Synthesis of amino acid derived enaminones via wolff rearrangement using vinylogous amides as carbon nucleophiles

Article abstract of DOI:10.1021/ja107329k

Cyclic enaminones were synthesized in high yields from amino acids in two steps via Wolff rearrangement. The cyclization represents a rare 6-exo-dig cyclization involving a ketene as an electrophile. No racemization was observed during this reaction.

Full text of DOI:10.1021/ja107329k

Published on Web 10/19/2010
Synthesis of Amino Acid Derived Enaminones via Wolff Rearrangement Using
Vinylogous Amides as Carbon Nucleophiles
Hajime Seki and Gunda I. Georg*
Department of Chemistry and Department of Medicinal Chemistry, Institute for Therapeutics DiscoVery and
DeVelopment, College of Pharmacy, UniVersity of Minnesota, 717 Delaware Street SE,
Minneapolis, Minnesota 55414
Received August 14, 2010; E-mail: georg@umn.edu
Scheme 1. Various Approaches for Enaminone Syntheses
Abstract: Cyclic enaminones were synthesized in high yields
from amino acids in two steps via Wolff rearrangement. The
cyclization represents a rare 6-exo-dig cyclization involving a
ketene as an electrophile. No racemization was observed during
this reaction.
Piperidine, indolizidine, and quinolizidine alkaloids (Figure 1)
display important biological properties and therefore have been
frequent targets for synthetic chemistry efforts.1 It is well-known
that monocyclic and bicyclic enaminones (2,3-dihydropyridin-
4(1H)-ones) can serve as versatile intermediates for their synthesis.2
Scheme 2. Optimization of Reaction Conditions
Figure 1. Examples of biologically active molecules containing piperidine,
indolizidine, and quinolizidine core structures.
The most common synthetic strategies (Scheme 1) to obtain
enaminones in optically active form are (1) the hetero Diels-Alder
reaction and (2) the nucleophilic addition to pyridinium salts
utilizing chiral auxiliaries or chiral catalysts.2,3 In 2006 we reported
a concise method that relies on the cyclization of amino acid derived
amino ynones to prepare enantioenriched enaminones under very
mild conditions.4 In some instances, however, partial racemization
of the reaction products was observed during these reactions.4 To
address this issue a different disconnection, which retained the use
of amino acids, was sought. We hypothesized that enaminones could
be derived from diazoketones carrying a pendant enamine moiety
that could trap the ketene generated by a Wolff rearrangement
(Scheme 2).5
prepare enaminones from amino acids via Wolff rearrangement
using vinylogous amides as carbon nucleophiles. The cyclization
represents a rare example of a 6-exo-dig cyclization involving a
ketene as the electrophile.10
Our efforts started with the synthesis of diazoketone 1 as a
starting material for the reaction in order to test the feasibility of
our hypothesis (Scheme 2). N-Benzylglycine readily underwent
Michael addition to ethyl propiolate, and the acid group of the
reaction product was subsequently converted into a diazo moiety.
With diazoketone 1 in hand, we embarked on screening reaction
conditions. A variety of silver salts, known to induce the Wolff
rearrangement, as well as other reaction conditions were tested.
We found that the use of halogenated solvents, PhCO2Ag,
The Wolff rearrangement and its ketene intermediate have been
studied extensively. Reactions involving the reactive ketene species
are classified as either cycloaddition or nucleophilic addition
reactions, exemplified by the Staudinger reaction and the Arndt-
Eistert homologation.6,7 While a C-C bond is formed in cycload-
ditions, C-C bond formation in nucleophilic addition reactions of
ketenes are less common. Although ketenes have been investigated
in reactions with organolithium and magnesium reagents, other types
of carbon nucleophiles have been studied less frequently8 and
typically involve intermolecular reactions. Only a few reports have
appeared where a carbon nucleophile was employed in an intramo-
lecular fashion.9 Herein, we detail our new synthetic strategy to
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15512 J. AM. CHEM. SOC. 2010, 132, 15512–15513
10.1021/ja107329k  2010 American Chemical Society

C O M M U N I C A T I O N S
CF3CO2Ag, and AcOAg readily facilitated the rearrangement to
furnish the desired product in excellent yields. The presence of
triethylamine, which is often used in Arndt-Eistert homologations
as an additive, however diminished the yield. As a result of this
study, we selected PhCO2Ag as the catalyst and CH2Cl2 as the
solvent for further studies of this method. With optimized reaction
conditions in hand, we investigated the scope of the reaction (Table
1). First, diazoketones 3, 5, and 7 (entries 1-3) were synthesized
from N-benzylglycine and the corresponding alkynes. Upon treat-
ment with PhCO2Ag, the desired enaminones 4, 6, and 8 were
obtained in good yields. Next, R-substituted diazoketone 9 and 11
(entries 4-5) were prepared from N-methylalanine and N-meth-
ylleucine respectively, which underwent cyclization to afford ꢀ-alkyl
enaminones 10 and 12. 19F NMR analysis of the Mosher ester of
(S)-12 in comparison to the Mosher esters of (()-12 revealed that
only a single diastereoisomer of the (S)-12 Mosher ester had formed
(see Supporting Information (SI)).11 Diazoketones 13, 15, 17, and
19 (entries 6-9) derived from cyclic amino acids afforded bicyclic
enaminones 14, 16, 18, and 20 in good yields. These derivatives
are known to be excellent intermediates for indolizidine, and
quinolizidine syntheses.2 Mosher ester derivatives of 14 and 16
showed single diastereoisomers by HPLC analysis (see SI).11
(2R,8aS)-18 was formed as a single diastereoisomer as determined
Table 1. Substrate Scope of the Reactiona
1
by H NMR.
In summary, we have developed a novel enantiospecific synthetic
method to obtain monocyclic, bicyclic, and tricyclic enaminones
from amino acids in two steps. Due to the lack of racemization, a
simple nucleophilic 6-exo-dig cyclization is a plausible mechanism,
which is a favorable transformation according to Baldwin’s rules.10
Further investigation regarding the synthetic utility of this meth-
odology is ongoing.
Acknowledgment. This work was supported by National
Institutes of Health Grant GM081267 and the University of
Minnesota through the Vince and McKnight Endowed Chairs. We
thank Dr. Subhashree Rangarajan for mass spectrometry assistance.
Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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1
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