Stereocontrolled Formal Synthesis of Platencin

Article abstract of DOI:10.1002/ejoc.201800806

A stereocontrolled formal synthesis of platencin was accomplished in 11 steps from a bromophenol derivative, with an overall yield of 13 %. The intermolecular Diels–Alder reaction of masked o-benzoquinone and an aldol condensation were the key steps in th

Full text of DOI:10.1002/ejoc.201800806

A Journal of
Accepted Article
Title: Stereocontrolled Formal Synthesis of Platencin
Authors: Day-Shin Hsu and Tai-Yu Hwang
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
Stereocontrolled Formal Synthesis of Platencin
Day-Shin Hsu* and Tai-Yu Hwang
Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung, Taiwan 621
E-mail: chedsh@ccu.edu.tw
http://deptche.ccu.edu.tw/faculty/dsh.html
Keywords: Formal synthesis, intermolecular Diels-Alder, masked o-benzoquinone, platencin,
stereocontrol
OH
O
HO
MeO
11 steps
O
O
N
H
CO H
2
13%
overall yield
OH
Br
O
O
7
3
platencin (1)
Abstract: A stereocontrolled formal synthesis of platencin was accomplished in 11 steps from
bromophenol 7, in 13% overall yield. The intermolecular Diels-Alder reaction of masked o-
benzoquinone and aldol condensation were the key steps in the construction of the tricyclic core of
platencin.
Introduction
The discovery of antibiotics was a huge step forward in sustaining human health, by preventing
deadly infections caused by microorganisms. With the emergence of penicillin, millions of human lives
could be saved from diseases for which there was previously no cure. With time, overuse and misuse of
antibiotics resulted in drug resistance, or even multidrug resistance. Modification of certain types of
1
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
drug can help in preventing loss of efficacy. Methicillin is one of the frequently used drugs for the
treatment of infections, but nowadays, the majority of infections are caused by the methicillin-resistant
Staphylococcus aureus (MRSA)1 in hospital facilities. Hence, there is an urgent need to develop new
antibiotics.
By screening a large number of natural product extracts, Singh and coworkers discovered
platencin2 (1) and platensimycin3 (2) (Figure 1), both of which showed highly potent and broad-
spectrum activity against many multidrug-resistant pathogens. Platencin (1) inhibits fatty acid acyl
carrier protein synthases II (FabF) and III (FabH),4 which are essential for bacterial fatty acid
biosynthesis, while platensimycin (2) selectively blocks FabF. Because 1 exhibits a broad range of
antibacterial/biological properties, the development of new and efficient strategies to synthesize
platencin has become a major focal point of synthetic chemistry. Hence, many total5,6 and formal7
syntheses of 1 have been reported to date, and different strategies have been adopted to construct its
tricyclic core. Among these, Diels-Alder approaches for the construction of the bicyclo[2.2.2]octane
skeleton were reported by several groups.5e,7b,7d,e,i One of these approaches involves an intramolecular
Diels-Alder reaction of masked o-benzoquinone.5e Masked o-benzoquinones, which can be easily
generated in situ by oxidation of the corresponding 2-methoxyphenols with hypervalent iodine in the
presence of an appropriate alcohol, have been used to construct various carbon frameworks in organic
synthesis,8 especially the bicyclo[2.2.2]octane ring system.9 Herein, we report a new approach for the
formal synthesis of 1 via an intermolecular Diels-Alder reaction of masked o-benzoquinone.
O
HO
HO
O
O
N
H
CO H
2
N
CO H
2
H
OH
OH
O
O
platencin (1)
platensimycin (2)
Figure 1. Structures of platencin (1) and platensimycin (2)
The retrosynthetic analysis is outlined in Scheme 1. Since the installation of a methyl and an
aromatic side chain on the tricyclic core 3 has been reported by several groups,5 we focused on the
2
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
preparation of tricyclic enone 3. We envisioned that the aldol condensation and regioselective
olefination of 4 would be a potentially viable synthetic route to 3. Aldol condensation precursor 4 would
be obtained from diol 5 through dehydroxylation, deprotection, and double bond oxidation. Diol 5 could
be derived from cycloadduct 6. Cycloadduct 6 with the desired stereostructure would be obtained from
the well-established Diels-Alder reaction of in situ generated masked o-benzoquinone and acrolein.
Scheme 1. Retrosynthetic analysis
HO
ref 5
CO2H
O
N
H
OH
O
O
O
platencin (1)
3
MeO
OMe
HO
O
OHC
O
OH
O
4
5
MeO
OMe
CHO
O
OH
O
Br
O
MeO
O
O
Br
6
7
Results and Discussion
Bromophenol 7 used in this synthesis was prepared from commercially available o-vanillin (8)
via bromination10 and protection of the aldehyde with acetal (Scheme 2). The intermolecular Diels-
Alder reaction of masked o-benzoquinone 10 (generated in situ by addition of a solution of
diacetoxyiodobenzene (DAIB) in methanol to 7 in methanol) and acrolein afforded 6 in quantitative
yield.8f The regiochemistry and stereochemistry of 6 were consistent with the literature precedents,8f and
3
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
this compound possessed the desired stereostructure for the tricyclic core of platencin. Debromination
and reduction of the double bond proceeded simultaneously under the hydrogenation conditions in the
presence of sodium bicarbonate to give ketoaldehyde 11.11
Scheme 2. Preparation of ketoaldehyde 11
OH
OH
OH OH
MeO
CHO
MeO
CHO
Br
2
pTSA
HOAc/H O,
r.t., 3 h
81%
2
PhMe,
reflux,
40 min
quant.
Br
o-vanillin (8)
9
OH
O
O
O
O
MeO
MeO
O
PhI(OAc)
2
MeO
MeOH,
r.t., 5 h
quant.
Br
Br
7
10
MeO
O
OMe
MeO
O
OMe
H , Pd/C,
Br
2
NaHCO
acrolein
3
O
O
iPrOH,
r.t., 3.5 h
CHO
CHO
O
O
85%
6
11
With ketoaldehyde 11 in hand, we attempted two-carbon elongation of the aldehyde. Selective
addition of vinylmagnesium bromide to the aldehyde moiety on 11, followed by reaction with lithium
aluminum hydride to reduce the ketone afforded diol 5 as a single stereoisomer (Scheme 3). In order to
determine its stereostructure, 5 was further subjected to acidic conditions12 and subsequently treated
with ferric chloride in methanol13 to form tricyclic acetal 15. The stereostructure of tricyclic acetal 15
was determined by a NOESY experiment, so that the stereochemistry of the allyl alcohol in 5 could be
revealed (Scheme 4). Dehydroxylation of 5 was achieved in a three-step sequence. Conversion of
hydroxyls to acetates was performed in neat acetic anhydride with a catalytic amount of p-
o
toluenesulfonic acid at 50 C for 7 h; under these conditions, the desired acetates were formed, and the
dimethyl ketal moiety was hydrolyzed into ketone. The allylic acetate was then reduced with ammonium
4
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
formate in the presence of palladium catalyst14 to form 13. The remaining acetate was reduced by a
reaction with samarium diiodide15 to obtain bicyclo[2.2.2]octanone 14 in quantitative yield.
Scheme 3. Preparation of bicyclo[2.2.2]octanone 14
MeO
O
OMe
MeO
OMe
MgBr
o
OH
THF, 0 C,
30 min
Ac O, pTSA,
2
O
O
o
then LiAlH
4
50 C, 7 h
CHO
O
O
o
THF, 0 C,
OH
2 h
66%
11
5
O
O
O
Pd(OAc) ,
2
OAc
OAc
nBu P,
SmI ,
3
2
HCO NH ,
MeOH
2
4
O
O
O
THF,
THF,
O
O
o
o
O
90 C,
0 C,
OAc
30 min
58%
(2 steps)
10 min
quant.
12
13
14
Scheme 4. Selected NOE correlations of tricyclic acetal 15
O
MeO
OMe
OH
H
H
1. HCO2H, H2O
r.t., 3 h
OH
H
2. FeCl3 6H2O
MeOH, CH2Cl2,
r.t., 6.5 h
O
MeO
H
O
O
OH
H
30% (2 steps)
5
15
With 14 in hand, we next focused on the formation of the cyclohexenone moiety to obtain the
desired tricyclic core of platencin. To this end, Wacker oxidation16 at the terminal double bond was
performed to afford methyl ketone 16 in 71% yield (Scheme 5). Hydrolysis of the acetal moiety was first
carried out with 5 M sulfuric acid17 in 1,2-dichloroethane at room temperature; however, the reaction
did not proceed under these conditions. We then employed aqueous formic acid which was previously
used for the hydrolysis of acetal, for the transformation of 5 to 15. To our delight, hydrolysis of the
acetal proceeded smoothly at room temperature to form ketoaldehyde 4, which was then heated to 90 oC,
to furnish the intramolecular aldol condensation product (tricyclic compound) 17 in 94% yield. The final
step was regioselective methylenation on the bicyclo[2.2.2]octanone moiety. Unfortunately, attempts to
5
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
achieve selective methylenation by using various methylenation reagents, such as CH2I2/Zn/TiCl4,18a
Mg/TiCl4,18b Petasis reagent,18c Al/AlMe3,18d CH2I2/Zn/AlMe3,18a and Wittig reagent,18e were
unsuccessful and afforded a complicated mixture of products.
Scheme 5. Preparation of key intermediate 3
O
O
O2, PdCl2,
Cu(OAc)2 H2O
HCO2H,
H2O
O
O
DMA, H2O,
60 oC, 62 h
71%
O
r.t. to
90 oC,
4 h
O
O
14
16
O
O
OHC
94%
O
O
O
4
17
3
Because the regioselective olefination of 17 to form key intermediate 3 was unsuccessful, we
decided to install the exo double bond at an early stage of the synthesis, as per the modified procedure
shown in Scheme 6. Methylenation of ketone 14 using the Wittig reagent, followed by Wacker
oxidation19 at the allyl side chain afforded 19. Hydrolysis of the acetal moiety was first carried out at 0
oC in aqueous formic acid, and then, the reaction mixture was warmed to room temperature for 7 h to
obtain ketoaldehyde 20 in 53% (74% brsm) yield. It is noteworthy that hydrolysis of the acetal moiety
should be performed at room temperature, at higher temperatures led to the addition of water and formic
acid to the exo double bond. Finally, ketoaldehyde 20 was allowed to react with a base to form the
desired product 3, which could be readily converted to platencin (1) according to the literature
procedure.5
Scheme 6. Alternative procedure for the preparation of key intermediate 3
6
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
O
PPh3MeBr,
O2, PdCl2,
nBuLi
benzoquinone
O
O
THF,
0 oC,
THF/H2O,
40 oC, 50 h
70%
O
O
15 min
90%
14
18
HCO2H
NaOH
O
EtOH/H2O,
r.t., 4 h
THF/H O,
OHC
O
2
O
0 oC to r.t.,
83%
5 min to 7 h
53%
(74% brsm)
O
20
19
HO
O
ref 5
N
CO2H
OH
H
O
O
3
platencin (1)
Conclusion
In summary, a stereocontrolled formal synthesis of platencin, in 13% overall yield, was
accomplished in 11 steps from bromophenol 7. Dearomatization/Diels-Alder reaction allowed for the
rapidly construction of bicyclo[2.2.2]octenone with the desired stereostructure. All the necessary
stereogenic centers of the tricyclic core of platencin were established by the Diels-Alder reaction in one
step. Further investigation in asymmetric formal synthesis of platencin using a carbohydrate-templated
asymmetric Diles-Alder reaction of a masked o-benzoquinone20 is currently underway.
Experimental Section
General Information. Unless stated otherwise, reagents were obtained from commercial sources and
used without further purification. All reactions were performed under an argon or nitrogen atmosphere
in anhydrous solvents, which were dried prior to use following standard procedures. Reactions were
monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254) using 7%
ethanolic phosphomolybdic acid as developing agent. Merck silica gel 60 (particle size 0.040–0.063 mm,
7
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
230–400 mesh) was employed for flash chromatography. Melting points are uncorrected. IR spectra
1
were recorded as films on KBr plates. H NMR spectra were obtained in CDCl3 at 400 MHz (Bruker
DPX-400). 13C NMR spectra were obtained at 100 MHz. Chemical shifts were reported in δ (ppm)
1
relative to the residual nondeuterated solvent signal for H (CHCl3: δ = 7.26 ppm) and relative to the
deuterated solvent signal for 13C (CDCl3: δ = 77.0 ppm). High resolution mass spectra (HRMS) were
obtained on a TOF MS instrument with an EI source.
5-Bromo-2-hydroxy-3-methoxybenzaldehyde (9).10 To a stirred solution of o-vanillin (8) (5.00 g, 32.9
mmol) in AcOH (25 mL) and water (5 mL) was added bromine (1.7 ml, 33.0 mmol) slowly at room
temperature. After stirred at room temperature for 3 h, the reaction mixture was diluted with water (75
mL). The solid was collected and washed with water. The solid was dissolved in EtOAc and then
washed successively with saturated aqueous Na2S2O3, brine, dried over MgSO4, filtered, and
concentrated to give phenol 9 (6.13 g, 81%) as yellow solid. Analytically pure 9 was obtained by
o
1
crystallization from EtOAc: Mp 128–129.5 C; H NMR (CDCl3, 400 MHz) δ 10.99 (s, 1H), 9.85 (s,
13
1H), 7.30 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H) ; C NMR (CDCl3, 100 MHz) δ
195.3 (CH), 150.9 (C), 149.3 (C), 126.1 (CH), 121.4 (C), 120.8 (CH), 111.0 (C), 56.6 (CH3).
4-Bromo-2-(5,5-dimethyl-1,3-dioxan-2-yl)-6-methoxyphenol (7). A mixture of phenol 9 (6.00 g, 26.0
mmol), 2,2-dimethyl-1,3-propanediol (4.05 g, 39.0 mmol) and pTSA (0.10 g, 0.53 mmol) in toluene
(110 mL) was heated to reflux with a Dean-Stark apparatus for 40 min. The reaction mixture was cooled
to room temperature and then washed successively with saturated aqueous NaHCO3, water, and brine.
The organic phase was dried over MgSO4, filtered, and concentrated to give phenol 7 (8.20 g,
quantitative) as pale yellow solid. Analytically pure 7 was obtained by crystallization from EtOAc: Mp
96–97 oC; IR (KBr) ν 3293, 2952, 2867, 1572, 1488, 1382, 1254, 1213, 1077, 1023, 847, 782, 691 cm−1;
1H NMR (CDCl3, 400 MHz) δ 7.18 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.85 (br, 1H), 5.63 (s,
13
1H), 3.85 (s, 3H), 3.78 (d, J = 11.2 Hz, 2H), 3.66 (d, J = 11.2 Hz, 2H), 1.29 (s, 3H), 0.80 (s, 3H); C
NMR (CDCl3, 100 MHz) δ 148.0 (C), 143.2 (C), 124.5 (C), 122.1 (CH), 115.0 (CH), 111.4 (C), 98.8
(CH), 77.7 (CH2), 56.4 (CH3), 30.3 (C), 22.9 (CH3), 21.8 (CH3); MS (EI) m/z (% base peak) 318 (25),
8
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
316 (M+, 26), 232 (100), 231 (17), 230 (88), 186 (20), 184 (19); HRMS (EI) calcd for C13H1779BrO4
316.0310, Found 316.0307; Anal. calcd for C13H17BrO4: C, 49.23; H, 5.40. Found: C, 49.37; H, 5.28.
(1S*,2R*,4S*)-5-Bromo-1-(5,5-dimethyl-1,3-dioxan-2-yl)-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-
ene-2-carbaldehyde (6). To a mixture of phenol 7 (1.02 g, 3.2 mmol) and freshly distilled acrolein (5.2
mL, 77.8 mmol) in anhydrous MeOH (16 mL) was added dropwise a solution of diacetoxyiodobenzene
(1.22 g, 3.8 mmol) in anhydrous MeOH (16 mL) through a dropping funnel under N2 at room
temperature over 1 h. Once the addition completed, dropping funnel was rinsed with anhydrous MeOH
(2 mL), reaction mixture was stirred at room temperature for another 5 h. The reaction mixture was
quenched with saturated aqueous NaHCO3. The solvent was evaporated in vacuo and extracted with
EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated.
The residue was purified by column chromatography (hexane/EtOAc = 3:1) to give aldehyde 6 (1.30 g,
quantitative) as pale yellow oil. IR (neat) ν 2957, 2918, 2850, 1746, 1724, 1612, 1470, 1395, 1188, 1106,
1059, 1028, 909, 732 cm−1; 1H NMR (CDCl3, 400 MHz) δ 9.46 (d, J = 4.3 Hz, 1H), 6.39 (d, J = 2.3 Hz,
1H), 4.96 (s, 1H), 3.67–3.61 (m, 2H), 3.54–3.46 (m, 2H), 3.38–3.33 (m, 1H), 3.36 (s, 3H), 3.33 (s, 3H),
3.07–2.99 (m, 1H), 2.23 (ddd, J = 13.6, 10.1, 3.1 Hz, 1H), 1.80 (ddd, J = 13.6, 5.6, 3.1 Hz, 1H), 1.11 (s,
13
3H), 0.72 (s, 3H); C NMR (CDCl3, 100 MHz) δ 198.2 (CH), 196.0 (C), 125.3 (CH), 124.4 (C), 98.9
(CH), 94.1 (C),77.7 (CH2), 77.3 (CH2), 60.3 (C), 50.8 (CH3), 50.2 (CH3), 48.7 (CH), 46.4 (CH), 30.1
(C), 23.3 (CH3), 23.1 (CH2), 21.8 (CH3); MS (EI) m/z (% base peak) 402 (M+, 0.1), 376 (100), 374 (99),
345 (54), 289 (38), 287 (35), 243 (46), 241 (46), 185 (30), 165 (27), 115 (41), 105 (50), 91 (47), 77 (91),
69 (100); HRMS (EI) calcd for C17H2379BrO6 402.0678, Found 402.0681.
(1R*,2R*,4S*)-1-(5,5-Dimethyl-1,3-dioxan-2-yl)-5,5-dimethoxy-6-oxobicyclo[2.2.2]octane-2-
carbaldehyde (11). To a mixture of 6 (1.20 g, 3.0 mmol), 10% Pd/C (240 mg) and NaHCO3 (599 mg,
7.1 mmol) was added iPrOH (50 mL). The mixture was stirred under a hydrogen balloon at room
temperature for 3.5 h. The mixture was filtered through a short pad of celite and filtrate was
concentrated in vacuo to give a residue. The residue was diluted with water, and extracted with EtOAc.
The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated to give
9
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
aldehyde 11 (826 mg, 85%) as white solid. Analytically pure 11 was obtained by crystallization from
o
Et2O: Mp 129–130 C; IR (KBr) ν 2949, 2882, 1738, 1717, 1466, 1392, 1194, 1139, 1062, 1035, 884,
790 cm−1; 1H NMR (CDCl3, 400 MHz) δ 9.97 (d, J = 2.8 Hz, 1H), 4.75 (s, 1H), 3.63–3.55 (m, 2H), 3.51
(d, J = 11.1 Hz, 1H), 3.40 (d, J = 11.1 Hz, 1H), 3.28 (s, 3H), 3.27 (s, 3H), 3.08–3.00 (m, 1H), 2.36–2.30
(m, 1H), 2.13–1.74 (m, 4H), 1.71–1.53 (m, 2H), 1.08 (s, 3H), 0.68 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 204.1 (C), 201.2 (CH), 101.0 (CH), 97.5 (C), 77.8 (CH2), 77.4 (CH2), 52.3 (C), 50.0 (CH3), 49.6 (CH3),
43.8 (CH), 32.6 (CH), 30.1 (C), 23.5 (CH3), 21.9 (CH3), 21.1 (CH2), 20.9 (CH2), 19.7 (CH2); MS (EI)
m/z (% base peak) 326 (M+, 0.1), 298, (6), 269 (100), 255 (8), 212 (2), 183 (25), 169 (6), 115 (6), 101
(83), 69 (8); HRMS (EI) calcd for C17H26O6 326.1729, Found 326.1729; Anal. calcd for C17H26O6: C,
62.56; H 8.03. Found: C, 62.40; H, 8.02.
(1S*,2S*,4S*,6R*)-1-(5,5-Dimethyl-1,3-dioxan-2-yl)-6-((R*)-1-hydroxyallyl)-3,3-
dimethoxybicyclo[2.2.2]octan-2-ol (5). To a stirred solution of aldehyde 11(1.17 g, 3.6 mmol) in
anhydrous THF (15 mL) was added vinylmagnesium bromide (0.7 M in THF, 12.8 mL, 9.0 mmol)
o
o
slowly at 0 C under Ar atmosphere. The reaction mixture was stirred at 0 C for another 30 min. The
mixture was transferred to a stirred solution of LiAlH4 (221 mg, 5.8 mmol) in anhydrous THF (3 mL)
through cannula at 0 oC under Ar atmosphere. The above residue was rinsed with anhydrous THF (2 x 4
o
mL). The reaction mixture was stirred for additional 2 h at 0 C. The mixture was then quenched with
brine (10 mL). Once reaction mixture separated into clear solution and white slurry, the solution was
decanted, and the slurry was washed twice with EtOAc. The combined decantate was filtered and
concentrated in vacuo. The crude product was purified by gradient silica-gel column chromatography
(hexane/EtOAc = 5:1 to 3:1, containing 0.5 % v/v of Et3N) to give diol 5 (811 mg, 66%) as colorless oil.
IR (neat) ν 3521, 2952, 2871, 1728, 1470, 1395, 1269, 1204, 1108, 1049, 1016, 919, 755 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 5.80 (ddd, J = 17.2, 10.7, 4.2 Hz, 1H), 5.29 (ddd, J = 17.2, 1.9, 1.9 Hz, 1H), 5.11
(ddd, J = 10.7, 1.9, 1.9 Hz, 1H), 4.58 (s, 1H), 4.43–4.35 (m, 1H), 3.81 (d, J = 5.9 Hz, 1H), 3.73–3.59 (m,
2H), 3.56–3.41 (m, 2H), 3.44 (d, J = 5.9 Hz, 1H), 3.29 (s, 3H), 3.24 (s, 3H), 3.22 (d, J = 3.7 Hz, 1H),
2.07–1.88 (m, 3H), 1.68–1.61 (m, 2H), 1.56–1.47 (m, 1H), 1.44–1.36 (m, 2H), 1.18 (s, 3H), 0.72 (s, 3H);
10
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10.1002/ejoc.201800806
European Journal of Organic Chemistry
13C NMR (CDCl3, 100 MHz) δ 138.9 (CH), 113.6 (CH2), 103.3 (CH), 100.9 (C), 77.4 (CH2), 77.2
(CH2),74.4 (CH), 71.8 (CH), 49.1 (CH3), 48.7 (CH3), 44.6 (C), 35.6 (CH), 32.2 (CH), 30.2 (C), 22.9
(CH3), 22.0 (CH2), 21.6 (CH3), 20.1 (CH2), 19.0 (CH2); MS (EI) m/z (% base peak) 356 (M+, 0.3), 341
(38), 269 (11), 268 (43), 209 (6), 193 (6), 149 (7), 131 (8), 115 (100), 101 (63), 69 (33); HRMS (EI)
calcd for C19H32O6 356.2199, Found 356.2197.
(1S*,2S*,4S*,6R*)-6-Allyl-1-(5,5-dimethyl-1,3-dioxan-2-yl)-3-oxobicyclo[2.2.2]octan-2-yl
acetate
(13). To a mixture of diol 5 (544 mg, 1.5 mmol) and Ac2O (3.0 mL, 31.8 mmol) was added pTSA (29
o
mg, 0.15 mmol) and then heated to 50 C for 7 h. The reaction mixture was then cooled to room
temperature, and quenched with saturated aqueous NaHCO3. After stirred for further 2 h, aqueous layer
was extracted with EtOAc. The combined extracted were washed with brine, dried over MgSO4, filtered,
and concentrated to give a residue. A mixture of Pd(OAc)2 (16 mg, 0.073 mmol) and ammonium
formate (367 mg, 5.8 mmol) was added a solution of the above residue in dry THF (7 mL) under Ar
atmosphere and the flask was rinsed with dry THF (3 mL). The mixture was added nBu3P (0.18 mL,
o
0.73 mmol) and then heated to reflux at 90 C for 30 min. The reaction mixture was cooled to room
temperature and filtered through a short pad of celite. Filtrate was concentrated in vacuo to give a
residue, which was purified by gradient silica-gel column chromatography (hexane/EtOAc = 7:1 to 4:1)
to give ketone 13 (295 mg, 58%) as white solid. Mp 99–100.5 oC; IR (KBr) ν 2949, 2860, 1755, 1736,
1642, 1473, 1394, 1372, 1228, 1106, 1027, 923, 800 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.82–5.63 (m,
1H), 5.42 (s, 1H), 5.15–4.94 (m, 2H), 4.27 (s, 1H), 3.68–3.52 (m, 2H), 3.35 (d, J = 11.1 Hz, 1H), 3.28 (d,
J = 11.1 Hz, 1H), 2.52–2.41 (m, 1H), 2.41–2.34 (m, 1H), 2.27–2.15 (m, 1H), 2.13 (s, 3H), 2.07–1.89 (m,
3H), 1.89–1.71 (m, 3H), 1.40 (ddd, J = 13.4, 8.3, 2.0 Hz, 1H), 1.12 (s, 3H), 0.69 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 211.8 (C), 169.8 (C), 136.9 (CH), 116.3 (CH2), 103.0 (CH), 77.6 (CH2), 77.2
(CH2), 75.7 (CH), 45.9 (C), 41.9 (CH), 36.1 (CH2), 32.7 (CH2), 31.3 (CH), 30.1 (C), 23.1 (CH3), 21.8
(CH3), 20.8 (CH3), 20.5 (CH2), 19.0 (CH2); MS (EI) m/z (% base peak) 336 (M+, 2), 293 (2), 249 (4),
227 (2), 180 (2), 155 (4), 141 (6), 115 (100), 91 (8), 69 (61); HRMS (EI) calcd for C19H28O5 336.1937,
Found 336.1933; Anal. calcd for C19H28O5: C, 67.83; H 8.39. Found: C, 67.62; H, 8.47.
11
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(1S*,4R*,5R*)-5-Allyl-4-(5,5-dimethyl-1,3-dioxan-2-yl)bicyclo[2.2.2]octan-2-one (14). To a stirred
o
solution of ketone 13 (142 mg, 0.42 mmol) in anhydrous THF (1.0 mL) and MeOH (0.14 mL) at 0 C
under Ar atmosphere was added SmI2 (0.1 M in THF, 13 mL, 1.3 mmol). The reaction mixture was
stirred at 0 oC for 10 min and quenched with saturated aqueous NH4Cl, saturated aqueous Na2S2O3 and
saturated aqueous Na2CO3. The solvent was removed under in vacuo and extracted with EtOAc. The
combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography (hexane/EtOAc = 2:1) to give ketone 13 (117
mg, quantitative) as pale yellow oil. IR (neat) ν 2952, 2869, 1728, 1640, 1472, 1395, 1364, 1343, 1185,
1
1105, 1023, 993 cm−1; H NMR (CDCl3, 400 MHz) δ 5.78–5.65 (m, 1H), 5.09–4.96 (m, 2H), 4.24 (s,
1H), 3.57 (d, J = 11.0 Hz, 2H), 3.36 (d, J = 10.8 Hz, 1H), 3.34 (d, J = 10.8 Hz, 1H), 2.44 (d, J = 19.1 Hz,
1H), 2.41–2.35 (m, 1H), 2.31 (dd, J = 19.1, 2.0 Hz, 1H), 2.25–2.20 (m, 1H), 1.93–1.84 (m, 3H), 1.78–
13
1.70 (m, 2H), 1.66–1.58 (m, 2H), 1.40–1.30 (m, 1H), 1.11 (s, 3H), 0.69 (s, 3H); C NMR (CDCl3, 100
MHz) δ 217.2 (C), 136.9 (CH), 116.0 (CH2), 102.6 (CH), 77.2 (CH2), 77.1 (CH2), 43.8 (CH2), 43.0
(CH), 42.2 (C), 35.7 (CH2), 35.0 (CH), 30.2 (CH2), 30.1 (C), 22.9 (CH2), 22.7 (CH3), 21.6 (CH3), 20.6
(CH2); MS (EI) m/z (% base peak) 278 (M+, 30), 267 (15), 250 (36), 193 (27), 155 (56), 141 (76), 115
(100), 105 (41), 91 (81), 79 (90), 69 (100); HRMS (EI) calcd for C17H26O3 278.1882, Found 278.1881.
(1R*,3aS*,4S*,6S*,7aR*)-4-Hydroxy-3-methoxy-1-vinyltetrahydro-3H-3a,6-ethanoisobenzofuran-
5(4H)-one (15). A mixture of diol 5 (109 mg, 0.31 mmol), HCO2H (1.0 mL) and water (0.1 mL) was
stirred at room temperature under N2 atmosphere for 3 h. The solvent was removed in vacuo to give a
residue. To a stirred solution of the above residue in CH2Cl2 (2 mL) was added MeOH (19 mg, 0.58
mmol) and FeCl3·6H2O (118 mg, 0.43 mmol) under N2 atmosphere and stirred at room temperature for
6.5 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2. The
combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. The
residue was purified by silica-gel column chromatography (hexane/EtOAc = 2:3, containing 1 % v/v of
Et3N) to give ketone 15 (22 mg, 30%) as colorless oil. IR (neat) ν 3453, 2950, 2877, 1731, 1643, 1453,
1402, 1191, 1146, 1093, 1017, 928, 756 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.89 (ddd, J = 17.0, 10.3,
12
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6.9 Hz, 1H), 5.36 (ddd, J = 17.0, 1.4, 1.4 Hz, 1H), 5.30 (ddd, J = 10.3, 1.4, 1.4 Hz, 1H), 4.79 (s, 1H),
4.78–4.72 (m, 1H), 4.52 (s, 1H), 4.11 (s, 1H), 3.44 (s, 3H), 3.13–2.99 (m, 1H), 2.39–2.33 (m, 1H),
2.08•1.91 (m, 2H), 1.80–1.56 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 214.2 (C), 136.5 (CH), 117.6
(CH2), 107.7 (CH), 80.3 (CH), 75.6 (CH), 54.8 (CH3), 49.9 (C), 41.0 (CH), 34.6 (CH), 25.2 (CH2), 24.2
(CH2), 20.7 (CH2); MS (EI) m/z (% base peak) 238 (M+, 4), 206 (21), 178 (67), 121 (49), 115 (47), 96
(100), 91 (77), 79 (70), 58 (93); HRMS (EI) calcd for C13H18O4 238.1205, Found 238.1208.
(1S*,4R*,5S*)-4-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-(2-oxopropyl)bicyclo[2.2.2]octan-2-one (14). To a
stirred solution of ketone 14 (79 mg, 0.28 mmol) in DMA (1.05 mL) and water (0.15 mL) was added
o
PdCl2 (6 mg, 0.034 mmol) and Cu(OAc)2·H2O (118 mg, 0.59 mmol). The mixture was stirred at 60 C
under an oxygen balloon for 48 h. Additional portion of PdCl2 (5.4 mg, 0.030 mmol) and water (0.1 mL)
was added to the above mixture and stirred additional 14 h at 60 oC under O2. The reaction mixture was
cooled to room temperature and diluted with EtOAc. The mixture was filtered through a short pad of
celite and the solvent was removed in vacuo to give a residue. The residue was added 10% aqueous LiCl
until color turned into yellowish brown and extracted with Et2O. The combined organic phase was
washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica-gel
column chromatography (hexane/EtOAc = 4:1) to give dione 16 (59 mg, 71 %) as colorless oil. IR (neat)
ν 2953, 2869, 1726, 1470, 1395, 1361, 1166, 1106, 1027, 991 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.08
(s, 1H), 3.55–3.45 (m ,2H), 3.27 (d, J = 11.0 Hz, 1H), 3.26 (d, J = 11.0 Hz, 1H), 2.80 (dd, J = 15.5, 5.1
Hz, 1H), 2.40 (d, J = 19.1 Hz, 1H), 2.37–2.16 (m, 4H), 2.14–2.03 (m, 1H), 2.09 (s, 3H), 1.77–1.55 (m,
4H), 1.18 (ddd, J = 13.6, 6.8, 2.1 Hz, 1H), 1.08 (s, 3H), 0.66 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
216.3 (C), 207.7 (C), 102.7 (CH), 76.9 (CH2), 76.8 (CH2), 46.7 (CH2), 44.6 (CH2), 42.7 (CH), 42.1 (C),
31.8 (CH), 31.4 (CH2), 30.1 (C), 29.7 (CH3), 22.8 (CH2), 22.8 (CH3), 21.6 (CH3), 19.6 (CH2); MS (EI)
m/z (% base peak) 294 (M+, 5), 208 (4), 179 (5), 115 (100), 95 (7), 79 (17), 69 (60); HRMS (EI) calcd
for C17H26O4 294.1831, Found 294.1828.
(2S*,4aR*,8aS*)-1,2,8,8a-Tetrahydro-7H-2,4a-ethanonaphthalene-3,7(4H)-dione (15). A mixture of
dione 14 (39 mg, 0.13 mmol), formic acid (1.5 mL) and water (0.15 mL) was stirred at room
13
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European Journal of Organic Chemistry
o
temperature for 3 h under N2 atmosphere and then heated to 90 C for 4 h. The reaction mixture was
cooled to room temperature and the solvent was removed in vacuo. The residue was purified by silica-
gel column chromatography (hexane/EtOAc = 2:1) to give enone 15 (24 mg, 94 %) as pale yellow oil.
1
IR (neat) ν 2945, 2871, 1725, 1683, 1455, 1404, 1275, 1157, 1106, 943, 851, 762 cm−1; H NMR
(CDCl3, 400 MHz) δ 6.59 (d, J = 10.1 Hz, 1H), 5.93 (d, J = 10.1 Hz, 1H), 2.56 (dd, J = 16.8, 4.1 Hz,
1H), 2.48–2.32 (m ,3H), 2.28–2.15 (m, 2H), 2.11 (dd, J = 18.4, 2.2 Hz, 1H), 1.99–1.85 (m, 3H), 1.73–
1.60 (m, 1H), 1.46–1.34 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 213.3 (C), 198.6 (C), 153.8 (CH),
128.4 (CH), 49.1 (CH2), 42.5 (CH), 41.2 (CH2), 37.3 (C), 36.0 (CH), 31.4 (CH2), 23.6 (CH2), 23.5
(CH2); MS (EI) m/z (% base peak) 190 (M+, 40), 162 (14), 146 (22), 134 (13), 120 (26), 105 (29), 91
(100), 77 (81), 65, (25); HRMS (EI) calcd for C12H14O2 190.0994, Found 190.0992.
2-((1R*,2R*,4S*)-2-Allyl-5-methylenebicyclo[2.2.2]octan-1-yl)-5,5-dimethyl-1,3-dioxane (18). To a
stirred solution of methyltriphenylphosphonium bromide (985 mg, 2.8 mmol) in anhydrous THF (6 mL)
o
at 0 C under Ar atmosphere was added nBuLi (2.5 M in nHexane, 1.1 mL, 2.8 mmol) dropwise. The
o
resulting orange solution was stirred at 0 C for 30 min. To this mixture was added dropwise a solution
of ketone 14 (154 mg, 0.55 mmol) in anhydrous THF (3 mL), the flask was rinsed with anhydrous THF
o
(3 mL). The mixture was stirred at 0 C for 15 min. The Reaction mixture was then quenched with
saturated aqueous NH4Cl and extracted with Et2O. The combined extracts were washed with brine, dried
over MgSO4, filtered, and concentrated. The residue was purified by silica-gel column chromatography
(hexane) to give diene 18 (137 mg, 90 %) as pale yellow oil. IR (neat) ν 3071, 2950, 2865, 1640, 1470,
1394, 1362, 1108, 1023, 993, 908, 872 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.82–5.66 (m, 1H), 5.07–
4.93 (m, 2H), 4.71 (d, J = 2.1 Hz, 1H), 4.61 (d, J = 2.1 Hz, 1H), 4.17 (s, 1H), 3.64–3.55 (m, 2H), 2.41–
3.30 (m, 2H), 3.48–2.27 (m, 3H), 2.21–2.14 (m, 1H), 1.91–1.65 (m, 3H), 1.65–1.43 (m, 4H), 1.22–1.15
(m, 1H), 1.17 (s, 3H), 0.70 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 151.8 (C), 138.0 (CH), 115.3 (CH2),
104.7 (CH2), 104.5 (CH), 77.4 (CH2), 77.3 (CH2), 39.8 (C), 36.2 (CH), 35.9 (CH2), 35.6 (CH), 34.9
(CH2), 33.9 (CH2), 30.2 (C), 26.1 (CH2), 23.0 (CH3), 21.8 (CH3), 21.7 (CH2); MS (EI) m/z (% base peak)
14
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276 (M+, 53), 233 (17), 205 (17), 190 (26), 155 (46), 141 (55), 115 (100), 91 (65), 69 (100); HRMS (EI)
calcd for C18H28O2 276.2089, Found 276.2088.
1-((1R*,2S*,4S*)-1-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-methylenebicyclo[2.2.2]octan-2-yl)propan-2-
one (19). To a stirred solution of diene 18 (60 mg, 0.22 mmol) in THF (1.75 mL) and water (0.25 mL)
was added freshly sublimated 1,4-benzoquinone (30 mg, 0.28 mmol) and PdCl2 (6 mg, 0.034 mmol).
o
The mixture was stirred at 40 C under an oxygen balloon for 50 h. The reaction mixture was diluted
with Et2O, and filtered through a short pad of celite. Filtrate was concentrated in vacuo to give a residue,
which was purified by gradient silica-gel column chromatography (hexane/Et2O = 15:1 to 3:1) to give
ketone 19 (44 mg, 70 %) as pale yellow oil. IR (neat) ν 3066, 2950, 2865, 1715, 1650, 1470, 1394, 1362,
1
1164, 1103, 1027, 989, 872 cm−1; H NMR (CDCl3, 400 MHz) δ 4.71 (d, J = 1.9 Hz, 1H), 4.61 (d, J =
1.9 Hz, 1H), 4.02 (s, 1H), 3.57–3.47 (m, 2H), 3.28 (d, J = 11.0 Hz, 1H), 3.27 (d, J = 11.0 Hz, 1H), 2.78
(dd, J = 15.1, 6.7 Hz, 1H), 2.45–2.34 (m, 1H), 2.34–2.21 (m, 2H), 2.21–2.12 (m, 2H), 2.09 (s, 3H),
1.93–1.82 (m, 1H), 1.60–1.43 (m, 4H), 1.13 (s, 3H), 1.06 (ddd, J = 12.6, 6.9, 1.8 Hz, 1H), 0.68 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 208.8 (C), 150.9 (C), 105.1 (CH2), 104.5 (CH), 77.1 (CH2), 77.0 (CH2),
47.3 (CH2), 39.8 (C), 36.0 (CH), 35.8 (CH2), 35.0 (CH2), 32.5 (CH), 30.1 (C), 29.6 (CH3), 25.9 (CH2),
23.0 (CH3), 21.7 (CH3), 20.5 (CH2); MS (EI) m/z (% base peak) 292 (M+, 16), 234 (9), 205 (6), 188 (8),
148 (18), 115 (100), 105 (14), 91 (38), 69 (80); HRMS (EI) calcd fo C18H28O3 292.2038, Found
292.2038.
(1R*,2S*,4S*)-5-Methylene-2-(2-oxopropyl)bicyclo[2.2.2]octane-1-carbaldehyde (20).5c To a stirred
solution of ketone 19 (9 mg, 0.031 mmol) in THF (0.5 mL) was added a mixture of formic acid (0.4 mL)
o
and water (0.05 mL) slowly at 0 oC. The reaction mixture was stirred at 0 C for 5 min and then stirred
at room temperature for 7 h. The mixture was quenched carefully with saturated aqueous NaCO3 and
extracted with Et2O. The combined organic phase was washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was purified by gradient silica-gel column chromatography
(hexane/EtOAc = 10:1 to 5:1) to give aldehyde 20 (3.4 mg, 53 %, 74 % brsm) as colorless oil and
recovered ketone 19 (2.6 mg). IR (neat) ν 3070, 2929, 2869, 2713, 1716, 1651, 1429, 1357, 1232, 1163,
15
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1025, 881, 782, 712 cm−1; 1H NMR (CDCl3, 400 MHz) δ 9.42 (s, 1H), 4.87–4.82 (m, 1H), 4.75–4.71 (m,
1H), 2.56–2.42 (m, 3H), 2.36 (dd, J = 17.8, 10.4 Hz, 1H), 2.31–2.24 (m, 2H), 2.12 (s, 3H), 2.10–2.02 (m,
1H), 1.86–1.75 (m, 1H), 1.69–1.47 (m, 3H), 1.14 (ddd, J = 13.3, 5.2, 2.5 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 207.4 (C), 205.2 (CH), 147.5 (C), 107.1 (CH2), 48.4 (C), 47.4 (CH2), 36.4 (CH2), 36.0 (CH),
34.4 (CH2), 31.2 (CH), 30.3 (CH3), 25.5 (CH2), 20.2 (CH2).
(2S*,4aR*,8aS*)-3-Methylene-1,2,3,4,8,8a-hexahydro-7H-2,4a-ethanonaphthalen-7-one (3).5c To a
stirred solution of ketoaldehyde 20 (15 mg, 0.073 mmol) in EtOH (1.0 mL) was added a solution of
NaOH (6 mg, 0.15 mmol) in water (0.05 mL). The mixture was stirred at room temperature for 4 h. The
solvent was removed in vacuo and added saturated aqueous NH4Cl. The mixture was extracted with
EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered, and
concentrated. The residue was purified by silica-gel column chromatography (hexane/EtOAc = 15:1) to
give enone 3 (12 mg, 83 %) as colorless oil. IR (neat) ν 2939, 2865, 1683, 1612, 1469, 1429, 1392, 1272,
1251, 1167, 877, 766 cm−1; 1H NMR (CDCl3, 400 MHz) δ 6.56 (d, J = 10.1 Hz, 1H), 5.87 (d, J = 10.1
Hz, 1H), 4.83 (dd, J = 4.2, 1.8 Hz, 1H), 4.68 (dd, J = 3.8, 1.8 Hz, 1 H), 2.50–2.38 (m, 2H), 2.37–2.26 (m,
2H), 2.21–2.05 (m, 2H), 2.05–1.94 (m, 1H), 1.83–1.65 (m, 3H), 1.56–1.46 (m, 1H), 1.20 (ddd, J = 12.2,
13
7.5, 1.5 Hz, 1H); C NMR (CDCl3, 100 MHz) δ 200.1 (C), 156.7 (CH), 148.9 (C), 127.7 (CH), 106.9
(CH2), 41.6 (CH2), 40.8 (CH2), 36.0 (CH), 35.6 (C), 35.5 (CH), 34.9 (CH2), 26.4 (CH2), 24.5 (CH2).
1
Supporting Information Available: The comparison tables of the H and 13C NMR data between
reported and synthetic 3. Copies of 1H and 13C NMR for compounds 3, 5–7, 9, 11, and 13–20.
Acknowledgement. We thank the Ministry of Science and Technology (MOST) of the Republic of
China for financial support (MOST 102-2113-M-194-001-MY3).
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European Journal of Organic Chemistry
Table of Contents
Key Topic：Formal Synthesis
A stereocontrolled construction of the tricyclic core of platencin was accomplished from bromophenol
7 in 11 steps via the dearomatization/Diels-Alder reaction and aldol condensation. All the necessary
stereogenic centers of the tricyclic core of platencin were established by the Diels-Alder reaction in
one step.
OH
O
HO
MeO
11 steps
O
O
N
H
CO H
2
13%
overall yield
OH
Br
O
O
7
3
platencin (1)
21
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