Model studies towards the challenging angularly-oxygenated core of several angucyclinones from an oxidative dearomatization strategy

Article abstract of DOI:10.1039/c3cc41221k

Up to six differently substituted highly challenging angularly-oxygenated tricyclic core models of natural angucyclinones were stereoselectively synthesized from a common p-quinol intermediate obtained from Oxone-mediated oxidative dearomatization of the corresponding tricyclic phenol.

Full text of DOI:10.1039/c3cc41221k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Model studies towards the challenging angularly-
oxygenated core of several angucyclinones from an
oxidative dearomatization strategy†
Cite this: Chem. Commun., 2013,
49, 3561
Received 15th February 2013,
Accepted 12th March 2013
Silvia Vila-Gisbert, Antonio Urbano* and M. Carmen Carren˜o*
DOI: 10.1039/c3cc41221k
www.rsc.org/chemcomm
Up to six differently substituted highly challenging angularly- activities have provided organic chemists with attractive targets
oxygenated tricyclic core models of natural angucyclinones were for the development of various synthetic methodologies.1,2
stereoselectively synthesized from a common p-quinol intermediate
Of particular importance are derivatives bearing one or two
obtained from Oxone-mediated oxidative dearomatization of the hydroxyl groups located at the angular 4a and 12b positions
corresponding tricyclic phenol.
connecting the rings A and B (Fig. 1). While the stereocontrolled
assembly of the members of the SF 2315-type, bearing an oxygen
Angucyclines and angucyclinones, a large group of aromatic poly- function at C-4a, has been achieved using a Diels–Alder reaction3 or a
ketide secondary metabolites, constitute an important family of biomimetic approach,4 the synthesis of angucyclinones with one
microbial antibiotics, isolated from various members of the hydroxyl group at C-12b (azicemycin-type) and specially those bearing
bacterial genus Streptomyces, exhibiting a broad spectrum of two oxygenated substituents at the AB ring junction (aquayamycin-
biological properties including antiviral, antifungal, antitumor, type) has been much less explored and remains a challenge for
and enzyme inhibitor activity.1 Most of these antibiotics are synthetic organic chemists.5 To the best of our knowledge, only three
structurally characterized by their benz[a]anthraquinone ABCD very particular and limited model studies of this subclass of angucy-
angular tetracyclic skeleton (Fig. 1) sharing a methyl group at clinones have been reported,6–8 together with two total syntheses: the
C-3 and oxygen functionalities at C-1 and C-8, with varying racemic 8-deoxy analogue of WP 3688-2 (1 in Scheme 1) by Krohn,9
degree of unsaturation and oxygenation. These fascinating and aquayamycin (2 in Scheme 1) by Suzuki.10 In addition to this
structural features as well as their diverse range of biological synthetic effort, new and general routes to the angularly-oxygenated
core of this type of angucyclinones are welcome.
We have recently reported a practical method for the simple and
selective oxidative dearomatization of differently substituted p-alkyl
phenols into p-peroxy quinols and p-quinols using Oxones in the
presence of NaHCO3, as a source of singlet oxygen.11 Herein,
we describe a direct and stereocontrolled access to six differently
Fig. 1 Diverse structure of angucyclinones and types of derivatives with angular
oxygens at 4a and/or 12b positions.
´
´
´
Departamento de Quımica Organica (Modulo 01), Facultad de Ciencias,
´
´
Universidad Autonoma de Madrid, c/ Francisco Tomas y Valiente 7, Cantoblanco,
28049-Madrid, Spain. E-mail: antonio.urbano@uam.es, carmen.carrenno@uam.es
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data and NMR spectra. CCDC 916332 (12), 916331 (14)
and 916330 (15). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3cc41221k
Scheme 1 Retrosynthesis towards tricyclic angularly-oxygenated core models
of angucyclinones.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3561--3563 3561

View Article Online
Communication
ChemComm
substituted angularly-oxygenated tricyclic core models of natural
angucyclinones from a common p-quinol intermediate obtained
from Oxone-mediated oxidative dearomatization of the corres-
ponding tricyclic phenol. We envisaged tricyclic structures A and B,
shown in Scheme 1, as convenient angularly-oxygenated core models
of aquayamycin-type and azicemycin-type angucyclinones, respec-
tively, to validate our oxidative dearomatization approach.
As can be seen in retrosynthetic Scheme 1, the angular tertiary
benzylic OH at C-10b present in both types of tricyclic models (C-12b
in tetracyclic angucyclinones) could come from the corresponding
p-quinol intermediate 4, formed from tricyclic phenol 5 after
oxidative dearomatization. On the other hand, epoxide 3 would give
rise to the second angular oxygenated substituent at C-4a present
in the aquayamycin-type derivatives.
Scheme 3 Synthesis of tricyclic models 11 and 14 from p-quinol 4: (a) H2,
10% Pd–C, 25% aq. NaNO2, EtOH, rt, 4 h, 78%; (b) RuCl3, NaIO4, CeCl3Á7H2O,
EtOAc–CH3CN–H2O, rt, 1.5 h, 99%; (c) Ac2O, Et3N, DMAP, CH2Cl2, 0 1C, 4 h, 83%;
Tricyclic phenol 5 was obtained in two steps from commercially
available substrates 6 and 7 (Scheme 2). Thus, the reaction of the (d) NaBH4, CH2Cl2, rt, 3 h, 60%.
Grignard reagent obtained from 2-bromo-1,4-dimethoxy benzene (6)
with ketone 7 afforded lactone 8 in 87% yield. The Friedel–Crafts
Streptomyces sp. P371, exhibiting inhibitory activity against the
acylation of compound 8 with PPA was followed by the aromatization
of the B ring, leading to tricyclic phenol 5, in 79% yield. The Oxone
treatment of tetrahydrophenanthrol 5 under our oxidative dearoma-
tization conditions11 gave rise, after [4+2] cycloaddition of the singlet
oxygen generated, to the endoperoxide intermediate 9, which evolved
to the corresponding p-peroxyquinol 10, isolated in 44% yield
after flash chromatography (Scheme 2). When the same reaction
was followed by the addition of a reducing agent such as Na2S2O3,
p-quinol 4 was obtained in 52% yield.
With p-quinol 4 in hand, we carried out the first approach to
synthesise one of the angularly-oxygenated core of natural angucycli-
nones, the azicemycin-type tricyclic model (B in Scheme 1). Azicemy-
cins A and B (Scheme 3) were isolated from Kibdelosporangium sp.
MJ126-NF4 and have antimicrobial activity against Gram positive
bacteria.12 They have a unique aziridine moiety13 at C-3 and, in the
B ring, angular OH at C-12b, saturated C4a–C5 bond and carbonyl
group at C-6. The access to the tricyclic model of azicemycins (11 in
Scheme 3) was possible after stereoselective hydrogenation of p-quinol
4 in the presence of 10% Pd–C and 25% aq. NaNO2,14 in 78% yield.
Our next synthetic goal was an aquayamycin-type tricyclic
model (A in Scheme 1) such as derivative 14 (Scheme 3), whose
all-cis tetraoxygenated B ring is present in the structure of
angucyclinone P371A1. This natural product was isolated from
pentagastrin-stimulated acid secretion.15 The cis-diol fragment at
C4a–C5 present in 14 was introduced after cis-dihydroxylation of 4
using RuO4,16 giving rise to all-cis triol 12 in 99% yield. The
relative configuration of this derivative was demonstrated after an
X-ray diffraction study (see ESI†). The selective acetylation of the
secondary OH at C-5 present in 12 afforded compound 13 in 83%
yield. Finally, the stereoselective reduction of 13 with NaBH4 gave
rise to 14, the aquayamycin-type tricyclic model of angucyclinone
P371A1, in 60% yield. The correct configuration at C-6 was
assigned after an X-ray diffraction study (see ESI†).
Next, we turned our attention to the synthesis of the other
aquayamycin-type tricyclic model (A in Scheme 1), lacking the
oxygenated substituent at C-5, whose structure is present in
several angucyclinones such as gaudimycin C and urdamicynone
F (Scheme 4). For this purpose, we considered epoxy p-quinol 3
(Scheme 1) as a convenient intermediate to install the angular
Scheme 4 Synthesis of epoxide 3 and tricyclic models 16 and 19: (a) 33% aq.
H2O2, 6 M NaOH, MeOH, rt, 3 h, 98%; (b) Al–Hg, NaHCO3, THF–EtOH–H2O, 0 1C,
45 min, 58%; (c) NaBH4, CeCl3Á7H2O, MeOH, À78 1C to rt, 3 h, 95%; (d) NaBH4,
EtOH, rt, 1.5 h, 92%; (e) i. LAH, THF, rt, 2 h; ii. flash chromatography, 69%.
Scheme 2 Synthesis of 10 and 4: (a) i. 6, Mg, THF, reflux, 2 h; ii. 7, THF, rt, 2 h,
87%; (b) PPA, 90 1C, 2 h, 79%; (c) Oxone, NaHCO3, CH3CN–H2O, rt, 2 h, 44%; (d) i.
Oxone, NaHCO3, CH3CN–H2O, rt, 2 h; ii. Na2S2O3, rt, 2 h, 52% for the two steps.
c
3562 Chem. Commun., 2013, 49, 3561--3563
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
The corresponding tricyclic model 21 was obtained after Wharton
reaction of 3, as described above, followed by hydrogenation of 20 in
the presence of 10% Pd–C, in 53% yield for the two steps.
In summary, the Oxone-mediated oxidative dearomatization of
a tricyclic phenol, easily accessible from commercially available
materials, led to the corresponding p-quinol, a common precursor
of six differently substituted highly challenging angularly-oxygenated
tricyclic core models of natural angucyclinones.
We thank MICINN (Grant CTQ2011-24783) for financial
support. S.V.-G. thanks Comunidad de Madrid for a fellowship.
Notes and references
Scheme 5 Syntheses of tricyclic models 20 and 21: (a) H2NNH2ÁH2O, AcOH, MeOH,
0 1C to rt, 2 h, 57%; (b) H2, 10% Pd–C, MeOH, rt, 24 h, 53% for the two steps.
1 (a) M. K. Kharel, P. Pahari, M. D. Shepherd, N. Tibrewal, S. E. Nybo,
K. A. Shaaban and J. Rohr, Nat. Prod. Rep., 2012, 29, 264;
(b) K. Krohn and J. Rohr, Top. Curr. Chem., 1997, 188, 127;
(c) J. Rohr and R. Thiericke, Nat. Prod. Rep., 1992, 9, 103.
OH at C-4a. Compound 3 was obtained after stereoselective
conjugate epoxidation of p-quinol 4 with H2O2 and NaOH, in
98% yield (Scheme 4).
˜
2 M. C. Carreno and A. Urbano, Synlett, 2005, 1.
3 (a) K. Krohn and J. Micheel, Tetrahedron, 1998, 54, 4827;
˜
(b) M. C. Carreno, A. Urbano and C. Di Vitta, J. Org. Chem., 1998,
¨
63, 8320; (c) R. Faust and B. Gobelt, J. Prakt. Chem., 1998, 340, 90;
With epoxy p-quinol 3 in hand, we first carried out the synthesis of
the all-cis trihydroxylated derivative 16, the tricyclic model of gaudimy-
cin C (Scheme 4). This angucyclinone had been obtained by chemo-
enzymatic synthesis, starting from a common angucycline precursor
2,3-dehydro-UWM6, by the sequential action of two flavoenzymes,
PgaE and PgaM, isolated from Streptomyces sp. PGA64.17 Firstly, the
reductive opening of epoxide 3 with Al–Hg gave rise to cis diol 15,
whose correct structure was assigned after an X-ray diffraction study
(see ESI†). In order to achieve the stereoselective reduction, by the lower
face of the carbonyl group at C-6 of 15, we used both small and bulky
reducing agents and, in all cases, the major diastereoisomer observed
was the desired all-cis triol 16. The best results were obtained using
NaBH4 in the presence of CeCl3Á7H2O, affording cis triol 16, as the
unique diastereoisomer, in 95% yield.
˜
(d) M. C. Carreno, A. Urbano and J. Fischer, Angew. Chem., Int. Ed.
Engl., 1997, 36, 1621; (e) K. Kim, V. A. Boyd, A. Sobti and
G. A. Sulikowski, Isr. J. Chem., 1997, 37, 3; ( f ) K. Kim, Y. Guo and
G. A. Sulikowski, J. Org. Chem., 1995, 60, 6866; (g) K. Krohn,
K. Khanbabaee and P. G. Jones, Liebigs Ann., 1995, 1981;
(h) K. Kim and G. A. Sulikowski, Angew. Chem., Int. Ed. Engl., 1995,
34, 2396; (i) K. Kim, J. Reibenspies and G. A. Sulikowski, J. Org.
Chem., 1992, 57, 5557.
¨
4 K. Krohn, U. Florke, C. Freund and N. Hayat, Eur. J. Org. Chem.,
2000, 1627.
5 A. Baranczak and G. A. Sulikowski, Angew. Chem., Int. Ed., 2009, 48, 6005.
6 T. E. Nicolas and R. W. Franck, J. Org. Chem., 1995, 60, 6904.
7 G. A. Kraus and Z. Wan, Tetrahedron Lett., 1997, 38, 6509.
8 (a) N. Lebrasseur, G.-J. Fan, M. Oxoby, M. A. Looney and S. Quideau,
Tetrahedron, 2005, 61, 1551; (b) N. Lebrasseur, G.-J. Fan and
S. Quideau, ARKIVOC, 2004, 13, 5.
9 (a) K. Krohn and P. Frese, Tetrahedron Lett., 2001, 42, 681;
(b) K. Krohn, P. Frese and U. Florke, Chem.–Eur. J., 2000, 6, 3887.
Another aquayamycin-type angucyclinone, similar to gaudimycin 10 (a) T. Matsumoto, H. Yamaguchi, M. Tanabe, Y. Yasui and
C, is urdamycinone F (Scheme 4),9a showing the OH at C-6 in a relative
trans disposition. Urdamycin F was isolated by Rohr in 1986 from
K. Suzuki, Tetrahedron Lett., 2000, 41, 8393; (b) H. Yamaguchi,
T. Konegawa, M. Tanabe, T. Nakamura, T. Matsumoto and
K. Suzuki, Tetrahedron Lett., 2000, 41, 8389; (c) T. Matsumoto,
H. Yamaguchi, T. Hamura, M. Tanabe, Y. Kuriyama and
Streptomyces fradiae.18 The access to the tricyclic model 19 was not
possible by direct reduction of the carbonyl group at C-6 of 15, since
the major diastereomer resulted from the lower face attack of the
hydride to the carbonyl group. We then decided to invert the order of
the required steps. Thus, the reduction of epoxy ketone 3 using NaBH4
led to an inseparable 15 : 85 mixture of diols 17 and 18, in 92% yield,
K. Suzuki, Tetrahedron Lett., 2000, 41, 8383.
˜
´
´
11 (a) M. C. Carreno, M. Gonzalez-Lopez and A. Urbano, Angew. Chem.,
˜
´
Int. Ed., 2006, 45, 2737; (b) S. Barradas, M. C. Carreno, M. Gonzalez-
´
Lopez, A. Latorre and A. Urbano, Org. Lett., 2007, 9, 5019;
˜
(c) S. Barradas, A. Urbano and M. C. Carreno, Chem.–Eur. J., 2009,
´
15, 9286; (d) S. Barradas, G. Hernandez-Torres, A. Urbano and
˜
M. C. Carreno, Org. Lett., 2012, 14, 5952.
where the major diastereomer resulted from the hydride attack from 12 (a) T. Tsuchida, H. Iinuma, N. Kinoshita, T. Ikeda, T. Sawa, M. Hamada
and T. Takeuchi, J. Antibiot., 1995, 48, 217; (b) T. Tsuchida, R. Sawa,
Y. Takahashi, H. Iinuma, T. Sawa, H. Naganawa and T. Takeuchi,
J. Antibiot., 1995, 48, 1148.
the upper face of the carbonyl group. The regioselective opening of
these epoxides with LiAlH4 gave rise, after chromatographic separa-
tion, to triol 19, the tricyclic model of urdamycinone F, in 69% yield. 13 Y. Ogasawara and H.-W. Liu, J. Am. Chem. Soc., 2009, 131, 18066.
14 A. Suksamrarn, T. Tanachatchairatana and C. Sirigarn, Tetrahedron,
We were also interested in two aquayamycin-type angucyclinones
namely capoamycin and sakyomicin D, bearing a double bond or
2002, 58, 6033.
15 (a) S. Uesato, T. Tokunaga and K. Takeuchi, Bioorg. Med. Chem. Lett.,
saturated carbons at C5–C6 positions (Scheme 5). Capoamycin,
obtained from Streptomyces capoamus, inhibited the growth of
Gram-positive bacteria, yeasts and fungi and prolonged the survival
periods of mice bearing Ehrlich ascites carcinoma.19 The access to
20, the tricyclic model of capoamycin, was possible after treatment
of epoxide 3 under the Wharton reaction20 conditions, giving rise to
the allylic diol 20, in 57% yield, after flash chromatography. The last
synthetic target, sakyomicin D, was isolated21a from an actinomycete
of genus Nocardia, showing activity against Gram-positive bacteria,
and characterized21b by the saturated bond at C5–C6 (Scheme 5).
1998, 8, 1969; (b) S. Uesato, T. Tokunaga, Y. Mizuno, H. Fujioka,
S. Kada and H. Kuwajima, J. Nat. Prod., 2000, 63, 787.
16 B. Plietker and M. Niggemann, J. Org. Chem., 2005, 70, 2402.
17 P. Kallio, Z. Liu, P. Maentsaelae, J. Niemi and M. Metsae-Ketelae,
Chem. Biol., 2008, 15, 157.
¨
18 (a) H. Drautz, H. Zahner, J. Rohr and A. Zeeck, J. Antibiot., 1986,
39, 1657; (b) J. Rohr and A. Zeeck, J. Antibiot., 1987, 40, 459.
19 Y. Hayakawa, K. Adachi, T. Iwakiri, K. Imamura, K. Furihata, H. Seto
and N. Otake, Agric. Biol. Chem., 1987, 51, 2237.
20 P. S. Wharton and D. H. Bohlen, J. Org. Chem., 1961, 26, 3615.
21 (a) T. Nagasawa, H. Fukao, H. Irie and H. Yamada, J. Antibiot., 1984,
37, 693; (b) H. Irie, Y. Mizuno, I. Kouno, T. Nagasawa, Y. Tani, H. Yamada,
T. Taga and K. Osaki, J. Chem. Soc., Chem. Commun., 1983, 174.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3561--3563 3563