Diastereoselective synthesis of δ-aminoacids through domino Ireland-Claisen rearrangement and michael addition

Article abstract of DOI:10.1021/ol8001464

A novel domino reaction-stereoselective Ireland-Clalsen rearrangement and asymmetric Michael addition-Is described. A protocol starting from Baylis-Hillman adducts 3a-f using chlral lithium amide affords optically active γ-substituted λ-aminoacids 4a-f with high diastereoselectivlties and enantioselectivities. The acid can be isolated easily from large-scale reactions and transformed to 2,3-disubstituted piperidines 11 or 2-substituted nipecotic acid derlvates 12.

Full text of DOI:10.1021/ol8001464

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1687-1690
Diastereoselective Synthesis of
δ-Aminoacids through Domino
Ireland-Claisen Rearrangement and
Michael Addition‡
Narciso M. Garrido,* Mercedes García, David Díez, M. Rosa Sánchez, F. Sanz,†
and Julio G. Urones
Departamento de Qu´ımica Orga´nica, UniVersidad de Salamanca Plaza de los Ca´ıdos 1-5,
37008, Salamanca, Spain
nmg@usal.es
Received January 21, 2008
ABSTRACT
A novel domino reactionsstereoselective Ireland-Claisen rearrangement and asymmetric Michael additionsis described. A protocol starting
from Baylis-Hillman adducts 3a-f using chiral lithium amide affords optically active γ-substituted δ-aminoacids 4a-f with high
diastereoselectivities and enantioselectivities. The acid can be isolated easily from large-scale reactions and transformed to 2,3-disubstituted
piperidines 11 or 2-substituted nipecotic acid derivates 12.
The design and development of new asymmetric domino
reactions is regarded as a fascinating challenge for organic
chemists. The increasing number of publications concerning
applications of this type of reaction is testimony to their
possibilities in organic synthesis, offering the advantages of
atom economy, simple procedures, and savings in cost and
time.1 We have recently demonstrated the asymmetric
synthesis of the stereoisomers of 2-amino-5-carboxymeth-
ylcyclopentane-1-carboxylate in enantiomerically pure form,
via a domino reaction involving an asymmetric Michael
addition of chiral lithium N-benzyl-N-R-methylbenzylamide
(R)-1 to (E,E)-octa-2,6-diendioate and a subsequent 5-exotrig
intramolecular cyclization.2 Later, the versatility of this
methodology was extended, and ꢀ and ꢀ-functionalized R,ꢁ-
unsaturated esters were shown to participate in conjugate-
addition-cyclization reactions.3 Several domino reactions
have been reported, incorporating Michael addition reactions,
especially in the initial step. The best-known of these is
probably the domino Michael addition-SN2 reaction also
known as the Michael-initiated ring closure (MIRC) reac-
tion;4 nonetheless, asymmetric Michael-terminated processes
are scarce in the literature,5 as are Claisen rearrangement-
initiated domino reactions. A number of these latter have
been reported, such as Claisen rearrangement/Bergman
cyclization,6 Claisen rearrangement/Diels-Alder cycload-
(2) (a) Urones, J. G.; Garrido, N. M.; D´ıez, D.; El Hammouni, M. M.;
Dom´ınguez, S. H.; Casaseca, J. A.; Davies, S. G.; Smith, D. Org. Biomol.
Chem. 2004, 2, 364–372. (b) Urones, J. G.; Garrido, N. M.; D´ıez, D.;
Dom´ınguez, S. H.; Davies, S. G. Tetrahedron: Asymmetry 1997, 8, 2683–
2685.
† Servicio de Rayos X. Facultad de Ciencias Qu´ımicas Universidad de
Salamanca 37008 Salamanca.
(3) Davies, S. G.; D´ıez, D.; Dom´ınguez, S. H.; Garrido, N. M.; Kruchinin,
D.; Price, P. D.; Smith, D. Org. Biomol. Chem. 2005, 3, 1284–1301.
(4) (a) Enders, D.; Scherer, H. J.; Raabe, G. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1664–1666. (b) Amputch, M. A.; Matamoros, R.; Little,
R. D. Tetrahedron 1994, 50, 5591–5614.
‡ Dedicated to Profesor Miguel Yus in the occasion of his 60th birthday.
(1) (a) For general reviews on domino reactions see: Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–
7186. (b) Pellissier, H. Tetrahedron 2006, 62, 1619–1665. (c) Pellissier,
H. Tetrahedron 2006, 62, 2143–2173. (d) Tietze, L. F. Chem. ReV. 1996,
96, 115–136.
(5) Ihara, M.; Taniguchi, N.; Suzuki, S.; Fukumoto, K. J. Chem. Soc.,
Chem. Commun. 1992, 976–977.
10.1021/ol8001464 CCC: $40.75
Published on Web 04/10/2008
2008 American Chemical Society

Table 1. Asymmetric Addition of Acetate 2 to (R)-1 (3.6 equiv)
entry
2
R1
R2
4a (%)
deb,c (%)
6 (%)
8 (%)
9 (%)
1
2
3
4
5
6
a
b
c
d
e
f
phenyl
phenyl
3,4-dimethoxyphenyl
pyridin-3-yl
fur-2-yl
Ph-CHdCH-
Me
t-Bu
Me
t-Bu
Me
Me
22
24
23
37
18
85 (>95)
>95 (>95)
86 (>95)
>95 (>95)
86 (>95)
2
50
51
27
29
33
6
2
5
3
5
1
6
25
a Yields are of isolated product. b Determined by 1H NMR spectroscopic analysis, and refer to (4S,5S)-4 over (4R,5S)-5, the only δ-amino acid
diastereoisomers detected. Even when the minor one could not be totally isolated, it was possible to determine its presence in the chromatography enriched
fraction or it could be obtained by base treatment of (4S,5S)-4 producing partial epimerisation at C-4. c Values in parenthesis after careful column chromatography
and in some cases crystallization from EtOAc/hexane.
dition,7 and Ireland-Claisen rearrangement/Schmittel cy-
clization.8 However, we report here the first one-pot highly
asymmetric Ireland-Claisen rearrangement/Michael addition
domino reaction, which, starting from readily accessible
acetylated Baylis-Hillman adducts, yields nonracemic δ-
amino acids (Scheme 1). These compounds could find
receptor antagonists (these are of continuing interest14 since
the natural ligand for the NK1 receptor, Substance P, has
been implicated in the pathophysiology of a wide of disease
conditions including neurogenic inflammation, transmission
of pain, emesis, and depression15) or the potent antimalarial
agent (+)-febrifugine,16 first reported as a metabolite of the
Chinese medicinal plant Dichroa febrifuga.17
Baylis-Hillman adducts have been obtained according to
the literature procedure;18 subsequent acetylation furnishes
the acetyl derivatives 2, which upon isomerization using
DABCO19 or CsF20 afford the trisubstituted olefins 3
(Scheme 1, Table 1 and 2). We obtained the δ-amino acid 4
by reaction of the above-mentioned acetates with chiral
lithium amide (R)-1, using sequential addition of n-butyl-
lithium in tetrahydrofuran at -78 °C to the chiral amine and
then adding the acetate (2 or 3) in tetrahydrofuran. As shown
Scheme 1. Asymmetric Synthesis of γ-Substituted δ-Amino
Acids and Transformation to 2,3-Disubstituted Piperidines
(6) Magriotis, P. A.; Kin, K. D. J. Am. Chem. Soc. 1993, 115, 2972–
2973.
(7) (a) Frank, S. A.; Works, A. B.; Roush, W. R. Can. J. Chem. 2000,
78, 757–771. (b) Soldermann, N.; Velker, J.; Vallat, O.; Stoeckli-Evans,
H.; Neier, R. HelV. Chim. Acta 2000, 83, 2266–2276.
(8) Yang, Y.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2003, 68,
8545–8549.
(9) Schwalbe, H.; Wermuth, J.; Richter, C.; Szalma, S.; Eschenmoser,
A.; Quinkert, G. HelV. Chim. Acta 2000, 83, 1079–1107.
(10) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180. (b) Horne,
W. S.; Price, J. L.; Keck, J. L.; Gellman, S. H. J. Am. Chem. Soc. 2007,
129, 4178–4180.
(11) (a) Genest, N.; Lubell, W. D. J. Pept. Sci. 2007, 13, 355–366. (b)
Sasaki, Y.; Niida, A.; Tsuji, T.; Shigenaga, A.; Fujii, N.; Otaka, A. J. Org.
Chem. 2006, 71, 4969–4979. (c) Lee, K. W.; Choi, H. W.; Lee, B. H.;
Choi, B. S.; Chang, J. H.; Kim, Y. K.; Lee, J. H.; Heo, T. H.; Nam, D. H.;
Shin, H. Synlett 2005, 20, 3136–3138.
(12) Lummis, S. C. R.; Beene, D. L.; Lee, L. W.; Lester, H. A.;
Broadhurst, R. W.; Dougherty, D. A. Nature 2005, 438, 248–252.
(13) Trabocchi, A.; Menchi, G.; Guarna, F.; Machetti, F.; Scarpi, D.;
Guarna, A. Synlett 2006, 331–353.
(14) Raubo, P.; Kulagowski, J. J.; Chicchi, G. G. Synlett 2006, 271–
274.
(15) Seward, E. M.; Swain, C. J. Expert Opin. Ther. Pat. 1999, 9, 571–
582.
various applications in organic and peptidomimetic synthesis:
for example, as monomers for the generation of oligomers9
that display a variety of specific secondary structures (named
“foldamers” by Gellman),10 as substituted ethylene dipeptide
isosteres,11 these isomeric peptides show different biological
functions,12 as chiral auxiliaries in asymmetric synthesis,13
and in the asymmetric synthesis of 2,3-disubstituted pip-
eridines (Scheme 1). Some of these have been the object of
considerable synthetic effort, such as for neurokinin-1 (NK1)
(16) Michael, J. P.; Koning, Ch. B.; Pienaar, D. P. Synlett 2006, 383–
386.
(17) Koepfli, J. B.; Brockman, J. A., Jr.; Moffat, J. J. Am. Chem. Soc.
1950, 72, 3323–3323.
(18) (a) For relevant reviews see : Basavaiah, D.; Rao, A. J.; Satya-
narayana, T. Chem. ReV. 2003, 103, 811–891. (b) Basavaiah, D.; Dharma
Rao, P.; Suguna Hymna, R. Tetrahedron 1996, 52, 8001–8062. (c) Ciganek,
E. Organic Reactions; Paquette, L. A., Ed.; Wiley: New York, 1997; Vol
51, p 201.
(19) Mason, P. H.; Emslie, N. Tetrahedron 1994, 50, 12001–12008.
(20) Foucaud, A.; El Guemmout, F. Bull. Soc. Chim. Fr. 1989, 403–
408.
1688
Org. Lett., Vol. 10, No. 9, 2008

Table 2. Asymmetric Addition of Acetate 3 to (R)-1 (3.6 equiv)
entry
3
R1
R2
4a (%)
deb,c (%)
7 (%)
8 (%)
9 (%)
1
2
3
4
5
6
a
b
c
d
e
f
phenyl
phenyl
3,4-dimethoxyphenyl
pyridin-3-yl
fur-2-yl
Ph-CH)CH-
Me
t-Bu
Me
t-Bu
Me
Me
54
56
48
54
32
70
89 (>95)
>95 (>95)
78 (>95)
>95 (>95)
72 (>95)
3
1
2
2
9
7
5
12
9
8
3
2
7
3
12
8
25 (ref 21)
a Yields are of isolated product. b Determined by 1H NMR spectroscopic analysis, and refer to (4S,5S)-4 over (4R,5S)-5, the only δ-amino acid
diastereoisomers detected. Even when the minor one could not be totally isolated, it was possible to determine its presence in the chromatography enriched
fraction or it could be obtained by base treatment of (4S,5S)-4 producing partial epimerisation at C-4. c Values in parenthesis after careful column chromatography
and in some cases crystallization from EtOAc/hexane.
in Figure 1 and Table 1, the reaction of acetate 2 in this
way gave rise stereoselectively to the diaddition product 8,
together with the acid 4. However, upon subjecting acetate
3 to the aforementioned conditions, the acid (4S,5S)-4 is
obtained as the major adduct (de ) 72-95%),21 which could
be obtained as a single diastereoisomer by column chroma-
tography or by crystallization either as the δ-amino acid or
at a later stage as the δ-lactam (vide infra).
4b was isolated in a 45% yield, ready to go for further
transformation. The nonacidic compounds 7, 8, and 9 (Table
1-entry 2, Table 2-entry 2) mentioned previously remained in
the organic layer, in 29% overall yield.
In a one-pot reaction, hydrogenolysis of δ-amino acid (4S,5S)-
4a and (4S,5S)-4b and subsequent in situ lactamization gave
the piperidin-2-ones (5S,6S)-10a ([R]20 ) +39.7 (c ) 1.2,
D
CHCl3) and (5S,6S)-10b ([R]20D ) +38.1 (c ) 1.3, CHCl3), in
81% and 85% yields, respectively. These products crystallize
easily from EtOAc/hexane. Reduction of (5S,6S)-10a with LAH
in THF furnished piperidine (2S,3S)-11 in 72% isolated yield,
which illustrates the applicability of the methodology to the
preparation of 2,3-disubstituted piperidines. Or, alternatively,
reduction of (5S,6S)-10b with BH3·THF22 provides compound
(2S,3S)-12 in 89% yield, keeping the ester functionality and
giving access to interesting nipecotic acid derivates.23 The
configuration of the newly formed stereogenic center was
determined to be 5S,6S through single-crystal X-ray structure
analysis in the case of product 10a;24 the packing of the
molecules is shown in Figure 2. This corroborates the antici-
pated stereochemistry for (4S,5S)-4, assigned taking into account
the established model of addition of (R)-1 to (E)-R,ꢁ-unsaturated
esters.25 Davies et al. have recently published a comprehensive
review in this area of chemistry covering the scope, limitations,
(21) (4S,5S)-4f and (4R,5S)-4f can be separated by column chromatog-
raphy. Interestingly, 2f and 3f have been obtained from trans-cinnamalde-
hyde, the only compound used in this work with the carbonyl function not
directly attached to the aromatic ring.
Figure 1. Compounds obtained in the addition of acetates 2 and 3
to (R)-1, as it is shown in Tables 1 and 2.
(22) Roeske, R. W.; Weitl, F. L.; Prasad, K. U.; Thompson, R. M. J.
Org. Chem. 1976, 41, 1260–1261.
(23) Hoesl, C. E.; Ho¨fner, G.; Wanner, T. Tetrahedron 2004, 60, 307–
318.
Monoaddition adducts 6 and 7 are the result of Michael
addition of (R)-1 via an SN2′ protocol to 2 and 3, respectively,
and diaddition adducts 8 and 9, the result of further addition
of the remaining lithium amide to 6 and 7, respectively. The
stereochemistry of monomer and diaddition compounds has
been established in a parallel investigation within our group
by chemical correlation and 1H NMR including two-
dimensional homonuclear COSY, heteronuclear HMQC and
HMBC, NOE, and ROESY experiments, and in the case of
8a by X-ray diffraction structure.
Importantly, the process can be scaled up; even when a
mixture of the acetate isomers 2b/3b (5.0 g) in a 1:1 ratio was
added to the lithium amide [(R)-1] as previously described, the
crude reaction product was obtained as expected. Upon extrac-
tion with NaOH(aq) (1 M) and the usual workup of the acid,
(24) Crystal data for (5S,6S)-10a: single crystals were obtained by
crystallization from ethyl acetate/hexane. A single crystal of 10a compound
was subjected to X-ray diffraction studies on a Seifert 3003 SC rotating
anode diffractometer with (Cu KR) radiation (graphite monochromator)
using 2θ-ω scans at 293(2) K. Crystal data for 10a: C13H15N1O3, M )
233.26, triclinic, space group P1 (No. 1), a ) 5.7310(11) Å, b ) 9.956(2)
Å, c ) 11.765(2) Å, R ) 106.35(3)°, ꢁ ) 96.43(3)°, γ ) 100.74(3)°, V )
623.1(2) Å3, Z ) 2, Dc ) 1.243 mg/m3, m ) (Cu KR) ) 0.726 mm-1
,
F(000) ) 248; 1081 reflections were collected at 4.75 e 2θ e 59.85, of
which 1612 with I > 2σ(I) were considered to be observed. The structure
was determined by direct methods using the SHELXTL suite of programs.
Full-matrix least-squares refinement based on F2 with anisotropic thermal
parameters for the non-hydrogen atoms led to agreement factors R1 ) 0.0441
and ωR2 ) 0.1213. Crystallographic data (excluding structure factors) for
the structures reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-
608236. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, U.K. (fax: (+44)1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).
Org. Lett., Vol. 10, No. 9, 2008
1689

Scheme 2
.
Proposed Mechanism To Obtain 4 from 2 and 3. (a)
Ireland-Claisen Rearrangement
Figure 2. X-ray crystal structure of (5S,6S)-10a.
through III would give rise II28 and consistently (E)-12 and
finally 4. The difficulty for initial Michael addition on 3, in
relation to 2, explain his better yield on acid 4. For acetate
2, Michael addition to the terminal double bond (which is
not very sterically hindered) is preferred over enolate
formation. Nonetheless, the solution structure and aggrega-
tion of the lithiated chiral enolates remains to be determined.
In conclusion, the novel domino protocolsstereoselective
Ireland-Claisen rearrangement and asymmetric Michael
additionsprovides the first practical and efficient one-pot
route to optically active γ-substituted δ-amino acids. In two
examples, hydrogenolysis has been proven to produce the
parent piperidin-2-ones, 2-substituted nipecotic acid derivates,
and 2,3-disubstituted piperidines upon concomitant reduction.
Importantly, the analogous series of reactions deploying the
enantiomer of lithium amide (R)-1 in the initial conjugate
addition step will allow simple access to ent-4, and conse-
quently to (2R,3R)-11. The highly enantioenriched title
compounds now available in this way are valuable substrates
for further synthetic transformations to polyamino natural
products and 2,3-disubstituted chiral piperidines, which are
currently being investigated in our laboratory.
and synthetic applications of the use of enantiomerically pure
lithium amides as homochiral ammonia equivalents in conjugate
addition reactions.26 Since we can postulate a uniform reaction
mechanism, all the examples described should possess the
related configuration accordingly.
The crystal contains two molecules in the asymmetric unit.
In the crystal structures the molecules of 10a are connected
by intermolecular N-H · · · O hydrogen bonds [N1 · · · O6 )
2.93(5) Å, H1N · · · O6 ) 2.12(1) Å, <N1-H1N · · · O6>
) 175(7)°; N2 · · · O3 ) 2.87(4) Å, H2N · · · O3 ) 1.84(5)
Å, <N2-H2N · · · O3> ) 167(3)°]. This demonstrates its
potential for peptidomimetic applications.
To explain the stereochemical course of the process that
generates 4 from 2 stereoselectively, it is necessary that the
Ireland-Claisen rearrangement go through transition state
II; this should be more stable than TS I due to chelation
(Scheme 2). This in turn furnishes 12 with the required E
geometry in the double bond for subsequent asymmetric
Michael addition.25 The high asymmetric induction for
stereocenters C-4 and C-5 is in accordance with the reported
model for asymmetric Michael addition of (R)-1 to R-alkyl
R,ꢁ-unsasturated ester.27,25 It is reasonable to think that amide
deprotonation is favorable on 3 over initial Michael addition
to a trisubstituted double bond, so a rearrangement probably
Acknowledgment. We are indebted to Junta de Castilla
y Leo´n and FSE for financial support (SA045A05) and
Spanish MEC (CTQ2006-08296/BQU). The authors thank
also support from Servicios de la Universidad de Salamanca:
Dr. A.M. Lithgow for the NMR spectra and Dr. Ce´sar
Raposo for the mass spectra. M.R.S. is grateful to Univer-
sidad de Salamanca for a fellowship.
(25) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry
1994, 5, 1999–2008.
(26) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833–2891.
(27) Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S.
J. Chem. Soc., Chem. Commun. 1993, 1153–1154.
(28) To our knowledge, this is the first example of O,O-allylic rearrangement
followed by Claisen rearrangement and Michael addition, promoted by lithium
amide. The allylic acetate rearrangement is well documented in basic medium
(see refs 17 and 18), with Pd(II) (see Overman, L. E. Angew. Chem., Int. Ed.
Eng. 1984, 23, 579–586) or TMSOTf as catalyst (see Basavaiah, D.;
Muthukumaran, K.; Sreenivasulu, B. Synthesis, 2001, 545–548). For anionic
O,N-carbamate allylic rearrangement see ref 18.
Supporting Information Available: Experimental proce-
dures and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL8001464
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Org. Lett., Vol. 10, No. 9, 2008