Formal syntheses of (±)-platensimycin and (±)-platencin via a dual-mode lewis acid induced cascade cyclization approach

Article abstract of DOI:10.1021/jo401105q

A mild and efficient dual-mode Lewis acid induced Diels-Alder (DA)/carbocyclization cascade cyclization reaction has been developed for construction of the tricyclic core of ent-kaurenoids in one pot with the aid of a theoretical study on the π,σ-Lewis acidities of a variety of Lewis acids. With ZnBr₂ as the dual-mode Lewis acid, a series of substituted enones and dienes underwent DA/carbocyclization cascade cyclization reaction smoothly at room temperature and provided the tricyclic cyclized products in one pot with good yields and high diastereoselectivity. The tricyclic cyclized product has been successfully utilized as a common intermediate for formal syntheses of (±)-platensimycin and (±)-platencin.

Full text of DOI:10.1021/jo401105q

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Article
Formal Syntheses of (±)-Platensimycin and (±)-Platencin via a
Dual-Mode Lewis Acid Induced Cascade Cyclization Approach
Lizhi Zhu, Congshan Zhou, Wei Yang, Shuzhong He, Gui-Juan Cheng, Xinhao Zhang, and Chi-Sing Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401105q • Publication Date (Web): 17 Jul 2013
Downloaded from http://pubs.acs.org on August 1, 2013
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Formal Syntheses of (±)-Platensimycin and (±)-Platencin via
a Dual-Mode Lewis Acid Induced Cascade Cyclization
Approach
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†
Lizhi Zhu, Congshan Zhou, Wei Yang, Shuzhong He, Gui-Juan Cheng, Xinhao
†,
‡
†
†
†
†
,
†,
Zhang * and Chi-Sing Lee *
†
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen University Town, Xili,
Shenzhen 518055, China
‡
College of Chemistry and Chemical Engineering, Hunan Institute of Science and
Technology, Yueyang 414006, China
* E-mail: zhangxh@pkusz.edu.cn, lizc@pkusz.edu.cn
Table of Contents/Abstract Graphic
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Abstract
mild and efficient dual-mode Lewis acid induced Diels Alder
DA)/carbocyclization cascade cyclization reaction has been developed for
construction of the tricyclic core of ent-kaurenoids in one pot with the aid of a
theoretical study on the π,σ-Lewis acidities of a variety of Lewis acids. With ZnBr as
A
(
0
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9
0
2
the dual-mode Lewis acid, a series of substituted enones and dienes underwent
DA/carbocyclization cascade cyclization reaction smoothly at room temperature and
provided the tricyclic cyclized products in one pot with good yields and high
diastereoselectivity. The tricyclic cyclized product has been successfully utilized as a
common intermediate for formal syntheses of (±)-platensimycin and (±)-platencin.
Introduction
1
2
Platensimycin (1) and Platencin (2) are potent bacterial type II fatty acid
biosynthesis inhibitors, which were isolated from Streptomyces patensis MA 7327
and 7339 by a research group at Merck & Co., Inc. in 2006 and 2007 respectively.
Both
platensimycin
(1)
and
platencin
(2)
bear
the
same
3-amino-2,4-dihydroxybenzoic acid side-chain with a different cage structure (an
oxatetracyclic structure for platensimycin and a tricyclic carbocycle for platencin)
(Figure 1). A recent study suggested that the biosynthesis of platensimycin (1)
involved an ent-kaurene type intermediate that was derived from ent-copalyl
3
pyrophosphate (CPP). Platensimycin (1) is a potent and selective inhibitor of FabF
-4
1
the enzyme that catalyzed the elongation step in bacterial fatty acid synthesis), while
(
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platencin (2) is a moderate inhibitor of both FabF and FabH (the enzyme that
2
catalyzed the initial condensation step in bacterial fatty acid synthesis). With their
unique mode of biological actions, these natural products showed potent antibacterial
activities against a broad spectrum of multi-drug resistant Gram-positive pathogens,
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including
methicillin-resistant
Staphylococcus
aureus
(MRSA)
and
5
-9
vancomycin-resistant Enterococcus (VRE) with no observed toxicity. However, the
development of platensimycin (1) and platencin (2) into promising drug candidates
has been greatly limited by their poor in vivo efficacy and pharmacokinetic
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11-18
properties. As such, a tremendous amount of effort
has been invested in the
19-51
52-72
synthesis of platensimycin
and platencin
as well as their structural analogues.
Up to now, only a very limited number of platensimycin and platencin analogues have
43
been reported to be more potent than the parent natural products; and the
development of structural analogues of platensimycin (1) and platencin (2) with
improved in vivo efficacy and pharmacokinetic properties remains a challenge.
Therefore, developing an efficient and versatile synthetic entry to platensimycin and
platencin analogues is important for facilitating the development of these natural
products into promising leads in drug discovery.
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FIGURE 1. Tricyclic core of ent-kaurenoids (I) and examples of ent-kaurene related
natural products
73-77
Dual-mode Lewis acids
are useful for developing cascade cyclization
reactions since they can induce cyclization reactions via forming σ- and/or
π-complexes with the substrates as well as the intermediate(s) that are generated in
situ. We are particularly interested in developing dual mode Lewis acid induced
cascade cyclization reactions for natural product syntheses since they can often
construct the core structure of the synthetic target in a single operation under mild
78-83
conditions.
Recently, we have developed the ZnBr catalyzed Diels Alder
2
(DA)/carbocyclization cascade cyclization reaction for the rapid construction of
80
cis-hydrindanes and demonstrated its utilities in natural product synthesis. As such,
we have decided to employ this strategy for developing a new cascade cyclization
reaction that could give a rapid access to the tricyclic fused ring system I (Figure 1),
84-86
which is an important structural motif of the ent-kaurene related natural products
and is anticipated to provide rapid access to the cage structures of platensimycin (1)
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and platencin (2).
As shown in Figure 2, our strategy involved a Lewis acid induced DA
cycloaddition of enone 3a with diene 4a. The resulting silyl enol ether of the DA
adduct 5a could undergo intramolecular carbocyclization with the alkyne to form the
bicycle[3.2.1]octane moiety of 6a in a one-pot manner. This strategy requires a mild
dual-mode Lewis acid that can form σ-complexes with enone 3a for inducing the DA
cycloaddition, and π-complexes with intermediate 5a for inducing the
carbocyclization without causing hydrolysis of silyl enol ethers 4a and 5a. We have
previously reported the dual-mode Lewis acid induced DA/carbocyclization cascade
cyclization reaction for construction of the 6,6,5-tricyclic cyclized product 6a, and its
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application in the formal synthesis of platensimycin (1). We herein report the
computational and experimental details on the method development, and demonstrate
the utilities of the cascade reaction by employing the cyclized product (6a) as a
common building block for the formal syntheses of (±)-platensimycin (1) and
(±)-platencin (2).
FIGURE 2. Rapid access to the 6,6,5-tricyclic fused ring system via the dual-mode
Lewis acid induced cascade cyclization approach
Results and Discussion
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1. Theoretical investigation of the binding enthalpies of Lewis acids towards σ-
and π-electrons
In search of a suitable dual-mode Lewis acid for developing the
DA/carbocyclization cascade cyclization reaction, the binding enthalpies between a
variety of Lewis acids and the π/σ complex partners, including propene/acetaldehyde
0
1
2
3
4
5
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7
8
9
0
1
2
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(Table 1) and styrene/benzaldehyde (Table S1 in Supporting Information), were
evaluated by density-functional theory (DFT) calculations. As shown in Table 1 and
Table S1, only slight differences in binding enthalpies were found between the alkyl
and aryl compounds. In general, Lewis acids based on the main-group elements, such
as MgX and AlX , have stronger σ-binding than π-binding. On the other hand, the
2
3
π-binding enthalpies of the transition metal based Lewis acids, such as AuCl and
Pd(OAc) , are higher, owing to the π back-bonding from the d-electrons of the
2
transition metal to π* orbital of substrates. These results are consistent with a similar
theoretical study on the B3LYP/SDD values of a smaller set of Lewis acids reported
75
by Yamamoto.
-1
TABLE 1. Binding enthalpies (in kcal mol ) of Lewis acids towards propene and
a
acetaldehyde and the differences calculated at M06/BSI
Entry
LA
AuCl
ꢀH - ꢀHσ Entry
LA
ꢀH - ꢀHσ
π
π
1
2
3
4
5
-41.9 -26.9
-16.8 -3.2
-45.6 -33.9
-37.8 -30.7
-27.3 -20.5
-15.0
-13.6
-11.7
-7.1
16
17
18
19
20
Zn(OTf)
2
-24.4 -27.5
-20.5 -24.1
-6.7 -11.5
-5.6 -11.4
-22.8 -28.6
3.1
3.6
4.8
5.8
5.8
Pd(OAc)
AuCl3
CuCl
2
ZnCl
2
BF3
BCl3
AgCl
-6.8
InBr3
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AgOTf
CuI
-34.9 -28.4
-33.7 -28.0
-24.9 -21.7
-6.5
-5.7
-3.2
-2.2
0.3
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InCl3
TiCl
In(OTf)
SnCl
MgBr
MgCl
AlMe
AlEt
AlCl
-23.1 -29.5
-5.9 -12.4
-14.2 -20.8
-7.3 -15.4
-19.0 -28.2
-18.6 -28.0
6.4
6.5
4
CuCl
Ni(acac)
Cu(OAc)
HgCl
FeBr
ZnI
2
3
6.6
2
-7.4
-5.2
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8.1
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1
0
1
2
3
4
5
2
-10.3 -10.6
-13.1 -14.4
-28.9 -30.8
-18.8 -21.3
-29.3 -32.1
-20.7 -23.8
2
9.2
1
1
1
1
1
2
1.3
2
9.4
3
1.9
2
Cl -12.8 -23.3
Cl -13.4 -24.2
-20.4 -31.8
10.5
10.8
11.4
2
2.5
2
FeCl
3
2.8
3
ZnBr
2
3.1
a
See the experimental section for the computational methods.
To induce the DA/carbocyclization cascade cyclization reaction, the π/σ-binding
energies of the Lewis acid should be high enough to promote sequential cyclization
reactions. To identify the appropriate Lewis acid for the cascade reaction, the
π-binding enthalpies (ꢀH
π
) were plotted against the differences of π/σ-binding
enthalpies (ꢀH – ꢀH ). As shown in Figure 3, Zn(II), In(III) and Fe(III) based Lewis
π
σ
acids have similar properties (within the box in Figure 3) with π-binding enthalpies of
-1
-
10 ~ -30 kcal mol and σ/π-binding enthalpy differences (ꢀH - ꢀH ) of -2 ~ -7 kcal
π
σ
-1
mol . More importantly, we have previously demonstrated that In(III) and Zn(II) are
7
8,81
effective dual-mode Lewis acids for inducing the Prins/Conia-ene
and
79,82
Michael/Conia-ene
cascade cyclization reaction respectively. Taking these results
into consideration, we identified a sub-group of Lewis acids that are promising for the
development of the DA/carbocyclization cascade cyclization reaction.
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FIGURE 3. The plot of π-binding enthalpies (ꢀH
π
) versus the differences of π/σ
binding enthalpies (ꢀH - ꢀH )
π
σ
2
. Screening of dual-mode Lewis acids
Based on the above analysis, the reaction between enone 3a and diene 4a was
studied using a variety of In(III), Zn(II) and Fe(III) based Lewis acids. As shown in
Table 2, InCl in acetonitrile led to an 80% yield of side-product 7, which could be
formed via hydration of the alkyne moiety of 3a even under anhydrous conditions
Table 2, entry 1). However, employing the same condition for various protected
3
(
but-3-yn-1-ols did not lead to any methyl ketone products (data not shown). These
results indicated that the ketone moiety of 3a could be cyclized with the
In(III)-activated alkyne and form the cyclic enol ether intermediate (9-[In] in Figure
5
), which could lead to the methyl ketone side-product (7) upon hydrolysis. Switching
the Lewis acid to InBr
3
resulted in only a trace amount of the expected cyclized
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product (6a) along with 60% of 7 (entry 2). In(OTf) also gave side-product 7 in 90%
yield (Table 2, entry 3). Switching the solvent to dichloromethane resulted in rapid
decomposition of the substrates (Table 2, entry 4-6).
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a
TABLE 2. In(III) as the dual-mode Lewis acid for the cascade reaction
b
Yield (6a)
b
Yield (7)
Entry Lewis acid
Solvent
1
2
3
4
5
6
InCl3
InBr3
CH CN
3
-
80
60
90
-
CH CN
3
trace
In(OTf)3
CH CN
3
-
-
-
-
InCl
InBr
In(OTf)
3
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
2
2
3
-
3
-
a
b
The general procedures were followed.
Isolated yields (%) after silica gel column
chromatography.
The activities of a number of Zn(II) and Fe(III) based Lewis acids were then
investigated. As shown in Table 3, no cyclization was observed when using Zn(II)
3 3
triflate or halides in acetonitrile (Table 3, entry 1-4). FeCl /CH CN resulted in the
hydrolysis of 4a (Table 3, entry 5). Switching the solvent to dichloromethane with
Zn(II) triflate did not give any cyclized product (Table 3, entry 6), and the silyl enol
ether diene (4a) was hydrolyzed slowly under these reaction conditions. Finally, we
found that the cascade cyclization went smoothly by using Zn(II) halides in
dichloromethane and afforded the tricyclic product (6a) bearing the cis-decalin
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efficiently and diastereoselectively (Table 3, entry 7-9). The reaction of 3a and 4a in
3 2 2
the presence of FeCl in CH Cl led to about 40% of 6a (Table 3, entry 10). Silyl enol
ether 4a was hydrolyzed rapidly under these conditions. The optimal reaction
conditions are ZnBr (1.5 equiv) in CH Cl at room temperature for 12 hours. These
2
2
2
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mild conditions afforded the expected cyclized product (6a) in 86% yield as a single
diastereomer (Table 3, entry 8), which was characterized unambiguously by NMR
87
88
2 2 2
experiments and X-ray crystallography . Interestingly, Zn(OTf) /LiBr in CH Cl
also afforded good yields of cyclized product 6a (Table 3, entry 11), suggesting that
the addition of LiBr could facilitate the formation of a Zn(II) bromide dimer, which is
89
presumably one of the active species under the reaction conditions. However,
ZnBr /LiBr gave only a trace amount of 6a (Table 3, entry 12) hence the effect of
2
LiBr is not clear in this situation. The extra LiBr might occupy the vacant site of the
active species or promote the formation of unreactive metal halide clusters. A brief
survey on the effects of solvents showed that ZnBr in chloroform afforded a similar
2
yield (Table 3, entry 13), but THF, 1,4-dioxane, toluene or hexanes did not provide
any cyclized product (Table 3, entry 14-17). The silyl enol ether diene (4a) was
2
hydrolyzed slowly under these conditions. Reducing the loading of ZnBr to 0.3
equivalents led to an incomplete reaction, and afforded only a 30% yield of 6a (Table
3, entry 18). Increasing the reaction temperature resulted in a similar result (Table 3,
entry 19).
a
TABLE 3. Zn(II) and Fe(III) as the dual-mode Lewis acid for the cascade reaction
c
Entry
Lewis acid
Equiv
Solvent
Temp
Yield
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Zn(OTf)
ZnCl
ZnBr
ZnI
FeCl
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.3
0.3
CH
CH
CH
CH
CH
3
3
3
3
3
CN
CN
CN
CN
CN
rt
rt
-
-
2
2
rt
-
2
rt
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
rt
-
Zn(OTf)2
ZnCl2
CH Cl2
2
rt
-
CH Cl2
2
rt
74
86
81
40
78
trace
80
-
ZnBr
ZnI
FeCl
2
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
rt
2
rt
10
3
rt
b
1
1
2
3
4
5
6
7
Zn(OTf)
2
/LiBr
rt
b
1
1
1
1
1
1
ZnBr
2
/LiBr
rt
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
2
2
2
2
2
2
CHCl
3
rt
THF
rt
1,4-dioxane
toluene
rt
-
rt
-
hexanes
rt
-
18
19
CH Cl
2
2
rt
30
28
ZnBr2
CH Cl2
2
reflux
a
b
The general procedures were followed. one equivalent of LiBr was added. Isolated yields (%)
c
after silica gel column chromatography.
Since Al(III) based Lewis acids are known effective promoters for DA
cycloadditions and are reported to be effective for carbocyclization with
90
endo-selectivity, a variety of Al(III) Lewis acids were studied. As shown in Table 4,
no reaction was observed with EtAlCl in acetonitrile and the silyl enol ether was
2
hydrolyzed under these conditions (Table 4, entry 1). Switching the solvent to toluene
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
gave only the DA adduct 5a, which was then hydrolyzed and gave modest yields of
side-product 5b (Table 4, entry 2) after aqueous work-up. Switching the solvent to
2 2
CH Cl provided only a trace amount of the 6,6,5-tricyclic product (6a) along with
about 30-40% of side-product 5b after aqueous work-up (Table 4, entry 3), while the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
potential 6,6,6-tricyclic product was not observed. Et AlCl or Me AlCl in CH Cl
2
2
2
2
2
followed by addition of ZnBr afforded 40 and 60% yields of the 6,6,5-tricylic
product 6a respectively (Table 4, entry 4-5). These results indicated that Al(III)
behaved more like an σ-Lewis acid in our system, which is consistent with the results
of the above theoretical study.
a
TABLE 4. Al(III) as the dual-mode Lewis acid for the cascade reaction
b
Yield (6a)
b
Yield (5b)
Entry
Lewis acid
Solvent
CH CN
Toluene
CH Cl
Temp
1
2
3
4
5
EtAlCl
EtAlCl
EtAlCl
2
2
2
3
0 ºC to rt
0 ºC to rt
0 ºC to rt
-
-
30
40
2
2
Trace
40
Et AlCl/ZnBr
2
CH Cl2 -78 ºC to rt
2
2
Me AlCl/ZnBr
2
CH Cl2 -78 ºC to rt
2
76
2
a
b
The general procedures were followed. Isolated yields (%) after silica column chromatography.
3
. Computational investigation on the mechanism of the cascade reaction
The mechanism of the DA/carbocyclization cascade cyclization reaction was
studied by DFT calculations. The potential energy surfaces (PES) of the cascade
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9
2
reaction, with and without ZnCl , are shown in Figure 4. The free energy barrier of
the DA reaction between unactivated 3a and 4a was calculated to be 32.1 kcal/mol,
implying that the reaction is unlikely to take place at room temperature. In the
presence of ZnCl , the free energy barrier for DA reaction is reduced to 25.4 kcal
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
1
mol (blue curve in Figure 4). ZnCl
2
activates 3a through a σ-coordination to the
carbonyl group. Following the rate-determining Diels Alder reaction, 5a-[Zn]-π,σ
-1
undergoes carbocyclization with a free energy barrier of 17.9 kcal mol . Inspired by
89
Yu’s work, we also considered the possibility of dimeric [ZnCl
2 2
] as a catalyst.
Indeed, the reaction catalyzed by [ZnCl ] was calculated to be more favorable with
2
2
-1
an overall activation free energy of 22.2 kcal mol . [ZnCl
and alkynyl with two Zn atoms, thus decreasing the strains. More importantly, dimeric
ZnCl stabilizes 8-[Zn] by distributing the negative charges over the dimeric Zn
2 2
] may bind to carbonyl
[
2 2
]
moiety. The computational finding of the dimeric model could also account for the
different reactivities of Zn(OTf) and Zn(OTf) /LiBr (entries 6 and 11 in Table 3).
2
2
FIGURE 4. Potential Energy Surfaces of the cascade cyclization reaction of enone with diene in
the absence (red lines) and presence of ZnCl
2
(blue line) or (ZnCl
)
2 2
(green line) calculated at
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
M06/BSII//M06/BSI. Relative free energies at 298K are given in kcal mol
4
. A comparison study on the effect of different Lewis acids
To understand the different reactivity of In(III), Al(III) and Zn(II) based Lewis
acids, further DFT calculations were conducted. The three potential energy surfaces of
the reactions involving InCl , AlMe Cl, or [ZnCl were shown in Figure 5. The
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
2 2
]
DA/carbocyclization cascade cyclization reaction is shown on the right side, while the
competitive heterocyclization is shown on the left side. The results of the DFT
calculations suggest different behaviors of these three Lewis acids. The [ZnCl2]2
catalyzed cascade reaction has been discussed above. Compared to the σ-complex
-1
3a-[Zn]-π,σ, the initial π-complex 3a-[Zn]-π is less favorable by 7.3 kcal mol . The
relative free energy of the transition state for heterocyclization HCy-TS-[Zn] is lower
than that of the DA reaction DA-TS-[Zn]. However, the following intermediate 9-[Zn]
-1
is rather unstable, with a reaction free energy of 11.0 kcal mol referring to 3a-[M].
This implies that the cascade reaction is much more favorable thermodynamically.
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9
10
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12
13
14
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
FIGURE 5. Potential-energy surfaces computed for the reaction of enone with diene catalyzed by
2 2 2 3
AlMe Cl (red), [ZnCl ] (green) or InCl (blue) calculated at M06/BSII//M06/BSI. Relative free
-1
energies at 298K are given in kcal mol .
For the case with InCl , both the activation free energy and reaction free energy
3
for the heterocyclization are significantly lower than those of ZnCl
2
. Combining the
DFT results with the experimental observations, we propose that InCl preferentially
3
mediated the intramolecular heterocyclic reaction which would lead to the product
9
-[In] and then the side product 7 after hydrolysis. The AlMe
2
Cl mediated
).
heterocyclization, however, is highly unfavorable (similar to that of ZnCl
2
Furthermore, the weak Al-π interaction cannot activate the carbocyclization process
both kinetically and thermodynamically. The free energy the barrier is 9.1 kcal/mol
2
higher than that of the ZnCl catalyzed process and the intermediate is 12.0 kcal/mol
higher in free energy than the DA intermediate, implying that the reaction catalyzed
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
by AlMe
results.
2
Cl is likely to stop at the first step. This is consistent with the experimental
Based on this theoretical study, InCl
triple bond to promote the intramolecular heterocyclic reactions of the enone.
AlMe
Cl is a better σ-Lewis acid that can only promote the DA reaction by
3
is a better π-Lewis acid that activates the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
coordinating to the carbonyl as a σ-Lewis acid whereas ZnCl is a dual-mode Lewis
2
acid that efficiently induces the cascade cyclization reaction, acting both as a σ and
then as a π Lewis acid.
5
. Study on the scope of substrates
With the optimal conditions in hand, the scope of the substrates was studied with
a series of substituted enones (3a-h) and dienes (4a-c). As shown in Table 5, methyl
substituents at C1 to C4 of the enone were well tolerated and gave comparable yields
and diastereoselectivity of the cyclized products (6b-e) (Table 5, entry 2-5). The
diastereoselectivities of 6b-c would be rationalized based on the preliminary
conformational analysis in Figure 6. Addition of diene 4a is expected from the face
that is anti to the methyl substituent. More importantly, the geminal dimethyl
substituent at C3 also afforded good yields of cyclized product 6f (Table 5, entry 6).
This result indicated that a quartenary carbon center adjacent to the reactive site can
be tolerated under this cyclization condition. Introducing an OTBS moiety at C5 also
afforded good yields and good diastereoselectivity (Table 5, entry 7). The observed
diastereoselectivity of 6g would be rationalized by a non-chelating Felkin-Anh model
in Figure 6. The OTBS group preferentially orientates anti to the carbonyl for
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9
minimization of the dipole, and addition of diene 4a is anticipated from the face that
is anti to the OTBS group. These results indicate that these substituted enones and
dienes not only afford comparable results, but also provide a handle for developing
asymmetric reactions via substrate control. Moreover, the 7-membered enone (3h)
also gave good yields and good diastereoselectivity for the cyclized product 6h (Table
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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39
40
41
42
43
44
45
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47
48
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52
53
54
55
56
57
58
59
60
5
, entry 8), which could be a useful building block for the syntheses of
91
grayanane-type diterpenes. Diene 4b, which bears two methyl substituents at the
reactive site (C6) for the DA cycloaddition also reacted smoothly and gave the
8
8
cyclized product (6i) as a single diastereomer (Table 5, entry 9). The intermediate
that arose from the double Michael reaction pathway was not observed under these
reaction conditions. Diene 4c, which bears a methyl group at C7 (the reactive site for
the carbocyclization), also afforded a very good yield (91%) of the cyclized product
(6j) diastereoselectively (Table 5, entry 10).
a
TABLE 5. The study on the scope of substrates.
b
Yields (dr)
Entry
1
Enones
Dienes
Product
c
86
O
2
81 (8:1)
*
O
H
6b
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
c
3
4
88
85 (16:1)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
c
80
5
6
c
80
7
75 (7:1)
c
82
8
9
c
79
c
91
1
0
a
b
The general procedures were followed. Isolated yields (%) after silica gel column
c
chromatography. A single diastereomer.
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9
diene 4a
diene 4a
diene 4a
diene 4a
X
X
H
H
H
H
H
H
Me
H
Me
H
H
O
O
O
O
H
H
Me
H
H
H
H
H
TBSO
H
H
H
H
3b
3c
3d
3g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
X
X
diene 4a
diene 4a
diene 4a
diene 4a
addition from
the bottom face
addition from
the top face
addition from
the bottom face
addition from
the top face
O
TBSO
O
O
O
O
O
O
H
O
H
H
H
6b
6c
6d
6g
FIGURE 6. A rationale for the observed diastereoselectivity of 6b-d and 6g.
6
. Applications in natural product synthesis
To demonstrate the utility of this cascade cyclization reaction, the cyclized
product 6a was employed as a common precursor for the formal synthesis of
platensimycin (1) and platencin (2). The retrosynthesis of 1 is showed in Scheme 1.
21
The cage structure of the Snider’s intermediate (10) could be established via
selective reduction of ketone 11, followed by acid-induced cationic cyclization.
Ketone 11 could be obtained via 1,2-carbonyl migration of compound 12, which
could be prepared readily by differentiation of the two ketone moieties of 6a. The
retrosynthesis of 2 also employs 6a as the starting material. As shown in Scheme 1,
5
2
the bicyclo[2.2.2]octane moiety of the Nicolaou’s intermediate (13) is expected to
be established by radical rearrangement of 14, which could be obtained from 15 via a
1,3-allylic rearrangement. Compound 15 could be also obtained from 6a via
differentiation of the ketone moieties.
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
SCHEME 1
.
Retrosynthetic analysis of platensimycin 1 and platencin 2 from 6a
7
. Formal synthesis of (±)-platensimycin 1
Since both synthetic strategies involve the differentiation of two ketone moieties
in 6a, the conditions for direction reaction with the ketones were first investigated.
Based on the preliminary conformational analysis of 6a, the two ketone moieties
should have significant differences in the steric hindrance that could be exploited for
differentiation. However, treatment with 1 equivalent of a bulky hydride, such as L,
K-selectride or DIBAL, resulted in a roughly 3:1 mixture of 16a and 16b (Scheme 2)
4
based on the NMR analysis of the crude product. Reduction of 6a with NaBH in a
variety of conditions resulted in non-selective reduction. Reaction between 6a and
tosyl hydrazine resulted in a roughly 1:1 mixture of hydrazones (17a and 17b) based
on the NMR analysis of the crude product.
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SCHEME 2. Attempts of ketone differentiation of 6a
Diketone 6a was thus converted to the silyl enol ethers (18a-c), which were
epoxidized using a variety of oxidants. As shown in Table 6, epoxidation of 16a with
DMDO resulted in decomposition of the substrate (Table 6, entry 1). Switching the
oxidant to
mCPBA selectively afforded 10% of α-hydroxy ketone 19 as a single
diastereomer along with about 20% of 6a recovered (Table 6, entry 2). More bulky
silyl enol ethers (18b and 18c) led to an increase in yields to 30 and 60% respectively
(
Table 6, entry 3-4). The yield of 19 was further optimized by using magnesium
monoperoxyphthalate (MMPP), which provided 19 in 65-80% (Table 6, entry 5-7).
The optimal yield was obtained from 18c with MMPP as the oxidant at room
temperature, which gave 80% yield of 19 with no hydrolysis of the silyl enol ethers
being observed (Table 6, entry 7).
a
TABLE 6. Selective α-hydroxylation of 6a
b
Entry
R
[O]
Temp
Yield
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
1
2
3
4
5
6
7
TMS
TMS
TES
TBS
TMS
TES
TBS
DMDO
mCPBA
mCPBA
mCPBA
MMPP
MMPP
MMPP
0 ºC
0 ºC
0 ºC
0 ºC
0 ºC
0 ºC
rt
-
10
30
60
65
75
80
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
The crude intermediates (18a-c) were used without purification. Isolated yields after silica gel
column chromatography. MMPP = magnesium monoperoxyphthalate
With 19 prepared, it was converted to ketone 12 via hydroxyl-directed reduction
92-93
followed by elimination of the resulting diol (Scheme 3).
This protocol provided
10 in 75% yield. Silyl enol formation followed by MMPP epoxidation of 12 provided
α-hydroxyl ketone 20 as a single diastereomer. However, acetylation of 20 under
various acidic conditions resulted in a mixture of acetal isomers (21a and 21b). After
a survey of different acid conditions, we found that 20 can be equilibrated to 22
qualitatively and diastereoselectively with 2 N aqueous HCl overnight. Indeed, the
α-hydroxylation of 22 with MMPP and equilibrium can be done conveniently in a
one-pot manner, and the diastereomer bearing the trans-decalin was not observed
under these reaction conditions. The resulting alcohol of 22 was then acetylated and
deacetoxylated using SmI . Finally, reduction of ketone 11 with K-selectride followed
2
70
21
by treatment of trifloroacetic acid afforded the Snider's intermediate (10), which
19-20
could be converted to 1 according to the literature procedures.
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SCHEME 3. Formal synthesis of Platensimycin 1
8. Formal synthesis of (±)-platencin 2
For the formal synthesis of 2, enone 15 was expected to be obtained via
dehydration of α-hydroxyl ketone 19. However, decomposition of 19 resulted under a
variety of dehydration conditions. Preparation of enone 15 via oxidation of 6a and
18a-c was then examined. As shown in Scheme 3, oxidation of 6a using IBX
provided 10-30% of the expected enone 13. Switching the substrate to 18a-c
increased the yield of 15 up to 58% (from 18c). Under these oxidation conditions, the
reactions needed to be stopped before completion to avoid over-oxidation. Finally, the
yield of 15 was optimized via bromination of 18c, followed by elimination.
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SCHEME 4. Synthesis of enone 15 via selective oxidation or bromination
With enone 15 in hand, the two ketones were reduced using Luche reduction
9
4
conditions (Scheme 5). The resulting diol 25 is a single diastereomer. Acetylation of
25 afforded diacetate 26 in good yield. The 1,3-allylic rearrangement of 25 and 26
95-97
98-102
were investigated with a variety of acids
and Pd catalysts
respectively.
However, these conditions resulted in either no reaction or decomposition of
substrates. The allylic alcohol of 25 was thus selectively oxidized with MnO
2
(
Scheme 6). After TBS protection of 28, enone 29 was converted to 31
1
03
stereoselectively via the Wharton transposition protocol.
After a number of
protecting and functional group manipulations, the bicycle[3.2.1]octane moiety was
7
converted to the bicycle[2.2.2]octane using Yoshimitsu’s procedures. Finally,
1
oxidative removal of the PMB ether followed by oxidation of the resulting alcohol
52
finished the synthesis of the Nicolaou's intermediate (13), which can also be
52
converted to 2 according to the literature procedures.
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SCHEME 5. Study on the 1,3-allylic rearrangement
O
O
MnO2
TBSCl
99%
25
9
5%
OH
OTBS
H
H
28
29
H2O2, NaOH
CH3OH, rt
96%
O
NH2NH2, AcOH
CH3OH, 0 °C to rt
O
93%
HO
OTBS
OTBS
31
30
H
H
single diastereomer
0%
PMBCl, NaH, DMF
single diastereomer
9
NaH, CS2, THF
then CH3I (95%)
PMBO
TBAF
OR
PMBO
O
H
H
32: R = TBS
14: R = H
33
S
S
1
00%
1) AIBN, Bu3SnH
then DDQ
2
) DMP oxidation
O
82%
O
H
13 (Nicolaou's intermediate)
SCHEME 6. Formal synthesis of Platencin 2
9. Optimization of the ketone differentiation
The differentiation was further optimized by exhaustive reduction of the diketone
with sodium borohydride (diol 34, a roughly 3:1 diastereomeric mixture) followed by
selective TBS protection, which afforded 35 in 78% yield as a roughly 3:1
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diastereomeric mixture from 6a (Scheme 7). The diastereomers are separable and the
stereochemistry of the major diastereomer of 35 was determined by NMR
87
experiments. Since the two newly generated stereogenic centers will be removed in
the late stage of the synthesis, all the diastereomers can be used for the synthesis of 1
and 2. Triflation of 35 followed by elimination afforded 37. Finally, desilylation of 36
followed by oxidation of the resulting alcohol provided ketone 12, which could lead
to Snider’s intermediate 10 in only 7 steps. Oxidation of alcohol 35 followed by
0
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9
0
104
Saegusa oxidation afforded enone 29, which can lead to Nicolaou’s intermediate 13
in 8 steps.
SCHEME 7. Optimization of the ketone differentiation of 6a.
Conclusion
In summary, we have evaluated the π/σ-binding properties of 29 commonly used
Lewis acids in a theoretical study and successfully identified a sub-class of Lewis
acids, including In(III), Zn(II) and Fe(III) halides, with similar π/σ-binding properties.
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With the aid of these theoretical studies, we have developed a mild
2
DA/carbocyclization cascade cyclization reaction with ZnBr (1.5 equiv) as the
dual-mode Lewis acid mediator, which rapidly provided the 6,6,5-trycylic fused
cyclized product 6a from two simple substrates (3a and 4a). The mechanism of this
cascade reaction was further studied via a comparison study between In(III), Zn(II)
and Al(III) induced reactions by DFT calculations. Under the optimal conditions
10
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2 2 2
(ZnBr in CH Cl at room temperature), a variety of substituted enones 3a-h and
dienes 4a-c underwent cascade cyclization smoothly and afforded the cyclized
products (6a-j) in one pot with good yields and high diastereoselectivity. The utility
of this new cascade reaction has been successfully demonstrated by employing
cyclized product 6a as the common building block for the formal synthesis of
(±)-platensimycin (1) and (±)-platencin (2) (43% in 10 steps and 38% in 11 steps
overall yields from 6a respectively).
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6
Experimental Section
General Computational Methods
All the calculations were carried out with the Gaussian 09 package. Geometry
1
05
1
06-110
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optimizations and frequency calculations were performed with the M06 method
111
with BSI (the LANL2DZ basis set and corresponding effective core potentials
1
12-114
(ECPs)
for elements with atomic number higher than 36, and the 6-31G(d) basis
1
set
15
for other atoms). The transition state (TS) were confirmed by frequency
1
16-119
calculation and intrinsic reaction coordinate (IRC) calculations.
All the TS
stationary points were correctly connected to the corresponding species. Vibrational
frequency calculations also provide thermal corrections for enthalpies and Gibbs free
energies (at 298.15 K and 1 atm). For reaction energy profile, single point energies
1
20-126
were calculated at the M06 level with a larger basis sets BSII (def2-TZVP
with
1
27
ECP for In and 6-311++G(3df,3pd) for other atoms). Solvent effects were taken
into account by using the SMD solvation model.
General Experimental Methods
All air- and water-sensitive reactions were carried out under a nitrogen atmosphere
with dry solvents under anhydrous conditions, unless otherwise noted. Reactions were
monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel
plates (60F-254) that were analyzed by fluorescence upon 254 nm irradiation or by
4 4 2 3
staining with KMnO (200 mL H2O of 1.5 g KMnO , 10 g K CO and 1.25 mL of 10%
aqueous NaOH). Silica gel (60, particle size 0.0400.063 mm) was used for flash
column chromatography. All the chemicals were purchased commercially and used
without
further
purification.
Anhydrous
THF
was
distilled
from
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3 2 2
sodium-benzophenone. Toluene was distilled over Na. CH CN and CH Cl were
distilled from calcium hydride. Molecular sieves were activated by heating at 200 ºC
for 12 hours at 1.0 Torr. Yields refer to the isolated yields after silica gel flesh
column chromatography, unless otherwise stated. NMR spectra were recorded on
∼
10
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1
3
1
13
either a 300 (1H: 300 MHz, C: 75.5 MHz) or 500 MHz ( H: 500 MHz, C: 125.8
MHz) spectrometer. The NOESY experiments were performed on a 500 or 600 MHz
spectrometer. The following abbreviations were used to explain themultiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. High-resolution
mass spectra were obtained from a MALDI-TOF mass Spectrometer. Melting points
were uncorrected and determined on a micro-melting point meter. Crystallographic
data were obtained from a single crystal X-ray diffractometer. All the IR spectra were
recorded with a FTIR spectrometer.
2
4
2
-(Prop-2-yn-1-yl)cyclohex-2-enone (3a),
,4-dimethyl-2-(prop-2-yn-1-yl)cyclohex-2-enone (3f) and
-(prop-2-yn-1-yl)cyclohept-2-enone (3h)
To a stirred solution of NaOMe (prepared from sodium (1.25 g, 5.43 mmol) and
CH OH (30 mL)) in methanol (50 mL) at 0 °C was added a solution of methyl
3
thioglycolate (5.52 g, 5.21 mmol) in methanol (20 mL). After 5 minute stirring at 0 °C,
a solution of the appropriate enone (5.21 mmol) in methanol (20 mL) was added
dropwise at the same temperature. The reaction mixture was allowed to warm to room
temperature slowly and heated under reflux for 10 hours. After removal of the
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