Oxidative 5-endo cyclization of enamides mediated by ceric ammonium nitrate

Article abstract of DOI:10.1021/ol030045f

(Matrix presented) Ceric ammonium nitrate mediates the oxidative 5-endo radical-polar crossover reactions of β-enamide esters to give 5,5-C,O-disubstituted-γ-lactams. Trapping of the intermediate cations leads to 5-hydroxy- or 5-alkoxy-γ-lactams depending

Full text of DOI:10.1021/ol030045f

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2063-2066
Oxidative 5-Endo Cyclization of
Enamides Mediated by Ceric Ammonium
Nitrate
,§
Andrew J. Clark,* Colin P. Dell,† John M. McDonagh,§ Joanna Geden,§ and
Peter Mawdsley§
Department of Chemistry, UniVersity of Warwick, CoVentry, CV4 7AL, UK, and
Lilly Research Centre Ltd, Erl Wood Manor, Sunninghill Road,
Widlesham, Surrey, GU20 6PH, UK
msrir@csV.warwick.ac.uk
Received March 18, 2003
ABSTRACT
Ceric ammonium nitrate mediates the oxidative 5-endo radical−polar crossover reactions of â-enamide esters to give 5,5-C,O-disubstituted-
γ-lactams. Trapping of the intermediate cations leads to 5-hydroxy- or 5-alkoxy-γ-lactams depending upon the reaction conditions. The
methodology was used to synthesize the basic heterocyclic ring fragments of the natural products L-755,807, Quinolacticin C, and PI-091.
The use of radical cyclization protocols to prepare hetero-
cyclic compounds continues to be widespread.1 By far the
Scheme 1. 5-Endo Cyclization Mediated by Mn(OAc)3
most popular methods for conducting such cyclizations
involve the use of Bu3SnH as a mediator. One distinct
disadvantage of this approach is that the cyclizations are
reductive in nature. We and others have recently reported
the use of Cu(I) halide complexes,2 nickel metal,3 or Mn-
(OAc)3 reagents4 in unusual oxidative 5-endo cyclization
reactions. In these reactions functionality is retained during
might be expected for very powerful one-electron oxidants,
the chemistry of Ce(IV) oxidations of organic molecules is
dominated by radical and radical cation chemistry.5
Nair and co-workers6 have carried out a number of studies
to compare the reactivity of Mn(OAc)3 with CAN in the
oxidative addition of 1,3-dicarbonyl radicals to unactivated
cyclization via an oxidative radical-polar crossover reaction
(e.g. Scheme 1). Cerium(IV) compounds represent some of
the most notable oxidants among lanthanide reagents. As
§ Chemistry Department University of Warwick.
† Lilly Research Centre Ltd.
(1) Bowman, W. R.; Fletcher, A. J.; Potts, E. B. S. J. Chem. Soc., Perkin
Trans. 1 2002, 2747.
(2) Clark, A. J. Chem. Soc. ReV. 2002, 1.
(5) Molander, G. A. Chem. ReV. 1992, 92, 29.
(6) (a) Nair, V.; Mattew, J.; Radhakrishnan, K. C. J. Chem. Soc., Perkin
Trans. 1 1996, 1487. (b) Nair, V.; Mattew, J. J. Chem. Soc., Perkin Trans.
1 1995, 187.
(3) Cassayre, J.; Quiclet-Sirre, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron
1998, 54, 1029.
(4) Davies, D. T.; Kapur, N.; Parsons, A. F. Tetrahedron 2000, 56, 3941.
10.1021/ol030045f CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003

alkenes, and discovered that CAN was often superior to Mn-
(OAc)3. More recently, CAN-mediated intermolecular radical
reactions in ionic liquids have been reported.7 Consequently,
we decided to investigate whether CAN could be used to
mediate 5-endo-trig cyclizations of â-enamide esters to give
γ-lactams of importance for natural product synthesis.
Our initial experiments examined the cyclization of the
â-amido ester precursor 4 (analogous to compound 1 from
Scheme 1). Compound 4 was prepared by N-acylation of
the imine derived from cyclohexanone 3 and p-methoxy-
benzylamine (PMB), with methyl malonyl chloride.4 Initial
reactions of 4 with 2 equiv of CAN in methanol at room
temperature gave the bicyclic lactam 5 in only 28% yield.
However, the yield of this reaction was found to improve
from 28% to 65% when 4 equiv of CAN was employed for
20 min. Addition of greater than 4 equiv was found to have
a detrimental effect on the product yield, Scheme 2. Under
Scheme 3. Proposed Mechanism of 5-Endo Cyclization of 4
Mediated by CAN
Scheme 2. 5-Endo Cyclization of 4 by CANa
aromatized structures 12 and 13 were isolated in poor yield
(compound 13 was contaminated with less than 5% of an
unknown inseparable impurity). Thus for 10 CAN-mediated
aromatization occurs after cyclization whereas for 11 cy-
clization is not observed at all.
a Reagents and conditions: (a) PMBNH2, Dean-Stark, toluene,
reflux; (b) MeO2CCH2COCl, toluene, 0 °C; (c) 4 equiv of CAN,
MeOH, rt.
Scheme 4a
these conditions no deprotection of the PMB group was
observed. Interestingly, while the Mn(OAc)3-mediated cy-
clization of 1 leads to the diene 2, the analogous CAN-
mediated cyclization of 4 furnishes the alkoxy trapped
product 5. Thus, the CAN and Mn(OAc)3 procedures are
complementary giving rise to different products.
Mechanistically 5 may be formed by initial radical
generation from 4 followed by a 5-endo cyclization and
oxidation to the acyl iminium ion 6 by a second equivalent
of CAN. Elimination, followed by a second radical genera-
tion and oxidation sequence furnishes the iminium ion 7,
which upon trapping with the solvent furnishes the observed
product 5. This is in keeping with the fact that 4 equiv of
CAN was required for efficient reaction. Cyclization of 4
did not proceed in other solvents (such as dichloromethane,
1,2-dichloroethane, benzene, or toluene) at room temperature
or at reflux.
The scope and limitation of the procedure was then
examined. Cyclization of 8 with use of the standard condi-
tions gave the expected 5-endo cyclization product 9 as an
inseparable 10:1 mixture of diastereomers (stereochemistry
of the major isomer unconfirmed) as well as an unknown
minor component (less than 3-4%) in 78% combined yield.
Reaction of the tetralone-derived enamides 10 and 11
proceeded in a slightly different manner. No solvent-trapped
products were isolated in either reaction. Instead the fully
a Reagents and conditions: (a) 4 equiv of CAN, MeOH, rt, 20
min.
As part of a progamme toward the synthesis of natural
products containing the highly functional 5,5-C,O-disubsti-
tuted-γ-lactam skeleton, such as 14-16,8 we next investi-
(8) Isolation: (a) L-755, 807: Lam, T. Y. K.; Hensens, D. D.; Ransom,
R.; Gaicobbe, R. A.; Polishool, J.; Zinc, D. Tetrahedron 1996, 52, 1481.
(b) PI-091: Kawashima, A.; Yosohimura, Y.; Sakai, N.; Kamigoori, K.;
Mizutani, T.; Omura, S. Jpn. Kokai Tokkyo Koho JP 02 62,859; Chem
Abstr. 1990, 113, 113856d. (c) Quinolactacin, C.; Tatsuta, K.; Misawa, H.;
Chikauchi, K. J. Antibiot. 2001, 54, 109.
(7) Bar, G.; Bin, F.; Parsons, A. F. Synth. Commun. 2003, 213.
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Org. Lett., Vol. 5, No. 12, 2003

Scheme 6. CAN-Promoted 5-Endo Cyclization to the
Heterocyclic Core of L,755,807 14a
a Reagents and conditions: (a) 4 equiv of CAN, MeCN, rt, 20
min; (b) 4 equiv of CAN, i-PrOH, rt, 20 min.
with 4 equiv of CAN in acetonitrile as solvent, followed by
aqueous workup furnished the desired hydroxy lactams
20a,b. In a similar manner changing the solvent from MeOH
to i-PrOH led to the isopropoxy-trapped lactam 21. Attempts
Figure 1. Structures of natural products 14-16.
gated the cyclization of enamides that contained no substi-
tution at the terminal carbon. Hence, cyclization of either
the methyl 17a or ethyl 17b esters with CAN in MeOH at
room temperature for 20 min furnished the desired 5-endo
products 18a,b in moderate yield (58-67%). We were
delighted that the reaction was successful and allowed access
to the desired heterocyclic core of the platelet inhibitor PI-
091, Scheme 5.
Scheme 7. CAN-Promoted 5-Endo Cyclization to the
Heterocyclic Core of Quinolactacin C 16a
Scheme 5. CAN-Promoted 5-Endo Cyclization to the
Heterocyclic Core of PI-091 15a
a Reagents and conditions: (a) 4 equiv of CAN, MeCN, rt, 20
min, H2O; (b) TFA, heat.
to mediate the reactions by using other Ce(IV) salts such as
CeO2 or Ce(OH)4 in MeCN led to unreacted starting material.
Scheme 8. 5-Endo CAN-Promoted Cyclization of 25 and 27a
a Reagents and conditions: (a) 4 equiv of CAN, MeOH, rt, 20
min; (b) 4 equiv of CAN, MeOH, reflux.
To maximize the yield in the synthesis of 18a the
temperature was increased and 17a was heated with CAN
in MeOH for 2 h at reflux. Under these conditions a 1:1
mixture of 18a and 19 was isolated in 50% yield. Presumably
19 arises from a Michael addition of MeOH to the unsatur-
ated heterocycle 18a followed by further CAN-mediated
oxidation.
We have recently published a route to the side-chain
tetraene fragment of L-755,807, 14.9 Consequently, we
wished to test our methodology to see if it was applicable
for the formation of γ-hydroxylated heterocycles as well as
γ-methoxylated heterocycles. In other words, could we
mediate the cyclization in the presence of other nucleophiles
(e.g. H2O instead of MeOH). Reaction of both 17a and 17b
a Reagents and conditions: (a) 4 equiv of CAN, MeCN, rt, 20
min; (b) 4 equiv of CAN, MeCN, rt, 20 min, H2O.
(9) Clark, A. J.; Ellard, J. M. Tetrahedron Lett. 1998, 39, 6033.
Org. Lett., Vol. 5, No. 12, 2003
2065

Utilizing our approach it was possible to prepare the
analogue 23 of the Quinolactacin C skeleton. Thus treatment
of 22 with 4 equiv of CAN in acetonitrile led to the desired
hydroxy lactams after aqueous workup (albeit as a 2:1
mixture of diastereomers). Attempts to deprotect the p-
methoxybenzyl group by using more CAN or TFA furnished
the eliminated lactam 24 as a 1.3:1 E:Z mixture, Scheme 7.
We further tested the scope and limitation of the CAN-
mediated 5-endo procedure by examining the reaction of the
precursor 25. Cyclization of 25 could in theory proceed either
via a 5-endo cyclization onto the enamide alkene or by a
5-exo cyclization onto the allyl group. Reaction with CAN
in MeCN gave rise exclusively to the 5-endo product 26,
and no 5-exo product was detected, Scheme 8.
intermediates by solvent instead of dienes. This may be due
to the milder reaction temperatures involved for the CAN-
mediated reactions (rt) compared to the Mn(OAc)3 reactions
(>70 °C), as the intermediate 5-hydroxylated or 5-alkoxy-
lated products undergo facile elimination of H2O or ROH
upon prolonged heating,10 or treatment with acid at room
temperature. The application of this methodology to the
synthesis of the heterocyclic cores of a range of 5,5-C,O-
disubstituted-γ-lactam natural products has been demon-
strated.
Acknowledgment. We acknowledge Lilly Research Ltd
for a studentship (J.P.M.).
Supporting Information Available: Selected experi-
mental procedures and characterization data for compounds
4, 8, 10, 11, 17a, 17b, 22, and 27 and representative 1H and
13C NMR spectra for 9, 13, 23, 24, and 28. This material is
available free of charge via the Internet at http://pubs.acs.org.
In the same way substrate 27 underwent exclusive 5-endo
cyclization to give 28 in 46% yield. No competing 6-exo
cyclization or tandem cyclization of the postulated intermedi-
ate acyl iminium ion onto the cyclohexenyl group was
observed.
In summary, we have demonstrated that efficient 5-endo
radical-polar crossover reactions can be mediated by CAN
in various solvents. The reactions differ from those mediated
by Mn(OAc)3 in that products arise from trapping of
OL030045F
(10) Compound 4 was observed to eliminate MeOH when heated or
treated with p-TSA in toluene at reflux.
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Org. Lett., Vol. 5, No. 12, 2003