them interesting synthetic targets. All quinocyclines show
an anthraquinoid tetracycle (ABCD) and are glycosylated
at C10 with γ-branched octoses. These are trioxacarcinose
B for (iso)quinocycline B and dihydro-trioxacarcinose B for
(iso)quinocycline A.5
Scheme 2. Synthesis of the Lactone 4
The most remarkable substructure of the (iso)quinocycline
aglycon is the bicyclic amidine (FG) that connects C7 and
C9O via an N,O-spiro center. This heterocycle, a 2,4,5,6-
tetrahydropyrrolo[2,3-b]pyrrole, is unique among natural
products and has so far only been found in the quinocyclines.
Having completed the stereoselective synthesis of dihydro-
trioxacarcinose B,6 we report here a synthetic access to the
pyrrolopyrrole substructure as the next step toward the total
synthesis of the quinocyclines.
A retrosynthetic analysis (Scheme 1) of the CDEFG-
substructure 2 of the (iso)quinocycline aglycon (1) reveals
Scheme 1
.
Retrosynthetic Analysis of the CDEFG-Substructure
of the (Iso)quinocycline Aglycon
the dihydronaphthalene 11. The ethyl ester could be hydro-
lyzed to the γ,δ-unsaturated carboxylic acid 5, which was
suitable for an iodolactonization. The resulting iodolactone
proved to be unstable and was therefore converted directly
with potassium methoxide into the epoxide 12. Under
aqueous acidic conditions, the epoxide was opened regiose-
lectively at the benzylic position, yielding a trans-diol that
underwent a subsequent lactonization to form the hydroxy-
lactone 13. The configuration of this compound could be
confirmed by an X-ray crystal structure (14). The TBS-
protection of the alcohol finally lead to the lactone 4.
It turned out that the reaction sequence from 11 to 4 works
quite well without intermediate chromatography. As com-
pounds 9, 10, and 11 can be purified by distillation, the TBS-
ether 4 can be prepared on a gram scale with only one final
chromatographic purification step.
The next steps of the synthesis are shown in Scheme 3.
The lactone 4 was allowed to react with double lithiated
3-butyn-1-ol to give the alkynone 15. No hemiacetal forma-
tion was observed for the case of the hydroxy alkynone 15.
The hydrocyanation of this alkynone was conducted accord-
ing to a method developed by Arzoumanian et al.8 By
generating [Ni0(CN)4]4- from a nickel precursor, potassium
cyanide, and zinc as a reducing agent, Arzoumanian et al.
were able to convert non-4-yn-3-one to 3-butyl-5-ethyl-5-
hydroxy-1H-pyrrol-2(5H)-one in 65% yield.8 By applying
these conditions to our alkynone 15, we therefore expected
to get the hydroxypyrrolone 17 or its condensation product
the possibility to construct the pyrrolopyrrole (FG) from the
(Z)-ꢀ-nitrilo alkenone 3. By converting the nitrile to an
amidine and the alcohol to a leaving group, the G-ring could
be closed by intramolecular substitution, while the F-ring is
established by formation of an N,O-acetal. Enone 3 should
be accessible by a cyanide addition to the corresponding
alkynone, which originates from lactone 4. The diol motif
in 4 leads to the olefin precursor 5, which could be prepared
from the arylacetic acid 6. This results in a synthetic strategy
that starts with the ring C and adds all other rings
sequentially. This approach should be applicable to the
isoquinocycline and quinocycline series.
The synthesis of the racemic lactone 4 is outlined in
Scheme 2. The starting point was the conversion of meth-
acrolein (7) to the iodo dioxolane 8.7 Fischer esterification
of 6 afforded the ethyl ester 9, which was alkylated with the
iodide 8 to obtain the dioxolane 10. Friedel-Crafts cycliza-
tion and subsequent elimination resulted in the formation of
(5) (a) Matern, U.; Grisebach, H.; Karl, W.; Achenbach, H. Eur.
J. Biochem. 1972, 29, 1–4. (b) Matern, U.; Grisebach, H. Eur. J. Biochem.
1972, 29, 5–11.
(6) Ko¨nig, C. M.; Harms, K.; Koert, U. Org. Lett. 2007, 9, 4777–4779.
(7) Larson, G. L.; Klesse, R. J. Org. Chem. 1985, 50, 3627.
(8) Arzoumanian, H.; Jean, M.; Nuel, D.; Garcia, J. L.; Rosas, N.
Organometallics 1997, 16, 2726–2729.
Org. Lett., Vol. 12, No. 17, 2010
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