A new catalytic Cu(II)/sparteine oxidant system for β,β-phenolic couplings of styrenyl phenols: Synthesis of carpanone and unnatural analogs

Article abstract of DOI:10.1021/ol801643t

(Chemical Equation Presented) A new catalytic Cu(ll)/sparteine system has been developed to promote β,β-phenolic couplings of styrenyl phenols en route to carpanone and related unnatural congeners in yields exceeding 85%.

Full text of DOI:10.1021/ol801643t

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4097-4100
A New Catalytic Cu(II)/Sparteine Oxidant
System for ꢀ,ꢀ-Phenolic Couplings of
Styrenyl Phenols: Synthesis of
Carpanone and Unnatural Analogs
R. Nathan Daniels, Olugbeminiyi O. Fadeyi, and Craig W. Lindsley*
Departments of Chemistry and Pharmacology, Institute of Chemical Biology,
Vanderbilt UniVersity, NashVille, Tennessee 37232
craig.lindsley@Vanderbilt.edu
Received July 18, 2008
ABSTRACT
A new catalytic Cu(II)/sparteine system has been developed to promote ꢀ,ꢀ-phenolic couplings of styrenyl phenols en route to carpanone and
related unnatural congeners in yields exceeding 85%.
Benzoxanthenones are a class of lignan natural products,
exemplified by a highly oxygenated tetracyclic ring system
with four to five contiguous stereocenters, isolated as single
diastereomers. Notable members include (Figure 1) car-
panone (1),1 polemannone (2),2 sauchinone (3),3 and the
unnatural CLL-19 (4).4 Benzoxanthenones have garnered a
great deal of attention since the classic biomimetic synthesis
of carpananone (1) by Chapman in 1971 (Scheme 1), which
utilized PdCl2 and NaOAc to promote the ꢀ,ꢀ-phenolic
coupling and subsequent endoselective, inverse-electron
demand Diels-Alder reaction.5
Chapman’s approach afforded carpanone (1) in 46% yield as a
single diastereomer, which was confirmed by single X-ray crystal-
lography.5 After this intial report, several laboratories disclosed
additional oxidative systems, both stoichiometric and catalytic, to
Figure 1. Structures of benzoxanthone natural and unnatural
(1) Brophy, G.; Mohandas, J.; Slaytor, M.; Sternhell, S.; Watson, T.;
Wilson, L. Tetrahderon Lett. 1969, 10, 5159–5162.
products.
(2) Jaupovic, J.; Eid, F. Phytochemistry 1987, 26, 2427–2429.
(3) Sung, S.; Kim, Y. C. J. Nat. Prod. 2000, 63, 1019–1021.
(4) Goess, B. C.; Hannoush, R. N.; Chan, L. K.; Kirchhausen, T.; Shair,
M. D. J. Am. Chem. Soc. 2006, 128, 5391–5403.
produce carpanone including metal(II) salen/O2 (metal ) Co, Mn,
Fe),6 O2 (hν, rose bengal),6 AIBN,6 dibenzoyl peroxide,6 and AgO7
in yields ranging from 14-94%. In 2001, Ley reported on the total
(5) Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am.
Chem. Soc. 1971, 93, 6696–6698.
10.1021/ol801643t CCC: $40.75
Published on Web 08/27/2008
2008 American Chemical Society

In order to extend this system to ꢀ,ꢀ-phenolic couplings and
the synthesis of carpanone and related analogs, we first had to
prepare the requisite styrenyl phenols. Starting from com-
mercially available 5-methoxysalicylaldehyde 8, an E-selective
Wittig reaction13 afforded styrenyl phenols 9 and 10 in >85%
yield and 11 in 30% yield (Scheme 3). The key styrenyl phenol
Scheme 1. Biomimetic Synthesis of Carpanone
Scheme 3. Synthesis of Styrenyl Phenols 9-11 and 13
synthesis of carpanone employing only solid-supported reagents
and scavengers.8 Around the same time, Lindsley and Shair9
described a hetero-ꢀ,ꢀ-phenolic coupling reaction, facilitated by
IPh(OAc)2, to deliver heterotetracyclic analogs of carpanone;
however, this oxidant system was unable to produce carpanone
itself but was able to produce less electron-rich homodimers.4
We were interested in alternative oxidant systems to
promote the ꢀ,ꢀ-phenolic coupling reaction, and one that
might afford enantioselectivity. Upon perusal of the literature,
we were attracted to the work of Hovorka,10 in which a
CuCl2/tert-butyl amine system (4.0 equiv CuCl2, 16.0 equiv
tert-butyl amine, 1.0 equiv of each naphthol) was able to
promote highly selective oxidative cross-couplings of sub-
stituted 2-naphthols, 5 and 6, to afford unsymmetrical 1,1′-
binaphthols 7 in >90% yields (Scheme 2). Subsequently,
13 to access carpanone was prepared according to literature
precendent from sesamol 12 in three steps.5
Our studies began by exposing 10 to 4.0 equiv of CuCl2
and 16.0 equiv of tert-butylamine in nondegassed MeOH
exposed to air at room temperature for different reaction
times (Scheme 4). When the reaction was quenched with
Scheme 4
.
CuCl2/tert-Butylamine Oxidative ꢀ,ꢀ-Phenolic
Coupling To Afford 14 and 15
Scheme 2. CuCl2/tert-Butylamine Oxidative Coupling of
2-Naphthols To Yield Unsymmetrical 1,1′-Binaphthols
catalytic, enantioselective variations were developed that
afforded unsymmetrical 1,1′-binaphthols with excellent enan-
tioselection (27-99% ee) employing (-)-sparteine in place
of tert-butylamine.11,12 However, these conditions had never
been applied to ꢀ,ꢀ-phenolic coupings of styrenyl phenols.
saturated NH4Cl after 45 min, the desired homocoupled
product 14 was isolated in 80% yield as a single diastere-
omer, and the relative stereochemistry was confirmed by
NOE measurements.14 When reactions were quenched after
8 h, two products were isolated in ∼1:1 ratio: the desired
14 along with a product 15 consistent with the conjugate
addition of MeOH to 14, which afforded a single diastere-
omer containing six contiguous stereocenters. If the reaction
was allowed to proceed in excess of 16 h, the conjugate
(6) Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1981, 22, 4437–4440.
(7) Iyer, M. R.; Trivedi, G. K. Bull. Chem. Soc. Jpn. 1992, 65, 1662–
1664.
(8) Baxendale, I. R.; Lee, A. I.; Ley, S. V. Synlett 2001, 9, 1482–1484.
(9) Lindsley, C. W.; Chan, L. K.; Goess, B. C.; Joseph, R.; Shair, M. D.
J. Am. Chem. Soc. 2000, 122, 422–423.
(10) Hovorka, M.; Gunterova, J.; Zavada, J. Tetrahedron Lett. 1990,
31, 413–416.
(11) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S-I.; Noji,
(13) Suzuki, Y.; Takahashi, H. Chem. Pharm. Bull. 1983, 31, 1751–
1753.
M.; Koga, K. J. Org. Chem. 1999, 64, 2264–2271
.
(12) Li, X.; Yang, J.; Kozloski, M. C. Org. Lett. 2001, 3, 1137–1140
.
(14) See Supporting Information for full experimental details.
4098
Org. Lett., Vol. 10, No. 18, 2008

addition product 15 formed exclusively with isolated yields
of 89% as a single diastereomer due to selective addition to
the convex face of the rigid tetracyclic scaffold.4,14
Table 1. Metal-Catalyzed ꢀ,ꢀ-Phenol Homocouplinga
Again, NOE measurements established the relative ster-
eochemistry for 15.14 We were surprised by the complex
molecular architecture of 15 that could arise in a single pot
from a starting material devoid of any chiral centers by a
ꢀ,ꢀ-phenolic coupling, inverse-electron demand DA, and
subsequent conjugate addition reaction cascade. Our attention
now turned to optimization of these two reactions and
evaluation of chiral amine ligands to provide enantioselec-
tivity in the ꢀ,ꢀ-phenolic coupling.
Utilizing 10, we next surveyed a variety of chiral amine
ligands 16-19, both monodentate and bidentate, under a
variety of temperatures (-20 °C to rt), concentrations, solvent
systems, and copper source with both stoichiometric and
catalytic manifolds in order to determine if alternative amine/
copper complexes would promote the ꢀ,ꢀ-phenolic coupling
reaction and engender a degree of enantioselectivity in the
product 14 (Figure 2). As shown in Table 1, we first
metal
source
ligand
time
(min)
entry
(equiv)a
yield (%)b
convnc
1
2
3
4
5
6
7
8
9
CuCl2
Cul
Cul
CuCl2
CuCl2
CuCl2
CuCl2
Cul
16, 16
16, 16
10
15
15
15
15
20
20
20
20
20
80
73
61
71
66
71
59
<5
42
61
100
89
72
79
81
79
65
<5
54
71
16, 0.5
17, 0.5
16, 0.5
16, 0.1
19, 0.5
17, 0.5
t-BuNH2, 16
18, 0.5
CuCl2
CuCl2
10
a All reactions were performed on a 0.05 mmol scale. b Isolated yields
c
1
of a single diastereomer. Conversion were estimated by LC/MS and H
NMR.
Table 2. Metal-Catalyzed ꢀ,ꢀ-Phenol Homocoupling
entry
metal source
liganda
16
16
16
16
16
17
18
17
17
18
17
17
19
19
t-BuNH2
yield (%)b
convnc
1
2
3
4
5
6
7
8
CuCl2
Cul
96
23
61
13d
67
89
81
12
83
3
100
88
72
75
85
91
89
24
92
10
95
15
73
<5
3.6
Figure 2. Chiral amine ligands surveyed to promote the ꢀ,ꢀ-
phenolic coupling reaction and potentially provide % ee.
CuCl
CuBr2
Cu(OTf)2
CuCl2
Cul
Cul
CuCl
Cul
Cu(OTf)2
CuBr2
CuCl2
Cul
examined conversion to 14 employing various Cu(I) and
Cu(II) salts with the four chiral amines 16-19 at -10 °C in
nondegassed MeOH. At this temperature, the standard
conditions with tert-butylamine (entry 9) suffered a dimu-
nition in yield, whereas the bidentate ligand 16 afforded
excellent conversion to 14 and an 80% isolated yield (entry
1). Catalytic quantities of amine ligand also afforded good
conversion to 14 with excess copper.
9
10
11
12
13
14
15
80
0
69
0
CuCl2
0
We next examined the conversion of 10 to 14 when utilizing
only 10 mol % copper source with 10 mol % of 16-19 in MeOH
at -20 °C for 24 h (Table 2). In addition to CuCl2, CuCl and
Cu(OTf)2 afforded good results, whereas CuI and CuBr2 faired
less well, delivering the Michael adduct 15 as a major side product.
Our original conditions of CuCl2/tert-butylamine failed entirely
under these low temperature, catalytic conditions.
Finally, we evaluated the effect of solvent on the conver-
sion of 10 to 14 (Table 3). For this study, we maintained 10
mol % copper, 10 mol % (-)-sparteine at -20 °C for 24 h
a All reactions were performed on a 0.05 mmol scale. b Isolated yields
of a single diastereomer. Conversion were estimated by LC/MS and H
NMR analysis. d For entries 2 and 4 Michael product 15 was obtained in
24% and 35% yield, respectively.
c
1
and examined CH2Cl2, CH3CN, and MeOH. Clearly, MeOH
is the optimal solvent to faciliate the ꢀ,ꢀ-phenolic coupling
reaction. After an exhaustive survey, only poor enantiose-
lectivity (<5% ee) was observed by analytical chiral LC;
however, we noted that bidentate (-)-sparteine was superior
Org. Lett., Vol. 10, No. 18, 2008
4099

carpanone 1 was in complete accord with the NMR spectra
of natural carpanone.5 Moreover, this oxidant system is quite
general and, unlike IPh(OAc)2,9 works for both the electron-
rich carpanone and less-electron-rich, unnatural congeners
in excellent isolated yields.
Table 3. Examination of Solvent in the Catalyzed ꢀ,ꢀ-Phenol
Homocouplinga
Conditions were also readily optimized to deliver the
conjugate addition product 15 (Table 4). Exposure of 10 to
Table 4. Diastereoselective Conjugate Addition
entry
metal source
solventa
yield (%)b
convnc
1
2
3
4
5
6
7
8
CuCl2
Cul
CuCl
CuBr2
CuCl2
Cu(OTf)2
Cul
CuCl2
CuBr2
CuCl
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
MeOH
MeOH
MeOH
MeOH
53
49
50
62
59
40
85
96
23
61
67
76
76
71
80
77
65
85
100
88
72
85
entry
ligand (equiv)a
time (h)
yieldb
9
10
11
1
2
3
4
16, 16
16, 8
16, 4
t-BuNH2, 16
4
4
5
4
89
91
81
Cu(OTf)2
a All reactions were performed on a 0.05 mmol scale. b Isolated yields
of a single diastereomer. Conversion were estimated by LC/MS and H
NMR.
<5
c
1
a All reactions were performed on a 0.5 mmol scale. b Isolated yields
of a single diastereomer.
to the monodentate tert-butylamine facilitating the ꢀ,ꢀ-
phenolic coupling reaction. Moreover, tert-butylamine failed
at temperatures below 0 °C to promote the ꢀ,ꢀ-phenolic
coupling, whereas (-)-sparteine 16 provided excellent results
at temperatures as low as -20 °C. These data suggest that
the reaction does not take place in the copper coordination
sphere due to rapid dissociation of the intermediate keto-
radical leading to no enantioselection.
Employing these optimized catalytic conditions with
styrenyl phenols 9, 11, and 13 provided unnatural benzox-
anthenones 20 and 21 in 87% and 89% yield, respectively,
as well as carpanone 1 in 91% yield (Figure 3). Our synthetic
4.0 equiv of CuCl2 with 8.0 equiv of 16 provided 15 in 91%
isolated yield as a single diasteromer in 4 h at room
temperature. If the reaction is performed in EtOH in place
of MeOH, the corresponding conjugate addition product is
obtained in equivalent yield.
In summary, we have developed a novel, catalytic CuCl2/(-)-
sparteine oxidative ꢀ,ꢀ-phenolic coupling reaction of styrenyl
phenols that, after a rapid inverse-electron demand Diels-Alder
reaction, affords the benzoxanthanone natural product carpanone
1 and related unnatural congeners in yields exceeding 85%. With
a slight variation of these reaction conditions, a simple achiral
styrenyl phenol undergoes a ꢀ,ꢀ-phenolic coupling, inverse-electron
demand Diels-Alder reaction, and subsequent conjugate addition
reaction to generate unnatural tetracyclic benzoxanthanones 15 with
six contiguous asymmetric centers set diastereoselectively in a one-
pot reaction. Unfortunately, <5% ee was observed when empoying
chiral amine ligands under a variety of reaction conditions,
indicating no influence of a chiral environment for ꢀ,ꢀ-phenolic
couplings. Further refinements are in progress along with a
synthesis of sauchinone 3 and libraries of related unnatural
congeners, which will be reported in due course.
Acknowledgment. We are very grateful to Professor Mat-
thew Shair, Harvard University, for helpful conversations. This
work was supported by the Department of Pharamacology,
Vanderbilt University.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
ThismaterialisfreeofchargeviatheInternetathttp://pubs.acs.org.
Figure 3. Optimized CuCl2/(-)-sparteine oxidative ꢀ,ꢀ-phenolic
couplings to afford 14, 20, 21, and carpanone, 1.
OL801643T
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Org. Lett., Vol. 10, No. 18, 2008