DMAP promoted tandem addition reactions forming substituted tetrahydroxanthones

Article abstract of DOI:10.1021/ol5002945

Substituted tetrahydroxanthones are constructed using a DMAP-promoted tandem nucleophilic addition process. The reaction yields range from 39% to 73%. Disubstituted tetrahydroxanthones are generated as a -2.3:1 mixture of diastereomers favoring the format

Full text of DOI:10.1021/ol5002945

Letter
pubs.acs.org/OrgLett
DMAP Promoted Tandem Addition Reactions Forming Substituted
Tetrahydroxanthones
Emmanuel B. Castillo-Contreras and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver, B.C., Canada, V6T 1Z1
S
* Supporting Information
ABSTRACT: Substituted tetrahydroxanthones are con-
structed using a DMAP-promoted tandem nucleophilic
addition process. The reaction yields range from 39% to
73%. Disubstituted tetrahydroxanthones are generated as a
∼2.3:1 mixture of diastereomers favoring the formation of the
trans-isomer.
he set of secondary metabolites formed through the type
2 polyketide biosynthetic pathway that produce xanthones
T
(9H-xanthene-9-one) is remarkable for their structural
complexity and biological potency.1 The synthesis of natural
products within this biosynthetic class has largely been limited
to those having substituted, yet fully aromatized, xanthone
units. Consequently, much synthetic effort has been expended
in the investigation of the synthesis of the aromatic xanthone
subunit.2 A fascinating subset of these xanthone polyketide
natural products feature substituted tetrahydroxanthone
(THX) subunits (Figure 1).3 Synthetic methods that generate
madurae in 1989−90,7 has been demonstrated to possess
significantly greater biological activity against two malaria
strains (IC50 0.045 ng/mL vs K1 strain; 0.0097 ng/mL vs FCR3
strain) compared to standard treatments such as artemisinin
and chloroquine. In addition, 1 has been recently shown to
arrest the cell cycle at the G1 phase with suppression of
retinoblastoma protein phosphorylation.8 It has a biological
profile suggesting that 1 may be an effective compound against
a variety of solid tumors that exhibit multidrug resistance.
In initiating a new program of scientific inquiry guided by the
medicinal potential of these tetrahydroxanthone natural
products, we were compelled to examine synthetic routes that
would enable the synthesis of the THX core of 1 and its
structural relatives. It should be noted that Ready and his
collaborators have completed an elegant total synthesis of ent-
1.9 Our synthetic work not only should assist in an approach to
the construction of 1 but also, and more importantly, should
enable access to structurally simplified analogs that might
maintain biological potency.
We were inspired by recent disclosures describing a
chromenone synthesis that incorporated a metal-catalyzed
oxymetalation of an alkynone.10 Thus, we postulated that a
suitably functionalized substrate in the presence of an
appropriate transition metal catalyst would undergo the
mechanistic equivalent of an oxametalation across a C−C
triple bond of an alkynone (Scheme 1). It was then conceived
that the organometallic intermediate thus generated would add
to an appropriate electrophile to produce the functionalized
THX fragment. An advantage to this route is that, in the event
the metal-catalyzed route failed, the desired transformation
Figure 1. Polyketide containing THX fragments.
substituted THX fragments are rare compared to the methods
developed to produce substituted xanthones.4 As a result, the
synthetic efforts required for the construction of THX
containing natural products such as kibdelone C or Sch
56036 become even more noteworthy and elegant.5,6
The synthetic work in this manuscript was inspired by the
structure and activities of simaomicin α (1) (Figure 1). This
secondary metabolite, isolated from the fungus Actinomadura
Received: January 27, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Approach to 1
Table 1. Experimental Attempts To Convert 3a to THXs 4a
a
c
d
entry
base/promoter
% conv
ratio 4a:5a
1
2
3
4
5
K2CO3 (1.2 equiv)
Cs2CO3 (1.1 equiv)
NaH (1.2 equiv)
KH (2.5 equiv)
144
24
NR
trace
dec
dec
dec
NR
−
−
−
−
0.5
0.3
0.5
b
LDA (1.05 equiv)
6
DBU (40 mol %)
DBU (100 mol %)
C5H5N (30 mol %)
2
47
48
55
15
14
95
49
70
47
50
35
76
98
1.4:1
2.4:1
1:1
7
2
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
9
2,6-lutidine (30 mol %)
NEt3 (30 mol %)
2.4:1
1.9:1
7.9:1
1:1
10
11
12
13
14
15
16
17
18
DMAP (30 mol %)
PPh3 (30 mol %)
PCy3 (30 mol %)
1:1
could in principle be coerced to occur through other
mechanistic manifolds including a base-promoted anionic
transformation or a nucleophile-promoted Baylis−Hilman-
type process followed by condensation.
P(i-C3H7)3 (30 mol %)
P(4-C6H4OCH3)3 (30 mol %)
P(NEt2)3 (30 mol %)
DABCO (30 mol %)
quinuclidine (30 mol %)
1.8:1
2.9:1
4.6:1
3.6:1
3.3:1
Ynone substrates such as 2a were synthesized using standard
synthetic methods that are described in detail in the Supporting
Information; the most interesting transformation within the
sequence is a duo of Moffatt−Swern oxidations on two
hydroxyl functions in one step that generates both an alkynone
and an aldehyde function in 70% yield (eq 1).11
a
Reaction T = 22 °C. Entries 6−18: NMR experiments using 1,4-
b
dimethoxybenzene as an internal standard. Reaction solvent: THF.
c
Conversion established by integration of signal of 3a and internal
d
standard in NMR spectrum of crude reaction extract. Ratio
established by integration of signals of 4a and 5a in crude reaction
extract.
4a was believed to be observed to be present as an equimolar
component in a relatively low conversion process (entries 6 and
7). The use of amine bases such as pyridine, 2.6-lutidine, and
triethylamine gave unsatisfactory results for either the
conversion or product ratio (entries 8−10). The breakthrough
came with the use of catalytic DMAP (30 mol %) as the
promoter (entry 11). This reaction featured excellent
conversion of starting material (95%) and generated a
remarkable product ratio favoring tricycles 4a to bicycle 5a in
an ∼8:1 ratio. Other prospects were scouted, including
phosphines (entries 12−16) and potential nucleophilic catalysts
such as DABCO (entry 17) and quinuclidine (entry 18). The
results of phosphine catalysis were largely unremarkable,
featuring roughly ∼50% conversions and poor ratios.
Triethylphosphine and tributylphosphine gave similar results
to tri(isopropyl)phosphine. Both DABCO and especially
quinuclidine catalysis featured rapid conversion of 3a, but the
product ratios were poor compared to the DMAP result in
entry 11.
Subjecting 2a to Ph3PAuCl (10 mol %) and AgSbF6 (23 mol
%) in acetonitrile at 23 °C produced only the phenol 3a in 70%
yield, a process that is more effectively carried out using p-
TsOH·H2O in CH2Cl2 (94%) (eq 1). Unfortunately, the
treatment of 2a to a variety of catalysis systems involving
Au(I)/Ag(I), Ag(I), Au(III)/Ag(I), Pd(II), Ni(0), Ni(II), or
Cu(I) species resulted in either no reaction or the generation of
3a followed by decomposition.
Attention was turned to the use of inorganic bases with 3a in
order to promote a conjugate addition−aldol reaction process
(Table 1).12 Inorganic Bronsted bases were disastrous,
providing either no reaction or a rapid decomposition (entries
1−5). Reactions of 3a with organic bases and nucleophilic
As the reaction shown in Table 1 indicates, THXs 4a are
formed as a diastereomeric mixture of trans- and cis-isomers.
The NMR chemical shift and coupling data suggested that the
major diastereomer was trans-configured, but the spectroscopic
data could not be unequivocally interpreted. Indeed, early on in
our studies, due to the well-documented cyclizations of
substituted phenols to aurones and benzofurans,13 even the
1
catalysts were surveyed by H NMR analysis of the conversion
of 3a to 4a (THX, mixture of diastereomers) and 5a
(chromenone). A reaction promoter that could maximize, at
room temperature for 30 min, both the conversion of 3a and
the formation of THX’s 4a was sought. Thankfully, the reaction
of 3a with DBU gave a first indication of a tandem reaction, as
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Letter
gross constitution of the diastereomeric set 4a was not
incontestably determined.
The NMR studies in Table 1 established the use of 30 mol %
of DMAP at rt as an empirically superior promotion system.
Milligram quantities of phenols 3a−c were subjected to this
process (eq 2). The NMR conversions of 3a−c to products
Similar comparative results to the reactions of 3a and 3b
were observed using substrates 7a and 7b that lack a benzyloxy
substituent (eq 3). The substituted p-bromophenol 7a cyclized
to form tricycle 8a as the major product in mediocre isolated
yield. The reaction of the (presumably) more electron-rich
phenol 7b was more effective in forming 8b. Isolation and
purification of the reaction products is clearly compromised by
the presence of the halogen substituent.
Although we have not found a direct literature precedent for
the conjugate addition activation of Michael acceptors with
DMAP, the results suggest that a conjugate addition process
between DMAP and the ynone function may be the activating
step in the mechanism of the reaction. Whether this conjugate
addition process initiates a Baylis−Hilman-type aldol reaction
or a phenoloxy-6-endo cyclization process is not clear. Our
attempts to catalyze Baylis−Hilman reactions on ynones that
were unable to undergo oxy-Michael additions using DMAP
lead to uncharacterizable decomposition products.
A tandem addition C−O, C−C bond-forming process
yielding diastereomeric substituted tetrahydroxanthones using
catalytic amounts of DMAP has been presented. Both cis- and
trans-configured THX patterns are observed in reduced
xanthone natural products. This procedure allows for the
formation of stereoisomeric analog structures. Future work will
focus on the development of structurally truncated THX
analogs having the appropriate three-dimensional structural
space for biological studies. This work will be reported in due
course.
4a−c and 5a−c appeared to be excellent for 3a and 3c (94%,
99%) and adequate for 3b (63%). Lowering the amounts of
DMAP to 10 mol % or the reaction temperature simply
lengthened the reaction time with no further advantage.
Unfortunately, isolation, diastereomer separation, and charac-
terization of these product mixtures were complicated by
solubility and chromatography problems. Therefore, the
product mixtures of 4a−c and 5a−c were treated with 3,5-
dinitrobenzoyl chloride and triethylamine to form aryl esters of
4a−c. Diastereomer separation was possible at this stage, but
clear product losses occurred during this sequence. Fortunately,
the 3,5-dinitrobenzoate derivatives of the major THX
diastereomers, 6b-t and 6c-t, were amenable to characterization
using X-ray crystallography. The solid state molecular structure
of 6b-t is provided in Figure 2. These solid state molecular
structures of 6b-t and 6c-t confirm the trans-configuration in
the major diastereomers 6a−c-t.14
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for
previously unreported compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gdake@chem.ubc.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank S. Serin (U.B.C.) for the solution of solid
state molecular structures in this manuscript. E.C. thanks
CONACYT of Mexico for a doctoral fellowship (172270). The
authors thank the University of British Columbia, the Natural
Science and Engineering Research Council (NSERC) of
Canada, and the Canada Foundation for Innovation (CFI)
for the financial support of our programs.
Figure 2. Solid state molecular structure of THX 6b-t.
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Letter
(11) Steps in the sequence include nucleophilic ethynylation,
protection (silyl ether), addition to 4-silyloxybutanal, protection
(benzyl ether), desilylation, and oxidation.
(12) Porco has used a halide ion initiated addition to an alkyne to
form a THX ring F synthetic equivalent: see ref 5e.
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