Manganese(III)-mediated transformations of phloroglucinols: A formal oxidative [4 + 2] cycloaddition leading to bicyclo[2.2.2]octadiones

Article abstract of DOI:10.1021/ol900590t

Manganese(III)-mediated oxidative transformations of dearomatized phloroglucinol (1,3,5-trihydroxybenzene) derivatives are reported. A number of cyclization modes have been observed, including polycyclization to afford bicyclo[2.2.2]octadiones via a forma

Full text of DOI:10.1021/ol900590t

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2285-2288
Manganese(III)-Mediated Transformations
of Phloroglucinols: A Formal Oxidative
[4 + 2] Cycloaddition Leading to
Bicyclo[2.2.2]octadiones
Branko Mitasev and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library,
DeVelopment (CMLD-BU), Boston UniVersity, Boston, Massachusetts 02215
porco@bu.edu
Received March 20, 2009
ABSTRACT
Manganese(III)-mediated oxidative transformations of dearomatized phloroglucinol (1,3,5-trihydroxybenzene) derivatives are reported. A number
of cyclization modes have been observed, including polycyclization to afford bicyclo[2.2.2]octadiones via a formal oxidative radical [4 + 2]
cycloaddition.
Oxidative transformations involving an enolized carbonyl
moiety have significantly attracted the attention of synthetic
chemists. Metal ions such as Mn(III), Cu(II), Fe(III), and
Ce(IV) are well-known for their potential to extract electrons
from electron-rich enols and enolates generally resulting in
the formation of an electrophilic R-carbonyl radical. This
general reactivity has found numerous synthetic applications.
Examples include Mn(III)-mediated oxidative free radical
cyclizations,1 Mn(III)-mediated cycloadditions,2 R-acetoxy-
lation3 and arylation,1b,4 and Fe(III)- or Cu(II)-mediated
enolate hetero-5 and homocoupling.6 Some of these methods
have found use in the synthesis of complex natural product
targets and medicinal agents.7 Mn(III)-based oxidative radical
cyclizations of carbonyl compounds onto unactivated olefins,
extensively studied by Snider and others,1,8 are particularly
attractive for their potential to rapidly generate molecular
complexity.
Our laboratory has a continuing interest in dearomatization
of electron-rich aromatic compounds in the synthesis of
(4) Bhowmik, D. R.; Venkateswaran, R. V. Tetrahedron Lett. 1999, 40,
7439
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(1) (a) Snider, B. B.; Patricia, J. J.; Kates, S. A. J. Org. Chem. 1988,
53, 2137. (b) Kates, S. A.; Dombroski, M. A.; Snider, B. B. J. Org. Chem.
1990, 55, 2425. (c) Snider, B. B.; McCarthy, B. A. J. Org. Chem. 1993,
58, 6217. (d) Snider, B. B. Chem. ReV. 1996, 96, 339. (e) Cole, B. M.;
Han, L.; Snider, B. B. J. Org. Chem. 1996, 61, 7832.
(5) (a) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006,
45, 7083. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc.
2008, 130, 11546.
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(b) Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97, 2912. (c)
Frazier, R. H., Jr.; Harlow, R. L. J. Org. Chem. 1980, 45, 5408–5411.
(7) (a) Snider, B. B.; Mohan, R.; Kates, S. A J. Org. Chem. 1985, 50,
3659. (b) Paquette, L. A.; Schaefer, A. G.; Springer, J. P. Tetrahedron 1987,
43, 5567. (c) Pettus, T. R. R.; Inoue, M.; Chen, X. T.; Danishefsky, S. J.
J. Am. Chem. Soc. 2000, 122, 6160. (d) Nicolaou, K. C.; Gray, D. L. F.
J. Am. Chem. Soc. 2004, 126, 607. (e) Baran, P. S.; Richter, J. M.; Lin,
D. W. Angew. Chem., Int. Ed. 2005, 44, 609.
(2) (a) Melikyan, G. G. Synthesis 1993, 833. (b) Mellor, J. M.;
Mohammed, S. Tetrahedron 1993, 49, 7557. (c) Snider, B. B.; Han, L.;
Xie, C. J. Org. Chem. 1997, 62, 6978. (d) Chowdhury, F. A.; Nishino, H.;
Kurosawa, K. Tetrahedron Lett. 1998, 39, 7931. (e) Tsai, A.-I.; Lin, C.-H.;
Chuang, C.-P. Heterocycles 2005, 65, 2381.
(3) (a) Williams, G. J.; Hunter, N. R. Can. J. Chem. 1976, 54, 3830.
(b) Dunlap, N. K.; Sabol, M. R.; Watt, D. S. Tetrahedron Lett. 1984, 25,
5839. (c) Gross, R. S.; Kawada, K.; Kim, M.; Watt, D. S. Synth. Commun.
1989, 19, 1127. (d) Tanyeli, C.; Sezen, B.; Iyigun, C.; Elmali, O.
Tetrahedron Lett. 2001, 42, 6397.
(8) (a) Corey, E. J.; Kang, M. C. J. Am. Chem. Soc. 1984, 106, 5384.
(b) Ernst, A. B.; Fristad, W. E. Tetrahedron Lett. 1985, 26, 3761. (c) Yang,
D.; Ye, X.-Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 121, 5579
.
10.1021/ol900590t CCC: $40.75
Published on Web 05/05/2009
 2009 American Chemical Society

bioactive natural products. For example, we have developed
synthetic approaches to polyprenylated acylphloroglucinol
natural products9 via alkylative dearomatization/annulation
of phloroglucinol (1,3,5-trihydroxybenzene) derivatives.
Along these lines, we have reported the synthesis of (()-
clusianone (1)10 employing a Michael addition/elimination/
Michael addition cascade for rapid assembly of the
bicyclo[3.3.1]nonane core.11 In studies aimed at developing
a related approach to the regioisomeric natural product
nemorosone (2),12 tetraene precursor 3 was prepared via
alkylative dearomatization of 4 with allylic bromide 5
(Scheme 1).13 With the aim of effecting the desired C3-C8
Scheme 3
Scheme 1
A proposed mechanism rationalizing the formation of 6
is outlined in Scheme 3. Formation of Mn(III) enolate 7 is
likely a facile and reversible process as 3 already exists in
the enol form.15 Next, an overall [4 + 2] cycloaddition may
occur leading to bicyclo[2.2.2]octadione 8 and a radical at
C5. A cascade of two 5-exo radical cyclizations of interme-
diate 8 via the sequence outlined in Scheme 3 then results
in cyclopentanemethyl radical 9 which reacts with Cu(II) to
give a Cu(III) intermediate 10.16 Finally, loss of AcOH and
Cu(OAc) affords polycycle 6. The most intriguing aspect of
this cascade cyclization is the initial [4 + 2]-cycloaddition
event which may be envisioned to occur in a concerted
manner (path A) or a stepwise cascade radical cyclization
(path B). The latter would proceed via an 8-endo cyclization
to intermediate 11. Early studies by Snider have shown a
similar preference for 8-endo cyclization in acyclic acetoac-
etate systems.1e,17 While oxidative conditions have been used
to promote formal [4 + 2] cycloadditions,18 to our knowledge
this is the first example of a Mn(III)/Cu(II)-mediated [4 +
bond formation (nemorosone numbering) via an oxidative
generation of a radical at C3 and subsequent cyclization onto
the tetrasubstituted olefin,14 we examined the reactivity of 3
in the presence of metal oxidants. It was serendipitously
found that treatment of 3 with Mn(OAc)3 (2.1 equiv) and
Cu(OAc)2 (1.0 equiv) in AcOH at rt led to formation of the
bridged pentacyclic compound 6 in 76% yield as a single
isolable product (Scheme 2). The structure of 6 was
unambiguously confirmed by X-ray crystallography.13
Scheme 2
(9) Ciochina, R.; Grossman, R. B. Chem. ReV. 2006, 106, 3963
(10) Mccandlish, L. E.; Hanson, J. C.; Stout, G. H. Acta Crystallogr.
1976, B32, 1793
(11) Qi, J.; Porco, J. A., Jr J. Am. Chem. Soc. 2007, 129, 12682
(12) Cuesta-Rubio, O.; Velez-Castro, H.; Frontana-Uribe, B. A.; Carde-
nas, J. Phytochemistry 2001, 57, 279
(13) See the Supporting Information for complete experimental details
.
.
.
.
.
(14) For previous use of Mn(III)-based oxidative cyclization toward
phloroglucinol natural products, see: Kraus, G. A.; Dneprovskaia, E.;
Nguyen, T. H.; Jeon, I. Tetrahedron 2003, 59, 8975
.
(15) In the 1H NMR spectra of dearomatized benzoylphloroglucinol
derivatives such as 3, the enolic hydrogen appears in the far downfield region
(16-18 ppm) suggesting complete enolization. The compound exists as a
mixture of two enol tautomers. See ref 1a,d for a discussion on the
mechanistic details of Mn(III)-based oxidations of 1,3-dicarbonyl com-
pounds
(16) Kochi; J. K. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York,
1973; Vol. 1, Chapter 11. (b) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351
(17) Snider, B. B.; Merrit, J. E. Tetrahedron 1991, 47, 8663
.
.
.
(18) (a) Yueh, W.; Bauld, N. L. J. Phys. Org. Chem. 1996, 9, 529. (b)
Gao, D.; Bauld, N. L. J. Org. Chem. 2000, 65, 6276. (c) Zhou, Y.; Jia, X.;
Li, R.; Liu, Z.; Liu, Z.; Wu, L. Tetrahedron Lett. 2005, 45, 8937.
2286
Org. Lett., Vol. 11, No. 11, 2009

2] cycloaddition process. Moreover, the central bicyclo[2.2.2]-
octanone core is present in numerous bioactive natural
products.19 These considerations prompted further studies
on this transformation.
To examine the unique cycloaddition event without
interference from subsequent tandem radical cyclization, we
prepared precursor 12 bearing n-propyl groups on the
phloroglucinol core (Table 1). Treatment of 12 under
identical reaction conditions (Mn(OAc)3 (2.1 equiv),
Cu(OAc)2 (1 equiv), AcOH, rt) led to formation of the
bridged tricyclic enone 13 in 66% yield as a 5:1 mixture of
Z and E isomers (Table 1, entry 1). Employment of 1 equiv
also tested. Use of Ce(NH4)2(NO3)6 in CH3CN resulted in a
complex mixture of products,20 whereas PhI(OAc)2 as an
oxidant resulted in no reaction (entries 8 and 9).
Next, we examined the scope of the oxidative [4 + 2]
cycloaddition on a series of phloroglucinol substrates (Table
2). Oxidation of 2,2-disubstituted alkene substrate 14 (entry
Table 2. Scope of the Mn(III)-Mediated Cycloadditiona
Table 1. Conditions for Oxidative Cycloaddition of 12
entry
1
oxidant (equiv)a
solvent
AcOH
time (h)
4
% yield
66b
Mn(OAc)3 (2.1)
Cu(OAc)2 (1.0)
Mn(OAc)3 (1.0)
Cu(OAc)2 (1.0)
Mn(OAc)3 (2.1)
Cu(OAc)2 (1.0)
Mn(OAc)3 (0.1)
Mn(OAc)3 (2.1)
Cu(OAc)2 (1.0)
Mn(OAc)3 (2.1)
Cu(OAc)2 (1.0)
Ce(NH4)2(NO3)6 (2.0)
PhI(OAc)2 (1.2)
AcOH
6
31d
2
3
4
5
AcOH
AcOH
AcOH
THF
16
16
16
16
tracec
d
traced
c
6
MeCN
16
c
7
8
9
MeCN
MeCN
3
16
e
NRd
a All reactions were carried out at ambient temperature except where
noted; Mn(OAc)3·2H2O and Cu(OAc)2·H2O were used. b Isolated as a 5:1
mixture of olefin isomers (1H NMR). c Slow decomposition of the starting
material occurred. d Starting material was recovered unreacted. e Reaction
performed at -20 °C and resulted in a complex mixture of products.
of Mn(OAc)3 led to incomplete reaction (entry 2). Omission
of Cu(OAc)2 led to slow decomposition of the starting
material (entry 3), suggesting that Cu(II) may be required
in the terminating oxidative elimination step. It was found
that Cu(II) alone does not promote the cycloaddition (entry
4). Attempts to use a catalytic amount of Mn(OAc)3 in the
absence of Cu(II) provided only trace amounts of product
13 (entry 5). It was also found that the reaction was not
compatible with nonprotic solvents (THF, MeCN) in ac-
cordance with previous observations made by Snider and
co-workers.1e A limited number of other metal oxidants were
a Reaction conditions: Mn(OAc)3·2H2O (2.1 equiv), Cu(OAc)2·H2O (1.0
equiv), AcOH, rt, 4 h. (a) Reaction performed at 65 °C for 15 min. (b)
Reaction performed at 35 °C for 4 h. (c) dr ) 4:1 (major diastereomer
shown).
1) resulted in clean conversion to cycloadduct 15 in 82%
yield (>10: 1 mixture of Z/E isomers). When a terminally
disubstituted olefin 16 was employed (entry 2), the cycload-
(19) (a) Carman, R. M.; Lambert, L. K.; Robinson, W. T.; Van Dongen,
J. M. A. M. Aust. J. Chem. 1986, 39, 1843. (b) Bringmann, G.; Lang, G.;
Gulder, T. A. M.; Tsuruta, H.; Mu¨hlbacher, J.; Maksimenka, K.; Steffens,
S.; Schaumann, K.; Sto¨hr, R.; Wiese, J.; Imhoff, J. F.; Peroviæ-Ottstadt,
S.; Boreiko, O.; Mu¨ller, W. E. G. Tetrahedron 2005, 61, 7252. (c) Chien,
S.-C.; Chang, J.-Y.; Kuo, C.-C.; Hsieh, C.-C.; Yang, N.-S.; Kuo, Y.-H.
Tetrahedron Lett. 2007, 48, 1567.
(20) These products appear to result from multiple cyclization modes
onto the tetrasubstituted olefin (O vs C, 6-endo vs 5-exo).
Org. Lett., Vol. 11, No. 11, 2009
2287

dition pathway was replaced by O-cyclization onto the
proximal tetrasubstituted olefin resulting in diene 17. A
related 5-exo O-cyclization was observed with the tripreny-
lated phloroglucinol derivative 18 affording dihydrofuran 19
in 76% yield (entry 3). It was reasoned that the unique
cycloaddition reactivity observed in substrates 3, 12, and 14
may be facilitated by conformational constraints imposed by
the tetrasubstituted olefin in the tether placing the terminal
alkene close to the reactive enol. To access substrate 20 that
does not contain a constraining element, a protocol for
alkylative dearomatization of phloroglucinol derivative 21
with the freshly prepared triflate of 4-penten-1-ol was
developed (Scheme 4).21 This procedure was used to prepare
three additional nonallylic derivatives (22-24, Table 2).13
reaction was bicyclo[3.3.1]nonane 27 (60%) resulting from
a 6-exo cyclization onto the olefin (entry 5).14 However, by
using a 2,2-disubstituted olefin, the cycloaddition mode of
reactivity was fully restored as substrate 23 afforded
bicyclo[2.2.2]octadione 28 as a single product in 69% yield
(entry 6). Similar reactivity was observed using diprenylated
substrate 24 leading to a cascade reaction to afford pentacycle
29 in 74% yield as a 3: 1 mixture of epimers (entry 7).13
The bicyclo[3.3.0]octane portion of 29 resembles the acylphlo-
roglucinol natural products ialibinones A-D.23
In conclusion, we have examined the reactivity of a
number of dearomatized acylphloroglucinol derivatives under
Mn(III)/Cu(II)-mediated oxidative radical conditions. It is
evident that a number of modes of cyclization are possible
(cycloaddition, O-cyclization, C-cyclization) and that the
reaction outcome is strongly influenced by the substitution
pattern of the olefin and the tether. A novel mode of oxidative
[4 + 2] cycloaddition was observed leading to a rapid
increase of molecular complexity via cascade radical cy-
clizations. Further studies aimed at extending the scope and
utility of this transformation are ongoing and will be reported
in future publications.
Scheme 4
Acknowledgment. Financial support from the NIH
(GM073855), Eisai, Merck, and Wyeth is gratefully ac-
knowledged. We thank Prof. Barry Snider (Brandeis Uni-
versity), Ji Qi, and Qiang Zhang (Boston University) for
helpful discussions and Dr. Emil Lobkovsky (Cornell
University) for X-ray crystallographic analysis.
As expected, precursor 20 reacted much slower at rt
(∼20% yield of 25 after 16 h at rt); however, only mild
heating at 35 °C led to the production of cycloadduct 25 in
72% yield (Table 2, entry 4).22 Reducing the tether length
by one carbon as in 22 resulted in only 23% isolated yield
of cycloaddition product 26. The major product of this
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all compounds. X-ray
crystal structure coordinates and files in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Attempts to use non-allylic bromides led to low reactivity mainly
resulting in alkylation of the phenolic oxygens. The alkyl triflate was
prepared using a modified literature procedure: Bashore, C. G.; Vetelino,
M. G.; Wirtz, M. C.; Brooks, P. R.; Frost, H. N.; McDermott, R. E.;
Whritenour, D. C.; Ragan, J. A.; Rutherford, J. L.; Makowski, T. W.;
Brenek, S. J.; Coe, J. W. Org. Lett. 2006, 8, 5947.
OL900590T
(22) Enones 25, 26, and 28 were isolated as a single (Z) isomer (1H
NMR).
(23) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J.
Nat. Prod. 2000, 63, 104.
2288
Org. Lett., Vol. 11, No. 11, 2009