Asymmetric synthesis of 3,4,5,6-tetrasubstituted piperidin-2-ones by three-component coupling

Article abstract of DOI:10.1055/s-2004-830887

The asymmetric three-component coupling of α,β-unsaturated esters and alkylidene malonates initiated with a homochiral lithium amide proceeds with high levels of diastereoselectivity, with hydrogenation of the resultant α-substituted β-amino acid derivatives giving a range of differentially protected 3,4,5,6-tetrasubstituted piperidinones with four contiguous stereogenic centres.

Full text of DOI:10.1055/s-2004-830887

LETTER
1957
Asymmetric Synthesis of 3,4,5,6-Tetrasubstituted Piperidin-2-ones by
Three-Component Coupling
Asymmetric
S
t
ynthesi
e
s of 3,4,5,6
p
-
Tetrasubstit
h
uted Piperid
e
a
Department of Organic Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
b
Chemical Crystallography, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
E-mail: steve.davies@chem.ox.ac.uk
Received 2 June 2004
upon the premise that two consecutive conjugate addi-
tions could be driven by the formation (in the second step)
of a stable enolate, preventing both polymerisation and
retro-conjugate addition by the efficient capping of the re-
Abstract: The asymmetric three-component coupling of a,b-unsat-
urated esters and alkylidene malonates initiated with a homochiral
lithium amide proceeds with high levels of diastereoselectivity,
with hydrogenation of the resultant a-substituted b-amino acid de-
rivatives giving a range of differentially protected 3,4,5,6-tetrasub- action. Alkylidenemalonates were considered to fulfil
stituted piperidinones with four contiguous stereogenic centres.
these properties, as conjugate addition of a b-amino eno-
late to an alkylidenemalonate would generate a stabilised
malonate enolate. Thus, addition of lithium amide (S)-1 (2
equiv) to tert-butyl cinnamate (1 equiv) gave the lithium
(Z)-b-amino enolate 2 and subsequent addition of diethyl
benzylidenemalonate (2 equiv) gave (2S,3S,1¢R,aS)-3 in
90% de (crude product ratio 3:one minor diastereoisomer
95:5),12 with chromatographic purification giving
(2S,3R,1¢R,aS)-3 in 81% yield and in >95% de. Hydro-
genolysis of b-amino ester 3 gave the tetrasubstituted pip-
eridinone (3S,4R,5S,6R)-4 in 81% yield and as a single
diastereoisomer (>98% de) after purification, the relative
configurations within which were assigned using NMR
Key Words: conjugate addition, three component coupling, oligo-
merisation, piperidin-2-one
The development of synthetic methodology for the con-
trolled construction of sophisticated molecular architec-
tures in a single step is highly desirable. Three component
anionic reactions are perhaps the most studied of such
processes, typically employing conjugate addition and al-
dol reactions,1,2 as demonstrated elegantly by Noyori et al.
for the synthesis of prostaglandin derivatives.3 Over the
past decade we have shown that the conjugate addition of
enantiomerically pure lithium amides4 to an a,b-unsatur-
ated ester or amide, followed by enolate functionalisation
via alkylation,5 hydroxylation6 or an aldol7 reaction gives
rise to a range of a-substituted b-amino acid derivatives.8
As part of our continuing research programme to extend
the utility of this methodology, we report herein a three
component coupling protocol for the bespoke oligomeri-
sation of a,b-unsaturated esters. Related investigations by
Hanessian et al. have shown that chiral phosphonamides
promote consecutive asymmetric conjugate additions, en-
abling the coupling of tert-butyl and iso-propyl cinnamate
in 74% de,9 while Ley et al. have demonstrated that the
lithium anion of a glycolic acid derivative promotes the
asymmetric coupling of a,b-unsaturated lactones and ni-
tro-olefins.10
1
spectroscopic analysis. H coupling constants were used
to indicate the axial and equatorial relationships between
the ring protons, with the 1,3-diaxial relationship between
C(4)H and C(6)H confirmed through NOE difference
analysis. The absolute (3S,4R,5S,6R) configuration of 3
was established on the assumption that the configuration
at C(6) derived from lithium amide conjugate addition
was R, by analogy with previous models developed to
explain the consistent stereoselectivity observed during
addition of lithium amide 1 to a,b-unsaturated esters
(Scheme 1).13
To understand where the stereochemical leakage had oc-
curred in this protocol, a stepwise [2+1] component cou-
pling procedure was investigated. Deprotonation of b-
amino ester (3R,aS)-5 with LDA gave the corresponding
lithium (E)-b-amino enolate-6,14 which upon addition of
diethyl benzylidenemalonate gave (2S,3R,1¢R,aS)-7 in
90% de (crude product ratio 7:3 95:5). This unoptimised
reaction proceeded to low conversion (40%), giving 7 in
33% isolated yield and >95% de after chromatographic
purification. Hydrogenolysis of 7 provided piperidinone
(3R,4S,5S,6R)-8 in 91% yield and as a single diastereo-
isomer (>98% de) after chromatography, the relative
Facilitating the controlled oligomerisation of discrete re-
action components, while ensuring insufficient reactivity
toward polymerisation, was considered the main synthetic
hurdle within this protocol. Indeed, oligomeric products
are rarely seen under standard lithium amide conjugate
addition reaction conditions,11 indicating that the rate of
lithium amide conjugate addition must be considerably
greater than the rate of polymerisation. To promote a con-
trolled oligomerisation protocol, our strategy centred
1
configuration within which was elucidated by H NMR
spectroscopy and NOE difference experiments
1
(Scheme 2). Comparison of the H NMR spectrum of 7
and that of the crude product mixture from the three com-
ponent coupling protocol indicated no trace of 7 in the tan-
dem reaction, indicating that the minor diastereoisomer in
SYNLETT 2004, No. 11, pp 1957–1960
Advanced online publication: 04.08.2004
DOI: 10.1055/s-2004-830887; Art ID: D14204ST
© Georg Thieme Verlag Stuttgart · New York
0
6
.0
9
.2
0
0
4

1958
S. G. Davies et al.
LETTER
Ph
C(3)H adopting an approximately eclipsed conformation
with the C=C bond of the enolate, with preferential alkyl-
ation anti- to the N-benzyl-N-a-methylbenzyl group.
Allowing for lithium chelation, and orientation of the
smallest C(3)H substituent of the electrophile toward the
sector occupied by the C(3)Ph substituent of the b-amino
enolate, reaction of enolate (E)-6 with diethyl benzyl-
idenemalonate via transition state 9 predicts 2,3-syn-se-
lectivity, while reaction of enolate (Z)-2 via transition
state 10 predicts 2,3-anti-selectivity, consistent with the
observed results (Scheme 3).
Ph
Ph
Ph
(ii)
N
1
Ph
N
Li
H
t
CO2 Bu
Li
1'
(i)
Ph
2
Ph
N
O
(S)–1
3
CO2Et
4
t
5
Ph
CO2 Bu
Ph
OtBu
H
Ph
CO2Et
2
3
Crude dr 95:5
81%, >95% de
after purification
8.5%
J H(6)ax–H(5)eq
5.2 Hz
J H(4)ax–H(3)ax 12.7 Hz,
J H(4)ax–H(5)eq 3.9 Hz
(iii)
H
H
H
Ph
H
O
OEt
O
Li
6
O
Ph
N
O
N
Ph
N
Ph
6
CO2Et
3
1
H
H
EtO
O
H
t
4
OtBu
CO2 Bu
5
5
3
CO2Et
tBuO2C
Ph
4
Ph
2
H
t
H
Ph
H
CO2 Bu
Ph
3
CO2Et
4
J H(3)ax–H(4)ax
Ph
R2N
Ph
5
4, 81%, >98% de
12.7 Hz
H
CO2Et
9
Scheme 1 Reagents and conditions: (i) Lithium (S)-N-benzyl-N-a-
methylbenzylamide (1), THF, –78 °C; (ii) diethyl benzylidenemalo-
nate (2 equiv), THF, –78 °C to 0 °C; (iii) Pd(OH)2 on C, MeOH, H2.
2,3–syn
Stepwise Protocol; E-enolate
Ph
OtBu
O
Ph
Ph
N
Li
OEt
1
H
H
t
O
CO2 Bu
the tandem coupling reaction manifold arises from incom-
plete stereocontrol at C(2) upon alkylation of b-amino
enolate 2. This is consistent with the known high, but in-
complete, stereocontrol observed upon tandem alkylation
of lithium (E)-b-amino enolates.5
Ph
2
H
3
CO2Et
4
CO2Et
Ph
R2N
H
5
Ph
H
CO2Et
10
2,3–anti
Tandem Protocol; Z-enolate
In these reactions, it is assumed that the favourable transi-
tion state for conjugate addition of the (E)- or (Z)-b-amino
enolate to the alkylidenemalonate has substituents on the
two prostereogenic centres staggered to minimise un-
favourable non-bonding interactions.15 Based upon 1,3-
allylic strain,16 the reactive conformation for b-amino
enolates (Z)-2 and (E)-6 is assumed to be that with the
Scheme 3 Rationale for the stereochemical outcome of the stepwise
and tandem conjugate addition reactions.
To test the generality of this three component coupling
protocol, the effect of structural variation within both
a,b-unsaturated ester components was investigated, with
a range of b-aryl- and b-alkylpropionates, and b-aryl-, b-
alkenyl- and b-alkyl-malonates combined, giving b-ami-
no esters 11–16 with high stereoselectivity (>78% de,
only two diastereoisomers observed in each case,
Scheme 2). Within this series of reactions, higher yields
and stereoselectivities were observed with b-aryl substitu-
tion in both acceptor components (typically >90% de),
although the reaction tolerates b-alkyl substitution.17 b-
Amino esters 11–13 were readily purified to >95% de and
isolated in good yield by chromatography, while 15 and
16 were purified to homogeneity by chromatography fol-
lowed by crystallization (Scheme 4, Table 1). The abso-
lute configuration of (2S,3R,1¢S,aS)-15 was confirmed
unambiguously by single crystal X-ray analysis relative to
the known (S)-a-methylbenzyl stereogenic centre, with
the absolute configurations within 11–14 and 16 assigned
by direct analogy (Figure 1).18
Ph
Ph
(ii)
N
1
Ph
Ph
H
t
CO2 Bu
(i)
1'
Ph
OtBu
OLi
2
Ph
N
Ph
N
3
CO2Et
4
t
CO2 Bu
5
Ph
Ph
Ph
H
CO2Et
5
6
7
Crude dr 7:3 95:5
33%, >95% de
after purification
1 H, app t,
J 12.3 Hz
J H(6)eq–H(5)ax
Ph
5.8 Hz
H
(iii)
H
O
H
6
N
H
EtO2C
t
CO2 Bu
Ph
N
O
3
4
5
Ph
6
H
H
tBuO2C
CO2Et
5
3
3%
4
Subsequent treatment of a-substituted b-amino esters 11
and 13–15 with Pd(OH)2 on C under H2 (5 atm) allowed
the isolation of the differentially protected tetrasubstituted
piperidinones 17–20 in high yields (>75%) and as a single
diastereoisomer in each case after chromatographic puri-
fication (Scheme 5, Table 2).
Ph
8, 91%, >98% de
J H(5)ax–H(4)ax 12.8 Hz,
J H(5)ax–H(6)eq 5.8 Hz
J H(3)ax–H(4)ax
11.8 Hz
Scheme 2 Reagents and conditions: (i) LDA, THF, –78 °C to 0 °C;
(ii) diethyl benzylidenemalonate, THF, –78 °C to 0 °C; (iii) Pd(OH)2
on C, MeOH, H2.
Synlett 2004, No. 11, 1957–1960 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of 3,4,5,6-Tetrasubstituted Piperidin-2-ones
1959
Ph
H
Ph
Ph
N
i.
Ph
R3
N
Li
CO2R2
CO2R4
CO2R4
CO2R2
R1
R1
CO2R4
ii.
R3
CO2R4
H
3, 11–16
Scheme 4 Reagents and conditions: (i) (S)-1, THF, 2 h; (ii) alkyl-
idene malonate (2 equiv), THF, –78 °C to 0 °C.
Ph
Ph
N
H
N
R1
O
H
H
CO2R2
CO2R4
CO2R4
(i)
R1
R2O2C
CO2R4
R3
R3
3, 11, 13–15
4, 17–20
Scheme 5 Reagents and conditions: (i) Pd(OH)2 on C, MeOH, H2
(5 atm).
In conclusion, an approach to the oligomerisation of dis-
crete a,b-unsaturated carbonyl components initiated by
the conjugate addition of homochiral lithium amides has
been realised. Lithium N-benzyl-N-a-methylbenzylamide
Figure 1 Chem 3D representation of the X-ray crystal structure of
(2S,3R,1¢S,aS)-15.
Table 1 Yields of Products 3, 11–16 (Scheme 4)
R1
R2
R3
R4
Et
Crude dra
>95:<5
>95:<5
>95:<5
94:6
Product
3
Yield (%)
81b
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
i-Pr
Ph
Ph
4-Br-Ph
4-Br-Ph
Me
Me
Me
Me
Et
11
63b
3,4(MeO)2Ph
12
70b
Ph
13
67b
Ph
PhCH=CH
PhCH=CH
Ph
91:9
14
64c
Me
Me
Et
92:8
15
63c (46)b
52c (37)b
Et
89:11
16
a As determined by 1H NMR (400 MHz) spectroscopic analysis of the crude product mixture, with only two diastereoisomers observed in each
case.
b Isolated yield of major diastereoisomer (>95% de).
c Isolated yield of diastereoisomeric mixture.
Table 2 Yields of Products 4, 17–20 (Scheme 5)
b-Amino ester
Piperidinone
Yield (%)
R1
Ph
Ph
Ph
Ph
Ph
R2
R3
R4
Et
3
11
13
14
15
4
17
18
19
20
81
91
78
80
75
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
Ph
Ph
Me
Me
Et
Me
PhCH2CH2
PhCH2CH2
Et
Synlett 2004, No. 11, 1957–1960 © Thieme Stuttgart · New York

1960
S. G. Davies et al.
LETTER
(9) (a) Hanessian, S.; Gomtsyan, A.; Payne, A.; Hervé, Y.;
Beaudoin, S. J. Org. Chem. 1993, 58, 5032. (b) Hanessian,
S.; Gomtsyan, A. Tetrahedron Lett. 1994, 35, 7509.
(10) Dixon, D. J.; Ley, S. V.; Rodriguez, F. Angew. Chem. Int.
Ed. 2001, 40, 4763.
(11) In our hands, oligomeric products have been identified
during the conjugate addition of lithium amides to tert-butyl
2,5-dihydrofuran-3-carboxylate. See: Bunnage, M. E.;
Davies, S. G.; Roberts, P. M.; Smith, A. D.; Withey, J. M.;
Org. Biomol. Chem.; 2004, submitted for publication.
(12) The configuration of the minor diastereoisomer arising from
this three-component coupling is unknown but is not
identical to either diastereoisomer obtained from the
stepwise [2+1] reaction manifold.
readily promotes the asymmetric three component cou-
pling of a,b-unsaturated esters and alkylidene malonates
with high levels of diastereoselectivity, with hydro-
genolytic deprotection furnishing a range of differentially
protected tetrasubstituted piperidinones. The application
of this methodology for the preparation of a range of scaf-
folds for incorporation into pseudopeptides and its appli-
cation toward the total synthesis of natural products of
biological significance is currently under investigation in
our laboratory.
Acknowledgment
(13) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1994, 5, 3919.
The authors wish to thank the EPSRC for an industrial CASE
award and New College, Oxford for a Junior Research Fellowship
(A. D. S.).
(14) Conjugate addition of lithium amides to a,b-unsaturated
esters proceeds only when the ester can achieve the syn-s-cis
conformation, giving the corresponding (Z)-lithium enolate.
See: (a) Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron
1990, 46, 4563. (b) Davies, S. G.; Hermann, G.; Smith, A.
D.; Sweet, M. J. Chem. Commun. 2004, 1128; and ref.5a.
(15) Oare, D. A.; Heathcock, C. H. Topics in Stereochemistry
1989, 19, 227.
References
(1) Ogiku, T.; Seki, M.; Takahashi, M.; Ohmizu, H.; Iwasaki, T.
Tetrahedron Lett. 1990, 31, 5487.
(2) Tanis, S. P.; McMills, M. C.; Scahill, T. A.; Kloosterman, D.
A. Tetrahedron Lett. 1990, 31, 1977.
(3) (a) Suzuki, M.; Kawagishi, T.; Noyori, R. Tetrahedron Lett.
1982, 23, 5563. (b) Noyori, R.; Suzuki, M. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 847. (c) Suzuki, M.; Morita, Y.;
Koyano, H.; Koga, M.; Noyori, R. Tetrahedron 1990, 46,
4809.
(16) For a review see: Hoffmann, R. W. Chem. Rev. 1989, 89,
1841.
(17) A minor reaction product in the preparation of 14 and 15 was
diethyl (E)-cinnamyl malonate, isolated in 19% and 15%
yield (with respect to diethyl phenylallylidenemalonate),
respectively, which arises from in situ conjugate reduction
by lithium amide (S)-1. For selected examples of lithium
amides acting as reducing agents see: (a) Wittig, G.;
Schmidt, H.-J.; Renner, H. Chem. Ber. 1962, 95, 2377.
(b) Wittig, G.; Frommeld, H.-D. Chem. Ber. 1964, 97, 3541.
(c) Scott, L. T.; Carlin, K. J.; Schultz, T. H. Tetrahedron
Lett. 1978, 19, 4637. (d) Newcomb, M.; Burchill, M. T. J.
Am. Chem. Soc. 1984, 106, 2450. (e) Majewski, M.;
Gleave, D. M. J. Organomet. Chem. 1994, 470, 1.
(f) Takeda, K.; Ohnishi, Y.; Koizumi, T. Org. Lett. 1999, 1,
237.
(18) X-ray crystal structure determination for 15: Data were
collected using an Enraf-Nonius DIP2000 diffractometer
with graphite monochromated Cu-Ka radiation using
standard procedures at 100 K. The structure was solved by
direct methods (SIR92), all non-hydrogen atoms were
refined with anisotropic thermal parameters. Hydrogen
atoms were added at idealised positions. The structure was
refined using CRYSTALS. X-ray crystal structure data for
15 [C38H43NO4]: M = 577.76, orthorhombic, space group P
21 21 21, a = 11.2640 (2) Å, b = 16.6340 (3) Å, c = 17.0480
(2) Å, V = 3194.21 (9) Å3, Z = 4, m = 0.077 mm–1, colourless
block, crystal dimensions = 0.4 × 0.4 × 0.5 mm. A total of
3793 unique reflections were measured for 3<q<27 and 3618
reflections were used in the refinement. The final parameters
were wR2 = 0.0310 and R1 = 0.0253 [I>3s(I)].
(4) (a) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820.
(b) Rudolf, K.; Hawkins, J. M.; Loncharich, R. J.; Houk, K.
N. J. Org. Chem. 1988, 53, 3879. (c) Hawkins, J. M.;
Lewis, T. A. J. Org. Chem. 1992, 57, 2114. (d) Rico, J. G.;
Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. J. Org. Chem.
1993, 58, 7948. (e) Sewald, N.; Hiller, K. D.; Helmreich, B.
Liebigs Ann. Chem. 1995, 925. (f) Koerner, M.; Findeisen,
M.; Sewald, N. Tetrahedron Lett. 1998, 39, 3463.
(5) (a) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1129. (b) Davies, S. G.; Ichihara, O.;
Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1141.
(6) (a) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J. Chem.
Soc., Perkin Trans. 1 1993, 1375. (b) Bunnage, M. E.;
Chernega, A. N.; Davies, S. G.; Goodwin, C. J. J. Chem.
Soc., Perkin Trans. 1 1994, 2373. (c) Bunnage, M. E.;
Burke, A. J.; Davies, S. G.; Goodwin, C. J. Tetrahedron:
Asymmetry 1994, 5, 203.
(7) (a) Uyehara, T.; Asao, N.; Yamamoto, Y. J. Chem. Soc.,
Chem. Commun. 1989, 753. (b) Asao, N.; Shimada, T.;
Tsukada, N.; Yamamoto, Y. Tetrahedron Lett. 1994, 45,
8425. (c) Davies, S. G.; Smethurst, C. A. P.; Smith, A. D.;
Smyth, G. D. Tetrahedron: Asymmetry 2000, 11, 2437.
(d) Yamamoto, Y.; Asao, N.; Uyehara, T. J. Am. Chem. Soc.
1992, 114, 5427.
(8) Yamamoto has shown that the limited application of this
asymmetric three component coupling process, see:
(a) Asao, N.; Shimada, T.; Tsukada, N.; Yamamoto, Y.
Tetrahedron Lett. 1994, 35, 8425. (b) Tsukada, N.;
Shimada, T.; Gyoung, Y. S.; Asao, N.; Yamamoto, Y. J.
Org. Chem. 1995, 60, 143. (c) Asao, N.; Uyehara, T.;
Tsukada, N.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 1996, 68,
2111. (d) Sewald, N.; Hiller, K. D.; Koerner, M.; Findeisen,
M. J. Org. Chem. 1998, 63, 7263.
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC240141. Copies
of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44
(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
Synlett 2004, No. 11, 1957–1960 © Thieme Stuttgart · New York