An efficient synthesis of β,γ,γ-trisubstituted-α- diethoxyphosphoryl-γ-lactams: A convenient approach to α-methylene-γ-lactams

Article abstract of DOI:10.1016/j.tetlet.2013.03.130

A general and efficient method for the preparation of β,γ, γ-trisubstituted-α-phosphono-γ-lactams is presented for the first time. This approach is based on the Michael addition of diethyl acetamidomalonate to methyl (E)-3-aryl-2-(diethoxyphosphoryl)acrylates. Application of the phosphono-lactams obtained for the preparation of α-methylene-γ-lactams is also reported.

Full text of DOI:10.1016/j.tetlet.2013.03.130

Accepted Manuscript
An efficient synthesis of β,γ,γ-trisubstituted-α-diethoxyphosphoryl-γ-lactams:
a convenient approach to α-methylene-γ-lactams
Dariusz Deredas, Łukasz Albrecht, Henryk Krawczyk
PII:
S0040-4039(13)00557-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.130
TETL 42760
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 February 2013
19 March 2013
28 March 2013
Please cite this article as: Deredas, D., Albrecht, Ł., Krawczyk, H., An efficient synthesis of β,γ,γ-trisubstituted-α-
diethoxyphosphoryl-γ-lactams: a convenient approach to α-methylene-γ-lactams, Tetrahedron Letters (2013), doi:
http://dx.doi.org/10.1016/j.tetlet.2013.03.130
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An efficient synthesis of β,γ,γ-trisubstituted-
α-diethoxyphosphoryl-γ-lactams: a
convenient approach to α-methylene-γ-
lactams
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Dariusz Deredas, Łukasz Albrecht, Henryk Krawczyk

1
Tetrahedron Letters
journal homepage: www.elsevier.com
An efficient synthesis of β,γ,γ-trisubstituted-α-diethoxyphosphoryl-γ-lactams: a
convenient approach to α-methylene-γ-lactams
Dariusz Deredas, Łukasz Albrecht, Henryk Krawczyk
Institute of Organic Chemistry, Technical University (Politechnika), 90-924 Łódź, Żeromskiego 116, Poland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general and efficient method for the preparation of β,γ,γ-trisubstituted-α-phosphono-γ-lactams
is presented for the first time. This approach is based on the Michael addition of diethyl
acetamidomalonate to methyl (E)-3-aryl-2-(diethoxyphosphoryl)acrylates. Application of the
phosphono-lactams obtained for the preparation of α-methylene-γ-lactams is also reported.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Michael addition
olefination
α-diethoxyphosphoryl-γ-lactams
α-methylene-γ-lactams
1,1,3,3-tetramethylguanidine
The development of methods for the synthesis of α-
alkylidene-γ-lactams is an important goal since these motifs are
found in compounds of biological interest. The presence of an α-
alkylidene-γ-lactam unit is a characteristic structural feature of
naturally occurring compounds such as pukeleimid E,1 anantine
and isoanantine.2
Another approach involves the allylboration of aldimines,
derived from aldehydes and ammonia, with 2-
(methoxycarbonyl)allylboronates.9 The asymmetric synthesis of
highly enantiomerically enriched β-monosubstituted and β,γ-
disubstituted-α-methylene-γ-lactams was achieved by zinc-
promoted addition of ethyl 2-(bromomethyl)acrylate or ethyl 2-
(bromomethyl)crotonate to chiral sulfinylimines followed by
hydrolysis to remove the chiral auxiliary.10 Enantiomerically pure
(S)-α-methylene pyroglutamic acid was synthesized from (S)-
pyroglutamic acid.11 Besides these well established approaches, a
route involving the synthesis of α-diethoxyphosphoryl-γ-lactams
followed by their Horner-Wadsworth-Emmons (HWE) reaction
with formaldehyde has emerged as a very attractive method for
the preparation of N-unsubstituted-β-monosubstituted or β,γ-
disubstituted-α-methylene-γ-lactams. All the previous successful
syntheses of N-unsubstituted-α-phosphono-γ-lactams involved
Figure 1. Natural products containing an α-alkylidene-γ-lactam
moiety.
chemoselective
reduction
of
2-diethoxyphosphoryl-4-
nitroalkanoates followed by lactamization of the resulting 2-
diethoxyphosphoryl-4-aminoalkanoates.3e,12 In the course of our
earlier studies, we reported that the conjugate addition of primary
nitroalkanes to t-butyl (E)-3-aryl-2-(diethoxyphosphoryl)-
acrylates constituted a key step in the synthesis of wide range of
α-phosphono-γ-lactams.3d
A number of substituted α-alkylidene-γ-lactams have been
shown to exhibit significant pharmacological activities such as
cytotoxicity,3 antitumor4 and anti-inflammatory.5 Although many
synthetic strategies have been developed for the preparation of
N-substituted-α-methylene-γ-lactams, methods to synthesise their
N-unsubstituted analogues are limited.6 β,γ-Disubstituted-α-
methylene-γ-lactams can be obtained by SN2 substitution
reactions of Baylis-Hillman acetates with nitroalkanes followed
by chemoselective reduction and lactamization.7 The synthesis of
β,γ-disubstituted-α-methylene-γ-lactams from Baylis-Hillman
alcohols has also been reported.8
In this paper, we disclose the first application of methyl (E)-3-
aryl-2-(diethoxyphosphoryl)acrylates 2 for the synthesis of β,γ,γ-
trisubstituted-α-phosphono-γ-lactams 6 based on the utilization of
diethyl acetamidomalonate (3) as a Michael donor. This approach
expands greatly the scope of the conjugate addition involving
(E)-3-aryl-2-(diethoxyphosphoryl)acrylic acids and their
———
 Corresponding author. Tel.: +48-42-636-3223; fax: +48-42-636-5530; e-mail: henkrawc@p.lodz.pl

2
Tetrahedron
Scheme 1. Reagents and conditions: (a) 1 (1.0 equiv), MeI (4.0
equiv), K2CO3 (2.1 equiv), acetone, r.t., 4 d; (b) 3 (1.1 equiv),
TMG (1.0 equiv), CH2Cl2, r.t., 1-4 d; (c) Boc2O (1.2 equiv),
Table 1. Reaction times (2→6) and yields of the products
produced via Scheme 1
t
DMAP (0.25 equiv), CH2Cl2, r.t., 3 h; (d) BuOK (1.2 equiv),
Ar
Time
Yield (%)
THF, r.t., 0.5 h then (HCHO)n, (5 equiv), r.t., 1 h; (e)
CF3COOH, CH2Cl2, r.t., 1 h.
derivatives,6,13 and provides a new and practical entry to β,γ,γ-
trisubstituted-α-methylene-γ-lactams 9.
(d)
1
2
6
7
8
9
4-Cl-C6H4
98
97
99
98
97
96
82
68
87
74
78
82
86
96
80
95
97
87
74
79
85
80
86
78
83
83
81
87
4-Me-C6H4
2
4-MeO-C6H4
3
Scheme
1
outlines the transformation of (E)-3-aryl-2-
(diethoxyphosphoryl)acrylic acids14 1 into the corresponding α-
methylene-γ-lactams 9. Our investigations began with the
preparation of methyl (E)-3-aryl-2-(diethoxyphosphoryl)acrylates
2a-f. The esterification of acids 1a-f was performed using methyl
iodide in the presence of potassium carbonate and provided the
corresponding esters 2a-f in high yields. Next, in our initial
studies, various bases were examined for their ability to mediate
the 1,4-addition of malonate 3 to methyl acrylate 2a. Attempts to
prepare the adduct 4a by means of the usual Michael catalysts
such as t-BuOK, EtONa or piperidine failed to give the desired
product. After much experimentation, it was found that the use of
1,1,3,3-tetramethylguanidine (TMG)15 in a stoichiometric amount
gave the best result in terms of reaction rate, as well as the yield
and purity of the product. The addition proceeded efficiently in
CH2Cl2 at room temperature and was complete within one day. It
was found that under these conditions, the initially formed adduct
4a lactamized completely into N-acetyl lactam 5a, which
subsequently underwent spontaneous deacylation to give N-
unsubstituted lactam 6a, exclusively. TMG acts as a catalyst for
the Michael addition step and the deacylation step;16 it is essential
to use it in an equimolar amount, otherwise product 6a becomes
contaminated with the unreacted N-acetyl-lactam 5a. Other
strong organic bases such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were also
found to be effective promotors of the Michael addition, but the
reaction was not chemoselective and led to the formation af
mixtures of 5a and 6a.
3,4-(OCH2O)-C6H3
3,4-(MeO)2-C6H3
4-NO2-C6H4
4
4
1
69a 91a
a Yields of compounds 10 and 11.
indicates that the diastereoisomeric products undergo rapid
epimerization due to the presence of the acidic hydrogen at C-3.
The trans relative stereochemistry at the stereogenic centers C-3
and C-4 of lactams 6 was assigned on the basis of H- and 13C-
1
3
NMR data. The observed values of the coupling constants JPH(3)
3
3
= 18.5-19.4 Hz, JH(3)H(4) = 6.8 – 8.5 Hz, JPC(2) = 7.0-8.4 Hz
clearly proved the trans arrangement of the phosphoryl and aryl
groups.3d
Transformation of the α-phosphono-γ-lactams 6 into the
corresponding α-methylene-γ-lactams 9 was realized using a
previously described procedure.3d N-Boc-α-diethoxyphosphoryl-
γ-lactams 7a-f were generated by treatment of the respective
lactams 6a-f with Boc2O in the presence of catalytic DMAP.
Notably, all the N-Boc-lactams 7a-f were obtained as single
trans-diastereoisomers. The N-Boc-lactams 7a-f displayed
similar coupling constant values to these observed for N-
unprotected lactams 6a-f. The HWE reaction of the N-Boc-α-
phosphono-γ-lactams 7a-e with excess paraformaldehyde in the
presence of t-BuOK afforded the corresponding α-methylene-γ-
lactams 8a-e. In contrast, the initially formed α-methylene-γ-
lactam 8f underwent spontaneous isomerisation into α,β-
unsaturated lactam 10. Free α-methylene-γ-lactams 9a-e and
endo-γ-lactam 11 were generated from the corresponding N-Boc
derivatives 8a-e and 10 by treatment with CF3COOH. Lactams
9a-e and 11 were isolated as crystalline solids in high yields.
This protocol was successfully extended to methyl (E)-3-aryl-2-
(diethoxyphosphoryl)acrylates 2b-f. Generally, reactions of
acrylates 2b-e, bearing electron-donating substituents on the ring,
required longer reaction times to achieve full conversion of the
starting materials and were complete within 2-4 days (Table 1).
The crude products 6a-f were formed as mixtures of
diastereoisomers. Notably, the crystalline α-phosphono-γ-lactams
6a-f were isolated as single trans-diastereoisomers. This
In conclusion, we have demonstrated that TMG-promoted
conjugate addition of diethyl acetamidomalonate to methyl (E)-3-
aryl-2-(diethoxyphosphoryl)acrylates provides access to β,γ,γ-
trisubstituted-α-phosphono-γ-lactams in
a single step. As
demonstrated, the latter compounds can be transformed into α-

3
methylene-γ-lactams. This protocol benefits from easily available
starting materials, experimental simplicity and high efficiency.
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Supplementary Material
Supplementary data associated with this article (experimental
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