Flexible synthesis of anthracycline aglycone mimics via domino carbopalladation reactions

Article abstract of DOI:10.3762/bjoc.9.258

A synthesis of anthracycline aglycone derivatives is described. The key step utilizes a powerful domino carbopalladation approach and subsequent ring closure. During this process two of the four rings of the anthracycline scaffold are formed. Differently substituted carbohydrates and dialkyne chains serve as versatile and simple starting materials for the reaction sequence. Diverse building blocks lead to a variety of different products and a broad range of structural diversity.

Full text of DOI:10.3762/bjoc.9.258

Flexible synthesis of anthracycline aglycone mimics
via domino carbopalladation reactions
Markus Leibeling and Daniel B. Werz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2194–2201.
Institut für Organische Chemie, Technische Universität Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
doi:10.3762/bjoc.9.258
Received: 28 August 2013
Accepted: 08 October 2013
Published: 24 October 2013
Email:
Daniel B. Werz* - d.werz@tu-braunschweig.de
* Corresponding author
This article is part of the Thematic Series "Natural products in synthesis
and biosynthesis".
Keywords:
anthracyclines; carbohydrates; carbopalladation; catalysis; domino
reaction; natural products
Guest Editor: J. S. Dickschat
© 2013 Leibeling and Werz; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A synthesis of anthracycline aglycone derivatives is described. The key step utilizes a powerful domino carbopalladation approach
and subsequent ring closure. During this process two of the four rings of the anthracycline scaffold are formed. Differently substi-
tuted carbohydrates and dialkyne chains serve as versatile and simple starting materials for the reaction sequence. Diverse building
blocks lead to a variety of different products and a broad range of structural diversity.
Introduction
Anthracyclines are a widespread class of natural products which of double-stranded DNA [4,5]. While the mode of action of
belong to the group of aromatic polyketides [1]. Most of them anthracyclines is still not fully understood, it is widely accepted
have been isolated from bacteria of the order Streptomycetales. that these chemotherapeutic agents form a ternary complex with
The group of Brockmann, who first found anthracyclines in double-stranded DNA and topoisomerase II thereby leading to
1963, described them as red to orange dyes [2]. Their structure DNA damage and cell death [6,7]. They are used to treat
elucidation revealed a linear fourfold annulated ring system different types of diseases such as leukemias, lymphomas,
including two benzene units (A-ring and C-ring). The substitu- breast, uterine, ovarian and lung cancers [8].
tion pattern of the D-ring bares most of the functionalities, i.e.,
a secondary and a tertiary alcohol, the former of which is Thus, many research groups faced the challenge of investi-
commonly glycosylated with 2,6-dideoxy sugars (Figure 1) [3]. gating suitable pathways for the synthesis of diverse anthracy-
These carbohydrates are of highest importance for the bio- cline natural products and mimics thereof. Because of the
logical activity of anthracyclines and bind to the minor groove inherent lack of efficient synthetic approaches to anthracyclines
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Figure 1: Several natural occurring anthracycline antibiotics.
Scheme 1: Total synthesis of daunomycinone 6 according to Hansen.
many industrial approaches still rely on the use of recombinant
microorganisms with a mutated gene of the anthracycline
metabolism [9].
In 2003, Saá published a concise route to anthraquinone deriva-
tives by using an intramolecular dehydro-Diels–Alder reaction
Different convenient synthetic transformations involve the of an aryldiacetylene system (Scheme 2) [15]. Compound 7
application of a Diels–Alder reaction as key step for the aspired reacts at high temperature in a mixture consisting of toluene and
synthesis [10-13]. A classical synthesis was published in 1988 triethylamine to an inseparable mixture of cyclized diol (52%)
by Hansen where a silyl-substituted diene 3 was used for the and quinone 8 (36%). Quantitative oxidation of the diol by
[4 + 2]-cycloaddition (Scheme 1) [14]. Starting from bisquinone MnO2 provided the desired tetracycle 8 in 88% overall yield
4 the annulated ring system 5 is obtained in a 1:1 mixture of cis- (over two steps). Another approach to non-linear systems
endo regioisomers. Subsequent aromatization of the C-ring and utilizes a cobalt-mediated intramolecular [2 + 2 + 2]-cycloaddi-
several additional steps generated the daunomycin aglycon 6 tion of a triyne system 9 leading to the fourfold annulated ring
and the corresponding isodaunomycin aglycone (dependent on system 10 in only one step [16]. Late stage functionalization led
the regioisomers) in a total of 16 steps.
to the anticipated structural motif in a few additional steps.
Scheme 2: Synthesis of simplified anthracycline derivatives.
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Results and Discussion
substituted diynes 16 can be traced back to phthalide (17). To
Retrosynthetic strategy
differentiate between the insertion of two differently substi-
After having established several methods of domino carbopalla- tuted silylacetylenes, the lactone 17 had to be first converted
dation reactions which employ dialkynyl-substituted bromogly- into a monoprotected diol for further transformations.
cals [17-20] or bromoarenes [21], we envisioned to apply a
similar procedure for the preparation of anthracycline deriva- Synthesis of dialkyne building blocks
tives. Therefore, the D-ring was exchanged for a pyranose, as The choice of the right diyne is crucial for a successful syn-
described in our previous synthetic approaches for the syntheses thesis of the target compound. Preliminary investigations had
of chromans, isochromans and biphenyls, respectively. These shown that both dialkynes with benzylic hydroxy functionali-
2-bromoglycals 15 are well-known compounds and their syn- ties and 1,2-bis(2-propynyl)benzene did not yield viable results
thesis was accomplished according to literature-known pro- in the domino reaction. The selective installation of only one
cedures [17,18]. The dialkyne unit provides both the A-ring and silyl group at a dialkyne with two terminal acetylene moieties
the information for the formation of the B and C-ring within the presented difficulties. Thus, we sought for a consecutive intro-
palladium-catalyzed domino transformation [22-27]. Such an duction of the corresponding silylacetylene functionalities. An
approach should allow an easy differentiation between all four appropriate starting material was selected to achieve a highly
annulated cycles and their possible modification, whereupon the convergent and convenient synthetic strategy. We started our
main focus was the preparation of several D-ring derivatives.
investigation with the reduction of commercially available
phthalide (17) by LiAlH4 into dialcohol 18 in quantitative yield
The anthraquinone moiety 11 should be formed within the last [28] (Scheme 4). The polar compound was easily converted into
steps of the synthetic approach by benzylic oxidation of com- the mono-TBS-protected substrate by utilization of 1 equiva-
pound 12 (Scheme 3). The terminal silyl group and the silyl lent of TBSCl [29]. Column chromatography afforded three
ether should be removed by using hydrolysis and fluoride-medi- fractions consisting of the starting material, the monoprotected
ated desilylation, respectively. It was assumed that the multiple and the diprotected product. The remaining alcohol moiety of
carbopalladation/cyclization sequence should give access to the compound 19 was converted into the respective iodide 20 by a
fourfold-annulated ring system 13 in a single step. However, we Mukaiyama redox-condensation using elemental iodine, triph-
knew that the domino process works much better in an intra- enylphosphine and imidazole [30]. The installation of a suitable
than in an intermolecular fashion [19]. Thus, we decided to leaving group sets the stage for the introduction of the first sily-
employ a silyl ether moiety to connect both subunits 15 and 16. lacetylene. Four different terminal alkynes 21 (a: Si = TMS;
As the terminus of the other alkyne unit we also chose a silyl b: Si = SiMe2Ph; c: Si = SiMe2Bn; d: Si = Si(iPr)2H) were
group. Depending on the kind of the silyl group a variety of employed. Best results with yields of over 80% were obtained
further functionalization might be envisioned. Respective silyl- by the use of acetylene 21a, ethylmagnesium bromide, and
Scheme 3: Retrosynthetic analysis of anthracycline aglycone mimics. Si: any silyl group.
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Scheme 4: Synthetic route for the synthesis of various dialkynes 16. aSi: TMS, SiMe2Bn (2.0 equiv); Si: SiMe2Ph (1.5 eq equiv); Si(iPr)2H (3.0 equiv).
bProducts for Si: SiMe2Ph and SiMe2Bn could not be isolated. cYield: over two steps. dConditions: Br2 (1.0 equiv), MeOH, 0.5 h, 0 °C, NEt3 (2.0
equiv), CCl4, MeOH, 1 h, 0 °C. eSi: TMS, Si(iPr)OMe, H (3.0 equiv of 25); Si: SiMe2Ph, SiMe2Bn (2.0 equiv of 25).
copper chloride in tetrahydrofuran for one hour at 75 °C, proach was not considered because of the low tolerance of 16e
successive addition of iodide 20 in THF at room temperature against base and the expensive starting materials for the syn-
and additional 16 h under reflux [31]. Products 22b and 22c thesis of 23e.
could not be isolated in pure form due to small impurities. The
deprotection of the silyl ethers proceeded smoothly with high Silyl ether formation and domino reaction
yields ranging from 62% to 86% over two steps [32]. Silane The union between both building blocks proved to be more
23d was converted into the corresponding silyl bromide and difficult than originally envisioned. During our previous studies
trapped with methanol to install an electron-deficient of chromans and isochromans the implementation of ether link-
substituent at the silane moiety 23d-2. The synthesis of 23e was ages afforded good results. The synthesis of anthracycline
accomplished according to a literature-known procedure derivatives requires a more labile connection to circumvent the
starting from isochromanone and trimethylsilyl-diazomethane formation of an additional cycle at the annulated ring system.
[33]. The initially formed alcohols 23 were again converted into Previous investigations revealed that silyl ether formations
the respective iodides 24 as described before and subsequently could be accomplished by the transformation of the silane into
substituted with diisopropylsilylacetylene 25 [34] providing five the corresponding silyl bromide by using NBS [35]. This highly
different dialkynes 16, each of them with a terminal silyl reactive species should be easily trapped by the hydroxy func-
substituent (or terminal hydrogen) at one side and a silane tionality of the respective 2-bromoglycal. Therefore, we chose
moiety at the other (Scheme 4). It is possible to access differ- 15a and 16a as model substrates to explore suitable reaction
ently substituted dialkynes 16 by the silylation of 16e. This ap- conditions for the silyl ether formation. Table 1 reveals that of
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Table 1: Optimization study for the silyl ether formation.
entry
conditionsa
yield [%]
1
2
3
4
5
6
7
8
9
10
1) 15a (1.1 equiv), NBS (1.1 equiv). 2) 16a (1.0 equiv), NEt3 (2.0 equiv), CH2Cl2
1) 15a (1.1 equiv), NCS (1.1 equiv). 2) 16a (1.0 equiv), NEt3 (2.0 equiv), CH2Cl2
1) 15a (1.1 equiv), NIS (1.1 equiv). 2) 16a (1.0 equiv), NEt3 (2.0 equiv), CH2Cl2
1) 15a (1.1 equiv), Br2 (1.1 equiv). 2) 16a (1.0 equiv), NEt3 (2.0 equiv), CH2Cl2
1) 15a (1.0 equiv), Br2 (1.1 equiv). 2) 16a (1.0 equiv), NEt3 (1.3 equiv), Et2O
1) 15a (1.1 equiv), Br2 (1.1 equiv). 2) 16a (1.0 equiv), NEt3 (1.1 equiv), THF
1) 15a (1.3 equiv), Br2 (1.4 equiv). 2) 16a (1.0 equiv), NEt3 (1.3 equiv), Et2O
1) 15a (1.0 equiv), Br2 (1.0 equiv). 2) 16a (1.0 equiv), NEt3 (2.0 equiv), Et2O
1) 15a (1.0 equiv), Br2 (1.0 equiv). 2) 16a (1.0 equiv), NEt3 (2.0 equiv), CCl4
1) 15a (1.2 equiv), Br2 (1.2 equiv), CCl4. 2) 16a (1.0 equiv), NEt3 (2.0 equiv), CCl4/Et2O (4:1)
23
12
–
27
42b
–
36
25
75
88
aFirst reaction: Br2 (1 M in CCl4), 1 h, 0 °C. Second reaction: DMAP (0.1 equiv), 2 h, 0 °C → 25 °C. b65% were obtained once for a small scale reac-
tion.
the halogenated succinimides only NCS and NBS are able to uct was formed in high yield. In addition, terminal alkynes were
convert the silane into a reactive species. However, the yields tolerated in the reaction. Contrary, benzyl and methoxide-
were low in all cases. Changing the bromination reagent to substituted silanes 14c and 14d provided inferior yields.
elemental bromine significantly improved the yields (Table 1,
entries 4 and 5) [36]. Diethyl ether proved to be important as a With several domino precursors in hand we started the investi-
solvent, the change to THF led to a total decomposition – most gation of the domino-carbopalladation sequence. To our delight,
probably due to ring-opening reactions with bromosilanes [37]. it was possible to adjust the catalytic system that we developed
Further, we investigated the influence of the amount of bromine for the synthesis of chromans and isochromans. Optimal reac-
on the reaction and concluded that stoichiometric quantities tion conditions comprise the use of Pd(PPh3)4 as a palladium
entirely fulfill the demands of the bromination (Table 1, entries source, (t-Bu)3PH·BF4 (Fu’s salt) [38] as an additional electron-
7 and 8). Finally, we found that the silyl bromide formation rich and sterically encumbered ligand and HN(iPr)2 as a base.
proceeded better in tetrachloromethane. However, to assure As solvent a mixture consisting of N,N-dimethylformamide,
solubility of the glycals, small amounts of diethyl ether were acetonitrile and N-methylpyrrolidone (8:8:1) was used. The
added for the coupling step (Table 1, entries 8–10). In all cases, reaction was performed in a sealed vial at 120 °C under
a very slow addition of bromine and bromosilane proved to be microwave irradiation for 3–5 h. The unusual combination of
necessary to ensure optimal yields.
Pd(PPh3)4 and (t-Bu)3PH·BF4 as an additional ligand proved
beneficial for the transformation of long-chained dialkynes. The
With optimized conditions in hand we explored the scope of the domino reaction proceeded smoothly and delivered the desired
silyl ether coupling. Therefore, two different glycals and five compounds as major products. Scheme 5 illustrates that all at-
different dialkynes were employed. In summary, seven different tached substituents at the terminal triple bond were tolerated.
coupling products 14 were prepared baring alkynes with Even unsubstituted alkyne 14e and electron-deficient silane 14d
terminal H, TMS, SiMe2Ph, SiMe2Bn and Si(iPr)2OMe groups furnished the product in high yields. TMS, SiMe2Ph and
(Scheme 5). The best results were obtained with TMS- Si(iPr)2OMe-substituted silanes delivered the best results with
substituents. Although the SiMe2Ph-substituted product was not yields of up to 89%. For the reaction mechanism we assume
synthesized under optimal reaction conditions the desired prod- that the palladium(0) inserts into the C(sp2)–Br bond to form a
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Scheme 5: Silyl ether synthesis and domino carbopalladation reaction. R,R (Glc): isopropylidene. R,R (Gal): benzylidene. aThe respective equiva-
lents of alkynes 16, glycals 15 and bromine as well as reaction times are given in the Experimental. bThe reaction was performed according to entry 5
of Table 1.
Pd(II) species. A sequence of two carbopalladation reactions tion conditions (KHCO3, H2O2, KF in THF and MeOH), i.e.,
form a triene system which is able to cyclize by a Heck-type both silyl ether and terminal silane were cleaved. However, it
reaction, a 6π-electrocyclization [39] or a direct CH-activation was not possible to utilize this procedure for compound 13a.
to the respective anthracycline precursor 13. The design of the Under these conditions, the silyl ether was cleaved without
dialkyne provides a simultaneous formation of the linear ring touching the trimethylsilyl moiety. Another approach of selec-
system. All four cycles were annulated in a single step, in which tive silyl ether cleavage was employed by utilization of Cs2CO3
the B and C-ring were formed as a consequence of the reaction (5.0 equiv) in methanol at 100 °C.
cascade.
Hydrolysis of the respective domino products 13a and 13f with
Derivatization to anthracycline derivatives
in situ formed HCl in methanol furnished the diols 26a and 26b
The derivatization of the domino products turned out to be chal- under loss of the terminal TMS group [46]. Opening of the silyl
lenging. Utilization of a fluoride source (e.g. tetrabutylammo- ether moiety was accomplished by treatment with TBAF in
nium fluoride or tetramethylammonium fluoride) and 13a lead quantitative yield and gained access to the natural substitution
to total decomposition of the starting materials. Application of pattern of the carbohydrate backbone. It was not possible to
Tamao–Fleming-like oxidative procedures provided only the open the silyl ether moiety of 26 by the utilization of Cs2CO3 in
mono-oxidized products in trace amounts [40-42]. The oxi- methanol starting from 13 as described before. To install the
dation of phenyl-substituted silanes to respective phenols is anthraquinone moiety it was necessary to reprotect the alcohol
difficult [43,44]. However, literature precedence revealed that functionalities. It has proven challenging to install the TBS
benzyl-substituted silane 13c or electron-deficient silane 13d protecting group at the substrates, particular for the galactose-
[43,45] should be more promising candidates. But none of these derived derivatives 12b which could be obtained in only poor
domino products 13b–13f provided better results in a yield [47-49]. For 27a the FeCl3-catalyzed benzylic oxidation
Tamao–Fleming reaction. When oxidizing reaction conditions proceeded smoothly with yields of up to 70% [50]. A final
were applied to silane 13b, only desilylation of the cyclic silyl hydrolysis with hydrochloric acid afforded the desired carbohy-
ether occurred. Interestingly, benzylsilane 13c afforded the drate-based anthracycline derivatives 11 in good yield
globally desilylated product in 90% yield under oxidative reac- (Scheme 6).
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Beilstein J. Org. Chem. 2013, 9, 2194–2201.
Scheme 6: Derivatisation of anthracycline derivatives. aR,R (Glc): isopropylidene. R,R (Gal): benzylidene. Reactions times: b1.5 h (Glc), 3.5 h (Gal).
c1.0 h (Glc), 4.0 h (Gal). d38 h (Glc), 86 h (Gal). e4.0 h (Glc), 3.0 h (Gal). f14 h (Glc), 17 h (Gal).
Conclusion
Acknowledgements
In conclusion, we have developed a concise and robust ap- We are grateful to the Deutsche Forschungsgemeinschaft
proach to anthracycline aglycone derivatives. Starting materials (DFG) and the Fonds der Chemischen Industrie (FCI) for finan-
were bromoglycals and benzene moieties with two propynyl cial support (Emmy Noether and Heisenberg Fellowships as
residues. The first key step is the union of these moieties by a well as Dozentenstipendium to D.B.W.). M.L. thanks the State
silyl ether linkage. In a second key step the tetracyclic anthracy- of Lower Saxony for his Ph.D. Lichtenberg Fellowship within
cline scaffold is formed by a domino carbopalladation sequence the CaSuS (Catalysis for Sustainable Synthesis) program. We
generating both, the B and the C-ring of the system in a single thank Prof. Dr. Lutz F. Tietze (University of Göttingen) for
step. Further derivatisation included the cleavage of the silyl helpful discussions and generous support of our work.
ether and two-fold benzylic oxidation to the quinone moiety.
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