afforded the corresponding diol, followed
by the selective TBDPS ether formation of the less hindered hydro-
xyl and then Swern oxidation to afford aldehyde 13. Aldehyde 13
was subjected to Horner–Wadsworth–Emmons reaction, followed
by reduction with NaBH4 in the presence of NiCl2,9 addition of
5b (Ar = Mes)
7b (Ar = Mes)
Bn Bn
O
O
O
O
N
N
N
N
6a
6b
Scheme 2. Preparation of 7 by catalytic asymmetric intramolecular cyclopropana-
tion (CAIMCP) of 5.
methyl phenyl sulfone, and diazo transfer reaction to afford a-dia-
zo-b-keto sulfone 5a (R = (CH2)2OTBDPS).
O
TBSO
The CAIMCPs of compound 5a (R = (CH2)2OTBDPS) with CuOTf
and ligand 6a–c were examined (Table 1). The CAIMCP with ligand
6a proceeded at room temperature to successfully afford cyclopro-
pane 12 (72%) with 95% ee (entry 1). The CAIMCP with the more
bulky ligand 6b was slow at room temperature and required heat-
ing to afford 7a (R = (CH2)2OTBDPS) (entry 2, 50%, 93% ee). The
reaction with ligand 6c did not improve the yield and gave the
same result as that obtained with ligand 6b (entry 3). Conse-
quently, we decided to employ the conditions in entry 1 to prepare
7a (R = (CH2)2OTBDPS). The absolute configuration of 7a
(R = (CH2)2OTBDPS) was not determined at this stage but was pro-
visionally assigned as shown in Table 1 according to our transition
state model.7a
HO
4
8
OHC
radical
cyclization
PhO2S
HO
X
H
PhO2S
10 (X=H or SPh)
X
9 (X=H or SPh)
TBDPSO
R
Next we examined the transformation of 7a (R = (CH2)2OTBDPS)
to 4 (Scheme 5). The ring-opening reaction of cyclopropane 7a
(R = (CH2)2OTBDPS) without removing the phenyl sulfonyl group
was attempted first. However, all the reactions with various reduc-
ing agents provided a mixture of products that lacked the phenyl
sulfonyl group. Consequently, we conducted the ring-opening
reaction with lithium thiophenoxide8a with the intention of
removing the phenyl sulfide at a later stage. The ring-opening reac-
tion with lithium thiophenoxide afforded the corresponding keto
O
H
H
PhO2S
X
PhO2S
H
11 (X=H or SPh)
7a (R = (CH2)2OTBDPS)
Scheme 3. Retrosynthetic analysis of 4.
nary stereogenic center. Therefore, we surmised that 7 would be
suitable for the synthesis of 4, and we undertook the retrosynthetic
analysis of 4 starting from 7.
Compound 4 was thought to be formed from alcohol 8 via oxi-
dation, Wittig olefination, deprotection, and oxidation (Scheme 3).
Alcohol 8 would be obtained from 9 by the removal of the sulfur-
containing functional group(s) and subsequent allylic oxidation. As
Table 1
CAIMCP of 5a (R = (CH2)2OTBDPS)
the
a,b-unsaturated sulfone is a good radical acceptor, tricyclic
R
H
R
[CuOTf]2PhMe
(5 mol %)
ligand
compound 9 could be formed by the reductive radical cyclization
O
O
(15 mol %)
N2
PhO2S
H
SO2Ph
1) Li, NH3(l), t-BuOH, THF
toluene
7a (R = (CH2)2OTBDPS)
5a (R = (CH2)2OTBDPS)
tBuO2C
MeO2C
-78 ºC
Bn Bn
Et
Et
2) MeOH, C6H6, c.H2SO4 (cat.)
reflux
HO2C
O
O
O
O
O
O
N
N
N
N
N
N
3) BrCH2CO2Bu-t, LDA
THF, –78 ºC, 96% (3 steps)
12
6a
6b
6c
OTBDPS
1) LiAlH4, Et2O, 0 ºC, 93%
2) TBDPSCl, Et3N, CH2Cl2
room temp, 92%
OHC
Entry
Ligand
Temp (°C)
Time (h)
Yielda (%)
eeb (%)
3) (COCl)2, DMSO, Et3N, CH2Cl2
–78 ºC to room temp, 93%
13
1
2
3
6a
6b
6c
rt
18
72
50
42
95
93
93
rt, 50c
rt, 50c
3.5, 13c
3.5, 15c
R
1) (EtO)2P(O)CH2CO2Et, t-BuOK
THF, –78 ºC to room temp, 91%
2) NaBH4, NiCl2•6H2O, MeOH, 0 ºC, 96%
a
Isolated yields.
O
b
ee determined by HPLC. HPLC conditions: Daicel CHIRALCEL OD-H
N2
3) CH3SO2Ph, n-BuLi, THF, –78 ºC, 95%
4) TsN3, Et3N, MeCN, room temp, 79%.
SO2Ph
0.46
u ꢁ 25 cm, hexane/2-propanol 9:1, flow rate = 0.4 ml/min, retention time
18.6 min for minor, 22.2 min for major.
5a (R = (CH2)2OTBDPS)
c
Reaction was carried out at the indicated temperatures for the indicated times,
respectively.
Scheme 4. Preparation of 5a (R = (CH2)2OTBDPS).

5078
S. Hirai, M. Nakada / Tetrahedron Letters 51 (2010) 5076–5079
uniquely functionalized tricyclo[4.4.0.0]decene derivative 7a
R
H
1) PhSLi, THF, reflux, 96%
2) NaBH4, MeOH, THF
0 ºC, 100%
R
(R = (CH2)2OTBDPS) as well as the usefulness of the CAIMCP in nat-
ural product synthesis. Studies on a new enantioselective approach
to (ꢀ)-platensimycin (1) via the same intermediate prepared in
this study are now underway and will be reported in due course.
O
PhO2S
H
3) MsCl, Et3N, (CH2Cl)2
(CH2Cl)2, 50 ºC, 98%
4) t-BuOK, THF, –78 ºC, 92%
H
PhO2S
X
11 (X = SPh)
7a (R = (CH2)2OTBDPS)
OHC
Acknowledgments
1) HF-py, THF, room temp, 87%
SmI2, MeOH
This work was financially supported in part by a Waseda Uni-
versity Grant for the Special Research Projects, a Grant-in-Aid for
Scientific Research on Innovative Areas (No. 21106009), and the
Global COE program ‘Center for Practical Chemical Wisdom’ by
MEXT.
2) (COCl)2, DMSO, Et3N
CH2Cl2, –78 ºC
THF, 0 ºC, 95%
H
PhO2S
X
to room temp, 88%
10 (X = SPh)
1) Li, naphthalene, THF, –20 ºC
69%
TBSO
2) SeO2, dioxane, reflux, 100%
PhO2S
HO
X
References and notes
HO
3) TBSCl, imidazole, DMF
–20 ºC, 69%
9 (X = SPh)
8
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O
1) DMP, CH2Cl2, room temp, 95%
2) Ph3PCH=CH2, THF, 50 ºC
3) TBAF, THF, room temp, 95% (2 steps)
4) DMP, NaHCO3, CH2Cl2, room temp, 82%
4
Scheme 5. Formal total synthesis of (ꢀ)-platencin (2).
sulfide in high yield, and subsequent reduction with NaBH4 affor-
ded the corresponding alcohol. Unfortunately, attempts to dehy-
drate the resultant alcohol under various conditions produced a
mixture of regioisomeric alkenes; hence, we prepared the corre-
sponding mesylate to prepare alkene 11 (X = SPh) by the elimina-
tion reaction under basic conditions.
Although double bond isomerization of 11 (X = SPh) during the
elimination reaction was a problem, when a pre-cooled (ꢀ78 °C)
THF solution of potassium tert-butoxide was added to a solution
of the mesylate in THF at ꢀ78 °C, 11 (X = SPh) was obtained in
92% yield with a trace amount of its regioisomeric alkene isomer.
With the key compound 11 (X = SPh) in hand, we examined the
synthesis of compound 4. Not only did removal of the TBDPS group
in compound 11 (X = SPh) with TBAF caused migration of the dou-
ble bond, but also did the use of TBAF with an acidic additive was
unsuccessful. Fortunately, the reaction of 11 (X = SPh) with HFꢂpy
proceeded cleanly and kept the alkene intact, and the subsequent
Swern oxidation afforded aldehyde 10 (X = SPh).
The key reductive radical cyclization of aldehyde 10 (X = SPh)
with SmI2 proceeded smoothly at 0 °C to afford compound 9
(X = SPh) which possessed the tricyclic core of (ꢀ)-platencin (2)
as a single isomer. Treatment of compound 9 (X = SPh) with lith-
ium naphthalenide removed the sulfide and sulfone simulta-
neously without problem. Subsequent allylic oxidation with
selenium dioxide followed by selective protection of the reactive
allylic hydroxyl with TBSCl at ꢀ20 °C afforded TBS ether 8. Dess–
Martin oxidation of alcohol 8, Wittig methylenation, removal of
the TBS group, and Dess–Martin oxidation in the presence of so-
dium bicarbonate successfully afforded compound 4. The synthe-
sized compound was proved to be identical in all respects to the
intermediate 4 described by Nicolaou (1H and 13C NMR, IR, MS,
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and [a
]D).10 This fact established the absolute structure of cyclo-
propane 7a (R = (CH2)2OTBDPS) and verified the formal enantiose-
lective total synthesis of (ꢀ)-platencin (2).
In summary, a new enantioselective approach to (ꢀ)-platencin
(2) has been developed via the unique chiral intermediate 11
(X = SPh), possessing a useful a,b-unsaturated sulfone functionality
which served as a good radical acceptor. This intermediate 11
(X = SPh) was derived from compound 7a (R = (CH2)2OTBDPS),
which was successfully prepared via the highly enantioselective
CAIMCP that we have developed. Therefore, the formal enantiose-
lective total syntheses reported herein prove the applicability of
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10. Compound 4: 1H NMR (400 MHz, CDCl3) d 6.57 (1H, d, J = 10.0 Hz), 5.88 (1H, d,
J = 10.0 Hz), 4.83 (1H, d, J = 1.7 Hz), 4.69 (1H, d, J = 1.7 Hz), 2.48–2.40 (2H, m),
2.36–2.29 (2H, m), 2.19–2.08 (2H, m), 2.03–1.96 (1H, m), 1.82–1.68 (3H, m),
1.55–1.48 (1H, m), 1.20 (1H, ddd, J = 12.6, 7.8, 1.2 Hz); 13C NMR (100 MHz,
CDCl3) d 200.1, 156.7, 148.9, 127.7, 106.9, 41.6, 40.8, 36.0, 35.5, 35.4, 34.8, 26.3,
24.5; IR (neat) m ;
max 2939, 2866, 1684, 1429, 1273, 1236, 1167, 877, 765 cmꢀ1
FAB HRMS [M+H]+ calcd for C13H17O: 189.1279, found: 189.1288; ½a D25
ꢃ
+21.2 (c
0.1, CHCl3) (lit.4f a 2D5
½ ꢃ +21.2 (c 1.0, CHCl3)).