Electron transfer-initiated Diels-Alder cycloadditions of 2′-hydroxychalcones

Article abstract of DOI:10.1021/ja803094u

An efficient approach to cyclohexenyl chalcones employing highly electron rich 2′-hydroxychalcone dienophiles via electron transfer-initiated Diels-Alder cycloaddition is described. Using the methodology, the total synthesis of nicolaiodesin C has been accomplished. Copyright

Full text of DOI:10.1021/ja803094u

Published on Web 06/25/2008
Electron Transfer-Initiated Diels-Alder Cycloadditions of 2′-Hydroxychalcones
Huan Cong, Dustin Ledbetter, Gerard T. Rowe, John P. Caradonna, and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment (CMLD-BU),
Boston UniVersity, Boston, Massachusetts 02215
Received April 26, 2008; E-mail: porco@bu.edu
A number of biologically active prenylflavonoid natural products
1
have been isolated from the mulberry tree and related plants. For
2
3
example, kuwanon G (1) and multicaulisin (2) are Diels-Alder
cycloadducts between prenylflavonoid dienes and 2′-hydroxychalcones
4
(
Figure 1). Related Diels-Alder cycloadducts include (-)-panduratin
5
6
A (3) and nicolaioidesin C (4). To access these natural products, we
wished to develop methodology to construct the cyclohexenyl chalcone
7
nucleus employing electron-rich 2′-hydroxychalcone dienophiles. In
this Communication, we report examples of such [4 + 2] cycloaddi-
8
tions in a process likely involving electron transfer.
Our studies began with model reactions of trans-2′-hydroxy
chalcone 5 and 2,3-dimethylbutadiene 6 (Table 1). Owing to our
inability to effect cycloaddition using Lewis acid-promoted (“LUMO”
Figure 1. Select Diels-Alder natural products derived from 2′-hydroxychal-
9
lowering) conditions, we considered alternative modes of catalysis.
cones.
On the basis of a recent report involving Diels-Alder dimerization of
a
10
11
Table 1. Optimization of the Diels-Alder Cycloaddition of 5 and 6
piperine, we evaluated Co(I) catalysis for cycloaddition. Initial
studies revealed that cycloadduct 7 was observed as a single trans
diastereomer using CoI
0/30/10 mol %) (entry 1), which is in contrast to the 1,4-
hydrovinylation of dienes and terminal alkenes employing a similar
2 2 4 4
/1,10-phenanthroline (8)/ZnI /Bu NBH (10/
12
1
b
11c
entry
CoI :8:ZnI :Bu NBH
4
conversion (%)
2
2
4
Co(I) catalyst system reported by Hilt and co-workers.
investigation revealed that the amount of ZnI had a significant effect
on the catalytic process (entries 1-3). Near quantitative conversion
and isolated yield of 7 were obtained with CoI /8/ZnI /Bu NBH (10/
0/60/10 mol %) as catalyst (entry 3). Lower conversion was obtained
in the absence of ligand 8 (entry 4). Remarkably, cycloaddition in the
absence of cobalt proceeded in slightly lower yield employing ZnI
and a catalytic amount of Bu NBH (entry 5), either of which did not
mediate the reaction alone (entries 6, 7). Moreover, no desired
cycloadduct was observed with Zn(BH as catalyst.
Further
1
2
3
4
5
6
7
10:10:30:10 mol %
10:10: 0:10 mol %
10:10:60:10 mol %
10: 0:60:10 mol %
0: 0:60:10 mol %
0: 0:60: 0 mol %
0: 0: 0:10 mol %
23
<2
96(95 )
2
d
c
2
2
4
4
74
85(82 )
<2
<2
1
c
d
d
2
4
4
a
b
1
See Supporting Information for experimental details. Based on H NMR
integration (average of two experiments). Isolated yield. Not observed.
c
d
4 2
)
Further studies were undertaken to probe modifications of the chalcone
Table 2. Chalcone Modifications
dienophile (Table 2). Removal or methylation of the 2′-hydroxyl group
(entries 1, 2) led to production of cycloadducts in lower overall yield in
comparison to 7. Reactions conducted without cobalt generally afforded
lower isolated yields. Surprisingly, 4′-hydroxychalcone 13 did not undergo
13
a
b
cycloaddition (entry 3), implying that chelation of 5 to ZnI
necessary for cycloaddition. Additionally, a counterion effect for the Zn(II)
source was observed (I > Br > Cl) with ZnF , Zn(OAc) , and Zn(OTf)
2
may be
entry
2′-hydroxychalcone
product
condition
yield (%)
1
2
1
9: R , R ) H
10
A
B
A
B
A
B
38
28
55
50
2
2
2
1
2
12
2
3
11: R ) OMe, R ) H
12
14
proving to be unreactive.
Encouraged by the success of the model reaction, we next evaluated
a range of dienes and 2′-hydroxychalcones. [4 + 2] cycloadditions of
select dienes and 5 were conducted in satisfactory isolated yield using
1
2
c
13: R ) H, R ) OH
<2
c
<2
a
CoI
2
/8/ZnI
2
/Bu
4
NBH
4
(10/10/60/10 mol %) at 40 °C (Table 3).
Condition A: 10/10/60/10 mol % CoI2/8/ZnI2/Bu4NBH4; condition B:
b
6
0/10 mol % ZnI2/Bu4NBH4, see Supporting Information. Isolated yield.
Reactions without cobalt showed decreased reactivity (entries 1, 2).
Notably, single regioisomers were observed for unsymmetrical dienes
c
Not observed.
(
entries 1, 4-6). Trisubstituted diene 25, poorly reactive in conventional
hydroxychalcones maintained high reactivity likely due to their less
electron-rich character (entries 2, 4, and 6).
14
[
4 + 2] cycloadditions, afforded cycloadduct 26 in moderate yield
entry 6). A number of highly electron-rich 2′-hydroxychalcones were
also investigated (Table 4). For these dienophiles, a 20/40/120/20 mol
CoI /8/ZnI /Bu NBH catalyst loading was found to be optimal.
(
The utility of acetylated 2′-hydroxychalcones in [4 + 2] cycload-
ditions was further established by the total synthesis of nicolaioidesin
6
12
%
2
2
4
4
C (4) (Scheme 1). Acetylated chalcone 39 was prepared in four steps
Lower yields were obtained with additional alkoxy substitution of the
chalcone (entries 1, 3, and 5). The corresponding acetylated 2′-
(74% overall yield) from commercially available 2′,6′-dihydroxy-4′-
methoxyacetophenone. Diels-Alder cycloaddition of 39 and myrcene
9
214 9 J. AM. CHEM. SOC. 2008, 130, 9214–9215
10.1021/ja803094u CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Generalized Mechanism for [4 + 2] Cycloadditions
Table 3. Diels-Alder Reactions of 5 and Dienes
2
cyclization to produce ketyl intermediate 43. Loss of ZnI from 43
and subsequent single electron transfer to another complex 40 may
afford cycloadduct 16 and radical anion 41, thereby restarting the
catalytic cycle.
a
In summary, we have developed [4 + 2] cycloadditions of highly
Condition A: 10/10/60/10 mol% CoI2/8/ZnI2/Bu4NBH4, 40 °C; condition
b
B: 60/10 mol% ZnI2/Bu4NBH4, 40 °C, see Supporting Information. Isolated
yields. Single regioisomer. Single endo isomer. 1.5:1 exo/endo ratio.
electron-rich 2′-hydroxychalcones and dienes using catalyst systems
c
d
e
-
composed of electron donor (Co(I) or BH
4
) and a Lewis acid (ZnI
2
).
Mechanistic studies and further applications toward the syntheses of
other natural product targets are currently in progress and will be
reported in due course.
Table 4. Diels-Alder Reactions of Electron-Rich 2′-Hydroxychalcones
Acknowledgment. Financial support from the NIH (Grant GM-
073855), Merck, and Wyeth is gratefully acknowledged. We thank
Dr. Aaron Beeler and Ms. Susan Cunningham (CMLD-BU) for HPLC
assistance, and Dr. Branko Mitasev (Boston University) and Dr. Bruce
Branchaud (Invitrogen) for helpful discussions.
a
b
entry
2′-hydroxychalcone
product
condition
yield (%)
1
2
3
4
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
27: R )OMe, R ,R ,R )H
28
A
B
A
B
A
A
A
A
68
36
84
55
33
72
18
61
1
2
3
4
2
29: R )OAc, R ,R ,R )H
30
References
1
2
3
4
3
4
5
6
31: R ,R )OMe, R ,R )H
32
34
36
38
1
2
3
4
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1
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2
35: R ,R ,R )OMe, R )H
(
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(
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(
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(
(
(
(
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5
3, followed by saponification, afforded 4 as a single regioisomer in
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(
1
2
4
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5
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4
NBH
4
/ZnI
2
in conjunction with literature reports documenting electron transfer
1
6
17
from Bu
may be involved in the catalysis. As shown in Scheme 2, coordination
of ZnI to 2′-hydroxychalcone 5 may afford complex 40. Preliminary
cyclic voltammetry studies indicate that 5 in the presence of ZnI
CH Cl shows two new irreversible reduction peaks (Ep,c -0.59, 0.36
4 4
NBH to acceptor substrates suggests that radical anions
(
12) See Supporting Information for complete experimental details.
2
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12
2
in
(
2
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(
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values is expected to parallel the promotion of electron transfer, and
may be attributed to carbonyl activation by ZnI
electron donors such as Co(I) or borohydride, 40 may undergo metal
ion-promoted single electron transfer to generate a chalcone radical
anion 41. Regioselective addition of 41 to isoprene should afford
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(
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1a
(
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19
20
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JA803094U
J. AM. CHEM. SOC. 9 VOL. 130, NO. 29, 2008 9215