Efficient and Direct Synthesis of γ-Amino-α,β-Unsaturated Amides by Catalyzed Allylic Substitution of α-Fluoroenamides: Toward to Synthesis of Hybrid Peptides and Indolizidines

Article abstract of DOI:10.1002/ejoc.201800110

A variety of γ-amino-α,β-unsaturated amides have been synthesized from readily available α-fluoroenamides precursors via an unprecedented intermolecular and intramolecular conjugative catalytic amination process. These γ-amino-α,β-unsaturated amides are useful intermediates for accessing rarely synthesized hybrid peptides, αγα sequences, and various classes of alkaloids containing a pyrrolidine ring, as illustrated by total synthesis of the indolizidine alkaloid coniceine.

Full text of DOI:10.1002/ejoc.201800110

A Journal of
Accepted Article
Title: Efficient and Direct Synthesis of γ-amino-α,β-unsaturated amides
by Catalyzed Allylic Substitution of α-Fluoroenamides: toward to
Synthesis of Hybrid Peptides and indolizidines.
Authors: Samir Bouzbouz, Harsha vardhan Reddy KASIREDDY, and
Matthieu Bédier
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800110
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800110
Supported by

10.1002/ejoc.201800110
European Journal of Organic Chemistry
Efficient and Direct Synthesis of -amino-,-unsaturated amides
by Catalyzed Allylic Substitution of -Fluoroenamides: Toward to
Synthesis of Hybrid Peptides and indolizidines.
K.Harsha vardhan Reddy, Matthieu Bédier, Samir Bouzbouz*
Dedication ((optional))
Over the past two decades, the catalytic allylic substitution
reaction has contributed greatly in the development of new
methodologies and synthesis strategies. In general, the
formation of C-N, C-O and C-S bonds has been achieved by
the metal-catalyzed allylic substitution.[6] Palladium or iridium
are used as metals in the great majority of allylic
substitutions. [7] On the other hand, despite the similarities with
the palladium, the platinum has not been extensively exploited in
allylic substitution [8] reactions, much less using substrates of
Abstract: A variety of -amino-,-unsaturated amides have been
synthesized from readily available -fluoroenamides precursors
via an intermolecular and intramolecular unprecedented
conjugative catalytic amination process. These -amino-,-
unsaturated amides are useful intermediates for accessing rarely
synthesized hybrid peptides  sequences and various classes of
alkaloids containing a pyrrolidine ring, as illustrated by total synthesis
of the indolizidine alkaloid coniceine.
allylic fluorides
.
The chemistry of allylic fluorides has been extensively studied [9] and
recent studies focused on the palladium catalysis of these allylic
fluorides have been reported. [10] One example has been reported[11]
of use of the platinum catalyst in an allylic substitution reaction with
an amine of an allyl fluoride nonfunctionalized. Recently, we have
The building block -amino--unsaturated amide is a key
fragment present in many bioactive natural products. Such as
example the family of thalassospiramides. [1] Recently, it has been
described that thalassospiramide C showed nanomolar inhibitory
activity (3.4 ± 1.2 nM) against the cysteine protease calpain 1.[2]
Another example, DNK333 is a potent antagonist of the dual
neurokinin receptor and clinical trials show that DNK333 inhibits
neurokinin A-induced bronchoconstriction in asthmatic patients
(Scheme 1). [3]
developed from -silylenamides [12a,b] a rapid process for access to
[12c]
functionalized -fluoroenamides.
Herein, we disclose an
efficient strategy for the synthesis of a variety of -amino-,-
unsaturated amides from readily available a-fluoroenamides
precursors via an intermolecular unprecedented conjugative
catalytic amination process. These -amino-,-unsaturated
amides are useful intermediates for accessing rarely synthesized
hybrid peptides aga sequences (Scheme 2).
Scheme 1. -amino--unsaturated amides are key moieties for biological
activity
The -amino--unsaturated amides can be considered as direct
intermediates for the synthesis of natural products. Moreover, they
are useful intermediates for access to hybrid peptide sequences.[4] At
this stage, there is no direct method of synthesis of highly
functionalized -amino--unsaturated amides. Indirectly, these
substrates are obtained from the g-amino-a,b-unsaturated esters,
which have been widely studied in the literature. [5]
Then, we will develop the substitution intramolecular allylic to
access the cyclic -amino-,-unsaturated amide. It will be used
as valuable intermediate in the synthesis of the indolizidine
alkaloid coniceine.[13] We set out to optimize the intermolecular
conjugative catalytic amination of the a-fluoroenamide 1 which
was readily synthesized in three steps from benzylamine.[14] In
the preliminary studies of this reaction, the main problem of
regioselectivity has been solved. These studies have shown that
the temperature of 40 °C is a good compromise between the
reactivity and a very low ratio of alpha product. A control reaction
conducted in the absence of catalyst with morpholine as a
nucleophile, demonstrating that transformation is only possible by
the presence the catalyst (Table 1, entry 1). We first investigated
the reactivity of the two catalysts Pt(PPh3)4 and Pd(PPh3)4 in
many solvents. Except in the acetonitrile (entries 2-3), the catalyst
Pt(PPh3)4 is more reactive than Pd(PPh3)4 (entries 4-13). In
toluene, the two catalysts have the same reactivity (entries 14-
15). In the same conditions, no reaction occured in the polar
aprotic solvent DMF and DMSO.
K. H. V. Reddy, M. Bédier, Dr S. Bouzbouz*
CNRS, University of Rouen, INSA, COBRA UMR 6014
76183 Mont Saint Aignan cedex France
E-mail: samir.bouzbouz@univ-rouen.fr
https://orcid.org/0000-0002-5544-7892
Supporting information and ORCID(s) from the author(s) for this article
are available on the WWW
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800110
European Journal of Organic Chemistry
Table 1. Optimization of reaction conditions.
entry
1
Solvant
THF
catalyst
-
Isolated yield %
No reaction
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Acetonitrile
Acetonitrile
Acetone
Acetone
Dioxane
Dioxane
DCM
Pt(PPh3)4
Pd(PPh3)4
Pt(PPh3)4
Pd(PPh3)4
Pt(PPh3)4
Pd(PPh3)4
Pt(PPh3)4
Pd(PPh3)4
Pt(PPh3)4
Pd(PPh3)4
Pt(PPh3)4
Pd(PPh3)4
Pt(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
61
82
89
75
91
74
94
33
95
82
93
56
84
85
42
DCM
Isopropylether
Isopropylether
THF
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
No reaction
81
Pd(OAc)2+ PPh3
Pd(OAc)2+ dppe
Pd(OAc)2+ PCy3
74
No reaction
The use of other sources of Pd (0) such as Pd2(dba)3 gives the
expected product with an moderate yield (entry 16).Then, a
number of phosphines and Pd(II) sources were screened. The
allylic substitution did not occur with Pd(OAc)2 without phosphine
(entry
17),
the
triphenylphosphine
and
1,2
Bis(diphenylphosphino)ethane associated with Pd(OAc)2 gives a
good yields (entries 18 and 19). However, by combining non-
aromatic phosphines such as PCy3 with Pd(OAc)2, no reaction is
observed (entry 20). A variety of solvents have been tested and
offer a choice for the study of the enantioselective version. With
the optimized reaction conditions in hand (Table 1, entry 12), we
next explored the scope and limitations of this intermolecular
catalytic amination of the -fluoroenamides reaction as shown in
(Scheme 3). In a first step, we tested whether other amines can
react with compound 1. Apart from the propargyl amine, which
gives a moderate yield of 43%[15] of compound 2b, the three other
amines have given very good yields of compounds 2c, 2d and 2e.
Subsequently, a number of non-chiral amides were studied in the
amination catalysed using morpholine as nucleophile, excellent
yields were obtained with the free amide 2f. However, the
compound 2g obtained with an average yield, this drop in yield is
related to the deprotection of the silyl group. Other chiral amines
such as a-methyl benzylamine, phenylalanine methylester and
leucine methylester were tested on the two fluoramides a free
amide and the amide derived from trifluoromethylaniline. These
amines provided good yields of compounds 2h, 2i, 2j and 2k (dr
= 1/1). We then tested chiral fluoro amides derived from amino
acids and chiral a-methyl benzylamine.
Scheme 3. Scope, limitations, and regioselectivity of the intermolecular
conjugative catalytic amination reaction
We then rapidly transformed two amides 2s and 2t into highly
desired tripeptide sequences 3s and 3t. Cleavage of the N-
phenylethyl group and reduction of the olefin moiety in 2t were
readily accomplished by catalytic hydrogenation with Pd(OH)2 in
methanol at room temperature. The crude amine was coupled
with Boc-L-valine in the presence of HBTU provided the tripeptide
aga sequence 3t. Indeed, the substituent R in the tripeptide
sequence  plays an important role on the conformation
adopted by the tripeptide.[17] The other important point of our
methodology is the obtention of tripeptide sequence N-methyl
never synthesized in the literature. After catalytic hydrogenation
of compound 2n with Pd(OH)2 in methanol at room temperature
the crude amine was coupled with Boc-L-valine in the presence
of PyBop. However, the desired tripeptide 3n was obtained as a
diastereomeric mixture (ratio 2:1). This rapid strategy (6 steps) of
synthesis of peptide sequences containing non-natural and
natural -aminoamides[18] is being investigated to study their folds
depending on the nature of the side chain R.
The choice of an amide derived from an amino acid is related to
the future target that is the synthesis of thalassospiramide. These
compounds were obtained after easy separation of the two
diastereoisomers fluorinated by column chromatography. The
absolute configuration of the fluoride stereogenic center was
determined after the synthesis of the same product by the
methodologie described by zakarian group.[16] On these
compounds were tested various cyclic and acyclic non-chiral
amines such as pyrolidine, morpholine, benzylamine, and
methylamine..We obtained the products 2l, 2m, 2n, 2o, 2p, 2q
and 2r as a single diastereoisomer with very good yields with
retention of configuration. Finally, in the last two examples we
used both chiral amides but also chiral nucleophiles to show the
potency of the method for the synthesis of -amino-,-
unsaturated amide 2s and 2t as a single diastereoisomer with
excellent yields. The original point of this method is the obtaining
of highly functionalized -amino-,-unsaturated amides which
can be derivatized in two steps to peptide sequences rarely
synthesized in the literature (Scheme 4).
Scheme 4. Derivatization of -amino-,-unsaturated amides 2t and 2n of the
tripeptide sequences 3t and 3n.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800110
European Journal of Organic Chemistry
We then explored the intramolecular conjugative catalytic
amination of functionalized allylic fluoride for the synthesis of a
model of indolizidines, conicein[19] (Scheme 5). The synthetic
route starts with the cross metathesis reaction of fluoroamide 5
and olefin 4 in the presence of the Hoveyda Grubbs catalyst in
dichloromethane to provide amino-fluoramide 6 (81% yield). After
the deprotection of Boc group of the compound 6 using TFA, the
Keywords: Fluorenamides•catalysis • -amino-,-unsaturated
amide • tripeptide • coniceine
The authors have no conflicts to declare
[1]
[2]
D. -C. Oh, W.K. Strangman, C. A. Kauffman, P. R. Jensen, W. Fenical,
Org. Lett. 2007, 9, 1525–1528.
A. C. Ross, Y. Xu, L. Lu, R. D. Kersten, Z. Shao, A. M. Al-Suwailem, P.
C. Dorrestein, P. -Y. Qian, B. S. Moore, J. Am. Chem. Soc. 2013, 135,
1155.
V. M. Swarna, B. J. Undem, V. L. Korlipara, Bioorganic Med.
Chem. Lett. 2007, 17, 890.
Recent review on the stereoselective synthesis of -amino acids, see: M.
Ordóñez, C. Cativiela, I. R.Estudillo, Tetrahedron Asymmetry 2016, 27,
999.
Selected publications for the synthesis of chiral α,β-unsaturated -amino
esters, see: a) C. Xia, J. Shen, D. Liu, W. Zhang, Org. Lett. 2017, 19,
4251; b) A. Kondoh, Y. Kamata, M. Terada, Org. Lett. 2017, 19, 1682; c)
M. Zhang, K. Watanabe, M. Tsukamoto, R. Shibuya, H. Morimoto, T.
Ohshima, Chem. - Eur. J. 2015, 21, 3937; d) G. Srikanth, K. V. S.
Ramakrishna, G. V. M. Sharma, Org. Lett. 2015, 17, 4576; e) J. H. Lee,
S.-G. Lee, Chem. Sci. 2013, 4, 2922; f) T. M. Pedersen, E. L. Hansen, J.
Kane, T. Rein, P. Helquist, P.-O. Norrby, D. Tanner, J. Am. Chem. Soc.
2001, 123, 9738.
amino fluoroallylic
7 was obtained in 96% yield. The
intramolecular process of this allylic substitution was applied to
the compound 7 in the presence of Pt(PPh3)4 to furnish easily the
cyclic -amino--unsaturated amide 8 (yield 77%). Compound 8
was obtained in the form of two diastereoisomers which are
readily separable to give access to the two isomers of coniceine.
The following synthesis was achieved by racemic version show
the feasibility of the synthesis process. Compound 8 was treated
with Pd(OH)2 in a mixture of methanol / AcOH under atmospheric
pressure of H2 to give the bicyclic amide compound 9. Finally, the
bicyclic amide is converted easily into coniceine 10.
[3]
[4]
[5]
[6]
Selected reviews of Pd-catalyzed asymmetric allylic substitutions, see:
a) N. Butt, G. Yang, W. Zhang, Chem. Rec. 2016, 16, 2687; b) R. L.
Grange, E. A. Clizbe, P. A. Evans, Synthesis 2016, 48, 2911; c) N. Butt,
W. Zhang, Chem. Soc. Rev. 2015, 44, 7929; d) S. Oliver, P. A. Evans,
Synthesis 2013, 45, 3179; e) B. M. Trost, Org. Process Res. Dev. 2012,
16, 185; f) B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci. 2010, 1, 427;
g) Z. Lu, S. Ma, Angew. Chem., Int. Ed. 2008, 47, 258; h) B. M. Trost, M.
L. Crawley, Chem. Rev. 2003, 103, 2921; i) G. Helmchen, A. Pfaltz, Acc.
Chem. Res. 2000, 33, 336; j) B. M. Trost, D. L. Van Vranken, Chem. Rev.
1996, 96, 395
[7]
Recent reviews are as follows. Pd: a) C. J. Engelin, P. Fristrup,
Molecules 2011, 16, 951; b) T. Jensen, P. Fristrup, Chem. Eur. J. 2009,
15, 9632. Ir: c) G. Helmchen, In Iridium Complexes in Organic Synthesis,
L. A. Oro, C. Claver, Eds.; Wiley-VCH: Weinheim, Germany, 2009, pp
211−250; d) J. F. Hartwig, M. J. Pouy, Top. Organomet. Chem. 2011, 34,
169−208; e) J. F. Hartwig, L. M. Stanley, Acc. Chem. Res. 2010, 43,
1461.
Scheme 5. intramolecular conjugative catalytic amination reaction and
application to the synthesis of -coniceine.
[8]
[9]
a) A. J. Blacker, M. L. Clark, M. S. Loft, J. M. J. Williams, Chem.
Commun. 1999, 913; b) A. J. Blacker, M. L. Clarke, M. S. Loft, M. F.
Mahon, J. M. J. Williams, Organometallics 1999, 18, 2867; c) A. J.
Blacker, M. L. Clarke, M. S. Loft, M. F. Mahon, M. E. Humphries, J. M. J.
Williams, Chem. Eur. J. 2000, 6, 353; d) L. Hintermann, F. Lang, P.
Maire, A. Togni,, Eur. J. Inorg. Chem. 2006, 1397.
a) B. Greedy, J. M. Paris, T. Vidal, V. Gouverneur, Angew. Chem.,Int.
Ed. 2003, 42, 3291; b) S. Thibaudeau, V. Gouverneur, Org. Lett. 2003,
5, 4891; c) S. Thibaudeau, R. Fuller, V. Gouverneur, Org. Biomol. Chem.
2004, 2, 1110; d) M. Tredwell, K. Tenza, M. C. Pacheco, V. Gouverneur,
Org. Lett. 2005, 7, 4495; e) S. C. Wilkinson, O. Lozano, M. Schuler, M.
C. Pacheco, R. Salmon, V. Gouverneur, Angew. Chem., Int. Ed. 2009,
48, 7083; f) M. C. Pacheco, S. Purser, V. Gouverneur, Chem. Rev. 2008,
108,1943.
Our strategy of synthesis is based in its majority on reactions
developed in our group and which can reach quickly and
efficiently a large number of heterocyclic molecular target. The
compound 8 is a common intermediate for the synthesis of
lentiginosine iminosugar indolizidine alkaloid which acts as
apoptosis inducer on tumor cells.[20] Work is underway in our
group to apply the present methodology (intramolecular process)
in bioactive molecule synthesis and to further extend the present
strategy to C-, S- and O-nucleophiles.
In conclusion, we have developed a new approach to the direct
and highly regioselective synthesis of branched -amino--
unsaturated that is operationally trivial and displays
unprecedented functional group tolerance. The utility of this
transformation has been highlighted via the synthesis of naturals
products and hybrids peptides. The advantage of this method is
the preparation of the two enantiomers of the -fluoroenamides
by simple purification at the gram scale, which has the advantage
of reaching the two enantiomers of the -amino--unsaturated
amides. For the enantioselective version, we're about to explore
the combination of Pd (II) with chirals phosphines, this work is in
progress.
[10] A. Hazari, V. Gouverneur, J. M, Brown,. Angew. Chem., Int. Ed. 2009,
48, 1296.
[11] E. Benedetto, M. Keita, M. Tredwell, C. Hollingworth, J. M. Brown, V.
Gouverneur, Organometallics, 2012, 31, 1408.
[12] a) S. Bouzbouz, Synlett, 2011, 22, 1888; b) L. Ferrié, S. Bouzbouz, J.
Cossy, Org. Lett. 2009, 11, 5446; c) M.; Bédier, S. Bouzbouz, Synlett,
2015, 26, 2531.
[13] For reviews on indolizidines, see: a) J. P. Michael, Nat. Prod. Rep., 2008,
25, 139; b) J. P. Michael, Nat. Prod. Rep. 2005, 22, 603; c) J. P. Michael,
In The Alkaloids: Chemistry and Pharmacology; Cordell, G. A., Ed.;
Academic Press: New York, 2001, 44, 99, and references cited therein.
d) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids: Chemistry
and Pharmacology; Cordell, G. A., Ed.; Academic Press: San Diego,
1993, 43, 185.
[14] The details see the supporting information.
[15] Despite the increase in the amount of propargylamine from 1.2 to 4 eq,
the reaction yield does not increase.
[16] J. Alvarado, A.T. Herrmann, A. Zakarian, J. Org. Chem. 2014, 79, 6206.
[17] a) K. Basuroy, B. Dinesh, N. Shamala, P. Balaram, Angew. Chem. Int.
Ed. 2013, 52, 3136; b) K. Basuroy, B. Dinesh, N. Shamala, P. Balaram,
Angew. Chem. Int. Ed. 2012, 51, 8736.
Acknowledgements
[18] a) T. Hintermann, K. Gademann, B. Jaun, D. Seebach, Helv. Chim. Acta
1998, 81, 983; b) S. Hanessian, X. Luo, R. Schaum, S. Michnick, J. Am.
Chem. Soc. 1998, 120, 8569 – 8570.
[19] Early syntheses of racemic coniceine: a) R. V. Stevens, Y. Luh, J.- T.
Sheu, Tetrahedron Lett. 1976, 17, 3799; b) M. T. Pizzorno, S. M.
Albonico, J. Org. Chem. 1977, 42, 909; c) S. R. Wilson, R. A. Sawicki, J.
Org. Chem. 1979, 44, 330; d) S. M. Weinreb, N. A. Khatri, J.
Shringarpure, J. Am. Chem. Soc. 1979, 101, 5073; e) M. E. Garst, J. N.
Bonfiglio, Tetrahedron Lett. 1981, 22, 2075; f) S. Danishefsky, E.
Taniyama, R. R. Webb, Tetrahedron Lett. 1983, 24, 11; g) B. P.
K. H. V. R thanks the Région Normandie post doc grant and M.B.
thanks the Ministére de l’Enseignement Supérieur et de la
Recherche for a a PhD grant. This work was partially supported
by the Centre National de la Recherche Scientifique (CNRS),
University of Rouen, INSA Rouen, Labex SynOrg (ANR-11-
LABX-0029)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800110
European Journal of Organic Chemistry
Branchaud, J. Org. Chem. 1983, 48, 3538; h) N. De Kimpe, E. Stanoeva,
A. Georgieva, M. Keppens, O. Kulinkovich, Org. Prep. Proc. Int. 1995,
27, 674; i) M. J. Martin-Lopez, R. Rodriguez, F. Bermejo, Tetrahedron
1998, 54, 11623; j) A. Padwa, S. M. Sheehan, C. S. Straub, J. Org.
Chem. 1999, 64, 8648; k) K. A. Tehrani, M. D’hooghe, N. De Kimpe,
Tetrahedron 2003, 59, 3099; l) P. M. Holstein, D. Dailler, J. Vantourout,
J. Shaya, A. Millet, O. Baudoin. Angew. Chem. Int. Ed. 2016, 55, 1.
[20] B. Macchi, A. Minutolo, S. Grelli, F. Cardona, F. M. Cordero, A. Mastino,
A. Brandi, Glycobiology 2010, 20, 500.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800110
European Journal of Organic Chemistry
COMMUNICATION
K. H. V. Reddy, M. Bédier,
S. Bouzbouz*
Text for Table of Contentsnnnnnnnnnnnnn
.
Efficient and Direct Synthesis of
-amino-,-unsaturated amides by
Catalyzed Allylic Substitution of
-Fluoroenamides:
Toward
to
synthesis Hybrid Peptides and
indolizidines
The intermolecular and intramolecular process Pt-catalyzed allylic amination was
developped for direct access of -amino-,-unsaturated amides from
-fluoroenamides. The utility of this transformation has been highlighted via the rapid and
efficient synthesis of hybrids peptides and naturals products
This article is protected by copyright. All rights reserved.