An efficient approach to the stereocontrolled synthesis of enamides

Article abstract of DOI:10.1021/ol070336e

A fast, flexible, and efficient approach for the stereocontrolled synthesis of enamides has been developed starting from lactams and amides through the use of imides. This new approach provides access to enamide systems not easily or currently accessible through other approaches.

Full text of DOI:10.1021/ol070336e

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1631-1633
An Efficient Approach to the
Stereocontrolled Synthesis of Enamides†
Mathew V. J. Villa,‡ Sarah M. Targett,§ John C. Barnes,
|
William G. Whittingham,§ and Rodolfo Marquez*,‡,
WestCHEM, UniVersity of Glasgow, Joseph Black Building, UniVersity AVenue,
Glasgow G12 8QQ, Scotland, Syngenta Ltd., Jealott’s Hill International Research
Centre, Bracknell, Berkshire RG42 6EY, and DiVision of Biological Chemistry and
Mol. Microbiology, School of Life Sciences, UniVersity of Dundee, Dundee DD1 5EH,
Scotland
r.marquez@chem.gla.ac.uk
Received February 9, 2007
ABSTRACT
A fast, flexible, and efficient approach for the stereocontrolled synthesis of enamides has been developed starting from lactams and amides
through the use of imides. This new approach provides access to enamide systems not easily or currently accessible through other approaches.
Enamides are very important subunits in various biologically
active natural products and pharmaceutical drug lead com-
pounds such as the antibiotic CJ-15,801 1, crocacin A 2,
the lituarines 3, and the anti-insecticidal agent 4 (Figure 1).1
Synthetically, enamides are highly reactive, which has made
them key intermediates in the synthesis of a variety of
heterocyclic compounds.2
The importance and relevance of enamides both as
building blocks and target units has been reflected in the
number of different approaches reported for their synthesis.3,4
The synthetic methods developed for the synthesis of
enamide systems thus far enjoy varying degrees of success,
† Dedicated to the memory of Vincent R. J. Villa.
‡ University of Glasgow.
Figure 1. CJ-15,801 1, crocacin A 2, lituarines 3, and anti-
insecticidal agent 4.
§ Syngenta Ltd.
| University of Dundee.
Ian Sword Lecturer of Organic Chemistry.
(1) (a) Vidal, J. P.; Escale, R.; Girard, J. P.; Rossi, J. C.; Chantraine, J.
M.; Aumelas, A. J. Org. Chem. 1992, 57, 5857. (b) Sugie, Y.; Dekker, K.
A.; Hirai, H.; Ichiba, T.; Ishiguro, M.; Shiomi, Y.; Sugiura, A.; Brennan,
L.; Duignan, J.; Huang, L. H.; Sutcliffe, J.; Kojima, Y. J. Antibiot. 2001,
54, 1060. (c) Kunze, B.; Jansen, R.; Hoefle, G.; Reichenbach, H. J. Antibiot.
1994, 47, 881.
(2) (a) McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds,
K.; Sarma, P. K. S.; Stevenson, P. J.; Thompson, N. J. Chem. Soc., Perkin
Trans. 1, 2002, 69. (b) Shirokawa, S. I.; Kamiyama, M.; Nakamura, T.;
Okada, M.; Nakazaki, A.; Hosowaka, S.; Kobayashi, S. J. Am. Chem. Soc.
2004, 126, 13604.
particularly with regard to yield and control of the double
bond stereochemistry. In a number of cases, the control of
double bond geometry is almost nonexistent.
A reliable, flexible, and stereoselective procedure for the
synthesis of enamide units would greatly improve current
approaches to the synthesis of enamide-bearing natural
(3) For an excellent review on the synthesis of enamides, see: Tracey,
M. R.; Hsung, R. P.; Antoline, J.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.;
Zhang, Y. Sci. Synth. 2005, 5, 387.
(4) (a) Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005,
44, 5992. (b) Han, C.; Shen, R. C.; Su, S.; Porco, J. A. Org. Lett. 2004, 6,
27.
10.1021/ol070336e CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/29/2007

products and pharmaceutically relevant heterocyclic systems.
We now report a novel and flexible approach that delivers
enamides in good yields and with high selectivity.
assigned on the basis of the alkene coupling constant (J )
14.4 Hz), on two-dimensional NOE experiments, and finally
through X-ray crystallography (Figure 2).7
In our approach, we envisioned the enamide unit as
originating from the unprecedented Wittig olefination of
the imide precursor 6. The desired imide intermediate could
in turn be obtained from the parent lactam unit 7 (Scheme
1).
Scheme 1. Proposed Synthesis of Enamides from Imides
Figure 2. Crystal structure of valerolactam-derived enamide 10.
Our newly developed conditions were then applied to a
number of lactam analogues of various ring sizes to assess
the reproducibility of this transformation. Treatment of
2-azetidinone 8a, 2-pyrrolidinone 8b, ꢀ-caprolactam 8c,
1-aza-2-cyclooctanone 8d, and 2-azonanone 8e with acetic
formic anhydride successfully generated the desired N-
formylimides (9a-e) in good yield after minimal purification.
The lower yield observed for the generation of N-formy-
lazetidinone 9a compared to the other imides can possibly
be explained through its lower boiling point and partial loss
during solvent removal under vacuum (Scheme 3).
Our decision to focus on the imide functionality emanated
from considering the formyl unit as potentially behaving as
a pseudoaldehyde unit due to the original lactam carbonyl.
It was reasoned that the nitrogen lone pair would be
effectively delocalized into the lactam carbonyl, thus render-
ing the formyl group more reactive than a typical formamide.
This approach would have the benefit of being able to take
advantage of the myriad of aldehyde olefination conditions
to stereoselectively generate polyfunctionalised enamides.5
Our initial formylation-olefination sequence studies began
with lactam 8, which upon formylation under nonstandard
conditions using acetic formic anhydride generated the
corresponding imide 9 in excellent yield (Scheme 2).6
Scheme 3
Scheme 2
Olefination of the stable imide intermediates (9a-e) under
Wittig conditions similar to those used before proceeded to
provide cleanly the desired enamides (10a-e) in moderate
to good yield and as a single E- double bond isomer in all
cases.
Treatment of imide 9 with ethyl triphenylphosphonoacetate
in benzene proceeded cleanly to generate the desired E-
enamide ester 10 in good yield and more importantly as a
single isomer (Scheme 2). The double bond geometry was
Having demonstrated the ability of our procedure to
generate lactam enamides efficiently and stereoselectively,
(5) For other non-imide-based olefination approaches to the synthesis
of enamides, see: (a) Paterson, I.; Cowden, C.; Watson, C. Synlett 1996,
209. (b) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett. 1993,
34, 1479.
(6) For traditional conditions for the formylation of lactams, see: (a)
Gramain, J. C.; Remuson, R. Synthesis 1982, 264. (b) Wells, G. J.; Bihovsky,
R.; Hudkins, R. L.; Ator, M. A.; Husten, J. Bioorg. Med. Chem. Lett. 2006,
16, 1151.
(7) The atomic coordinates for 10 (CCDC deposition no. CCDC603107)
are available upon request from the Cambridge Crystallographic Data Centre,
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW,
U.K. The crystallographic numbering system differs from that used in the
text; therefore, any request should be accompanied by the full literature
citation of this paper.
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Org. Lett., Vol. 9, No. 9, 2007

we decided to test the flexibility of our conditions on acyclic
amide-based systems.
Scheme 5 a
Unfortunately, treatment of a sample of acyclic amides
(11a-c) with acetic formic anhydride failed to generate the
corresponding imides in greater than 20% conversion despite
prolonged and more strenuous reaction conditions.
However, treatment of the amides (11a-c) with N-formyl-
benzotriazole and n-butyllithium proceeded cleanly to
generate the expected imide units (12a-c) in good yields
(Scheme 4).8 Surprisingly, treatment of lactams (8, 8a-e)
under the same N-formylbenzotriazole and n-butyllithium
conditions failed to generate any of the corresponding
N-formyl imides.
Scheme 4
a Reagents and conditions: (a) Ph3PCHCO2Et, PhH, 95 °C; (b)
Ph3PC(Me)CO2Et, PhH, 95 °C.
In conclusion, we have demonstrated that N-formylimides
are a viable starting point for the efficient, flexible, and
stereocontrolled synthesis of both simple and substituted
enamide systems.
Rewardingly, subjecting the newly generated acyclic
imides to the previously used olefination conditions afforded
the desired enamides (13a-c) in excellent yields. In all cases,
the E-enamide is the preferred isomer although various
amounts of the Z-isomer are formed in these cases (Scheme
5).
Scheme 6
The highly successful olefination of imides (13a-c)
encouraged us to apply this approach to the synthesis of
2-methyl-substituted enamides. 2-Substituted enamides have
proven to be remarkably difficult to access through traditional
approaches with any degree of stereocontrol.
Hence, we are pleased to report that treatment of imides
(12a-c) with the corresponding methyl-substituted phos-
phorus ylide proceeded to generate the desired 2-methyl-
substituted enamides (14a-c) in good yields and with high
E/Z selectivity (Scheme 5). Significantly, no double-bond
isomerization has been detected under the reaction con-
ditions.
We are currently working on the expansion and optimiza-
tion of this method for the synthesis of more complicated
enamide and dienamide systems, their synthetic derivatives,
and their applications to natural product synthesis.
Acknowledgment. M.V. thanks the EPSRC and Syngenta
Ltd. for support. R.M. is grateful to Dr. Ian Sword, Syngenta
Ltd., and the University of Glasgow for financial support.
Very recent results in our group indicate that imides can
also be successfully olefinated using nonstabilized ylides to
generate other functionalized enamide building blocks, for
example, bromo enamide 15 (Scheme 6).
Supporting Information Available: Experimental pro-
cedures and characterization data of the described compounds
and intermediates. This material is available free of charge
via the Internet at http://pubs.acs.org.
(8) Couty, S.; Barbazanges, M.; Meyer, C.; Cossy, J. Synlett 2005,
905.
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