The imidato-alkenyllithium route for the synthesis of the isoquinocycline-pyrrolopyrrole substructure

Article abstract of DOI:10.1021/ol200085g

A convergent and effective synthesis of the pyrrolopyrrole substructure (CDEFG) of the isoquinocyclines is reported. A key step is a tin-lithium exchange of an imidato-alkenyltin compound (a ring G equivalent) and the subsequent acylation with a lactone.

Full text of DOI:10.1021/ol200085g

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1402–1405
The Imidato-Alkenyllithium Route for the
Synthesis of the Isoquinocycline-
Pyrrolopyrrole Substructure
ꢀ
M. Andre Breuning, Klaus Harms, and Ulrich Koert*
Fachbereich Chemie, Philipps-University Marburg, Hans-Meerwein-Strasse, D-35032
Marburg, Germany
koert@chemie.uni-marburg.de
Received January 11, 2011
ABSTRACT
A convergent and effective synthesis of the pyrrolopyrrole substructure (CDEFG) of the isoquinocyclines is reported. A key step is a tin-lithium
exchange of an imidato-alkenyltin compound (a ring G equivalent) and the subsequent acylation with a lactone. The resulting acetal is used
successfully for the ring F closure to the pyrrolopyrrole. The sole formation of the isoquinocycline N,O-acetal epimer is in accordance with the
proposed mechanism for the isomerization of quinocyclines to isoquinocyclines.
Strepomyces aureofaciens produces the four antibiotic
compounds quinocycline A, quinocycline B, isoquino-
cycline A, and isoquinocycline B (Figure 1).1 The quino-
cyclines were isolated in 1957 and microbiological testing was
conducted.1,2 The γ-branched octoses of the quinocyclines
were isolated through hydrolysis under protic conditions.3,4
The structure of isoquinocycline A was confirmed by
Tulinsky via X-ray crystal structure analysis.5 Quinocycline
B and isoquinocycline B were also isolated from
(1) (a) Celmer, W. D.; Murai, K.; Rao, K. V.; Tanner, F. W.; Marsh,
W. S. Antibiotics Annual 1957-1958; Medical Encyclopedia Inc.: New
York, 1958; pp 484-492. (b) Martin, J. H.; Shay, A. J.; Pruess, L. M.;
Porter, J. N.; Mowat, J. H.; Bohonos, N. Antibiotics Annual 1954-1955;
Medical Encyclopedia Inc.: New York, 1955; pp 1020-1024. (c) Cosulich,
D. B.; Mowat, J. H.; Broschard, R. W.; Patrick, J. B.; Meyer, W. E.
Tetrahedron Lett. 1963, 7, 453–458. Erratum: Tetrahedron Lett. 1964,
13, 750.
(2) McBride, T. J.; English, A. R. Antibiotics Annual 1957-1958;
Medical Encyclopedia Inc.: New York, 1955; pp 493-501.
(3) Isolation of the anhydro sugar: Webb, J. S.; Broschard, R. W.;
Figure 1. Quinocycline structures.
Cosulich, D. B.; Mowat, J. H. J. Am. Chem. Soc. 1962, 84, 3183–3184.
(4) (a) Matern, U.; Grisebach, H.; Karl, W.; Achenbach, H. Eur. J.
Biochem. 1972, 29, 1–4. (b) Matern, U.; Grisebach, H. Eur. J. Biochem.
nocycline B possesses a strong cytotoxicity against human
1972, 29, 5–11.
micromonspora sp.6 and streptomyces violaceusniger.7 Qui-
myeloid leukemia U937 cells (IC50 = 0.09 μM).6
(5) Tulinsky, A. J. Am. Chem. Soc. 1964, 86, 5368–5369.
(6) (a) Furumai, T.; Igarashi, Y.; Higuchi, H.; Saito, N.; Oki, T.
J. Antibiot. 2002, 55, 128–133. Corrections: J. Antibiot. 2003, 56, C1. (b)
Igarashi, Y.; Higuchi, H.; Oki, T.; Furumai, T. J. Antibiot. 2002, 55, 134–
140. Corrections: J. Antibiot. 2003, 56, C1.
(7) El-Naggar, M. Y. J. Microbiol. 2007, 45, 262–267.
r
10.1021/ol200085g
Published on Web 02/21/2011
2011 American Chemical Society

Scheme 1. Synthetic Routes to the Pyrrolopyrrole Substructure
Scheme 2. Synthesis of a Metalated Ring G Equivalent
The formation of an imino ether in the presence of a vinyl
stannane is noteworthy, without precedence, and should
be applicable in general. A tin-lithium exchange (13 f 14)
was achieved by using methyl lithium at -78 °C.10 The
resulting Z-alkenyl lithium compound 14, which corres-
ponds to key reagent 6, was allowed to react with benzal-
dehyde to afford the addition product 15 in 97% yield.
The addition of the ring G equivalent to the lactone 1
was examined next (Scheme 3). Reaction of 1 with the
lithiated alkene 13 led to a ketone/hemiacetal mixture that
was converted into the mixed acetal 7 upon treatment with
trimethyl orthoformate and p-TosOH. Only one epimer
was observed in the mixed acetal formation. The imino
ether 7 could be transformed smoothly into the amidine 8
with ammonium chloride in refluxing methanol. Attempts
to achieve a closure of ring F at the stage of the amidine 8
(CSA; p-TosOH; AlMe3) led to decomposition of the
starting material only. To disfavor amidine protonation,
which may prevent nucleophilic N-attack at the acetal, the
amidine functionality was tosylated (8 f 16). With the
increased acidity of the tosylated amidine, the reaction of a
base like lutidine8 withcompound 16 was of interest. When
the tosylated amidine 16 was heated to 155 °C in lutidine
two stereoisomeric nitriles 17 and 18 were obtained, which
could be separated by chromatography. The stereochemi-
cal assignment was possible by NOE measurements and
the later X-ray structural analysis.
A synthetic challenge of the quinocyclines is the bicyclic
amidine (rings FG), which is connected to the rest of the
molecule via an N,O-spiro acetal. One synthetic access to
the isoquinocycline-pyrrolopyrrole substructure was re-
ported recently (route A in Scheme 1).8 After conversion
of the lactone 18 into the ketone 2, a Ni(0)-mediated
cyanation gave the imino ether 3. N,O-Tosylation and
conversion of the O,O-acetal into an N,O-acetal (4) af-
forded the ring F first. Ring G was closed at last in route A
by intramolecular N-alkylation and subsequent deprotection
(4 f 5). Considering shorter, even more efficient solutions
for the introduction of the pyrrolopyrrole substructure
(1 f 5) we devised an alternative synthetic solution (route
B in Scheme 1). Here, an already formed ring G would be
added to the lactone first. The exocyclic metalated olefin 6
carrying an imino ether could be a key reagent for this
transformation. The resulting imino ether 7 should be con-
vertible into the amidine 8. At last, the attack of the amidine
at the O,O-acetal should lead to the closure of ring F.
A tin-lithium exchange was chosen to access a metalated
ring G equivalent of type 6 (Scheme 2). The corresponding
organostannyl lactam 11 was prepared according to Ryu’s
procedure9 by using acyl-radical chemistry in two steps with
77% overall yield (9f 10 f 11). Attempts for a tin-lithium
exchange reaction with the stannyl lactam 11 to prepare a
dilithium reagent 12 failed.
Nitrile formation by tosylation of an amide and heating
up under basic conditions is already known in literature.11
In the present case a migration of the tosyl group from the
Treatment of the lactam 11 with trimethyloxonium
tetrafluoroborate gave the imino ether 13 in excellent yield.
(10) (a) Piers, E.; Karunaratne, V. J. Org. Chem. 1983, 48, 1774–1776.
(b) Piers, E.; Yeung, B. W. A. J. Org. Chem. 1984, 49, 4567–4569. (c)
Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1986, 108, 5655–5656.
(11) (a) Boshta, N. M.; Bomkamp, M.; Waldvogel, S. R. Tetrahedron
2009, 65, 3773–3779. (b) Wright, K.; Dutot, L.; Wakselman, M.;
Mazaleyrat, J.-P.; Crisma, M.; Formaggio, F.; Toniolo, C. Tetrahedron
2008, 64, 4416–4426. (c) Carlier, P. R.; Zhang, Y. Org. Lett. 2007, 9,
1319–1322.
(8) Cordes, J.; Harms, K.; Koert, U. Org. Lett. 2010, 12, 3808–3811.
€
For synthesis of the quinocycline A sugar moiety see: Konig, C. M.;
Harms, K.; Koert, U. Org. Lett. 2007, 9, 4777–4779.
(9) (a) Uenoyama, Y.; Fukuyama, T.; Ryu, I. Org. Lett. 2007, 9, 935–
937. (b) Tojino, M.; Uenoyama, Y.; Fukuyama, T.; Ryu, I. Chem.
Commun. 2004, 21, 2482–2483.
Org. Lett., Vol. 13, No. 6, 2011
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Scheme 3. Addition of the Ring G Equivalent to Lactone 1,
Amidine Formation and Conversion to Nitrile, and X-ray
Structure of Nitrile 19
Scheme 4. Mechanistic View for the Nitrile Formation and E,Z-
Isomerization
Scheme 5. Closure of Ring F and Formation of the
Pyrrolopyrrole Isoquinocycline Substructure
exocyclic amidine nitrogen to the endocyclic nitrogen has to
occur before sulfonamide elimination leads to the nitrile. A
mechanistic view for the reaction (16 f 17 þ 18) is given in
Scheme 4: Deprotonation of the tosylated amidine 20 results
in the anion 21, which after 1,3-N-tosyl migration leads to
22. An elimination results in the Z-unsaturated nitrile 23.
The subsequent Z,E-isomerization can be explained by
nucleophilic addition (23 f 24) followed by elimination
(24 f 25). While the formation of amidines by addition of
amines to nitriles is standard, this observed elimination of a
tosylated amidine to form a nitrile is a rare example.12
A cyclization of the E-nitrile 18 to form the N,O-acetal
19 was possible under acidic conditions. Only that epimer
of the N,O-acetal is formed, which corrresponds to the
isoquinocycline series. NOE data and an X-ray crystal
structure were used for the structural and stereochemical
assignment of compound 19 (Scheme 3).
equivalents of TFA at ambient temperature in methylene
chloride were found to be optimal conditions. NMR control
of the reaction progress showed a nearly complete migration
of tosyl group from the exocyclic nitrogen to the endocyclic
position (16 f 26) after 30-45 min. The ring F closure to the
desired pyrrolopyrrole substructure 28 required prolonged
reaction times (7 d). The yield for the TFA-mediated ring F
closure (16 f 28) was 96%. The structural assigment of
compound 28 was possible by comparison with the spectro-
scopic data of this compound obtained by route A, which are
secured by an X-ray crystal structure.8 After deprotection
(TBAF, HF-Et3N) the amidine 5 is accessible.
Noteworthy is the sole formation of the isoquinocyline
epimer 28 in the ring F closure reaction. Celmer1 observed
isomerization of quinocycline A into isoquinocycline A
under protic conditions. Igarashi and Furumai proposed a
mechanism for this isomerization: protonation of the
amidine 29 and subsequent ring-opening to the oxonium
ion 30 (Scheme 6);6b attack of the amidine from the
The closure of the ring F starting with the tosylated amidine
16 was examined under acidic conditions (Scheme 5). Five
(12) Golec reported formation of nitriles out of alkylated isothiazole
amines that is compareable to our results: Golec, J. M. C.; Scrowston,
R. M. J. Chem. Res. (S) 1988, 1, 46.
1404
Org. Lett., Vol. 13, No. 6, 2011

closure) has 7 steps with 17% overall yield; route B
(premade ring G and final ring F closure) has 7 steps with
67% overall yield. Clearly, the novel route B is more
efficient.
Scheme 6. Proposed Mechanism for Isomerization of Quino-
cycline A to Isoquinocycline A Adapted from Igarashi and
Furumai6b
In summary, a novel efficient synthesis for the CDEFG
substructure of isquinocyclines was developed. Key steps
of the synthesis were the reaction of the alkenyllithium
iminoether 14 with lactone 1 and the acid-catalyzed F-ring
closure of a tosylated amidine. The sole formation of the
isoquinocycline N,O-acetal epimer supports the presence
of an oxonium ion intermediate during the isomerization
of quinocyline to isoquinocycline. Of mechanistic interest
is the base-mediated N-tosyl migration followed by nitrile
formation.
opposite side of the oxonioum ion leads to the isoquinocy-
cline compound 31.
Future work will concern the extension of the novel
developed route B to the stereoselective total synthesis of
isoquinocycline A and B.
The ring closure of the tosylated amidine under acidic
conditions (16 f 26 f 28) should follow a related reaction
pathway via formation of the oxonium ion intermediate
27. The fact that in our case only the isoquinocycline and
no quinocycline substructure was observed is in accor-
dance with the proposed mechanism for isomerization of
the natural products.
A comparison of the two routes A and B from the
lactone 1 to the isoquinocycline substructure 5 gives the
following result: Route A (first ring F closure, then ring G
Acknowledgment. Generous support by the Deutsche
Forschungsgemeinschaft (KO1349/8-2) is gratefully
acknowledged.
Supporting Information Available. Full experimental
and characterization details for all new compounds and
X-ray crystallographic data of 19. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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