Practical synthesis of p- and o-amino- and methoxyphenolic anthraquinones

Article abstract of DOI:10.1002/anie.201507007

New versatile and selective methods for the syntheses of substituted amino- and methoxyphenolic anthraquinones (I-IV) based on fusion of cyanophthalides (V) and semiquinone aminals (VI, VII) under basic conditions are described. Fusion: 3-Cyanophthalides (V) react with substituted amino semiquinone aminals (VI, VII) under basic conditions to provide selectively a diverse array of substituted amino- and methoxyphenolic anthraquinones (I-IV).

Full text of DOI:10.1002/anie.201507007

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507007
German Edition: DOI: 10.1002/ange.201507007
Anthraquinones
Practical Synthesis of p- and o-Amino- and Methoxyphenolic
Anthraquinones
K. C. Nicolaou,* Min Lu, Pengxi Chen, and Akshay A. Shah
Abstract: New versatile and selective methods for the syntheses
of substituted amino- and methoxyphenolic anthraquinones
(I–IV) based on fusion of cyanophthalides (V) and semi-
quinone aminals (VI, VII) under basic conditions are
described.
A
mino- and methoxy-anthraquinones and related systems
are common structural motifs of natural and designed
molecules of biological, medical and industrial importance.
Examples of such compounds abound and include the
biologically active enediynes[1,2] (e.g. uncialamycin, Fig-
ure 1a),[3–6] tetracycline antibiotics[7] (e.g. viridicatumtox-
in B),[8–10] and trioxacarcins[11–14] (e.g. DC-45-A2) classes of
natural products as well as the brightly colorful compounds
alizarin and carminic acid (crimson, cochineal). The former
and their analogues are of particular interest as potential
ligands, lead compounds and drug candidates while the latter
are classic red dyes. And yet methods for their synthesis lack
practicality and generality. Here we report practical, versatile
and selective methods for the construction of p- and o-
aminophenolic anthraquinones (I and II, Figure 1a) and o-
and p-methoxyphenolic anthraquinones (III and IV, Fig-
ure 1a). Involving fusion of 3-cyanophthalides (e.g. V,
Figure 2) with p- and o-alkoxy semiquinone aminals (VI
and VII, Figure 2) under basic conditions, these methods are
currently enabling synthetic efforts toward uncialamycin and
its analogs[15] and other biologically active molecules and are
expected to find further applications as useful technologies in
chemical synthesis, chemical biology, medicinal chemistry,
and dye development.
The problematic nature of the existing methods for the
construction of p-substituted aminophenolic anthraquinones
is documented by the isolated examples[4,16] and limited
success with complex substrates (see Figure 1b).[17,18] In the
latter cases directed toward the total synthesis of dynemycin,
Myers[17] and Danishefsky[18] reported formation of undesired
products C[17] and D[17,18] instead of the desired amino
anthraquinone advanced intermediates (E and thence F,
Figure 1b) through a Hauser–Kraus type[19–21] reaction from
the corresponding cyanophthalide (A) and iminoquinones
(B) (Figure 1b).
Figure 1. Amino- and methoxyphenolic anthraquinones and related
systems. a) Uncialamycin and targeted amino- and methoxy-anthra-
quinone structures (I–IV); b) unsuccessful attempts to construct p-
substituted aminophenolic anthraquinones. Abbreviations: Pg=pro-
tective group; LDA=lithium diisopropylamide; LiHMDS=lithium
bis(trimethylsilyl)amide.
[*] Prof. Dr. K. C. Nicolaou, Dr. M. Lu, P. Chen, Dr. A. A. Shah
Department of Chemistry, BioScience Research Collaborative
Rice University
Figure 2 depicts the mechanistic rationale for the pro-
posed expanded annulation reaction to form p- and o-
substituted amino- (I and II, Figure 2, pathways a and c,
respectively) and methoxyphenolic anthraquinones (III and
IV, Figure 2, pathways d and b, respectively) from the
corresponding cyanophthalides (V, Figure 2) and p- and o-
6100 Main Street, Houston, TX 77005 (USA)
E-mail: kcn@rice.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507007.
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Figure 2. Mechanistic rationale for selective formation of anthraqui-
nones I–IV.
alkoxy semiquinone aminals (VI and VII, Figure 2). In order
to develop this strategy, we undertook studies to determine
the feasibility of the expected carbon–carbon bond forming
and breaking reactions and explored the optimization of the
required base, conditions, and substrates. Upon extensive
experimentation with substrates 1 and 6 (Figure 3) (see
Supporting Information (SI) for details), it was found that
pathway a [V+ VI!I, Figure 2] could be achieved smoothly
by the use of LiHMDS in THF (or DME) at À78!258C to
afford p-aminophenolic anthraquinone 10 as demonstrated in
Figure 3 (e.g. 1 + 6!10, 88% yield). This process is presumed
to proceed through intermediate G (Figure 2), which prefer-
entially collapses via departure of the methoxy group rather
than the amino group to afford the observed product.
Exploration of the generality and scope of the reaction
using a variety of cyanophthalides V (1–5, Figure 3) and p-
methoxy semiquinone aminals VI (6–9, Figure 3) employing
the above optimized conditions led to a series of novel p-
aminophenolic anthraquinones I (10–17) in good to excellent
yields as shown in Figure 3. Noteworthy is the applicability of
this process to the construction of substituted p-aminophe-
nolic anthraquinones with additional fused rings in their
structures (i.e. compounds 12, 13, and 16, Figure 3).
Figure 3. Selective formation of p-aminophenolic anthraquinones I
(10–17). Abbreviations: Alloc=allyloxycarbonyl; MOM=methoxy-
methyl; Phth=phthalimide. Reactions were carried out on 0.09–
0.2 mmol scale. For preparation of substrates and further details, see
the Supporting Information.
Attempts to implement a similar strategy for the synthesis
of o-aminophenolic anthraquinones II (pathway c, Figure 2)
employing cyanophthalides V and o-methoxy semiquinone
aminals (VII) under the same optimized conditions at À60!
258C (LiHMDS, THF) led to the targeted o-aminophenolic
anthraquinones II (Figure 2) as only the minor products.
Their o-methoxyphenolic counterparts (III, Figure 2) were
the major products in these reactions formed via pathway d
(Figure 2) as demonstrated in Figure 4a with substrates
cyanophthalide 1 and semiquinone 18 (1 + 18!22, 20%
yield; 21, 70% yield). o-Methoxyphenolic anthraquinone 21
is presumably formed through intermediate H (Figure 4a),
Figures 4b and 5, respectively. Thus, employing substrates
1 and 18, and using LiOtBu, instead of LiHMDS, at lower
temperature (i.e. À78!258C) resulted in the formation of the
o-methoxyphenolic anthraquinone 21 (85% yield) as
depicted in Figure 4b. This reaction proved of general
applicability and scope, accommodating cyanophthalides V
(e.g. 1–3) and semiquinone aminals VII (R2 = Me) (e.g. 18 and
24) as substrates, furnishing a variety of o-methoxyphenolic
anthraquinones III (e.g. 21, 25–27) in good yields as summar-
ized in Figure 4b. It should be noted that the more obvious o-
dimethoxy semiquinone 29[21] (Figure 4c) is a fleeting inter-
mediate, undergoing rapid and quantitative self [4+2]-cyclo-
addition to form dimer 30 upon generation from o-methoxy-
phenol (28) at 08C through the action of PhI(OAc)2, and
therefore, cannot be conveniently used as a precursor to this
type of anthraquinones.
whose formation from 18 and collapse to 21 (expulsion of
À
= =
MeN C O and CN ) are shown in Figure 4a. Unexpected
and not ideal, this observation prompted us to optimize the
process further in order to deliver either product (i.e. 21 or 22)
in high yield. Our results from this study are summarized in
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would inevitably lead to the
desired o-aminophenolic anthra-
quinone 22 (as indicated by the
arrows) instead of its methoxy
counterpart (21, see Figure 4a).
Indeed, trifluoroethoxy substrate
19 (Figure 4a, see SI for prepa-
ration details) suffered attack
from the anion generated from
cyanophthalide
1
(LiHMDS,
THF, À60!258C) to afford,
cleanly and exclusively, the tar-
geted anthraquinone 22 (62%
yield), presumably through tran-
sient intermediate I as shown in
Figure 4a.
Figure 5
shows
a number of examples of this
reaction (V+ VII!II), leading
to a variety of o-aminophenolic
anthraquinones (22, 32–36),
employing cyanophthalides 1–5
and o-trifluoroethoxy semiqui-
none aminals 19 and 31, demon-
strating its generality and scope.
Placing a methyl group (Me)
at the position adjacent to the p-
methoxy aminal of semiquinone
partners VI diverted its annula-
tion reaction with cyanophtha-
lides V (e.g. 1: R1 = H) from
pathway a to pathway b, leading
to p-methoxyphenolic anthraqui-
nones IV (e.g. 1: R = H, R3 =
Me) through elimination of
AllocNHMe, instead of MeOH
(LiOtBu, THF, À78!258C,
85% yield as the major product
with < 5% of the corresponding
p-aminophenolic
anthraqui-
none) as shown in Figure 2 and
6a. The additional examples of
this reaction, shown in Figure 6a
(38–42), demonstrate its versatil-
ity as a means to construct this
Figure 4. Exploratory studies with o-methoxy semiquinone aminals and synthesis of o-methoxyphenolic
anthraquinones III. a) Selective formation of o-methoxyphenolic- (21), o-aminophenolic (22) anthraqui-
nones, and o-methoxyphenolic tricycle 23; b) examples of o-methoxyphenolic anthraquinones (21, 25–
27); c) preparation and chemical reactivity of o-dimethoxy semiquinone (29) and stability of
o-semiquinone aminals 18–20. Abbreviation: Ts =tosyl. Reactions were carried out on 0.14–0.2 mmol
scale. For preparation of substrates and further details, see the Supporting Information.
type
anthraquinones
of
p-methoxyphenolic
(i.e. IV,
Figure 2). Interestingly, the
selectivity effect of the Me
group on the semiquinone part-
ner was reversed back to the p-
aminophenolic anthraquinone
product upon switching the
In our search for an exclusive pathway to o-amino-
phenolic anthraquinones (II, Figure 2), we reasoned that
switching the methoxy (OMe) within the semiquinone aminal
substrate 18 (Figure 4a) to a better leaving group, such as the
trifluoroethoxy (OCH2CF3), may override the reactivity of
the Alloc group, thus avoiding the formation of species H in
favor of intermediate I (see Figure 4a), an occurrence that
methoxy to the trifluoroethoxy group as shown in Figure 6b
(1 + 43!44, 83% yield). This option provides an avenue for
the preparation of p-aminophenolic anthraquinones with
substitution patterns beyond those shown in Figure 3.
Replacement of the Alloc group on the nitrogen of the
o-semiquinone aminal 18 (Figure 4a) with a tosylate (p-
MeC6H4SO2) group (i.e. o-amino semiquinone 20) resulted in
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Figure 5. Selective formation of o-aminophenolic anthraquinones II
(22, 32–36). Reactions were carried out on 0.023–0.2 mmol scale. For
preparation of substrates and further details, see the Supporting
Information.
Figure 6. Selective formation of trisubstituted p-methoxyphenolic IV
and p-aminophenolic anthraquinones I. a) Methyl-substituted p-meth-
oxyphenolic anthraquinones (38–42); b) methyl-substituted p-amino-
phenolic anthraquinone (44). Reactions were carried out on 0.08–
0.2 mmol scale. For preparation of substrates and further details, see
the Supporting Information.
the formation of o-methoxyphenolic tricycle 23 (1 + 20!23,
LiHMDS, À78!258C), presumably formed through inter-
mediated J, as the major product (75% yield), together with
o-methoxyphenolic anthraquinone 21 as a minor product
(6% yield, Figure 4a). This finding opens up yet another
productive pathway toward novel molecular diversity rele-
vant to biology and medicine. It should be noted that the
chemical stabilities of o-semiquinone aminals 18–20 (Fig-
ure 4a) are considerably higher than that of the fleeting o-
dimethoxy semiquinone (29),[22] as summarized in Figure 4c,
making the former substrates practical building blocks for
chemical synthesis purposes.
The versatility of the developed synthetic technologies
was further demonstrated by the preparation and use of p-
methoxyiodo semiquinone aminal 45 as a partner in the
described annulation reaction with cyanophthalide 1 to gen-
erate iodo-substituted p-aminophenolic anthraquinone 46
and derivatives thereof as shown in Figure 7. Thus, reaction
of 1 with 45 under the optimized conditions (LiHMDS,
À788C!258C) furnished 46 in 81% yield). The latter was
successfully employed as a substrate in an array of metal-
catalyzed coupling reactions to afford a variety of substituted
aminoanthraquinones, including the phenyl- [47: PhB(OH)2,
Pd(dppf)Cl2 cat., K3PO4, 77% yield], methyl- [48: MeB-
(OH)2, Ag2O, K3PO4, Pd(PPh3)4 cat., 63% yield], acetylenic-
ꢀ
[49: PdCl2(PPh3)2 cat., CuI cat., TMSC CH, 66% yield], and
carbomethoxy- [50: PdCl2(PPh3)2 cat., (ethoxyvinyl)tributyl-
tin; then 1.0m aq. HCl, 61% yield] substituted derivatives
shown in Figure 7.
In conclusion, we have developed versatile and selective
methods for the practical synthesis of p-amino- and p-
methoxyphenolic anthraquinones and o-amino- and o-
methoxyphenolic anthraquinones from simple and readily
available 3-cyanophthalides and p-methoxy- and o-trifluoro-
methoxy semiquinone aminals. The described chemistry is
expected to find applications in the synthesis of natural and
designed molecules relevant to biology and medicine as well
as dye and imaging technologies.
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Acknowledgements
We thank Drs. L. B. Alemany (Rice) and Q. Kleerekoper
(Rice) for NMR spectroscopic assistance, Dr. C. Pennington
(Rice), Dr. I. Riddington (UT Austin) and J. Dinser (UT
Austin) for mass spectrometric assistance. This work was
supported by Bristol-Myers Squibb, The Cancer Prevention &
Research Institute of Texas (CPRIT) and The Welch Foun-
dation.
Keywords: 3-cyanophthalides · semiquinone aminals ·
substituted anthraquinones
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12687–12691
Angew. Chem. 2015, 127, 12878–12882
Received: July 28, 2015
Published online: August 31, 2015
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