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Photoinduced Decarbonylative Rearrangement of Bicyclo[2.2.2]Octenones: Synthesis of the Marasmane skeleton Chun-Chieh Wang, Yi-Chen Ku, and Gary Jing Chuang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02140 • Publication Date (Web): 16 Oct 2015 Downloaded from http://pubs.acs.org on October 18, 2015
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The Journal of Organic Chemistry
Photoinduced Decarbonylative Rearrangement of Bicyclo[2.2.2]Octenones: Synthesis of the Marasmane Skeleton Chun-Chieh Wang, Yi-Chen Ku and Gary Jing Chuang* Department of Chemistry, Chung Yuan Christian University, Chung-Li, Taiwan
[email protected] ABSTRACT: The marasmane sesquiterpenoid structure can be found in the skeleton of a variety of natural products bearing interesting bioactivity. The unique fused-5,6,3-tricyclic ring structure, in which the rings are cis-fused and the 5 and 3-membered rings are mutually trans, provides a synthetic challenge for organic chemists. In this work, we took advantage of the photo-induced decarbonylative rearrangement of bicyclo[2.2.2]octenone to develop new methodology for construction of the highly functionalized fused-5,6,3-tricyclic ring structure in a concise reaction sequence.
KEYWORDS : Introduction Figure 1. The marasmane skeleton and related natural products.
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9 11 12
2
1
4
5
3
10 6
8
14
7
marasmane
O
H
15
13
*
CHO CHO
isovelleral
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O H
OH OH
lactapiperanol A
Isolated from basidiomycete species of the genus Lactarius,1 marasmane sesquiterpenoids are known for their unique fused-5,6,3-tricyclic ring skeleton.2(Figure 1) Aside from being a synthetic challenge for organic chemists, the antifeedant, 3 antifungal, antibacterial, 4 and other bioactivities of these secondary metabolites are also of interest to medicinal chemists.5 Over the years, Heathcock,6 Wilson,7 Groot,8 Woodward,9 and others have demonstrated a variety of methods to synthesize members of the marasmane family of natural products.10 Within the marasmane family, isovelleral caught our attention with its densely-functionalized tricyclic ring structure, in which the 5-membered ring and cyclopropane ring are fused to a cyclohexene core at adjacent carbons and a di-aldehyde group is featured. Isovelleral was also identified to be antibiotic and mutagenic.5a, 11 In previously reported syntheses of isovelleral and its derivatives,6, 12 multiple steps were needed to assemble the fused-5,6,3-tricyclic core structure. We envisioned that a short and functional group compatible construction of the isovelleral skeleton could be potentially important for evaluation of bioactivities of this family of compounds. Photochemical rearrangement of bicyclo[2.2.2]octenones has been a fruitful area in natural product synthesis; namely, the oxa-di-π-methane rearrangement of bicyclo[2.2.2]octenones has been utilized in the synthesis of a number of complex molecules.13 Pioneered by Yates and Stevens in the early 1980s,14 Singh,15 Banwell,16 Liao,17 and other groups have successfully employed the oxa-di-π-methane (ODPM) rearrangement of bicyclo[2.2.2]octenones in syntheses of a great diversity of natural products. 18 Additionally, the photo-induced 1,3-acyl migration of bicyclo[2.2.2]octenones has also been demonstrated as an effective method in natural product synthesis.15a,19 As shown in Scheme 1, it has been reported that in some cases of the 1,3-acyl migration pathway, a secondary product was found that resulted from an additional decarbonylation.14b,16g,17b, 20 With the structural resemblance of this secondary product to marasmane’s skeleton, we anticipated that this photo-induced decarbonylative 1,3-
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migration (PIDM) of bicyclo[2.2.2]octenones could be an effective synthetic pathway for isovelleral and related compounds. We herein report a rapid synthesis of functionalized marasmane anolgues by PIDM of bicyclo[2.2.2]octenones. Scheme 1. Photochemical rearrangement of bicyclo[2.2.2]octenones. H O
oxa-di-π-methane H
O
hυ
1,3-acyl migration
H
O H hυ
decarbonylative 1,3-migration
-CO
H H
H CHO H
CHO
isovelleral
Results In order to construct the bicyclo[2.2.2]octenone starting materials with diverse functionality, we took advantage of the Diels-Alder (D-A) reaction chemistry of masked-o-benzoquinone (MOB) developed by Liao and Quideau. 21 Using readily available 2-methoxyphenols, with an oxidative dearomatization using hypervalent iodine reagent (PhI(OAc)2) in MeOH, MOBs were formed for the subsequent D-A reaction. We selected three dienophiles: N-phenylmaleimde (3) for its high reactivity allowing for generation of a wide variety of D-A adducts; and 2,2-dimethylcyclopent-4-ene-1,3-dione (4) and cyclopentadiene (5) for their all-carbon ring structures that resemble the 5-membered ring in marasmane. The results of the D-A reaction of MOB with 3 are shown in Table 1. Table 1. Diels-Alder reaction of 2a~u with 3, N-phenylmaleimde.
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R5 4
R
R5 OMe
R 1
R3
OH R
DAIB MeOH
R3
2
O OMe OMe
4
O Ph
O
3
R
N R5 OMe OMe
O R4
solvent reflux
O 2
1a~u
Ph N
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R3
R2
O
6a-u
MOB 2a~u
Diels-Alder Product
Yielda
Product
Solvent
H
6a
Mesitylene
92b
CH3
H
6b
Toluene
68
H
H
H
6c
MeOH
74
H
CH3
H
H
6d
Mesitylene
87b
H
H
H
CH3
6e
Toluene
68
H
H
H
6f
MeOH
72c
H
H
6g
MeOH
70c
H
6h
Toluene
72
Entry
R2
R3
R4
R5
1
H
H
H
2
H
H
3
CH3
4 5 6
(%)
7
H
8
H
H
9
H
CO2Me
H
H
6i
MeOH
88
10
H
H
CO2Me
H
6j
MeOH
74c
11
OMe
H
CO2Me
H
6k
MeOH
80c
12
H
H
Acetyl
H
6l
MeOH
55
13
OMe
H
H
H
6m
MeOH
62
14
H
H
H
OMe
6n
Toluene
88
15
H
H
CN
H
6o
MeOH
25
16
H
H
TMS
H
6p
MeOH
74
17
H
H
allyl
H
6q
MeOH
84
18
OMe
H
H
6r
Toluene
72
19
OMe
H
H
6s
MeOH
37
CO2Me
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H
tBu
H
H
6t
MeOH
51
21
H
H
tBu
H
6u
MeOH
60
a
DAIB: (diacetoxy)iodobenzene; bReaction done by using dimer of MOB in retro-Diels-Alder reaction with 3; cReaction at R.T. As shown in Table 1, yields of D-A reaction of MOBs 2a~2u with 3 range from 25 to 92%. It should be noted that because of the rapid self-dimerization of some MOBs, the generation of 6a and 6d (entry 1 and 4, Table 1) were carried out by the cycloaddition using the dimer of the corresponding MOB and dienophile, 3 in a retro-D-A/D-A reaction sequence.
22
In most examples the product
bicyclo[2.2.2]octenones (6) were isolated in moderate yield. To further expand the diversity of functionality in our photorearrangement-precursors, we hydrolyzed 6g and 6h to form 6v and 6w. The aldehyde moieties were found to be important for the bioactivities of isovelleral and its analogous natural products.5a Thus we wanted to inspect necessity of aldehyde protection during the photorearrangement. To examine the compatibility of conjugate extension at olefinic position 6 in the photolysis, we also synthesized vinylated 6x and 6y from 6v and 6w by Wittig reaction. (Scheme 2) This wide variety of substituents on the bicyclo[2.2.2]-core structure is useful for later examination of substitution effects on the photochemical reaction. Scheme 2. Syntheses of 6v, 6w, 6x and 6y. O Ph
O Ph
N OMe OMe
O R4 R3 6g : R3 =
O
, R4 = H
6h : R3 = H, R4 =
O
O
N OMe OMe
O R4 R3
O O
HCl EA
O Ph Ph3P+CH3Br-, NaH THF, rt
O
N OMe OMe
O R4 R3
O
6v : R3 = CHO, R4 = H (67%)
6x : R3 =vinyl , R4 = H (73%)
6w : R3 = H, R4 = CHO (95%)
6y : R3 = H, R4 = vinyl (20%)
We next examined the photo-induced rearrangement of 6. As shown in Table 2, parent compound 6a was selected as the initial substrate. We were pleased to find that, using benzene or acetonitrile as solvent, compound 6a was transformed into desired 7a as the sole detectable product after 3h irradiation
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with a broadband UV light centered at 306 nm. Product from the competing oxa-di-π-methane rearrangement was not observed. In addition, we were not able to detect the product from 1,3-acyl migration of 6a, neither at partial conversion nor upon total consumption of starting material. This efficient decarbonylation process could be explained by the dimethyl ketal group adjacent to the carbonyl group: the decarbonylation of biradical-I (resulting from Norrish type I cleavage) would be favored due to formation of the more stable dimethoxy radical terminus of biradical-II, thus facilitating the sequential extrusion of CO and recombination of the biradical species to form product 7a (Scheme 3). As an optimized condition for the irradiation of other substrates, acetonitrile was selected as solvent, with a concentration of 1 mg/ml (selected for economical reasons, although 0.5 mg/ml resulted in slightly higher yields). Table 2. Optimization of photo-induced decarbonylative 1,3-migration of 6a. O N
hυ (306 nm, Concentration) OMe
O
OMe
MeO
OMe
O N
solvent, 3 h
O
O 6a
7a
Entry
solvent
Concentration (mg/mL)
Isolated Yield (%)
1
Acetone
1
26
2
Benzene
1
85
3
Methanol
1
83
4
ACN
1
85
5
ACN
0.5
89
6
ACN
2
78
7
ACN
3
76
b
Scheme 3. Proposed reaction pathway for the generation of 7a from 6a.
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The Journal of Organic Chemistry O Ph
Ph
N OMe OMe
O 6a O
O
O
hυ Norrish type I cleavage
CO
N OMe OMe
O
Ph
N OMe OMe
O
O biradical-I MeO O H
OMe
O H
H
OMe OMe
Ph N
Ph N O H 7a
O H biradical-II
We then applied the optimized conditions for the photolysis of 6a~y. The result of cases where decarbonylated 1,3-migrated products 7 were successfully obtained are shown in Table 3.
The
structures of photoreaction products 7 were established by 1H, 13C, DEPT NMR, and HRMS. As shown in Figure 2, the stereochemistry of photoproduct 7 was confirmed by X-ray crystallography and NOE experiments, using compound 7d as a representative example. As desired, the 5-membered ring from phthalimide is cis-fused to the cyclohexene, and is trans to the neighboring cyclopropane ring. In all cases, no product from 1,3-acyl migration without decarbonylation was found. Substrates 6 with alkyl groups at olefinic and bridgehead positions resulted 69~99% isolated yield of the corresponding PIDM product 7. (entries 1~4, 14 and 15, Table 3) It should be noted that the tert-butyl group shows no retardation of the rearrangement, even in the generation of 7u (entry 15, table 3) in which three tetrasubstituted carbon centers (t-Bu, and two of the carbons on the cyclopropane ring) were formed in close proximity. Starting materials with 6-membered ring acetals at R2, R3, or R4 showed moderate yields of 75~90 % yield in the photoreaction. (entries 5~7, Table 3). Substrate 6 with a methoxy group installed at the bridgehead positions gave the corresponding products in high yield (entries 9 and 10, Table 3), whereas 7r was isolated in 49% yield.
The PIDM products with trimethylsilyl, allyl, or vinyl
substituents at R4 were also isolated in 87~99% yield from their photo-precursors. Substrates with electron withdrawing CO2Me or formyl groups at R3 shown moderate reactivity (entries 8 and 16, Table 3), however product 7x with a vinyl group at the same position was isolated in only 33%.
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Figure 2. NOE correlations of 7d
O H1 2.2%
N
2.4%
H4 OCH3 H5 OCH3
O H6
1.1%
2.5%
2.6%
1.8%
Table 3. Photo-induced decarbonylative 1,3-migration of 6. O N R
O R4 R3
hυ (306 nm, 1 mg/mL)
5
OMe OMe
ACN, time
MeO
OMe 5 R
O
4
R
N
R3
O
R2
R2 O 6
7
Substituents on 6 and 7
Time (hr)
Isolated Yield
Product
Entry
R2
R3
R4
R5
1
H
H
CH3
H
7b
5
90
2
CH3
H
H
H
7c
3
77
3
H
CH3
H
H
7d
3
69
4
H
H
H
CH3
7e
3
92
H
H
H
7f
5
52
H
H
7g
5
75
H
7h
5
90
5
(%)
6
H
7
H
H
8
H
CO2Me
H
H
7i
3
69
9
OMe
H
H
H
7m
3
86
10
H
H
H
OMe
7n
3
90
11
H
H
TMS
H
7p
3
99
12
H
H
allyl
H
7q
3
90
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13
OMe
H
H
7r
3
49
14
H
tBu
H
H
7t
3
87
15
H
H
tBu
H
7u
3
85
16
H
CHO
H
H
7v
4
86
17
H
vinyl
H
H
7x
3
33
18
H
H
vinyl
H
7y
4
87
During the photolysis of bicyclooctenones 6, examples of incompatibility of the substitution pattern on the starting compound to the desired PIDM were also found. In cases where an electron-withdrawing group (EWG) is installed at the R4 position, either the oxa-di-π-methane rearrangement is the preferred photoreaction pathway, or complex mixtures were produced. As shown in Scheme 4, acetyl and formyl groups at R4 (6l and 6W) lead to formation of ODPM products (8l and 8w, respectively) in optimized conditions for the desired PIDM reaction. When R4 = CO2Me or CN (6j, 6k, and 6o), or is a conjugated elongation of an ester (6s), inseparable mixtures were found during the photolysis. This observation is in accordance with a previous report, where EWG at R4 governed the photoreaction pathway and yielded primarily ODPM products.17b Scheme 4. Photolysis of 6j~l, 6o, 6s and 6w.
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O
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Ph
R4
N OMe OMe
O R4
H
O
hυ (306 nm) ACN 2h
O 6l : R4 = Acetyl 4 6w : R = CHO
O
H
N Ph
MeO OMe O 8l (R4 = Acetyl) : 90% 8w (R4 = CHO) : 45%
MeO R
O Ph
OMe
O
4
N 7
O
N
O R4 R2
OMe hυ (306 nm) OMe ACN O 2h
Not observed complex mixture
6j : R2 = H, R4 = CO2Me 6k : R2 = OMe, R4 = CO2Me 6o : R2 = H, R4 = CN CO2Me 6s : R2 = OMe, R4 =
As the intended PIDM reaction was successful for a wide variety of bicyclo[2.2.2]octenones 6, we next investigated examples where the embedded 5-membered ring is constructed with all-carbon unit, as in the skeleton of marasmane (Figure 1). Substrates 4 (2,2-dimethylcyclopent-4-ene-1,3-dione) and 5 (cyclopentadiene) were selected as dienophiles for the construction of bicyclo[2.2.2]octenones with allcarbon frameworks via Diels-Alders reaction. The geminal dimethyls on 9 or the extra olefin on 10 would provide synthetic handles to facilitate later conversion of the cyclopentane ring to mimic the natural product skeleton if needed. The result of D-A reactions of 4 and 5 with selected MOBs is shown in Table 4. The structures of the Diels-Alder adducts were identified by 1H and 13C NMR, and HRMS.23 Comparing to 3 in the synthesis of compounds 6, 4 was found to be less reactive in the cycloaddition, as a retro-Diels-Alder procedure was required to obtained the corresponding cycloadducts 9 (Table 3, entries 1, 3~6, and 9). Isolated yields of bicyclo[2.2.2]octeneones 9 were lower comparing to 6. In the case of R3 = acetal, 9g was not found in the reaction mixture. In this series of photoreaction precursors, our intention was to examine the application of PIDM strategy in synthesis of isovelleral derivatives, thus we focused on examples of acetal (protected formyl group) substituted compounds. In case of using 5 as dienophile, 10a and 10b were obtained in 53 and 75% yield, respectively. Table 4. Diels-Alder reactions of MOBs with 4 and 5.
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O
O R5
R5
R4
OMe
R3
OH R2
DAIB MeOH 0oC
R4
OMe OMe
R3
O
4
O R4 R3
solvent heat
R5
2
R4 5
Diels-Alder Product
OMe OMe
R2 O 9
R2
1
R5
R3
OMe OMe
R2 O 10
Yielda Dienophile
Product
H
4
9a
51b
CH3
H
4
9b
23a
H
H
H
4
9c
75b
H
CH3
H
H
4
9d
75b
H
H
H
CH3
4
9e
42b
H
H
H
4
9f
15b
H
H
4
9g
0b
H
4
9h
62a
H
OMe
4
9i
74b
H
H
5
10a
53b
H
5
10b
75a
Entry
R2
R3
R4
R5
1
H
H
H
2
H
H
3
CH3
4 5 6 7
H
8
H
H
9
H
H
10
H
11
H
H
(%)
a
Diels-Alder reaction carried out in refluxing toluene. bReaction done by using dimer of MOB in retroDiels-Alder reaction at 220oC in mesitylene. We then applied our optimized PIDM conditions to cycloadducts 9 and 10, to inspect whether their reactivity is similar to 6. In preliminary results, products 11 from the photoreaction of 9 were not stable under the conditions of photolysis process, and were isolated in
