Homoallylic amines as efficient chiral inducing frameworks in the conjugate addition of amides to α,β-unsaturated esters. An entry to enantio-enriched diversely substituted amines

Article abstract of DOI:10.1039/d0ob00034e

The diastereoselective conjugate addition of secondary homoallylamines, obtained in the enantioenriched form via allylmetallation of imines, to α,β-unsaturated esters is reported. This method allows access to valuable building blocks as well as heterocyclic skeletons, providing tertiary amines bearing two chains integrating a stereogenic center adjacent to the nitrogen atom.

Full text of DOI:10.1039/d0ob00034e

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DOI: 10.1039/D0OB00034E
Journal Name
COMMUNICATION
Homoallylic amines as efficient chiral inducing framework in the
conjugate addition of amides to α,β-unsaturated esters. An entry
to enantio-enriched diversely substituted amines.
Received 00th January 20xx,
Accepted 00th January 20xx
Johann Rogier,a Lilia Anani,a Aurélien Coelho,a Fabien Massicot,a Carine Machado-Rodrigues,a
DOI: 10.1039/x0xx00000x
Jean-Bernard Behr,a Jean-Luc Vasse*a
www.rsc.org/
flexibility in the choice of the N-protection allows a selective
The diastereoselective conjugate addition of secondary
homoallylamines, obtained in the enantioenriched form via
deprotection, extending further the scope of the reaction.6
allylmetallation of imines, onto α,β-unsaturated esters is Recently, Davies described the conjugate addition of a lithium
amide containing
a chloropropyl chain, which can be lately
reported. Leading to tertiary amines bearing two chains
integrating a stereogenic center adjacent to the Nitrogen, this
incorporated into the skeleton of the target.10
method allows the access to valuable building blocks as well as Previously, we reported, the synthesis of disubstituted piperidines,
based on Davies methodology (figure 1). In our approach, the allyl
group was considered as an electrophilic chain precursor rather
heterocyclic skeletons.
Due to their ubiquity in naturally occurring substances,1 amines than a protecting group.11
incorporating configurationnaly defined stereogenic center(s)
constitute a fundamental class of molecules of biological interest. In
this context, the development of synthetic approaches aimed at
preparing diversely substituted amines in a stereoselective manner2
remains an important objective for enriching libraries of potentially
active compounds.
A possible evolution of interest would be to envision the addition of
amides containing both an achiral protecting group and
a
functionalizable chain able to act as the chiral inducing pattern. This
typical design within the amides may open the way to the synthesis
of secondary amines where each chain contains a configurationnaly
controlled stereogenic center closely located to the nitrogen atom
Among interesting targets, amines featuring two chiral (Figure 1).
functionalized chains appear as valuable building blocks for
numerous applications. Therefore, the development of stereo-
controlled C-N bond forming reactions involving chiral amines,
Fig. 1 Context of the study
notably 1,4-addition reactions,3 are of marked interest, in this
perspective.
pioneering work
- Chiral auxiliary
- Protection
Highly enantioselective organo-catalyzed4 and biocatalyzed5 1,4
addition of amines were reported in the literature. Nevertheless,
the method of choice to secure the stereocontrolled introduction of
an ammonia equivalent in β-position with respect to a carbonyl
remains the Davies’ conjugate addition of lithium amides onto α,β-
Me
Me
CO2R'
R
NH2
Ph
N
Ph
Ph
N
Li
Ph
CO2R'
CO2R'
R
R
- Chiral auxiliary
- Convertible chain
unsaturated esters.6 Providing
a
highly efficient and
Me
Cl
diastereoselective access to diversely substituted -aminoesters in
the enantiopure form, this method was extensively studied7 and
applied for the preparation of a large panel of molecules of
biological interest as well as naturally occurring substances.8
Me
Cl
CO2t-Bu
R
HN
NH
O
Ph
N
Ph
Ph
N
Li
CO2t-Bu
CO2t-Bu
R
Me
R
Me
Me
CO2t-Bu
R
Ph
N
Implying secondary amines integrating the -methylbenzylamine
scaffold and a removable unit (typically a benzyl or an allyl group),
the original sequence involved the 1,4 addition followed by a
hydrogenolysis to afford the corresponding primary amines.9 High
Ph
N
N
R
Li
R
CO2t-Bu
this work - Convertible chiral inducing fragment
- Protection
R"
R"
R"
CO2R'
N
R
Ph
N
Ph
N
Li
CO2R'
R
a. Institut de Chimie Moléculaire de Reims, CNRS (UMR 7312) and Université de
Reims Champagne Ardenne, 51687 Reims Cedex 2, France.
b. E-mail: jean-luc.vasse@univ-reims.fr.
R
Electronic Supplementary Information (ESI) available: [Experimental details, NMR
data of all new compounds]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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In this communication, we disclose the diastereoselective synthesis To illustrate the potential of the present methodology in
asymmetric synthesis, we next decided to preparVeiewaArsteicrleieOsnlionef
DOI: 10.1039/D0OB00034E
of amines bearing two stereogenic centers in the ‘-positions
secondary homoallylamines in the enantio-enriched form.
with respect to the nitrogen, based on the conjugated addition of
secondary homoallylic amides onto α,β-unsatured esters.
Among the large literature dealing with the synthesis of
homoallylamines, the diastereoselective allylmetallation of tert-
butylsulfinimines, emerges as one of the more efficient and
stereoselective methods providing highly enantio-enriched primary
Readily available by addition of organometallic reagents onto
imines, secondary allyl-12 and homoallylamines13 appear as
potential mimicks of the -methylbenzylamine framework. In an
initial experiment, the lithium amide of homoallylamine (±)-1a was
generated at -70°C by using n-BuLi, then methyl cinnamate was
added and the reaction mixture was stirred at -70°C for 1h prior to
hydrolysis. The 1H NMR analysis of the crude reaction mixture
15
homoallylamines after removal of the chiral auxiliary by acidic
methanolysis.16 A series of non-racemic primary amines was thus
prepared according to this approach. Subsequent reductive
amination afforded the desired secondary amines 1a,b,e,k,l
carrying the additional protecting group (Scheme 2).
revealed the presence of adduct 2, as
a 95:5 mixture of
diastereomers, along with several side-products resulting in a poor
27% isolated yield. In contrast, when the analogous tert-butyl ester
was used, a cleaner reaction was observed, providing the β-
Table 1 Scope of the reaction.
aminoester 3a in 82% isolated yield with
a
similar
n-BuLi, THF
R
N
R'
diastereoselectivity. The same protocol was next applied to the
allylic amine 1’a. While the addition reaction proceeded well, the
diastereoselectivity was lower (dr = 87:13), prompting us to focus
the study on homoallylamines.
R
N
R'
CO2t-Bu
then
CO2t-Bu
H
R"
-70°C
R"
1
(±)-
3
(±)-
entry
1
1
R, R’
R”
C5H11
Ph-CH=CH
2-Furyl
3-Pyridyl
Ph
3yield (%)a
3b (73)
3c (60)
3d (92)
3e (89)
3f (71)
3g (74)
3h (83)
3i (92)
drb
Scheme 1 Initials results.
1a
1b
1a
1a
1c
1d
1e
1e
1f
Ph, Ph
Ph, PMP
Ph, Ph
>95:5
>95:5
>95:5
96:4
2
( )n
( )n
3
n-BuLi, THF
Ph
N
Ph
Ph
N
H
Ph
CO2R
CO2R
4
Ph, Ph
then
Ph
Ph
1a
1'a
, n = 1
, n = 0
-70°C
2
(±)- , R = Me, n = 1, 27%, dr > 95:5
3a
5
4-Cl-C6H4, PMP
4-Br-C6H4, PMP
95:5
(±)- , R = t-Bu, n = 1, 82%, dr > 95:5
6
Ph
95:5
4
(±)- , R = Me, n = 0, 81%, dr 87:13
7
2-Thiophenyl, Ph
2-Thiophenyl, Ph
2-Furyl, Ph
Ph
>95:5
>95:5
55:45
95:5
8
Ph-CH=CH
Ph
A series of racemic homoallylamines was next tested towards tert-
butyl α,β-unsaturated esters to identify the structural elements that
allow efficient diastereofacial discrimination. Nearly complete
diastereoselective additions were observed using most
homoallylamines. The configuration of the newly created
stereogenic center was deduced by analogy with the selectivity
reported by Davies.6,7 Thus, homoallylamines bearing aromatic
(Table 1, entries 2-6), 2-thiophenyl (entries 7 and 8), 3-furyl (entries
10 and 11) or 3-pyridyl fragment (entries 12 and 13) provided the
expected adducts with a high level of diastereoselectivity. In
contrast, the 2-furyl group (entry 9) is not suitable to induce a
diastereoselective process, as the consequence of its smaller size or
due to detrimental Li-O interactions that would disorganize the
approach of the amide.14 Additionally, vinylic fragments may also be
incorporated, however the level of diastereoselectivity is related to
the number and positioning of the substituents on the C=C double
bond. In the case of homoallylamine containing a styryl group, a
moderate 80:20 dr was observed (entry 14). In this particular case,
warming the reaction mixture to room temperature prior to
quenching resulted in a better diastereomeric ratio, along with an
increased amount of side-product. One may assume that the minor
diastereomeric form of the resulting enolate may be unstable.
Ultimately, the presence of an additional methyl group onto the
C=C double bond would secure a nearly total diastereoselectivity
(entry 16).
9
3j (90)
10
11
12
13
14
15d
16
1g
1g
1h
1h
1i
3-Furyl, Ph
Ph
3k (80)
3l (78)
3-Furyl, Ph
C5H11
Ph
94:6
3-Pyridyl, Ph
3-Pyridyl, Ph
Ph-CH=CH, Ph
Ph-CH=CH, Ph
Ph-CH=CMe, Ph
3m (92)
3n (90)
3o (83)
3o (50)
3p (75)
>95:5
>95:5
80:20
92:8
iPr
Ph
1i
Ph
1j
Ph
96:4
a Isolated yield. b Determined by 1H NMR analysis of the crude reaction mixture. c
NMR yield. d After 1h at -70°C, the reaction mixture was warmed to 0°C prior to
NH4Cl quench.
Attempts to prepare the homoallylamine containing a 3-pyridyl
moiety from the analogous imine were unsatisfactory using either
allylmagnesium bromide or allylzinc bromide as the organometallic
reagent, in these cases,
diastereoselectivity were respectively obtained.
a complex mixture, and poor 2:1
In contrast, when employing the imine derived from (R)-
phenylglycinol in the presence of allylbromide and In,17 a high level
of stereo-induction can be achieved (scheme 2). The resulting
amino-alcohol 5h was next successively treated with Pb(OAc)4, and
NH2OH.HCl17 to give the expected primary homoallylamine which
was ultimately converted into 1h (Scheme 2).
2 | J. Name., 2012, 00, 1-3
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With the enantio-enriched homoallylamines in hand,
a
access building blocks bearing two similarly substituted chains that
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representative panel of tertiary amines bearing two chains with a could be selectively transformed. Thus, 6t was converted into
DOI: 10.1039/D0OB00034E
controlled stereogenic centers adjacent to the nitrogen was carbamate 8,19 prior to RuCl3-mediated oxidative cleavage of the
prepared. Thus amino-esters 3q-y were obtained with a similar level C=C moiety20 providing the acid-ester 9 (Scheme 3).
of diastereoselective induction. Among them, amino-esters
including an aryl and alkyl substituent (Table 2, entries 2-4 and 6),
two aryl (entry 5), two heteroaryl (entry 9), an aryl and a vinyl
(entries 1 and 7), a heteroaryl and a vinyl fragment (entry 8) were
prepared in a non racemic fashion (ee > 90%, as deduced from the
diastereselectivity of the allylmetallation reaction).
Scheme 3 Synthetic applications.
i)
ii)
Ph
iPr
NH
Ph
NH
3s, 3t
CO2tBu
83%
97%
iPr
OH
7
i)
80%
6s
CO2H
iv)
iii)
CO2Me
Scheme 2 synthesis of enantioenriched homoallylic amines 1.
CO2Me
Ph
N
Ph
C5H11
NH
Ph
N
CO2tBu
84%
CO2tBu
CO2tBu
80%
C5H11
C5H11
t-Bu
6t
9
8
t-Bu
S
5a
5e
5k
, R = Ph, 78%, dr 98:2,
, R = 2-thiophenyl, 87%,dr 95:5,
, R = PMP, 81%, dr 97:3
MgBr
CH2Cl2
S
HN
O
N
O
Reagents and conditions i) CAN, CH3CN/H2O; ii) LiAlH4, THF; iii) ClCO2Me,
K2CO3, acetone,  iv) cat.RuCl3, NaIO4, CCl4/CH3CN/H2O.
R
R
5l
, R = PhCH=CMe, 74%,dr 97:3,
1) HCl, MeOH
2) R'CHO, then NaBH4
Nitrogen-containing heterocycles constitute highly potent skeletons
with a wide range of applications, notably in catalysts and
biologically active molecules syntheses. In this context, chemical
transformations aimed at launching a cyclisation reaction were next
envisioned for this series of β-aminoesters.
'
(S)-1a
(S)-1b
(S)-1e
(S)-1k
, R = R = Ph, 89%
'
, R = Ph, R = PMP, 93%
HN
R'
'
, R = 2-thiophenyl, R = Ph, 85%
'
, R = PMP, R = Ph, 87%
R
'
(S)-1l
, R = PhCH=CMe, R = PMP, 86%
OH
Ph
OH
Ph
Firstly, by applying the following dihydroxylation/oxidative
cleavage/reduction sequence21 to 3b, alcohol 10 was prepared.
Subsequent tosylation and LiHMDS-promoted intramolecular
displacement afforded the trisubstituted-piperidine 11 as a single
diastereomer.22
1) Pb(OAc)4
then NH2OH.HCl
Br
N
HN
HN
Ph
In, MeOH
77%
2) PhCHO
then NaBH4
5h
N
N
(R)-1h
47%
N
Secondly, the present method leading to homoallylaminoesters, we
naturally turned out our attention to a metathesis-based approach
to access heterocycles. The required dienic precursor 12 was
obtained through a three-step sequence (e.g. ester reduction to
alcohol, Swern oxidation and Wittig-olefination).23 Subsequent RCM
using Grubbs II catalyst gave the cis dehydro-azepane 13 (Scheme
4).
Table 2 Acces to enantio-enriched tertiary amines 3.
n-BuLi, THF
R
N
R'
R
N
R'
CO2t-Bu
then
CO2tBu
H
R"
R"
Finally, the direct access to enantio-enriched trans-2,6-
disubstituted 1,2,3,6-tetrahydropyridine 1424 was achieved in 94%
yield under identical reaction conditions from 3q.25
1
-70°C
3
or enantiomer
or enantiomer
3 yield (%)a
entry
R, R’
R”
drb
1
(R)-1a
(S)-1a
Ph, Ph
Ph, Ph
C3H7-CH=CH 3q (69)
1
2
>95:5
>95:5
BnO-(CH2)4
3r (66)f
3s (89)
3t (80)
3u (56)
3v (46)
3w (70)
3x (68)
3y (69)
Scheme 4 Access to heterocycles.
(S)-1b
(S)-1b
Ph, PMP
Ph, PMP
iPr
>95:5
>95:5
96:4
3
4
5
6
7
8
9
CO2tBu
C5H11
11
OH
Bn
C5H11
vi)
v)
Bn
Ph
N
Ph
N
(S)-1k
(S)-1k
(S)-1l
4-MeO-C6H4, Ph
4-MeO-C6H4, Ph
PhCH=CMe, PMP
3-Pyridyl, Ph
Ph
Ph
N
CO2tBu
CO2tBu
10
70%
74%
C5H11
C5H11
Bn
C5H11
96:4
3b
(±)-
Ph
95:5
viii)
Bn
Bn
(R)-1h
(S)-1e
Ph-CH=CH
2-Furyl
>95:5
94:6
vii)
N
N
N
Ph
CO2tBu
81%
O
O
2-Thiophenyl, Ph
Bn
13
47%
Ph
12
Ph
O
3k
(±)-
a Isolated yield. b calculated from the crude 1H NMR.
viii)
Bn
CO2tBu
Ph
N
Ph
N
CO2tBu
94%
Bn
The synthetic potential of the present methodology was next
illustrated. Firstly, standard 4-methoxybenzyl removal conditions
using CAN18 were applied to 3s and 3t, leading respectively to the
corresponding secondary amines 6s and 6t which can undergo
further transformations. As example, amino-alcohol 7 was obtained
quantitatively by treating 6s with LiAlH4. We next envisioned to
C3H7
3q
14
Reagents and conditions v) a- cat. OsO4, NMO, tBuOH/THF/H2O, b- NaIO4,
THF/H2O, c- NaBH4, MeOH; vi) a-TsCl, E3N, DMAP, CH2Cl2, b-LiHMDS, THF, -70°C to
rt; vii) a- LiAlH4, THF, b- (COCl)2, DMSO, Et3N, CH2Cl2, c- EtPh3PBr, LiHMDS, THF;
viii) Grubb’s II catalyst, CH2Cl2, .
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Davies, A. D. Smith and P. D. Price, Tetrahedron: Asymmetry,
View Article Online
2005, 16, 2833; (b) S. G. Davies, A. M. Fletcher, P. M.
Roberts, and J. E. Thomson, TetrahedDroOnI::1A0.s1y0m39m/De0tOryB,020003142E,
23, 1111; (c) S. G. Davies, A. M. Fletcher, P. M. Roberts and J.
E Thomson, Tetrahedron: Asymmetry 2017, 28, 1842.
Conclusions
8
(a) S. G. Davies, A. M. Fletcher, M. S. Kennedy, P. M. Roberts,
and J. E. Thomson, Tetrahedron 2018, 74, 7261; (b) S. G.
Davies, A. M. Fletcher, S. M. Linsdall, P. M. Roberts and J. E.
Thomson, Org. Lett., 2018, 20, 4135; (c) S. G. Davies, A. L. A.
Figuccia, A. M. Fletcher, P. M. Roberts and J. E. Thomson, J.
Org. Chem., 2016, 81, 6481; (d) S. G. Davies, A. M. Fletcher, I.
T. T. Houlsby, P. M. Roberts, S. Rowe and J. E. Thomson, J.
Org. Chem., 2016, 81, 4907; (e) M. Brambilla, S. G. Davies, A.
M. Fletcher, P. M. Roberts and J. E. Thomson, Tetrahedron,
2016, 72, 4523; (f) S. G. Archer, K. Csatayová, Davies, S. G.; A.
M. Fletcher, P. M. Roberts and J. E. Thomson, Tetrahedron
Lett., 2016, 57, 1270; (g) S. G. Davies A. M. Fletcher, R. S.
Shah, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2015,
80, 4017; (h) K. Csatayová, S. G. Davies, A. M. Fletcher, J. G.
Ford, D. J. Klauber, P. M. Roberts and J. E. Thomson,
Tetrahedron, 2015, 71, 7170; (i) S. G. Davies, A. M. Fletcher,
E. M. Foster, I. T. T. Houlsby, P. M. Roberts, T. M. Schofield
and J. E. Thomson, Chem. Commun. 2014, 50, 8309; (j) S. G.
Davies, A. M. Fletcher, J. A. Lee, T. J. A. Lorkin, P. M. Roberts
and J. E. Thomson, Tetrahedron, 2013, 69, 9779; (k) S. G.
Davies, A. M. Fletcher, Lebée, P. M. Roberts, J. E. Thomson
and J. Yin, Tetrahedron,. 2013, 69, 1369; (l) E. A. Brock, S. G.
Davies, J. A. Lee, P. M. Roberts and J. E. Thomson, Org. Lett.,
2012, 14, 4278; (m) S. G. Davies, J. A. Lee, P. M. Roberts, J. E.
Thomson and C. J. West, Tetrahedron 2012, 68, 4302.
In summary, secondary homoallylic amides, accessible in both
enantiomeric forms via diastereoselective allylmetallation of
imines, were proven to induce a high level of diastereoselectivity in
the conjugated addition to α,β-unsaturated esters. Constituting an
extension of the Davies’ methodology, the present work provides a
direct access to diversely substituted tertiary and secondary
amines, bearing two configurationnaly-controlled stererogenic
centers adjacent to the N. The synthetic potential of this series of
amines may be of interest for the preparation of dissymetric linear
building-blocks as well as N-heterocycles.
Acknowledgements
The University of Reims Champagne Ardenne and the CNRS for
financial support are gratefully acknowledged.
Conflicts of interest
There are no conflicts to declare.
Notes and references
9
(a) S. G. Davies and 0. Ichihara, Tetrahedron: Asymmetry,
1991, 2, 183; (b) S. G. Davies, N. M. Garrido, O. lchihara and
l. A. S. Walters, J. Chem. Soc., Chem. Commun. 1993, 1153.
1
(a) J. W. Daly, H. M. Garraffo and Spande T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon Press: New York, 1999, 13, 1-161. (b) J. Cossy and
P. Vogel, In Studies in Natural Products Chemistry, Part H;
Atta-ur-Raman, Ed; Elsevier: Amsterdam, 1993, 12, 275. (c)
Angle, S. R.; Breittenbucher, J. G. In Studies in Natural
Products Chemistry, Part J; Atta-ur-Raman, Ed; Elsevier:
Amsterdam, 1995, 16, 453; (d) J. A. Joule Adv. Heterocyclic
Chem. 2016, 119, 81. (e) D. J. Newman and G. M. Cragg, J.
Nat. Prod., 2012, 75, 311.
10 S. G. Davies, J. A. Lee, P. M. Roberts, J. P. Stonehouse and J.
E. Thomson, J. Org. Chem., 2012, 77, 9724.
11 M. Ahari, A. Perez, C. Menant, J.-L. Vasse and J. Szymoniak,
Org. Lett., 2008, 10, 2473.
12 (a) R. Almansa, J. F. Collados, D. Guijarro and M. Yus,
Tetrahedron: Asymmetry, 2010, 21, 1421; (b) R. Almansa, D.
Guijarro, M. Yus, Tetrahedron: Asymmetry, 2008, 19, 2484;
(c) M. Atobe, N. Yamazaki and C. Kibayash, J. Org. Chem,.
2004, 69, 5595; (d) M. A. Scialdone and A. I. Meyers,
Tetrahedron Lett., 1994, 35, 7533.
13 For recent examples of stereoselective allylmetallation of
imines see: (a) N. Yuika, U. Masafumi, H. Masataka, T.
Norihiko, and M. Okiko, Eur. J. Org. Chem., 2016, 22; (b) K.-H.
Shenn and C.-F. Ya, J. Org. Chem., 2006, 71, 3981; (c) A. K.
Jha and R. A. Fernandes, Eur. J. Org. Chem., 2019, 2857; (d)
R. A. Fernandes and J. L. Nallasivam, Org. Biomol. Chem.,
2012, 10, 7789; (e) N. Momiyama, H. Nishimoto and M.
Terada, Org. Lett., 2011, 13, 2126; (f) J.-M. Huang, X.-.X
Wang and Y. Dong, Angew. Chem., Int. Ed., 2011, 50, 924; (g)
P.-O. Delaye, M. Ahari, J.-L. Vasse and J. Szymoniak,
Tetrahedron: Asymmetry, 2010, 21, 2505; (h) S. Lou, P. N.
Moquist and S. E. Schaus, J. Am. Chem. Soc., 2007, 129,
15398.
14 S. G. Davies, A. M. Fletcher, K. E. Holder, P. M. Roberts, J. E.
Thomson and David Zimmer, Heterocycles, 2019, 99, 919.
15 (a) D. A. Cogan, G. Liu and J. Ellman, Tetrahedron, 1999, 55,
8883; (b) M. B. Tait, S. Butterworth and J. Clayden, Org. Lett.,
2015, 17, 1236; (c) X.-W. Sun, M.-H. Xu and G.-Q. Lin, Org.
Lett., 2006, 8, 4979; (d) X.-W. Sun, M. Liu, M.-H. Xu and G.-Q.
Lin, Org. Lett., 2008, 10, 1259; (e) S. Ouizem, F. Chemla, F.
Ferreira and A. Perez-Luna, Synlett, 2012, 23, 1374; (f) F.
Foubelo and M. Yus, Tetrahedron: Asymmetry, 2004, 15,
3823.
2
3
T. C. Nugent Chiral Amine Synthesis; Wiley VCH: Verlag
GmbH, 2010.
For reviews on stereoselective conjugate addition of amine
onto α,β-unsaturated carbonyl compounds see : (a) M. G.
Vinogradov, O.V. Turova and S. G. Zlotin, Org. Biomol. Chem.,
2019, 17, 3670; (b) Z. Amara, J. Caron and D. Joseph, Nat.
Prod. Rep., 2013, 30, 1211; (c) J. L. Vicario, D. Badia, L.
Carillo, J. Etxebarria, E. Reyes and N. Ruiz, Org. Prep. Proced.
Int., 2005, 37, 513; (c) P. R. Krishna, A. Sreeshailam and R.
Srinivas, Tetrahedron 2009, 65, 9657.
for a review on organo-catalyzed conjugate addition of
amines see : D. Enders, C. Wang and J. X. Liebich, Chem. Eur.
J., 2009, 15, 11058; for selected examples see : (a) I. Arenas,
A. Ferrali, C. Rodriguez-Escrich, F. Bravo and M. A. Pericàs,
Adv. Synth. Catal., 2017, 359, 2414; (b) J. Vesely, I. Ibrahem,
R. Rios, G.-L. Zhao, Y. Xu and A. Córdova, Tetrahedron Lett.
2007, 48, 2193; (c) H. Jiang, J. B. Nielsen, M. Nielsen and K. A.
Jørgensen, Chem., Eur. J., 2007, 13, 9068; (d) C. Appayee and
S. E. Brenner-Moyer, Org. Lett., 2010, 12, 3356.
4
5
(a) B. Weiner, G. J. Poelarends, D. B. Janssen and B. L.
Feringa, Chem. Eur. J. 2008, 14, 10094; (b) V. Puthan Veetil,
H. Raj, M. de Villiers, P. G. Tepper, F. J. Dekker, W. J. Quax
and G. J. Poelarends, Chem. Cat. Chem., 2013, 5, 1325.
J. F. Costello, Davies, S. G. and O. Ichihara, Tetrahedron:
Asymmetry, 1994, 35, 1999.
6
7
16 G. Liu, D. A. Cogan and J. A. Ellman, J. Am. Chem. Soc., 1997,
119, 9913;
For reviews dealing with the use of enantiomerically pure
lithium amides in conjugate addition reactions see: (a) S. G.
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
COMMUNICATION
17 T. Vilaivan, C. Winotapan, V. Banphavichit, T. Shinada and Y.
Ohfune, J. Org. Chem., 2005, 70, 3464.
View Article Online
DOI: 10.1039/D0OB00034E
18 (a) A. E. Al-Sarabi, A. Bariau, M. Gabant, J.-C. Wypych, P.
Chalard and Y. Troin, Arkivoc, 2007, 119; (b) S. G. Davies, A.
M. Fletcher, J. A. Lee, P. M. Roberts, A. J. Russell, R. J. Taylor,
A. D. Thomson and J. E. Thomson, Org. Lett., 2012, 14, 1672.
19 S. G. Davies, J. R. Haggitt, O. Ichihara, R. J. Kelly, M. A. Leech,
A. J. Price Mortimer, P. M. Roberts and A. D. Smith, Org.
Biomol. Chem., 2004, 2, 2630.
20 C. Pousset, R. Callens, M. Haddada and M. Larchevêque,
Tetrahedron: Asymmetry, 2004, 15, 3407.
21 B. L. Chen, B. Wang and G. Q. Lin, Sci. China. Chem. 2014, 57,
945.
22 A similar strategy for preparing trisubstituted piperidines
was previously reported see: Y.-L. Li, E. Shi, D. Burns, Y. Li, M.
B. Covington, M. Pan, P. Scherle, S. Friedman, B. Metcalf and
W. Yao, Bioorg. Med. Chem. Lett., 2009, 19, 5037.
23 S. G. Davies, J. A. Lee, P. M. Roberts, J. E. Thomson and C. J.
West, Tetrahedron, 2012, 68, 4302.
24 The trans configuration was assigned by chemical
correlations and comparison with known cis and trans
analogous methyl esters, see ESI.
25 A. Naresh, K. Marumudi, A. C. Kunwar and B. Venkateswara
Rao, Org. Lett., 2017, 19, 1642.
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The diastereoselective conjugate addition of chiral secondary homoallylamides onto α,β-unsaturated
DOI: 10.1039/D0OB00034E
esters, providing tertiary amines bearing two chains integrating a stereogenic center adjacent to the
Nitrogen, is reported.
Bn
R
N
Li
Bn
R
N
CO2tBu
CO2tBu
R'
R'
dr up to >95:5
CO2H
CO2Me
Ph
N
Ph
N
CO2tBu
Bn CO2tBu
C5H11