Total synthesis of isoquinocyclinone

Article abstract of DOI:10.1002/chem.201403880

The total synthesis of the heptacyclic natural product isoquinocyclinone has been achieved. A Hauser annulation was used to assemble the anthraquinone core structure. The unique 2,4,5,6-tetrahydropyrrolo[2,3-b]pyrrole substructure was prepared by alkyne addition to a lactone intermediate and subsequent Ni ⁰-mediated cyanide addition, the conversion of an O,O- into an N,O-acetal, and final intramolecular N-alkylation. Hauser annulation: An efficient total synthesis of isoquinocyclinone was achieved using a pentacyclic lactone as the key intermediate (see scheme). The pyrrolo-pyrrole substructure was elaborated by acetylide acylation, conversion of an O,O-acetal into an N,O-acetal, and intramolecular amidine alkylation.

Full text of DOI:10.1002/chem.201403880

DOI: 10.1002/chem.201403880
Communication
&
Natural Products
Total Synthesis of Isoquinocyclinone
Mike Dischmann, Timo Frassetto, M. Andrꢀ Breuning, and Ulrich Koert*[a]
cinose B.[4] Synthetic solutions for this rare sugar have already
been reported, while no synthesis of the quinocyclines or the
aglycones exists so far.[5] Here, a total synthesis of isoquinocy-
clinone is communicated.
Abstract: The total synthesis of the heptacyclic natural
product isoquinocyclinone has been achieved. A Hauser
annulation was used to assemble the anthraquinone core
structure. The unique 2,4,5,6-tetrahydropyrrolo[2,3-b]pyr-
role substructure was prepared by alkyne addition to a lac-
tone intermediate and subsequent Ni0-mediated cyanide
addition, the conversion of an O,O- into an N,O-acetal, and
final intramolecular N-alkylation.
The heptacyclic structure of isoquinocylinone consists of an
anthraquinoide tetracycle (rings A–D) and a bicyclic amidine
(rings F,G) that connects C7 and C9O by an N,O-spiro center
C2’ in ring E (Scheme 1). The bicyclic F,G-heterocycle, a 2,4,5,6-
Isoquinocyclinone is the common aglycone of isoquinocycli-
ne A and B. Both natural products belong to the quinocyclines,
a class of anthracycline natural products consisting of quinocy-
cline A and B as well as isoquinocycline A and B (Figure 1).
These antimicrobial and cytotoxic compounds were isolated
first from Streptomyces aureofaciens[1] and later from micromo-
nospora sp. (TP-A0468)[2] and Streptomyces violaceus niger.[3]
The structure of isoquinocycline A was established by X-ray
crystal structure analysis.[1e] The sugar part of quinocycline A
and isoquinocycline A is the branched octose dihydrotrioxacar-
Scheme 1. Retrosynthetic analysis for isoquinocyclinone.
tetrahydropyrrolo[2,3-b]pyrrole, is unique among natural prod-
ucts.
A retrosynthetic consideration that takes account model
studies for the construction of the pyrrolopyrrole[6,7] leads from
isoquinocyclinone to a lactone 1 as a key intermediate. This
anthraquinoide tetracycle of 1 could be assembled by annula-
tion of the cyanoisobenzofuranone 2 and the cyclohexenone
3. The starting point for the synthesis of enone 3 is the iodide
4[8] (Scheme 2), which was transformed via its organolithium
Figure 1. Structures of quinocyclines.
[a] Dipl.-Chem. M. Dischmann, Dr. T. Frassetto, Dr. M. A. Breuning,
Prof. Dr. U. Koert
Fachbereich Chemie
Philipps-Universitꢀt Marburg
Hans-Meerwein-Straße, 35043 Marburg (Deutschland)
Fax: (+49)6421-2825677
E-mail: koert@chemie.uni-marburg.de
Scheme 2. Synthesis of enone 3: a) tBuLi, THF, ꢀ788C, methacroleine;
b) Ac2O, py; c) cat. PdCl2, PPh3, Na2CO3, dioxane, 1108C; d) Me2AlCl, CH2Cl2,
ꢀ78!ꢀ358C, 80 h; e) 17% HCl, THF/H2O, RT; f) TBSCl, imidazole, DMF, RT.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403880.
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Communication
compound into acetate 5. A Pd-mediated elimination resulted
in the E-selective formation of diene 6.[9] The subsequent
Diels–Alder reaction with enone 7 led to the racemic cyclohex-
ene 8. An acid-catalyzed aldol condensation produced the de-
sired cyclohexenone 3. An enantioselective variant (82% ee) of
this cycloaddition/aldol condensation sequence is described in
the Supporting Information.
Hauser annulation[10] of cyano-1(3H)-isobenzofuranone 2[11]
with enone 3 gave after oxidative aromatization anthraqui-
none 9 (Scheme 3). Methyl ether formation and subsequent
Scheme 4. a) TBSO(CH2)2CCH, LiHMDS, THF, ꢀ788C, 45 min; then 15, THF,
ꢀ788C to RT, 6 h; b) K2[Ni(CN)4], KCN, Zn, H2O, RT, 4 h; then 08C, MeOH, 16
THF/MeOH, 08C, 30 min; c) TsCl, Et3N; d) HCl; e) TsCl, Et3N; f) TMSCl, NH3,
CHCl3; g) CAN, MeCN, H2O; h) 2,6-lutidine, 1208C; i) TBAF, THF, 90 min, RT;
j) 3HFꢂNEt3, CH2Cl2, RT, 18 h; k) BCl3 (1m in CH2Cl2), CH2Cl2, ꢀ108C then 1 h
RT. CAN=cerium ammonium nitrate; LiHMDS=lithium hexamethyl disila-
zide; TBAF=tetrabutylammonium fluoride.
confirmed by comparison with NMR spectroscopic data of a re-
lated structure, in which an X-ray structure had been ob-
tained.[7] The following conversion into the ditosylate 18 re-
quired a three-step sequence with a separate introduction of
the sulfonamide first and the sulfonate second. Attempts for
a simultaneous introduction of both tosyl groups led to side
reactions (lactam formation). Treatment of compound 18 with
ammonia and TMSCl resulted in a conversion of the O,O-acetal
into an epimeric mixture of the N,O-acetals 19 and 20. Com-
pound 19 corresponds to the configuration of isoquinocycli-
ne A/B, whereas compound 20 shows the configuration of qui-
nocycline A/B. Both epimers could be separated by chromatog-
raphy. While focussing on the final ring-closure of the pyrrolo-
pyrrol substructure it was found advantageous to regenerate
the anthraquinone first. CAN-oxidation of anthrahydroquinone
dimethyl ether 19 resulted in the corresponding anthraqui-
none. After lutidine-mediated[7] ring G closure via intramolecu-
lar amidine alkylation, the complete isoquinocyclinone struc-
ture 21 was obtained. The optimal order for final deprotection
of the three different protective groups was TBAF-initiated
TBS-cleavage first, HF-mediated sulfonamide removal second,
and last methyl-ether deprotection by BCl3. Racemic isoquino-
cylinone obtained after deprotection matched the reported an-
alytical and spectroscopic data for the natural product.[2,12] The
Scheme 3. a) LDA, THF, ꢀ788C, then 3, ꢀ788C!RT, 8 h; b) DMF, O2, 958C,
16 h; c) Me2SO4, K2CO3, acetone reflux. 4 h; d) HCl; e) Dess–Martin reagent;
f) KH2PO4, NaClO2, amylene, tBuOH, RT, 1 h; g) KI/I2, NaHCO3; h) K2CO3,
MeOH/THF 08C; i) 3m H2SO4, acetone/H2O; j) Na2S2O4, KOH, Me2SO4, phase-
transfer catalysis, CH2Cl2/H2O; k) TBSCl, imidazole.
TBS deprotection led to the primary alcohol 10 that was oxi-
dized to the carboxylic acid 11. An iodolactonization afforded
lactone 12 and subsequently the epoxy methyl ester 13. The
latter was converted into the hydroxyl lactone 14. The direct
epoxidation of 11 gave a mixture of diastereomers and caused
purification problems. Initial experiments revealed an interfer-
ence of the anthaquinone structure with the introduction of
the pyrrolopyrrol part. Therefore, this substructure was protect-
ed as anthrahydroquinone dimethyl ether. After TBS protection
of the benzylic alcohol the TBS-lactone 15 was obtained.
Elaboration of the bicyclic amidine (rings F,G) is summarized
in Scheme 4. Acylation of lactone 15 with 4-tert-butyldimethyl-
silyloxy-butyne gave hydroxyketone 16, which was isolated as
a 1:1 mixture of the hemiacetal and the hydroxyl ketone. Hy-
drocyanation of the alkynone 16 with in situ generated
[Ni0(CN)4]4ꢀ gave the cyclic imidate 17. The structure of 17 was
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Communication
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epimeric N,O-acetal 20 could not be cyclised towards quinocy-
clinone by using lutidine. Instead, it could be epimerized with
trifluoroacetic acid (TFA) to the isoquinocyclinone precursor
19.
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In conclusion, an efficient synthesis of the heptacyclic isoqui-
nocyclinone structure was achieved. Noteworthy is the con-
struction of the pyrrolopyrrol substructure in the presence of
the anthracyclinone moiety. The 2,4,5,6-tetrahydropyrrolo[2,3-
b]pyrrole substructure was prepared by acylation of a lactone
intermediate, subsequent conversion of an O,O- into an N,O-
acetal and ring G-closure by intramolecular N-alkylation. The
synthesis opens the route for the study of the mode of action
of this structurally unique natural product, which may result
from intercalation of the anthracyclinone part between DNA
base pairs and covalent fixation of the N,O-acetal to DNA
amino groups.
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Acknowledgements
Financial support by the DFG (KO 1349/8-2) is gratefully ac-
knowledged.
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Keywords: acetals · Hauser annulation · isoquinocyclinone ·
natural products · total synthesis
[12] We thank Prof. Igarashi for kindly supply of copies of the NMR spectra
of isoquinocycline A and isoquinocyclinone. The NMR spectra of the
pyrrolo–pyrrol substructure, in particular, C3’, C4’, and C5’ exhibited
signal broadening that indicates a dynamic process associated with
amidine tautomers.
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Received: June 9, 2014
Published online on July 22, 2014
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