Synthesis of (±)-Idarubicinone via Global Functionalization of Tetracene

Article abstract of DOI:10.1021/jacs.9b05370

Anthracyclines are archetypal representatives of the tetracyclic type II polyketide natural products that are widely used in cancer chemotherapy. Although the synthesis of this class of compounds has been a subject of several investigations, all known approaches are based on annulations, relying on the union of properly prefunctionalized building blocks. Herein, we describe a conceptually different approach using a polynuclear arene as a starting template, ideally requiring only functional decorations to reach the desired target molecule. Specifically, tetracene was converted to (±)-idarubicinone, the aglycone of the FDA approved anthracycline idarubicin, through the judicious orchestration of Co- and Ru-catalyzed arene oxidation and arenophile-mediated dearomative hydroboration. Such a global functionalization strategy, the combination of site-selective arene and dearomative functionalization, provided the key anthracycline framework in five operations and enabled rapid and controlled access to (±)-idarubicinone.

Full text of DOI:10.1021/jacs.9b05370

Subscriber access provided by ALBRIGHT COLLEGE
Communication
Synthesis of (±)-Idarubicinone via Global Functionalization of Tetracene
David G. Dennis, Mikiko Okumura, and David Sarlah
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05370 • Publication Date (Web): 17 Jun 2019
Downloaded from http://pubs.acs.org on June 17, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Synthesis of (±)-Idarubicinone via Global Functionalization of
Tetracene
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
David G. Dennis, Mikiko Okumura, and David Sarlah*
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA
Supporting Information Placeholder
The need for tailored analogs has made anthracyclines the
ABSTRACT: Anthracyclines are archetypal representatives of
subject of rigorous investigation within the synthetic
the tetracyclic type II polyketide natural products that are widely
community.10 Thus, many innovative pathways to the aglycon
used in cancer chemotherapy. Although the synthesis of this class
anthracyclines (anthracyclinones) have been established, all of
which rely upon annulation to forge one of the rings (see Figure
2a). The most commonly employed unifying disconnection is C-
ring annulation, achieved through cycloadditions, cationic
cyclizations, or anionic processes (Figure 2a, left inset).11
Moreover, cycloadditions were also explored to forge other rings
of the tetracyclic core of these molecules (Figure 2a, right
of compounds has been a subject to several investigations, all
known approaches are based on annulations, relying on the union
of properly pre-functionalized building blocks. Herein, we
describe a conceptually different approach using a polynuclear
arene as a starting template, ideally requiring only functional
decorations to reach the desired target molecule. Specifically,
tetracene was converted to (±)-idarubicinone, the aglycone of the
FDA approved anthracycline idarubicin, through the judicious
orchestration of Co- and Ru-catalyzed arene oxidation and
arenophile-mediated dearomative hydroboration. Such a global
functionalization strategy, the combination of site-selective arene
and dearomative functionalization, provided the key anthracycline
framework in five operations and enabled rapid and controlled
access to (±)-idarubicinone.
The Streptomyces-produced type II polyketides doxorubicin
(1)1 and daunorubicin (2)2 are among the most effective and most
often used chemotherapeutics owing to their broad-spectrum of
anticancer activity (Figure 1).3 For example, doxorubicin (1) is
used for the treatment of breast and bladder cancers, childhood
solid tumors, soft tissue sarcomas, and aggressive lymphomas.4
Similarly, daunorubicin (2) is primarily used as an antileukemic
drug for multiple myeloma, acute myeloid leukemia, acute
lymphocytic leukemia, and Kaposi's sarcoma.5 Although
extremely effective, anthracyclines threaten patients with
cumulative dose-dependent cardiotoxicity, severely limiting their
long-term application as well as their use in patients with pre-
existing cardiovascular risk.6 Therefore, significant research
efforts have been devoted to the identification of derivatives with
improved pharmacological properties.7 The successful result of
one such medicinal chemistry campaign is idarubicin (3),8 an
FDA approved anticancer agent with superior therapeutic efficacy
and reduced cardiotoxicity relative to daunorubicin (2). 9
Figure 2. (a) Selected annulation-based strategies to
anthracyclinones. (b) This work: synthesis of (±)-idarubicinone
(4) from tetracene (5) using a non-annulative approach.
Figure 1. Structures of doxorubicin (1), idarubicin (2), and
daunorubicin (3).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
insets).12 Herein, we report a conceptually different, non-
the cationic rhodium complex [Rh(cod)2BF4] with 1,4-
bis(diphenylphosphino)butane (dppb) and catecholborane
provided the best outcome (for optimization details see Table S1
in Supplementary Information).20 Although catecholborane was
essential for the hydroboration step, the inherent instability of the
resulting alkyl catechol boronic ester required immediate
transesterification of catechol to pinacol to enable product
isolation in higher yields.21 Importantly, following this protocol,
we were able to prepare multigram quantities of boronic ester 10
in a single pass in 55% yield and an endo/exo 3:1 dr (see Figure 3,
bottom inset for an X-ray diffraction structure of 10).
1
2
3
4
5
6
7
8
annulative approach to anthracyclinones, starting from a simple
aromatic hydrocarbon via a global functionalization strategy
(Figure 2b). Specifically, (±)-idarubicinone (4) was synthesized
from tetracene (5), an ideal aromatic precursor containing the
essential tetracyclic framework, through a manifold of arene
functionalizations and a site-selective dearomative elaboration.
Following this global functionalization strategy, we
commenced our studies by exploring functionalization reactions
of tetracene (5), which would establish the proper oxidation states
of the internal rings B and C within idarubicinone (4) (Figure 3).
Thus, inspired by a similar transformation reported on anthracene,
we achieved the first oxidation of 5 with catalytic amounts of
9
Elaboration of organoborate 10 to the full skeleton of
idarubicinone required installation of a two-carbon fragment
through a seemingly straightforward B-alkyl Suzuki coupling
reaction. However, since several standard Pd- and Ni-catalyzed
reaction conditions failed,22 we decided to explore the C–C bond
forming strategies involving the rich chemistry of boron 1,2-
metalate rearrangements. Particularly, we were keen to explore
Zweifel olefination with lithiated ethoxyvinyl ether,23 which
would provide rapid access to the C-9 acetyl group. Nevertheless,
a major pitfall of this design was the presence of the quinone and
its general incompatibility with organolithium reagents. Indeed,
prospecting experiments involving boronic ester 10 and 1-
ethoxyvinyllithium resulted in the addition of organolithium
species to quinone, delivering a mixture of products without any
traces of the desired olefinated product. To address this
chemoselectivity issue, we developed a one-pot process that
involved in situ masking of the quinone. Thus, a THF solution of
boronic ester 10 was sonicated with Zn powder in the presence of
TMSCl, resulting in the formation of a fully protected bis-
hydroquinone.24 This intermediate was exposed to a freshly-
prepared 1-lithioethyl vinyl ether to form the boronate complex I-
2, which was immediately subjected to Zweifel olefination by
addition of iodine and base.25 Concurrently with olefination, the
excess iodine also oxidized the labile silylated hydroquinone back
to the quinone, and workup of the reaction mixture with an
aqueous HCl solution hydrolyzed the newly introduced vinyl
ether to the corresponding methyl ketone 11. Remarkably, this
one-pot operation involved several distinct transformations and
was performed on a multigram scale in 72% yield.26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cobalt(II) tetraphenylporphyrin (CoTPP,
5
mol %) and
phenyliodine(III) sulfate as an oxidant,13 delivering 5,12-
tetracenequinone (6) in 77% yield. Although this transformation
proceeded readily, the second oxidation to the corresponding
6,11-dihydroxy-5,12-tetracenequinone derivative 7 proved more
challenging. Several oxidants known for direct arene oxidation,
such as CAN, Frémy's salt, hypervalent iodine reagents, or
oxidizing metal complexes14 were found to be unsuitable for this
transformation. This setback was not surprising, as this type of
peri-oxidation remains a largely unsolved synthetic challenge
owing to the high oxidation potential of quinones. Therefore, we
decided to evaluate C–H activation, anticipating that the quinone
carbonyl groups, would serve as weakly coordinating directing
groups for the peri-(C-6) and (C-11) positions.15 After examining
several carbonyl-directed hydroxylation protocols, we developed
a one-pot procedure involving a modification of Ru-catalyzed sp2
C–H oxygenation pioneered by Ackermann ([Ru(cymene)Cl2]2
and PIFA),16 followed by sequential one-pot hydrolysis and
methylation to give desired product 7. Control experiments
revealed that this functionalization likely proceeds through the
peri-selective formation of ruthenacycle intermediate I-1,
delivering phenol derivative, which underwent further oxidation
to the hydroquinone stage in the presence of excess PIFA.17
With arene oxidation completed, which set the required
oxidation state of the B and C rings, we turned our attention to the
dearomative functionalization of the terminal ring A. We have
recently reported a series of dearomatization strategies that
employ visible-light-promoted para-cycloaddition between arenes
and the arenophile N-methyl-1,2,4-triazoline-3,5-dione (MTAD,
8) and subsequent in situ manipulation of the resulting
cycloadducts.18 With polynuclear arenes, we consistently
observed highly site-selective cycloadditions onto the terminal
rings. Because tetracenequinone derivative 7 contains two such
regions, rings A and D, amenable to cycloaddition with MTAD,
another level of complexity to this process is introduced.
However, based on previous studies, we know that the relevant
mechanistic feature of this process is a photoinduced charge- and
electron-transfer from the arene to the arenophile;19 therefore, the
HOMO of the arene should dictate the site-selectivity in
polynuclear aromatic settings. Accordingly, computational studies
(at the B3LYP/def2-TZVPPD level of theory) of 7 predicted a
strong bias for the A ring, which has profoundly larger HOMO
orbital coefficients, (see Figure 3, bottom inset for the
corresponding HOMO surface). Indeed, this prediction correlated
well with experiment, as we observed exclusive cycloaddition
onto the A-ring to provide intermediate 9. With this site-selective
dearomatization, we explored several strategies to introduce the
remaining two carbon atoms needed to complete the
idarubicinone framework. We found that the arenophile-based
cycloaddition in combination with in situ Rh-catalyzed alkene
hydroboration (7→[9]→10) installed the boron moiety as a
suitable handle for the introduction of the requisite acetyl group.
Several hydroboration procedures were evaluated, but ultimately
Although the arenophile-mediated dearomative hydroboration
and subsequent Zweifel olefination introduced the desired methyl
ketone, this sequence also installed a bridging urazole moiety,
which had to be strategically transmuted to reveal the fully
decorated A ring of idarubicinone (4). This task was partially
accomplished by treatment of ketone 11 with base followed by
Me2SO4, initiating β–elimination of urazole at position C-10 with
subsequent methylation of the urazole hydrazyl nitrogen,
furnishing α,β–unsaturated ketone 12 in 79% yield. The N-
alkylation of the urazole motif proved necessary to prevent
undesired side reactions during subsequent manipulations (for
details see Table S2 in Supplementary Information). Finally,
subjecting olefin 12 to Mukaiyama hydration conditions27
selectively introduced the tertiary alcohol at position C-9, as α–
ketol product 13 was obtained in 70% yield as a single
diastereoisomer. Notably, the use of recently reported silane,
PhSiH2(Oi-Pr),28 was beneficial for high conversions of this
hydrogen-atom transfer process.
This hydration achieved the proper oxidation state of the A-
ring, and the only difference between intermediate 13 and
idarubicinone (4) at this stage resided in two hydroquinone
protecting groups and the urazole moiety instead of a hydroxy
group at C-7 position. Although deprotection of methyl ethers to
hydroquinone proceeded without any difficulties using BCl3
(13→14, 98% yield), the removal of the urazole proved to be an
arduous task. Eventually, the inspiration for the direct urazole-to-
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Synthesis of (±)-idarubicinone (4) from tetracene (5). Reagents and conditions: 1. CoTPP (5 mol%), (PhIO)3SO3, CH2Cl2, 25 °C,
2 h, 77%; 2. [Ru(p-cymene)Cl2]2 (2.5 mol%), PIFA, DCE, 100 °C, 12 h; then H2O, 100 °C, 12 h; then Me2SO4, K2CO3, (CH3)2CO, 74 °C,
24 h, 42%; 3. MTAD (8), CH2Cl2, –50 °C, 36 h; then [Rh(cod)2]BF4 (10 mol%), dppb (10 mol%), HBcat, THF, –30 °C, 12 h; then
pinacol, –78 to 25 °C , 12 h, 55% (3:1 dr); 4. Zn0, TMSCl, THF, ultrasonication, 40 °C, 30 min; then CH2C(Li)OEt, –78 to –25°C, 30 min;
then I2, –78 to –25 °C, 30 min; then NaOMe, –78 to 25 °C, 4 h; then 1 M HCl, 25 °C, 2 h, 72%; 5. KOt-Bu, THF, –78 °C, 20 min; then
Me2SO4, –78 to 0 °C, 1.5 h, 79%; 6. Mn(dpm)3 (10 mol%), PhSiH2(Oi-Pr), O2, i-PrOH/DCE 1:1, 0 to 25 °C, 2 h, 70%; 7. BCl3, CH2Cl2, –
78 °C, 1 h, 98%; 8. Na2S2O4, H2O/THF/MeOH 1:1:1, –20 °C, 20 min; then NaOH, –20 °C, 60 s; then O2, –20 °C, 5 min, 88%, 4:15 =
1:1.8.
hydroxy exchange was found in the Moore hypothesis for the
biological mode of reactivity known as bioreductive alkylation.29
Thus, it was proposed that anthracyclines undergo in vivo quinone
reduction and subsequent C-7 amino sugar elimination, producing
a reactive species in the form of a phenylogous quinone methide.
Moreover, this concept was demonstrated in solution with several
anthracyclines, which formed the corresponding semiquinone
intermediates upon subjection to specific reducing agents.30 The
direct translation of these findings to our system, for example the
addition of sodium dithionite to precursor 14, did not eliminate
the urazole; however, after the addition of base (NaOH) we
observed elimination and exclusive formation of 7-
deoxyidarubicinone (15) under anaerobic conditions. This result
was in accordance with the literature, since deoxygenated
anthracyclinones were commonly observed upon reduction of
anthracyclines.31 Mechanistically, the reduction of quinone 14 to
hydroquinone, followed by base-induced elimination of the
urazole, likely formed the semiquinone methide I-3, which after
protonation gave deaminated product 15. However, we noticed
that in the presence of oxygen, this reactive intermediate
underwent competitive oxidation,32 delivering idarubicinone (I-
3→4). Accordingly, short exposure of 14 to an aqueous solution
of sodium dithionite and NaOH, followed by rapid saturation of
reaction mixture with oxygen provided (±)-idarubicinone (4) and
(±)-7-deoxyidarubicinone (15) in 88% yield and 1:1.8 ratio.
Although extensive optimization of this protocol did not result in
a higher ratio of desired anthracyclinone 4 to 15 (for details see
Table S3 in Supplementary Information), this deoxygenated side-
product could be readily converted to aglycone 4 in one or two
steps using known protocols.33
In summary, we have described a functionalization-based
approach to (±)-idarubicinone (4) from tetracene (5). The salient
feature of this strategy is a judicious orchestration of two arene
functionalizations and dearomatization, introducing the
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
4. Hortobagyi, G. N. Anthracyclines in the Treatment of Cancer. An
Overview. Drugs 1997, 54 (suppl. 4) 1–7
functionality of the A, B, and C rings of the anthracyclinone
skeleton. Specifically, Co- and Ru-catalyzed arene oxidations,
site-selective arenophile-mediated dearomative hydroboration,
and subsequent Zweifel olefination provided the fully decorated
anthracyclinone framework. Moreover, adjustment of the A ring,
including a formally redox neutral urazole-to-hydroxy exchange
delivered (±)-idarubicinone (4) in 8 operations and 2% overall
yield from tetracene (5).
1
2
3
4
5
6
5. (a) Anthracycline Antibiotics in Cancer Therapy. (Developments in
Oncology, 10). Edited by Muggia, F. M.; Young, C. W.; Carter, S. K.
The Hague: Martinus Nijhoff Publishers; 1982. (b) See also Ref. 5.
6. (a) Cummings, J.; Anderson, L.; Willmott, N.; Smyth, J. F. The
Molecular Pharmacology of Doxorubicin in vivo. Eur. J. Cancer 1991,
27, 532–535. (b) Zucchi, R.; Danesi, R. Cardiac Toxicity of
Antineoplastic Anthracyclines. Curr. Med. Chem.: Anti-Cancer Agents
2003, 3, 151–171.
7
8
9
Importantly, by employing a simple polynuclear hydrocarbon
aromatic starting material, the described work also presents a
notable departure from previously reported syntheses of
anthracyclinones in which annulations were critical to the overall
synthetic design. In fact, polynuclear arenes are not commonly
considered in synthetic planning for construction of
stereochemically complex scaffolds. However, through the
development and application of new methods, the present study
provides a compelling case in which tetracene serves as an ideal
template for imprinting of desired functionality. Thus, the range
of available polynuclear arenes, as well as numerous
functionalization opportunities, can be combined to render this
global functionalization approach an appealing and
complementary entry for the preparation of other type II
polyketide-like compounds.
7. For example, see: Binaschi, M.; Bigioni, M.; Cipollone, A.; Rossi, C.;
Goso, C.; Maggi, C. A.; Capranico, G.; Animati, F. Anthracyclines:
Selected New Developments. Curr. Med. Chem. Anti-Cancer Agents
2001, 1, 113–130.
8. For syntheses of idaroubicinone, see: (a) Di Marco, A.; Casazza, A. M.;
Giuliani, F.; Pratesi, G.; Arcamone, F.; Bernadi, L.; Franchi, G.;
Giradino, P.; Patelli, B.; Penco, S. Synthesis and Antitumor Activity of
4-Demethoxyadriamycin and 4-Demethoxy-4'-epiadriamycin. Cancer
Treat. Rep. 1978, 62, 375−380. (b) Swenton, J. S.; Freskos, J. N.;
Morrow, G. W.; Sercel, A. D. A Convergent Synthesis of (+)-4-
Demethoxydaunomycinone and (+)-Daunomycinone. Tetrahedron
1984, 40, 4625–4632. (c) Gupta, C. R.; Harland, P. A.; Stoodley, R. J.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
An
Efficient
Enantiocontrolled
Synthesis
of
(+)-4-
Demethoxydaunomycinone. Tetrahedron 1984, 40, 4657–4667. (d)
Tanno, N.; Terashima, S. Asymmetric Synthesis of Optically Active
Anthracyclinone Intermediate and 4-Demethoxyanthracyclinones by
the Use of a Novel Chiral Reducing Agent. Chem. Pharm. Bull. 1983,
31, 821–836. (e) Tamura, Y.; Sasho, M.; Akai, S.; Kishimoto, H.;
Sekihachi, J.; Kita, Y. A Highly Convergent Strategy for the Synthesis
ASSOCIATED CONTENT
Supporting Information
of 4-Demethoxydaunomycinone and Daunomycinone:
A Novel
Synthesis of C4-Acetoxylated Homophthalic Anhydrides. Tetrahedron
Lett. 1986, 27, 195–198. (f) Krohn, K.; Rieger, H.; Broser, E.; Schiess,
P.; Chen, S.; Strubin, T. Konvergente Synthese enantiomerenreiner
Daunomycinon-Derivate. Liebigs. Ann. Chem. 1988, 943–948. (g) Carr,
K.; Greener, N. A.; Mullah, K. B.; Somerville, F. M.; Sutherland, J. K.
A Synthesis of ()-Demethoxydaunomycinone. J. Chem. Soc. Perkin
Trans. 1992, 1975–1980. (h) Achmatowicz, O.; Szechner, B. New
Chiral Pool Approach to Anthracyclinones. The Stereoselective
Synthesis of Idarubicinone. J. Org. Chem. 2003, 68, 2398–2404. (i)
Rho, Y. S.; Park, J.; Kim, G.; Kim, H.; Sin, H.; Suh, P. W.; Yoo, D. J.
Facile Total Syntheses of Idarubicinone-7--D-glucuronide:
Convenient Preparations of AB-Ring Synthon Using Some Carboxylic
Acid Derivatives. Synth. Commun. 2004, 34, 1703–1722. (j) Gupta,
R.C.; Jackson, D. A.; Stoodley, R. J. Studies Related to Anthracyclines.
Part 2. Synthesis of ()-4-Demethoxydaunomycinone. J. Chem. Soc.
Perkin Trans. 1985, 525–533. (k) Cambie, R. C.; Larsen, D. S.;
Rickard, C. E. F.; Rutledge, P. S.; Woodgate, P. D. Experiments
Directed Towards the Synthesis of Anthracyclinones. X. A Synthesis of
()-4-Demethoxydaunomycinone. Aust. J. Chem. 1986, 39, 487–502.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental procedures and spectral data for all new
compounds (PDF)
X-ray crystallographic data.
AUTHOR INFORMATION
Corresponding Author
*sarlah@illinois.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support for this work was provided by the University of
Illinois, the NIH/National Institute of General Medical Sciences
(R01 GM122891), and the donors of the American Chemical
Society Petroleum Research Fund (PRF#57175-DNI1). D.S. is an
Alfred P. Sloan Fellow. M.O. thanks the Honjo International
Scholarship Foundation. Solvias AG is acknowledged for a
generous gift of chiral ligands. We thank Prof. S. E. Denmark
(University of Illinois) for critical proofreading of this manuscript.
We also thank Dr. D. Olson and Dr. L. Zhu for NMR
spectroscopic assistance, Dr. D. L. Gray and Dr. T. Woods for X-
ray crystallographic analysis assistance, and F. Sun for mass
spectrometric assistance.
(l) Carr, K.; Sutherland, J. K.;
A
Simple Synthesis of
Demethoxydaunomycinone. J. Chem. Soc., Chem. Commun. 1987,
567–568. (m) Krohn, K.; Tolkiehn, K. Stereoselektive Synthese Des 4-
Desmethoxydaunomycinons. Tetrahedron Lett. 1978, 42, 4023–4026.
(n) Garland, R. B.; Palmer, J. R.; Schulz, J. A.; Sollman, P. B.; Pappo,
R.
A
New Synthetic Route to 4-Demethoxydaunomycinone.
Tetrahedron Lett. 1978, 39, 3669–3672. (o) Kende, A. A.; Curran, D.
P.; Tsay, Y.; Mills, J. E. The Isobenzofuran Route to Anthracyclinones.
Tetrahedron Lett. 1977, 40, 3537–3540. (p) Broadhurst, M. J.; Hassall,
C. H.; Thomas, G. J. Anthracyclines. Part 3. The Total Synthesis of 4-
Demethoxydaunomycin. J. Chem. Soc. Perkin Trans. I 1982, 2249–
2255. (q) Broadhurst, M. J.; Hassall, C. H.; Thomas, G. J. Total
Synthesis of 4-Demethoxydaunomycin. J. Chem. Soc., Chem. Commun.
1982, 158–160. (r) Allen, J. G.; Hentemann, M. F.; Danishefsky, S. J.
A Powerful O-Quinone Dimethide Strategy for Intermolecular Diels–
Alder Cycloadditions J. Am. Chem. Soc. 2000, 122, 571–575. (s)
Kimura, Y.; Suzuki, M.; Matsumoto, T.; Abe, R.; Terashima, S. A
Simple and Efficient Synthesis of Optically Active (+)-4-
Demethoxydaunomycinone. Bull. Chem. Soc. Jpn. 1986, 59, 415–421.
9. (a) Hollingshead, L. M.; Faulds, D. Idarubicin. Drugs 1991, 42, 690.
(b) Cersosimo, R. J. Idarubicin: an Anthracycline Antineoplastic Agent.
Clin. Pharm. 1992, 11, 152–167.
REFERENCES
1. (a) Arcamone, F.; Cassinelli, G.; Fantini, G.; Grein, A.; Orezzi, P.; Pol,
C.; Spalla, C. Adriamycin 14-Hydroxydaunomycin, a New Antitumor
Antibiotic From S. peucetius var. caesius. Biotechnol. Bioeng. 1969,
11,1101–1110.
2. DiMarco, A.; Gaetani, M.; Orezzi, P.; Scarpinato, B.; Silvestrini, R.;
Soldati, M.; Dasdia, T.; Valentini, L. Daunomycin, a New Antibiotic of
the Rhodomycin Group. Nature 1964, 201, 706–707.
3. Arcamone, F. Doxorubicin, Anticancer Antibiotics; Academic Press:ꢀ
New York, 1984. (b) Arcamone, F. Antitumor Anthracyclines: Recent
Developments. Med. Res. Rev. 1984, 4, 153–188.
10. For selected reviews on synthesis of anthracyclines, see: (a) Krohn, K.,
Building Blocks for the Total Synthesis of Anthracyclinones, Prog.
Chem. Org. Nat. Prod. 1989, 55, 37–88. (b) Krohn, K. Synthesis of
Anthracyclinones by Electrophilic and Nucleophilic Addition to
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
Anthraquinones. Tetrahedron 1990, 46, 291–318. (c) Thomas, G. J.
(g) Liu, W.; Ackermann, L. Ortho- and Para-Selective Ruthenium-
Catalyzed C(sp2)–H Oxygenations of Phenol Derivatives. Org. Lett.
2013, 15, 3484–3486. (h) Yang, F.; Rauch, K.; Kettelhoit, K.;
Ackermann, L. Aldehyde-Assisted Ruthenium(II)-Catalyzed C–H
Oxygenations. Angew. Chem., Int. Ed. 2014, 53, 11285–11288.
Synthesis of Anthracyclines Related to Daunomycin. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lukacs, G.; Ohno,
M.; Eds.; Springer-Verlag; 1990, 467–496. (d) Wheeler, D. M. S.;
Wheeler, M. M. Stereoselective Syntheses of Doxorubicin and Related
Compounds. In Studies in Natural Products Chemistry; Rahman, A.
Ed.; Elsevier:ꢀ Amsterdam, 1994; Vol. 14, 3−46. (e) Achmatowicz, O.;
Szechner, B.; Synthesis of Enantiomerically Pure Anthracyclinones.
Top. Curr. Chem. 2007, 282, 143–186.
1
2
3
4
5
6
7
8
9
17. Control experiments confirmed the requirement of a specific Ru-
catalysis for this transformation, as well as excess of PIFA for further
oxidation. See Supplementary Information.
18. For selected examples, see: (a) Southgate, E. H.; Pospech, J.; Fu, J.;
Holycross, D. R.; Sarlah, D. Dearomative Dihydroxylation with
Arenophiles. Nat. Chem. 2016, 8, 922–928. (b) Okumura, M.;
Nakamata Huynh, S. M.; Pospech, J.; Sarlah, D. Arenophile-mediated
Dearomative Reduction. Angew. Chem., Int. Ed. 2016, 55, 15910–
15914. (c) Okumura, M.; Shved, A. S.; Sarlah, D. Palladium-Catalyzed
Dearomative syn-1,4-Carboamination. J. Am. Chem. Soc. 2017, 139,
17787–17790. (d) Hernandez, L. W.; Klöckner, U.; Pospech, J.; Hauss,
11. For selected examples, see: (a) Ref. 8r. (b) Wong, C. M.; Popien, D.;
Schenk, R.; Te Raa, Synthetic Studies of Hydronaphthacenic
Antibiotics. I. The Synthesis of 4-Demethoxy-7-O-methyl
Daunomycinone. J. Can. J. Chem. 1971, 49, 2712–2718. (c) Ishizumi,
K.; Ohashi, N.; Tanno, N. Stereospecific Total Synthesis of 9-
Aminoanthracyclines: (+)-9-Amino-9-deoxydaunomycin and Related
Compounds J. Org. Chem. 1987, 52, 4477–4485. (d) Ref. 8b (e)
Hauser, F. M.; Prasanna, S. Total Syntheses of (±)-Duanomycinone.
Regiospecific Preparations of (±)-7,9-Dideoxydaunomycinone and
6,11-Dihydroxy-4-methoxy-7,8,9,10-tetrahydronaphthacene-5,9,12-
trione. J. Am. Chem. Soc. 1981, 103, 6378–6386.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
L.;
Sarlah,
D.
Nickel-Catalyzed
Dearomative
trans-1,2-
Carboamination. J. Am. Chem. Soc. 2018, 140, 4503–4507. (e) Wertjes,
W. C.; Okumura, M.; Sarlah, D. Palladium-Catalyzed Dearomative syn-
1,4-Carboamination. J. Am. Chem. Soc. 2019, 141, 163−167.
12. For selected examples, see: (a) Kelly, T. R.; Ananthasubramanian, L.;
Borah, K.; Gillard, J. W.; Goerner, R. N.; King, P. F.; Lyding, J. M.;
Tsang, W.-C.; Vaya, J. An Efficient, Regiospecific Synthesis of (±)-
Daunomycinone. Tetrahedron 1984, 40, 4569–4577. (b) Ref. 8s.(c)
Krohn, K.; Tolkiehn, K. Synthetische Anthracyclinone, XIV. Synthese
neuer Derivate des Daunomycinons und des β‐Rhodomycinons. Chem.
Ber. 1980, 113, 2976–2993. (d) Dienes, Z.; Antonsson, T.; Vogel, P.
Enantioselective Synthesis of (R)-(−)-2-Acetyl-2,5,12-trihydro-1,2,3,4-
tetrahydro-6,11-naphthacenequinone via Diastereoselective Diels-Alder
Cycloaddition. Tetrahedron Lett. 1993, 34, 1013−1016.
13. (a) Geraskin, I. M.; Pavlova, O.; Neu, H. M.; Yusubov, M. S.;
Nemykin, V. N.; Zhdankin, V. V. Comparative Reactivity of
Hypervalent Iodine Oxidants in Metalloporphyrin-Catalyzed
Oxygenation of Hydrocarbons: Iodosylbenzene Sulfate and 2-
Iodylbenzoic Acid Ester as Safe and Convenient Alternatives to
Iodosylbenzene Adv. Synth. Catal. 2009, 351, 733–737. (b) Yusubov,
M. S.; Nemykin, V. N.; Zhdankin, V. V. Transition Metal-Mediated
Oxidations Utilizing Monomeric Iodosyl- and Iodylarene Species
Tetrahedron 2010, 66, 5745–5752.
14. For selected comprehensive reviews on direct oxidation of arenes, see:
(a) Dudfield, P. J. Synthesis of Quinones. In Comprehensive Organic
Synthesis; Ley, S. V., Ed.; Pergamon Press:ꢀ Oxford, 1991; Vol. 7, 345–
356. (b) Naruta, Y.; Maruyama, K. Recent Advances in the Synthesis of
Quinonoid Compounds. In The Chemistry of Quinonoid Compounds;
Patai, S., Rappoport, Z., Ed.; John Wiley:ꢀ New York, 1988; Vol. 2, pp
241–402.
15. For selected reviews on this topic, see: (a) Gensch, T.; Hopkinson, M.
N.; Glorius, F.; Wencel-Delord, J. Mild Metal-Catalyzed C–H
Activation: Examples and Concepts. Chem. Soc. Rev. 2016, 45, 2900–
2936. (b) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G.
Transition Metal-Catalyzed Ketone-Directed or Mediated C–H
Functionalization. Chem. Soc. Rev. 2015, 44, 7764–7786. (c) De
Sarkar, S.; Liu, W.; Kozhushkov, S.; Ackermann, L. Weakly
Coordinating Directing Groups for Ruthenium(II)-Catalyzed C–H
Activation. Adv. Synth. Catal. 2014, 356, 1461–1479.
(d) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak Coordination
19. (a) Hamrock, S. J.; Sheridan, R. S. Para photoaddition of N-
methyltriazolinedione to benzene. Synthesis of Energy-Rich Azo
Compounds Comprising Benzene + Nitrogen. J. Am. Chem. Soc. 1989,
111, 9247. (b) Kjell, D. P.; Sheridan, R. S. Photochemical
Cycloaddition of N-methyltriazolinedione to Naphthalene. J. Am.
Chem. Soc. 1984, 106, 5368. (c) Kjell, D. P.; Sheridan, R. S. A
Photochemical Diels–Alder Reaction of N-methyltriazolinedione. J.
Photochem. 1985, 28, 205–214. (d) Hamrock, S. J.; Sheridan, R. S.
Photochemical Diels–Alder Addition of N-methyltriazolinedione to
Phenanthrene. Tetrahedron Lett. 1988, 29, 5509–5512.
20. (a) Männig, D.; Nöth, H. Catalytic Hydroboration with Rhodium
Complexes. Angew. Chem., Int. Ed. Engl. 1985, 24, 878–879. (b)
Evans, D. A.; Fu, G. C.; Hoveyda, A. H. Rhodium(I)-Catalyzed
Hydroboration of Olefins. The Documentation of Regio- and
Stereochemical Control in Cyclic and Acyclic Systems. J. Am. Chem.
Soc. 1988, 110, 6917–6918. (c) Evans, D. A.; Fu, G. C.; Hoveyda, A.
H. Rhodium(I)- and Iridium(I)-Catalyzed Hydroboration Reactions:
Scope and Synthetic Applications. J. Am. Chem. Soc. 1992, 114, 6671–
6679.
21. For an insightful perspective on stability of borates, see: Hall, D. G.
Structure, Properties, and Preparation of Boronic Acid Derivatives.
Boronic Acids; Wiley-VCH Verlag GmbH & Co. KGaA: 2011; pp 1–
133.
22. For recent reviews on the C(sp2)–C(sp3) bond formation, see: (a)
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. The B‐Alkyl Suzuki–
Miyaura Cross‐Coupling Reaction: Development, Mechanistic Study,
and Applications in Natural Product Synthesis. Angew. Chem., Int. Ed.
2001, 40, 4544– 4568. (b) Jana, R.; Pathak, T. P.; Sigman, M. S.
Advances in Transition Metal (Pd, Ni, Fe)-Catalyzed Cross-Coupling
Reactions Using Alkyl-organometallics as Reaction Partners. Chem.
Rev. 2011, 111, 1417–1492. (c) Cherney, A. H.; Kadunce, N. T.;
Reisman, S. E. Enantioselective and Enantiospecific Transition-Metal-
Catalyzed Cross-Coupling Reactions of Organometallic Reagents to
Construct C–C Bonds. Chem. Rev. 2015, 115, 9587–9652.
23. (a) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. A Convenient
Stereoselective Synthesis of Substituted Alkenes via Hydroboration-
Iodination of Alkynes. J. Am. Chem. Soc. 1967, 89, 3652–3653. (b) For
a recent review, see: Armstrong, R. J.; Aggarwal, V. K. 50 Years of
Zweifel Olefination: a Transition-Metal-Free Coupling. Synthesis 2017,
49, 3323–3336.
as
a Powerful Means for Developing Broadly Useful C–H
Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788–802.
16. (a) Thirunavukkarasu, V. S.; Ackermann, L. Ruthenium-Catalyzed C-H
Bond Oxygenations with Weakly Coordinating Ketones. Org. Lett.
2012, 14, 6206–6209. For selected examples of Ru-catalyzed C-H
hydroxylation, see: (b) Yang, F.; Ackermann, L. Ruthenium-Catalyzed
C–H Oxygenation on Aryl Weinreb Amides. Org. Lett. 2013, 15, 718–
720. (c) Yang, X.; Shan, G.; Rao, Y. Synthesis of 2-Aminophenols and
Heterocycles by Ru-Catalyzed C–H Mono- and Dihydroxylation. Org.
Lett. 2013, 15, 2334–2337. (d) Yang, Y.; Lin, Y.; Rao, Y.
Ruthenium(II)-Catalyzed Synthesis of Hydroxylated Arenes with Ester
as an Effective Directing Group. Org. Lett. 2012, 14, 2874–2877. (e)
Thirunavukkarasu, V. S.; Hubrich, J.; Ackermann, L. Ruthenium-
Catalyzed Oxidative C(sp2)-H Bond Hydroxylation: Site-Selective C-O
Bond Formation on Benzamides. Org. Lett. 2012, 14, 4210–4213. (f)
Shan, G.; Han, X.; Lin, Y.; Yu, S.; Rao, Y. Broadening the Catalyst and
Reaction Scope of Regio- and Chemoselective C-H Oxygenation: a
Convenient and Scalable Approach to 2-Acylphenols by Intriguing
Rh(II) and Ru(II) Catalysis. Org. Biomol. Chem. 2013, 11, 2318–2322.
24. (a) Rasmussen, J. K.; Krepski, L. R.; Heilmann, S. M.; Smith, H. K., II;
Tumey,
M.
L.
A
Convenient
Synthesis
of
1,2-
Bis[trimethylsiloxy]alkenes from α-Diketones. Synthesis 1983, 457–
595. (b) Boudjouk, P.; So, J. H. Organic Sonochemistry. Ultrasonic
Acceleration
of
the
Reaction
of
Dicarbonyls
with
Trimethylchlorosilane in the Presence of Zinc. Synth. Commun. 1986,
16, 775–778.
25. Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier, R.;
Scott, H. K.; Aggarwal, V. K. Enantioselective Construction of
Quaternary Stereogenic Centers from Tertiary Boronic Esters:
Methodology and Applications. Angew. Chem., Int. Ed. 2011, 50,
3760–3763.
26. For beneficial use of pot economy in organic synthesis, see:
Hayashi, Y. Pot
Economy
and
One-Pot
Synthesis. Chem.
Sci. 2016, 7, 866–880.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
27. Isayama, S.; Mukaiyama, T. A New Method for Preparation of
Alcohols from Olefins with Molecular Oxygen and Phenylsilane by the
Use of Bis(acetylacetonato)cobalt(II). Chem. Lett. 1989, 18, 1071–
1074.
1
2
3
4
28. Obradors, C. L.; Martinez, R. M.; Shenvi, R. A. Ph(i-PrO)SiH2: An
Exceptional Reductant for Metal-Catalyzed Hydrogen Atom Transfers.
J. Am. Chem. Soc. 2016, 138, 4962–4971.
5
29. (a) Moore, H. W. Bioactivation as a Model for Drug Design
Bioreductive Alkylation. Science 1977, 197, 527–532. (b) Moore, H.
W.; Czerniak, R. Naturally Occurring Quinones as Potential
Bioreductive Alkylating Agents. Med. Res. Rev. 1981, 1, 249–280.
30. (a) Gaudiano, G.; Frigerio, M.; Bravo, P.; Koch, T. H. Reduction of
Daunomycin in Dimethyl Sulfoxide. Long-Lived Semiquinones and
Quinone Methide and Formation of an Enolate at the 14-Position via
the Quinone Methide. J. Am. Chem. Soc. 1992, 114, 3107−3113 (b)
Gaudiano, G.; Frigerio, M.; Sangsurasak, C.; Bravo, P.; Koch, T. H.
Reduction of Daunomycin and 11-Deoxydaunomycin with Sodium
Dithionite in DMSO. Formation of Quinone Methide Sulfite Adducts
and the First NMR Characterization of an Anthracycline Quinone
Methide. J. Am. Chem. Soc. 1992, 114, 5546−5553. (c) Schweitzer, B.
A.; Koch, T. H. Synthesis and Redox Chemistry of 5-
Deoxydaunomycin. A Long-Lived Hydroquinone Tautomer. J. Am.
Chem. Soc. 1993, 115, 5440−5445.
31. (a) Kleyer, D. L.; Koch, T. H. Spectroscopic Observation of the
Tautomer of 7-Deoxydaunomycinone from Elimination of
Daunosamine from Daunomycin Hydroquinone. J. Am. Chem. Soc.
1983, 105, 2504–2505. (b) Bird, D. M.; Gaudiano, G.; Koch, T. H.
Leucodaunomycins, New Nntermediates in the Redox Chemistry of
Daunomycin. J. Am. Chem. Soc. 1991, 113, 308−315. (c) Schweitzer,
B. A.; Koch, T. H. Glycosidic Cleavage from Anaerobic Saponification
of the Heptaacetate of Daunomycin Hydroquinone. J. Am. Chem. Soc.
1993, 115, 5446−5452. (d) See also Ref. 30.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
32. Gaudiano, G.; Koch, T. H. Reaction of the Quinonemethide from
Reductive Glycosidic Cleavage of Daunomycin with Molecular
Oxygen. Evidence for Semiquinonemethide Formation. J. Am. Chem.
Soc. 1990, 112, 25, 9423–9425.
33. (a) Ref. 8i. (b) For similar hydroxylation at C-7 in other
anthracyclinones, see: (b) Kende, A. S.; Tsay, Y.-G.; Mills, J. E. Total
Synthesis of (±)-Daunomycinone and (±)-Carminomycinone. J. Am.
Chem. Soc. 1976, 98, 1967–1969. (c) Wong, C. M.; Schwenk, R.;
Popien, D.; Ho, T. L. The Total Synthesis of Daunomycinone. Can. J.
Chem. 1973, 51, 466–467. (d) Smith, T. H.; Fujiwara, A. N.; Lee, W.
W.; Wu, H. Y.; Henry, D. W. Synthetic Approaches to Adriamycin. 2.
Degradation of daunorubicin to a nonasymmetric tetracyclic ketone and
refunctionalization of the A ring to adriamycin. J. Org. Chem. 1977,
42, 3653–3660. (e) Kimball, S. D; Walt, D. R.; Johnson, F.
Anthracyclines and Related Substances. 3. Regiospecific Total
Synthesis of 11-Deoxydaunomycinone. J. Am. Chem. Soc. 1981, 103,
1561–1563.
ACS Paragon Plus Environment